ABIM182 • Internal Medicine #2 - Reportable to ABIM

Table of Contents

ABIM182 • Internal Medicine #2 - Reportable to ABIM

How to Receive Credit

NetCE 5 Hour Course #95072 • Antibiotics Review

95072 • Antibiotics Review

1. INTRODUCTION

2. GENERAL CHARACTERISTICS OF ANTIBIOTICS

3. ANTIBIOTIC RESISTANCE

4. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. PENICILLINS

6. CEPHALOSPORINS

7. CARBAPENEMS

8. MONOBACTAMS

9. AMINOGLYCOSIDES

10. MACROLIDES AND TELITHROMYCIN

11. QUINOLONES

12. SULFONAMIDES

13. TETRACYCLINES

14. VANCOMYCIN

15. LIPOGLYCOPEPTIDES

16. PLEUROMUTILINS

17. INVESTIGATIONAL ANTIBIOTICS FOR DRUG-RESISTANT MICRO-ORGANISMS

18. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #96402 • Depression and Suicide

96402 • Depression and Suicide

1. INTRODUCTION

2. EPIDEMIOLOGY

3. BACKGROUND

4. PATHOPHYSIOLOGY OF DEPRESSION AND SUICIDE

5. ASSESSMENT AND DIAGNOSIS OF DEPRESSION

6. INITIAL TREATMENT OF DEPRESSION

7. TREATMENT-RESISTANT DEPRESSION

8. PERINATAL DEPRESSION

9. SUICIDE

10. SUICIDE LOSS SURVIVORS

11. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #90213 • Diagnosing and Managing Headaches

90213 • Diagnosing and Managing Headaches

1. INTRODUCTION

2. EPIDEMIOLOGY

3. BASIC PATHOPHYSIOLOGY

4. WORK-UP OF HEADACHES

5. PRIMARY HEADACHES

6. SECONDARY HEADACHES

7. ACUTE VERSUS CHRONIC

8. REFERRAL

9. MEDICO-LEGAL ISSUES

10. CONCLUSION

11. ADDITIONAL SOURCES OF INFORMATION

Works Cited

Evidence-Based Practice Recommendations Citations

ABIM182 • Internal Medicine #2 - Reportable to ABIM

Donna Coffman, MD

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

ABIM182 • Internal Medicine #2 - Reportable to ABIM

Expiration Date: 07/31/2020

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

95072 • Antibiotics Review

Donna Coffman, MD

www.netce.com

Copyright © 2018 NetCE, All rights reserved.

Choosing an antibacterial agent can be challenging, given the wide array of drugs available. Learning the important properties and uses of these drugs is made easier by the fact that they are grouped in classes based on their biochemical structure. Members of a drug class share characteristics such as clearance, mechanism of action, absorption, and side effects; knowing these shared properties makes it easier to choose the appropriate agent for a particular patient. In addition, it is easier to quickly grasp the strengths and weaknesses of a newly marketed antibiotic if you understand the general pharmacology of its class. A good grasp of the use of specific agents to target specific bacteria leads to improved clinical response to treatment and a decrease in the likelihood of the development of microbial resistance. This course is intended as an overview of the general characteristics of the major antibiotic classes, with a brief discussion of the individual agents and indications, giving greater perspective to the actions and characteristics of antibiotics. Due to the large number of antibiotics available, this course focuses on eight major classes of antibiotics: the penicillins, cephalosporins, other beta-lactams, aminoglycosides, macrolides, quinolones, sulfonamides, and tetracyclines. A brief discussion of vancomycin and the newer glycopeptide analogues is also included.

Table of Contents

95072 • Antibiotics Review

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. GENERAL CHARACTERISTICS OF ANTIBIOTICS

3. ANTIBIOTIC RESISTANCE

4. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. PENICILLINS

MECHANISM OF ACTION

PHARMACOKINETICS

ABSORPTION/ELIMINATION

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

6. CEPHALOSPORINS

MECHANISM OF ACTION

PHARMACOKINETICS

ABSORPTION/ELIMINATION

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

7. CARBAPENEMS

MECHANISM OF ACTION

PHARMACOKINETICS

ABSORPTION/ELIMINATION

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

8. MONOBACTAMS

MECHANISM OF ACTION

PHARMACOKINETICS

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

9. AMINOGLYCOSIDES

MECHANISM OF ACTION

PHARMACOKINETICS

TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

10. MACROLIDES AND TELITHROMYCIN

MECHANISM OF ACTION

PHARMACOKINETICS

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

11. QUINOLONES

MECHANISM OF ACTION

PHARMACOKINETICS

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

12. SULFONAMIDES

MECHANISM OF ACTION

PHARMACOKINETICS

ABSORPTION/ELIMINATION

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

13. TETRACYCLINES

MECHANISMS OF ACTION AND PHARMACOKINETICS

ABSORPTION/ELIMINATION

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

14. VANCOMYCIN

MECHANISMS OF ACTION AND PHARMACOKINETICS

ABSORPTION/ELIMINATION

SIDE EFFECTS/TOXICITY

15. LIPOGLYCOPEPTIDES

16. PLEUROMUTILINS

17. INVESTIGATIONAL ANTIBIOTICS FOR DRUG-RESISTANT MICRO-ORGANISMS

18. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95072 • Antibiotics Review

Education Category. Pharmacology

Release Date. 02/01/2018

Expiration Date. 01/31/2021

Course Overview

Choosing an antibacterial agent can be challenging, given the wide array of drugs available. Learning the important properties and uses of these drugs is made easier by the fact that they are grouped in classes based on their biochemical structure. Members of a drug class share characteristics such as clearance, mechanism of action, absorption, and side effects; knowing these shared properties makes it easier to choose the appropriate agent for a particular patient. In addition, it is easier to quickly grasp the strengths and weaknesses of a newly marketed antibiotic if you understand the general pharmacology of its class. A good grasp of the use of specific agents to target specific bacteria leads to improved clinical response to treatment and a decrease in the likelihood of the development of microbial resistance. This course is intended as an overview of the general characteristics of the major antibiotic classes, with a brief discussion of the individual agents and indications, giving greater perspective to the actions and characteristics of antibiotics. Due to the large number of antibiotics available, this course focuses on eight major classes of antibiotics: the penicillins, cephalosporins, other beta-lactams, aminoglycosides, macrolides, quinolones, sulfonamides, and tetracyclines. A brief discussion of vancomycin and the newer glycopeptide analogues is also included.

Audience

This course is designed for healthcare providers who prescribe and administer antibiotics to patients, including physicians, physician assistants, pharmacists, pharmacy technicians, nurses, nurse practitioners, and surgical technologists and assistants.

Course Objective

The purpose of this course is to provide a review of the major classes of antibiotics and their characteristics as well as an overview of selected individual agents within each class that are most useful for today's clinical practitioner.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe the general characteristics and mode of action of antibiotics commonly in use.

2. Employ best practice principles for limiting the emergence and transmission of anti-microbial resistant strains within the healthcare environment.

3. Discuss the mechanism of action, pharmacokinetics, and spectrum of activity of natural and extended-spectrum penicillins.

4. Select the most appropriate, cost-effective cephalosporin based on "generational" characteristics and spectrum of activity.

5. Describe the role of carbapenems and monobactams.

6. Discuss the characteristics, expected toxicities, and indications for the use of aminoglycosides, macrolides, and sulfonamides.

7. Outline the mechanism of action, pharmacokinetics, and advantages inherent to quinolones and the tetracyclines.

Faculty

Donna Coffman, MD, attended medical school at the University of Louisville and completed her residency in Family Practice at St. John's Mercy Medical Center in St. Louis, Missouri. She is board-certified in Family Medicine and currently on staff at John Cochran VAMC in St. Louis.

Faculty Disclosure

Contributing faculty, Donna Coffman, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Shannon E. Smith, MHSC, CST, CSFA

Abimbola Farinde, PharmD, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

The number of antibiotic agents available is remarkable, and new agents are added regularly. This course is intended as an overview of the general characteristics of the major antibiotic classes, emphasizing mechanism of action, pharmacokinetics, and potential toxicities, with a brief discussion of the individual member agents and their clinical indications. The purpose of this course is to enlarge clinical perspective and enhance the understanding and confidence required for the selection of appropriate therapy of bacterial infections. The goal is to improve efficacy and safety while limiting the risk for selection and transmission of antimicrobial-resistant pathogens.

Given the large array of available antimicrobial agents, the scope of this course is confined to the eight major classes of antibiotics commonly employed for acute bacterial infection: the penicillins, cephalosporins, carbapenems, aminoglycosides, quinolones, macrolides, sulfonamides, and tetracyclines. A brief discussion of vancomycin and the newer glycopeptide analogues is also included.

For the purposes of the course, it is impractical to list or describe all of the possible adverse effects, recommended uses, and off-label uses of the antibiotics discussed. Before using a specific antimicrobial, it is important to review the manufacturer's package insert and dosing recommendations for the drug.

2. GENERAL CHARACTERISTICS OF ANTIBIOTICS

Evidence Based Practice Recommendation

According to the Centers for Disease Control and Prevention, administration of currently available probiotics is not recommended to prevent primary Clostridium difficile infection, as there are limited data to support this approach and there is a potential risk of bloodstream infection.

https://www.cdc.gov/HAI/pdfs/cdiff/Cohen-IDSA-SHEA-CDI-guidelines-2010.pdf

Last Accessed: January 22, 2018

Level of Evidence: CIII (Poor evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees)

There are some characteristics that all antibiotics share. All antibiotics can elicit allergic responses, although some are more allergenic than others. Allergic reactions can range from mild, annoying rashes to life-threatening reactions like anaphylaxis and Stevens-Johnson syndrome. In some cases, there is a cross-sensitivity between agents in different classes. In addition, all antibiotics affect normal body flora as well as pathogens, which may result in overgrowth of Candida and pathogenic bacteria such as Clostridium difficile. Overgrowth of C. difficile is a serious complication of antimicrobial therapy that can produce symptoms ranging from mild diarrhea to severe, life-threatening complications, such as pseudomembranous colitis [1]. Most cases resolve with supportive care and discontinuation of the offending antibiotic, but many require treatment. In addition, diarrhea and pseudomembranous colitis can develop weeks after antimicrobial therapy has been discontinued. A high degree of suspicion and judicious use of laboratory testing are the keys to recognizing and managing these complications.

3. ANTIBIOTIC RESISTANCE

Repeated exposure to an antibiotic may lead to the emergence of selective subpopulations of the same or related bacteria now resistant to the therapeutic agent. The Centers for Disease Control and Prevention (CDC) note that approximately 2 million people become infected with bacteria that are resistant to antibiotics, and approximately 23,000 people die annually because of these infections [164]. Mechanisms of microbial resistance include altered cellular permeability (leading to greatly diminished intracellular concentration of the drug), increased efflux of the antibiotic from the cell, and elaboration of deactivating enzymes that alter the antibiotic's interaction at binding sites within the cell wall or cytoplasm [2].

Decreased cell membrane permeability is an important mechanism of bacterial resistance to beta-lactams, quinolones, and vancomycin. Microbial resistance to tetracyclines and quinolones is often mediated by increased efflux of the antibiotic from the cell. Enzymatic deactivation by beta-lactamases is the common mechanism of resistance to penicillins and cephalosporins. Resistance to aminoglycosides may result from altered cytoplasmic membrane transport (influx) or from intracellular enzymes (e.g., phosphotransferases and acetyltransferases) that deactivate the drug.

There are various mechanisms by which the interaction of an antibiotic with its binding site may be altered or bypassed, resulting in loss of antimicrobial activity. One such example, affecting the target site for quinolone activity, is an acquired structural alteration of deoxyribonucleic acid (DNA) gyrase, an enzyme essential for bacterial DNA synthesis. As a result, quinolones are no longer able to bind to the enzyme and the drug loses its antimicrobial effect. Another example is the methylation of ribosomal ribonucleic acid (rRNA) that prevents the binding of macrolides. The effectiveness of trimethoprim/sulfamethoxazole, which acts through disruption of folate synthesis by the cell, may become diminished by the adaptive ability of some bacteria to utilize an alternate metabolic pathway, thereby avoiding the effects of trimethoprim [3].

These resistance mechanisms may be acquired through mutations in the genes that encode for the target or affected transport proteins. As the bacterial cells without the adaptive mutations succumb to the action of the antibiotic, the subpopulation that has the adaptive mutation continues to replicate, replacing the original population with a resistant one.

Bacterial resistance can be transferred from one bacterium to another, or from one bacterial species to related group, by means of plasmids or transposons that gain entry to the cell. These agents are small segments of DNA that are readily exchanged between bacteria. A plasmid that contains a gene for an adaptive mutation can be shared with a large number of nearby bacteria, which may or may not be the same species. In this manner, resistance can quickly spread from species to species [4].

Many strategies have been used in an attempt to circumvent the multiple mechanisms of resistance encountered in bacteria. Among these are the addition of beta-lactamase inhibitors to extended-spectrum penicillins, alteration of cephalosporin side chains to produce new generations of the drug with broader activity, and pairing two drugs to enhance the antimicrobial effect (e.g. sulfamethoxazole with trimethoprim).

In addition, new categories of antibiotics are being created in an attempt to stay ahead of the rapid evolution of bacterial resistance. Linezolid and tedizolid, the only two FDA-approved drugs in the oxazolidinone category, are examples of this, with linezolid being the first of the two to be developed. Oxazolidinones are a unique category of drugs that prevent formation of the 70S protein synthesis complex in bacteria, and may be useful in the treatment of vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus [149,171]. Nonetheless, development of resistance in bacteria is relentless.

In light of the efficient means by which bacteria develop resistance, it is important to avoid practices that contribute to the process. The CDC has issued a position paper outlining recommendations for minimizing nosocomial infection and the emergence of resistant organisms [5]. In this paper, the CDC recommended a multistep approach.

The first step recommended by the CDC is to prevent infection. Many infections in hospitalized or institutionalized patients are the direct result of indwelling urinary catheters, central venous catheters, and intubation. These invasive medical devices should be avoided unless they are clearly indicated. In addition, proper vaccination of medical staff and patients is an effective method to prevent the spread of Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.

Evidence Based Practice Recommendation

A meta-analysis published by the Cochrane Database of Systematic Reviews found high-certainty evidence that any professional or structural interventions are effective in increasing compliance with antibiotic policy and reducing duration of antibiotic treatment in the hospital setting.

http://www.cochrane.org/CD003543/EPOC_improving-how-physicians-working-hospital-settings-prescribe-antibiotics

Last Accessed: January 22, 2018

Level of Evidence: Meta-analysis

The next step is to tailor medical treatment to fit the infection. Antimicrobial therapy should be based on the likely pathogens or results of culture, so broad-spectrum antibiotics may be avoided when possible. Consideration should be given to pathogens common to the area of infection (e.g., skin, intra-abdominal) and to pathogens common in the environment locally (e.g., hospital environment). Prolonged treatment regimens increase the likelihood of emerging resistance, so the duration of therapy should be carefully monitored and undue prolongation avoided.

The last step is to prevent the transmission of resistant bacteria between patients. A simple, effective method of infection containment is hand washing. As noted in the CDC position paper, participation in hospital infection control programs is also necessary [5]. A coordinated effort to contain pathogens within hospital infection control guidelines makes it easier to prevent the spread of multidrug-resistant bacteria.

Despite the remarkable rate of the development of new antibiotics, the emergence of drug-resistant bacteria continues unabated. Therefore, it is important to use antibiotics wisely to maintain their usefulness for the future.

4. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

Obtaining a detailed patient history is a vital aspect of the appropriate prescription of antibiotics, particularly in empirical treatment. Furthermore, communication with patients regarding treatment regimens and compliance depends on clear communication between the patient and clinician. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. The interpreter should be considered an active agent in the diagnosis and/or treatment processes, negotiating between two cultures and assisting in promoting culturally competent communication and practice [151].

5. PENICILLINS

Alexander Fleming discovered penicillin in 1928. After observing that Penicillium colonies inhibited the growth of staphylococci on agar plates, Fleming made an extract from the mold and proved that it inhibited bacterial growth. Penicillin became available for general use in the 1940s [150].

MECHANISM OF ACTION

Penicillin is bactericidal, killing susceptible bacteria by interrupting cell wall synthesis. The drug exerts its effect by preventing cross-binding of the peptidoglycan polymers necessary for cell wall formation and by binding with carboxypeptidases, endopeptidases, and transpeptidase ("penicillin-binding proteins" [PBPs]) that participate in cell wall synthesis [6]. Although the exact mechanisms involved are not known, the end result is that the cell wall is structurally weakened and lyses, leading to cell death.

The basic form of penicillin is structured around the beta-lactam ring (a thiazolidine ring) and can be altered by substituting side chains. By doing so, the antimicrobial spectrum, absorption characteristics, and resistance to beta-lactamase deactivation can be favorably modified.

Bacterial resistance to penicillins may take different forms. The most significant is the bacterial production of beta-lactamases, which can destroy the beta-lactam ring by means of hydrolysis, effectively preventing antimicrobial activity by the agent [7]. In addition, some bacteria are able to prevent binding to the PBPs by various means, including altered binding sites for the penicillins [8].

Various strategies have been employed to circumvent these microbial adaptations. Altering the structure of the penicillin molecule to produce agents that are more resistant to the hydrolysis from the beta-lactamases has resulted in the development of the extended-spectrum penicillins.

Another strategy has been to combine penicillins with other agents that block bacterial beta-lactamases. Examples include amoxicillin plus clavulanic acid, ampicillin plus sulbactam, piperacillin plus tazobactam, and ticarcillin plus clavulanic acid. Clavulanic acid is produced by Streptomyces clavuligerus. Sulbactam and tazobactam are derived from the basic penicillin ring. These agents have little intrinsic antimicrobial activity, but they bind irreversibly to many beta-lactamases, preventing hydrolytic activity against the beta-lactam ring.

PHARMACOKINETICS

Penicillins can be separated into groups based on their pharmacokinetics and spectrum of antibacterial activity. These groups are the natural penicillins, the aminopenicillins, the penicillinase-resistant penicillins, and the antipseudomonal penicillins [9].

Table 1: THE PENICILLINS

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

Natural Penicillins

Penicillin G benzathine

1.2–2.4 MU

50,000 U/kg in one dose

Max: 2.4 MU divided between 2 injection sites

IM

Rash, GI upset

Indicated for syphilis, gonorrhea, and group A strep infections.

Note: Do not administer IV (except parenteral/aqueous preparation) or IM near nerve or artery. Cardiopulmonary arrest and death have occurred from accidental IV administration.

Penicillin G benzathine or penicillin G procaine

2.4 MU in one dose

<14 kg: O.6 MU

14 to 27 kg: 1.2 MU in one dose

IM

Rash, GI upset

Penicillin G (parenteral/ aqueous)

12–24 MU per day

100,000–300,000 U/kg/day in divided doses every 4 to 6 hours

Max: 24 MU/day

IM, IV

Rash, GI upset

Penicillin V potassium

125–500 mg every 6 to 8 hours

Pneumonia (off label): 50–75 mg/kg/day in 3 to 4 divided doses

Pharyngitis: 250 mg 2 to 3 times per day

PO

Rash, GI upset

––

Aminopenicillins

Amoxicillin

250–500 mg every 8 hrs, or 500–875 mg twice daily

Manufacturer recommendation: >3 months and <40 kg: 20–100 mg/kg/day in divided doses every 8 to 12 hrs

≤3 months: 20–30 mg/kg/day divided every 12 hrs

AAP recommendation:

All infants and children <40 kg: 25–50 mg/kg/day in divided doses every 8 hrs

PO

Rash, diarrhea

Not to be confused with amoxicillin/clavulanate ES formulation.

Extended-release tablet 775 mg once daily for adults and children ≥12 years of age

Amoxicillin/ clavulanate

250–500 mg every 8 hrs, or 875 mg every 12 hrs

15–40 mg/kg/day divided every 8 hrs, or 25–45 mg/kg/day divided every 12 hrs

Max: 4g/day

<3 mos: 30 mg/kg/day every 12 hrs (125 mg/5 mL suspension only)

PO

Rash, diarrhea

Dosing for amoxicillin/ clavulanate is based on the amoxicillin component; the ES formulation of amoxicillin/clavulanate is not interchangeable with the regular suspension and requires product specific dosing.

Ampicillin

250–500 mg every 6 hrs

PO: 50–100 mg/kg/day in 4 divided doses

Max:2–4 g/day

IV, IM: 25–200 mg/kg/day every 3 to 4 hrs

Max: 12 g/day

PO, IV, IM

Rash, GI symptoms (very common)

The IV form can be given in divided doses or in a continuous infusion.

Ampicillin and sulbactam

1.5–3 g every 6 hrs IV

≥1 year: IV: 100–400 mg/kg/day in 4 divided doses

Max: 8 g/day

IV, IM

Rash, diarrhea, local pain at injection or infusion site (very common with IM use)

Dosing for ampicillin/sulbactam is based on the ampicillin component.

Penicillinase-Resistant Penicillins

Dicloxacillin

125–500 mg every 6 hrs

<40 kg: 12.5–25 mg/kg/day in 4 divided doses every 6 hrs

>40 kg: 125–250 mg every 6 hrs

PO

Rash, diarrhea

Use with caution in neonates, as elimination of drug is slow.

Nafcillin

IV: 0.5–2 g every 4 to 6 hrs

IM: 0.5 g every 4 to 6 hrs

Neonates: 50 mg/kg/day in 4 divided doses

Children: IV: 50–200 mg/kg/day in 4 divided doses

IM: 25 mg/kg every 12 hrs

IV, IM

Phlebitis at IV site, neutropenia, rash

Tissue necrosis can occur with IV extravasation.

Oxacillin

0.25–2 g every 4 to 6 hrs

<40 kg: 50–100 mg/kg/day in divided doses every 6 hrs

>40 kg: 250–1,000 mg every 4 to 6 hrs

IV, IM

Phlebitis at IV site, hepatitis, rash

Drug-induced hepatitis is usually reversible if drug is discontinued. Neonatal dosing may require the use of alternate container system/dosage forms.

May contain a significant amount of sodium.

Antipseudomonal Penicillins

Piperacillin

V, IM: 3–4 g every 4 to 6 hrs

Max: 24 g/day

Neonates: IV, IM: 100 mg/kg every 12 hrs

Infants/children: IV, IM: 200–300 mg/kg/day divided every 4 to 6 hrs

IV, IM

Rash, GI upset, phlebitis at infusion site

—

Piperacillin/tazobactam

IV: 3.375–4.5 every 6 to 8 hrs

Max: 18 g/day

Infants 2 to 9 months: 80 mg piperacillin/kg/dose every 8 hrs

Infants and children >9 months: 100 mg piperacillin/kg/dose

IV

Rash, GI upset

Dosing for adults and pediatrics based on traditional infusion method (IV infusion over 30 minutes).

Dosage in pediatric patients based on piperacillin component.

Pediatric dose is mg/kg/dose, not mg/kg/day.

Ticarcillin or ticarcillin/clavulanate

<60 kg: 200–300 mg/kg/day divided every 4 to 6 hrs

>60 kg: 3.1 g every 4 to 6 hrs

Max: 18 g/day

Use adult dosing by weight

IV

Rash, GI upset

Potential warfarin interaction. Ticarcillin/clavulanate doses are based on the ticarcillin component.

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

AAP = American Academy of Pediatrics; MU = million units; ES = extra strength.

Source: [148,149]

The Natural Penicillins

The natural penicillins include various penicillin G preparations and penicillin V potassium. Penicillin G is very unstable in stomach acid and must be given parenterally. Penicillin V potassium is more acid-stable and is the appropriate form for oral administration.

The natural penicillins are active against gram-positive organisms such as streptococci, Enterococcus faecalis, and Listeria monocytogenes. However, most S. aureus isolates are now resistant. They are also active against anaerobic species, such as Bacteroides species and Fusobacterium species. At serum levels achieved by parenteral administration, the natural penicillins are effective against some gram-negative bacteria, such as Escherichia coli, H. influenzae, Neisseria gonorrhoeae, and Treponema pallidum. For the treatment of moderate-to-severe infections in which resistant organisms are considered a possibility, reliance upon penicillin alone should be avoided unless the identity and sensitivity of the infecting organism have been confirmed. Labeled uses include treatments for infections of the upper and lower respiratory tract, throat, skin, and genitourinary tract and prophylaxis of recurrent rheumatic fever and pneumococcal infections [149].

The Aminopenicillins

The aminopenicillins have about the same activity as the natural penicillins against susceptible gram-positive organisms, plus improved coverage of selected gram-negative bacilli, including Enterobacteriaceae. Amoxicillin/clavulanic acid and ampicillin/sulbactam have better coverage against H. influenzae and Klebsiella species than the natural penicillins and the aminopenicillins alone.

The aminopenicillins include ampicillin and amoxicillin. Ampicillin can be given parenterally or orally. These agents are useful for the management of sinusitis/bronchitis, endocarditis, meningitis, susceptible urinary tract infection, and salmonellosis [149]. Amoxicillin is the best absorbed of the oral penicillins. It is acid-stable and its absorption, unlike ampicillin, is not much affected by food. Improved absorption is also thought to provide an advantage over ampicillin in reducing the risk of antibiotic-associated diarrhea. Labeled uses include endocarditis prophylaxis and as a component of a multidrug H. pylori eradication regimen [149].

The Penicillinase-Resistant Penicillins

The penicillinase-resistant penicillins were developed in response to the emergence of penicillinase-producing S. aureus. These penicillins are resistant to hydrolysis by the lactamase produced by the staphylococci, and they include nafcillin and oxacillin, which are parenteral formulations, and dicloxacillin, which is given orally. Methicillin and cloxacillin are no longer available in the United States [149].

While the penicillinase-resistant penicillins are effective against many of the same gram-positive organisms that the natural penicillins are effective against, they lack significant activity against gram-negative or anaerobic organisms. They are, however, notable for their usefulness against penicillin-resistant (methicillin-sensitive) Staphylococcus species.

The Antipseudomonal Penicillins

The antipseudomonal penicillins are often also referred to as extended-spectrum penicillins; these include ticarcillin and piperacillin (both of which are parenteral). Mezlocillin, which was also parenteral, and carbenicillin, which was oral, are no longer available in the United States.

These agents retain much of their activity against gram-positive bacteria, but they also have more activity against gram-negative bacteria, including Pseudomonas aeruginosa. Additional gram-negative species that are treated by these agents include H. influenzae, Serratia species, and Klebsiella species.

The Addition of Beta-Lactamase Inhibitors

The addition of clavulanic acid, sulbactam, or tazobactam increases the spectrum of activity of the penicillin derivative with which they are combined. They are generally active against the beta-lactamases produced by H. influenzae, Moraxella catarrhalis, and S. aureus. However, their activity is variable against some of the gram-negative bacteria, such as some species of Pseudomonas, Enterobacter, E. coli, Klebsiella, and Serratia, due to resistance to these beta-lactamase inhibitors [10].

ABSORPTION/ELIMINATION

While most penicillins can be absorbed via the oral route, the bioavailability varies considerably, and food may interfere with absorption. Penicillin V, amoxicillin, ampicillin, and dicloxacillin can be given orally; the remaining penicillins are either too unstable in the acidic environment of the stomach or must be given intravenously in order to achieve sustained therapeutic levels. Amoxicillin is the best absorbed of the oral penicillins and the least affected by a recent meal.

Once absorbed, these agents are widely distributed throughout the body. Therapeutic concentrations of penicillins are readily achieved in tissues and secretions (e.g., joint fluid, pleural fluid, pericardial fluid, and bile). Low concentrations are found in prostatic secretions, brain tissue, intraocular fluid, and phagocytes. Cerebrospinal fluid (CSF) concentrations vary but are less than 1% of serum concentration when the meninges are normal. When the meninges are inflamed, CSF concentrations may rise to 5% and can be increased by co-administration of probenecid (500 mg 4 times daily) [11,149]. Concentration in urine is high due to renal clearance mechanisms.

Penicillins are excreted in the kidney by means of glomerular filtration and renal tubular secretion. Probenecid markedly reduces the tubular secretion of the penicillins and decreases the apparent volume of distribution, resulting in higher serum levels. All of the penicillins are excreted to some degree in the bile, but biliary excretion is most important for antipseudomonal penicillins and nafcillin [12].

In patients with mild renal insufficiency, dosage adjustment is not needed, except with the use of ticarcillin [13]. If the creatinine clearance is less than 50 mL/min, then dosage adjustments of parenteral penicillins should be made to avoid excess serum levels. Nafcillin undergoes extensive hepatic metabolism, and the dosage must be adjusted for severe renal and hepatic insufficiency.

SIDE EFFECTS/TOXICITY

These drugs are usually well tolerated. However, gastrointestinal (GI) disturbances may occur with all oral penicillins.

Allergy to any of the penicillins is the only absolute contraindication to use of a penicillin agent. However, studies have found that penicillin allergy is less common than previously thought [165,166,167,168]. Traditionally, allergic reactions were believed to occur in up to 10% of patients; however, more recent studies have found the rate to be much lower. While penicillin-induced anaphylaxis death rate estimates are similar to previous statistics (i.e., approximately 0.002% among the general population), the percentage of individuals with a true penicillin allergy as defined by immunoglobulin E (IgE)-mediated reaction is generally less than 10%, with some studies showing a true penicillin allergy rate of only 0.7% [14,165,166,167]. It is also important to note that approximately 90% of patients previously diagnosed with a penicillin allergy will show no reactivity if not exposed to the antibiotic for 10 years or more, due to the absence of a true allergy or loss of allergy over time [165,167,168]. Allergy skin testing is the most reliable way to determine true penicillin allergy and may allow for previously avoided antibiotics to be used as indicated.

Reactions commonly misdiagnosed as true allergic responses vary and can include a mild rash (the most common) and urticaria. Rarely, serum sickness, exfoliative dermatitis, and Stevens-Johnson syndrome may develop [12,149]. These responses were originally thought to develop in response to the beta-lactam ring and its derivatives and, therefore, there is a common misperception that penicillins are cross-reactive with other antibiotics with the same beta-lactam structure (e.g., cephalosporins) [149]. However, the major determinant in the immunologic reaction is now recognized to be the similarity in the side chain of first-generation cephalosporins and penicillins (not the beta-lactam structure), with the reaction nearing 0% in third-generation cephalosporins [165,166,167].

Rarely, penicillins may cause hematologic reactions with neutropenia due to reversible bone marrow suppression. Abnormal platelet aggregation may occur, particularly with ticarcillin [15]. Other rare reactions include hepatitis, seizures, interstitial nephritis, and hypokalemia due to local effects in the renal tubules.

DRUG INTERACTIONS

The penicillins should not be given concurrently with tetracycline or other bacteriostatic agents. Penicillin works in cells that are actively synthesizing cell wall components, and if metabolism is prevented, then the actions of penicillin may be impaired. The antipseudomonal penicillins also may affect warfarin metabolism. Therefore, the prothrombin time, using the international normalized ratio (INR), should be monitored [16].

SPECIAL POPULATIONS

The penicillins are pregnancy category B, indicating no adverse events noted in animal studies [17]. These agents are secreted in breast milk, and breastfeeding should be avoided if the infant is allergic to any of the penicillins [18]. Use while breastfeeding may cause modifications of normal intestinal flora and allergic sensitization in the infant [149].

6. CEPHALOSPORINS

Giuseppe Brotzu discovered the first cephalosporin in 1948, observing that the fungus Cephalosporium acremonium produced a substance that inhibited the growth of S. aureus and other bacteria. The initial substance was identified and modified to create the cephalosporins that are now used. The cephamycins were created by adding a methoxy group on the beta-lactam ring of the original compound, based on the structure of cefoxitin, produced by Streptomyces lactamdurans. By altering the chemical groups substituted on the basic molecule, greater antimicrobial activity and longer half-lives have been obtained [19].

MECHANISM OF ACTION

Like penicillins, the cephalosporins are beta-lactams in which the beta-lactam ring is joined to a dihydrothiazine ring. Their antimicrobial effect is based on the same mechanism of action as that for the penicillins. The cephalosporins inhibit bacterial cell wall synthesis by blocking the transpeptidases and other PBPs involved in the synthesis and cross-linking of peptidoglycan [20,21].

Because each bacterial species has a unique chemical structure in its cell wall, the cephalosporins may have different mechanisms of action by which they inhibit cell wall synthesis.

As with penicillins, resistance to the action of cephalosporins results from mutations in the penicillin-binding proteins (preventing the cephalosporins from binding to them) and from the production of extended-spectrum beta-lactamases that deactivate the drug [22]. An additional source of resistance in gram-negative bacteria is alteration in the cell-membrane porins that normally allow passage of the cephalosporins [23].

Of these mechanisms, the production of beta-lactamase is the most clinically significant. This form of resistance may occur through mutations or may be carried on plasmids [24].

PHARMACOKINETICS

The cephalosporins have been classified in different ways, based on chemical structure and pharmacologic activities. The most commonly used classification system groups the agents into "generations" based on their similarities in antimicrobial coverage.

Table 2: THE CEPHALOSPORINS

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

1st Generation

Cefadroxil

1–2 g/day in 2 divided doses

30 mg/kg/day in 2 divided doses

Max: 2 g/day

PO

Rash, diarrhea

Can interfere with some urine glucose tests.

Cefazolin

1–2 g every 8 hrs

Max: 12 g/day

>1 mo: 25–100 mg/kg/day divided every 6 to 8 hrs

Max: 6 g/day

IV, IM

Phlebitis at infusion site, seizure,rash, diarrhea

Can interfere with some urine glucose tests.

Cephalexin

250–1,000 mg every 6 to 12 hrs

Max: 4 g/day

>1 yr to <15 yrs: 25–100 mg/kg/day in 3 to 4 divided doses

Max: 4 g/day

PO

GI upset, rash

Can interfere with some urine glucose tests.

2nd Generation

Cefaclor

250–500 mg every 8 hrs

>1 mo: 20–40 mg/kg/day in 2 to 3 divided doses

Max: 1 g/day

PO

Rash, GI upset

Can interfere with some urine glucose tests.

Cefotetan

1–2 g every 12 hrs

Max:4–6 g/day

AAP recommendation: 30–50 mg/kg/dose every 12 hrs

Max: 4,000 mg/day

IV, IM

Phlebitis at infusion site, rash, GI upset

Disulfiram-like reaction with alcohol. Can interfere with some urine glucose tests.

Not recommended for treatment of community-acquired intra-abdominal infections.

Cefoxitin

1–2 g every 6 to 8 hrs

Max: 12 g/day

>3 mos: 80–160 mg/kg/day in 4 to 6 divided doses

Max: 12 g/day

IV, IM

Phlebitis at infusion site, rash

IM injection is painful. Can interfere with some urine glucose tests.

In pediatrics, for group A beta-hemolytic streptococcal infections, antimicrobial therapy should be given for at least 10 days to guard against the risk of rheumatic fever or glomerulonephritis.

Cefprozil

250–500 mg every 12 to 24 hrs

>6 mos: 7.5–20 mg/kg every 12 hrs

>2 yrs: 7.5–15 mg/kg/day in 2 divided doses, or 20 mg/kg every 24 hrs

Max: 1 g/day

PO

Rash, GI upset, elevated liver enzymes

Avoid use in phenylketonuria. Can interfere with some urine glucose tests.

Cefuroxime

PO: 250–500 mg every 12 hrs for 10 days

IV, IM: 0.5–1.5 g every 6 to 8 hrs

Max: 6 g/day

PO: 20–30 mg/kg/day in 2 divided doses

IV, IM: 75–150 mg/kg/day in 3 divided doses

Max: 6 g/day

PO,

IV, IM

Phlebitis at infusion site, rash, GI upset

Tablets and oral suspension forms require different dose. Oral doses noted here are for tablet formulation.

Higher doses can be used for severe infection.

3rd Generation

Cefdinir

300 mg every 12 hrs, or 600 mg every 24 hrs for 10 days

7 mg/kg/dose twice daily or 14 mg/kg/dose for 10 days

Max: 600 mg/day

PO

Rash, diarrhea

Iron and antacids can reduce absorption. Can interfere with some urine glucose tests.

Cefditoren

200–400 mg every 12 hrs for 10 to 14 days

Not studied for patients <12 yrs

PO

GI upset, headache

Interaction with proton-pump inhibitors, H2 blockers, antacids. Contraindicated with milk protein allergy.

Cefixime

400 mg/day in 1 or 2 doses

>6 mos and <45 kg: 8–20 mg/kg/day every 12 to 24 hrs

Max: 400 mg/day

>12 yrs or >50 kg: Use adult dosing

PO

Diarrhea, rash

Can interfere with some urine glucose tests.

Cefotaxime

1–2 g every 4 to 12 hrs

1 mo to 12 yrs and <50 kg: 50–225 mg/kg/day in 3 to 4 divided doses

IV, IM

Phlebitis at infusion site, rash, GI upset

Single dose can be given for GC. Transient arrhythmias have developed after administration of this agent through central venous catheter.

Cefpodoxime

100–400 mg every 12 hrs for 7 to 14 days

10 mg/kg/day in 2 divided doses

PO

Diarrhea, nausea, vomiting

Decreased absorption with antacids and H2 blockers. Can be given as a single dose for GC.

Ceftazidime

500–1,000 mg every 8 hrs

IV: 30–50 mg/kg every 8 hrs

Max: 6 g/day

AAP recommendation for IV: 90–200 mg/kg/day every 8 hours

Max: 6 g/day

IV, IM

Phlebitis at infusion site, rash, GI upset

Can interfere with some urine glucose tests. The L-arginine formulation should not be used in children.

Ceftibuten

400 mg every 24 hrs for 10 days

9 mg/kg/day

Max: 400 mg/day for 10 days

PO

Rash, GI upset, headache

Can interfere with some urine glucose tests.

Ceftriaxone

IV, IM: 1–2 g every 12 to 24 hrs

50–100 mg/kg/day in 1 to 2 divided doses

Max: 4 g/day

IV, IM

Phlebitis at infusion site, rash

Avoid in neonates with hyperbilirubinemia. Higher doses are used for meningitis. A ceftriaxone-calcium salt can precipitate in the gallbladder, causing sonographically detectable abnormalities.

4th Generation

Cefepime

IV: 1–2 g every 8 to 12 hrs

IM: 0.5–1 g every 12 hrs

IV, IM: 50 mg/kg every 8 to 12 hrs

Not to exceed adult dosing

IV, IM

Phlebitis at infusion site, GI upset

Can interfere with some urine glucose tests.

5th Generation

Ceftaroline fosamil

600 mg every 12 hours for 5 to 14 days

>2 mos to <2 yrs: 8 mg/kg/dose every 8 hrs for 5 to 14 days

>2 yrs to <18 yrs and <33 kg: 12 mg/kg/dose every 8 hrs for 5 to 14 days

>2 yrs to <18 yrs and >33 kg: 400–600 mg every 8 to 12 hrs for 5 to 14 days

IV

Phlebitis at infusion site, GI upset, headache

Slow IV infusion over 60 minutes. Can interfere with some urine glucose tests.

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

GC = gonococcal infection.

Source: [148,149]

First-Generation Cephalosporins

The first-generation cephalosporins are most active against aerobic gram-positive cocci. These agents include cefazolin, cephalexin, and cefadroxil, and they are often used for skin infections caused by S. aureus and Streptococcus and for susceptible urinary tract infections. They have activity against E. coli and some activity against H. influenzae and Klebsiella species, but because of the limited gram-negative coverage, they are not first-line agents for infections that are likely to be caused by gram-negative bacteria.

Second-Generation Cephalosporins

The second-generation cephalosporins are more active against gram-negative organisms, such as Moraxella, Neisseria, Salmonella, and Shigella. Cefoxitin and cefotetan, which are included in this group under this classification system although they are technically cephamycins, also have more coverage against anaerobic bacteria. The true cephalosporins that are also part of this class are cefprozil, cefuroxime, cefaclor, cefoxitin, and cefotetan. These drugs are used primarily for respiratory tract infections because they are better against some strains of beta-lactamase producing H. influenzae.

Third-Generation Cephalosporins

The third-generation cephalosporins have enhanced activity and a broader spectrum against gram-negative organisms, including Neisseria species, M. catarrhalis, Klebsiella, and other Enterobacteriaceae. Of these agents, ceftriaxone has the best activity against gram-positive cocci, specifically S. pneumoniae and methicillin-sensitive S. aureus. Ceftazidime is active against P. aeruginosa. Other cephalosporins in this class include cefdinir, cefditoren, cefixime, cefotaxime, cefpodoxime, ceftibuten, and ceftriaxone. These drugs are useful for more severe community-acquired respiratory, intraabdominal, and urinary tract infections and for nosocomial infections (because of the high incidence of resistant organisms) [25].

Fourth-Generation Cephalosporins

Cefepime is classed as a fourth-generation cephalosporin because it has good activity against both gram-positive and gram-negative bacteria, including P. aeruginosa and many Enterobacteriaceae. The gram-negative and anaerobic coverage makes cefepime useful for intra-abdominal infections, respiratory tract infections, and skin infections.

Fifth-Generation Cephalosporins

Ceftaroline fosamil is a novel advanced-generation cephalosporin approved by the U.S. Food and Drug Administration (FDA) in 2010, for the treatment of community-acquired bacterial pneumonia and bacterial skin and soft-tissue infections. As with other beta-lactams, ceftaroline exerts its antimicrobial affect by binding to PCP and inhibiting cell wall synthesis. This agent is unique in that it also has a high affinity for PBP2a, which is associated with resistance to methicillin. Consequently, ceftaroline is highly active against methicillin-sensitive and resistant strains of S. aureus and against multidrug-resistant S. pneumoniae [152]. It is ineffective for P. aeruginosa, and its activity against Enterobacteriaceae is variable. Beta-lactamase-producing Enterobacteriaceae and AmpC mutants are resistant. Prospective clinical trials have shown that the efficacy of ceftaroline is comparable to vancomycin plus aztreonam for the treatment of bacterial skin and soft-tissue infection (including methicillin-resistant S. aureus [MRSA]) and to ceftriaxone for the treatment of community-acquired bacterial pneumonia [153]. Among cases of pneumonia caused by S. pneumoniae, clinical cure rates were higher with ceftaroline (83.3%) than with ceftriaxone (70%) in a phase III clinical trial, and the agent was well tolerated [154].

ABSORPTION/ELIMINATION

The orally administered cephalosporins include cefaclor, cefadroxil, cephalexin, cefprozil, cefuroxime axetil, cefixime, cefpodoxime proxetil, ceftibuten, and cefdinir. In general, the orally administered cephalosporins are absorbed rapidly. Cephalexin, cefadroxil, cefaclor, cefixime, ceftibuten, and cefdinir are nonesterified and are absorbed from the GI tract by active transport in the small intestine. Other agents, such as cefuroxime axetil and cefpodoxime proxetil, are prodrug esters and are passively absorbed. Once absorbed into the cells lining the small intestine, these agents are hydrolyzed and then excreted into the blood stream as active cephalosporins [26].

The presence of food or antacids may increase or decrease the absorption, depending on the drug. Cefuroxime axetil and cefpodoxime proxetil have increased absorption when taken with food. Cefaclor, cefadroxil, and cephalexin have slowed absorption when food is in the stomach. Cefixime, cefprozil, and ceftibuten are not affected by the presence of food. Cefpodoxime is the only cephalosporin whose absorption is decreased by the presence of antacids or H2 antagonists [27].

There is extensive distribution of the cephalosporins into body tissues and fluids. They readily cross the placenta and are also found in synovial fluid. Concentrations in bile and urine are high. Most cephalosporins do not cross into the CSF in sufficient concentration to be recommended for the treatment of meningitis, but there are some exceptions. Cefuroxime, cefotaxime, ceftriaxone, cefepime, and ceftaroline all have good penetration into the CSF [28,152].

Most cephalosporins are eliminated by the kidney. The exception in the oral cephalosporins is cefixime, half of which is excreted in the urine. The remaining half is partly metabolized to inactive metabolites and partly excreted in the bile. Cefotaxime is deacetylated by the liver to a bioactive metabolite and inactive forms. The deacetylated metabolites are excreted by the kidney. Cefpiramide is excreted predominantly in the bile.

In severe hepatic insufficiency, compensatory changes in renal excretion of the hepatically metabolized drugs may occur [29]. In the presence of severe renal and/or hepatic insufficiency, dosage adjustment of cefotaxime is necessary.

SIDE EFFECTS/TOXICITY

As a group, cephalosporins are relatively well tolerated [30]. The most common complaints are GI upset, resulting in nausea, vomiting, or diarrhea. Thrombophlebitis can occur with intravenous (IV) administration. One to three percent of patients develop an allergic reaction. Rash, fever, eosinophilia, and urticaria can develop. Anaphylaxis is rare. Infrequently, there is some cross-sensitivity with true penicillin allergy (estimated nearly 0%to 10% of cases); this occurs mostly with first-generation cephalosporins [13,165,166,167]. If a patient develops urticaria, anaphylaxis, or angioedema with penicillins or a cephalosporin, avoid using any of the other cephalosporins.

Although uncommon, nephrotoxicity has been reported [31]. Cephalosporins that contain the methylthiotetrazole (MTT) side chain (cefotetan) may induce a disulfiram-like reaction with alcohol ingestion (e.g., flushing, tachycardia, nausea and vomiting, diaphoresis, dyspnea, hypotension, and confusion). This is due to increased circulating acetaldehyde.

Ceftriaxone has been associated with cholelithiasis and cholestatic hepatitis due to precipitation in the bile [32]. Rare reactions include hematologic toxicity with resultant eosinophilia, thrombocytopenia, and leukopenia, all of which resolve after stopping treatment [33]. Rarely, hemolytic anemia develops [34]. Hypoprothrombinemia may occur with cephalosporins with the MTT side chain as a result of interference by the MTT moiety with the synthesis of vitamin-K-dependent clotting factors [35]. For patients at high risk of bleeding, exogenous vitamin K may help alleviate this side effect. False-positive glucosuria testing with a copper reduction test (Clinitest) may occur with many cephalosporins [36].

DRUG INTERACTIONS

The serum levels of all the cephalosporins are increased with co-administration of probenecid. The effects of warfarin may be enhanced by co-administration of cefotetan, cefazolin, cefoxitin, and ceftriaxone.

SPECIAL POPULATIONS

Cephalosporins are generally considered safe to use in pregnancy and are designated as category B. They are excreted in breast milk in low concentrations, and the American Academy of Pediatrics (AAP) considers this compatible with breastfeeding [37,38].

7. CARBAPENEMS

Meropenem, imipenem/cilastatin, doripenem, and ertapenem are parenteral synthetic beta-lactams derived from thienamycin, an antibiotic produced by Streptomyces cattleya [39]. They have a lactam ring, like the penicillins and cephalosporins, but have a methylene moiety in the ring.

MECHANISM OF ACTION

Like other beta-lactams, the carbapenems inhibit mucopeptide synthesis in the bacterial cell wall by binding to PBPs, leading to lysis and cell death. Bacterial resistance may occur due to a specific beta-lactamase that affects carbapenems. Another significant source of resistance is a mutation that results in the absence of the outer membrane porin, thus not allowing transport of the drug into the cell [40]. Cross-resistance may occur between the carbapenems.

PHARMACOKINETICS

Imipenem and ertapenem have a wide antimicrobial spectrum with excellent activity against anaerobic bacteria, including Bacteroides species. They also cover many gram-positive cocci, such as Enterococcus and Streptococcus, as well as many gram-negative bacteria [41]. Meropenem has somewhat greater activity against gram-negative bacteria, which are not affected by most beta-lactamases. Doripenem has good activity against Pseudomonas aeruginosa.

Imipenem and ertapenem are approved by the FDA for use in urinary tract infections, pneumonia, intra-abdominal infections, and skin and soft-tissue infections [149]. Meropenem is approved by the FDA for treatment of intra-abdominal infections, skin and skin structure infections, and meningitis in patients older than 3 months of age [149]. Combination meropenem/vaborbactam is approved for the treatment of complicated urinary tract infections caused by susceptible micro-organisms [163].

ABSORPTION/ELIMINATION

Imipenem/cilastatin, meropenem, and ertapenem are given parenterally, as they are unstable in stomach acid. Imipenem is combined with cilastatin, which inhibits dehydropeptidase I in the proximal renal tubular cells. Dehydropeptidase I inactivates imipenem by hydrolysing the beta-lactam ring, so adding the cilastatin allows increased levels of imipenem in the urine and also prevents the production of the nephrotoxic metabolites of imipenem [42]. Meropenem, doripenem, and ertapenem do not require a dehydropeptidase I inhibitor.

Meropenem is well distributed in body tissues and fluids, including the CSF. Imipenem/cilastatin and ertapenem are distributed throughout body tissues, but with only low concentrations in the CSF [43].

Most of the imipenem/cilastatin dose is excreted in the urine. The remaining 20% to 25% of the dose is excreted through an unknown mechanism. Meropenem is excreted unchanged into the urine by means of glomerular filtration and tubular secretion [44]. Ertapenem is metabolized by hydrolysis of the beta-lactam ring, and then both the metabolite and parent drug are excreted in the urine.

The carbapenems require dosage adjustment in patients with renal insufficiency. No changes in dosage are necessary for patients with hepatic insufficiency.

SIDE EFFECTS/TOXICITY

The carbapenems are generally well tolerated. Occasional reactions include nausea and vomiting, phlebitis at the infusion site, elevation of liver enzymes, and leukopenia. Seizures may occur. The risk is higher in patients with underlying central nervous system (CNS) disease and in patients with renal disease, which results in high serum levels of the drug [45]. Hypersensitivity reactions may occur, and while there is a degree of cross-sensitivity with penicillins, this risk is lower than previously believed [165,166,167]. Carbapenems should be used with caution in patients allergic to the carbapenems or penicillins.

DRUG INTERACTIONS

There are few drug interactions associated with the carbapenems, but probenecid may increase the serum levels of meropenem, ertapenem, and imipenem/cilastatin and should be avoided. Ertapenem cannot be infused with dextrose or other medications. Meropenem may reduce levels of valproic acid [46].

SPECIAL POPULATIONS

Meropenem, doripenem, and ertapenem are pregnancy category B, with animal studies showing no adverse reactions [47]. Imipenem/cilastatin is pregnancy category C, based on studies in monkeys that showed increased embryonic loss and side effects in the mother [48]. No data is available regarding breastfeeding and carbapenem administration.

The safety of doripenem use has not been studied in children. Meropenem has been used in children and is indicated by the FDA for the treatment of pediatric meningitis but has not been studied in infants younger than 3 months of age [49]. Ertapenem can be used in infants older than 3 months of age, and imipenem can be used from birth; these agents are useful for treating complicated infections in pediatric patients (e.g., complicated urinary tract infections).

8. MONOBACTAMS

Monobactams have a single beta-lactam core, distinguishing them from the other beta-lactam drugs [50]. Aztreonam is the only available example of this class of drugs. Aztreonam was originally extracted from Chromobacterium violaceum. It is now manufactured as a synthetic antibiotic.

Table 3: THE OTHER BETA-LACTAMS

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

Carbapenems

Doripenem

500 mg every 8 hours for 5 to 14 days

Not studied for pediatric use

IV

Headache, rash, nausea, vomiting, diarrhea, phlebitis

Dosage adjustment necessary for renal impairment. Cannot be used in patients with known hypersensitivity to any beta-lactam antibiotic. Seizure risk in patients with CNS disorders.

Ertapenem

1 g/day for 3 to 14 days

15 mg/kg every 12 hrs

Max: 1 g/day for 3 to 14 days

IV, IM

Diarrhea, nausea, phlebitis at infusion site

Seizure risk in patients with CNS disorders. IV therapy may be administered for up to 14 days; IM for up to 7 days.

Imipenem/cilastatin

500–1,000 mg every 6 to 8 hrs

Max: 4 g/day

>3 mos: 15–25 mg/kg every 6 hrs

Max: 4 g/day

IV

Phlebitis at infusion site, rash

Documentation of cross-allergy with penicillin allergy is limited. Seizure risk in patients with CNS disorders. Adults <70 kg may require decreased dosing.

Meropenem

1.5–6 g/day in 3 divided doses

Infants <3 mos (IV): Gestational age <32 weeks AND postnatal age <14 days: 20 mg/kg/dose every 12 hrs Postnatal age ≥14 days: 20 mg/kg/dose every 8 hrs

Gestational age ≥32 weeks AND postnatal age <14 days: 20 mg/kg/dose every 8 hrs Postnatal age ≥14 days: 30 mg/kg/dose every 8 hrs

>3 mos and <50 kg: 30–120 mg/kg/day in 3 divided doses

Max: 6 g/day

>50 kg: Same as adult dosing

IV

Diarrhea, nausea, inflammation at the injection site, headache

Can cause elevated LFTs. Seizure risk in patients with CNS disorders.

Meropenem/vaborbactam

4 g every 8 hrs for <14 days

Not studied in pediatric patients

IV

Headache, GI symptoms, phlebitis at infusion site

Dosage adjustment necessary for renal impairment.

Monobactams

Aztreonam

IV: 1–2 g every 8 to 12 hrs

Nebulizer: 75 mg 3 times/day at least 4 hours apart for 28 days; do not repeat for 28 days after completion.

>9 mos: 30–50 mg/kg/dose every 6 to 8 hrs

Max: 120 mg/kg/day

>7 years of age (nebulizer): Same as adult dosing

IV, IM, oral inhalation

Rash, nausea, vomiting, phlebitis at infusion site

Rare cross-sensitivity with allergy to other beta-lactams. For oral inhalation, pretreatment with a bronchodilator is recommended.

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

CNS = central nervous system; LFTs = liver function tests (liver enzymes).

Source: [148,149]

MECHANISM OF ACTION

As with other beta-lactams, aztreonam inhibits mucopeptide synthesis in the bacterial cell wall by binding to the penicillin-binding proteins of gram-negative bacteria, leading to cell lysis and death. Aztreonam is resistant to most beta-lactamases. Treatment in combination with an aminoglycoside appears to be synergistic against Pseudomonas.

PHARMACOKINETICS

Aztreonam does not have significant activity against gram-positive or anaerobic bacteria and is primarily used as an alternative therapy for gram-negative bacterial infections, including P. aeruginosa and Klebsiella, that are resistant to the first-line beta-lactams or carbapenems. It is indicated for use in pneumonia, soft-tissue infections, urinary tract infections, and intra-abdominal and pelvic infections that are caused by gram-negative aerobic bacteria.

There is no oral form of aztreonam, and intravenous is the preferred mode of parenteral administration. It is distributed widely in body tissues and fluids, including inflamed meningeal tissue [51]. Aztreonam is mainly excreted in the urine as an unchanged drug, although there is also minimal hepatic metabolism [52]. Doses must be adjusted for renal insufficiency based on glomerular filtration rate [53].

SIDE EFFECTS/TOXICITY

Frequent adverse reactions include elevations of liver enzymes and transient eosinophilia. Less common reactions include phlebitis at the infusion site, rash, diarrhea, and nausea [54].

There have been a few reports of cross-allergy reactions in patients who are allergic to ceftazidime, but patients with penicillin and cephalosporin allergy can usually tolerate aztreonam [55]. Aztreonam is contraindicated in patients with prior allergic reactions to it or to any component of the formulation.

DRUG INTERACTIONS

No drug interactions have been reported with aztreonam [56].

SPECIAL POPULATIONS

Aztreonam is pregnancy category B, based on animal studies that have shown no ill effects of the drug. There is no human data available [57].

Aztreonam is secreted in breast milk in low concentrations; breastfeeding is not recommended because the effects of the drug have not been studied in young infants.

Aztreonam has not been studied for use in children younger than 1 month of age but appears safe in children older than 1 month of age, although it should be noted that manufacturer recommendations are for children older than 9 months of age [149]. It has been shown to be very useful in children with respiratory symptoms of cystic fibrosis [58].

9. AMINOGLYCOSIDES

The first aminoglycoside, streptomycin, was derived from Streptomyces griseus during the 1940s. Actinomycetes were studied for possible antimicrobial byproducts, and it was found that Micromonospora and Streptomyces produced useful agents. As newer, safer, and more effective aminoglycosides have been developed, the use of streptomycin is now confined primarily to certain management strategies for the treatment of tuberculosis.

Table 4: THE AMINOGLYCOSIDES

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

Amikacin

5 mg/kg every 8 hrs or 7.5 mg/kg every 12 hrs

15–22.5 mg/kg/day every 8 hrs OR 15–20 mg/kg/dose every 24 hours

IV, IM

Renal failure, vestibular nerve damage, auditory nerve damage

Predisposition to auditory/vestibular nerve damage may be genetic; check family history. Check serum levels. Doses are based on lean body mass; maintenance dose is based on calculation with creatinine clearance. Additional dose adjustments are needed in renal failure.

Gentamicin

3–5 mg/kg/day in divided doses every 8 to 12 hrs, or 5–7 mg/kg once daily

Infants: 2–2.5 mg/kg/dose every 6 to 8 hrs

IV, IM, topical

Kanamycin

5–7.5 mg/kg/day divided every 8 to 12 hrs

Max: 1.5 g/day

15 mg/kg/day in 2 to 3 divided doses

IV, IMa

Neomycin

4–12 g/day in 4 to 6 divided doses for 5 to 6 days, or 4 g/day for an indefinite period

50–100 mg/kg/day in 3 to 4 divided doses

PO, topical

Systemic absorption is possible, resulting in the same side effects as amikacin.

Used as a bowel prep for surgery. Is also formulated in some topical eye, ear, and skin preparations.

Streptomycin

15–30 mg/kg/day or 1–2 g daily

20–40 mg/kg/day every 6 to 12 hrs in divided doses

Max: 1 g/dose or 2 g/day

IV, IM

Renal failure, vestibular nerve damage, auditory nerve damage

This is the most ototoxic of aminoglycosides; levels must be monitored closely.

Can cause neuromuscular blockade and respiratory paralysis, especially when given soon after muscle relaxants or anesthesia.

Tobramycin

1–2.5 mg/kg every 8 to 12 hrs, or4–7 mg/kg once daily dose

<5 yrs: 2.5 mg/kg every 8 hrs

>5 yrs:2–2.5 mg/kg every 8 hrs

IV, IM inhalation solution, ophthalmic ointment or solution

Renal failure, vestibular nerve damage, auditory nerve damage

Effects of nondepolarizing muscle relaxants can be increased.

Total body weight (as opposed to ideal body weight) should be used for underweight patients.

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

aIM formulation no longer available in the United States.

Source: [148,149]

MECHANISM OF ACTION

The basic structure of the aminoglycosides is an aminocyclitol ring. Different members of the family have different glycosidic linkages and side groups.

The aminoglycosides have at least two effects on the bacterial cell that ultimately result in cell death. These agents bind negative charges in the outer phospholipid membrane, displacing the cations that link the phospholipids together. This leads to disruption in the wall and leakage of cell contents. In addition, they inhibit protein synthesis by binding to the 30S subunit of the ribosome, causing miscoding and termination [59].

Although resistance to aminoglycosides is less common than with many other antibiotics, it can develop as a result of three known mechanisms. The most common pattern of resistance involves modification of the aminoglycoside molecule itself by enzymes produced by some bacteria. After the aminoglycoside is altered, it cannot bind as well to the ribosomes. The genes that encode for these enzymes are carried on plasmids, allowing rapid transfer of resistance between bacteria. Of note, amikacin has an S-4 amino 2-hydroxybutyryl (AHB) side chain that protects it against deactivation by many bacterial enzymes and is therefore less susceptible to this bacterial defense mechanism [60].

The binding site for aminoglycosides on the rRNA of the ribosome may also be altered, reducing binding. In addition, mutations that cause reduced uptake of aminoglycosides have been documented [60].

To combat resistances and overcome the relative natural resistance of enterococcus, other agents that target the cell wall are often used in conjunction with the aminoglycosides. Damage to the cell wall from the additional agents may be bactericidal in some cases and also makes the cell wall more permeable to the aminoglycosides [61].

PHARMACOKINETICS

The aminoglycosides are effective for the treatment of aerobic gram-negative bacilli, such as Klebsiella species, Enterobacter, and P. aeruginosa. There is very little activity against anaerobes and gram-positive organisms, so combination therapy with a beta-lactam, vancomycin, or other agents active against gram-positive organisms and anaerobes is commonly used. The aminoglycosides are indicated for infections caused by susceptible organisms of the urinary tract, respiratory tract, skin and soft tissues, and sepsis due to gram-negative aerobic bacilli.

The aminoglycosides commonly used at present for treatment of systemic bacterial infection include gentamicin, tobramycin, amikacin, and kanamycin. Aminoglycosides have negligible oral absorption and thus require parenteral administration. They also can be administered directly into body cavities and have a role in the management of pleural and peritoneal infection. Tobramycin is particularly useful for treatment of recurrent Pseudomonas infection in patients with cystic fibrosis and can be administered by aerosolized inhalation to facilitate optimal local antimicrobial effect [58]. Neomycin is often used orally as part of a pre-operative bowel decontamination protocol.

The aminoglycosides are widely distributed in extracellular fluid, including pleural fluid, synovial fluid, abscesses, and peritoneal fluid. They are relatively insoluble in lipid, so the volume of distribution is lower in obese patients. They have poor distribution in bile, aqueous humor, bronchial secretions, sputum, and the CSF [9].

Aminoglycosides are excreted unchanged by the kidneys. There is no reduction of dosage necessary in liver failure, as there is no hepatic metabolism of these agents. In renal failure, the dosage must be carefully adjusted based on glomerular filtration rate and measured serum levels. Serum levels should be monitored in all patients with reduced renal function [63].

TOXICITY

The most common adverse effect associated with aminoglycoside usage is renal failure, which is usually reversible when the drug is discontinued. The exact mechanism of renal injury and how that injury results in decreased glomerular filtration is unknown [64]. It appears that, although there is no hepatic metabolism of the aminoglycosides, concomitant liver disease increases the likelihood of the development of nephrotoxicity [65].

Less commonly, vestibular and auditory impairment may develop during treatment with aminoglycosides. These effects are usually reversible, and because there is some data suggesting that there is a genetic predisposition to ototoxicity, this drug class should be avoided in patients who have a family history of ototoxicity with aminoglycosides [66]. When aminoglycoside therapy is expected to exceed five to seven days, baseline testing of auditory function should be performed and monitored weekly for the duration of treatment.

Neuromuscular blockage has also been observed as a side effect. Aminoglycosides may aggravate muscle weakness in patients with neuromuscular disorders, such as myasthenia gravis and Parkinson disease, due to a curare-like effect on neuromuscular function [67].

Hypersensitivity reactions are not common with aminoglycosides, but rash, fever, urticaria, angioneurotic edema, and eosinophilia may occur. Very rare reactions include optic nerve dysfunction, peripheral neuritis, arachnoiditis, encephalopathy, pancytopenia, exfoliative dermatitis, and amblyopia. Bronchospasm and hoarseness have been known to occur with tobramycin inhalation solution [62].

The aminoglycosides are contraindicated in patients with hypersensitivity to the drug. Cross-sensitivity between aminoglycosides does occur. Streptomycin also contains metabisulfite and should be avoided if the patient is allergic to sulfites (more common in asthmatics) [68].

DRUG INTERACTIONS

There are numerous drug interactions that should be taken into consideration when using the aminoglycosides. The risk of nephrotoxicity may be increased with co-administration of other drugs that are nephrotoxic or in patients receiving loop diuretics (e.g., furosemide). Respiratory depression may occur if aminoglycosides are given with nondepolarizing muscle relaxants. Neomycin may affect digoxin levels by altering the bowel flora responsible for the metabolism of digoxin in the GI tract. Gentamicin may also cause increased serum digoxin levels [69].

In vitro deactivation of penicillins due to acylation has been observed, so the drugs should not be mixed in vitro. Tobramycin inhalation solution cannot be mixed in the nebulizer with dornase alfa [70].

SPECIAL POPULATIONS

Amikacin, streptomycin, tobramycin, and kanamycin are pregnancy category D due to eighth cranial nerve toxicity that has occurred in the fetus with some aminoglycosides. Gentamicin is pregnancy category C due to animal studies that show dose-related nephrotoxicity. Ototoxicity has not been reported with gentamicin, but it may occur. Neomycin is pregnancy category C due to minimal systemic absorption of the oral dose. Despite these categorizations by the manufacturers, some authorities think that these agents may be used if the benefit outweighs the potential risk [71].

Traces of aminoglycosides are excreted in breast milk, but the AAP considers this compatible with breastfeeding because aminoglycosides are very poorly absorbed from the GI tract [38]. However, they may cause alterations in the normal bowel flora of the infant.

Half-life alterations occur in patients at extremes of age. The half-life in neonates and low-birth-weight infants may be considerably prolonged. The elderly may also have a longer aminoglycoside half-life due to an age-related decrease in renal function [62]. Geriatric dosing should be based on ideal body weight estimates [149].

10. MACROLIDES AND TELITHROMYCIN

The original macrolide, erythromycin, was discovered in 1952 by J.M. McGuire. It is produced by Saccharopolyspora erythraea (formerly known as Streptomyces erythreus). Semisynthetic derivatives (clarithromycin, azithromycin) have been produced from the original erythromycin, with modifications that improve acid stability, antibacterial spectrum, and tissue penetration.

Table 5: THE MACROLIDES AND TELITHROMYCIN

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

Macrolides

Azithromycin

PO: 250–600 mg/day, or 1–2 g/day

IV: 250–500 mg/day

PO: 5–12 mg/kg/day

Max: 500 mg/day

Otitis media: 30 mg/kg as single dose (not to exceed 1,500 mg)

PO, IV, ophthalmic drops

GI upset

One dose of 1 g given PO can be used for non-GC urethritis/cervicitis. Interaction with pimozide/cyclosporine.

Clarithromycin

250–500 mg every 12 hrs, or 1 g/day extended-release formulation for 7 to 14 days

>6 mos of age: 7.5 mg/kg every 12 hrs

PO

GI upset, metallic taste

Inhibits liver CYP 450 enzyme 3A4, resulting in multiple significant drug interactions. Special dosing combined with omeprazole and amoxicillin is one regimen used for H. pylori treatment.

Erythromycin

Base: 250–500 mg PO every 6 to 12 hrs

Max: 4 g/day

Ethylsuccinate: 400–800 mg PO every 6 to 12 hrs

Max: 4 g/day

Lactobionate: 15–20 mg/kg/day IV in 4 divided doses, or 0.5–1 g IV every 6 hrs, or continuous infusion over 24 hrs (Max: 4 g/day)

Base: 30–50 mg/ kg/day PO in 2 to 4 divided doses

Max: 2 g/day

Ethylsuccinate: 30–50 mg/kg/day PO in 2 to 4 divided doses

Max: 4 g/day

Stearate: 30–50 mg/kg/day PO in 2 to 4 divided doses

Max: 2 g/day

Lactobionate: 15–50 mg/kg/day IV in 4 divided doses

Max: 4 g/day

PO, IV, ophthalmic solution, topical ointment, gel, or pad

GI intolerance (common), phlebitis at IV infusion site

Inhibits liver CYP 450 enzymes 3A4 and 1A2, resulting in multiple significant drug interactions.

Fidaxomicin

200 mg twice daily for 10 days

Not studied in pediatric patients

PO

Nausea, abdominal pain

Used for treatment of diarrhea due to C. difficile

Ketolides

Telithromycina

800 mg every 24 hrs for 7 to 10 days

Not studied for children <13 yrs of age

>13 yrs: Use adult dosing

PO

Nausea, diarrhea

Occasionally causes visual changes (reversible). Inhibits liver CYP 450 enzyme 3A4, resulting in multiple significant drug interactions.

Cases of serious or fatal respiratory failure have occurred in patients with myasthenia gravis.

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

Non-GC = nongonococcal infection.

aDrug discontinued by manufacturer in 2016.

Source: [148,149]

MECHANISM OF ACTION

The macrolides are bacteriostatic, inhibiting protein synthesis by binding at the 50S ribosomal unit and by blocking transpeptidation and translocation. At high concentrations or with rapid bacterial growth, the effects may be bactericidal [72].

Telithromycin is technically a ketolide, but it is structurally related to the macrolides. It also functions by binding the ribosomal subunit with subsequent inhibition of bacterial protein synthesis. By binding in two places, telithromycin remains active against bacteria that produce methylases, which alter binding at the domain V site on the ribosomal subunit [73].

Many bacteria that are resistant to the penicillins are also resistant to erythromycin. Bacterial resistance may result from decreased permeability of the cell membrane; in addition, an increase in active efflux of the drug may occur by incorporating a transporter protein into the cell wall [74]. The gene for this mechanism is transferred on plasmids between bacteria. Mutations of the 50S ribosomal receptor site may also develop, preventing binding of the erythromycin. Lastly, bacterial enzymes have been described that may deactivate erythromycin [75]. It is likely that this form of resistance is also transferred on plasmids.

Many strains of H. influenzae are resistant to erythromycin alone but are susceptible to a combination with a sulfonamide [76]. Erythromycin ethylsuccinate and sulfisoxazole are manufactured as suspensions for use in treating acute otitis media in children older than 2 months of age. They are useful for targeting H. influenzae, one of the common pathogens in otitis media in this age group.

PHARMACOKINETICS

Erythromycin has a wide spectrum of activity. Gram-positive bacteria that are usually susceptible to erythromycin include the Streptococcus species. Erythromycin is a second-line agent for gram-negative bacteria, such as H. influenzae and M. catarrhalis. Macrolides are particularly useful for their coverage of atypical bacteria, such as Mycoplasma and Chlamydia. Some spirochetes and mycobacteria are also susceptible to the macrolides. These drugs are indicated for upper respiratory tract infections, such as sinusitis, otitis media, pharyngitis, and bronchitis. They are also useful in the treatment of pertussis, Legionnaires disease, and diphtheria. Telithromycin, which has a long half-life and can be given once daily, has proved useful for the management of community-acquired pneumonia [149]. However, in 2016, the manufacturer of telithromycin announced the discontinuation of the drug [149].

Erythromycin base is deactivated by gastric acid, so it is formulated in enteric-coated tablets or capsules that protect the drug until it reaches the duodenum, where it is absorbed. Eating increases stomach acid secretion and may slow absorption as a result. The ester forms of the erythromycin base (stearate, estolate, and ethylsuccinate) were all formulated to improve absorption. The estolate is the best absorbed of the three after eating; the ethylsuccinate form is best absorbed in the fasting state [77]. Erythromycin may also be given intravenously.

Clarithromycin and azithromycin have excellent absorption after oral dosing. Clarithromycin and telithromycin may be given with food, but for azithromycin, the presence of food in the stomach causes significant delays in absorption [78].

All the macrolides have extensive tissue distribution, with less than adequate penetration into the brain tissue and the CSF [79]. Erythromycin and azithromycin are primarily excreted unchanged into the bile. Clarithromycin is excreted in the bile and in the urine, both unchanged and as the hydroxy metabolite. Telithromycin undergoes hepatic metabolism and is eliminated mainly in the bile, but also in the urine [80].

It may be necessary to adjust the doses of the macrolides in the presence of severe hepatic insufficiency. Azithromycin and clarithromycin doses may have to be reduced in severe renal failure. Because telithromycin is eliminated by more than one mechanism, hepatic or renal insufficiency is unlikely to affect serum levels unless they are both present [81].

SIDE EFFECTS/TOXICITY

While serious side effects with the macrolides are rare, milder side effects are common. Erythromycin stimulates motility in the GI tract, and this may cause abdominal cramping, diarrhea, nausea, and vomiting. Hepatic dysfunction with or without jaundice has occasionally been reported. There have also been some reports of reversible hearing loss in patients treated with erythromycin in high doses or in the presence of renal insufficiency. With IV erythromycin, prolongation of the QT interval and ventricular tachycardia may occur [82].

Clarithromycin may cause nausea, diarrhea, abnormal taste, dyspepsia, and headache. There have been reports of tooth discoloration that is reversible with professional cleaning. Transient CNS changes with anxiety and behavioral changes, which resolve when the drug is discontinued, have also been reported [83].

Side effects from telithromycin include nausea and diarrhea in up to 10% of treated patients [84]. Occasional side effects include headache, dizziness, vomiting, reversible liver function test (LFT) elevation, and hepatitis. Reversible vision blurring and diplopia occurs in 1% of patients [84]. Exacerbations of myasthenia gravis have been reported as well. QT interval elongation may occur, so telithromycin should be avoided in patients at risk for arrhythmias [84].

Allergic reactions to macrolides are rare, but may include rash and eosinophilia. Very rarely, severe reactions such as Stevens-Johnson syndrome have occurred. The drugs are contraindicated in patients with known hypersensitivity to the macrolides.

DRUG INTERACTIONS

Drug interactions are extensive. Erythromycin and clarithromycin are inhibitors and substrate for the 3A isoform subfamily of the cytochrome P450 enzyme system (CYP3A4). If they are given with a drug that is primarily metabolized by CYP3A, the drug serum levels may be increased and/or prolonged [85]. Erythromycin and clarithromycin are contraindicated with concurrent use of cisapride, pimozide, astemizole, or terfenadine. Serum levels of theophylline, cyclosporine, digoxin, ergotamine, carbamazepine, benzodiazepines, warfarin, amiodarone, and tacrolimus may also be affected by concurrent administration with erythromycin and clarithromycin. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors levels may also be elevated, with increased risk for rhabdomyolysis [86].

Azithromycin is not likely to interact with drugs metabolized by CYP3A4. However, azithromycin interacts with pimozide, potentially resulting in QT interval prolongation and arrhythmia [87]. Co-administration with pimozide is therefore contraindicated. Levels of cyclosporine could potentially be increased and therefore should be monitored closely [88].

Telithromycin is metabolized in the liver, partly by the P450 enzyme system and partly by other mechanisms. It may interact with the following drugs: cisapride, pimozide, quinidine, procainamide, dofetilide, rifampin, ergot alkaloids, itraconazole, ketoconazole, midazolam, digoxin, cyclosporine, carbamazepine, hexobarbital, phenytoin, tacrolimus, sirolimus, metoprolol, theophylline, and statins. Telithromycin is contraindicated in patients allergic to macrolides or telithromycin. It should not be given with cisapride or pimozide [84]. An interaction between warfarin and telithromycin has also been reported [89].

SPECIAL POPULATIONS

Erythromycin is pregnancy category B, with an erythromycin estolate preparation as the preferred form because it is less likely to cause hepatotoxicity. Surveillance studies have not shown any increase in adverse outcomes. The CDC recommends the use of erythromycin for the treatment of Chlamydia during pregnancy [90]. Azithromycin is also category B, based on animal studies. It has been used safely to treat Chlamydia in pregnant women [91]

Clarithromycin is pregnancy category C, based on the finding that it causes growth retardation in monkeys and adverse effects on other mammals. A postmarketing surveillance study did not find any evidence of teratogenicity, but another study found a higher rate of spontaneous abortion in those treated with clarithromycin [92,93].

Erythromycin is excreted in breast milk, but the AAP considers it usually compatible with breastfeeding [38]. Clarithromycin is excreted in breast milk in lactating animals, but the effects have not been studied in humans. There have been some reports of infantile hypertrophic pyloric stenosis following treatment of newborns with erythromycin [94].

11. QUINOLONES

The first quinolone, nalidixic acid, was introduced in 1962. It was developed as a result of chloroquine synthesis. Later, derivatives with broader spectrum antimicrobial coverage were produced, leading to the current class of quinolone drugs. As with other classes of synthetic and semisynthetic antimicrobials, alterations of side chains affect antimicrobial activity and pharmacokinetics [95].

MECHANISM OF ACTION

Quinolones cause bacterial cell death by inhibiting DNA synthesis. They inhibit DNA gyrase and DNA topoisomerase, enzymes that mediate DNA supercoiling, transcription, and repair [96]. The exact mechanism by which this leads to cell death has not yet been determined.

Bacterial resistance develops as a result of spontaneous mutations that change the binding sites for quinolones on the DNA gyrase and the DNA topoisomerase [97]. Mutations that decrease the ability of quinolones to cross the cell membrane also occur. Some of these resistances may be transferred from other bacteria by means of plasmids [98].

PHARMACOKINETICS

The quinolones are active against many gram-positive cocci, gram-negative bacilli, and atypical bacteria (e.g., Legionella, Mycoplasma). Quinolone activity against streptococci and anaerobes, at achievable serum levels, is relatively poor, although newer agents, such as moxifloxacin, have better coverage for anaerobes [99]. Gram-negative coverage includes Campylobacter, Enterobacter, E. coli, H. influenzae, Klebsiella, Salmonella typhi, Shigella, and Vibrio cholerae. Indications for the use of quinolones include urinary tract infections, non-gonococcal infections of the urethra and cervix, pneumonia, sinusitis, soft-tissue infections, and prostatitis. Ciprofloxacin is indicated for post-exposure prophylaxis for anthrax, and levofloxacin has an indication for the treatment of inhalation anthrax infection. The quinolones are absorbed well after oral administration, and peak serum levels in the elderly and those with reduced renal function approximate those achieved with intravenous usage. Food may delay the time to reach peak serum concentration but does not decrease total absorption. The drugs are distributed well throughout all tissues, including the prostate, although the levels in the CSF and prostatic fluid are lower than serum levels [100].

Clearance mechanisms vary between the quinolones. Levofloxacin and ofloxacin are mainly cleared by renal excretion and have minimal hepatic clearance [101]. Moxifloxacin is mainly excreted nonrenally. Moxifloxacin is metabolized, via glucuronide and sulfate conjugation in the liver, to an inactive metabolite [102].

Norfloxacin, ciprofloxacin, and gemifloxacin have mixed routes of elimination. Norfloxacin has some hepatic metabolism to active metabolites; the metabolites and parent drug are excreted by the kidney. About 30% of the dose of norfloxacin is excreted in the stool, in the bile, and as unabsorbed drug. As much as 50% of the ciprofloxacin dose is excreted renally, and 40% is excreted in the bile after hepatic metabolism. Approximately 60% of gemifloxacin is excreted in the feces, and the remainder is excreted in the urine.

In renal insufficiency, the quinolones that are primarily excreted renally and those with mixed routes of elimination require dosage adjustments [103]. Moxifloxacin doses do not have to be adjusted for mild hepatic insufficiency, although this has not been studied in severe hepatic insufficiency [102].

Table 6: THE QUINOLONES

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

Besifloxacin

1 drop 3 times daily (4 to 12 hrs apart) for 7 days

Same as adult dosing

Ophthalmic drops

Headache

Contact lenses should not be worn during treatment

Ciprofloxacin

PO: 250–750 mg every 12 hrs

IV: 200–400 mg every 12 hrs

PO: 20–30 mg/kg/day in 2 divided doses

Max: 1.5 g/day

IV: 20–30 mg/kg/day in 2 divided doses

Max: 800 mg/day

PO, IV, topical, otic, ophthalmic solution or ointment

GI upset, headache

Photosensitivity can occur. Antacids decrease absorption. Can prolong QT interval.

Quinolones may cause tendon inflammation and rupture and may exacerbate myasthenia gravis associated muscle weakness.

Delafloxacin

PO: 45 mg every 12 hrs for 5 to 14 days

IV: 300 mg every 12 hrs for 5 to 14 days

Not studied in pediatric patients

PO, IV

Gatifloxacin

Day 1: 1 drop every 2 hrs while awake

Max: 8/day

Days 2–7: 1 drop 2 to 4 times/day

>1 yr: same as adult dosing

Ophthalmic drops

Headache, GI upset, conjunctival irritation, keratitis

Gemifloxacina

320 mg once daily for 5 to 7 days

N/A

PO

GI upset, headache, rash

Levofloxacin

250–750 mg/day for 5 to 14 days

N/A

PO, IV, ophthmalmic drops, inhalation

GI upset, headache, phototoxicity

Moxifloxacin

400 mg/day for 5 to 14 days

N/A

PO, IV, ophthalmic drops

GI upset, headache

Norfloxacina

400 mg every 12 hrs, or 800 mg as a single dose for GC

N/A

PO

GI upset, headache

Antacids decrease absorption.

Ofloxacin

200–400 mg every 12 hrs

N/A

PO, otic, ophthalmic drops

Ozenoxacin

Apply thin layer to affected area (up to 100 cm^2) twice/day for 5 days

Infants >2 mos to 12 yrs: Same as adult dosing, except treated area may only be up to 2% of total body surface area (Max: 100 cm^2)

>12 yrs: same as adult dosing

Topical

<1% experience rosacea-like face eruption, seborrheic dermatitis

Novel drug for treatment of impetigo caused by Staphylococcus aureus or Streptococcus pyogenes

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

aNo longer available in the United States.

Source: [148,149]

SIDE EFFECTS/TOXICITY

The most common side effect with the use of quinolones is GI upset. Less common side effects include headache, insomnia, dizziness, peripheral neuropathy, tendon rupture, elevated liver enzymes, and interstitial nephritis [104,105]. Rarely, hematologic toxicities have occurred, resulting in hemolytic anemia (more likely to occur in patients with glucose-6-phosphate dehydrogenase [G6PD] deficiency), aplastic anemia, and agranulocytosis [106]. Very rarely, hepatic necrosis and hepatic failure have been reported [107].

Although allergic reactions are not common, they may occur and range from a rash to severe reactions, such as Stevens-Johnson syndrome. Very rare cases of severe fatal hypoglycemia have been reported with concurrent treatment with glyburide and ciprofloxacin [108]. Use quinolones with caution in patients with medical problems that predispose the patient to seizures.

There is also a risk of disabling peripheral neuropathy associated with the use of oral or injectable fluoroquinolones [155]. The onset can be rapid, and patients should be advised to contact their healthcare provider if any signs or symptoms develop. In these cases, the fluoroquinolone should be stopped and an alternative non-fluoroquinolone drug used, unless the benefit of continued treatment outweighs the risk [155].

In 2018, the FDA strengthened the warnings about the risks of mental health side effects (e.g., disorientation, agitation, delirium) and serious blood sugar disturbances (including hypoglycemia coma) associated with fluoroquinolones [176].

DRUG INTERACTIONS

Drug interactions are common and vary among the quinolones. Antacids may decrease the absorption of these agents. Iron supplements and other supplements with divalent and trivalent cations cause quinolone-cation complexes and impair absorption [109]. Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) appears to increase the risk of seizures [110].

Theophylline, phenytoin, warfarin, and mexiletine levels may be elevated in patients concurrently treated with ciprofloxacin. Serum levels or prothrombin time should be monitored, and the doses of these drugs should be altered as appropriate. Dosage adjustments are not typically needed with other quinolones [111].

SPECIAL POPULATIONS

Quinolones are not recommended during pregnancy. Animal studies have demonstrated arthropathy in immature animals [112]. It is presumed that quinolones are excreted in breast milk, and due to the risk for arthropathy, breastfeeding while taking a quinolone should be avoided.

It is unclear if these effects cause clinically significant changes in humans, so there is debate over whether it is safe to use the drugs in children [113]. Quinolones have been used in pediatric patients with cystic fibrosis, but they should only be used in patients younger than 18 years of age if the benefits outweigh the risks [114].

12. SULFONAMIDES

Sulfonamides, the first true antibiotics, are derived from azo dyes. The first agent was sulfachrysoidine, used in 1935, which released sulfanilamide in vivo [115]. Modifications were made to the sulfanilamide to reduce side effects, resulting in the development of the modern sulfonamides. Many of the sulfonamides are no longer used as parenteral agents, but they continue to be used as topical agents or for treatment in specific conditions (e.g., prophylaxis for drug-resistant malaria). Some of these agents are no longer available in the United States but are still commonly used in other countries.

MECHANISM OF ACTION

The sulfonamides are bacteriostatic, exerting their effect as competitive antagonists of para-aminobenzoic acid (PABA). They inhibit dihydropteroate synthase from using PABA to synthesize dihydropteroic acid, a precursor of folic acid. The lack of folic acid intermediates ultimately results in impaired synthesis of nucleotides. Bacteria that use pre-formed folate are not susceptible to the bacteriostatic action. Silver sulfadiazine is one exception, as it exerts its effects on the cell membrane and cell wall and is bactericidal.

Unfortunately, bacterial resistance to sulfonamides is common, with cross-resistance between agents frequently occurring. Mutations that result in additional production of PABA or changes in the enzyme binding sites for sulfonamides are responsible for the resistance [116]. Genes for these resistant mutations may be carried on plasmids, allowing rapid transfer to other similar bacteria and resulting in more rapid development of resistance patterns than through random mutation alone [117].

One method for improving bacterial activity against potentially resistant strains is the addition of trimethoprim [118]. Trimethoprim is a competitive inhibitor of dihydrofolate reductase, another enzyme active in the synthesis of folate. Trimethoprim resistance is also common [119].

PHARMACOKINETICS

The sulfonamides can be divided into four groups based on absorption and excretion characteristics. They are classified as short-to medium-acting agents, long-acting agents, agents limited to activity in the GI tract, and topical agents.

Table 7: THE SULFONAMIDES

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

Short- to Medium-Acting

Sulfadiazine

2–4 g/day in 3 to 6 divided doses

>2 mos (initial): 75–150 mg/kg/day in 4 to 6 divided doses

>2 mos (maintenance): 150 mg/kg/day in 4 to 6 divided doses

Max: 6 g/day

PO

Rash, pruritus

Multiple drug interactions. Contraindicated in infants <2 mos of age.

Sulfamethoxazole/trimethoprim

PO: 1–2 DS tablets every 12 to 24 hrs

IV: 8–20 mg TMP/kg/day in 2 to 4 divided doses

>2 mos PO: 6–20 mg TMP/kg/day in 2 divided doses

IV: 6–20 mg TMP/kg/day every 12 to 24 hours

Max single dose: 160 mg TMP/dose

PO, IV

Rash, pruritus

Multiple drug interactions.

Weight-based dosing recommendations based on trimethoprim content.

Long-Acting

Sulfadoxine/pyrimethaminea

Single dose of 3 tablets (total: sulfadoxine 1,500 mg and pyrimethamine 75 mg)

Weight-based dosing: Sulfadoxine 25–70 mg/kg and pyrimethamine 1.25–3.5 mg/kg as a single dose

PO

Folic acid deficiency, blood dyscrasias, GI upset

For malaria prophylaxis: A single dose should be carried for self-treatment in the event of febrile illness when medical attention is not immediately available. Note: Discontinue at first sign of rash, myelosuppression, or active bacterial/fungal infection.

Limited to GI Tract

Sulfasalazine

RA: Initial: 0.5–1 g every 6 to 8 hrs

Maintenance: 2 g/day in divided doses

UC: Initial: 3–4 g in evenly divided doses every 8 hours

Titrate to 4–6 g in 4 divided doses

>2 yrs: 40–60 mg/kg/day in 3 to 6 divided doses

PO

Anorexia, headache, GI upset

Contraindicated with hypersensitivity to salicylates, sulfasalazine, sulfonamides, or mesalamine.

Topical

Mafenide

Cream: Apply 1.6 mm thick layer to burn area every 12 or 24 hrs

Solution: Wet dressing gauze every 4 hrs or as needed

Use adult dosing

Cream, powder for solution

Burning at application site, rash, allergic reaction

Used for treatment of second- and third-degree burns to prevent infection.

Burn area should be covered with cream/wet at all times.

Apply with sterile gloved hand.

Silver sulfadiazine

Apply 1.6-mm layer to burn area once or twice daily

Use adult dosing

Cream

Rash, allergic reaction

Sulfacetamide

Dosage varies with the preparation.

Use adult dosing

Prepared in complex with other topical medications as a solution or ointment

Rash, local irritation

Combinations with fluorometholone, prednisolone, and phenylephrine are available, each with differing dosing, indications, and contraindications. Common for ophthalmic and topical use.

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

DS = double strength; RA = rheumatoid arthritis; TMP = trimethoprim; UC = ulcerative colitis.

aNot currently available in the United States.

The Short- to Medium-Acting Sulfonamides

The first group, the short- to medium-acting agents, includes sulfisoxazole, sulfamethoxazole, and sulfadiazine. Sulfisoxazole is partly metabolized to N-acetyl sulfisoxazole; both the drug and the metabolite are excreted in the urine [120]. Because of a limited spectrum of action, sulfisoxazole is indicated primarily for uncomplicated urinary tract infection and chloroquine-resistant malaria. Sulfamethoxazole is combined with trimethoprim and is indicated for Pneumocystis jiroveci prophylaxis and treatment, upper respiratory tract infections, and urinary tract infections. The only FDA indication for sulfadiazine is toxoplasmosis [149].

The Long-Acting Sulfonamides

The long-acting agents have been associated with severe allergic reactions and for the most part been replaced in use by the less-toxic sulfonamides. The last long-acting agent available in the United States was sulfadoxine, which is given as a combination with pyrimethamine; however, as of 2018, this agent is no longer available. This drug was reserved for the treatment of drug-resistant malaria and certain cases of Toxoplasma gondii infestation. Pyrimethamine inhibits dihydrofolate reductase in Plasmodium species during the erythrocytic stage [149].

Sulfadoxine/pyrimethamine is absorbed quickly from the small intestine and, like the shorter acting agents, is widely distributed in tissue and body fluids [149].

Sulfonamides Limited to Gastrointestinal Tract Activity

The agents limited to the GI tract are very poorly absorbed and have been used for reducing bacterial flora in the bowel before surgery. The only available agent in this class is sulfasalazine, which is used in the treatment of ulcerative colitis. Although absorption of sulfasalazine from the intact intestine is very low, inflammation in the bowel may result in significant absorption of the metabolite sulfapyridine.

Topical Sulfonamides

The topical sulfonamides include mafenide acetate and silver sulfadiazine, which are used in the treatment of burns. Mafenide is used less often because it may cause a metabolic acidosis as a result of carbonic anhydrase inhibition. An additional topical agent is sulfacetamide, which is used in ophthalmic and lotion formulations. Topical sulfonamides may be absorbed systemically, and if large burn areas are treated, absorption may be significant [149].

ABSORPTION/ELIMINATION

The sulfonamides are quickly absorbed after administration unless they have been altered to stay in the lumen of the intestine (e.g., sulfasalazine). After absorption, they are acetylated in the liver into a toxic but inactive form. The acetylated form is mostly excreted in the urine, with a small amount excreted in bile. These drugs are widely distributed throughout body tissue and fluids, including the CSF and peritoneal fluid [121].

The sulfonamides undergo acetylation and glucuronidation in the liver. Both the unchanged and metabolized forms are excreted in the urine through glomerular filtration and renal tubular secretion.

Mafenide may be used in renal failure, but monitoring of acid-base balance is recommended. Dosage and frequency of administration of other sulfonamides must be adjusted in renal failure based on serum levels. No data is available on dosing in hepatic insufficiency.

SIDE EFFECTS/TOXICITY

Allergic reactions with rash and itching are relatively common. Nausea, vomiting, diarrhea, headache, and photosensitivity may occur. Rare but severe hypersensitivity reactions, including vasculitis, anaphylaxis, serum sickness, and Stevens-Johnson syndrome, may occur [122]. Sulfacetamide lotion also contains metabisulfite, which may cause an allergic reaction in patients allergic to sulfites.

Sulfonamide ophthalmic preparations may cause local irritation. The topical mafenide may cause pain or burning locally. Systemic reactions may develop during treatment with ophthalmic and topical preparations of sulfonamides due to systemic absorption.

Less common reactions include metabolic acidosis that may occur with absorption of mafenide due to a byproduct, (rho) carboxybenzenesulfonamide, that inhibits carbonic anhydrase. Very rare reactions with sulfonamides include blood dyscrasias (agranulocytosis, aplastic anemia, thrombocytopenia, hemolytic anemia), hepatitis and hepatocellular necrosis, and toxic nephrosis due to crystalluria [123]. Hemolysis is more likely to develop in patients with G6PD deficiency [124].

Sulfonamides are contraindicated in patients who are known to be allergic to sulfa drugs and in cases where there have been previous adverse effects to sulfonamides.

DRUG INTERACTIONS

Warfarin, phenytoin, and sulfonylureas may all be potentiated due to displacement of the drugs from serum albumin by the sulfonamides [125]. Cyclosporine levels may be decreased, and levels should be monitored [126]. Administration of PABA may antagonize the effects of sulfa drugs.

SPECIAL POPULATIONS

Sulfa drugs should be avoided in pregnancy near term due to the increased potential for kernicterus in the newborn [127]. Animal studies with sulfamethoxazole show bone abnormalities and a higher incidence of cleft palate.

Mafenide, sulfacetamide ophthalmic drops, and sulfadiazine are pregnancy category C. Sulfacetamide lotion has not been studied in pregnancy. Silver sulfadiazine is pregnancy category B, based on animal studies that showed no ill effects [128].

Sulfonamides are excreted in breast milk. Sulfamethoxazole and sulfisoxazole are considered compatible with breastfeeding by the AAP, although they should be avoided if hyperbilirubinemia or G6PD deficiency is present [38]. Sulfacetamide lotion and silver sulfadiazine have not been studied in breastfeeding but would presumably also be excreted in breast milk; use with caution in breastfeeding women [149].

Because of the risk of neonatal kernicterus, use of sulfonamides should be avoided in the newborn. Sulfacetamide eye drops have not been studied in children younger than 2 months of age [149].

13. TETRACYCLINES

Chlortetracycline, the first tetracycline, was developed in 1948 as a product of Streptomyces aureofaciens. Chlortetracycline was altered to produce tetracycline. Doxycycline and minocycline are semisynthetic derivatives.

Tetracyclines bind to the 30S ribosomal subunit, blocking the binding of aminoacyl transfer-RNA [129]. This results in inhibition of protein synthesis, with bacteriostatic effects.

Bacterial resistance is typically the result of mutations that either prevent entrance of tetracyclines into the cell or increase the export of tetracycline out of the cell [130]. The resistance may be transmitted by plasmids [131].

MECHANISMS OF ACTION AND PHARMACOKINETICS

The tetracyclines have a broad spectrum of activity that includes aerobic gram-positive and gram-negative bacilli, atypical bacteria (such as Chlamydia trachomatis, Chlamydia psittaci, and Mycoplasma pneumoniae), and spirochetes (such as Borrelia burgdorferi). Tetracycline is also a second-line agent for T.pallidum. It is approved by the FDA for treatment of rickettsial infections, typhus, Rocky Mountain spotted fever, trachoma, nongonococcal urethritis, and lymphogranuloma venereum [149].

As a result of decades of clinical and agricultural use, the prevalence of resistance to tetracyclines is now high among common gram-positive and gram-negative pathogens. For this reason, and because they are bacteriostatic, the role of tetracyclines is limited for treatment of most pyogenic infections. Primary indications for this class are atypical infections (e.g. mycoplasma and chlamydia) and zoonoses (e.g. tularemia and brucellosis).

The tetracyclines may be divided into three groups based on their pharmacokinetic traits. These groups are the short-acting group, intermediate-acting group, and long-acting group. The varying half-lives are the result of different rates of renal excretion [149].

Table 8: THE TETRACYCLINES

Agent

Adult Dosing Range

Pediatric Dosing Rangea

Route

Common Side Effects

Comments

Short-Acting

Tetracycline

250–500 mg every 6 to 12 hrs

25–50 mg/kg/day in 4 divided doses

PO

Photosensitivity, tooth enamel deformities in children <8 yrs of age

Polyvalent cations decrease absorption.

Intermediate-Acting

Demeclocycline

150 mg every 6 hrs or 300 mg every 12 hrs

≥8 years:8–12 mg/kg/day in 2 to 4 divided doses

PO

GI upset, tooth enamel deformities in children <8 yrs of age

Polyvalent cations decrease absorption. Use caution if used with warfarin.

Long-Acting

Doxycycline

PO: 100–200 mg/day in 1 to 2 divided doses

IV: 100 mg every 12 hrs

<45 kg: 2–5 mg/kg/day in 1 to 2 divided doses

Max: 200 mg/day

>45 mg: Same as adult dosing

PO, IV

Phlebitis at IV site, photosensitivity, tooth enamel deformities in children <8 yrs of age

Polyvalent cations decrease absorption. Use caution if used with warfarin.

Minocycline

Initial: (IV, PO): 200 mg

Maintenance: (IV): 100 mg every 12 hrs

Max: 400 mg/day

Maintenance (PO): 100 mg every 12 hrs, OR 100–200 mg initially, followed by 50 mg 4 times daily

Initial: (IV, PO): 4 mg/kg/dose

Maintenance: 2 mg/kg/dose every 12 hrs

Max: 400 mg/day

PO, IV

GI upset, tooth enamel deformities in children <8 yrs of age

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

SIADH: syndrome of inappropriate antidiuretic hormone hypersecretion.

aAll pediatric doses are for children older than 8 years of age.

Source: [148,149]

Short-Acting Tetracyclines

The short-acting tetracyclines include oxytetracycline and tetracycline, the namesake of the class. Frequent dosing is needed because of the very short half-life of these agents. Oxytetracycline is no longer available in the United States [149]. Tetracycline is inexpensive but requires dosing every six hours for most indications. A less frequent dosage protocol is commonly used for the treatment and prevention of acne [149].

Intermediate-Acting Tetracyclines

The only intermediate-acting agent available in the United States is demeclocycline. Demeclocycline is no longer used as an antibiotic but rather has been used as an off-label drug to treat the syndrome of inappropriate antidiuretic hormone (SIADH) [132]. However, studies have suggested that there is limited high-quality evidence to suggest that demeclocycline is effective in managing this condition, and European clinical practice guidelines recommend against the use of demeclocycline for the management of hyponatremia in patients with SIADH [149,169].

Long-Acting Tetracyclines

The long-acting tetracycline agents, doxycycline and minocycline, are the more recently developed drugs. The main difference between these and the short-acting agents is that these may be dosed less frequently (once or twice daily), which is an advantage in ensuring compliance. The spectrum of bacterial coverage is essentially the same and the indications are the same, with the additional indication for the treatment of inhalation anthrax as part of a multidrug regimen.

ABSORPTION/ELIMINATION

Tetracycline is well absorbed after an oral dose taken in the fasting state. Doxycycline and minocycline are well absorbed after an oral dose and may be given with or without food.

The tetracyclines are well distributed throughout body tissues and fluids; distribution in the CSF is adequate for the treatment of some infections [133,134]. The excellent tissue penetration results in the ability of the drug to cross into the dentin, where the tetracycline permanently chelates with the calcium [135].

Most of the tetracycline dose is excreted unchanged into the urine by glomerular filtration, although there is some biliary excretion as well. Nonrenal, possibly hepatic, mechanisms account in large part for excretion of doxycycline and minocycline. Only 20% to 26% of doxycycline and 4% to 19% of minocycline is excreted in the urine [136].

Tetracycline should be avoided in the presence of renal insufficiency, because it accumulates rapidly in the serum in the presence of decreased renal function. Doxycycline may be used in renal failure, as it will be excreted into the bile [137]. Because tetracyclines have been known to cause hepatic toxicity, they should not be used in patients with hepatic insufficiency [138].

SIDE EFFECTS/TOXICITY

Tetracyclines commonly cause GI upset, including nausea, vomiting, and diarrhea. There is conflicting evidence of staining and deformity of the teeth in children younger than 8 years of age. Photosensitivity, idiopathic intracranial hypertension, esophageal ulceration, and hepatotoxicity occur rarely [149].

Minocycline is often associated with vertigo, nausea, and vomiting, and it may increase azotemia in renal failure. In addition, prolonged use of minocycline may cause reversible discoloration of the fingernails, the sclera, and the skin [139]. Minocycline has been associated with a lupus-like reaction [140].

Allergic reactions to tetracyclines are not common but may range from mild rashes to anaphylaxis. Tetracyclines are contraindicated in patients who have shown hypersensitivity to any tetracyclines.

DRUG INTERACTIONS

Several types of drug interactions result in alterations in serum levels of tetracyclines. Agents that alkalinize the urine will increase excretion of the tetracyclines. Polyvalent metal cations (calcium, aluminum, zinc, magnesium, and iron) and bismuth decrease absorption [141]. Drugs that induce hepatic enzymes may decrease the half-life of doxycycline.

Interactions that affect the efficacy of other drugs also occur. The bactericidal effect of penicillins may be decreased by co-administration with tetracyclines. Concurrent use of oral contraceptives may make the contraceptive less effective [142,143]. The effects of warfarin are increased, probably because tetracyclines depress plasma prothrombin activity, resulting in a synergistic effect [144]. Digoxin effects may be increased because of changes in the bowel flora that are responsible for digoxin metabolism [145].

SPECIAL POPULATIONS

Evidence Based Practice Recommendation

The American Optometric Association asserts that tetracycline and its derivatives should not be given to children younger than 8 years of age or pregnant or nursing women.

https://www.aoa.org/documents/optometrists/CPG-10.pdf

Last Accessed: January 22, 2018

Level of Evidence: Expert Opinion/Consensus Statement

Tetracycline and doxycycline are pregnancy category D because of impaired bone development in the fetus. Hypoplasia of the enamel and discoloration of fetal teeth may occur, and maternal hepatic toxicity has been reported as well [146,147].

Tetracyclines are excreted into the breast milk in small amounts. Most exposed infants have very low blood levels of the drug and probably are not at risk [38]. In the past, tetracyclines were contraindicated in children younger than 8 years of age because of the risk for tooth deformity. However, doxycycline is the current first-line therapy for Rocky Mountain spotted fever in children of all ages, including those younger than 8 years of age [179]. Limited studies indicate that short courses of the medication were not associated with dental side effects in this population [180].

14. VANCOMYCIN

Vancomycin is the oldest member of the glycopeptide antibiotics class, a group of large molecules that inhibit bacterial cell wall synthesis. Glycopeptides have a high binding affinity for peptides found only in bacterial cell walls. This interaction disrupts peptidoglycan polymerization, the late-stage reaction that imparts rigidity to the cell wall [156]. Gram-positive organisms, both cocci and bacilli, are highly susceptible to glycopeptides.

Vancomycin was developed more than 50 years ago as an alternative intravenous therapy for serious staphylococcal and streptococcal infections in patients allergic to beta-lactams. In this early period, vancomycin usage was associated with a high incidence of vestibular and renal toxicity. The cause was attributed in large part to impurities in the formulation, a problem solved in subsequent years. At present, the major role for vancomycin is in the treatment of serious infections caused by MRSA, methicillin-resistant S. epidermidis (MRSE), and ampicillin-resistant enterococci. An oral formulation is available for the treatment of C. difficile-associated diarrhea/colitis.

MECHANISMS OF ACTION AND PHARMACOKINETICS

Vancomycin is not absorbed by the intestinal tract and must be administered by intravenous infusion, with the exception of the formulation for the treatment of C. difficile-associated diarrhea/colitis [149]. The determination of a safe, effective dosage regimen, and decisions regarding monitoring of therapy, are complex matters that require consideration of multiple factors, including the site and severity of infection, the patient's weight and renal function, the susceptibility of the infecting organism, and the anticipated duration of therapy [157]. The usual adult dose is 15–20 mg/kg/dose every 12 hours. The rate of infusion should be no more than 500 mg/hour, as rapid infusion causes an uncomfortable generalized erythroderma ("red man" syndrome). The red man syndrome is a histamine-mediated flushing that occurs during or immediately following infusion and does not mandate discontinuation unless slowing the infusion rate fails to mitigate the reaction.

ABSORPTION/ELIMINATION

Vancomycin is cleared almost entirely by the kidneys. Prolonged usage at excessively high therapeutic serum levels has been associated with nephrotoxicity and ototoxicity. In treating patients with invasive staphylococcal infection and MRSA, it is considered important to use the maximum dosage (target trough serum vancomycin level of 15–20 mcg/mL) in order to assure optimal therapeutic effect [157]. The serum creatinine and trough vancomycin level (target <20 mcg/mL) should be monitored once or twice weekly in such cases, as well as in all patients who are elderly or have impaired renal function.

SIDE EFFECTS/TOXICITY

Apart from the (avoidable) red man syndrome, vancomycin administration is well tolerated and side effects are uncommon. As with beta-lactams and sulfonamides, vancomycin is a good sensitizing agent; allergic manifestations such as fixed drug eruptions and drug fever are relatively common. Vancomycin nephrotoxicity does occur. The incidence is low, the exact mechanism is poorly understood, and the impact is usually reversible upon discontinuation of the drug. Risk factors for nephrotoxicity include total daily dose in excess of 3–4 grams, trough serum vancomycin levels >20 mcg/mL, pre-existing renal disease, concomitant use of other nephrotoxic drugs (e.g. aminoglycosides), and duration of therapy longer than one week [158].

In 2017, the FDA published a safety review that indicated that use of intraocular vancomycin prophylactically during cataract surgery, alone or in a compound formula, should be avoided because of the risk of hemorrhagic occlusive retinal vasculitis [149,170].

Reversible neutropenia, presumably from bone marrow toxicity, is sometimes seen in patients receiving prolonged vancomycin therapy (e.g., for endocarditis and osteomyelitis). Oral vancomycin is not absorbed and thus imposes no risk of nephrotoxicity or ototoxicity.

15. LIPOGLYCOPEPTIDES

In response to the increasing prevalence of multidrug resistance among clinical isolates of staphylococci and streptococci, glycopeptide analogues (lipoglycopeptides) with enhanced activity and favorable pharmacokinetics have been developed. In comparison to vancomycin, the lipoglycopeptides have greater potency against gram-positive bacteria, are active against vancomycin-resistant strains, and appear to be less likely to lead to emergence of resistant organisms [159,160]. As with vancomycin, lipoglycopeptides must be administered intravenously. The lipophilic side chain prolongs plasma half-life and helps anchor these agents to the outer structure of the bacterial cell. In animal studies, lipoglycopeptides have proven effective in treating a variety of serious gram-positive infections, including bacteremia, pneumonia, and endocarditis [159,160]. Clinical studies of efficacy in humans have been limited to date.

At present, three lipoglycopeptides, telavancin, dalbavancin, and oritavancin, have been approved by the FDA for the treatment of acute bacterial skin and soft-tissue infection. Clinical trials have shown equivalent or superior efficacy against MRSA skin infection compared with vancomycin [160,161,171]. The side effect profile is mild and comparable to other effective regimens. Reported adverse effects include headache, nausea, pruritus, pain at injection site, and fever.

Of note, a risk/benefit analysis should be conducted when using telavancin in patients with pre-existing moderate-to-severe renal impairment treated for hospital-acquired or ventilator-associated bacterial pneumonia, as mortality is increased compared with administration of vancomycin [149].

Dalbavancin has the advantage of a prolonged plasma half-life (6 to 10 days), allowing for weekly administration and perhaps obviating the need for an indwelling central line. In adults and children 12 to 17 years of age, the best-studied treatment protocol is 1 g IV, followed by 500 mg weekly [161,162]. In a randomized trial comparing dalbavancin (1 g IV on days 1 and 8) with vancomycin (IV for 3 days followed by the option of oral linezolid to complete 10 to 14 days) for treatment of skin infection, the clinical response outcomes were similar in both treatment arms. For patients with S. aureus infection, including MRSA, clinical success was observed in 90.6% of patients treated with dalbavancin and 93.8% of those who received vancomycin-linezolid [161].

16. PLEUROMUTILINS

Pleuromutilins were discovered as natural-product antibiotics in 1950. However, their use was limited to veterinary medicine until 2007, when the first agent (retapamulin) was approved for use in humans [177]. Retapamulin was only approved for topical application, but in 2019 the first pleuromutilin—lefamulin—was approved for human use via oral and intravenous delivery. Pleuromutilin derivatives are designed primarily through modifications at the C(14) side chain [177].

These agents inhibit bacterial protein synthesis through interactions (hydrogen bonds, hydrophobic interactions, and Van der Waals forces) with the A- and P- sites of the peptidyl transferase center in domain V of the 23s ribosomal RNA of the 50S subunit [149]. The binding pocket of the bacterial ribosome closes around the mutilin core for an induced fit that prevents correct positioning of transfer RNA.

Retapamulin is used for the topical treatment of impetigo. A small amount is applied to the affected area twice per day for five days [149]. Possible side effects include eczema, application site reactions, diarrhea, headache, and nasopharyngitis.

Lefamulin is approved for the treatment of community-acquired bacterial pneumonia [178]. The usual dose is 600 mg every 12 hours for oral administration or 150 mg every 12 hours for IV use [149]. Treatment is generally at least five days; patients should be afebrile for ≥48 hours and clinically stable prior to discontinuation. The most common adverse reactions include diarrhea, nausea, injection site reactions, elevated liver enzymes, and vomiting [178]. It is contraindicated in patients with certain arrhythmias or who are prescribed drugs to prolong QT intervals.

17. INVESTIGATIONAL ANTIBIOTICS FOR DRUG-RESISTANT MICRO-ORGANISMS

Researchers continue to seek new methods and drugs to aid in the prevention of antibiotic resistance. Progress has been made in recent years, with two new antibiotics void of cross-resistance to existing antibiotics being discovered through soil sample screening: teixobactin and pseudouridimycin.

Teixobactin, a cyclic depsipeptide antibiotic, works by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid), inhibiting bacterial cell wall biosynthesis [172,173]. Teixobactin has been shown effective at treating an array of gram-positive pathogens, including MRSA, vancomycin-resistant Enterococcus, and Mycobacterium tuberculosis, with no known cross-resistance to other antibiotics [172,173]. With reports in 2016 of efficient syntheses of two teixobactin analogues, this class of drugs may be part of the solution to bacteria resistant to currently available antibiotics [172,173].

Pseudouridimycin, a nucleoside-analog inhibitor, acts by inhibiting bacterial RNA polymerase, an enzyme responsible for bacterial RNA synthesis, through a binding site. The structure is similar to rifampin, an antitubercular agent that inhibits the enzyme; however, the mechanism of action does differ so as not to cause a cross-reaction with rifampin [174,175]. Pseudouridimycin has been shown effective for a broad spectrum of drug-sensitive and drug-resistant bacteria.

Researchers are currently attempting to conduct synthesis of these two new classes of drugs with varying, but promising, success. Although it may take several years for these or other new antibiotics with no cross-resistance to be developed, promising progress is continuing, and researchers estimate that, once approved, resistance to these novel drugs could take decades, rather than years, to develop [172,173,174,175].

18. CONCLUSION

Antibiotics are commonly used drugs that have diverse actions, side effects, and toxicities. The large number of antibiotics available makes it challenging to understand the characteristics of each antimicrobial class, including important information such as indications, action, dosage, and toxicities. Knowing the general characteristics by antibiotic class and having experience with one or two key agents within each class improves recall and facilitates the selection of the most appropriate antibiotic for a given bacterial infection.

An understanding of the mode of action, spectrum of activity, and potential toxicity enables the practitioner to tailor a therapeutic regimen that is specific and of appropriate duration. This in turn lessens the likelihood developing microbial resistances and reduces risk of adverse effects.

It is important to remember that the indications given by the FDA are guidelines. Many antibiotics are used for off-label purposes, and occasionally in doses that differ from those recommended for the usual indications. This may be necessary when faced with managing severe and life-threatening infections or for special populations, such as premature infants, neonates, and the elderly. Before using a specific agent, one should always consider carefully reviewing the detailed information (package insert) provided by the manufacturer.

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96402 • Depression and Suicide

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2017 NetCE, All rights reserved.

Depression is a common, debilitating mood disorder. Depression is highly prevalent in medically ill populations, and many persons with depression are either unaware they need professional help or are reluctant to seek it. Although contact with the primary care setting represents a potential opportunity for timely identification and intervention, abundant evidence indicates that many patients with depression are inadequately diagnosed by nonpsychiatrist physicians, with one study showing inadequate assessment and diagnosis even after training. In addition to depression being underdiagnosed in the primary care setting, even when a valid diagnosis is made, treatment is often inconsistent with current practice guidelines. Provider competence and confidence related to the diagnosis and treatment of depression is one factor; other factors that influence patient outcomes have been identified. One of these factors is treatment adherence, and studies have shown that treatment adherence can be positively influenced by the degree of treatment preference for the prescribed treatment modality and by the process of shared decision-making between physician and patient. These widespread shortcomings in the proper diagnosis, treatment, and implementation of treatment adherence strategies among primary care physicians and other primary care professionals represent an ideal educational target.

Table of Contents

96402 • Depression and Suicide

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. EPIDEMIOLOGY

INCIDENCE AND PREVALENCE OF DEPRESSION

DEMOGRAPHIC CHARACTERISTICS

PERSONAL AND SOCIETAL COSTS OF DEPRESSION

3. BACKGROUND

RISK FACTORS

NATURAL HISTORY OF DEPRESSION

DEFINITIONS

4. PATHOPHYSIOLOGY OF DEPRESSION AND SUICIDE

PATHOPHYSIOLOGY OF DEPRESSION

5. ASSESSMENT AND DIAGNOSIS OF DEPRESSION

SIGNS AND SYMPTOMS OF DEPRESSION

SCREENING

ASSESSMENT

DIAGNOSIS OF DEPRESSION

ASSESSING AND DIAGNOSING DEPRESSION IN SPECIAL POPULATIONS

DIFFERENTIAL DIAGNOSIS

COMORBID CONDITIONS

6. INITIAL TREATMENT OF DEPRESSION

INITIAL COMMUNICATION WITH THE PATIENT

DEVISING A TREATMENT PLAN

OPTIONS FOR INITIAL THERAPY

PSYCHOTHERAPY

PHARMACOTHERAPY

ADDITIONAL CONSIDERATIONS WITH INITIAL THERAPY

HERBAL MEDICATIONS, DIETARY SUPPLEMENTS, AND ALTERNATIVE THERAPIES

STRATEGIES FOR INADEQUATE RESPONSE TO INITIAL THERAPY

7. TREATMENT-RESISTANT DEPRESSION

OPTIONS FOR TREATMENT-RESISTANT DEPRESSION

8. PERINATAL DEPRESSION

MILD-TO-MODERATE DEPRESSION

SEVERE DEPRESSION

PHARMACOLOGY AND PERINATAL DEPRESSION

LACTATION

9. SUICIDE

EPIDEMIOLOGY

PATHOPHYSIOLOGY OF SUICIDAL BEHAVIOR

SUICIDE AND SPECIAL POPULATIONS

SUICIDE AND PUBLIC PERCEPTION

SUICIDE MODELS AND RISK FACTORS

SUICIDE MEANS AND METHODS

SUICIDE MOTIVATION

SUICIDE PREVENTION

TREATMENT OF SUICIDALITY

ASSESSMENT OF SUICIDE RISK

10. SUICIDE LOSS SURVIVORS

11. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

96402 • Depression and Suicide

Education Category. Psychiatric / Mental Health

Release Date. 08/01/2017

Expiration Date. 07/31/2020

Course Overview

Depression is a common, debilitating mood disorder. Depression is highly prevalent in medically ill populations, and many persons with depression are either unaware they need professional help or are reluctant to seek it. Although contact with the primary care setting represents a potential opportunity for timely identification and intervention, abundant evidence indicates that many patients with depression are inadequately diagnosed by nonpsychiatrist physicians, with one study showing inadequate assessment and diagnosis even after training. In addition to depression being underdiagnosed in the primary care setting, even when a valid diagnosis is made, treatment is often inconsistent with current practice guidelines. Provider competence and confidence related to the diagnosis and treatment of depression is one factor; other factors that influence patient outcomes have been identified. One of these factors is treatment adherence, and studies have shown that treatment adherence can be positively influenced by the degree of treatment preference for the prescribed treatment modality and by the process of shared decision-making between physician and patient. These widespread shortcomings in the proper diagnosis, treatment, and implementation of treatment adherence strategies among primary care physicians and other primary care professionals represent an ideal educational target.

Audience

This course is designed for physicians, nurses, physician assistants, social workers, therapists, and counselors in the primary care setting who may identify and treat depressed and suicidal patients.

Course Objective

Although contact with the primary care setting represents a potential opportunity for timely identification and intervention, abundant evidence indicates that many patients with depression are inadequately diagnosed and treated in these settings. The purpose of this course is to provide the information and encouragement necessary to allow primary care providers to properly diagnose, treat, and follow-up with patients with depression.

Learning Objectives

Upon completion of this course, you should be able to:

1. Outline the epidemiology of depression and suicide.

2. Identify populations at increased risk for depression.

3. Describe the natural history and pathophysiology of depression.

4. Evaluate the signs and symptoms of depression utilizing appropriate screening tools.

5. Employ the appropriate diagnostic criteria for depression, including modifier subtypes.

6. Assess patients for depressive signs and symptoms, with particular attention to unique features in special populations.

7. Identify other conditions that can mimic or co-occur with depression.

8. Create a treatment plan for patients diagnosed with depression.

9. Compare pharmacotherapies and psychosocial therapies used in the treatment of depression.

10. Assess patients' reactions to depression treatments and identify treatment-resistance depression.

11. Recognize and appropriately treat perinatal depression.

12. Review the epidemiology of suicide.

13. Describe the impact of suicide in the treatment of special populations, including among the elderly.

14. Identify risk and protective factors for suicide.

15. Evaluate tools available for the assessment and evaluation of suicide risk.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Alice Yick Flanagan, PhD, MSW

James Trent, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Depression is a common, debilitating mood disorder that is highly prevalent in medically ill populations, but many persons with depression are unaware they need, or are reluctant to seek, professional help. Primary care contact represents a potential opportunity for timely identification and intervention, but many patients with depression are inadequately diagnosed by non-psychiatrist clinicians, even after additional training [1,2]. Even with accurate diagnosis, treatment is often inconsistent with current evidence, reflecting poor provider competence and confidence related to diagnosing and treating depression [3]. Adverse outcomes may result from treatment non-adherence, which can be positively influenced by patient preference for the prescribed modality and shared decision-making between physician and patient [4,5]. Shortcomings in the delivery of care by primary care physicians, nurses, and behavioral health professionals represent an opportunity to alleviate patient distress and improve functioning through education.

For some patients with major depressive disorder (MDD), their initial antidepressant is ineffective or intolerable, and others remain impaired despite substantial symptom reduction. Inadequate patient outcomes may result from limitations in the foundation of clinical care for depression: MDD is a highly heterogeneous disorder but is diagnosed as a unitary syndrome, and almost all FDA-approved medications for depression are based on a 60-year-old mechanistic hypothesis. Knowledge advances are transforming the understanding and treatment of MDD. This course will discuss optimal use of standard diagnostic and therapeutic approaches, knowledge advances, and their consideration and integration into best practices of clinical care for patients with depression.

2. EPIDEMIOLOGY

INCIDENCE AND PREVALENCE OF DEPRESSION

Depressive disorders afflict approximately 17.6 million, or 1 in 6, Americans each year [6,7,8]. MDD affects approximately 22.2 million American adults, or about 7% of the U.S. population 18 years of age and older in a given year. The lifetime incidence of depression in the United States is 20% in women and 12% in men, or about 16% of all Americans. Depression is more common in persons with medical illnesses, with 11% to 36% of general medical inpatients fulfilling diagnostic criteria for MDD [9,10,11,12].

DEMOGRAPHIC CHARACTERISTICS

Data from the National Health and Nutrition Examination Survey 2007–2010 found that nearly 8% of persons 12 years of age and older had current (past two-week) diagnosable depression [13]. Women have higher rates of depression than men in every age group, with the highest rate occurring in individuals 40 to 59 years of age (12% in women; 7% in men). The lifetime incidence of depression in the United States is 20% in women and 12% in men [14]. Another factor that appears to affect the incidence of depression is race, with 6.3% of Mexican Americans and 8% of non-Hispanic blacks reporting depression compared to 4.8% of non-Hispanic whites [13]. Persons living below the poverty level are five times more likely to have current depression than those living at or above the poverty line [15].

Roughly 80% of all persons with depression reported some level of difficulty in functioning due to their depressive symptoms; 35% of men and 22% of women with depression reported that their depressive symptoms made it very or extremely difficult for them to work, get things done at home, or get along with other people [16]. Also, more than 50% of persons with mild depression reported some difficulty in daily functioning attributable to their symptoms.

Older Adults

The rate of depression in adults older than 65 years of age ranges from 1% to 5% in the community but increases to 13.5% in those who require home healthcare and to 11.5% in the hospitalized elderly [17]. The recurrence rate of MDD in the elderly is also extremely high, at 40% [18]. Chronic health conditions contribute to an increased risk of depression in the elderly [17].

Peripartum Women

The peripartum period may be the most common time in a woman's life for depression to develop. Between 14% and 23% of women will experience a depressive disorder while pregnant, and 10% to 15% of women will experience a depressive disorder postpartum [19,20,21].

Persistent Depressive Disorder

Persistent depressive disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) represents a consolidation of DSM-IV-defined chronic MDD and dysthymic disorder. The 12-month prevalence in the United States is approximately 0.5% for persistent depressive disorder and 1.5% for chronic MDD [9]. The median age of onset of persistent depressive disorder is 31 years [22].

PERSONAL AND SOCIETAL COSTS OF DEPRESSION

Major depressive disorder exacts an enormous toll on afflicted persons and is recurrent or chronic in approximately 35% of patients. It is associated with numerous chronic medical comorbidities and complications from acute medical illness, such as myocardial infarction [22]. Interpersonal connections and role functioning as spouse, parent, or worker are impaired. MDD is the leading cause of disability in the United States for persons 15 to 44 years of age and is second only to chronic back and neck pain in disability days per year among all Americans [22].

MDD is among the most costly illnesses in the world. The cost of depression in the United States was estimated at $210.5 billion in 2010, accounted for by workplace costs (62%), direct costs (31.4%), and suicide-related costs (6.6%) [23,24]. Even low-grade depression is associated with decreased work productivity [25]. A study in 2002 estimated the economic burden of depression to represent a 30% to 75% increase in healthcare costs after controlling for medical comorbidity [26,27]. Patients who do not achieve full treatment response use twice as many healthcare services, and cost employers almost four times as much as patients achieving remission [28]. Women with early-onset depression (before 22 years of age) often fail to graduate from college and earn substantially less income than women with later-onset depression or no depression [29]. In the United States, the annual cost of suicidal behaviors (attempts and deaths) was estimated to be $93.5 billion in 2016 [30]. Depression causes an estimated 200 million lost workdays each year at a cost to employers of $17 to $44 billion [31]. However, attempts to quantify such costs on a national scale are hampered by incomplete data, such as the under-reporting of suicides [32].

3. BACKGROUND

RISK FACTORS

Several demographic/socioeconomic, psychosocial, familial, medical, and psychologic factors are associated with higher risk for depression. Adverse early life events such as early childhood parental abandonment or death, or emotional trauma from physical, sexual or emotional abuse are major risk factors for depression and other psychiatric disorders in adulthood. In adulthood, recent loss (e.g., death, divorce), domestic abuse/violence, traumatic civilian (assault, serious car accident) or military (battlefield injury, witnessing death and dismemberment) events, and major life changes (e.g., job change, financial hardships) are all potential red flags for depression [21,33].

Women have greater risk of depression, with a lifetime prevalence almost twice that of men [34]. Among women, severe obesity (body mass index greater than 40) is strongly associated with depression [35]. Lower socioeconomic status and being single are also risk factors for both genders [33].

Family history of psychopathology, affective disorders in general, and major depression are particularly robust risk factors. MDD is two to four times more common among persons with an afflicted first-degree biologic relative (a parent or sibling) than among the general population [9]. Relative risks appear to be higher for early-onset and recurrent forms [9]. However, family studies indicate that major depression is not caused by any single gene but is a disease with complex genetic features. No specific genetic risk factor has been reliably identified and associated with the development of depression [36].

Certain neurologic disorders are risk factors, such as Parkinson disease, stroke, multiple sclerosis, and seizure disorders. Among persons with certain general medical conditions, such as cancer, diabetes, myocardial infarction, or stroke, 20% to 25% will go on to experience a major depressive episode (MDE) [22]. Chronic pain, medical illness, and persistent or severe psychosocial stress elevate the risk of MDD [33].

Risk factors for late-onset depression include widowhood, physical illness, educational attainment less than high school, impaired functional status, and heavy alcohol consumption [21,37].

As noted, peripartum women are particularly vulnerable to depression. Risk factors for peripartum depression include [21]:

- Depression or anxiety during pregnancy

- Previous history of a mood disorder

- Poor social support

- Stressful life events

- Pre-pregnancy and gestational diabetes

- Fragmented or poor sleep

- Substance abuse

- Current or past abuse experiences

- Difficulty breastfeeding in the first two months postpartum

NATURAL HISTORY OF DEPRESSION

Onset of a first major depressive episode (MDE) can be triggered by a serious psychosocial stressor and is associated with a history of panic attackshttp://www.netce.com/ and alcohol or substance use disorder [38,39]. A prodromal syndrome of anxiety or low-grade depression symptoms may persist for several months before onset of an initial MDE. Major depression has a variable age of onset, but the mid- to late-20s is typical [9,22].

After the initial onset of MDD, around 15% of patients have a chronic and unremitting course. An additional 35% recover but experience one or more future recurrent episodes, and roughly 50% of first lifetime onsets recover and do not have future MDE episodes [9,39]. The risk of recurrence becomes progressively lower over time as the duration of remission increases. Preceding severe depressive episodes, younger age, and previous multiple depressive episodes increase the risk of recurrence [9].

Antidepressant medication can alter the disease course by reducing relapse rates, while premature antidepressant discontinuation is associated with marked increases in risk of relapse [40,41,42]. Relapse prevention is a clinical priority, and a collaborative care model with ongoing pharmacotherapy and/or psychotherapy and regular follow-up can improve treatment adherence and reduce the risk of depressive relapse [21,43]. A single episode of major depression is associated with a 50% chance of a subsequent episode, two episodes with a 70% chance, and three or more episodes with a 90% chance [44]. A greater number of depressive episodes predicts poor treatment response [22].

Depression is an illness with a potentially fatal outcome. Among persons with a mood disorder, 12% to 20% will ultimately die by suicide. The first three months is the period of highest risk for a first attempt, with the three months following the first attempt being the highest risk period for a second attempt [27].

DEFINITIONS

Several similar but distinct terms are used to describe depression. The DSM-5 states the common feature of depressive disorders is the "presence of a sad, empty, or irritable mood, accompanied by somatic and cognitive changes that significantly affect a person's ability to function" [9]. Depressive disorder is an umbrella term that includes MDD (including major depressive episode), persistent depressive disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder. A new diagnosis, disruptive mood dysregulation disorder (a chronic, severe, persistent irritability), is included in the DSM-5 to address concerns of potential overdiagnosis and treatment of bipolar disorder in children 12 years of age and younger [9]. MDD, formerly called major depression or clinical depression, is the classic condition in this group of disorders, characterized by discrete episodes of at least two weeks' duration involving clear-cut changes in affect, cognition, and functioning, with inter-episode remissions [9]. Persistent depressive disorder is a chronic, lower-grade depression that does not have the level of severity of MDD. A depressed mood (i.e., feeling sad) that occurs for most of the day, for more days than not, and for at least two years (or at least one year for children and adolescents) is the essential feature of this disorder [9].

4. PATHOPHYSIOLOGY OF DEPRESSION AND SUICIDE

PATHOPHYSIOLOGY OF DEPRESSION

The understanding of MDD pathophysiology and treatment is substantially changing. Until recently, the explanatory model of depressive illness and antidepressant drug efficacy was the monoamine hypothesis. Modern antidepressants were introduced in the 1950s following serendipitous discovery of anti-depressant effects with tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Selective serotonin reuptake inhibitors (SSRIs) were induced in the late 1980s, followed by atypical antidepressants and serotonin-noradrenaline reuptake inhibitors (SNRIs) [45]. The monoamine hypothesis, proposed to explain the unexpected effects of TCAs/MAOIs in the 1950s, posits that depression results from deficient brain serotonin (5-HT) and/or norepinephrine levels. This remained the dominant paradigm of depression and basis of nearly all FDA-approved antidepressants for the next five decades [46,47]. Limitations of the monoamine hypothesis and mechanistic homogeneity of standard antidepressants are now understood. MDD is vastly more complex and diverse than previously assumed, and novel pathways that underlie its pathophysiology have been identified [48,49].

Inflammatory Pathways

"Inflammation" broadly describes immune-related processes within the body, a protective immuno-vascular response involving immune cells, blood vessels and molecular mediators. Inflammatory response is activated by external (microbial infection) or internal (artherosclerosis) causes to maintain homeostasis, by eliminating initial cause of injury, clearing dead and damaged cells, and initiating tissue repair. A normal immune system produces pro- and anti-inflammatory mediators. When anti-inflammatory mediators cannot inhibit the pro-inflammatory immune response, a chronic inflammatory state may develop. Acute inflammation is adaptive (for clearing infection), but chronic inflammation is usually maladaptive and destructive and may persist for years as a low-grade state without clinical symptoms [50].

An inflammatory response produces prostaglandins, white-blood cells, and cytokines that generate other inflammatory molecules, including tumor necrosis factor-alpha, interleukins, and C-reactive protein. These mediators communicate with other immune system elements. Central nervous system (CNS) inflammation (neuroinflammation) involves diverse cell types, microglia, and astrocytes that both induce and limit brain inflammatory processes [50]. Peripheral and central immune systems communicate through bidirectional pathways [51]. Inflammation is a core component of chronic mood disorders.

Early-Life Adversity

Early-life adversity (ELA) describes childhood trauma, abuse, or caregiver abandonment, and research demonstrably links ELA with inflammation and later depression. The brain and immune system are incompletely formed at birth; maturation is shaped by interaction with the postnatal environment. ELA can affect immune development, which can adversely affect development of brain regions involved in mood, cognition and behavior [51]. ELA can also promote neuroendocrine, physiologic, behavioral, and psychologic changes that impair normal development of brain systems involved in learning, motivation, and stress response. A chronically over-reactive stress response system can impair stress response, emotional regulation, and impulse control in adulthood—a biologic priming for later depression [52,53,54,55,56]. The neurobiologic correlates of ELA and inflammation are striking, and impact on adverse clinical outcomes are demonstrated across psychiatric disorders [57].

Depression as Systemic Illness

More than 80% of patients with depression have medical comorbidity, and depression is viewed as a systemic illness [58]. Chronic inflammatory states and hyper-reactive immune response to stress in patients with MDD and ELA likely contribute to the high prevalence of inflammatory medical disorders in this population. The relationship between inflammation, inflammatory disorders, and depression is bidirectional; as these medical disorders persist, the chronic inflammatory state promotes the onset of depression [59,60].

Patient-Treatment Matching

The limitations of standard pharmacotherapy for MDD have prompted efforts to identify patient subtypes for effective treatment matching. In a 2017 study, functional magnetic resonance imaging (MRI) brain scans of 1,200 patients with MDD were analyzed and four unique biotypes (subtypes), distinct by patterns of abnormal functional connectivity in limbic and frontostriatal networks, were identified. For example, patients with biotype 1 showed severely impaired connectivity in brain regions that regulate fear-related behaviors and reappraisal of negative emotional stimuli. Treatment response to repetitive transcranial magnetic stimulation differed by subtype and was predicted with very high accuracy [61].

5. ASSESSMENT AND DIAGNOSIS OF DEPRESSION

As noted, depression is a disorder of mood involving disturbances in emotional, cognitive and behavioral regulation. The mood disorder is considered secondary if it occurs in association with substance abuse or withdrawal and/or certain medications. The mood disorder is called primary if it does not occur in association with these conditions. Primary mood disorders are categorized into depressive (unipolar) and manic depressive (bipolar) conditions. Unipolar mood conditions are divided into MDD and persistent depressive disorder [21].

Biologic measures of depression are not available for clinical practice, and diagnosis is made through psychometric findings, fulfillment of diagnostic criteria, patient history, and clinical impression [62].

SIGNS AND SYMPTOMS OF DEPRESSION

Depression is often difficult to diagnose because patient presentation is diverse, and a mood disorder may not be obvious. Patients with MDD may not seek help for mood problems, but their presentation can reflect current depression. Presentations associated with depression in patients not complaining of depressed mood or anhedonia [9,63]:

Clinical Factors

- Previous personal or family history of depression

- Psychosocial adversity (divorce, domestic violence)

- High healthcare system utilizers

- Chronic medical conditions (especially cardiovascular disease, diabetes, neurologic disorders)

- Other psychiatric conditions

- Times of hormonal challenge (e.g., peripartum)

Symptom Factors

- Unexplained physical symptoms

- Chronic pain

- Fatigue

- Anxiety

- Substance abuse

- Weight gain or loss

- Sleep disturbance

- Dampened affect

- Complaints about memory, concentrating, making decisions

Assessment of the presence of depression can also be made through signs and symptoms of the following cognitive, affective, and behavioral domains [9,21,22].

Appearance and Affect

Although most patients with MDD appear normal upon initial presentation, patients with severe symptoms can exhibit poor grooming and hygiene and changes in weight from previous contact. Psychomotor retardation may be present, reflected by a slowing or absence of spontaneous movement, flat affect, and sighs and long pauses. This represents a diminished reactivity in emotional expression. Some patients with MDD may display psychomotor agitation, reflected by pacing, hand wringing, or hair pulling [9,21,22].

Mood and Thought Process

Patients may appear tearful or sad and often report a dysphoric mood state expressed as sadness, heaviness, numbness, or irritability and mood swings, as well as a loss of interest or pleasure in their recreational or leisure activities, difficulty concentrating, or loss of energy and motivation. Feelings of worthlessness, hopelessness, helplessness, or other negative thoughts may pervade their thinking, and ruminative thinking is not uncommon in MDD. Eye contact may be absent [9].

In the context of MDD, psychotic thought processes are congruent in content with the patient's mood state, examples being delusions of worthlessness or progressive physical decline. Evidence of psychotic symptoms requires careful assessment to rule out other contributing conditions such as bipolar disorder, schizophrenia or schizoaffective disorder, substance abuse, or organic brain syndrome [9,22].

Cognition and Sensorium

Poor memory or concentration is a frequent complaint of patients with MDD, but actual cognitive deficits are infrequent and when present may represent pseudodementia. A fluctuating or depressed sensorium suggests delirium, and the patient should be evaluated for organic contributors [21,22].

Speech

Speech in patients with MDD may be normal, slow, monotonic, or lacking in spontaneity and content. Pressured speech and racing thoughts are suggestive of mania, and disorganized speech may reflect psychosis [9,21,22].

Thought Content, Suicidality, and Homicidality

The thought content of patients with depression is usually consistent with the dysphoric mood and should always be assessed for hopelessness, suicidal ideation, or homicidal/violent ideation or intent. Previous suicide attempts or violence predicts future behavior, and command hallucinations are associated with increased suicidal and homicidal actions [21].

SCREENING

Evidence Based Practice Recommendation

According to the Institute for Clinical Systems Improvement, clinicians should routinely screen all adults for depression using a standardized instrument.

https://www.guideline.gov/summaries/summary/50406

Last Accessed: June 22, 2017

Strength of Recommendation/Level of Evidence: Strong Recommendation, Low Quality Evidence

In 2016, the U.S. Preventive Services Task Force recommended depression screening in the general adult population, including pregnant and postpartum women. Screening should be implemented with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up [64].

Depression screening instruments are used to identify patients who should undergo a fuller assessment for depressive disorders [65]. The Patient Health Questionnaire-2 (PHQ-2) is a two-question screen widely recommended for use in primary care [66]:

- ''In the last month, have you been bothered by little interest or pleasure in doing things?''

- ''In the last month, have you been feeling down, depressed, or hopeless?''

An answer of ''yes'' to either question requires a more detailed assessment.

The Patient Health Questionnaire-9 (PHQ-9) is the most-recommended instrument following a positive screen. It consists of nine questions that ascertain depressive symptoms and symptom severity in the past two weeks and takes two minutes to complete. The PHQ-9 is recommended for use to measure severity before treatment and for periodic use during therapy to help assess response [65,67]. Positive response to the last item ("Thoughts that you would be better off dead or of hurting yourself in some way?") is associated with increased risk for suicide attempt [68].

Other screening and assessment tools are more complex, and others have extensive use in research. Some may be useful in assessing comorbid conditions or in differential diagnosis. They include [21,65,69,70,71,72]:

- Zung Self-Rating Depression Scale: A widely used depression measure.

- Beck Depression Inventory II (BDI-II): Widely used as a depression outcome measure in research and practice.

- Geriatric Depression Scale (GDS): Developed to assess depression in older adults.

- Hamilton Rating Scale for Depression (HAM-D or HDRS): Extensively used in clinical research.

- Montgomery-Åsberg Depression Rating Scale (MADRS): Greater sensitivity to medication or other treatment response than the HAM-D.

- Edinburgh Postnatal Depression Scale (EPDS): The most widely used assessment tool for postpartum depression, administered to patients six weeks after delivery.

- CAGE Questionnaire: Recommended due to high rates of excessive alcohol and substance in depression, use to screen patients undergoing further evaluation. Ask the patient if they have ever:

- Felt you ought to cut down on your drinking (or drug use)?

- Had people annoy you by criticizing your drinking (or drug use)?

- Felt bad or guilty about your drinking (or drug use)?

- Had a drink (or drug use) as an eye opener first thing in the morning to steady your nerves or get rid of a hangover or to get the day started?

Each affirmative response earns one point. One point indicates a possible problem. Two points indicate a probable problem.

- The Distress Thermometer: Developed for patients with significant language or communication difficulties, this one-question screen identifies distress from any source. The person marks a scale that asks: "How distressed have you been during the past week on a scale of 0 to 10?" Scores of 4 or more indicate significant distress that requires further investigation.

ASSESSMENT

Evidence Based Practice Recommendation

According to the American Psychiatric Association, patients should receive a thorough diagnostic assessment in order to establish the diagnosis of major depressive disorder, identify other psychiatric or general medical conditions that may require attention, and develop a comprehensive plan for treatment.

https://www.guideline.gov/summaries/summary/24158

Last Accessed: June 22, 2017

Strength of Recommendation: I (Recommended with substantial clinical confidence)

As noted, a positive screen may indicate the presence and severity of depression, but it does not provide the clinical information required for diagnosis and treatment. Additional psychologic testing with the Millon Clinical Multiaxial Inventory-III (MCMI-III) or Minnesota Multiphasic Personality Inventory-2 (MMPI-2) can help determine diagnosis or differential diagnoses [73]. Both instruments should only be interpreted by licensed psychiatrists or psychologists with training in psychologic testing and assessment. Assessing for self-harm is also important. Persons who survive a serious suicide attempt may sustain injuries such as broken bones, brain damage or organ failure and often experience continued depression and other mental health problems [74,75].

An appropriate patient history includes information about the present illness, the medical history and medication history, including any substance abuse or dependence [69]:

- History of present illness: Determine onset, severity, prior history, concurrent psychiatric conditions, and psychosocial stressors

- Medical history: Rule out medical disorder cause of major depression

- Medication history and substance use disorder

DIAGNOSIS OF DEPRESSION

In 2013, the American Psychiatric Association (APA) published their most recently revised diagnostic criteria for depression and other psychiatric illness in the DSM-5, including major depression (i.e., MDD) [9].

As stated, the DSM-5 umbrella of depressive disorders includes MDD (including major depressive episode), persistent depressive disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, and disruptive mood dysregulation disorder, a new diagnosis added to address concerns about the potential overdiagnosis of and treatment for bipolar disorder in children up to 12 years of age [9].

Persistent Depressive Disorder

Persistent depressive disorder is a depression of less severity than MDD that usually begins in childhood and adolescence. The depressed mood lasts for most of the day, for more days than not, must be present for at least two consecutive years (at least one year in children and adolescents), and must include the presence (while depressed) of two or more of the following symptoms [9]:

- Poor appetite or overeating

- Insomnia or hypersomnia

- Low energy or fatigue

- Low self-esteem

- Poor concentration or difficulty making decisions

- Feelings of hopelessness

Major Depressive Disorder

To meet the diagnosis of MDD, a person must have at least five of the following symptoms for at least two weeks' duration and represent a change from previous functioning. At least one of the symptoms must be either depressed mood or loss of interest or pleasure [9]:

- Depressed mood most of the day, nearly every day

- Markedly diminished interest or pleasure in all or almost all activities most of the day or nearly every day

- Significant weight loss or gain (>5% body weight) or increase or decrease in appetite

- Insomnia/hypersomnia nearly every day

- Psychomotor agitation or retardation nearly every day

- Fatigue/loss of energy nearly every day

- Feelings of worthlessness or inappropriate guilt nearly every day

- Diminished concentration or indecisiveness nearly every day

- Recurrent thoughts of death or suicide, suicide attempt, or a specific plan for committing suicide

In addition, the symptoms must not meet the criteria for a mixed episode. The patient with MDD has never experienced a manic, mixed, or hypomanic episode. Symptoms should cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. Additionally, the symptoms may not be due to the direct physiologic effects of a recreational or prescribed drug or be better accounted for by bereavement (i.e., after the loss of a loved one, the symptoms persist for longer than two months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation) [9].

The diagnostic symptoms of MDD represent the domains of affective, behavioral, cognitive, and somatic impairment. Affective or mood symptoms include depressed mood and feelings of worthlessness or guilt, while behavioral symptoms include social withdrawal and agitation. Cognitive symptoms include difficulties with concentration or decision making, and somatic or physical symptoms include insomnia or fatigue.

The DSM-5 diagnostic criteria for MDD also include several specifiers to further describe the nature of the current episode of MDD. These specifiers include [9]:

- Anxious distress

- Mixed features

- Melancholic features

- Atypical features

- Mood-congruent psychotic features

- Mood-incongruent psychotic features

- Catatonic features

- Peripartum onset

- Seasonal pattern

Criteria for Anxious Distress Specifier

In order for a patient with MDD to be classified as meeting the criteria for anxious distress, he or she must have at least two of the following symptoms during the majority of days [9]:

- Feeling keyed up or tense

- Feeling unusually restless

- Having difficulty concentrating due to worry

- Fearing that something awful may happen

- Worrying about losing control

High levels of anxiety are associated with higher suicide risk, longer duration of illness, and greater likelihood of treatment nonresponse. It is therefore clinically useful to accurately specify the severity level of anxious distress:

- Mild: Two symptoms

- Moderate: Three symptoms

- Moderate-to-severe: Four or five symptoms

- Severe: Four or five symptoms, with motor agitation

Criteria for Mixed Features Specifier

MDD with mixed features is a significant risk factor for the development of bipolar I or II disorder. A patient with MDD may be classified as meeting the criteria for mixed features when at least three of the following manic/hypomanic symptoms are present nearly every day [9]:

- Elevated, expansive mood

- Inflated self-esteem, grandiosity

- More talkative than usual or feeling pressure to continue talking

- Ideas, thoughts are racing

- Increase in energy or goal-directed activity

- Increased or excessive involvement in activities with high potential for painful consequences

- Decreased need for sleep

Criteria for Melancholic Features Specifier

For a patient with MDD to be classified as meeting the DSM-5 criteria for melancholic features he or she must have either a loss of pleasure in all, or almost all, activities or a lack of reactivity to usually pleasurable stimuli (i.e., does not feel much better, even temporarily, when something good happens). In addition, three (or more) of the following symptoms must be present [9]:

- Distinct quality of depressed mood (e.g., the depressed mood is experienced as distinctly different from the kind of feeling experienced after the death of a loved one)

- Depression regularly worse in the morning

- Early morning awakening (at least two hours before usual time of awakening)

- Marked psychomotor retardation or agitation

- Significant anorexia or weight loss

- Excessive or inappropriate guilt

Criteria for Atypical Features Specifier

Mood reactivity (i.e., mood brightens in response to actual or potential positive events) is the characteristic feature of MDD with atypical features. In addition, at least two of the following symptoms must be present [9]:

- Significant weight gain or increase in appetite

- Hypersomnia

- Leaden paralysis (i.e., heavy, leaden feelings in arms or legs)

- Long-standing pattern of interpersonal rejection sensitivity (not limited to episodes of mood disturbance) that results in significant social or occupational impairment

Essentially, atypical MDD is characterized by vegetative symptoms of reversed polarity (e.g., increased rather than decreased sleep, appetite, weight), marked mood reactivity, hypersensitivity to rejection, phobic symptoms, or a sense of severe fatigue that creates a sensation of leaden paralysis or extreme heaviness of the extremities [22].

Criteria for Mood-Congruent Psychotic Specifier

According to the DSM-5, MDD with psychotic features includes the presence of delusions and/or hallucinations. Specifically, with mood-congruent psychotic features, the content of all delusions/hallucinations is consistent with the typical depressive themes (i.e., personal inadequacy, guilt, disease, death, nihilism, deserved punishment) [9].

Criteria for Mood-Incongruent Psychotic Specifier

The criteria for MDD with mood-incongruent psychotic features is satisfied when the content of delusions/hallucinations does not involve typical depressive themes or the content is a mix of mood-incongruent and mood-congruent themes [9].

Criteria for Catatonia Specifier

The specifier for catatonia can apply to an episode of depression if catatonic features are present during most of the episode. The clinical picture of the catatonic type of MDD is dominated by at least three of the following [9]:

- Stupor (i.e., motoric immobility; not actively relating to environment)

- Catalepsy (i.e., passive induction of a posture held against gravity)

- Waxy flexibility (i.e., slight, even resistance to positioning by examiner)

- Mutism (i.e., no, or very little, verbal response)

- Negativism (i.e., opposition or no response to instructions or external stimuli)

- Posturing (i.e., spontaneous and active maintenance of a posture against gravity)

- Mannerism (i.e., odd, circumstantial caricature of normal actions)

- Stereotypy (i.e., repetitive, abnormally frequent, non-goal-directed movements)

- Agitation, not influenced by external stimuli

- Grimacing

- Echolalia (i.e., mimicking another's speech)

- Echopraxia (i.e., mimicking another's movements)

Criteria for Peripartum Onset Specifier

Mood episodes can have their onset either during pregnancy or postpartum. Between 3% and 6% of women will experience the onset of a major depressive episode during pregnancy or in the weeks or months following delivery. Fifty percent of "postpartum" major depressive episodes actually begin prior to delivery [9]. Thus, these episodes are referred to collectively as peripartum episodes. Peripartum-onset mood episodes can present either with or without psychotic features. Postpartum mood (major depressive or manic) episodes with psychotic features appear to occur in from 1 in 500 to 1 in 1,000 deliveries. After a woman has had a postpartum episode with psychotic features, the risk of recurrence with each subsequent delivery is between 30% and 50%. This specifier may be applied to a current episode of MDD if the onset is within four weeks postpartum [9].

Criteria for Seasonal Pattern Specifier

According to the DSM-5, MDD with seasonal pattern specifier can be applied to the pattern of major depressive episodes in MDD, recurrent. The essential feature is the onset and remission of major depressive episodes at characteristic times of the year. Criteria include [9]:

- A regular temporal relationship between the onset of MDD and a particular time of the year (e.g., fall, winter)

- Full remissions (or a change from MDD to mania or hypomania) at a characteristic time of the year (e.g., depression disappears in the spring)

- In the last two years, two MDD episodes have occurred that demonstrate the temporal seasonal relationships defined above and no nonseasonal major depressive episodes have occurred during that same period.

- Seasonal MDD episodes substantially outnumber the nonseasonal MDD episodes that may have occurred over the individual's lifetime.

Bereavement

With bereavement, the loss of a loved one is a particularly severe stressor. Bereavement is commonly accompanied by the signs and symptoms of MDD, with roughly 25% of bereaved persons exhibiting a diagnosable major depression at two months and seven months following the loss [76]. Individuals with more severe and prolonged major depressive manifestations tend to be younger with a history of previous episodes of major depression, and antidepressant medications or psychotherapy should be used in cases with prolonged depressive reaction with significant functional impairment [9,22].

Complicated grief is a chronic serious condition that develops in roughly 7% of bereaved persons [77]. It is characterized by persistent, intense grief resulting from troubling thoughts related to the death and excessive avoidance of reminders of the loss that slow or halt the process of adapting to the loss. Depressive symptoms that may or may not be present in complicated grief include persistent depressed mood, anhedonia, worthlessness, and psychomotor and neurovegetative symptoms [77].

ASSESSING AND DIAGNOSING DEPRESSION IN SPECIAL POPULATIONS

Evidence Based Practice Recommendation

The assessment and treatment of major depressive disorder should consider the impact of language barriers, as well as cultural variables that may influence symptom presentation, treatment preferences, and the degree to which psychiatric illness is stigmatized.

http://www.guideline.gov/content.aspx?id=24158

Last Accessed: June 22, 2017

Strength of Recommendation: I (Recommended with substantial clinical confidence)

Healthcare providers can create a more comfortable environment for a patient of another culture by acknowledging the impact of culture and cultural differences on physical and mental health [78,79]. Symptom presentation is influenced by cultural factors, and in some cultures, depression and anxiety may be expressed through somatic symptoms, such as musculoskeletal pain and fatigue. Providers may consider starting the conversation with the patient by focusing on physical symptoms. The concept of depression also varies across cultures, and patients may not seek medical treatment unless symptoms manifest as psychosis, conversion disorders, or significant physical ailments [80].

Women with somatization are more likely to indicate interest in medication and their faith as sources for mental health care. However, ethnic differences tend to be very pronounced regarding medication preferences, with ethnic minority women showing less interest in medication than U.S.-born whites [81].

African Americans

In general, African Americans are more likely than whites to seek help for psychologic distress in the primary care settings and are more likely to believe that mental health professionals can be helpful, but also are more likely to believe mental illness will improve on its own [82]. They tend to seek services later and, therefore, face worse outcomes [83]. When they perceive they need help for an emotional problem, African American women tend to prefer individual or group therapy over medication [81].

Latino/Hispanic Americans

Latino/Hispanic Americans often show psychologic distress differently, and assessment for depressive symptoms alone may not adequately capture their psychologic distress [84]. Latino/Hispanic Americans may be more likely to seek treatment for depression in primary care settings, although cultural values may be inconsistent with accepting treatment [82,85]. Latina women are more likely to express distress via depressive symptoms while Latino men are more likely to externalize distress [84]. When they perceive they need help for an emotional problem, Latina women tend to prefer individual or group therapy over medication [81].

Asians

Asian immigrants, especially Chinese Americans, are less likely to use mental health services than other ethnic groups [86]. The discrepancy between aspiration and achievement may better predict psychiatric illness and emotional disturbance than socioeconomic status [87].

Elderly Patients

Evidence Based Practice Recommendation

In individuals with late-life depression, the American Psychiatric Association states that the identification of co-occurring general medical conditions is essential, as these disorders may mimic depression or affect choice or dosing of medications.

https://www.guideline.gov/summaries/summary/24158

Last Accessed: June 22, 2017

Strength of Recommendation: I (Recommended with substantial clinical confidence)

Major depression or persistent depressive disorder (dysthymia) with an age of onset after 60 years is referred to as late-onset depression. It is characterized by a greater presence of apathy and less lifetime presence of personality pathology than depression of earlier onset. Older patients tend to exhibit more vegetative signs and cognitive disturbance and complain less of dysphoria. In this population, major depression may be misattributed to physical illness, dementia, or the aging process itself [88]. Depression in the elderly is widespread, often undiagnosed, and usually untreated. Several factors contribute to missed diagnoses of depression in the elderly, including differences in presenting symptoms, stereotyping, provider and organizational barriers, and polypharmacy [21].

Differences in Symptom Presentation

While DSM-based epidemiology studies suggest that the frequency of MDD declines with age, symptom-based assessment studies show increased rates of depression in older adults, especially women [21]. Older adults are less likely than younger adults to report feelings of dysphoria such as sadness, unhappiness, or irritability, suggesting that the standard diagnostic criteria for depression may be more difficult to apply to older adults or that older adults are disinclined to disclose such feelings [88,89].

Similar to other subgroups, depressed elderly often present with nonspecific somatic complaints such as insomnia, appetite disturbances, lack of energy, fatigue, chronic pain, constipation, and musculoskeletal disorders [21]. Stigma also contributes to the denial among elderly patients of the psychologic symptoms of depression and refusal to accept the diagnosis. This appears to be particularly the case with older men, who also have the highest rates of suicide in later life [88,90].

Provider-Related Factors

Provider-specific factors contributing to under-detection and under-treatment of depression include reluctance to inform older patients of a depression diagnosis due to uncertainty over the diagnosis and proper treatment, reluctance to stigmatize, concern regarding medication interactions, lack of access to psychiatric care, and doubts regarding treatment effectiveness and cost-effectiveness [91]. Additional factors are physician overconfidence in their ability to diagnose, treat, and manage depression in the absence of sufficient training and education and a presumption (based on their familiarity with the patient) that they have nothing new to learn about the patient [91,92,93].

Stereotyping

Healthcare professionals are not immune from harboring the stereotypes of the elderly often found among society in general. These can include attitudes that a depressive response to interpersonal loss, physical limitation, or changing societal role is an inevitable and even normal aspect of aging [91,94,95,96]. The elderly may view their suicidal thoughts as age-appropriate [93]. When held by patients and family members, these erroneous beliefs can lead to under-reporting of symptoms and lack of effort on the part of family members to seek care for patients [95,96]. When held by clinicians, these beliefs can result in delayed or missed diagnoses, less effective treatment, or suicide in the elderly patient. Studies have shown that a great majority of geriatric suicide cases have visited a physician within one month of their suicide [91,93].

Systemic Barriers

The healthcare system itself has increasingly restricted the time allocated for patient care, forcing mental health concerns to compete with general medical conditions for provider attention. Primary care providers often report feeling too time-pressured to investigate depression in older patients [97].

Polypharmacy

First-episode depression in elderly patients may have an undiagnosed neurologic or other medical disorder etiology. Because some medications, such as beta-blockers, can precipitate depression in the elderly, consideration should be given to the potential role of medication side effects, particularly because this population is likely to be taking many different medications [22].

Women

As noted, women have a higher lifetime prevalence of depression and are particularly vulnerable during their childbearing years [6,8,10]. In one study, depressed women were found to mention mental symptoms when visiting a primary care provider for medical concerns (e.g., respiratory infection), giving practitioners clues as to their mental state that were not often explored [98]. Primary care providers should be alert to these clues, and screen and follow up with these women, as appropriate.

When depression develops during pregnancy, the course and presentation of the disease is often unique [19]. It is important that perinatal depression be identified and treated as early as possible to minimize the risks to the mother and fetus. Screening during the antepartum and postpartum periods should focus on signs and symptoms experienced in the previous week, utilizing a tool designed specifically for this population (e.g., the Edinburgh Postnatal Depression Scale) [99].

Children

Depression does develop in children, in some cases at a young age, and the long-term effects can be significant even after resolution of depressive symptoms [99]. There are several inherent barriers in the accurate assessment of younger children, including limited cognitive, language, and reading abilities [100]. For this reason, multiple "informants" are used to gain a clear clinical picture; however, it is important to remember that the child has the greatest knowledge regarding his or her own internal state. Several screening tools have been developed specifically for children and adolescents, but these are generally recommended for those 7 years of age and older [101,102].

Gay, Lesbian, Bisexual, and Transgender Individuals

Some depression risk factors occur with greater frequency in gay, lesbian, bisexual, and transgender (GLBT) communities, including family rejection, ostracism, bullying and peer victimization, and negative self-image, and depression is more common in this group than in the general population [103,104]. However, there is some evidence that available screening tools may overestimate the incidence of mental disorders among GLBT patients [105]. Because the risk of suicide is high in this population, any possible depressive signs or symptoms should be fully explored.

DIFFERENTIAL DIAGNOSIS

Because depression can be a manifestation of other psychiatric conditions, substance use disorders, CNS disorders, general medical conditions, or medication side effects, a differential diagnosis should be performed to rule out other conditions that may account for the depression. MDD can co-occur with any medical condition, but depression can also be a biologic manifestation of certain neurologic and medical conditions. In these cases, primary depression is ruled out. Considerations for the conditions discussed in the following section should be made in the differential diagnosis [9,22,106].

CNS Conditions

A broad range of CNS processes and conditions can produce changes in mood, cognition, and behavior that resemble MDD. These include Alzheimer disease, Parkinson disease, Huntington disease, multiple sclerosis, stroke, and seizure disorders; neoplastic lesions of the CNS; inflammatory conditions such as systemic lupus erythematosus; sleep disorders, particularly obstructive sleep apnea; and infectious diseases such as syphilis, Lyme disease, and human immunodeficiency virus (HIV) encephalopathy.

Pharmacologic Agents

Medications that can induce mood changes include antihypertensive medications, steroids, medications that affect sex hormones, H2 histamine blockers, sedatives, muscle relaxants, appetite suppressants, and cytotoxic chemotherapy agents. Patients taking several medications are at increased risk.

Endocrine Disorders

Several endocrine disorders, including Addison disease, Cushing disease, hyper- and hypothyroidism, prolactinomas, and hyperparathyroidism, have been linked to symptoms of depression. Treatment of the underlying disease should alleviate depressive symptoms.

Other Psychiatric Conditions

Depressive symptoms or mood disturbance can be due to psychiatric conditions other than MDD. Intoxication or acute withdrawal associated with alcohol and almost all recreational drugs can disrupt mood, cognition, and behavior. Furthermore, depressive symptoms may be a phase of bipolar disorder. It is important to distinguish bipolar from unipolar depression, as treatment decisions are based on this distinction. Assessment should always involve inquiry about manic or hypomanic episodes, using the following DSM-5 criteria for bipolar disorder [9]:

- A distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased goal-directed activity or energy, lasting at least one week and present most of the day, nearly every day (or any duration if hospitalization is necessary)

- During the period of mood disturbance and increased energy or activity, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree and represent a noticeable change from usual behavior:

- Inflated self-esteem or grandiosity

- Decreased need for sleep

- More talkative than usual or pressure to keep talking (pressured speech)

- Flight of ideas or subjective experience that thoughts are racing

- Decreased need for sleep

- Increase in goal-directed activity or psychomotor agitation

- Excessive involvement in pleasurable or hedonistic activities with a high potential for painful consequences

- The mood disturbance sufficiently severe to cause marked impairment in social or occupational functioning or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features

- The episode is not attributable to the physiologic effects of a substance (e.g., an illicit drug, a medication, other treatment) or to another medical condition

These criteria constitute a manic episode. At least one lifetime manic episode is required for the diagnosis of bipolar I disorder.

Other psychiatric conditions with similar presentation to MDD include seasonal affective disorder, persistent depressive disorder, anxiety disorders, eating disorders, and personality disorders, especially borderline personality disorder. Many patients with MDD who appear labile, demanding, or pathologically dependent look dramatically different after the depressive episode has been treated adequately.

COMORBID CONDITIONS

Additional psychiatric disorders are present in many patients with MDD. Comorbidity rates differ between studies conducted with community compared with clinical populations. However, the most commonly occurring psychiatric comorbidities and their rates of occurrence in persons with MDD are [22,107,108,109,110]:

- Generalized anxiety disorder (62%)

- Social phobia (52%)

- Post-traumatic stress disorder (PTSD) (50%)

- Panic disorder (48%)

- Specific phobia (43%)

- Obsessive-compulsive disorder (42%)

- Any personality disorder (30%)

- Impulse control disorders (30%)

- Substance use disorders (24%)

- Borderline personality disorder (10% to 15%)

In addition, depression and certain medical conditions co-occur at very high rates. One large clinical trial found that depressed study participants had an average of 3.3 general medical conditions, including chronic pain, diabetes, cancer, HIV, Parkinson disease, and cardiovascular disease [111]. Medical comorbidity is highest among the elderly, with very high rates of depression found in patients with stroke (30% to 60%), coronary artery disease (up to 44%), cancer (up to 40%), Parkinson disease (40%), and Alzheimer disease (20% to 40%). The recurrence rate of MDD in the elderly is also extremely high, at roughly 40% [18].

Pseudodementia

Cognitive impairment often accompanies MDD. Some patients have both MDD and dementia, while others have cognitive impairment that is secondary to MDD, termed pseudodementia. Pseudodementia should resolve when MDD is successfully treated. Several clinical features help differentiate pseudodementia from true dementia. When performing cognitive tasks, pseudodemented patients generally exert relatively less effort but report more incapacity than demented patients. In the latter group, especially in the advanced stages, patients typically neither recognize nor complain of their cognitive failures, as insight is impaired. In contrast, pseudodemented patients often vehemently complain that they cannot think or remember clearly. Pseudodementia also lacks the signs of cortical dysfunction (e.g., aphasia, apraxia, agnosia) that are seen in degenerative dementia. It is essential that individuals with MDD-related cognitive disturbance not be misdiagnosed and subsequently denied aggressive treatment [22].

6. INITIAL TREATMENT OF DEPRESSION

Although the DSM-5 criteria require the presence of five of nine symptoms for MDD diagnosis, significant impairment in functioning can occur with as few as two symptoms [9,112]. Therefore, the goal of treatment should be to achieve remission, to reduce relapse and recurrence, and to return patients to their previous level of occupational and psychosocial function. Remission is defined as the absence of depressive symptoms, response is defined as a 50% or greater reduction in symptoms, and partial response is defined as a 25% to 50% reduction in symptoms [21,113].

An estimated 70% to 80% of antidepressants are prescribed in primary care, making it critical that clinicians understand their use and have a system that supports best practices [69]. However, evidence suggests that nonpsychiatric practitioners underdiagnose and undertreat depressive illnesses [27,114]. Primary care clinicians who diagnose a patient with MDD face several challenges in achieving remission in the patient. These include time constraints on the treatment of a time-intensive disorder; potential comorbidities; lack of training on differential diagnoses; initial patient presentation for a medical and not a psychiatric problem; potential for poor adherence to treatment; unavailability of psychotherapy in many primary care clinics; potential discomfort among primary care providers in providing nonmedical, psychologic care; and patient expectation of a "quick fix" [27].

INITIAL COMMUNICATION WITH THE PATIENT

Patient Education

An essential aspect of treating major depression is the active engagement of patients and their families during the process. Engagement is the foundation for communication between providers and patients, and at the time of diagnosis, patient education represents a useful and important topic of communication. Patient education is also important to help counter the negative effects of pessimism, low motivation, low energy, social isolation, and guilt on treatment engagement and adherence [21,22].

Diagnosis, prognosis, and treatment options should be addressed in patient education, which should also include a discussion of the costs, duration, side effects, and expected benefits of treatment. Patients should be reassured that depression is a medical condition, not a character defect, and recovery is the rule, not the exception [21,22]. Treatment is effective for many patients, and it is important to stress the treatment goal is complete remission—not just getting better but staying well. However, the risk of recurrence is high (50% after one episode, 70% after two episodes, and 90% after three episodes), and patients and family members should be alert to early signs and symptoms of depression recurrence and seek treatment as soon as possible if depression returns [44]. Clinicians should include the following topics related to treatment and follow-up in discussions with the patient before directly addressing specific therapy options [21,22]:

- The causes, symptoms, and natural history of major depression

- Treatment options and the process of finding the best fit for each patient

- Information on what to expect during the course of treatment

- How to monitor symptoms and side effects

- The desired follow-up protocol, such as office visits and/or telephone contacts

- Early warning signs of relapse or recurrence

- The duration of treatment

- Communication with the provider

- The frequency of visits

- Patient expectations and beliefs in the controllability of their depressive symptoms

Patient Self-Management

Self-management refers to patient ability to manage treatment, lifestyle modifications, and associated physical and psychosocial challenges necessary to better ensure recovery from depression. Supported self-management typically includes action planning to change behavior. Techniques include behavioral activation, communication skills, emotion coping skills, patient education, healthy lifestyle, relapse-prevention planning, skill development, and self-monitoring. Effective self-management reduces patient reliance on healthcare providers and increases empowerment and self-efficacy [63,115].

Behavioral Activation

Patients can be instructed to increase their daily involvement in pleasant activities and positive interactions with the environment as one of the aspects of their overall recovery plan [116]. Behavioral activation is appealing to patients in that it is simple and easily taught, effective in reducing milder depression, and can be continued following the conclusion of therapy. Behavioral activation can also be used in difficult-to-treat populations, such as depressed dementia patients. Among the elderly, regular outings and get-togethers, participation in a senior day care program, or available nursing home activities can reduce depression [21,117,118]. Results of a 2010 meta-analysis suggest that among patients with mild or subclinical depression, antidepressants may be no better than placebo, and that behavioral activation plus lifestyle modifications alone may offer sufficient symptom reduction [119].

Physical Activity

A robust body of evidence indicates that physical activity at a dose consistent with public health recommendations can lessen or alleviate symptoms of depression. Exercise therapy is very beneficial to patients with major depression, but the exercise must be continued over time to provide maximum benefit. Greater antidepressant effects occur when training continues beyond 16 weeks. Walking is a good initial option for many patients, and physically healthy adults should be encouraged to set a goal of 30 minutes of moderate-intensity aerobic exercise, three to five days per week [21].

DEVISING A TREATMENT PLAN

The two primary treatment options for most patients with MDD are psychotherapy and pharmacotherapy [113]. Evidence-based guidelines recommend that the process of treatment selection involve shared decision making between provider, patient, and family members, and that the values, priorities, and goals of the patient be included in discussions of risks and benefits of treatment options [120]. Ongoing communication with other providers involved in the care of a patient is essential for coordination and monitoring and can involve different care providers in the same primary care clinic or the primary care provider and therapist or psychiatrist [22].

Combining pharmacotherapy and psychotherapy treatments should be considered for patients with MDD when practical, feasible, available, and affordable. Both approaches combined show better outcomes than either as monotherapy. When unable to combine therapy because of patient preference or problems with availability or affordability, consider psychotherapy when the presentation is mild-to-moderate, and antidepressants when depression is severe or chronic [21,69]. Patients with MDD with psychotic features should receive an antipsychotic and an antidepressant medication or electroconvulsive therapy (ECT). Lithium can be added in patients unresponsive to antipsychotic/antidepressant therapy [22]. Other specific factors should be considered in treatment planning, including the presence of substance abuse, specific features, and other comorbid disorders. If a patient displays signs of potential suicide, increasing the treatment intensity, including hospitalization if needed, should be considered, and pharmacotherapy and psychotherapy should both be provided [22].

Alcohol or Substance Abuse/Dependence

With active substance abuse, detoxify the patient before antidepressant initiation when possible. Identifying patients who require antidepressants following the initiation of abstinence is difficult, because ongoing substance abuse can cause or amplify depressive symptoms that will dissipate with abstinence. Factors suggestive of benefit from early medication initiation include a family history of MDD, patient history of depression preceding alcohol or other substance abuse, or a history of significant depression during periods of abstinence. Use of some drugs of abuse, especially stimulants, may create a toxic interaction with monoamine oxidase inhibitors (MAOIs), and benzodiazepines and other sedative-hypnotics should be used with great caution, except as part of a detoxification regimen [22].

Specific Features

As discussed, patients with MDD may present with features that specify the current episode as catatonic, melancholic, or atypical. Rapid alleviation of potentially life-threatening catatonia in patients with MDD with catatonic features may be necessary with intravenous lorazepam or amobarbital. ECT should be used immediately in unresponsive patients. Initiation of antidepressant medication should also begin, and catatonic patients given antipsychotic medication should be monitored for neuroleptic malignant syndrome [22].

Many treatment studies in symptom-based MDD subtypes (e.g., melancholic, atypical, anxious depression) have compared an active drug to placebo. Some report efficacy, but few have evaluated preferential subtype response [121,122].

Comorbid Psychiatric Disorders

Both depressive and anxiety symptoms respond to antidepressant medication treatment, although SSRIs and TCAs may initially worsen anxiety symptoms. Benzodiazepines may be needed as short-term adjunctive therapy but should not be used as monotherapy. Clomipramine and SSRIs are efficacious in managing obsessive-compulsive symptoms, and all antidepressants should be initiated at a low starting dose [22].

Patients with MDD and comorbid personality disorders, especially borderline personality disorder, poorly respond to standard antidepressants, and MAOIs should not be used in patients with borderline personality disorder [22]. Psychodynamic psychotherapy may be beneficial in modifying the personality disorder in selected patients, although antisocial personality traits often interfere with treatment adherence and the psychotherapeutic relationship [22]. Other evidence suggests that comorbid personality disorders in patients with depression interfere with treatment response to interpersonal psychotherapy but not cognitive-behavioral therapy (CBT) [123].

Eating disorders can co-occur with depression. CBT is suggested in patients with bulimia nervosa; other effective therapies include interpersonal therapy, group therapies, family therapy, and SSRIs. Bupropion should be avoided due to lowered seizure threshold, and ECT has not been shown effective [22].

If depression is identified as seasonal affective disorder, bright-light therapy is recommended as first-line therapy and can be used adjunctively with antidepressants in more severe cases. The entire range of MDD treatments may also be used for seasonal affective disorder, either combined with, or in place of, bright-light therapy [22].

Persistent Depressive Disorder and Pseudodementia

Antidepressants appear to benefit some patients with persistent subthreshold depressive symptoms (dysthymia) but lack benefit in patients with recent-onset subthreshold depressive symptoms. No clear advantage has been shown among specific antidepressants, and psychotherapy should be considered [7,70]. For patients with persistent subthreshold depressive symptoms or depression with mild-to-moderate severity, consider an antidepressant or CBT, interpersonal therapy, or behavioral activation [70]. Unlike true dementia, cognitive impairment in pseudodementia is secondary to MDD, and should resolve with adequate antidepressant or ECT response [22].

Demographic and Psychosocial Factors Influencing the Treatment Plan

Female Sex

Some women experience mood fluctuation with gonadal hormone levels, and assessment should include a detailed assessment of mood changes across the reproductive life history. Potential drug-drug interaction should also be considered when selecting an antidepressant in women taking oral contraceptives. In perimenopausal women, SSRI and SNRI antidepressants are useful in ameliorating depression as well as in reducing somatic symptoms such as hot flashes [22].

Major Psychosocial Stressors

A MDE may follow an adverse life event, often surrounding the loss of an important relationship or life role. Antidepressant treatment decisions for MDE following such events do not differ from other contexts, but the influence of past and current psychosocial stressors on MDE severity should be considered. Adding a psychologic treatment to medication may be particularly useful [22]. Antidepressant medications and/or psychotherapy should be used in prolonged reaction to relationship loss with significant functional impairment, and some patients may benefit from bereavement support groups [22].

A history of early life trauma, such as physical/sexual abuse or parental loss or abandonment, should be considered in treatment selection. A study of 681 patients with chronic MDD found that among patients with childhood trauma, CBT was consistently more effective than antidepressant monotherapy, and that combining both therapies had no significant advantage over CBT monotherapy [124]. Remission was estimated to be twice as likely with psychotherapy than antidepressants, with special benefit noted in patients with early parental loss. These results suggest a preferential response to psychotherapy in patients with chronic MDD and a history of childhood trauma [124].

An ongoing family stressor can interfere with treatment response. Ambivalent, abusive, rejecting, or highly dependent family relationships can influence development or persistence of MDD. Such families should be evaluated for family therapy, which may be used in conjunction with individual and pharmacologic therapies [22].

Other Psychosocial Factors

Psychosocial stressors such as housing, food, child care, transportation, employment, immigration status, and financial stability may be more prevalent in certain populations and should be considered during treatment planning [125]. Also, financial factors such as insurance coverage or generic versus brand name medications can affect treatment adherence. Among low-income minority women in the United States, availability of child care and transportation are associated with significant improvement regardless of treatment modality. Medication noncompliance rates are higher in intercultural settings due to cultural expectations and communication problems [21,126].

Cultural Factors

Essential to effective diagnostic assessment and clinical management of depression is an understanding of the cultural context of a patient's illness experience. Culture is the systems of knowledge, concepts, rules, and practices that the patient has learned over time and includes language, religion and spirituality, family structures, life-cycle stages, ceremonial rituals, customs, and moral and legal systems [9].

Ethnic minority and immigrant patients can experience many barriers to accessing mental health services, including stigma, deficits in knowledge/understanding, economic hardship, and language barriers [127]. Clinicians should take steps to address their own cultural competency when working with minority patients and ensure that all communications are clear and thorough, utilizing an interpreter when necessary. Different beliefs, values, and terms for depression will impact the perceived effectiveness of treatments. In addition, some cultures may be more likely to utilize alternative treatments (e.g., saffron) [127].

Older Age

The same factors used in therapy selection with younger patients also apply to the elderly, although treatment response may take longer to achieve [22]. The starting dose of pharmacotherapy and rate of dose escalation should be carefully considered, as the elderly are more susceptible to medication side effects, especially hypotension and anticholinergic effects [22]. Weight loss may be a concern for some older patients, who may benefit from medication that promotes weight gain [21].

The collaborative care approach with the elderly involves a treatment team composed of a depression care manager, primary care physician, and psychiatrist who provide a tailored approach to meet individual patient's needs and preferences. This approach is based on education, behavioral activation, antidepressants, brief problem-solving therapy, and relapse prevention [128]. Collaborative care has demonstrated considerably greater and more sustained improvement of depressive symptoms in the elderly than usual care [129].

Family History

A family history of bipolar disorder or acute psychosis indicates the need to monitor the patient for signs of bipolar disorder and treatment-emergent mania. A family history of recurrent MDD increases the likelihood of recurrent episodes and underscores the importance of maintaining treatment response. A family member with positive treatment response to a specific antidepressant offers important information to guide antidepressant selection [22].

Comorbid Medical Conditions

As with psychiatric conditions, comorbid medical conditions can impact the treatment plan for patients with depression. Pharmacologic agents should be chosen carefully in these patients due to the increased risk for adverse events and drug-drug interactions, and the following considerations are suggested [22]:

- Hypertension or cardiac conditions: Monitor vital signs and cardiac rhythm when treating with TCAs, SNRIs, or antidepressants with anticholinergic effects.

- Seizure disorders: Use with caution antidepressants that lower the seizure threshold, such as bupropion, clomipramine, and maprotiline.

- Parkinson disease: Serotonergic agents may worsen symptoms, and bupropion may benefit the illness but worsen psychosis if present. Selegiline may interact with L-DOPA, an agent used in the treatment of Parkinson disease.

- Obesity: Monitor for weight gain with most antidepressants.

- Sleep apnea: Choose an antidepressant with little daytime sedation.

- HIV infection: Carefully consider the potential drug-drug interactions between psychotropics and antiretrovirals.

- Chronic pain: SNRIs and TCAs are preferred over SSRIs and MAOIs.

OPTIONS FOR INITIAL THERAPY

In mild-to-moderate depression, psychotherapy can be equally as effective as medication, although with severe depression, antidepressant medication is usually necessary [130,131]. Psychotherapy can significantly reduce symptoms, restore psychosocial and occupational functioning, and prevent relapse in patients with major depression [132]. It is especially useful in addressing the psychosocial stressors and psychologic factors that impact the development or maintenance of depressive symptoms [22]. Support and education in the primary care setting are critical to improving patient adherence and follow-through with treatment. Patient factors such as the nature and duration of depressive symptoms, beliefs and attitudes toward psychotherapy, and early-life experiences (e.g., history of trauma) contribute to psychotherapy treatment response [22]. Because antidepressants and psychotherapy are both effective, careful consideration of patient preference for mode of treatment is appropriate, and a referral for psychotherapy should be given whenever psychologic or psychosocial issues are prominent or if the patient requests it [133,134,135].

Phases of Treatment

With the traditional three-phase model of acute, continuation and maintenance, the distinction between continuation and maintenance phases was based on a theoretical difference between relapse (symptom recurrence before resolution of current episode) and recurrence (symptoms that constitute a new episode, after recovery from previous episode) [136,137]. However, studies have highlighted the lack of evidence to support distinct demarcations between relapse and recurrence episodes, and a two-phase model (acute and maintenance) is now recommended [63,138].

Acute Phase

The primary goals for the initial 8- to 24-week acute treatment phase are symptom remission, meaning that signs and symptoms of depression are absent or nearly so, and restoration of psychosocial functioning. Full symptom remission is important because residual depressive symptoms are risk factors for relapse and negative predictors of long-term outcomes. Clinicians can help patients achieve these goals through establishing a therapeutic alliance, providing patient education and self-management support, selecting appropriate treatment, and monitoring the patient for treatment response, side effects, functional status, adherence, risk of harm to self or others, and co-occurring psychiatric and medical comorbidities [27,63,139,140].

Maintenance Treatment Phase

Preventing recurrence is a key goal during the maintenance phase of 6 to 24 months or longer. Clinicians should focus on healthy life strategies, personality vulnerabilities, long-term self-management, and clinical strategies to reduce recurrence and help the patient return to full functioning and quality of life. For a significant proportion of patients with MDD, maintenance pharmacologic, psychologic, complementary and alternative medicine, and neurostimulation treatments play a role in preventing recurrence. Other key clinician activities include treating comorbidities and monitoring for recurrence [63,138,141].

Treatment Duration

As noted, the antidepressant dose that leads to a satisfactory acute therapeutic response should be maintained during long-term treatment to prevent relapse and recurrence of depression [142,143]. Historically, practice guidelines recommended initial treatment continuation for 6 to 12 months, but this is not supported by evidence and discontinuation decisions should not be based on treatment duration alone [144]. The two most important factors are maintaining current response and preventing relapse. Risk factors associated with chronic MDD or recurrent MDE include [63]:

- Earlier age of onset

- Severity of the initial episode (e.g., higher number of symptoms, suicidal ideation, psychomotor agitation)

- Greater number of previous episodes

- Disrupted sleep-wake cycle

- Comorbid psychopathology

- Family history of psychiatric illness

- Presence of negative cognitions

- High neuroticism

- Poor social support

- Stressful life events

The duration of untreated MDD is strongly linked to antidepressant nonresponse [63,145].

When patients with these characteristics show substantial response or remission, the focus is helping the patient maintain their level of treatment response. When antidepressants are discontinued, have a contingency plan in place for prompt intervention if relapse occurs [40]. Early antidepressant discontinuation usually results from side effects, lack of improvement, inadequate education about the illness, failure to engage the patient during follow-up, and psychosocial factors [146,147].

PSYCHOTHERAPY

Evidence Based Practice Recommendation

The American Psychiatric Association recommends use of a depression-focused psychotherapy alone as an initial treatment choice for patients with mild-to-moderate major depressive disorder, with clinical evidence supporting the use of cognitive-behavioral therapy.

https://www.guideline.gov/summaries/summary/24158

Last Accessed: June 22, 2017

Strength of Recommendation: I (Recommended with substantial clinical confidence)

The objective of psychotherapy (sometimes referred to as psychologic or psychosocial therapy) is to change thinking and behavior patterns, which in turn reduces emotion and stress reactivity in limbic regions and increases connectivity in limbic-cortical pathways and inhibitory control functions of prefrontal cortical regions [148]. Psychosocial treatments are preferred by many individuals with MDD, and psychotherapies can be sequenced as add-on approaches for insufficient initial antidepressant response or used as initial treatment, with antidepressants reserved for poor response to psychosocial treatment. However, many patients with more severe depression or cognitive impairment will require some degree of pharmacologic treatment to engage and maintain participation in psychotherapy [149].

Cognitive-Behavioral Therapy

CBT is a structured, circumscribed psychologic intervention that is grounded in the cognitive-behavioral model of affective disorders, which posits that irrational beliefs and distorted attitudes toward the self, the environment, and the future perpetuate depressive affects and compromise functioning [22]. When CBT is used for depression, the patient works collaboratively with the therapist to identify maladaptive or self-defeating thoughts, beliefs, and interpretations and their impact on current symptoms, feelings states, and/or problem-solving abilities. Therapeutic techniques include patient education and patient-therapist collaboration to choose goals, identify unhelpful thoughts, develop experiments to challenge the accuracy of such thoughts, and identify alternative beliefs through questions that explore beliefs that exacerbate depression. Treatment incorporates structured practice outside of therapy, with scheduled activities, mood tracking, thought recording and challenging, and interpersonal skills practice. CBT can be delivered via computer software and/or by group therapy format [65].

Mindfulness-Based Cognitive Therapy

Mindfulness-based cognitive therapy integrates standard CBT with mindfulness-based skills, including mindfulness meditation, guided imagery, experiential exercises, and other techniques. The goal is to assist patients with MDD in recognizing, detaching from, and accepting negative thoughts or affect while embracing self-compassion, without necessarily attempting to change them. With practice, patients can become more detached from dysfunctional thoughts by observing them as objects [65].

Interpersonal Psychotherapy

Derived from attachment theory, interpersonal psychotherapy focuses on improving interpersonal functioning and exploring relationship patterns. It addresses the connection between patients' feelings and current relationship difficulties by targeting four primary areas: interpersonal loss, role conflict, role change, and interpersonal skills [65].

Short-Term Psychodynamic Psychotherapy

Derived from longer-term psychoanalysis and psychodynamic psychotherapy, short-term psychodynamic psychotherapy assists patients in gaining insight into unconscious conflicts as they manifest in daily life and relationships, including the therapeutic relationship (i.e., transference). This approach considers these conflicts to originate in the past, usually childhood relationships to parental figures. Patients gain insight into and work through such conflicts by exploring their feelings and therapist interpretation [65].

Marital/Family Therapy

Marital and family problems are common in mood disorders, and can predate, perpetuate, or develop as consequence to the mood disorder. Marital/family therapy approaches effective in depression treatment include behavioral approaches, problem-focused approaches, and strategic marital therapy. Marital/family therapy is a helpful adjunct to medications and hospitalization in severely ill patients [22].

Complicated Grief Therapy

Complicated grief therapy involves history-taking, psychoeducation about complicated grief and its treatment, work with memory and pictures, and imagined conversations with the deceased, over a 16-week period. In one study, adults with complicated grief were randomized to combinations of complicated grief therapy, citalopram, or placebo. Complicated grief was very much improved with complicated grief therapy; adding citalopram had no further benefit. Depressive symptoms showed greater decrease with citalopram added to complicated grief therapy; citalopram response at 20 weeks was comparable to placebo. Suicidal ideation rates showed greatest reduction with complicated grief therapy [77].

Problem-Solving Therapy

Problem-solving therapy is a time-limited, structured intervention involving therapist-patient collaboration to identify and prioritize problems; break problems down into specific, manageable tasks; problem solve and develop appropriate coping behaviors for problems. It was developed to specifically address social problem-solving deficits common in chronic depression [150,151]. Problem-solving therapy is designed for use in primary care settings [152,153].

Psychotherapy Treatment Recommendations

For patients with moderate-to-severe depression, a combination of antidepressant medication and CBT or interpersonal therapy should be provided. The choice of intervention should be influenced by the duration of the episode of depression and symptom trajectory, previous course of depression and treatment response, likelihood of adherence to treatment, any potential adverse effects, and individual treatment preference and priorities [70]. A 2017 evaluation of whether CBT response was influenced by baseline depression severity suggested that patients with MDD can expect as much benefit from CBT across the wide range of illness severity [154].

For patients with persistent subthreshold depressive symptoms or mild-to-moderate depression who decline an antidepressant, CBT, or interpersonal therapy, consider counseling. Short-term psychodynamic psychotherapy should be offered to patients with mild-to-moderate depression. Individual CBT is an option for patients who have either relapsed despite antidepressant medication or have a significant history of depression and residual symptoms despite treatment and are unable or unwilling to continue antidepressant treatment. Mindfulness-based cognitive therapy should be offered to patients who are currently remitted but have experienced three or more previous episodes of depression [70].

Psychotherapy is preferred as a first-line treatment for elderly patients because of potential increased toxicity and drug-drug interactions. The evidence does not support superiority of one psychotherapy modality over another in elderly patients with MDD [65].

PHARMACOTHERAPY

Treatment with antidepressant medications can involve dosage adjustments and/or trials of a different medication at some point to maximize response and minimize side effects [22]. Patient adherence to the medication regimen is essential in achieving the maximum clinical benefit. Strategies to enhance adherence are discussed below. Providers should closely monitor patients for worsening depressive symptoms and emergent suicidality; appropriate intervention includes stopping or modifying the drug therapy or hospital admission [21]. Providers should instruct patients and caregiver(s) to be alert for emerging agitation/irritability, suicidality, and worsening depression, and to report this immediately to a healthcare provider [21].

The treatment efficacy of antidepressants in MDD is broadly similar. Other factors to help guide medication selection include previous patient or family member response to antidepressants (if any); impact on psychiatric or medical comorbidities; clinician familiarity; patient preference; safety in overdose; availability and cost; and drug-drug interactions [21]. Most second-generation antidepressant drugs are recommended as first-line treatment due to the quality of published data, side effect tolerability, and safety in overdose relative to TCAs and MAOIs [21,22,155].

The three most distressing side effects for patients treated with antidepressants are sleep disturbance, sexual dysfunction, and weight gain [156]. Choice of medication should be guided by knowledge of comparative side effects and patient priorities; some patients will be more concerned about sexual side effects, while for others, nausea, sleep disturbances, or weight gain may be more distressing [157]. In addition, available evidence regarding the optimal pharmacotherapeutic selection for the treatment of dimensions of depression and DSM-5 specifiers should be considered (Table 1).

Table 1: RECOMMENDATIONS FOR MDD SPECIFIERS AND DIMENSIONS

Specifier or Dimension

Recommended Agent(s)

Anxious distress

Antidepressants with efficacy in generalized anxiety disorder (SSRIs, SNRIs, and bupropion comparable in efficacy)

Mixed features

Lurasidone

Asenapine

Quetiapine

Aripiprazole

Ziprasidone

Melancholic features

TCAs

SNRIs

Atypical features

MAOIs (superior to TCAs in older studies)

Psychotic features

Antipsychotic-antidepressant combinations

Catatonic features

Benzodiazepines

Seasonal pattern

SSRIs

Agomelatine

Bupropion

Moclobemide

Cognitive dysfunctiona

Vortioxetine (highest efficacy)

Bupropion

Duloxetine

Modafinil

Moclobemide

Sleep disturbancea

Agomelatine (highest efficacy)

Mirtazapine

Quetiapine

Trazodone (high rates of somnolence and daytime sedation)

Fatiguea

Bupropion (highest efficacy)

SSRIs

Low energya

Duloxetine

Neuropathic pain and fibromyalgiaa

Duloxetine (highest efficacy)

Amitriptyline

Other SNRIs

aClinical dimension not recognized in the DSM-5.

Source: [158,159,160]

Selective Serotonin Reuptake Inhibitors

SSRIs are thought to act by inhibiting serotonin transporters (SERT) that reuptake serotonin (5-HT) into the presynaptic cell, increasing 5-HT in the synaptic cleft. SSRIs have advantages of low overdose lethality and better tolerability than first-generation antidepressants, which can improve adherence. SSRIs are particularly effective in patients with obsessive-compulsive symptoms, but may initially worsen anxiety or panic symptoms [7,21,22]. This class includes the agents fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), escitalopram (Lexapro), and vortioxetine (Brintellix). Citalopram may have fewer drug-drug interactions than other SSRIs, and fluoxetine may be a better choice in patients with poorer adherence due to its long half-life [7,21,22].

Common Side Effects

The most common side effects with SSRIs are gastrointestinal (nausea, vomiting, and diarrhea), activation/insomnia (restlessness, agitation, anxiety, akathisia, and sleep disturbances), sexual, headache, fatigue, and weight gain [7,21,22]. Many of these side effects dissipate over time. Sertraline is particularly associated with diarrhea, and paroxetine with weight gain [7,22].

Multimodal Antidepressants

Vilazodone and vortioxetine are multimodal antidepressants that combine SSRI properties with other pharmacologic actions affecting monoamine and non-monoaminergic targets. Evidence does not suggest greater efficacy than SSRI/SNRIs, but these agents may improve tolerability or efficacy on specific clinical domains [161].

Vilazodone, approved in 2011, primarily acts as a SERT inhibitor and 5-HT1A receptor partial agonist, and modestly inhibits dopamine and norepinephrine transporters. This antidepressant may be most helpful in patients lacking response to initial SSRIs. Vilazodone must be taken with food, which increases its absorption and bioavailability by 72% [162,163].

Vortioxetine, approved in 2013, acts through various serotonin receptors as an antagonist (5-HT3/7/1D), partial agonist (5-HT1B), or agonist (5-HT1A), and inhibits SERT. It also activates the glutamate system in the frontal cortex. Vortioxetine displays a specific clinical efficacy in the treatment of cognitive deficits associated with MDD. The most common side effects are nausea, vomiting, and constipation [161].

Serotonin-Norepinephrine Reuptake Inhibitors

SNRIs act by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in an increase in the extracellular concentrations of serotonin and norepinephrine and therefore an increase in neurotransmission [7,21,22]. Most SNRIs, including venlafaxine (Effexor), desvenlafaxine (Pristiq), levomilnacipran (Fetzima), and duloxetine (Cymbalta), are several-fold more selective for serotonin than norepinephrine.

Safety, tolerability, and side effect profiles of SNRIs resemble SSRIs, with the exception that the SNRIs have been associated (rarely) with sustained elevated blood pressure. SNRIs can be used as first-line agents, particularly in patients with significant fatigue or comorbid chronic pain, and have an important role as second-line agents in patients who have not responded to SSRIs [7,21,22].

Venlafaxine is especially beneficial in treating anxiety and panic attacks in patients with depression, and acts like an SSRI at lower doses (75 mg/day) but more like an SNRI at doses ≥150 mg/day [7,21,22].

Common Side Effects

SNRIs are associated with greater likelihood of increased pulse rate, dilated pupils, dry mouth, excessive sweating, and constipation [21]. Venlafaxine has a greater incidence of nausea and vomiting than SSRIs and may be associated with an increased risk for cardiovascular events [7,22].

Tricyclic Antidepressants

TCAs are predominantly serotonin and/or norepinephrine reuptake inhibitors that act by blocking the serotonin transporter and the norepinephrine transporter, respectively, which results in an elevation of the extracellular concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission. TCAs also have varying but typically high affinity for the H1 and H2 histamine receptors and muscarinic acetylcholine receptors. As a result, they also act as potent antihistamines and anticholinergics. These properties are generally undesirable in antidepressants, however, and likely contribute to their large side effect profiles [164].

TCAs are classified by the nature of the final amine group on the side chain, with the tertiary amines amitriptyline (Elavil), clomipramine (Anafranil), doxepin (Sinequan), trimipramine (Surmontil), imipramine (Tofranil), and lofepramine (Lomont); the secondary amines nortriptyline (Pamelor), desipramine (Norpramin), and protriptyline (Vivactil); and the tetracyclic antidepressants amoxapine (Asendin) and maprotiline (Ludiomil).

TCAs are comparable in efficacy to SSRIs/SNRIs, but their side effect profile makes them seldom used as first-line therapy [7,21,22]. TCAs may initially worsen anxiety or panic symptoms. Due to side effect potential of cardiac arrhythmia, TCAs should be used very cautiously, if at all, in patients with heart problems. Secondary amine TCAs cause less orthostatic hypotension and sedation than tertiary amines, which should be avoided in elderly patients due to the risk for orthostatic hypotension, sedation, cognitive problems, and cardiac effects. The secondary amine nortriptyline is especially effective for elderly patients with moderate-to-severe depression. Clomipramine is particularly effective in patients with obsessive-compulsive symptoms [7,21,22].

Common Side Effects

Anticholinergic and antihistamine activity accounts for many side effects, including dry mouth, blurred vision, reduced gastrointestinal motility or constipation, urinary retention, cognitive and/or memory impairment, and increased body temperature [7,21,22]. Other side effects may include drowsiness, anxiety, emotional blunting (apathy/anhedonia), confusion, restlessness, dizziness, akathisia, hypersensitivity, changes in appetite and weight, sweating, sexual dysfunction, muscle twitches, weakness, nausea and vomiting, hypotension, tachycardia, and arrhythmia. Tolerance to side effects often occurs if treatment is continued. Side effects may also be less troublesome if treatment is initiated with low doses and gradually increased [164,165].

Monoamine Oxidase Inhibitors

MAOIs inhibit monoamine oxidase (MAO), an enzyme that degrades and inactivates 5-HT, norepinephrine, and dopamine. This increases monoamine levels and activity. Earlier MAOIs were irreversible MAO inhibitors, deactivating the enzyme until slowly replenished over a two-week period [166,167]. MAOIs includes phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), linezolid (Zyvox, Zyvoxam, Zyvoxid), moclobemide (Aurorix, Manerix), pirlindole (Pirazidol), and selegiline (Deprenyl, Eldepryl, Emsam).

Evidence Based Practice Recommendation

In general, the American Psychiatric Association recommends that the use of nonselective monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, tranylcypromine, isocarboxazid) should be restricted to patients who do not respond to other treatments.

https://www.guideline.gov/summaries/summary/24158

Last Accessed: June 22, 2017

Strength of Recommendation: I (Recommended with substantial clinical confidence)

Most MAOIs appear broadly effective in a range of depressive and anxiety disorders, and may be more effective than other antidepressant classes in MDD with pronounced anxiety or panic symptoms [7,21,22]. MDD with atypical features may preferentially respond to MAOIs over other antidepressant classes. Although effective, MAOIs are rarely the first- or second-line treatment choice due to serious side effect potential from medication interactions, and dietary restriction. The selegiline transdermal patch (Emsam) used at the lowest strength (6 mg delivered over 24 hours) may lack the dietary restrictions required of oral MAOIs [168]. Moclobemide is a reversible inhibitor of monoamine oxidase type A, greatly improving its safety, including overdose safety (i.e., 20,000 mg ingestion was non-fatal). This drug lacks TCA side effects or SSRI/SNRI sexual side effects; improved libido, erection, or orgasm is more commonly reported [169,170]. Moclobemide may be superior to other antidepressants in treatment-resistant depression [171]. This drug is approved for use in Canada and throughout Europe and Asia, but is not available in the United States [169].

Common Side Effects

With oral ingestion, MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine are consumed, the individual may suffer from hypertensive crisis (Table 2) [166]. If foods containing tryptophan are consumed, hyperserotonemia may result. The amount required to cause a reaction varies greatly from individual to individual and depends on the degree of inhibition, which in turn depends on dosage and selectivity.

Table 2: MAOI INTERACTION TO TYRAMINE CONTENT IN FOOD

None to Little

Moderate

Severe

Avocados

Bananas

Bouillon

Chocolate

Fresh cheeses

Fresh meats

Peanuts

Soy milk

Yeast extracts

Red wine

White wine

Canned beer

Aged cheeses

Aged and fermented meats

Broad (fava) bean pods

Spoiled meats and fish

Soy sauce

Tap beer

Smoked or pickled fish

Sauerkraut

Source: [166]

MAOIs should not be combined with psychotropic drugs or with any other psychoactive substance except under expert care. This includes a wide range of prescribed, over-the-counter, and illicit drugs and nutritional supplements, such as St. John's wort. Common side effects include orthostatic hypotension, weight gain, sexual dysfunction, sedation, headache, and insomnia [166].

Atypical Antidepressants

The atypical antidepressants are diverse in monoamine activity and do not fit the profile of other classes. They include bupropion (Wellbutrin), nefazodone (Serzone), mirtazapine (Remeron), and trazodone (Desyrel). Nefazodone and trazodone block postsynaptic serotonin type-2 receptors and inhibit presynaptic serotonin reuptake. Bupropion inhibits activity of norepinephrine and dopamine transporters, and the active metabolite hydroxybupropion contributes to the drug's effects. Mirtazapine is a potent antagonist at 5-HT2, 5-HT3, alpha2, and H1 histamine receptors. As a group, these agents show low toxicity in overdose and may have an advantage over the SSRIs by causing less sexual dysfunction and gastrointestinal distress [7,21,22].

Each agent has apparent benefits and drawbacks, with some better suited for specific patient populations. Bupropion is associated with a risk of seizure at higher doses, especially in patients with a history of seizure or eating disorders, and should be used cautiously in anxious patients [7,21,22]. It may be more effective for atypical MDD than other antidepressants.

Mirtazapine can be very sedating and promotes appetite and weight increase, which in some patients may be desirable. It has a faster onset of action than fluoxetine, paroxetine, or sertraline, and may be superior to SSRIs in depression associated with severe insomnia and anxiety. Trazodone is also very sedating and is usually used as a sleep aid rather than as an antidepressant [7,21,22].

Common Side Effects

The side effects of atypical antidepressants vary considerably. With bupropion, the most common side effects are agitation, jitteriness, mild cognitive dysfunction, insomnia, gastrointestinal upset, and possible increased risk for seizures [7]. Patients taking mirtazapine may experience dry mouth, sedation, weight gain, and increased serum cholesterol [22]. Sedation is the most common side effect associated with trazodone, followed by cardiovascular side effects (such as orthostasis) and sexual side effects [22]. Finally, nefazodone is associated with sedation, dry mouth, nausea, constipation, orthostasis, visual alterations, and possible increased risk of hepatotoxicity have led to nefazodone being seldom prescribed [7].

CNS Stimulants

Although the role of psychostimulants for antidepressant monotherapy is very limited, they may have a role in the treatment of apathetic major depression in which apathy imperils adherence to treatment and self-care, in patients who cannot tolerate the side effects of standard antidepressants, in terminally ill and medically ill patients with depression, and in elderly patients with complicating medical conditions [9,172,173,174].

This medication class includes amphetamine derivatives such as dextroamphetamine (Dexedrine, Adderal), methylphenidate (Ritalin), and modafinil (Provigil). Methylphenidate inhibits dopamine reuptake by its transporter and, to a lesser degree, norepinephrine reuptake. Dextroamphetamine increases cytosolic dopamine and norepinephrine by blocking vesicular sequestration of dopamine and norepinephrine through inhibition of vesicular monoamine transporter-2 activity [7,21,22].

Common Side Effects

In general, CNS stimulants are associated with side effects related to hyperarousal (e.g., agitation, aggression, tachycardia, restlessness, insomnia). Other potential side effects include headache, anorexia, nausea, and irritability [175]. Modafinil is associated with markedly lower subjective stimulation

CNS stimulants are contraindicated in patients with a history of substance use disorder, with agitated states, and with moderate-to-severe hypertension [175]. In addition, patients who have initiated MAOIs within the last 14 days should not begin therapy with a dopamine agonist.

Pharmacotherapy to Improve Cognitive Dysfunction

Full functional recovery is the overarching therapeutic goal of MDD treatment. Cognitive symptoms of depression critically impact social, occupational, and physical functioning; often persist after mood symptoms have lessened or remitted; and elevate recurrence risk in remitted patients. Functional outcomes modestly correlate with mood symptom outcomes but are strongly influenced by persistent cognitive impairment [176,177,178]. Mood symptoms are a primary focus of depression assessment and treatment, and standard depression pharmacotherapies have minimal benefit on improving cognitive dysfunction.

Vortioxetine has demonstrated efficacy in improving multiple domains of cognitive function, including executive function, processing speed, attention and learning/memory, independent of its effect on core mood symptoms [46,179,180]. Duloxetine can improve learning and memory in patients with MDD [181]. Lisdexamfetamine has some benefit in improving executive function, while single-dose modafinil (200 mg) significantly improved performance on tests of episodic memory and working memory in remitted MDD subjects without side effects [159,182].

Potential Complications with All Antidepressants

Sexual Dysfunction

All commercially available antidepressants are associated with sexual side effects. SSRI/SNRIs show the highest rates of sexual dysfunction, including impaired sexual motivation, desire, arousal and orgasm affecting men and women. Prescribing physicians greatly underestimate the prevalence and patient burden of sexual side effects from antidepressants and other medications [183]. Among antidepressants, prevalence rates of sexual side effects are highest with venlafaxine and SSRIs; moderate with TCAs and MAOIs; low with bupropion, trazodone, nefazodone, mirtazapine, agomelatine, and vilazodone; and lowest with the reversible MAOI moclobemide [184,185]. Compared to spontaneous patient reporting, systematic inquiry increases the rate of identifying sexual side effects by ≥60% [185].

Management of sexual side effects in men includes the use of phosphodiesterase-5 inhibitors such as sildenafil, vardenafil, tadalafil, and avanafil as first-line treatment or switching to bupropion [186]. In women, sexual side effect management considers symptoms, age, and potential hormonal contribution when peri- or post-menopausal.

Increased Suicidality

Several papers documenting an increased risk of suicidal thoughts and behavior with antidepressants, primarily SSRIs, have been published over the past decade. A review of the literature found that antidepressant use, including SSRIs, carried a small short-term risk of inducing suicidal thoughts and suicide attempts in persons younger than 25 years of age, with persons 30 to 40 years of age having a lower risk than those younger than 25 years. This risk should be balanced against the well-known beneficial effects of antidepressants that include reduced suicidal ideation and behavior, particularly in the long term. Clinical decision making should weigh the benefits and potential risks and strive to keep the potential risks of antidepressant treatment to a minimum [187,188].

Discontinuation Symptoms

Antidepressant discontinuation (more appropriately termed withdrawal) symptoms are described by the FINISH mnemonic (flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, hyperarousal), may be experienced by up to 40% of patients when antidepressants are stopped abruptly, and may occur with any antidepressant [158,189,190,191]. SSRI withdrawal symptoms are far more frequent with paroxetine. Common symptoms include dizziness, nausea, headache, confusion, low energy, weakness, sleep disturbance, flu-like symptoms, restlessness, agitation, anxiety, panic, anger and irritability. Less common and more severe symptoms include electric-shock sensations, vertigo, paresthesia, intensified suicidal ideation, aggression, derealization, depersonalization, and visual/auditory hallucinations. Gradual tapering is a reasonable strategy but does not prevent the onset of SSRI withdrawal [192]. SSRI withdrawal syndrome is least likely with fluoxetine and vortioxetine [158].

Symptoms usually begin within five days of treatment cessation or occasionally during taper or after missed doses [193,194]. Symptoms are usually mild and self-limiting but may also be severe and prolonged, particularly following abrupt withdrawal. Some symptoms occur more frequently with specific drugs, such as dizziness and electric shock-like sensations with SSRIs and sweating and headache with TCAs [189,195]. Risk factors include taking antidepressants longer than eight weeks, development of anxiety symptoms during antidepressant initiation (particularly with SSRIs), use of other medications with CNS activity (e.g., antihypertensives, antihistamines, antipsychotics), and a history of previous discontinuation symptoms [195,196]. Outpatients who discontinued escitalopram and developed a withdrawal syndrome (56%) had significantly higher mean escitalopram doses and higher plasma concentrations reflecting delayed clearance of escitalopram, than patients without withdrawal. Escitalopram treatment duration, age, and sex were unrelated to withdrawal risk [197].

Symptoms may be severe enough to interfere with daily functioning, and although a four-week taper is usually suggested, some patients may require longer periods, particularly with paroxetine and venlafaxine [198]. Treatment is pragmatic. If symptoms are mild, reassure the patient that this is a common occurrence and that the symptoms will pass in a few days. If symptoms are severe, reintroduce the original antidepressant or a replacement from the same class with a longer half-life, and taper gradually while monitoring for symptoms. Patients should be emphatically informed that the possible or actual emergence of discontinuation symptoms is not a manifestation of addiction to the antidepressant [70]. SSRI withdrawal can also be approached by switching to a course of fluoxetine, such as 10 mg for several weeks, which is slowly tapered and discontinued [22].

Extended-release venlafaxine has the most severe withdrawal syndrome of any antidepressant. In addition to serotonergic withdrawal symptoms, persistent visual images and sensory disturbances are frequently reported. Electrical shock-like sensations in the brain or the sensation of the brain shivering has also been described. This sensory disturbance, often accompanied by dizziness, headache, and disorientation, is distressing to patients and may persist for months after cessation of the drug [199,200]. Other unexpected symptoms that may emerge include gait difficulties, delirium, suicidal ideation, hypomania or mania. The usual onset of withdrawal is one to four days post-cessation or with dose reduction [201].

The origin and treatment of these highly distressing sensory symptoms are unknown, but case reports describe positive response to noradrenergic agents. Abrupt cessation of extended-release venlafaxine 37.5 mg led to sensations that "felt like the brain was shaking inside the skull," with anhedonia, anxiety, tinnitus, headache, nausea, and increased noise sensitivity. A trial of atomoxetine (40 mg/day), a morepinephrine transporter inhibitor, led to immediate improvement in "brain shivers" two to three hours from the first dose [199]. Post-cessation electric shock-like sensations and dizziness were greatly reduced by low-dose clonidine (0.05 mg twice-daily). These positive responses suggest an underlying noradrenergic rebound mechanism [200].

Medication Interactions

Most antidepressant drugs have clinically significant drug interactions and it is beyond the scope of this course to discuss all possible interactions. Practitioners are encouraged to consult references such as the Physician's Desk Reference or the American Hospital Formulary Service for information about adverse drug-drug interactions.

Strategies to Manage Side Effects

Research has found that prescribing clinicians consistently underestimate both the frequency of side effects and patient discomfort caused by them, with distress caused by blurred vision and constipation being the most underestimated [202]. The suggested management of many side effects consists of either reducing the dose or discontinuing the medication. However, several focused interventions for specific side effects can be implemented when patients are reluctant to discontinue or switch to another medication, when the side effect is mild-to-moderate in severity, or when there is evidence of treatment response (Table 3) [22].

Table 3: TREATMENT OF SIDE EFFECTS ASSOCIATED WITH ANTIDEPRESSANT USE

Side Effect

Treatment

Orthostatic hypotension

Fludrocortisone

Add salt to diet

Dry mouth

Pilocarpine oral rinse

Gum and/or hard candy

Constipation

Hydration

Bulk laxatives

Urinary hesitancy

Bethanechol

Visual changes

Pilocarpine eye drops

Sedation

Bedtime dosing

Modafinil, armodafinil, methylphenidate

Insomnia

Morning dosing

Trazodone or melatonin at bedtime

Myoclonus

Clonazepam

Seizures

Antiepileptic medication

Impaired sexual arousal, erectile dysfunction, orgasm dysfunction

Sildenafil

Tadalafil

Buspirone

Bupropion

Flibanserin

Hyperlipidemia

Statin medication

Akathisia

Beta-blocker

Benzodiazepines

Diaphoresis

Terazosin

Clonidine

Benztropine

Weight gain

Exercise

Other antidepressant with less weight promotion, if necessary

Source: [22]

ADDITIONAL CONSIDERATIONS WITH INITIAL THERAPY

Duration of Initial Treatment

Response trajectories are highly variable following antidepressant initiation for MDD. Some patients show robust improvements within one to three weeks, while others have a slower velocity of symptom change. A sizeable subgroup lacks response, and an underidentified subgroup worsens [149,203].

In predicting substantive response or remission six to eight weeks after treatment initiation, symptomatic improvement by two to three weeks is a modest predictor, but minimal symptomatic improvement by two to three weeks is a far more robust negative predictor of poor or non-response that signals the need to optimize treatment intensity [149,203,204,205].

From a clinical perspective, it is unrealistic to expect patients with MDD and minimal treatment response to continue with their antidepressant beyond two to four weeks. Integrating best evidence with pragmatism, intervention is recommended with insufficient outcome (symptom reduction ≤20%) after two to four weeks of treatment [63,149]. With minimal improvement by two to four weeks, the recommended approach is to increase the dose, if the initial antidepressant is tolerated, or switch to another antidepressant if side effects are problematic [158].

Comparative Discontinuation Rates Due to Side Effects

A meta-analysis of randomized controlled trials involving second-generation antidepressants found that overall discontinuation rates did not differ significantly between SSRIs as a class and bupropion, mirtazapine, nefazodone, trazodone, and venlafaxine. The higher discontinuation rate of venlafaxine versus SSRIs due to side effects (11.5% vs. 8.5%) was balanced by lower discontinuation rates due to lack of efficacy (3.5% vs. 4.4%) [7].

Collaboration with Mental Health Professionals

Primary care providers should consider collaborating with behavioral healthcare providers when caring for patients with depression, especially in the following situations [21]:

- Patient request for psychotherapy

- Severe symptoms and impairment in patient

- High suicide risk

- The presence of other psychiatric condition (e.g., personality disorder, history of mania)

- Suspicion or history of substance abuse

- Clinician discomfort with the case

- Medication advice (psychiatrist or other mental health prescriber)

- Patient request for more specialized treatment

Integrate Measurements into Monitoring and Follow-Up

Measurement-based care refers to the systematic use of measurement tools, such as validated rating scales, to monitor the trajectory of disease course and treatment response, and support clinical decision-making. Using simple rating scales for measurement-based care of depression can improve outcomes such as symptom remission and adherence [63]. Many of the same instruments previously mentioned in this course can be used for this purpose. Among the most widely used instruments are the Inventory of Depressive Symptoms (IDS), the HAM-D, the MADRS, the PHQ-9, and the BDI [22].

Routine monitoring of patient outcomes should go beyond assessing depression symptoms by including the ongoing evaluation of functional impairment and quality of life. These outcomes are more important and relevant to patients, and each may vary independently of symptoms. Assessing functionality should include evaluating social and occupational/educational functioning. Quality-of-life assessments offer the opportunity to more broadly evaluate patient well-being and overall health satisfaction [63]. The use of measurement tools should supplement and not replace clinician judgment [206,207].

HERBAL MEDICATIONS, DIETARY SUPPLEMENTS, AND ALTERNATIVE THERAPIES

Use of complementary medicines by patients with depression is extensive and may exceed 40% [208]. Herbal medications, dietary supplements, and alternative therapies for depression are appealing to many patients because they are perceived as being natural, helpful, and free of the potentially troubling side effects associated with pharmaceutical antidepressant treatment. Patients ambivalent about taking psychiatric medication are also likely to gravitate to these therapy approaches [209].

All patients should be asked if they are taking over-the-counter dietary supplements or herbal medications, to avoid adverse drug-drug interactions. Because many patients use complementary/alternative therapies, clinicians should have a clear understanding of the most common modalities and potential impact on treatment course and outcomes.

Acupuncture

Acupuncture treatment of depression has shown mixed results, with some randomized controlled trials showing a significant treatment effect and others showing no significant difference from controls. Acupuncture may be an option for those who reject convention treatments, for patients with milder depression, or for pregnant or nursing women for whom the risks of pharmacotherapy are greater [21].

S-adenosylethionine (SAMe or Sam-E)

S-adenosylethionine (SAMe) is a naturally occurring compound that is present in most parts of the human body and is involved in immune processes and the metabolism of dopamine, serotonin, and melatonin. Several studies have found that compared with placebo, SAMe is efficacious in oral doses of 800–1,600 mg/day, with side effects that were mild and transient. Overall, parenteral and oral formulations of SAMe are comparable to TCAs in efficacy in the treatment of MDD and are better tolerated. SAMe may also have comparable efficacy to TCAs in subgroups such as postpartum women and patients with HIV [22].

Hypericum perforatum (St. John's Wort)

St. John's wort possesses an SSRI-like mechanism, and although considered a first-line antidepressant in many European countries for mild-to-moderate depression, there is no consensus on its efficacy in MDD. Overall, the data suggests that St. John's wort has efficacy comparable to low-dose TCAs in mild-to-moderate depression, but is better tolerated by patients. However, St. John's wort interacts with many drugs, including other antidepressants, warfarin, oral contraceptives, and antiretroviral, anticancer, and antirejection drugs. With numerous potential drug interactions, St. John's wort cannot be considered a benign agent, and further studies are needed [175,210,211,212,213,214,215].

Inositol

Myo-inositol is a glucose isomer and an essential component of the phosphatidylinositol second messenger system, which is critically linked to several CNS receptor signaling systems [216,217,218,219]. Randomized controlled trials have found inositol treatment superior in efficacy to placebo in the treatment of major depression, panic disorder, and obsessive-compulsive disorder, and equivalent to fluvoxamine 150 mg/day in panic disorder [216,220,221,222]. The effective daily dose is 12–18 grams, and inositol at 18 g/day is free of side effects other than loose stools and drowsiness [223]. These results need replication in larger trials but are intriguing. A 2010 study demonstrated that patients with severe depression receiving repetitive transcranial magnetic stimulation therapy showed significantly elevated myo-inositol levels in the left prefrontal cortex; greater elevation correlated with more robust clinical improvement [224]. Myo-inositol is available in nutritional supplement stores but is largely unknown as an antidepressant and anxiolytic in the United States.

Folate

The use of folate in non-folate-deficient patients with MDD may be most effective as augmentation to SSRIs such as fluoxetine. Persons receiving fluoxetine and folate may have fewer side effects from the SSRI than those receiving fluoxetine alone [22].

Saffron (Crocus sativus L.)

Saffron is a spice that has been used for the treatment of depression in Persian traditional medicine. Its proposed mechanism involves serotonergic, antioxidant, and anti-inflammatory effects [225]. Several well-designed clinical trials have evaluated the efficacy of saffron 30 mg daily over six to eight weeks in mild-to-moderate depression. The results suggest saffron may be more effective than placebo, at least comparable in efficacy to therapeutic-dose imipramine and fluoxetine in reducing depressive symptoms, and without significant side effects. However, this evidence should ideally be replicated in Western populations [226,227,228,229,230].

Omega-3 Fatty Acids

Evidence suggests omega-3 fatty acids may be beneficial in mood disorders. Treatment efficacy in MDD cannot be determined, but subgroups such as children and pregnant women may show meaningful clinical response. Side effects are minimal [22].

Sleep Deprivation

Sleep deprivation therapy involves staying awake through one night and the following day, without any sleep. Although the proposed antidepressant mechanism is poorly understood, clinical trials have consistently shown that around 60% of depressed persons experience moderate improvement to total remission. However, relapse occurs in 50% to 80% of responders within several days of treatment. Persons with mild depression usually experience a worsening of symptoms [209].

Bright-Light Therapy

Bright-light therapy is effective in patients with MDD with season variation (i.e., seasonal affective disorder) and may also be efficacious as monotherapy treatment of MDD without season variation. The correct intensity of light is essential, and should be 3,000 to 10,000 lux-hours of white light, administered at least 30 minutes per day [22].

Botulinum Toxin A Injection

Botulinum toxin A injection is emerging as a novel, effective treatment for MDD. It is widely used in aesthetic medicine to treat glabellar frown lines and has been introduced in the treatment of headaches, muscle pain, and tremor. Patient reports of diminished irritable, depressed, and anxious mood following injection led to its evaluation as treatment of MDD. The first trial of botulinum toxin A (29 units in women, 39–40 units in men) in moderate-to-severe chronic MDD found remission in eight of nine subjects after a single injection in the glabellar region [231]. Functional MRI of patients with MDD shows diminished amygdala responses to negative stimuli after injection of botulinum toxin A, confirming that afferent feedback from the corrugator muscle to the amygdala is reversibly severed [232].

In pooled results from three subsequent randomized controlled trials, single-treatment botulinum toxin A led to significantly greater reductions in mean depression scores (47% vs. 16%), response (52% vs. 8%), and remission (42% vs. 8%) rates than placebo. Age, sex, depression severity, and current antidepressant use were not significantly related to response [232]. One small trial found greater response in patients with higher anxious or agitation levels [233]. Symptom reduction is noted around two weeks post-injection and efficacy wears off by three to six months; maintenance injections every three months can be used for relapse prevention. Use of botulinum toxin A for MDD is currently in phase 3 clinical trials and is off-label [232].

STRATEGIES FOR INADEQUATE RESPONSE TO INITIAL THERAPY

If a patient fails to adequately respond to an initial antidepressant and/or psychotherapy trial, the clinician should consider adjusting the treatment plan, re-evaluating the initial diagnosis, and/or optimizing the prescribed therapy. If the patient remains unresponsive to treatment, referral to a psychiatrist may be indicated.

Optimize Treatment

Optimizing treatment helps to ensure the patient is receiving the most potential benefit from their initial antidepressant. This involves optimizing the dosage and adherence to treatment.

Increase the Dose of the Initial Antidepressant

Evidence Based Practice Recommendation

The American Psychiatric Association recommends optimizing the medication dose as a reasonable first step for patients treated with an antidepressant who have not responded fully to treatment if the side effect burden is tolerable and the upper limit of a medication dose has not been reached.

https://www.guideline.gov/summaries/summary/24158

Last Accessed: June 22, 2017

Strength of Recommendation: II (Recommended with moderate clinical confidence)

There is substantial evidence that many patients receive sub-therapeutic doses. When the antidepressant is tolerable but partial or no response is shown by three to four weeks, increase the dose by increments to the highest recommended dose [158]. SSRI dose escalation is supported by a 2016 meta-analysis that found greater response in high-dose ranges, with a plateau at doses greater than 250 mg imipramine-equivalent. This benefit is somewhat offset by decreased high-dose tolerability [234].

Enhance Treatment Adherence

Patient nonadherence can result in nonresponse to the optimal antidepressant regimen, and intolerance of side effects strongly influences therapy nonadherence [235]. Poor adherence is a major problem for patients receiving antidepressant treatment, with discontinuation rates ranging from roughly 30% in clinical trial settings to as high as 60% in clinical practice [236,237]. In an evaluation of patient adherence to antidepressant medications, 28% had discontinued treatment within the first month and 51.2% had stopped their antidepressant medication by the fourth month [238]. At all timepoints, roughly 64% of patients cited side effects as the reason for stopping their medication.

Compared with usual care, support programs (i.e., a collaborative care model) that educate patients on the value of medication adherence and the potential side effects of antidepressants and provide follow-up to ensure continued compliance have been found to improve the efficacy of depression treatment (Table 4) [239,240]. Other research has shown that patients receiving five specific instructions were significantly more likely to continue their medication through the first month of therapy [157,238]:

- Take the antidepressant daily.

- Antidepressants must be taken for at least two to four weeks to see a noticeable effect.

- Continue to take the antidepressant even if you feel better.

- Do not stop taking antidepressants without checking with your healthcare provider.

- Follow instructions to contact your healthcare provider when questions arise about antidepressants.

Table 4: EVIDENCE-BASED INTERVENTIONS TO IMPROVE PATIENT ADHERENCE TO ANTIDEPRESSANT MEDICATION

Intervention

Overview

Patient education

Inform patient of the causes and course of depression, and the effects, duration, and side effects of treatment.

Patient-provider empathy/alliance

Establish a good relationship between patient and provider, with an emphasis on communication, consensus, and understanding.

Clinical management strategies

Provide advice regarding a standardized approach to taking medications and compliance, and allow for frequent follow-up visits, especially during initial phases of treatment.

Simplicity of treatment

Minimize the number and doses per day of medication.

Active management of side effects

Inform patient about side effects, monitor their occurrence, provide reassurance, and adjust the treatment if needed.

Behavioral feedback

Help patients incorporate treatment into daily routine (e.g., modify schedule to fit medication routine, behavioral reminders, pill boxes, easy-to-read prescription labels).

Preference for SSRIs

When possible, use SSRIs due to greater tolerability relative to TCAs.

Physician training

Improve skills on caring for patients with depression and patient adherence to treatment.

Source: [237]

Re-Evaluate the Diagnosis

Most patients with MDD have comorbid conditions that can contribute to disease burden and interfere with treatment response [241]. Especially when undiagnosed, MDD with highly anxious features, comorbid panic disorder, social anxiety disorder, or obsessive-compulsive disorder is strongly predictive of poor medication response, side effect intolerance, treatment discontinuation, and worse overall prognosis. Alcohol or substance use disorder contributes to poor treatment response; in these cases, involve addiction specialists as needed [236]. A behavioral health provider should be involved if a personality disorder is present [242]. Patients with bipolar disorder may require a different treatment approach, and hypomanic, mixed, or manic histories may not be apparent during the initial evaluation [21].

Patients with chronic subtypes of depression (i.e., chronic MDD, double depression, recurrent MDD) may take longer to respond to treatment; clinicians or patients may assume non-response and prematurely discontinue treatment. Different depression subtypes may respond preferentially to various antidepressants [243].

Adjust the Treatment

Options for patients lacking benefit from their initial antidepressant include switching antidepressants, switching to or adding psychotherapy, and adjunctive strategies (i.e., adding a second medication). The decisions to switch or add medications should be individualized and based on clinical factors [158]. Clinicians may consider switching to another antidepressant when [158]:

- It is the first antidepressant trial.

- Side effects are poorly tolerated.

- Minimal or no response (i.e., <25% improvement).

- There is more time to wait for a response (e.g., less severe, less functional impairment).

- Patient prefers switching to another antidepressant.

An adjunctive medication may be added when [158]:

- There have been two or more antidepressant trials.

- The initial antidepressant is well tolerated.

- There is partial response (i.e., >25% improvement).

- There are specific residual symptoms or side effects to the initial antidepressant that can be targeted.

- There is less time to wait for a response (e.g., more severe, more functional impairment).

- Patient prefers to add on another medication.

Switch to Another Antidepressant

Lack of response to one first-line antidepressant does not preclude potential benefits from other antidepressants, but the value of switching between classes or within classes of antidepressants is debatable. Switching to an antidepressant with evidence of superior efficacy is recommended over switching to a lower-efficacy antidepressant based on it being in a different class [158]. Among switching strategies for poor initial SSRI response or tolerance, switching to venlafaxine seems most effective [112].

Combining or Switching Antidepressants and Psychotherapy

Switching from an antidepressant to psychotherapy or vice versa appears useful for non-responders to initial treatment [244]. The addition of CBT or another medication can result in similar rates of improvement, although the addition of medication may result in a more rapid response [245].

Psychotherapy may provide better outcomes on adjustment and functional measures such as mood, suicidal ideation, work, and interests. Medication treatment may be superior on vegetative symptoms such as sleep [246].

Improvement with initial treatment with psychotherapy is typically slower than with pharmacotherapy. A decision regarding progress with psychotherapy and the need to change or augment this treatment modality may require 8 to 10 weeks before evaluation [21,247]. If a patient has received psychotherapy and not responded, evaluate the treatment and consider another type.

Augmentation

Patients with MDD often prefer augmentation (add-on) to switching if with partial improvement is achieved with the initial agent [248]. Standard antidepressants are frequently used as add-on therapy to enhance efficacy. For example, combining a TCA and an SSRI may be helpful for some patients, but the TCA dose should be adjusted because SSRIs may increase TCA levels [249,250]. Combining an SSRI, SNRI, or TCA with a presynaptic a2-autoreceptor antagonist (e.g., mirtazapine, trazodone) has shown significantly greater benefit than other combinations, with dosage differences accounting for about 50% of the total difference in treatment effect. Tolerability, as measured in patient dropout, was lower than expected with this combination [251].

Adverse effects are higher in combination pharmacotherapy, and combining antidepressants at treatment initiation is not recommended [158]. In patients lacking response to their initial or switched standard antidepressant, evidence indicates that standard monoamine antidepressants are not sufficient for many patients, and that other mechanistic targets are needed [149].

Aripiprazole has been found superior to switching antidepressants in patients with current depressive episodes despite adequate antidepressant dosage, and in patients with antidepressant non-response [252]. Brexpiprazole is another atypical antipsychotic effective as add-on therapy; aripiprazole and brexpiprazole are approved by the U.S. Food and Drug Administration (FDA) as augmentation therapies in MDD [149,192].

The evidence base for lithium and triiodothyronine shows efficacy, but mainly involves studies that combined these agents with TCAs or MAOIs [149]. Methylphenidate has mostly shown mixed results in reducing depressive symptoms [253,254].

Modafinil has not shown consistent efficacy in core MDD symptoms, but it has demonstrated improvements in symptoms/dimensions of psychopathology highly relevant to patient function, including fatigue, apathy, anhedonia, amotivation, and cognitive impairment [255]. Adverse effects have not differed from placebo [159,256].

Lisdexamfetamine, a dextro-amphetamine prodrug, showed some evidence of efficacy as an adjunctive agent for partial SSRI responders in two placebo-controlled randomized controlled trials [182,257]. Pramipexole is a dopamine receptor agonist and a standard therapeutic in Parkinson disease. Preliminary evidence shows some benefit in patients with MDD lacking response to multiple antidepressant regimens [258,259].

The optimal duration of add-on therapy is not known, but it seems prudent that patients who are tolerating treatment and achieving therapeutic objectives should continue for at least 6 to 12 months with ongoing reassessment, with indefinite continuation for many [149].

7. TREATMENT-RESISTANT DEPRESSION

Most definitions of treatment response compare changes in depression rating scale scores between pre-treatment and follow-up. Standardized rating scales such as the MADRS and HAM-D are widely used to quantify treatment response [243]. As discussed, the definition of antidepressant response falls into four categories [21,113]:

- Remission: The absence of depressive symptoms or minimal symptoms (HAM-D score ≤7)

- Response: A 50% or greater reduction in symptoms

- Partial response: A 25% to 50% reduction in symptoms

- Nonresponse: The absence of meaningful response (symptom reduction ≤25%)

Standard antidepressants fail to produce adequate response in 30% to 50% and remission in up to 70% of patients with MDD [260,261,262]. Partial response, instead of full remission, leaves patients with impairing residual symptoms and high risk of relapse. Each relapse increases symptom severity, decreases treatment response, and heightens risk of treatment-resistant MDD [263].

Treatment-resistant depression is a problem increasingly encountered by primary care and mental health providers. Contributors to treatment-resistant depression include illness severity, medical and psychiatric comorbidity, and the limitations of FDA-approved drug options. The definition of treatment resistance lacks consensus, but the most common definition is inadequate response to two or more antidepressants. This does not consider adjunctive strategies or distinguish patients with partial versus non-response [158,180].

In addition to augmentation strategies discussed, a diverse and growing range of interventions are available as options for treatment-resistant depression. Most engage novel therapeutic targets.

OPTIONS FOR TREATMENT-RESISTANT DEPRESSION

Bright-Light Therapy

As mentioned, use of bright-light therapy for treatment of major depression with a seasonal specifier (seasonal affective disorder) is well established [264,265]. There is also evidence supporting its use for additional types of depressive symptom patterns, including non-seasonal depression, milder variations of seasonal depressive patterns, and depression in pregnant and postpartum women [266,267,268,269]. Bright-light therapy may quicken and enhance the effects of antidepressants [270]. The interaction between light intensity and duration of exposure requires two hours daily with 2,500 lux, one hour with 5,000 lux, and 30 minutes daily with 10,000 lux for efficacy [271]. Light therapy must also use equipment that eliminates ultraviolet frequencies.

Neurostimulation Therapies

The limitations of standard antidepressants, frequent treatment resistance, and the paradigm shift in psychiatry away from specific neurotransmitter focus and toward an integrative neural network perspective has prompted the development of novel depression treatment approaches, such as neurostimulation therapy. Neurostimulation therapies include a range of techniques that deliver electrical or magnetic stimulation to specific brain region targets for the treatment of refractory psychiatric and pain conditions. Neurostimulation efficacy in neurologic disorders led to their introduction in psychiatry. In addition to ECT, several others are now FDA-approved for use in MDD and related disorders.

The dorsolateral prefrontal cortex is a common brain stimulation target in patients with MDD. Its normal regulatory function of control over stress and emotion reactivity is thought to be hypoactive in MDD. The dorsolateral prefrontal cortex and rostral anterior cingulate cortex areas are closely inter-connected; decreased activity in these frontal areas accounts for apathy, psychomotor slowness, and impaired executive functioning common in patients with MDD [272,273,274].

Electroconvulsive Therapy

ECT remains established as a potent and rapidly acting treatment for severe or refractory MDD and is considered unrivaled among standard options for rapidly inducing antidepressant effects. ECT is effective as acute treatment, but multiple treatments are required and many who respond experience symptoms again within six months [275]. ECT generates electrical stimuli for seizure induction through electrodes applied to the scalp, with the patient in general anesthesia and pre-medicated with a muscle relaxant. Clinical outcomes are highly influenced by electrode placements, electrical intensity, and pulse width [276]. Seizure-induced changes in neurotransmitter activity, neuroplasticity, and functional connectivity account for its effects. ECT also increases brain-derived neurotrophic factor, which may promote neuroplasticity and contribute to the antidepressant effect [276,277].

As first-line treatment, ECT is used for severe melancholic, catatonic, psychotic, or refractory depression and for patients who refuse to eat or drink, have very high suicide risk or severe distress, pregnant women with severe depression, or who have a previous positive ECT response [65,275,278]. A large study reported 95% remission in study completers [279].

Full ECT response requires at least four to six sessions delivered two to three times per week. Twice weekly ECT requires longer treatment duration, but more than three treatments per week is not recommended due to the greater cognitive side effect risk [276]. Relapse rates are greatest in the first six months post-ECT (37.7%). Even patients with maintenance ECT show high relapse rates at one year (51.1%) [280]. Severity of treatment resistance predicts poor ECT response [281,282].

Adverse Effects

Headaches (45%), muscle soreness (20%), and nausea (1% to 25%) during ECT are transient and treated symptomatically; 7% of patients with MDD switch into a manic or mixed state [276]. Cognitive impairment includes transient post-ECT disorientation, retrograde amnesia (i.e., difficulty recalling information learned pre-ECT), and anterograde amnesia (i.e., difficulty retaining information learned post-ECT). Mild, short-term memory and cognitive impairments are common during, and just after, ECT [278]. Within two to four weeks, impaired anterograde memory usually returns to normal or may improve from pre-ECT levels [283]. Retrograde impairment can persist for prolonged periods [284]. Most distressing to some patients is loss of autobiographic memory recall, infrequently reported to persist beyond six months [278]. ECT lacks absolute contraindication, but increased safety risk is associated with space-occupying cerebral lesion, increased intracranial pressure, recent cerebral hemorrhage, or aneurysm [276,277].

Vagus Nerve Stimulation

Vagus nerve stimulation uses an implantable device to provide intermittent stimulation to the left vagus nerve (80% afferent to the CNS) [21]. It received FDA approval for treatment-resistant depression in 2005 due to the lack of approved drug treatments and concerns over the long-term efficacy and safety of ECT [285].

Controlled studies with follow-up six months or longer have found significant improvements in depressive symptoms that were often sustained over time, with relapse rates relatively low [286]. Long-term vagus nerve stimulation can lead to significant side effects, including decreases in airway flow and respiratory effort and laryngopharyngeal dysfunction [287]. Given the profound negative impact of treatment-resistant depression and lack of durable response in some patients, vagus nerve stimulation may be a useful option [288]. In a 2017 trial, patients with treatment-resistant MDD and four or more failed depression treatments (including ECT) received vagus nerve stimulation or treatment as usual and were followed five years. Response was a ≥50% decrease in MADRS score at any follow-up visit. Subjects who received vagus nerve stimulation (compared with usual treatment) had more severe treatment-resistant depression on several dimensions [289]. Vagus nerve stimulation led to greater five-year cumulative response (67.6%) and remission (43.3%) rates compared with usual treatment (40.9% and 25.7%, respectively). However, vagus nerve stimulation response often required 12 or more months to appear [289].

Deep Brain Stimulation

With deep brain stimulation, an electrode is surgically implanted to stimulate the subgenual cingulate gyrus with high-frequency impulses to reduce depressive symptoms [21]. Deep brain stimulation is invasive and carries the risk of infection, hemorrhage, and other surgical complications. Stimulation-induced adverse effects such as facial contractions, facial paresthesias, olfactory phenomena, anxiety, and mood fluctuations have been reported, particularly at higher levels of stimulation [290].

Most clinical improvement shows delayed onset; one trial in patients with treatment-resistant depression reported remission rates of 27%, 24%, and 37% at three-month, six-month, and two-year follow-up, respectively [291]. Deep brain stimulation can increase the risk of suicide ideation, attempts, and death, strongly indicating that patients should be pre-screened for suicide risk and monitored closely for suicidal behavior pre- and postoperatively [292]. Deep brain stimulation is investigational for treatment-resistant depression and is reserved for use in patients with severe refractory psychiatric, neurologic, or chronic pain conditions [276,290].

Transcranial Magnetic Stimulation

Repetitive transcranial magnetic stimulation delivers high-intensity magnetic pulses to the cortex through a stimulating coil placed to the forehead [293,294]. It is a first-line MDD treatment in patients with one or more failed antidepressant trial [276]. Efficacy in treatment-resistant depression was established using stringent criteria; analysis of 23 trials found significantly greater efficacy and effect size for repetitive transcranial magnetic stimulation over sham [295]. In randomized clinical trials, 20 to 30 sessions over four or more weeks achieved 40% to 55% response and 25% to 35% remission rates [296].

The most frequent side effects are transient scalp pain (40%) and headache (30%). Both diminish with repeated treatment and respond to over-the-counter analgesics. The cognitive safety profile is benign. Seizures are the most serious side effect, but fewer than 25 cases have been reported worldwide [276,337]. Repetitive transcranial magnetic stimulation is contraindicated in patients with any metal or metallic hardware in the head (except the mouth), with a history of seizures, and who take medications that lower seizure threshold [276,297].

Transcranial Direct-Current Stimulation

A sham-controlled trial randomized patients with MDD to escitalopram (20 mg/day) or prefrontal transcranial direct-current stimulation for 10 weeks. With mean decrease in HAM-D score from baseline, both treatment groups were superior to placebo, but transcranial direct-current stimulation was inferior to escitalopram. New-onset manic switch during transcranial direct-current stimulation therapy is a concerning adverse event not previously reported in MDD studies [277].

Magnetic Seizure Therapy

Magnetic seizure therapy uses focused brain stimulation (generally of the right frontal area) to induce a focal seizure. It intends to produce the efficacy of ECT without the cognitive side effects by sparing the hippocampus from seizure activity [21]. A meta-analysis of 1,092 patients with treatment-resistant depression found response and remission rates for active vs. sham magnetic seizure therapy of 25% and 17%, versus 9% and 6%, respectively [298]. Magnetic seizure therapy add-on to SSRI treatment in treatment-resistant depression improves outcome , but more data is needed before it can be considered a first-line therapy for treatment-resistant depression [298,299].

Pharmacotherapies

Ketamine

Ketamine is an N-methyl-D-aspartate receptor (NMDA-R) antagonist that was approved for use as an anesthetic in 1970. Demonstration that a single IV dose in patients with treatment-resistant depression reliably produced rapid, robust antidepressant effects for one week was a breakthrough discovery for research and a turning point for patients for whom all other treatment approaches had failed [300]. The short-term efficacy of ketamine treatment of refractory MDD and bipolar depression is now established; over a dozen placebo-controlled trials have shown that patients with refractory MDD or bipolar depression have significantly greater response, remission, and depressive symptom reduction to single-dose IV ketamine than placebo from 40 minutes through days 10 to 12 post-treatment [301,302]. The approach has become standardized, using a sub-anesthetic dose: 0.5 mg/kg IV over a 40-minute infusion. In a 2015 analysis, ketamine was designated as one of two psychiatric treatments that had highest potential impact on patient outcomes. This designation was based on the serious unmet need for fast-acting, well-tolerated antidepressants with efficacy in refractory MDD and bipolar depression [48].

Substantial interest and optimism among patients, families, patient advocacy groups, and clinicians has been generated by clinical reports of unique antidepressant effects with ketamine and frequent media coverage of potential ketamine treatment benefits. Demand for clinical access to ketamine treatment is rapidly escalating, and a growing number of clinics and practitioners are now offering various forms of ketamine treatment for mood and anxiety disorders throughout the United States [303]. However, many in the field suggest greater caution, and concerns that enthusiasm and desperation of patients and families may be leading to ketamine used in ways that are not yet supported by existing evidence. Others note the lack of large-scale or long-term studies of ketamine treatment in refractory MDD [303].

Rapastinel

Rapastinel is an NMDA-R partial agonists with robust cognitive enhancement and rapid, long-lasting antidepressant effects. This drug comes as a pre-filled IV syringe, administered in less than one minute. After one injection, therapeutic effects appear within two hours and last up to seven days. Rapastinel is well-tolerated, and antidepressant effects last up to 10 weeks with repeat dosing. The drug has no psychotomimetic effects, may be neuroprotective, and may enhance aspects of learning and memory. The long-lasting therapeutic benefits are explained by significant effects on metaplasticity processes in the medial prefrontal cortex and hippocampus [304,305].

Buprenorphine

Opioids were widely used as depression treatment from roughly 1850 until 1956, when they were replaced by standard antidepressants. Their antidepressant potential has rarely been studied in the past 60 years, but this seems to be changing. The synthetic opioid buprenorphine is a partial mu opioid receptor agonist and kappa opioid receptor antagonist. It is safer in overdose with substantially less euphoria than traditional opioid analgesics such as morphine and oxycodone. A small, open-label study in 1995 hinted that buprenorphine might have benefit in refractory depression [306]. These preliminary results are begging for replication in larger studies, but follow-up studies have not been conducted due to the stigma surrounding opioid drugs and their association with addiction, and governmental restrictions.

Celecoxib

The cyclooxygenase-2 inhibitor celecoxib has demonstrated significant reductions in depressive symptoms compared to placebo as an SSRI add-on in MDD treatment. The decrease in depressive symptoms begins after the first week. However, celecoxib and all other nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with risk of serious cardiovascular events [307].

Statins

Two studies compared statins to placebo as add-on therapy to fluoxetine in the treatment of MDD. In one trial, 30 mg/day lovastatin for six weeks improved antidepressant effects compared to placebo [308]. The other trial found simvastatin 20 mg/day for six weeks significantly decreased depressive symptoms but remission did not differ from placebo [309].

Statins have relatively few side effects; the most dangerous—rhabdomyolysis—is a very rare event. Statins are primarily used in prevention of cardiovascular events but may have a more favorable benefit/risk balance than other drugs, such as NSAIDs, considering the high cardiovascular comorbidity in persons with depression [310].

Silexan

Silexan is a substance derived from Lavandula angustifolia flowers that increases extracellular serotonin levels. Approved in Germany for the treatment of restlessness related to anxious mood, its antidepressant effects were tested in a randomized controlled trial of 318 patients with mixed anxiety and depressive disorder. Silexan (vs. placebo) significantly reduced MADRS and Hamilton Rating Scale for Anxiety (HAM-A) scores. Antidepressant effects were noted after 2 weeks, became statistically significant at 4 weeks, and remained significant through the 10-week trial [124,307].

Psilocybin

Psilocybin is a classical psychedelic and naturally occurring alkaloid found in the Psilocybe genus of mushrooms [311]. Its potential efficacy in the treatment of depression is a recent focus of research interest.

The feasibility, safety, and efficacy of open-label psilocybin were studied in 12 patients with treatment-resistant depression (2 to 13 failed antidepressant trials). All patients received 10-mg (low-dose) oral psilocybin, 25-mg (high-dose) psilocybin one week later, and psychologic support during all sessions. Relative to baseline, depressive symptoms were markedly reduced one week and three months after high-dose treatment. Remission was achieved by 67% at one week and 42% at three months. Marked and sustained improvements in anxiety and anhedonia were also noted. Psilocybin was well tolerated by all patients, without serious or unexpected adverse events [311].

Two psilocybin treatment studies in patients with life-threating cancer and high levels of depressive and anxious distress were published in 2016. One trial compared low-dose psilocybin (0.3 mg/kg) with niacin placebo, and the other trial compared low-dose (1 or 3 mg/70 kg) and high-dose (22 or 30 mg/70 kg) psilocybin [312,313]. Patients in all sessions were accompanied by trained therapy support. Both studies reported significant improvements in depression and anxiety scores, measures of spiritual well-being, emotional distress related to the cancer, and quality of life. Immediate post-treatment gains were sustained for six-month study durations by 60% to 80% of subjects. These studies confirmed psilocybin could be given safely without significant adverse effects in a controlled environment with trained therapists [312,313].

8. PERINATAL DEPRESSION

Approximately 5% to 14% of women experience significant mood or anxiety symptoms during pregnancy, and the goal of perinatal treatment is to minimize the risks of both depression and its treatment to the mother and child [314,315]. Misperception about treatment risk can result in the termination of otherwise wanted pregnancies or avoidance of needed pharmacotherapy. By informing patients of both the nature of medication risks and the risks of untreated illness, providers can help patients reach their own educated decisions.

For depressed pregnant women, both continuous SSRI exposure and continuous untreated depression are associated with preterm birth rates in excess of 20% [316]. The potential impact of untreated maternal depression on pregnancy outcome and infant health include preterm birth and low birth weight, birth defects, developmental delay and cognitive impairment, behavioral and emotional maladjustment, and poor maternal health behaviors such as smoking and alcohol and substance use, which secondarily affect birth outcome [317].

MILD-TO-MODERATE DEPRESSION

Several non-drug therapies effective in mild-to-moderate depression are available for pregnant and breastfeeding women, including interpersonal psychotherapy, bright-light therapy, and CBT [269,318,319]. Interpersonal therapy is efficacious in postpartum depression and can improve functioning for six months postpartum [319]. While these interventions are more efficacious than routine care for postpartum depression, there is little indication of superiority for any one intervention [319]. Other nonpharmacologic treatments that may be effective include acupuncture, progressive relaxation, music therapy, sleep deprivation, and exercise [317]. Empirical support for nutritional or supplemental omega-3 fatty acids is lacking, although they pose little to no risk of adverse effects [320]. Progesterone is ineffective in postpartum depression and may intensify depressive symptoms in some patients [317].

SEVERE DEPRESSION

In many circumstances, the risks of untreated illness may outweigh the potential negative effects of certain antidepressant medications. Partial SSRI treatment during pregnancy to reduce the risk of preterm birth is not recommended, as inadequate dosing does not successfully treat the depression. When possible, medication choice should be based on what has worked previously and the risk/benefit of continuing the current medication during pregnancy and/or postpartum. Optimal dosing and safety is best ensured by consultation with a health professional with perinatal expertise.

PHARMACOLOGY AND PERINATAL DEPRESSION

The largest amount of reproductive safety information is available for TCAs and SSRIs (Table 5). Available pregnancy data have found no evidence that fluoxetine, sertraline, fluvoxamine, venlafaxine, or bupropion are associated with an increased risk of major congenital malformations. In 2006, the FDA warned that paroxetine was associated with increased risk for cardiovascular malformations compared to other antidepressants. Therefore, women of childbearing age taking paroxetine should be advised of the potential risk, and other treatment options should be considered [175,321,322].

Table 5: FDA RATINGS OF ANTIDEPRESSANT PREGNANCY RISK

Rating

Definition and Examples

A

No currently available antidepressant medications are rated A, which would indicate a failure to demonstrate risk to the fetus in well-controlled studies of pregnant women.

B

Maprotiline—no evidence of risk in humans, and either animal findings show risk but human findings do not, or animal findings are negative if no adequate human studies have been performed.

C

Amitriptyline, amoxapine, bupropion, protriptyline, sertraline, trazodone, trimipramine, and venlafaxine—risk cannot be ruled out, and although human studies are lacking and animal studies are either positive for fetal risk or are lacking, potential benefits may justify the potential risks.

D

Imipramine, nortriptyline, and paroxetine—positive evidence of risk. Investigational or postmarketing data show risk to the fetus. The potential benefits may outweigh the potential risks, and if needed in a life-threatening situation or a serious disease, the drug may be acceptable if safer drugs cannot be used or are ineffective.

X

No currently used antidepressant medications are rated X, which would indicate that use is contraindicated in pregnancy due to animal or human studies that conclude that fetal risk clearly outweighs potential benefits.

Source: [21]

The use of SSRIs before the 20th week of gestation has not been associated with persistent pulmonary hypertension, but use of SSRIs in late pregnancy has shown a small but significantly increased risk of persistent pulmonary hypertension [323,324,325]. Several case reports document a perinatal syndrome in infants (e.g., jitteriness, irritability, bowel obstruction, urinary retention) with maternal use of TCAs and most of the SSRIs, although it is unclear whether the neonates were exhibiting symptoms of SSRI toxicity or SSRI withdrawal at birth. Also, they may have been more irritable and difficult to settle due to maternal depression and anxiety [314,323,326,327]. There is a lack of evidence suggesting that reducing or discontinuing antidepressants in late pregnancy will reduce adverse neonatal effects [323].

Women with a history of depression who are planning to become pregnant should carefully consider the choice and timing of an antidepressant [326]. Although SSRIs taken during pregnancy may be associated with adverse neonatal effects that are mostly mild and short-lived, women with a history of recurrent or severe depression who discontinue antidepressants during pregnancy increase the risk of potentially adverse outcomes for both the mother and fetus/infant. The minimum effective antidepressant dose to achieve and maintain remission should be used throughout pregnancy in women who continue their medication, and these patients should be monitored on an ongoing basis [323]. Women who discontinue medication relapse significantly more frequently over the course of their pregnancy compared with women who maintain their medication [328]. The decision to continue treatment during the pregnancy should balance the risks and benefits to the mother and child and should be made on a case-by-case basis [21].

LACTATION

The Academy of Breastfeeding Medicine Protocol Committee suggests that TCAs and SSRIs are relatively safe, but they should only be used when clearly needed. Assessments weighing the potential benefits with the potential risks to the nursing infant should be performed in all cases [329]. Also, the mother-infant pair should be monitored for the emergence of adverse effects or complications [330]. Regarding the use of specific medications during lactation, several observations and recommendations have been made [21,331,332]. Sertraline, paroxetine, nortriptyline, and imipramine are the most evidence-based medications for use during breastfeeding; nortriptyline, paroxetine, and sertraline may be preferred choices in breastfeeding women. The lack of adverse effects among infants exposed to fluoxetine justifies its use, especially if prescribed during the pregnancy or if there is a preferential response history. However, its use during breastfeeding is not recommended by the manufacturer [175]. The TCA doxepin should be avoided due to a case report of infant respiratory distress [175]. Data on citalopram, fluvoxamine, bupropion, and venlafaxine are more limited and their use cannot be recommended during breastfeeding [175]. One study evaluating the potential consequences of TCA exposure through breast milk followed exposed children through preschool age and found that exposed children were developmentally similar to non-exposed children. No similar studies have been performed with SSRIs [21].

9. SUICIDE

For the past 50 years, suicide prevention research has focused on identifying demographic and clinical factors that reliably predict suicide risk. Examining population-level data, researchers found clinical and demographic factors that correlated with suicidality [333]. These variables, including depression, most psychiatric disorders, trait impulsivity, family history of suicide, previous suicide attempts, and current suicidal ideation, became established as suicide risk factors [334,335]. Suicide risk assessment intends to reduce clinician uncertainty of short-term patient risk of suicide so patients at imminent risk can receive rapid intervention [336,338]. Decades-old convention holds that assessing suicide risk should culminate in a probability judgment of "low," "moderate," or "high" risk level [333]. Obtaining larger amounts of patient information was believed to be the best means to identify risk factors and reduce uncertainty [338,339].

However, there is evidence that challenges these foundational assumptions of suicide, including risk factors and risk stratification, long-standing organizing principles of clinical suicide prevention. A 1983 study first identified the limitations of risk factors in suicide prediction, finding that 96.3% of high-risk suicide predictions were false positives and more than 50% of suicides occurred in low-risk patients (false negatives) [340]. Subsequent studies confirmed these results, demonstrating the clinical reliance on traditional suicide risk assessment, risk factors, and scales were largely overstated [341,342,343,344,345,346,347,348].

Traditional suicide risk factors are nonspecific, common, non-modifiable, and to varying degrees represent underlying vulnerabilities. These risk factors demonstrably predict lifetime and 12-month suicide ideation, but fail to predict suicide completion, suicide, or movement from ideation to suicide behavior [336]. Many patients have elevated risk profiles, but their lifetime odds of suicide are remote. No study using population-based risk factors or combinations, rating scales, or assessment instruments has successfully predicted suicide in individual patients [334,335,349,350,351]. The failure to improve suicide prevention and the limited benefit of suicidality interventions suggest inadequate understanding of the mechanisms leading to suicidal behavior [352].

Acute suicide risk is now thought to result from recent psychosocial stressors superimposed on non-modifiable (traditional) risk factors, with psychosocial stressors the precipitants or "triggering events" to suicidal behaviors [349,353]. Warning signs, or the acute patient response to precipitants, are considered more useful to assess than risk factors [353]. The strongest suicide risk factor—previous suicide attempts—is a static, non-acute factor with low predictive power [354]. While nearly half of suicides made previous attempts, only 5% to 15% of attempters ultimately die by suicide [355,356]. This seems a robust predictor, but with distribution of risk across the lifespan, even this risk factor does little to inform of acute patient risk level in any given contact [354].

EPIDEMIOLOGY

Suicide rates declined 24% between 1977 and 2000, but then increased 28% between 2000 and 2015. From 1999 to 2015, approximately 600,000 Americans died by suicide [357,358]. In 2015 alone, 44,193 Americans died of suicide, an average of 121 suicides every day. Suicide is the 10th leading cause of death, and the annual cost of suicide in the United States is $44 billion [359,360].

White individuals accounted for 90% of all suicides in the United States in 2015. Suicide is especially prevalent among white boys and men; the suicide rate in this population is 2.5 times greater than that for nonwhite boys/men. White men 45 to 64 years of age had the highest suicide rate and number of any demographic in 2015 [361,362]. White girls and women also have markedly higher suicide rates than their nonwhite counterparts [360].

In 2015, suicide rates by race/ethnicity were highest in American Indians/Alaska Natives, followed by whites, Asians and Pacific Islanders, Hispanics, and Blacks [357,358]. Overall, suicide rates are highest in persons 45 to 64 years of age and 85 years of age or older and lowest in persons 15 to 24 years of age, despite suicide being the second leading cause of death in this age group [360]. American Indians/Alaska Natives show a pattern of suicide by age distinct from other racial/ethnic groups; in this group, the highest rates occurred in persons aged 15 to 29 years of age [364].

Suicide rates in urban and rural areas diverged during 1999–2015, especially after 2008. This could reflect more prevalent social isolation, financial hardship, access to lethal means (guns), and limited access to mental health care [357].

Aside from measures of suicide-related deaths, various levels of suicidality among adults have been studied, with suicidal thoughts, plans, and attempts quantified (Table 6). Among adults with past-year suicidal ideation, around 1 in 4 plan suicide and 1 in 7 attempt suicide. There are 25 attempts for every suicide, increasing to 100 to 200 attempts per suicide in individuals 15 to 24 years of age and decreasing to 4 attempts per suicide among the elderly. For each male attempt are three female attempts, and there are 3.3 male suicides for each female suicide [360].

Table 6: SUICIDALITY IN ADULTS IN THE UNITED STATES, 2015

Demographic Group

Past-Year Suicidal Thoughts

Past-Year Suicide Plans

Past-Year Suicide Attempts

All adults

9.8 million (4.0%)

2.7 million (1.1%)

1.4 million (0.6%)

18 to 25 years of age

8.3%

2.7%

1.6%

26 to 49 years of age

4.1%

1.1%

0.5%

50 years of age and older

2.6%

0.7%

0.3%

Males

3.9%

1.1%

1.3%

Females

4.2%

1.2%

2.0%

Past-year use of alcohol or illicit drugs

4.5%

1.3%

0.6%

Past-year use of any illicit drug

9.8%

3.0%

1.8%

Methamphetamine use

21.6%

Not available

4.3%

Tranquilizer misuse

17.5%

Not available

3.9%

Cocaine use

15.0%

Not available

3.8%

Cannabis use

9.8%

Not available

1.7%

Past-year substance use disorder

12.7%

4.1%

2.2%

Past-year major depressive episode

28.6%

9.9%

4.2%

Treated for suicide attempt(s)

Population

Any Medical Attention

Hospitalization

All adults

845,000 (60.4%)

571,000 (40.8%)

18 to 25 years of age

50.4%

28.6%

26 to 49 years of age

70.5%

48.5%

50 years of age and older

Not available

Not available

Source: [364]

PATHOPHYSIOLOGY OF SUICIDAL BEHAVIOR

Suicidality is a distinct, multidimensional clinical condition now thought to result from interactions among biologic, social, and psychologic vulnerability factors, proximal biopsychosocial events acting as precipitants, and epigenetic factors [334,335,365]. The pathophysiology of suicide is distinct from comorbid psychiatric diagnoses. Previous research identified underlying processes in suicidal ideation, but assumptions that ideation predicted suicide attempts is now disproven, with efforts focused on identifying the underlying pathways to suicide.

To advance this research, two empirically confirmed models of suicide have been developed. The stress-diathesis model of suicidal behavior describes long-term vulnerability to suicide, activated by psychosocial or psychiatric crises [365]. The interpersonal theory of suicide proposes desire and capability as the principal factors contributing to suicidal behavior. Suicidal desire is explained by high levels of burdensomeness (i.e., a belief one is an unwanted burden to family/peers) and thwarted belongingness (i.e., social alienation and loneliness). Capability of suicide reflects the sum of noxious stimuli, traumatic events, and experiences of death and pain [366].

Some suicide neurobiology has also been established, such as associations between suicide and gene variations in the HPA axis, serotonin systems, noradrenergic systems, and polyamines that promote functional alterations. In the absence of gene variations, gene expression can become altered by exposure to extreme or chronic stress, becoming both cause and effect of neurobiologic response [365,367].

Abnormal function in several neurobiologic systems is associated with suicidal behavior, including the HPA axis, serotonergic system, and noradrenergic system. Dysfunction of these systems is associated with impaired regulation of anxiety, impulsivity, and aggression, which may result from genetic variation and environmental stressors (and their interaction) [368,369]. This may lead to dysfunctional information processing, eventually contributing to increased capability of suicide [359,367]. Immune system dysregulation is also believed to contribute to suicidality, but the role of inflammatory conditions has not been clearly delineated [370].

SUICIDE AND SPECIAL POPULATIONS

Youth

Before 18 years of age, 12.1% of youth report suicide ideation and 4.1% make at least one attempt [371]. In 2015, 409 children died by suicide, a rate of 2.0 for every 100,000 children between the ages 10 and 14 years [357,358]. Between 2008 and 2015, encounters for suicide ideation or attempt at children's hospitals nearly doubled [484]. The presence of acne is associated with social and psychologic problems, and certain acne medications have been linked with an increased risk of suicidal ideation [372].

College Students

The rate of college students seriously considering or attempting suicide increased from 25% and 8%, respectively, in 2008 to 31% and 9% in 2014. An estimated 77% who died by suicide in 2014 were white, and 86% did not seek campus counseling services before their suicide, despite unique access to mental health care without fees attached for most students. Students leaving home for college face unique challenges that may increase suicide risk in vulnerable students, including separation from support systems and social networks, academic stress, pressure to succeed, feelings of isolation, poor coping skills, and mental health stigma [373].

Gender and Sexual Minority Youth

The Centers for Disease Control and Prevention published the first-ever nationally representative survey on the health risks of gay, lesbian, and bisexual high school students in 2016 [374]. Nationwide, 88.8% of students identified as heterosexual, 2.0% as gay or lesbian, 6.0% as bisexual, and 3.2% as unsure of their sexual identity [374]. Overall, sexual minority youth are more likely than their heterosexual counterparts to experience adverse experiences and suicidality (Table 7).

Table 7: ADVERSE EXPERIENCES AND SUICIDALITY AMONG HETEROSEXUAL AND SEXUAL MINORITY HIGH-SCHOOL STUDENTS

Adverse Experience

Percentage of Students Reporting Experiencea

Heterosexual

Gay, Lesbian, or Bisexual

Threatened or injured with weapon (e.g., gun, knife, club) on school property

5.1%

10.0%

Avoided school because of safety concernsb

4.6%

12.5%

Cyberbullied

14.2%

28.0%

Bullied on school property

18.8%

34.2%

Forced to have sexual intercoursec

5.4%

17.8%

Physical dating violence

8.3%

17.5%

Sexual dating violence

9.1%

22.7%

Probable major depressive episode

26.4%

60.4%

Seriously considered attempting suicide

14.8%

42.8%

Made a suicide plan

11.9%

38.2%

Attempted suicide

6.4%

29.4%

Suicide attempt received medical care

2.0%

9.4%

aAll rates are past-year unless otherwise stated.

bIn the past 30 days

cOver the lifetime

Source: [374]

Sexual orientation or gender identity harassment and being threatened or injured with a weapon at school are the most damaging forms of school-based victimization for sexual minority adolescents, and these factors have the greatest association with suicidality [375]. For sexual minority youth, risk factors for bullying and violence include social isolation, lack of parental support, lack of safety or support at school, and harmful norms about masculinity and femininity associated with violence against those seen as not masculine or feminine enough [374].

Bullying and violent victimization of youth perceived as violating gender norms can occur through sexual orientation-based victimization (from perceived or actual same-sex attraction) or gender-variant-based victimization (from presentation perceived to resemble gay or lesbian stereotypes) [376,377]. Heterosexual youth whose appearance, mannerisms, or behaviors are perceived by peers as violating gender norms are also vulnerable to gender-variant-based victimization. This type of victimization is significantly associated with suicidal thoughts and behaviors in middle and high school students and potentially serious psychologic outcomes similar to those experienced by same-sex attracted adolescents [378].

Bullying and Cyberbullying

Adults are not immune to victimization from bullying or cyberbullying, but the bulk of research has focused on adolescent and young adult age groups. Bullying is defined as the use of power and aggression to control and distress another [379]. Intentionality, repetition, and abuse of power primarily distinguish bullying from other forms of aggression [380]. Cyberbullying does not induce distress through physical aggression and harm, but through the reach of Internet and social media. The emotional harm can be severe, in part from the ease that humiliating or threatening information, photos, and other content are spread, and by recruitment of other cyberbullying participants [381].

A study of 15,425 high-school students found higher rates of girls being bullied (31.3%) or cyberbullied (22.0%) compared with boys (22.9% and 10.8%, respectively). Suicide attempts were made by 4.6% of those never-bullied, 9.5% of those bullied at school, 14.7% of those cyberbullied, and 21.1% of those victimized both at school and online [382].

Peer victimization in childhood or adolescence can have long-lasting adverse effects. Among 30,436 U.S. soldiers in basic training, more frequent physical assault/theft by childhood peers was associated with increased odds of lifetime suicidal ideation and attempts; more frequent bullying comments/behaviors was associated with increased risk of ideation, planning and attempts among ideators. Relative to non-exposure, exposure to the most persistent bullying carried a two- to fourfold increase in risk of suicidality [383].

Gender and Sexual Minority Adults

In Western countries, the lifetime prevalence of suicide attempts is 4% among heterosexuals and 17% among sexual minorities [384]. Among sexual minority populations, a history of suicide attempts increases subsequent risk of repeat attempts and fatal outcomes [366,394]. Reports suggest high suicide attempt rates among gay/bisexual African Americans, gay/bisexual men of lower socioeconomic status, and sexual minority Latinos [385,386,387].

Suicidality disproportionately affects gender minorities, who may represent up to 0.5% of the adult population. Transgender or transsexual men and women are roughly 5 times more likely to attempt suicide and 19 times more likely to die by suicide than non-trans adults [388]. The suicide attempt prevalence in trans populations is 22% to 43% for lifetime and 9% to 11.2% for past-year [389]. Violent victimization, experienced by 43% to 60% of trans persons, predicts a fourfold increase in suicide risk [388]. Physical assault increases the odds of attempting suicide, but physical abuse directed at gender identity or expression has greater relative impact on suicidal behavior [388]. Experiencing fewer transphobia events has been associated with a 66% reduction in ideation and a 76% reduction in suicide attempts among ideators [389].

Armed Forces and Combat Veterans

The historically low U.S. Army suicide rate began climbing in 2004 and has exceeded the civilian rate since 2009 [390]. In response, the Army has invested significant resources in suicide prevention efforts [354].

In one study, veterans during the Iraq and Afghanistan war era (317,581 deployed to war zones, 964,493 nondeployed) were followed from the time of discharge to 2010. With 1,868 suicide deaths, both veteran cohorts had 41% to 61% higher risk of suicide relative to the general population, but suicide risk was not associated with a history of war zone deployment and multiple deployments were not associated with greater suicide risk among deployed veterans [391].

Among U.S. Armed Forces veterans, the estimated lifetime prevalence of suicide ideation was 12.7% for men and 20.1% for women, and the prevalence of lifetime suicide attempts was 2.5% and 5.1%, respectively [392]. Among active Armed Forces suicide decedents, roughly 50% accessed health care in the month before their death and more than 25% accessed care in the week before their death. Male, never married, and non-Hispanic black individuals were less likely to access care prior to death. The number of mental health encounters was the only predictor of suicide risk documentation among decedents at 4 weeks and 52 weeks prior to death [393].

Incarcerated Individuals

Jails and juvenile justice facilities have exceptionally high suicide rates, and suicide is often the single greatest cause of death in correctional settings. Inmates at highest risk are young men, persons with mentally illness, those who are socially disenfranchised and socially isolated, individuals with substance use disorders, those who have previously attempted suicide, and juveniles placed in adult correctional facilities. Factors that increase suicidal risk include the psychologic effects of arrest and incarceration; intense stressors of prison life, including physical and sexual predation and assault from other inmates; and absence of formal policies for managing suicidal patients, staff training, or access to mental health care [395].

At greatest suicide risk are young (i.e., 20 to 25 years of age), unmarried, male, first-time offenders arrested for minor, usually substance-related, offences. Typically intoxicated at the time of arrest, these individuals tend to commit suicide at an early stage of confinement, often within the first few hours, from the impact of sudden isolation, shock of imprisonment, lack of information, and fear about the future [395]. This suggests an important role for medical assessment of substance abuse and suicide proneness and inmate suicide prevention programs [32,396].

SUICIDE AND PUBLIC PERCEPTION

Stigma often surrounds persons with suicidal behavior and suicide itself. Stigma and negative attitudes interact with postmortem determinations and media reporting, and stigma can be antecedent or consequence.

Misclassification of Suicide Deaths

Suicide determinations are not easy, even after the event, and coroners vary considerably in the verdicts they give to individuals who probably died by suicide [345]. Stigma can influence under-reporting, with families or physicians hiding evidence. Death determination may be judged by variable local standards, and ambiguous cases involving suicide may be classified "accidental" or "undetermined" deaths [397]. Context can influence how ambiguous cases of suicides are classed. Institutions such as prisons, hospitals, and religious orders may consider a suicide less embarrassing than homicide. Despite substantial doubt, declaring death a suicide can be motivated by the required investigation of homicide and apprehension of a murderer and negligence lawsuits with accidental death [397].

Suicide Reporting in the Media

Especially among youth, suicide rates may temporarily spike with intense coverage of a suicide in media reports or movies and television [398,399,400]. Imitation is the core factor, which is most powerful illustrated by highly publicized suicides of celebrity figures [401].

Media coverage of suicide can misinform by attributing suicide to a single event (e.g., job, relationship loss) without acknowledging a broader context of ongoing depression, substance abuse, or lack of access to treatment for these conditions. The time from media exposure to action is brief, typically a few minutes. This gives media outlets little time for mitigating actions after population exposure to a harmful story, stressing the need to evaluate news items before publication [402]. Responsible suicide coverage can educate audiences about the causes, warning signs, treatment, and prevention of suicide [398].

Shortcomings are also found in media reporting of cyberbullying-related suicide. Few media outlets follow guidelines to protect against suicidal contagion. Few reports reference suicide or bullying prevention resources, and most suggest suicide has a single cause. A subset of reports use individual suicides as cautionary tales to elevate cyberbullying awareness [403].

Stigma and Suicide

The stigma of mental illness and substance abuse, both closely linked to suicide, prevents many persons from seeking help over fears of prejudice and discrimination [404]. People with a substance use disorder face added stigma over prevalent beliefs that addiction is a moral failing of persons capable of controlling these behaviors [32,405]. The stigma of suicide inhibits many from seeking treatment. Family members of suicide attempters often hide the behavior from friends and relatives, believing it reflects badly on their own relationship with the attempter or that suicidal behavior itself is shameful or sinful. These same feelings are held by many who attempt suicide [32]. Systemic, persistent stigma contributes to inadequate funding for preventive services and insurance reimbursement for treatments, perpetuates under-treatment of substance use and mental health disorders, limits access to tailored services, and maintains unnecessarily high suicide rates [32].

Holiday Suicide Myth

The idea that suicide is more frequent during the holiday season is a debunked myth partially perpetuated by the media [358]. Suicide rates are lowest in December and highest in the spring and fall [406]. The holiday suicide myth is important to counter because it provides misinformation about suicide that may interfere with prevention efforts [407].

SUICIDE MODELS AND RISK FACTORS

As discussed, the lack of predictive value for risk factors is now recognized [408]. The predictive disparity of traditional suicide risk factors (strong for ideation, poor for behavior) suggests that development of suicide ideation and movement from ideation to potentially lethal attempts are distinct processes, with distinct explanations and predictors. This has prompted efforts to identify novel, more effective risk factors guided by strong theoretical models [334,409].

Other lines of research have identified the need to address acute and immediate factors influencing suicide risk. Many patients have long-term (i.e., one to five years) ideation or tentative planning before a suicide attempt, but almost all proximal planning occurs within two weeks and the majority occurs within 12 hours of a suicide attempt [410]. Assessment of outpatients with past-year suicide attempts and inpatients admitted for suicidality over two to four weeks showed suicidal ideation, hopelessness, burdensomeness, and loneliness varied dramatically over the course of most days in nearly all patients [411].

The suicide prevention field is in transition. Suicide risk factors, assessment tools, and risk level stratification are largely ineffective in short-term prediction of suicide but have not yet been replaced by more effective methods.

The Interpersonal-Psychological Theory of Suicide

The Interpersonal-Psychological Theory of Suicide posits that persons will not make lethal suicide attempts unless they have developed the desire (i.e., low belongingness, high burdensomeness) and ability to do so [366]. Thwarted belongingness is defined as the experience of having little or no social connectedness, a result of living alone, death of a spouse, or disabling physical or psychiatric illness. The need to belong is a core aspect of human nature; when unfulfilled, suicide risk increases [412]. Perceived burdensomeness is evident when persons feel their family members and the world in general would be better off if they were no longer living, and this can initiate suicidal ideation [412]. Acquired capability for suicide refers to reaching the point at which a patient overcomes his or her innate fears of pain, injury, and death with suicide. Opponent process theory suggests with repeated exposure, the effects of previously noxious, aversive, or provocative stimuli may recede, and the opposite effect of the stimuli becomes strengthened and amplified [413]. Persons can habituate to pain, injury, or death through previous suicide attempts, exposure to trauma, armed combat, violence, or death and diverse experiences related to psychologic and physical pain [334,335].

The Cubic Model

The cubic model defines psychologic pain—psychache—as one of three essential dimensions in suicide risk (along with stress and perturbation) [414]. Psychache often underlies the desire to escape from unbearable pain and represents a state of anguish sufficiently aversive to over-ride innate fears of pain, injury, and death [335]. Psychologic pain distinguished attempters from ideators among 378 adults with history of suicidality [334].

Non-Suicidal Self-Injury

Non-suicidal self-injury (NSSI) is intentional, non-socially accepted damage to the bodily surface, without suicidal intent, by cutting, scratching, hitting/banging, carving, or scraping. Roughly 17% to 18% of teens have one or more NSSI event; up to 60% of adolescent psychiatric patients have one NSSI event and 50% have repetitive NSSI [415,416]. NSSI prevalence is higher in girls and women. It rises from late childhood to early adolescence, peaks in mid- to late-adolescence, and generally declines by young adulthood [371]. NSSI can occur without a psychiatric diagnosis [417].

NSSI serves as a means to escape aversive emotional (e.g., sadness, anxiety) or cognitive (e.g., negative thoughts or memories) states, relieve tension or anger, or regain perception of control [371,418]. Adolescents with repetitive NSSI remain at high risk of dysfunctional emotion regulation strategies after ceasing the behaviors and show increased substance abuse as the behaviors decrease [419]. Those who cut themselves on body areas other than arms or wrists have the greatest risk of subsequent suicide [420]. Identifying with "goth" or "emo" youth subculture, sexual minority status, social media exposure to self-injury behaviors, bullying, and childhood emotional abuse are risk factors for NSSI [421].

There is a temporal relationship between nonsuicidal and suicidal self-injury in adolescent outpatients and inpatients. On average, suicide ideation occurs before initial NSSI behavior, suggesting that pathways to NSSI and suicidal behavior may occur simultaneously rather than sequentially from nonsuicidal to suicidal self-injury. The transition from nonsuicidal to suicidal self-injury is relatively fast, and a key period for intervention and prevention is within the first 6 to 12 months after the onset of suicidal thinking [422].

Chronic Pain

Chronic uncontrolled pain is second only to bipolar disorder as medical cause of suicide [423,424,425]. The distress, exhaustion, and hopelessness of chronic unrelieved pain can invite intended overdose. Death is no longer feared, but instead becomes a welcome prospect of permanent relief from suffering and anguish [426]. Individuals with physical pain are substantially more likely than those without pain to report lifetime death wish; to have current and lifetime suicidal ideation, plans, and attempts; and to die from suicide. Chronic uncontrolled pain is a consistent risk factor for suicidality, even after controlling for demographics and psychiatric and substance use disorders [427,428].

The perception of being a burden significantly predicts wishing to die, active suicide ideation, presence of a suicide plan, history of suicide attempts, and preference for death over disability in patients with chronic pain [429]. Chronic uncontrolled pain elevates the risk of suicide to escape unbearable suffering, in part by promoting (or becoming amplified by) depression and hopelessness. This intensifies a desire to escape that erodes the natural fear of dying, promoting the development of fearlessness about death—a key risk factor for suicide [430].

Psychologic Pain

Suicide is viewed as behavior motivated by the desire to escape from unbearable pain, and suicide risk research implicates two related constructs: psychache and pain tolerance, defined as the greatest duration or intensity of painful stimuli one can withstand before pain is intolerable and unbearable [431,432]. Psychache is a crucial link between suicidal risk and behavior, and mediates the relationship between depression or other psychologic conditions and suicidality [431,432,433,434,435]. As discussed, numerous studies indicate that psychache highly predicts suicidality and distinguishes attempters from ideators. Changes in suicide preparation and intent over three years significantly correlates with changes in psychache but not depression or hopelessness [436]. Evidence links pain tolerance to self-injurious behaviors and suicide risk. Psychache and physical pain are linked to other predictors of suicide, including impaired reward processing, hopelessness, and depression [432].

Mental pain is a uniquely intolerable experience that exceeds the sum of negative emotions, thoughts, and sensations. Beliefs can develop that change or improvement is not possible and self-destruction is the only resolution [431,437]. Unbearable, persistent psychologic pain is also thought to reduce awareness of the body and its signals, making it more likely to perceive the body as an object and an easier target to attack [438].

Among patients in residential treatment with serious psychopathology, history of suicide ideation or attempts is associated with proportionally greater psychic pain and fewer reasons for living. Treatment of such patients should include both an understanding of the sources of psychic pain and promotion of individual discovery of reasons for living [439].

Psychiatric Disorders

Traditional suicide risk factors include mood (e.g., bipolar disorder, MDD), anxiety, impulse control, personality, psychotic, and alcohol/substance use disorders [353]. There is little evidence that trait impulsivity increases risk of attempts in ideators, although suicidal behavior can occur during transient impulsive states [440]. In patients with MDD, the condition most associated with suicide, the lifetime suicide prevalence is 4% for hospitalized individuals, 2.2% in mixed inpatient/outpatient populations, and 8.6% if hospitalized for suicidality [67]. However, it is important to remember that MDD alone does predict acute risk of suicide and depression and most psychiatric disorders alone do not predict transition from ideation to suicidal plans or attempts.

Acute Anxious Agitated Distress

While symptomatic panic disorder, PTSD, and generalized anxiety disorder influence suicide behavior more than any other psychiatric disorders, it is the acute state of anxious agitated distress (not an anxiety disorder diagnosis) that greatly increases risk of ideators moving to suicide attempts [353,441]. Among inpatient suicides, 79% met diagnostic criteria for severe or extreme anxiety and/or agitation.

Anxious agitated distress is characterized by intense/severe anxiety, agitation, or panic and mental anguish and unrest with restless or repetitive behaviors, heightened arousal, expressions of emotional turmoil, irritability, anger outbursts, insomnia, and nightmares [335,353,393,442,443]. It is commonly observed immediately before suicide and is a documented precursor of near-fatal attempts. Clinicians should inquire regarding perceived anxious agitated distress, and may ask patients if they feel like "jumping out of their skin" or "going to explode" or if feel they must "take action" or "do something" from overwhelming inner restlessness.

Bipolar Depression

An estimated 5 to 10 million Americans currently suffer from bipolar disorder. Bipolar depression is the depressive phase of bipolar disorder, when suicidal behavior is most frequent but least responsive to standard treatment. On average, patients with bipolar disorder spend three times longer in the depressive phase than in the manic phase. It is a highly disabling disorder, causing marked occupational and social impairment. Patients with bipolar depression have a 25% to 56% lifetime prevalence of suicide attempts, and 10% to 19% die by suicide [444].

Alcohol and Substance Use Disorders

More than 33% of suicides occur during alcohol use, typically at high levels of ingestion, and controlled trials confirm that acute alcohol use is a potent suicidal risk factor [445,446,447,448]. Alcohol intoxication significantly increases suicide risk and may heighten psychologic distress and aggression, encourage suicide attempts, and inhibit adaptive coping strategies [449]. During intoxication, disinhibition facilitates movement from ideation to impulsive action, and alcohol intoxication predicts use of lethal means in suicide [449,450]. However, substance use disorder and suicidality can be temporarily linked, as patients are likely to deny suicidality after intoxication has resolved [451,452].

Psychotic Disorders

Suicide is the greatest cause of premature death in individuals with schizophrenia, with the highest risk in young, unemployed men. Other risk factors include recurrent relapses, fears of deterioration in persons with high intellectual ability, positive symptoms of suspiciousness and delusions, and depressive symptoms [453,454]. The suicide risk is greatest during early-stage illness, early relapse, and early recovery; risk declines with prolonging illness duration [453,454].

Persecutory panic (a state of terror often associated with command hallucinations and delusions) has been observed in many psychotic disorders . These patients are described as terrified of a threatening and imminent annihilation or dismemberment, imagine that suicide is survivable, and desperately attempt to escape from the danger of imaginary menace by suicide [455]. Therefore, the presence of persecutory panic is considered a risk factor for suicide and should be addressed immediately.

SUICIDE MEANS AND METHODS

In 2015, guns were the most common means used in suicide deaths (49.8%), followed by suffocation/hanging (26.8%) and poisoning (15.4%) [360]. In the United States, the rate of suicide by firearm is eight times greater than the rates in other economically developed countries [456]. Household gun ownership strongly correlates with firearm suicide, and storage practices impact suicide rates, which are higher in geographic areas with greater household prevalence of loaded guns. The presence of loaded, unlocked firearms within reach is a risk factor for fatal outcomes from suicidal behavior [457].

Suicide by cop is defined as an event in which a suicidal subject intends to die and, aware of the finality, directs behavior against police that is sufficiently life-threatening to compel a deadly force response [458]. Although usually intending to die, the subject is ambivalent about taking his or her own life. Suicide by cop victimizes the suicidal subject, and the police who are often placed in near-impossible situations. In 707 officers-involved shootings between 1998 and 2006, 36% were attempted suicides and 51% of subjects were killed [459]. Suicide by cop is characterized by one of the following [459,460]:

- Direct confrontation: The attack on police is premeditated with intent to die from a deadly force response.

- Disturbed intervention: Emotionally disturbed behavior that draws police intervention, without evidence of wanting police involvement.

- Criminal intervention: A criminal, believing there is no way out, prefers death to arrest and incarceration.

SUICIDE MOTIVATION

Most suicides and attempts are driven by the motivation to escape unbearable pain. Other motives include revenge, shame, humiliation, delusional guilt, command hallucinations, gaining attention or reaction from others, loneliness, self-hatred, or a sense of being a burden, not belonging, feeling trapped, or having no purpose [349]. Individuals have a unique balance between their personal motivations for suicide and their reasons for living. Reasons for living can include religious beliefs, a sense of responsibility to children or others, plans for the future, or a sense of purpose in life. A strong social support network is also protective against suicide [349]. Importantly, "reasons for living" become irrelevant when suicidal intent is moderate or greater.

SUICIDE PREVENTION

Large-scale suicide prevention efforts in the United States began in 1958 with the first suicide prevention center in Los Angeles, followed by nation-wide crisis intervention centers [32]. The risk factor approach to suicide prevention was introduced in 1966; organizations and national strategies were established to further these efforts. Survivors of suicide started the Suicide Prevention Advocacy Network USA (SPAN USA) in 1996 to campaign for a national suicide prevention strategy, prompting the creation of the National Strategy for Suicide Prevention (NSSP) in 2001 [461].

Recognizing that decades of suicide prevention research has not decreased suicides, the NSSP partnered with the National Action Alliance for Suicide Prevention in 2012 to develop national priorities for suicide prevention science. Suicide research was prioritized to delineate promising research pathways toward a set of 12 "aspirational goals" considered areas of focus necessary for preventing substantial numbers of suicide deaths and attempts [462].

The revised NSSP was launched in 2013, elaborating on methods for systemic change in healthcare delivery, public and media conversations around suicide and suicide prevention, the timeliness and utility of suicidality surveillance data, prevention, and clinical care [463]. "Zero suicides" is an aspirational goal based on the belief that suicide of patients receiving care in any setting is preventable, and one area of commitment is to program approaches that prevent suicidal patients from failing to receive adequate care. Universal suicide risk screening in primary, specialist, and emergency care settings was recommended [464].

Suicide Prevention in the Elderly

The elevated suicide risk in the elderly is influenced by the prevalence of isolation, chronic pain, chronic illness, and/or depression (often undiagnosed). Many at-risk elderly adults suffer from intense loneliness, bereavement, or loss of social roles; fears of disability, dependency, or burdensomeness to others are common [465]. Enhancing connectedness to others is a suicide protective factor and formal strategy to prevent suicide in the elderly [464].

TREATMENT OF SUICIDALITY

Psychotherapy

Highly-structured, problem-solving, coping-oriented psychotherapies have the greatest research support for effectively treating suicidal risk, and include dialectical behavioral therapy, cognitive therapy, and collaborative assessment and management of suicidality [466].

Dialectical behavioral therapy is the most thoroughly studied and effective psychotherapy for suicidal behavior. It has been shown in multiple studies to decrease suicide attempts, self-harm, and other suicide-relevant markers such as suicidal ideation and hopelessness. This psychotherapy emphasizes skills training and mindfulness-based emotion regulation [466].

Cognitive therapy is the next most studied and supported suicide-relevant psychotherapy. The initial randomized controlled trial of suicide-specific cognitive therapy in persons presenting to the emergency department with suicide attempt gave convincing evidence that 10 sessions decreased follow-up suicide attempts compared to the control group. The primary focus of this modality is identification of patient "suicidal mode," activated by certain experiences, memories, thoughts, and situations. Patients learn what triggers their suicidal mode and develop and use alternate non-suicidal coping responses [466].

Collaborative assessment and management of suicidality is a therapeutic framework that emphasizes collaborative assessment, crisis response planning, and problem-focused interventions designed to identify and treat the "drivers" of suicidal risk. In one study, it was shown to effectively treat suicidal ideation, overall symptom distress, hopelessness, and reasons for living at 12-month follow-up compared to enhanced usual care [466].

Pharmacotherapy

Effective pharmacotherapy for suicidality has been elusive. Antidepressants are standard treatment for acutely suicidal patients, but delayed onset imposes unacceptable distress and elevates risk of lethal self-harm [48]. In MDD and bipolar disorder, lithium is protective against suicidal behavior and has extensive evidence support, but it is underprescribed for this purpose. In schizophrenia, clozapine is superior to other antipsychotic agents in lowering suicide rates. However, the need for close toxicity monitoring has limited its use in preventing suicide. In severe MDD with high suicide risk, ECT is established as rapid, effective treatment, but practical issues and stigma constrain its use [48,467,468].

Aside from clozapine and lithium, pharmacotherapy approaches have traditionally been based on the belief that suicidality as an extension of MDD [469]. However, breakthroughs have been made in rapid-active drug interventions for suicidal individuals, with ketamine, esketamine, and buprenorphine now being explored for this use [469,470,471,472,473,474,475]. In 2016, the FDA granted breakthrough therapy designation for intranasal esketamine in patients with MDD at imminent risk for suicide [307].

ASSESSMENT OF SUICIDE RISK

Standard suicide risk assessment intends to gather clinical information sufficient to determine patient risk level for suicide, culminating with clinician estimation of risk based on suicide thoughts, intent, behaviors; protective and risk factors, precipitants, warning signs; and behavioral observation during assessment [349,351,353]. Patients with any of the following conditions should be assessed for suicide risk, although many are nonspecific factors that do not predict current risk [349,351,353]:

- Psychiatric (e.g., MDD, bipolar depression, schizophrenia, PTSD) and medical (e.g., chronic pain, sleep disturbance, frequent headaches) disorders

- Positive depression screening results (e.g., very high scores, suicidality concerns, suicidal thoughts in perinatal women)

- Patients seeking help or self-reporting suicidal thoughts

- Referrals from close others over concerns about patient behavior

- Clinical judgment

Eliciting Information

Guidelines recommend an empathetic and direct, yet objective and non-judgmental, approach to eliciting information from patients believed to be at risk for suicide. The gravity of high acute suicide risk and vital need for information suggests an assertive approach. The following recommendations have been made for these situations [349,476]:

- Be clear and use specific, open-ended questions. Be flexible to frame questions more clearly.

- Avoid assuming patients and families understand clinical terms, even if clarification is not requested.

- Ask for clarification, and do not accept vague answers. Ask follow-up questions.

- Document positive and negative specifics carefully, in narrative form.

Clinical suicide assessment guidelines give little attention to dealing with patients suspected of being at acute risk for suicide who are unable or unwilling to cooperate with the risk assessment process. Patients evaluated for suicide are often in crisis and may fear that sharing their suicidality will result in loss of autonomy through hospitalization, behavioral restriction, or loss of esteem from a psychiatric diagnosis. In response to these fears, patients can minimize or deny their suicidality when directly asked or make statements to decrease clinician vigilance; clinicians should be aware of these tactics [351].

Thinking and cognition are often clouded, and intentionally or not, many patients with increased suicide risk give inaccurate, incomplete, and unreliable histories. Patients can misunderstand their symptoms, condition, and risk and usually cannot predict their impulses and behaviors [476,477]. Clinicians often believe suicidal patients view them as allies, but they are more likely seen as adversaries with conflicting goals: preserving versus ending life. This is a fundamental change in the patient-provider relationship after a patient decides to attempt suicide [477].

As such, alternative lines of evidence may be necessary to confirm suspicions of suicide risk, including obtaining objective evidence and collateral information/permissions [476,477]. Patients who attempt suicide may communicate intent to relatives before clinicians [477]. Among inpatients who complete suicide, 78% denied suicidal ideation in their last communication with staff, 60% told their spouse, and 50% told other relatives; however, only 18% told their physician [443]. Other providers, relatives, and close others can be a vital information source to help ascertain acute suicide risk level and are often more reliable than severely suicidal patients.

Assessing Suicidality

As discussed, many areas of patient information emphasized by standard practice guidelines as crucial for patient risk assessment have been found to lack risk prediction value. Instead, clinicians should focus on critical factors related to suicide risk, identified by studies of callers to suicide prevention hotlines, including [476,478]:

- Suicidal desire: Suicidal ideation, psychologic pain, hopelessness, helplessness, perceived burden to others, feeling trapped, feeling intolerably alone

- Suicidal capability: History of suicide attempts, exposure to someone else's death by suicide, available means of killing self/ others, current intoxication, substance abuse, acute symptoms of mental illness, extreme agitation/rage

- Suicidal intent: Attempt in progress, plan to kill self/others, preparatory behaviors, expressed intent to die

Suicide Warning Signs: Indications for Urgent/Immediate Action

Suicide warning signs are recent, unusual changes in the patient, often an acute response to precipitants and proximally associated with imminent suicide risk. Intent may be signaled through emotions, thoughts, or behaviors. Danger is elevated with previous suicide attempts, family history of suicide, or possession of a lethal method. Presence of any of the following warning signs requires immediate attention, mental health evaluation, and possibly hospitalization to ensure patient safety, stability and security:

- Suicide communication—threatening to harm or kill self

- Preparations for suicide

- Seeking access, or recent use, of lethal means

Other warning signs may further elevate acute suicide risk include [351,353]:

- Verbalizations: Hopelessness (feeling of defeat, that nothing can improve their situation), purposelessness (sense of purpose or reason to live is absent), feeling trapped (no way out, no escape possible), or guilt/shame (overwhelming self-blame, remorse, self-hatred)

- Behaviors: Anger, rage, revenge-seeking, reckless/impulsively risky behavior, marked mood changes, anhedonia, withdrawal from family, friends, society

- Inability to sleep

- Command hallucinations

Acute Suicidality Risk Level and Intervention

After a patient's suicide risk level has been assessed and assigned, based on clinical judgment, the level of intervention may be selected (Table 8).

Table 8: ACUTE SUICIDE RISK LEVEL AND INTERVENTION

Risk Level

Contributing Factors

Suicidality Level

Possible Interventions

High

Acute, severe psychiatric illness or symptoms

Acute precipitating event

Lethal attempt

Ideation, strong intent to act/plan

Cannot control impulses

Rehearses/prepares suicide

Continuous observation; limit access to lethal means; immediate transfer to emergency department for hospitalization

Moderate

Multiple warning signs or risk factors

Ideation

No intent to act

Impulse control intact

Prompt referral to mental health clinician

Limit access to lethal means

Low

Risk factors modifiable

Protective factors strong

Ideation

No plan, intent, behavior

Outpatient referral

Give emergency/crisis numbers

Source: [349,351,353]

The Cognitive State

The cognitive/affective state of suicidal patients is typified by ambivalence, impulsivity, and rigidity. The desire to die and live alternates; clinicians may explore ambivalence to reinforce reasons for living. The transient nature of impulse permits clinicians to defuse a suicide crisis by support at an impulsive moment. Rigidity constricts patient thinking, mood, and motivation; perception of problems and outlook is dichotomized into black-and-white reasoning. With gentle reasoning, clinicians may help the patient understand and consider alternative options to death [453,454].

Acute Anxious Agitation

Treat patients with anxious agitated distress states aggressively with benzodiazepines and/or antipsychotics, considering age and past/current medication exposure. Frequently monitor these patients for efficacy and side effects, and strongly consider emergency evaluation [353,479].

Safety Precautions

In all clinical settings, scrutinize patient belongings and nearby medical equipment, such as intravenous tubing, for use in self-harm. Decline family or friends' insistence on driving patients to treatment; transfer patients for emergency evaluation or hospitalization safely by ambulance with trained personnel following standard protocols. During hospital or emergency department discharge or outpatient visits, recommend that close others secure or remove firearms, large quantities of medication, and other obvious means of self-harm. Make an effort to involve family and significant others in crisis planning and treatment [353].

Suicide Prevention Contracts

Written and verbal "no harm" and "no-suicide" contracts do not prevent suicide and tend to give clinicians a false sense of safety that decreases vigilance and may communicate an uncaring "brush-off" to patients, especially in busy clinics and emergency departments. In one study, approximately 50% of suicides completed by an inpatient had a prevention contract in place. It is recommended that suicide prevention contracts not be used [351,476,480,481,482].

10. SUICIDE LOSS SURVIVORS

Suicide loss survivors are those family members and friends affected by the death of a loved one through suicide. Estimates suggest that each suicide death exposes 147 people, of whom 6 or more experience a major life disruption. With 851,660 suicides completed in the United States between 1991 and 2015, there are more than 5.1 million suicide loss survivors [360].

The death of a loved one by suicide can be shocking, painful, and unexpected for survivors, with significant impact on health and mental health. A Danish study found that within five years of the loss, spouses bereaved by a partner's suicide had higher risks for mental disorders, suicidal behaviors and mortality, use of public assistance, and mental health care utilization than spouses bereaved by other manners of death [483]. The ensuing grief can be intense, complex, chronic, and nonlinear.

Working through grief is a highly individual and unique process that survivors experience in their own way and at their own pace. Grief does not always move in a forward direction, and there is no timeframe for grief. Survivors should not expect their lives to return to their previous state and should strive to adjust to life without their loved one. The initial emotional response may be overwhelming, and crying is a natural reaction and an expression of sadness following the loss of a loved one [465].

Survivors may struggle to comprehend why the suicide occurred and how they could have intervened, and the guilt over perceiving missed opportunities with hindsight can be agonizing. Relief may be felt if the loved one was prone to difficult mood or temperament. The stigma and shame surrounding suicide may inhibit family members and friends from contacting survivors and can prevent survivors from reaching out for help. Ongoing support remains important to maintain family and relationships during the grieving process [465].

Many survivors find support groups for suicide loss survivors the most beneficial means to feel supported and understood. The shared experience of group members enables survivors to openly discuss their story and feelings without pressure, fear of judgment, or shame [465].

http://www.netce.com/The American Foundation for Suicide Prevention maintains an international directory of suicide bereavement support groups on their website at https://afsp.org/find-support.

11. CONCLUSION

Depression is a debilitating and potentially life-threatening mood disorder that afflicts millions of Americans. Depressed persons are more likely to develop chronic medical conditions, including type 2 diabetes and cardiovascular disease, and depression is projected to be the leading cause of disability over the next 20 years. Furthermore, suicide is a major preventable public health problem and cause of mortality. Depression, especially with comorbid substance abuse, represents a significant risk factor for suicide. Depression causes enormous pain and suffering to the afflicted and substantial economic cost to society, and the emotional impact on survivors of a depressed person who has completed suicide is often devastating. Many persons with depression do not seek treatment; among those who do, only a fraction receive treatment consistent with current practice guidelines. Primary care contact may represent the last opportunity for intervention in the severely depressed suicidal patient, making the thorough comprehension of identification and treatment of depression and suicide risk imperative.

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Evidence-Based Practice Recommendations Citations

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90213 • Diagnosing and Managing Headaches

John J. Whyte, MD, MPH

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Headaches are considered one of the most common types of pain and one of the most frequent causes of presentation to physician offices and clinics. Millions of adults seek treatment from physicians each year related to headache pain. As a result, headaches represet a significant cause of morbidity. It has been estimated that headaches result in billions of dollars in expenses, job absenteeism, and decreased annual productivity. They also result in decreased quality of life. Coping with a chronic headache disorder may predispose the individual to other illnesses. For example, depression is three times more common in people with migraine or severe headache than in healthy individuals. A clear understanding of the types and causes of headache pain is essential for physicians and other healthcare providers to adequately address and manage the patient with headaches.

Table of Contents

90213 • Diagnosing and Managing Headaches

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. EPIDEMIOLOGY

ECONOMICS

3. BASIC PATHOPHYSIOLOGY

TYPES OF HEADACHES

4. WORK-UP OF HEADACHES

ASSESSING HEADACHES IN PATIENTS WITH THE ASSISTANCE OF AN INTERPRETER

HISTORY

PHYSICAL EXAM

WARNING SIGNS OF SIGNIFICANT DISEASE

LAB STUDIES

ELECTROENCEPHALOGRAM

LUMBAR PUNCTURE

IMAGING

5. PRIMARY HEADACHES

MIGRAINE HEADACHES

CLUSTER HEADACHES

TENSION HEADACHES

OTHER PRIMARY HEADACHES

6. SECONDARY HEADACHES

TRAUMATIC CAUSES OF HEADACHES

VASCULAR HEADACHES

NEOPLASTIC CAUSES OF HEADACHES

INFECTIOUS CAUSES OF HEADACHES

PRESSURE HEADACHES

METABOLIC/TOXIC CAUSES OF HEADACHES

OTHER CAUSES OF SECONDARY HEADACHES

7. ACUTE VERSUS CHRONIC

8. REFERRAL

9. MEDICO-LEGAL ISSUES

10. CONCLUSION

11. ADDITIONAL SOURCES OF INFORMATION

Works Cited

Evidence-Based Practice Recommendations Citations

90213 • Diagnosing and Managing Headaches

Education Category. Medical / Surgical

Release Date. 09/01/2019

Review Date. 04/01/2022

Expiration Date. 08/31/2023

Course Overview

Headaches are considered one of the most common types of pain and one of the most frequent causes of presentation to physician offices and clinics. Millions of adults seek treatment from physicians each year related to headache pain. As a result, headaches represet a significant cause of morbidity. It has been estimated that headaches result in billions of dollars in expenses, job absenteeism, and decreased annual productivity. They also result in decreased quality of life. Coping with a chronic headache disorder may predispose the individual to other illnesses. For example, depression is three times more common in people with migraine or severe headache than in healthy individuals. A clear understanding of the types and causes of headache pain is essential for physicians and other healthcare providers to adequately address and manage the patient with headaches.

Audience

This course is designed for physicians and will be of interest to nurses, pharmacists, and other medical personnel who may encounter patients who complain of headaches.

Course Objective

Given the common and difficult diagnoses associated with headaches, the purpose of this course is to educate the healthcare professional about the epidemiology and treatment of the various types of headaches so they may make early and accurate diagnoses, begin effective treatment, and/or refer patients to a specialist when necessary.

Learning Objectives

Upon completion of this course, you should be able to:

1. Illustrate the epidemiology and economic impact of headaches.

2. Demonstrate the pathophysiology of headaches.

3. Recognize the signs and symptoms of headaches, focusing on history and physical exam, and discuss the role of an interpreter in assessing non-English-proficient patients.

4. Identify the appropriate imaging modalities for headaches and their specific indications.

5. Describe the epidemiology, diagnosis, and treatment of migraine headaches.

6. Differentiate the signs and treatments for cluster and tension headaches.

7. Identify the secondary causes of headaches.

8. Compare and contrast the differences between acute and chronic headaches.

9. Recognize indications for specialist referral.

10. Analyze medico-legal issues surrounding headache diagnosis and management.

Faculty

John J. Whyte, MD, MPH, is currently the Chief Medical Officer at WebMD. In this role, he leads efforts to develop and expand strategic partnerships that create meaningful change around important and timely public health issues. Previously, Dr. Whyte was the Director of Professional Affairs and Stakeholder Engagement at the FDA’s Center for Drug Evaluation and Research and the Chief Medical Expert and Vice President, Health and Medical Education at Discovery Channel, part of the media conglomerate Discovery Communications.
Prior to this, Dr. Whyte was in the Immediate Office of the Director at the Agency for Healthcare Research Quality. He served as Medical Advisor/Director of the Council on Private Sector Initiatives to Improve the Safety, Security, and Quality of Healthcare. Prior to this assignment, Dr. Whyte was the Acting Director, Division of Medical Items and Devices in the Coverage and Analysis Group in the Centers for Medicare & Medicaid Services (CMS). CMS is the federal agency responsible for administering the Medicare and Medicaid programs. In his role at CMS, Dr.Whyte made recommendations as to whether or not the Medicare program should pay for certain procedures, equipment, or services. His division was responsible for durable medical equipment, orthotics/prosthetics, drugs/biologics/therapeutics, medical items, laboratory tests, and non-implantable devices. As Division Director as well as Medical Officer/Senior Advisor, Dr. Whyte was responsible for more national coverage decisions than any other CMS staff.
Dr. Whyte is a board-certified internist. He completed an internal medicine residency at Duke University Medical Center as well as earned a Master’s of Public Health (MPH) in Health Policy and Management at Harvard University School of Public Health. Prior to arriving in Washington, Dr. Whyte was a health services research fellow at Stanford and attending physician in the Department of Medicine. He has written extensively in the medical and lay press on health policy issues.

Faculty Disclosure

Contributing faculty, John J. Whyte, MD, MPH, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Abimbola Farinde, PharmD, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

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It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Headaches are considered one of the most common types of pain and one of the most frequent causes of presentation to physician offices and clinics. Nearly 50 million adults seek treatment from physicians each year related to headache pain [1,2]. As a result, headaches represent a significant cause of morbidity. It has been estimated that headaches result in billions of dollars in expenses, job absenteeism, and decreased annual productivity. They also result in decreased quality of life. Coping with a chronic headache disorder may predispose the individual to other illnesses. For example, depression is three times more common in people with migraine or severe headache than in healthy individuals [3]. A clear understanding of the types and causes of headache pain is essential for physicians and other healthcare providers to adequately address and manage the patient with headaches.

Headaches may be categorized as either primary or secondary. Most headaches are primary in origin—this includes migraine, cluster, and tension headaches. Secondary headaches, which are secondary to another cause (e.g., trauma, infections) are fewer in number; however, because most of the secondary causes have been well studied, secondary headaches generally can be effectively treated. Before assuming a diagnosis of primary headache, it is necessary to rule out headaches secondary to an underlying cause. It is important to keep in mind that malignancy is fairly unusual, even though anecdotal reports of individuals who have been diagnosed with a brain tumor following a headache abound. Many imaging technologies have become available to help in the diagnosis of headaches. These include computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and nuclear medicine studies. It is important that physicians understand the indications and limitations of each test so that patients are not put through unnecessary and/or costly procedures.

Several therapies exist to treat headaches. These include pharmacologic medications and nonpharmacologic interventions (e.g., alternative medicines and therapies). There are also new approaches to preventing headaches for those patients who are experiencing chronic headaches. Physicians and other clinicians should familiarize themselves with the latest evidence regarding diagnosis and management of headaches. International Headache Society (IHS) diagnostic criteria have been used throughout this course; however, it should be noted that changes to these specific criteria may be made in the future.

The following case study will be referenced throughout the text to illustrate the challenges of treating a patient who presents with a headache.

Mrs. T is an African American woman, 68 years of age, with a past medical history significant for type 2 diabetes, hypertension, hyperlipidemia, osteoarthritis, and coronary artery disease. She presents to the clinic with a chief complaint of "headache." Mrs. T describes the headache as a dull pain that has been intermittent over the past several weeks. It is not localized to any particular area, but rather seems to be more diffuse. It does not radiate to the neck, back, or any other parts of the body. It first started about a month ago.

She has taken ibuprofen and aspirin sporadically with some relief. As the headache has been persistent over the past few weeks, she thought it was important to come in and be evaluated. She states that she has been looking up information on headaches on various health websites and she now thinks she needs a "brain scan." She has no prior history or family history of migraines; she does report a history of what she considers to be some tension-type headaches in the past few years. She believes these are due to stress at work, as they usually resolve within a day with relaxation, rest, and ibuprofen. She has never been evaluated for these episodes. The patient also remarks that over the past several days she has occasionally felt a little dizzy and light-headed, but those symptoms have largely resolved. She denies any confusion or loss of consciousness, but her daughter, who accompanies her to the clinic, states that Mrs. T had an episode about a week ago where she seemed disoriented in the morning for approximately an hour. According to the daughter, "Lately, Mom sometimes seems in a fog."

2. EPIDEMIOLOGY

Almost everyone experiences a headache at some point in their life. In fact, approximately three-fourths of all adults in the United States experience some type of headache each year. The prevalence of headache varies by gender, with women having a greater incidence of headaches than men. It has been estimated that nearly nine out of ten women, and seven out of ten men, have a headache at least once during her/his lifetime [4]. In developed countries, tension-type headache is more common in women, usually by a factor of about two to one [3].

In the overwhelming majority of cases, headaches are transient and benign. People simply treat the headache with either rest and/or relaxation, or they utilize various over-the-counter analgesics. In fact, the public spends more than $2 billion annually on over-the-counter medications to treat headaches [5]. Less than 5% of adults with headaches actually seek medical attention. Even with this small percentage, however, headaches are one of the most common complaints addressed by primary care physicians and clinicians and represent the reason for nearly 3% of all visits to the emergency department [1].

People typically seek medical care when they have increased headache frequency, an unusually intense headache, or persistent symptoms. Headaches can be one of the most difficult and challenging disorders to accurately diagnose and treat, so it is important for physicians and other clinicians to become familiar with the latest evidence on headache diagnosis and management.

ECONOMICS

Headaches are a costly condition. It has been estimated that headaches are responsible for nearly 30 million days of lost productivity, both in terms of lost days at work, as well as decreased effectiveness while at work. Headaches cost an estimated $18 billion in both direct and indirect expenditures yearly. Most costs are indirect as the majority of headache sufferers do not seek medical attention [2,7,8,9].

Although migraine is more disabling than tension-type headache, tension-type headache is more common. Each year, more than 70% of the global population has episodic tension-type headache and 1% to 3% has chronic tension-type headache (i.e., headache occurring at least 15 days per month). The World Health Organization (WHO) has confirmed that the problem of lost productivity in the workplace is worldwide, with headache disorders being the third most common cause of years lost to disability and migraine alone being the sixth most common cause [2,3,6,10].

Headaches also represent a significant socioeconomic burden. Along with lost and reduced work, headaches also affect other activities, such as one's ability to perform effectively in school or enjoy time with family and friends. In essence, headaches reduce the quality of life.

3. BASIC PATHOPHYSIOLOGY

The pathophysiology of headaches is multifactorial and complex. When lesions of the brain cause headache (e.g., mass, fluid, hemorrhage), they do so by involving pain-sensitive structures inside the skull, such as arteries at the base of the brain, the dura area blood vessels, and certain cranial nerves (e.g., CN V, VII, IX, X) that carry pain fibers. In addition, the external structures of the head are all pain-sensitive and give rise to a variety of headaches.

TYPES OF HEADACHES

As noted, headaches may be categorized as either primary or secondary in nature. Primary headaches are pure headache syndromes, meaning they are self-originating and not triggered or produced by other disorders. Primary headaches include migraine, cluster, and tension-type headaches [11]. Nearly 90% of all headaches are primary in nature [12]. Although migraine headaches receive a great deal of press in medical and lay literature, of the primary headaches, tension-type is the most common, followed by migraines, and then cluster [13]. It is important to note that primary headaches are diagnosed only when other underlying disease processes have been eliminated.

Secondary headaches, as the name indicates, occur secondary to another cause (i.e., they are a symptom of other diseases). These may include vascular, traumatic, neoplastic, infectious, pressure, and metabolic disorders [11]. Secondary headaches account for only 10% of headaches. Although some causes of secondary headache are common, others are important to recognize because they are dangerous and may require specific treatment [12]. For example, patients with chronic tension headaches may present with an epidural hematoma, and patients with migraine may actually have a brain tumor. Primary and secondary headaches should not be considered mutually exclusive when evaluating a patient with headache. It is helpful to consider secondary headaches in terms of etiologic categories. Some of the more common causes of secondary headaches are as follows [13]:

Traumatic

- Epidural hematoma

- Subdural hematoma

Vascular

- Subarachnoid hemorrhage

- Giant cell arteritis

- Arterial dissection

- Stroke

Neoplastic

- Primary brain tumor

- Metastatic brain tumor

Infectious

- Meningitis

- Encephalitis

- Sinusitis

- Abscess

Pressure

- Hypertension

- Idiopathic intracranial hypertension

Metabolic

- Toxic ingestions (e.g., carbon monoxide, lead poisoning)

Other

- Syringomyelia

- Dental and myofascial

- Cervicogenic

- Medication overuse

- Herbal medications

4. WORK-UP OF HEADACHES

The work-up of headaches includes the patient's history and a thorough physical examination and may also include laboratory studies, imaging procedures, and a lumbar puncture.

ASSESSING HEADACHES IN PATIENTS WITH THE ASSISTANCE OF AN INTERPRETER

As a result of the evolving demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient history is such a vital aspect of the assessment of headaches, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Many view interpreters merely as neutral individuals who communicate information back and forth. However, another perspective is that the interpreter is an active agent, negotiating between two cultures, and assisting in promoting culturally competent communication and practice [15]. Interpreters who are professionally trained have covered aspects of ethics, impartiality, accuracy, and completeness [16]. They are also well-versed in interpreting both the overt and the latent content of information without changing any meanings and without interjecting their own biases and opinions [16]. Furthermore, knowledge about cross-cultural communication and all the subtle nuances of the dynamics of communicating in a mental health or general health setting is vital [17].

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. In any case in which information regarding diagnostic procedures, treatment options, and medication/treatment measures is being provided, the use of an interpreter should be considered.

HISTORY

As with any disease, history-taking is critical in determining the correct diagnosis. The goals of history taking are to classify the headache type(s) and screen for secondary headache. An inadequate history is the probable cause of most misdiagnoses of the headache type [11,18,19].

It is important to focus on the following characteristics when interviewing a patient who presents with a headache [13,20]:

Position/Location

- Where on the head does the pain occur?

- Is the headache unilateral or bilateral?

- Does the pain radiate anywhere (e.g., neck, back, jaw)?

- Is the face involved?

Quality/Character

- What does the headache feel like? Is it pounding, throbbing, aching, piercing, squeezing, etc.?

- How intense is the headache on a scale of 1 to 10? Is it mild, moderate, severe, or incapacitating? Is it the worst headache one has ever had?

Frequency/Duration

- How often do the headaches occur?

- How long do they last?

- What time of day do the headaches occur?

- What time of year do the headaches occur?

- If the headaches are recurrent, what is the interval between headaches?

- What is the minimum, maximum, and usual duration?

- How long has this particular type of headache been affecting the patient?

Associated Factors

- Is there a fever?

- Any nausea, vomiting, congestion, flushing, arthralgia, depression, weight loss, etc.?

- Is there photophobia?

- Any neck stiffness?

- Any dental problems?

Aggravating Factors

- What makes the headache worse?

- Does head or body position make the headache better?

- Does coughing, sneezing, or bending affect the headache?

- Is the headache associated with menses?

Alleviating Factors

- What makes the headache better?

- Does ice or compression minimize the headache?

- Does a dark, cool room make it better?

- How does movement affect the headache?

- What types of medications have been tried? Have they been effective?

Environmental Exposures

- How does the environment affect the headache? For example, does exposure to bright light, loud noises, odors, cigarette smoke, temperature, foods, or alcohol affect the headache?

- Does the patient work around any metals or an industrial plant?

Associated Neurologic Symptoms

- Any visual, sensory, or motor abnormalities?

- Any dizziness or confusion?

- Any loss of consciousness?

- Is there any weakness?

- Does the patient exhibit ataxia?

Current and Past Medical History

- At what age did headaches first occur?

- What other medical conditions does one currently have (e.g., coronary artery disease, hypertension, depression, psychiatric disorder)?

- What are the current medications, including over-the-counter medications as well as supplements and herbal medicines? Is caffeine ingested on a regular basis?

- What medications have been recently terminated?

- Any recent trauma?

- Any recent falls?

Family History

- Does anyone else in the family have these types of headaches?

- Do any diseases or other medical conditions (e.g., cancer, stroke, diabetes, hypertension) run in the family?

Social History

- How are matters at home and at work?

- Is there any significant current stress?

- Are any illicit drugs used?

- Does the patient engage in unprotected sexual intercourse? In the past?

The above sample list of questions may seem daunting, especially in the context of a brief office visit. However, it is critical that a detailed history be obtained. It may be more efficient to have a questionnaire available for patients to fill out while they are waiting, or even prior to the office visit.

Upon further questioning, Mrs. T denies any fever, nausea, or vomiting. She denies depression or weight loss. She has not had visual disturbances. She does not recall any environmental exposures. Her current medications include metformin, lisinopril, simvastatin, and celecoxib. She remarks that her job is going quite well, and she does not feel particularly stressed from work. She works as a senior account manager at a consulting firm.

She has not had any change in medications and does not use any herbs or supplements. She drinks two cups of coffee a day, and there has been no recent change in her coffee consumption. There is neither family history of headaches nor family history of cancer. Both parents died of heart disease. She does note that she recently tripped and fell outside (almost a month ago) while playing with her grandson, but denies any serious consequences from the fall other than a sore left wrist. She denies any residual weakness. She notes that she does not feel "quite 100%" but does not feel confused or "in a fog."

PHYSICAL EXAM

A thorough physical exam is necessary for all patients who present to either the physician's office or the emergency department with a headache. The goal of the history and physical evaluation is to rule out findings that may suggest a headache of secondary pathology [13,18,19,20,21,22]. All parts of the physical exam are important, but consider paying particular attention to the following:

- Vital signs: Carefully check blood pressure, respirations, heart rate, and temperature. Determine whether the patient is orthostatic.

- Skin: Observe color and texture, and carefully inspect for any rashes, petechiae, bruising, or lesions.

- Head, eyes, ears, nose, and throat (HEENT): Note the size, symmetry, and shape of the head. Inspect for bruises, masses, and/or nodules while palpating the head and neck. Palpate the temporal arteries. Be sure to auscultate for bruits over the scalp, eyes, and carotids. Assess the temporomandibular joint for clicking. Check for nuchal rigidity. Palpate the thyroid gland. Determine any decreased arterial pulsations. Check for sinus tenderness, especially frontal and maxillary areas.

- Eyes: Check visual function and extra-ocular movements, specifically looking for ptosis or miosis. Perform funduscopy to evaluate disc margins, papilledema, and any evidence of retinal hemorrhages.

- Oral cavity: Check for decay, abscesses, loose teeth, etc.

- Cardiac: Listen carefully for murmurs or abnormal heart sounds.

- Extremities: Assess thoroughly range of motion.

- Neurologic: Assess all cranial nerves, muscle strength, reflexes, and cerebellar function. Consider performing the Mini-Mental Status Exam.

WARNING SIGNS OF SIGNIFICANT DISEASE

Although most headaches are benign, clinicians should be aware of the following "red flags" or warning signs that should prompt an immediate and exhaustive work-up and possible referral to an appropriate specialist for further assessment [5,13,20,21,23]:

- Onset in or after middle age (>50 years of age)

- Sudden onset, rapid time to peak headache intensity (i.e., seconds to five minutes)

- First or worst sudden, severe headache

- Accelerating pattern, progressively worsening

- Fever

- Seizure

- Change in level of consciousness

- Abnormal neurologic, physical, or systemic findings

- New headache in patients with cancer, immunosuppression, or pregnancy

On physical exam, Mrs. T's blood pressure is 135/82 mm Hg, heart rate is 78 BPM, respirations are 18/minute, temperature is 98 degrees, height is 5'5", and weight is 135 lbs. The physical exam is largely unremarkable. There are no masses appreciated, no petechiae noted, no sinus pain or tenderness, no scalp tenderness, and no neck stiffness. There are no visual defects and no focal neurologic deficits with the exception of minimal decrease in muscle strength in lower extremities bilaterally. She scored a 26 (maximum score: 30) on the Mini-Mental Status Exam, with some difficulty remembering three objects as well as performing serial 7s.

Given the patient's age and the fact that the headache has been persistent, a clinician should order a more extensive work-up. The patient seems to be dismissive of the minor fall, but this should be explored further. Although it would be easy to attribute this headache complaint to a tension-type headache, secondary causes should be excluded.

LAB STUDIES

In general, most headache diagnoses will be made based upon the history and physical exam [13,20]. However, laboratory studies may aid in the diagnosis. For example, clinicians may want to measure basic serum chemistries, complete blood count with differential, liver function tests, and thyroid function tests. These tests will provide a general overview of the patient's health and help guide diagnosis and treatment choices.

A resting electrocardiogram (EKG) should be considered if the history or cardiac exam is abnormal or if the patient has signs of an arrhythmia. Some headaches may have a cardiac etiology, and some treatments for headaches may have an impact on cardiac function.

Mrs. T's laboratory tests are as follows:

Na 138; Cl 100; K 4.0; CO_2 26; BUN 15; Creatinine 0.9; Glucose 125; Hgb 12.5; Hct 38; WBCs 5,000; Platelets 200,000; TSH 0.9; T3 120; ALT 30; AST 32; Alk phos 70; Total bili 1.0; LDH 120; GGT 22; ESR 35

EKG: normal sinus rhythm at 78 BPM; left axis deviation; evidence of old anterior infarct. No acute changes.

ELECTROENCEPHALOGRAM

Electroencephalogram (EEG) is not frequently used and not recommended in the routine work-up of headaches. It has minimal value in determining any structural causes of headaches. It may be useful, however, when patients present with encephalopathy, focal neurologic deficits, atypical aura symptoms, or altered consciousness [21,22,24].

LUMBAR PUNCTURE

In general, lumbar puncture is indicated when there is clinical suspicion of central nervous system (CNS) infection, cancer, hemorrhage, or conditions that result in a change in cerebrospinal fluid (CSF) pressure; it is not recommended in the routine evaluation of headaches [13,21,23]. Examples of indications include meningitis, encephalitis, idiopathic intracranial hypertension, meningeal carcinomatosis, or subarachnoid hemorrhage [5,25]. If an intracranial mass lesion is suspected, or if the patient has papilledema on funduscopic exam, lumbar puncture should be deferred until after CT evaluation to reduce the possibility of cerebellar herniation [23,25,26].

When lumbar puncture is performed, it is helpful to measure the opening pressure and perform a complete analysis of CSF, including glucose, protein, and differential blood count. In addition, opening pressure, supernatant color, and latex agglutination are sometimes useful. CSF examination is helpful in diagnosing subarachnoid bleeding, infection, and high and low CSF pressure syndromes [27]. It is important to avoid a traumatic tap. Such a tap, which leads to bleeding, could make it more difficult in establishing the diagnosis of subarachnoid hemorrhage [5]. In addition, the procedure itself may actually cause a headache [28,29]. This usually occurs 48 to 72 hours following the procedure if too much fluid has been removed [30].

IMAGING

In general, routine neuroimaging, such as CT, MRI, MRA, or positron emission tomography (PET), of people with headaches and normal physical examinations has a very low yield and is not considered to be cost-effective. However, it is important to remain cognizant of the strengths and weaknesses of each imaging modality when considering and ordering such studies [31,32]. MRI may be more sensitive than CT for identifying clinically insignificant abnormalities. However, MRI may not be more sensitive for identifying clinically significant pathology that is relevant to the cause of headache [22].

CT scans may be performed either with or without contrast. Unless there is a contraindication to the use of contrast agents, most scans are performed with contrast in the diagnostic work-up of headaches. A contrast-enhancing CT scan can be an effective test for identifying several serious lesions that may be causing headaches [33,34].

Evidence Based Practice Recommendation

According to the American College of Radiology, the imaging mode of choice for patients who present with sudden onset of severe headache ("worst headache of one's life" or "thunderclap headache") is CT without contrast.

https://acsearch.acr.org/docs/69482/Narrative

Last Accessed: April 5, 2022

Level of Evidence: Expert Opinion/Consensus Statement

CT is usually obtained in the setting of trauma or the abrupt onset of headache [27]. Primary indications include acute head trauma, suspected acute intracranial hemorrhage, mental status changes, headache, acute neurologic deficits, suspected intracranial infection or hydrocephalus, brain herniation, and suspected mass tumor. It may also be used in cases in which MRI is primarily indicated but unavailable, contraindicated, or delayed [34].

In general, CT scans are widely available, quickly performed, and well-tolerated by patients. The technology has been around for quite some time, and most patients are familiar with it [34]. In addition, there are "open" CT scanners that help minimize the feeling of claustrophobia some patients experience. This scan detects most space-occupying lesions such as brain tumors, subdural hematomas, and CNS abscesses. It can also show fluid from hydrocephalus and cerebral edema, and it can reveal bleeding and structural abnormalities such as some arteriovenous malformations. However, CT scanning can miss aneurysms, and it also does not provide adequate views of the sphenoid sinus. Adding "bone windows" on CT provides much better detection of skull fractures, especially as compared to plain films.

MRI is the diagnostic test of choice for most patients [27]. However, it is not as readily available as CT [34]. MRI is more sensitive for detecting lesions within the posterior fossa (specifically because of bony artifacts that limit CT's visualization), pituitary area, paranasal sinuses, and leptomeninges [34,35]. It has also proven effective in identifying some otherwise occult tumors and infarcts. MRI is also more sensitive for detecting vascular abnormalities, although it is not as sensitive as CT in revealing early subarachnoid bleeding. In addition, special MRI images can evaluate problems with the orbit or optic nerve areas. When abnormalities of the cervical spine are suspected, MRI is the preferred imaging technique, especially compared to plain films. "Open" MRI scanners may be used to help diminish claustrophobia or to accommodate obese patients [34].

MRA is essentially an MRI of the blood vessels. MRA can be useful when suspecting circulatory causes of headache. For example, it provides increased sensitivity for unruptured aneurysms, as well as arterial stenosis. It is rarely useful, however, as a first-line study but rather helps to determine who may ultimately require an angiogram. This technology is not universally available. Many institutions also lack the appropriate staff for this procedure [32].

Plain films are rarely useful for diagnosing the etiology of headache unless CT and MRI are unavailable [34]. These films can demonstrate bony defects, such as fractures or other skeletal abnormalities, but usually there are others sources to obtain this data. In addition, the use of plain films for most cases of sinusitis is not usually cost effective in the work-up of headaches. In some institutions, nuclear medicine brain scans, or PET imaging scans, have been used with success as an ancillary procedure.

The choice of a specific imaging study depends on numerous factors, including clinical suspicion, availability of a given test, time necessary to perform the test, and the amount of time available to make a treatment decision. A patient should not undergo a test simply because it is available, but rather the information obtained from an imaging study should impact decision making. Ideally, one wishes to avoid additive tests, such as a situation in which an MRI is a better study (e.g., for posterior fossa infarcts), but a CT is ordered because it is more rapidly available.

The U.S. Headache Consortium has issued guidelines relating to neuroimaging in patients with nonacute headache. The guidelines include three consensus-based general principles of management [22]:

- Testing should be avoided if the test results will not lead to a change in management.

- Testing is not recommended if the individual is not significantly more likely than anyone else in the general population to have a significant abnormality.

- Testing that normally may not be recommended as a population policy may make sense at the individual level, resources notwithstanding. For example, exceptions might be made for patients who are disabled by their fear of serious pathology.

The Consortium additionally has issued the following specific recommendations regarding neuroimaging [22]:

- Neuroimaging should be considered in patients with nonacute headache and an unexplained abnormal finding on the neurologic exam.

- Neuroimaging is not usually warranted for patients with migraine and normal neurologic examination. For patients with atypical headache features or patients who do not fulfill the strict definition of migraine, or have some additional risk factor(s), a lower threshold for neuroimaging may be applied.

Relating to CT and MRI, the panel did find that MRI appears to be more sensitive in finding white matter lesions and developmental and/or venous anomalies than CT. However, it noted that this difference had little clinical relevance, and thus did not make any recommendations on preferred testing methods in the evaluation of headaches [22].

5. PRIMARY HEADACHES

As noted earlier, there are three types of primary headaches: migraine, cluster, and tension-type (Table 1).

Table 1: CHARACTERISTICS OF PRIMARY HEADACHES

Characteristics

Migraine

Cluster

Tension

Position

Unilateral

Unilateral

Bilateral

Quality

Throbbing, pulsating, pounding; moderate to severe

Burning, piercing, sharp; severe

Tightness, aching, pressure; mild to moderate

Radiation

None

None

None

Duration

4 to 72 hours

15 to 180 minutes

30 minutes to seven days

Triggers

Foods, oversleeping, stress, depression, decreased barometric pressure, hormonal variations, caffeine withdrawal

Alcohol, change in temperature, breezes on the face, a change in physical, mental, or emotional activity

Stress

Associated symptoms

Nausea, vomiting, photophobia

No nausea, vomiting, or photophobia

No nausea/vomiting; occasional photophobia or phonophobia

Therapies

Lifestyle modification, biofeedback, acupuncture, medications, exercise, consistent sleep schedule

100% oxygen, medications

Hot/cold packs, ultrasound, exercise, consistent sleep schedule, medications

Source: Compiled by Author

MIGRAINE HEADACHES

A migraine is a type of neurovascular headache that is initiated by a neurologic event that causes vasodilation, which in turn is interpreted by the brain as pain. It is important to realize that the event that initiates this cascade is not dilation of the blood vessels in the brain but rather a primary neural event. The exact neural event that is occurring is not completely understood, but it seems to involve the dysfunction of an ion channel in the brain stem that normally controls sensory input and exerts influences on cranial vessels [36]. Migraine is believed to have a genetic basis [3].

Adults with migraine headache describe episodic attacks with pain of moderate-to-severe intensity that are often throbbing in quality, unilateral in position, and aggravated by physical exertion. Migraines are usually associated with nausea, vomiting, and sensitivity to light and sound. Nausea is the most common characteristic. The duration of these attacks, when not treated, may last anywhere from 4 to 72 hours [3].

The prevalence of migraine headache in developed countries is in the range of 16% to 25%, with women approximately two to three times more likely to have migraines than men [3,6,37]. In children, however, prevalence is equal between males and females. It is during adolescence that a female predominance occurs. The incidence of migraine is highest among individuals 35 to 45 years of age, but it may affect much younger people, including children [3,38]. The prevalence of migraine in children has increased in the past 20 to 30 years. Environmental factors may precipitate migraine attacks in persons with a predisposition to migraine [38].

Data from the American Migraine Study II showed that the overall prevalence of migraine was higher in whites than in blacks, highest in middle life, and inversely related to household income. The frequency of severe headache was similar for males and females, with 62% reporting one or more severe headaches per month, and 36.8% reporting one to three severe headaches per month. The results of this and other studies have also indicated that the burden of migraine in the United States remains substantial (more than $13 billion per year) due to misdiagnosis, underdiagnosis, and improper treatment [37,38,39,40,41].

A study published in 2003 has suggested the use of the following three screening questions to identify migraine sufferers. A "yes" response to two of the questions can effectively identify patients who have true migraines [42]:

- Has a headache limited your activities for a day or more in the last three months?

- Are you nauseated or sick to your stomach when you have a headache?

- Does light bother you when you have a headache?

Although this set of questions has been validated, more studies are still necessary to determine its general applicability. It may be helpful, however, in identifying complicated cases. Additionally, the IHS has incorporated the criteria into their guidelines.

Migraine headaches are essentially a syndrome with a range of neurologic and non-neurologic characteristics. They are classified into two major categories (Table 2 and Table 3):

- Migraine without aura

- Migraine with aura

These were formerly referred to as "common" and "classic" migraines [43].

Table 2: CRITERIA FOR DIAGNOSIS OF MIGRAINE WITHOUT AURA

At least five attacks with the following characteristics:

1. Episodic attacks of headache lasting 4 to 72 hours

2. At least two of the following headache characteristics:

- Unilateral location

- Throbbing or pulsating quality

- Pain of moderate or severe intensity

- Aggravated by or causing avoidance of routine physical activity

3. At least one of the following symptoms during headache:

- Nausea

- Vomiting

- Photophobia

- Phonophobia

4. Not better accounted for by another diagnosis

Source: [43]

Table 3: CRITERIA FOR DIAGNOSIS OF MIGRAINE WITH AURA

At least two attacks not better accounted for by another diagnosis (particularly transient ischemic attack) fulfilling two criteria:

1. One or more of the following fully reversible aura symptoms:

- Visual

- Sensory

- Speech and/or language

- Motor

- Brainstem

- Retinal

2. At least two of the following four characteristics:

- At least one aura symptom spreads gradually over five or more minutes and/or two or more symptoms occur in succession.

- Each individual aura symptom lasts 5 to 60 minutes.

- At least one aura symptom is unilateral.

- The aura is accompanied, or followed within 60 minutes, by headache.

Source: [43]

Migraines without aura are migraine headaches without an associated neurologic disturbance. Typical characteristics include headache of unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea and/or photophobia and phonophobia. These are the most common type of migraine, accounting for nearly 80% of migraines. They have a higher average attack frequency and are usually more disabling than migraine with aura [43].

Migraines with aura, seen in approximately 15% to 20% of patients with migraine, are preceded or accompanied by transient focal neurologic symptoms that usually develop gradually over 5 to 20 minutes and last for less than 60 minutes [43]. Aura symptoms may be sensory, motor, or visual but most commonly present as visual symptoms. The visual symptoms tend to manifest as scintillating scotomata, such as flashing lights, zigzags of light, and small blind spots [13]. On average, they last 20 to 30 minutes.

Premonitory symptoms occur hours to a day or two before a migraine attack (with or without aura). They include various combinations of fatigue, difficulty in concentrating, irritability, neck stiffness, sensitivity to light or sound, nausea, blurred vision, yawning, and pallor. The IHS has recommended that the terms "prodrome" and "warning symptoms" be avoided because they are often mistakenly used to include aura [43]. Migraines with aura have been additionally subdivided into typical migraine, migraine with brainstem aura, hemiplegic migraine, and retinal migraine [43]. Additional types of migraines include episodic syndromes that may be associated with migraine, chronic migraine, complications of migraine, and probable migraine [43].

Familial hemiplegic migraine (FHM) is a type of hemiplegic migraine that is often earlier in onset than typical migraine, frequently beginning in the first or second decade. These attacks are characterized by visual disturbance, dysphasia, and severe unilateral weakness and may also be accompanied by unilateral numbness of the face, arms, and legs. The attacks tend to be prolonged and may last for hours or days [43,44]. The diagnosis of FHM requires at least one affected first-degree or second-degree relative, and most individuals diagnosed with FHM have an affected parent [44]. Three subtypes of FHM have been identified: FHM1, FHM2, and FHM3 [44]. In approximately 50% of FHM1 families, chronic progressive cerebellar ataxia occurs independently of the migraine attacks. FHM is often mistaken for epilepsy and (unsuccessfully) treated as such [43]. Molecular genetic testing is available for the three genes known to be associated with FHM [44]. In many cases, FHM1 additionally has brainstem symptoms [43].

Sporadic hemiplegic migraine is migraine with aura including motor weakness but no affected first- or second-degree relative. Sporadic cases occur with approximately the same prevalence as familial cases and have similar clinical characteristics. Sporadic cases require neuroimaging and other tests to rule out other cause. A lumbar puncture is also necessary to rule out pseudomigraine with temporary neurologic symptoms. This condition is more prevalent in males and is often associated with transient hemiparesis and aphasia [43].

Migraines with brainstem aura (previously referred to as basilar migraines) occur in adolescence and young adulthood. The origin of the neural event is in the brain stem; as a result, the basilar artery dilates and causes a variety of bilateral aura symptoms. The aura of these migraines includes two or more of the following symptoms: diplopia, vertigo, tinnitus, hypoacusis, ataxia, and decreased level of consciousness [43]. These migraines are associated with a slightly increased risk of migrainous infarction when compared to other migraine types.

Retinal migraine is a type of migraine with aura associated with repeated attacks of monocular visual disturbance, including scintillations, scotomata or blindness [43]. Diagnosis is confirmed with a clinical visual field examination and/or the patient's drawing (made after clear instruction) of a monocular field defect.

Approximately 3% to 5% of patients with migraine experience an aura without headache. This presentation, formerly known as a "migraine equivalent," tends to occur in older individuals who have had a history of migraines with aura in their earlier years [45]. They predominantly occur in men of advanced age.

The symptoms of a migraine do not always end with resolution of the headache. Following a migraine, individuals tend to have continued symptoms. These symptoms are quite varied in scope and may manifest as impaired concentration, fatigue, irritability, listlessness, muscle weakness, anorexia, food cravings, and euphoria. Keep in mind that migraine headaches are quite heterogeneous and vary widely in scope. Not only do they vary from patient to patient, they even vary in the same individual [46].

Triggers

Many different factors work to trigger migraines. These factors vary greatly from one individual to another and often no precipitating events can be clearly identified. Trigger factors increase the probability of a migraine attack in the short term (i.e., usually in less than 48 hours) in a person with migraine. Some of the more common triggers include stress, sleep disturbances, depression, low barometric pressure, food, hormonal variations, and caffeine withdrawal. Some trigger factors have been reasonably well studied epidemiologically (e.g., menstruation) or in clinical trials (e.g., chocolate, aspartame); however, causal attribution in individual patients may be difficult [43].

For individuals who are not certain of what triggers their headaches, it may be helpful to recommend keeping a headache diary. This diary allows individuals to chronicle their headaches and document details, such as warning signs, time duration of headache, location of pain, intensity of pain, and treatment attempts/effects, along with details of their diet, sleep patterns, medications, stress, and menstrual cycle (if applicable). This is a useful tool in elucidating the relationship between events, environment, and migraines. The headache diary has been shown to improve diagnostic accuracy and allow a more precise judgment of medication consumption. It may also help in judging the quantity of two or more different headache types or subtypes, and it teaches the patient how to distinguish between different headaches.

Evidence Based Practice Recommendation

The Institute for Clinical Systems Improvement asserts that migraines occurring in association with menses and not responsive to standard cyclic prophylaxis may respond to hormonal prophylaxis with use of estradiol patches, creams, or estrogen-containing contraceptives.

https://www.icsi.org/wp-content/uploads/2019/01/HeadacheRR.pdf

Last Accessed: April 5, 2022

Level of Evidence: Expert Opinion/Consensus Statement

Migraine headaches in premenopausal women often correlate with menses, when estrogen and progesterone levels precipitously drop. These same women, when on birth control pills, develop a similar headache pattern with initiation of their placebo pills, when estrogen and progesterone levels are low. It has been suggested that altering the schedule of birth control pills may significantly reduce the number and severity of the headaches; however, women who experience migraine with aura should not use a combined oral contraceptive pill [11,47]. Despite the increased prevalence of headache and migraine in premenopausal women, migraine is underdiagnosed in this population [48].

Approximately two-thirds of women with migraines experience headache improvement during the course of a pregnancy [49]. Usually, symptoms during the first trimester determine whether pregnant patients will experience relief—if symptoms resolve during the first trimester, patients usually remain headache-free throughout the pregnancy; if symptoms persist during first the trimester, they usually remain throughout the pregnancy [13]. Keep in mind that although most headaches during pregnancy are typically migraine or tension, secondary causes should be ruled out.

People who are prone to migraines also find that caffeine, which can acutely help with headaches, may work to precipitate headaches if it is withdrawn after a period of continuous daily use. Many different foods contain chemicals that may act to initiate the headache cascade (Table 4).

Table 4: COMMON FOOD TRIGGERS

Trigger

Causal Factor

Food

Chemical trigger

Cheese

Tyramine

Chocolate

Theobromine

Citrus fruits

Phenolic amines

Hot dogs, ham, cured meat

Nitrites, nitric oxide

Dairy products, yogurt

Allergenic proteins (casein)

Chinese food

Monosodium glutamate

Coffee, tea, cola

Caffeine

Artificial sweeteners

Aspartame

Wine, beer

Histamine, tyramine, sulfites

Source: Compiled by Author

In addition to determining what may trigger a headache, it is important to have an understanding of the impact of a headache on an individual's quality of life and productivity. One way to get a fast yet effective understanding is with the use of the validated questionnaire called the Migraine Disability Assessment Scale (MIDAS) (Table 5) [50]. The MIDAS was developed to measure headache-related disability and improve communication between patient and physician about the functional consequences of migraine. Scores on the MIDAS have been highly correlated with physician judgments about the severity of illness and need for treatment. It may play a role in improving the care of patients with migraine and other types of headache [51].

Table 5: MIGRAINE DISABILITY ASSESSMENT SCALE (MIDAS)

- On how many days in the last three months did you miss work or school because of your headaches?

- How many days in the last three months was your productivity at work or school reduced by half or more because of your headaches?

- On how many days in the last three months did you not do household work because of your headaches?

- How many days in the last three months was your productivity in household work reduced by half or more because of your headaches?

- On how many days in the last three months did you miss family, social, or leisure activities because of your headaches?

- On how many days in the last three months did you have a headache?

- On a scale of 0–10, on average how painful were these headaches?

Source: [50]

Treatment Goals

The goals of both pharmacologic and nonpharmacologic long-term migraine treatment are to [52,53]:

- Reduce attack frequency, severity, and disability

- Reduce reliance on poorly tolerated, ineffective, or unwanted acute pharmacotherapies

- Improve quality of life

- Avoid acute headache medication escalation

- Educate and enable patients to manage their disease to enhance personal control of their migraine

- Reduce headache-related distress and psychologic symptoms

Behavioral and physical interventions are used for preventing migraine episodes rather than for alleviating symptoms after an attack has begun. Although these modalities may be effective as monotherapy, they are more commonly used in conjunction with pharmacologic management [52].

Nonpharmacologic Treatment for Migraines

The cornerstone of nonpharmacologic therapy for treating migraine headaches involves empowering patients with knowledge. Educating patients about their diagnosis allows them to have a better understanding of what is occurring and what factors may be contributing to their headaches. Patients should be involved in formulating a management plan. Regular re-evaluation of therapy is also important [54,55].

Migraine is a chronic neurologic disorder that may require patients to undergo some level of lifestyle change. Lifestyle modification is one of the most important aspects of nonpharmacologic therapy. Lifestyle modification includes dietary changes, stress management techniques, establishment of regular sleeping and eating habits, and moderate exercise. These may help ease both the severity and frequency of migraine headaches. After the early signs of headaches are identified, additional attempts may be made to further reduce symptoms.

As noted, patients' headaches are often precipitated by food triggers. Patient education includes teaching patients to recognize these triggers and then avoid them, which may help patients to become headache-free. A headache diary, as discussed previously, may help patients to identify these food triggers [20,55]. Consultation with a nutritionist may help patients find alternative foods. In addition, patients should be counseled to maintain a regular diet and avoid skipping meals. Moreover, they should consume at least eight 8-ounce glasses of water daily [56].

It has been estimated that more than 85% of headache patients use complementary and alternative medicine (CAM) therapies. Some CAM techniques have been shown to be beneficial and effective in preventing migraine. Behavioral interventions (e.g., biofeedback, stress management, psychotherapy) should be part of the standard of care for a difficult migraine patient, especially when stress is a major trigger or when analgesics are being overused [13,55]. Stress management techniques, including biofeedback and acupuncture, have been successful for some patients and have been recommended to help patients reduce the frequency and severity of migraine headache [11,23]. These techniques are most successful with a motivated patient, especially one who is trying to avoid pharmacologic therapy. It should be considered, particularly for pregnant patients and those not easily treated with pharmacologic agents. However, it is time-consuming and requires a commitment on the part of the patient [20].

Acupuncture is another therapy with which some patients have found success. It may be used as preventive management in patients with migraine and tension headache but should be used with caution in patients with severe bleeding disorders, who are pregnant, or who wear a cardiac pacemaker [11,23]. Available studies have suggested that acupuncture is at least as effective as, or possibly more effective than, prophylactic drug treatment, with fewer adverse effects [57]. It can be a valuable nonpharmacologic tool and should be considered a treatment option for patients willing to undergo this treatment [58,59,60].

Sleep disturbances are a well-known cause of headaches [61]. Insomnia has been identified as a risk factor for tension-type headache, and sleep problems have been reported as a trigger of headaches [62]. Therefore, it is important for patients to maintain regular sleep habits. This involves going to sleep and awaking at about the same time every day. It also includes avoiding stimulants around bedtime and trying to receive at least six to eight hours of sleep daily [13,56]. Patients should avoid sleep fragmentation, if possible. Interestingly, patients with a family history of hypersomnia may also experience headache [63].

Moderate exercise has also been found to be helpful in decreasing headache frequency and intensity for some migraine patients [56,64]. Exercise that decreases stress and concurrently improves cardiovascular fitness seems to be the most effective. Simply walking 30 minutes per day during a lunch hour or after work can make quite a difference in terms of decreasing headache frequency. Other migraine patients have found some relief with regular yoga classes, especially those that focus on breathing and relaxation. At a minimum, patients should be encouraged to engage in an exercise program, especially because exercise improves overall health. Ideally, patients should exercise 30 to 60 minutes, at moderate intensity, at least three times per week.

All patients who smoke should be encouraged to quit smoking. Nicotine is a well-known vasoconstrictor, and carbon monoxide is a vasodilator. Combined they can trigger the migraine process. Therefore, current smokers should be counseled to quit.

Often, a multidisciplinary approach can be effective for some patients and may lead to a decrease in migraine pain, frequency, and intensity; improved overall health status and quality of life; and improved functional status [65]. Treatment choices should be based on the severity and frequency of the headache as well as on associated symptoms and comorbidities [24].

Pharmacologic Treatment for Migraines

Unfortunately, even if a patient has some success with nonpharmacologic options, many will still need medications. Some data have suggested an enhanced effect with a combination of treatments [66].

The pharmacologic options for migraine headache fall into two main categories: acute attack treatment (also known as abortive treatment) and preventive therapies.

Acute Attack Treatments

The U.S. Headache Consortium has identified goals for the successful treatment of acute attacks of migraine [53]:

- Treat attacks rapidly and consistently without recurrence.

- Restore the patient's ability to function.

- Minimize the use of back-up and rescue medications.

- Optimize self-care and reduce subsequent use of resources.

- Be cost-effective for overall management.

- Have minimal or no adverse events.

To meet these goals, the Consortium has recommended that clinicians [52,53,54]:

- Educate migraine sufferers about their condition and its treatment; encourage patients to participate in their own management.

- Use migraine-specific agents (i.e., triptans, dihydroergotamine [DHE]) in patients with moderate or severe migraine or whose mild-to-moderate headaches respond poorly to nonsteroidal anti-inflammatory drugs (NSAIDs) or combinations such as aspirin plus acetaminophen plus caffeine. Note: The American Academy of Family Physicians/American College of Physicians-American Society of Internal Medicine has recommended the use of migraine-specific agents only when a first-line therapy of NSAIDs (e.g., aspirin, ibuprofen, naproxen sodium, acetaminophen-aspirin-caffeine combination) has failed.

- Select a non-oral route of administration for patients with migraine associated with severe nausea or vomiting.

- Consider a self-administered rescue medication for patients with severe migraine who do not respond to (or fail) other treatments.

- Guard against medication-overuse headache.

The goal of acute attack treatment should be for the patient to be pain-free within two to four hours. The patient should be able to return to full function after this time. In addition, the headache should not return within 24 hours of being pain-free. A stepwise approach is typically recommended [38]. This approach suggests that patients are to be treated with the safest, least expensive medication during the first migraine attack, and subsequently progress to more expensive medications for subsequent attacks, if the initial ones are not effective [53,67]. As a general rule, medications used to alleviate the pain of a migraine attack should be taken early after onset, when the headache is still mild, if possible.

In 2015, the American Headache Society (AHS), in cooperation with the American Academy of Neurology (AAN), provided an updated assessment of the evidence for individual pharmacotherapies for acute attack treatment (Table 6). This assessment will form the basis of new treatment guidelines [173]. The assessment was based on a systematic review of clinical trials published from 1998 to 2013 that compared the efficacy of various acute attack treatments versus placebo. It did not compare the efficacy of individual therapies [173]. Where no new studies for a particular drug were found, classifications were based on previous AAN guidelines.

Table 6: AHS EVIDENCE ASSESSMENT OF ACUTE MIGRAINE PHARMACOTHERAPIES)

Drug Class

Specific Agents and Doses

Level A (Effective)

Analgesics

Acetaminophen 1,000 mg (for non-incapacitating headache)

Ergots

DHE nasal spray 2 mga

NSAIDs

Aspirin 500 mga

Diclofenac 50 mg, 100 mg

Ibuprofen 200 mg, 200 mg

Naproxen 500 mg, 550 mga

Opioids

Butorphanol nasal spray 1 mga

Triptans

Almotriptan 12.5 mg

Eletriptan 20, 40, 80 mg

Frovatriptan 2.5 mg

Naratriptan 1, 2.5 mga

Rizatriptan 5, 10 mga

Sumatriptan (oral 25 mg, 50 mg, 100 mga; nasal spray 10 mg, 20 mg; subcutaneous 4 mg, 6 mg)

Zolmitriptan (nasal spray 2.5 mg, 5 mg; oral 2.5 mg, 5 mga)

Combinations

Acetaminophen/aspirin/caffeine 500 mg/500 mg/130 mga

Sumatriptan/naproxen 85 mg/500 mg

Level B (Probably Effective)

Antiemetics

Chlorpromazine 12.5 mg IVa

Droperidol 2.75 mg IV

Metoclopramide 10 mg IVa

Prochlorperazine 10 mg IV/IMa

Ergots

DHE 1 mg IV, IM, SCa

Ergotamine/caffeine 1 mg/100 mga

NSAIDs

Flurbiprofen 100 mga

Ketoprofen 100 mg

Ketorolac 30–60 mg IV/IM

Other

Magnesium sulfate 1–2 g IV (for migraine with aura)

Isometheptene 65 mga

Combinations

Codeine/acetaminophen 25 mg/400 mga

Tramadol/acetaminophen 75 mg/650 mg

Level C (Possibly Effective)

Antiepileptics

Valproate 400–1,000 mg IV

Ergots

Ergotamine 1–2 mga

NSAIDs

Phenazone 1,000 mg

Opioids

Butorphanol 2 mg IMa

Codeine 30 mg POa

Meperidine 75 mg IMa

Methadone 10 mg IMa

Tramadol 100 mg IVa

Steroids

Dexamethasone 4–16 mg IV

Other

Butalbital 50 mga

Lidocaine intranasala

Combinations

Butalbital/acetaminophen/caffeine/codeine 50 mg/325 mg/40 mg/30 mga

Butalbital/acetaminophen/caffeine 50 mg/325 mg/40 mga

Level U (Conflicting or Inadequate Evidence)

NSAIDs

Celecoxib 400 mg

Other

Lidocaine IVa

Hydrocortisone 50 mg IVa

For an agent to be classified as Level A, it must be supported by at least two Class I studies (randomized controlled trials in the representative population). Level B requires one Class I study or two Class II studies (randomized controlled trials not meeting the standards of Class I), and Level C required one Class II study or two Class III studies (nonrandomized controlled studies). An agent was classified Level U when evidence to support its use was either conflicting or inadequate.

aBased on 2000 American Academy of Neurology evidence review.

Source: [173]

Acute attack pharmacologic options are used at the onset of the attack. They can be divided into nonspecific and specific drugs. The nonspecific therapies are single or combination analgesics. Routes of administration include oral, nasal, parenteral, and rectal. Appropriate situations for use, including potential side/adverse effects, drug-drug interactions, and patient-specific contraindications, should be addressed. Opioids are generally avoided, if possible, due to concerns about tolerance and dependence [54,173].

The more common analgesics used include acetaminophen, NSAIDs (e.g., aspirin, ibuprofen, naproxen sodium), and narcotics (e.g., oxycodone, morphine sulfate) [38]. Acetaminophen-aspirin-caffeine combination may also be used to treat migraines. The evidence for efficacy is most consistent for aspirin, ibuprofen, naproxen sodium, and the acetaminophen-aspirin-caffeine combination. Acetaminophen alone has been found to be ineffective [53,66,173].

In the 2000 AAN guidelines, the NSAID diclofenac was considered "probably effective" for the acute treatment of migraine. Class I studies conducted since that time resulted in the agent being reassessed by the AHS as "effective" (Level A) [14,176,177].

The nonspecific therapeutic drugs may be used to relieve the pain through many different mechanisms, although most typically work by dulling pain receptors. These are usually considered first-line therapeutic options for many individuals who find these adequate in obliterating headaches [54]. In order to increase the likelihood of efficacy it is important that these are taken as early as possible in the headache cycle [38]. In addition, a large single dose tends to be more effective than repeated smaller doses. When any of these medications are used, many clinicians add an antiemetic or pro-motility agent to increase the chance of absorption, especially during an attack when nausea is a major component [53].

Over-the-counter analgesics are often effective in treating migraine. In an observational study of the impact of over-the-counter analgesics for migraines on a patient's quality of life, nearly 100 patients who used over-the-counter medications, such as acetaminophen-aspirin-caffeine combination, and who also received educational migraine materials over a four-month period completed a general health status questionnaire. At the end of the study, patients reported significant improvements in several quality-of-life measures and increased frequency of relief [69].

Ergotamines

The specific therapies include ergotamines and triptans. The ergotamines and triptans both work as vasoconstrictors. Ergotamine derivatives, although less expensive, are more nonspecific and tend to increase the likelihood of rebound headaches after their use [53,67].

The U.S. Headache Consortium reviewed the results from 23 controlled trials of ergotamine tartrate, ergotamine-containing compounds, and ergostine-containing compounds and has recommended the following regarding the use of ergot alkaloids and derivatives, all of which are supported by the recent AHS evidence assessment of migraine pharmacotherapies [53,173]:

- In the treatment of selected patients with moderate-to-severe migraine, ergot derivatives may be considered.

- Because of their inability to tolerate or take oral medication, patients with nausea and vomiting may be given DHE subcutaneous, IV, or intramuscular (IM). Initial treatment with DHE subcutaneous or IM is a reasonable choice when the headache is moderate-to-severe or an adequate trial of NSAIDs or other nonopiate analgesics has failed to provide adequate relief in the past. The use of DHE IM or subcutaneous may be considered in patients with moderate- to-severe migraine.

- DHE IV plus antiemetics is an appropriate treatment choice for patients with severe migraine.

- The use of DHE nasal spray is an appropriate treatment choice and should be considered for use in patients with moderate-to-severe migraine. Because of their inability to tolerate or take oral medications, patients with nausea and vomiting may be given intranasal DHE. Initial treatment with DHE nasal spray is a reasonable choice when the headache is moderate-to-severe or an adequate trial of NSAIDs or other nonopiate analgesics has failed to provide adequate relief in the past.

Triptans

The triptans are serotonin 5-HT1B/1D receptor agonists and act through three possible mechanisms: vasoconstriction of intracranial vessels, inhibition of neuropeptide release from the trigeminal nerve, and inhibition of central pain transmitters. The newer triptans have fewer side effects and are much less likely to cause rebound headaches as compared to their predecessors.

Although many of the serotonin 5-HT1B/1D receptors are located in the brain, some 5-HT1B receptors are located in the heart, as determined by anatomical studies using selective antibodies [70]. Triptans have been shown to constrict coronary arteries and prevent the release of pro-inflammatory neuropeptides [71]. In rarer circumstances, they may actually cause myocardial infarction [72]. Because of this, it is contraindicated to use these drugs in the setting of ischemic heart disease, uncontrolled hypertension, pregnancy, and cerebrovascular disease, such as ischemic stroke [36,38,53,73]. They should also be avoided in the treatment of FHM and basilar migraine. Triptans should not be prescribed to patients who are also taking monoamine oxidase inhibitors (MAOIs), nor should they be given within 24 hours of use of ergotamines [73]. No evidence has supported the use of triptans during the aura phase of a migraine attack [53].

Several triptan drugs are available. The drugs may be taken orally as tablets or capsules, sublingually as quick-dissolving wafers, or intranasally as a spray. Sumatriptan is also available in subcutaneous injection form [71,74].

The U.S. Headache Consortium has found that triptans are effective and relatively safe for the acute treatment of migraine headaches. They are an appropriate initial treatment choice in patients with moderate-to-severe migraine who have no contraindications for their use [52]. Patient-reported satisfaction with triptans is modest [75]. It is advisable to switch from one oral triptan to another if three migraine attacks have been treated without success [192].

Almotriptan: Almotriptan is available in oral form. It has the highest oral bioavailability of the triptans, with approximately 70% of the dose absorbed within the first hour [73,76]. A meta-analysis of 53 randomized controlled trials demonstrated almotriptan 12.5 mg to be of comparable efficacy to sumatriptan 50 mg or 100 mg [77]. Side effects include dizziness, dry mouth, paresthesia, nausea, and somnolence [53,73].

Eletriptan: Eletriptan is available in oral form. It has been suggested as one possible therapy for those patients who have a poor response to NSAIDs. In an open-label treatment study, 113 patients who suffered from migraines and did not experience a satisfactory response to NSAIDs were given eletriptan 40 mg for one migraine attack [78]. Headache, pain-free response, absence of associated symptoms, and functional response were assessed at 1, 2, 4, and 24 hours after receiving the medication. By four hours post-dose, the pain-free response rate was greater than 40% and relief of baseline symptoms was 82%. By 24 hours post-dose, only 24% of patients had headache recurrence. In a randomized double-blind study comparing eletriptan 40 mg to naratriptan 2.5 mg and placebo, 548 patients with migraines were evaluated [79]. At four hours post-dose, 67% of patients taking naratriptan experienced headache relief versus 80% for patients taking eletriptan and 44% for placebo. Patients taking eletriptan also used fewer rescue medications. Side effects include asthenia, dizziness, dysphagia, abdominal pain/discomfort, and chest tightness [53,73]. Diagnosis should be re-evaluated if the first dose is ineffective.

Frovatriptan: Frovatriptan, available in oral form, appears to have the highest potency of the triptans and may be cerebro-selective [76]. It has one of the lowest rates of headache recurrence after use. In a review of three randomized placebo-controlled trials involving almost 2,700 patients, patients using frovatriptan 2.5 mg experienced greater headache relief than placebo [80]. Side effects include fatigue, dizziness, flushing, dyspepsia, skeletal pain, and chest tightness [73].

Naratriptan: Naratriptan has the longest half-life of all the triptans. As a result, it may be particularly effective in reducing recurrence headaches in some patients. The use of naratriptan 2.5 mg was compared to naproxen 500 mg in a small, double-blind crossover study [81]. At six hours post-dose, naratriptan was more effective in relieving headache, nausea, and vomiting and did so more quickly than naproxen. Side effects include dizziness, drowsiness, malaise, paresthesias, and throat tightness [73].

Rizatriptan: Rizatriptan is one of the quickest acting oral preparations, typically reaching peak concentration in 1 to 1.5 hours. It is also available as an orally-disintegrating wafer [73,76]. In a study comparing rizatriptan 10 mg versus zolmitriptan 2.5 mg versus placebo, both drugs showed improvement in headache relief compared to placebo but there was no significant difference in symptom relief between the two drugs [82]. When taken orally, rizatriptan 10 mg is superior to sumatriptan 100 mg and naratriptan 2.5 mg on some, but not all, efficacy outcomes [71,74]. Compared to sumatriptan 100 mg and naratriptan 2.5 mg, greater proportions of patients taking rizatriptan 10 mg have measurable pain relief one hour after taking medication and/or are completely pain-free after two hours. There is insufficient evidence to determine whether rizatriptan (or any triptan) is superior overall [71,74]. Side effects include asthenia, dry mouth, nausea, paresthesia, dizziness, and chest discomfort. The wafer preparation contains phenylalanine [53,73].

Sumatriptan: Sumatriptan is available in oral, subcutaneous, and intranasal preparations and in combination with naproxen [73]. It was the first triptan on the market and thus has been the most studied. Oral sumatriptan has been found to be significantly more effective than placebo at relieving migraine headache pain within two hours [83]. A systematic review of 61 studies involving 37,250 participants found that oral sumatriptan (100 mg) significantly improved headache relief compared to placebo [83].

Side effects include tingling/flushing, dizziness, fatigue, muscle pain or weakness, and chest discomfort [73]. There may be taste disturbance with the use of the nasal spray [53,73]. Although sumatriptan is the most commonly prescribed treatment for migraine, current formulations may be associated with limitations (e.g., difficulty taking oral medication) that can result in patients' delaying or avoiding treatment. Transdermal patches have proved effective for the delivery of sumatriptan. In 2013, the U.S. Food and Drug Administration (FDA) approved Zecuity, a sumatriptan iontophoretic transdermal system [84,85]. In 2016, the manufacturer of Zecuity suspended sale of the drug pending an FDA evaluation of reports of burns and scars associated with the patch [86]. Additional novel formulations include needle-free injectable sumatriptan [75].

Zolmitriptan: Zolmitriptan is available in oral form, nasal spray, and orally disintegrating wafers [73]. In a randomized controlled trial of nearly 1,200 patients comparing oral zolmitriptan to placebo, zolmitriptan 2.5 mg was found to significantly decrease headache symptoms, resulting in headache relief in the majority of patients [87]. Of note, a dose response effect was observed, with lower doses resulting in fewer adverse events. In a randomized controlled trial comparing the use of zolmitriptan to sumatriptan of nearly 1,500 patients with migraines, there was no significant difference in headache relief [87]. Side effects include asthenia, nausea, paresthesia, dizziness, and chest discomfort. The use of the nasal spray can cause taste disturbances. The wafer preparation contains phenylalanine [53,73].

The triptans are all closely related although they differ slightly in terms of half-life, oral bioavailability, and metabolism. Side effects vary but in general they are mild and include tingling, flushing, dizziness, somnolence, and the sensation of pressure in the head; their safety profiles are all quite similar [36]. Because sumatriptan was the first on the market and the most commonly prescribed, it is often used as a comparison in studies with newer triptans [53].

A comparative review of the safety and efficacy of the triptans has indicated that [71,73,74]:

- Indirect comparisons from placebo-controlled trials of oral triptans suggest that sumatriptan 100 mg, almotriptan 12.5 mg, eletriptan 40 mg, and zolmitriptan 5 mg all have similar efficacy, whereas frovatriptan 2.5 mg is probably inferior.

- Evidence remains inconclusive as to how the orally disintegrating wafer, nasal, and injectable forms of triptans compare in efficacy to the more conventional oral capsule or tablet forms.

- For the oral forms of eletriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan, there are no differences in adverse effects (e.g., chest tightness, CNS symptoms); data are lacking for almotriptan and frovatriptan.

- For all the triptans, the safety of treating an average of more than four headaches in a 30-day period has not yet been established.

Note that, like NSAIDs, failure with one triptan does not imply that the patient will not find relief with another triptan. At least two medications in a class should be tried before the class of medications is considered unsuccessful in headache treatment. Ultimately, individuals will need to try the different triptans and determine what works best for them. One might also consider adding an NSAID to a triptan to potentially enhance effectiveness. The first combination product of a triptan and an NSAID (Treximet) was approved by the FDA in 2008. Treximet contains sumatriptan (85 mg) and naproxen sodium (500 mg) and has found to be more effective than placebo or either sumatriptan or naproxen sodium alone [38,74].

Treating pregnant patients with migraines can be particularly challenging. In general, most medications should be avoided, and patients should be treated with behavioral intervention and nonpharmacologic measures. The triptans are considered FDA Pregnancy Risk Category C, which means risk to humans has not been ruled out [73].

Management of Acute Attack in the Emergency Department

Acute migraine attack results in 1.2 million visits to emergency departments in the United States each year [174]. While more than 20 different parenteral medications and combinations of medications are used to treatment acute migraine in U.S. emergency departments, fewer than 25% of patients experience sustained freedom from headache after treatment [175]. The ideal parenteral treatment should offer rapid, sustained freedom from headache, no short- or long-term sequelae, a rapid return to normal activities, and no adverse effects; however, no such treatment exists. This led the AHS to develop a guideline on the management of acute migraine in the emergency department, with the goal of determining which injectable medications should be considered first-line treatment for acute migraine in the emergency setting, and whether parenteral corticosteroids can prevent recurrence of migraine in adults discharged from the emergency department (Table 7) [175].

Table 7: AHS RECOMMENDATIONS FOR MANAGEMENT OF ACUTE MIGRAINE IN THE ED

Medication, Dose, Route of Administration

Pharmacologic Category

Efficacy

Recommendation

First-Line Treatment

Acetaminophen, 1 g, IV

Analgesic

Possibly effective

May offer

Acetylsalicylic acid, 0.5–1.8 g, IV

NSAID

Likely effective

May offer

Chlorpromazine, 0.1–25 mg, IV

Antimanic, antipsychotic

Possibly effective

May offer

Diclofenac, 75 mg, IM

NSAID

Possibly effective

May offer

Droperidol, 2.5–8.25 mg, IM

Antiemetic

Likely effective

May offer

Haloperidol, 5 mg, IV

Antipsychotic

Likely effective

May offer

Ketorolac, 30–60 mg, IM/IV

NSAID

Likely effective

May offer

Metoclopramide, 10–20 mg, IV

Antiemetic

Highly likely to be effective

Should offer

Prochlorperazine, 10 mg, IV

Antiemetic

Highly likely to be effective

Should offer

Sumatriptan, 6 mg, SC

Triptan

Highly likely to be effective

Should offer

Valproic acid, 500–1,000 mg, IV

Anticonvulsant; antimanic

Possibly effective

May offer

Migraine Recurrence Prevention

Dexamethasone, 8–24 mg, IV

Corticosteroid; antiemetic

Highly likely to be effective

Should offer

Source: [175]

Other Medications

Although the triptans provide effective relief from migraine for many patients, a substantial number will be unresponsive. Calcitonin gene-related peptide (CGRP) is believed to contribute to pain transmission and inflammation and, for these reasons, to the mechanisms of migraine. CGRP receptor antagonists have been shown to terminate migraine with efficacy similar to triptans by inhibiting neurogenic vasodilatation and inflammation. Four CGRP receptor antagonists (erenumab, fremanezumab, galcanezumab, and ubrogepant) have been tested in clinical trials and have shown clinical benefit and excellent tolerability [88,89,90,91].

Selective serotonin reuptake inhibitors (SSRIs) block the passage of serotonin, a neurotransmitter, in brain cells and are typically used to treat depression. In view of research suggesting that serotonin may play a role in the genesis of headache pain, SSRIs have been tested for their potential benefit in preventing headaches. Results suggest, however, that SSRIs are no better than placebo for preventing migraine or tension-type headaches [92]. Additionally, the FDA has issued a public health advisory regarding the combined use of 5-hydroxytryptamine receptor agonists (triptans), SSRIs, or selective serotonin/norepinephrine reuptake inhibitors (SNRIs). A life-threatening condition called "serotonin syndrome" may occur when triptans are used together with an SSRI or an SNRI (Table 8). Symptoms may include restlessness, hallucinations, loss of coordination, tachycardia, rapid changes in blood pressure, increased body temperature, overactive reflexes, nausea, vomiting, and diarrhea. Serotonin syndrome may be more likely to occur when starting or increasing the dose of a triptan, SSRI, or SNRI. The FDA has requested that all manufacturers of triptans, SSRIs, and SNRIs update their prescribing information to warn of the possibility of serotonin syndrome when triptans and SSRIs or SNRIs are taken together [93].

Table 8: MEDICATIONS IMPLICATED IN SEROTONIN SYNDROME

SSRIs

Citalopram

Fluvoxamine

Escitalopram

Paroxetine

Fluoxetine

Olanzapine/fluoxetine

Sertraline

SNRIs

Duloxetine

Venlafaxine

Sibutraminea

Triptans

Naratriptan

Almotriptan

Frovatriptan

Sumatriptan

Rizatriptan

Eletriptan

Zolmitriptan

Ditans

Lasmiditan

aSibutramine, a drug approved for weight loss but not depression, is an SNRI and should therefore be used with caution with triptans and other serotonergic drugs.

Source: [93]

In 2019, lasmiditan, a ditan, was approved for the treatment of migraine [73]. Lasmiditan is similar to a triptan but is a high-affinity, highly selective 5-HT1F receptor agonist. The selective targeting of the 5-HT1F receptor is hypothesized to decrease stimulation of the trigeminal system and treat migraine pain without causing vasoconstriction. In a phase 3 study, patients reporting being free of headache after two hours with lasmiditan 200 mg (32.2%) or 100 mg (28.2%) compared with placebo (15.3%). Patients who received lasmiditan were also significantly more likely to report alleviation of their most bothersome symptom compared with placebo [193]. Adverse events were mostly mild or moderate in intensity.

Botulinum Toxin

Botulinum toxin type A (Botox) injections were discovered as a treatment for migraines after individuals who had injections for cosmetic purposes found that it lessened or obliterated their migraine headaches. These observations subsequently led to a series of clinical research studies designed to assess the value of botulinum toxin type A therapy for headache prevention; however, the results from these studies have been mixed [68,94,95,96,97].

For example, a review of botulinum toxin studies was performed by the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. The Subcommittee examined evidence of the toxin's effectiveness for a variety of conditions, including migraine. According to the Subcommittee's report, the evidence indicated that botulinum toxin may be useful in the treatment of lower back pain but that it is probably not effective against episodic migraine and chronic tension-type headache. The report also stated that the available evidence was not strong or consistent enough to determine botulinum toxin's usefulness in the treatment of chronic daily headache (primarily, transformed migraine) [95,96].

In a double-blind, randomized, placebo-controlled study, researchers compared the number of headache-free days experienced by patients four weeks prior to injections of botulinum toxin type A with the number of such days occurring four to eight weeks after treatment. The number of headache-free days increased for the study's placebo and nonplacebo groups, but the difference in increase between the two groups was not significant. The researchers did find, however, that when compared with the placebo group, the patients who received botulinum toxin type A injections experienced a significant reduction in the duration of their headaches [95]. Additionally, pooled results from two large trials indicated that treatment with up to five cycles of botulinum toxin type A at 12-week intervals was effective in reducing headache symptoms, decreasing headache-related disability, and improving health-related quality of life in patients with chronic migraine [97].

Evidence Based Practice Recommendation

The American Academy of Neurology has stated that botulinum toxin type A injections should be offered as a treatment option to patients with chronic migraine (but not episodic migraine) to increase the number of headache-free days and reduce headache impact on health-related quality of life.

http://n.neurology.org/content/86/19/1818.full

Last Accessed: April 5, 2022

Strength of Recommendation: A (Established as effective for the given condition in the specified population)

It is generally recommended that use of botulinum toxin type A be restricted to patients who fail to respond to conventional preventative therapy or experience intolerable side effects from such therapy. It is important to note that botulinum toxin type A is not FDA-approved for migraine treatment [73,94]. Because its effects on a developing fetus are unknown, women who are pregnant should not receive botulinum toxin type A [73,94].

The mechanism of action of botulinum toxin type A is thought to be secondary to relieving pressure on certain nerves, such as branches of the trigeminal nerve, and thus reducing the release of neuropeptides. The actual process involves 20 to 30 injections in the forehead, temple, and neck. Side effects may include pain and bleeding at the site, exacerbation of the headache, and ptosis (eyelid droop) [73]. In those patients for whom it works, the effect typically lasts three to six months, at which time the headaches often return. This necessitates repeat injections every three to six months. This treatment is still considered to be experimental. Much more research is needed before this therapy can be considered effective.

Neuromodulation Devices

In recent years, there has been more research and development of neuromodulation devices for the treatment and prevention of headache disorders. Benefits of this type of device include proven efficacy, non-invasive nature, and very limited side effects. Due to the limited amount of time these devices have been available, ongoing research is needed to determine long-term safety and efficacy for headache disorders.

Cerena

In 2013, the Cerena transcranial magnetic stimulation (TMS) device was approved to treat migraine with aura. Patients use both hands to hold the device against the back of the head, then press a button to release a pulse of magnetic energy to stimulate the occipital cortex in the brain, which may stop or lessen the pain associated with migraine headaches. The maximum recommended dosage is one treatment in 24 hours [191].

Approval for Cerena was based on a study in which 39% of users were pain-free two hours post-treatment, compared with 22% of the control group. At 24 hours post-treatment, 34% of patients were pain-free, compared with 10% in the control group. However, studies and research on Cerena are limited [191].

Cefaly

In 2014, the first neuromodulation device received approval from the FDA for prevention of episodic migraines and received approval for acute treatment in 2017 [182,183]. The Cefaly is a prescription external trigeminal nerve stimulation (e-TNS) device that is placed on the forehead. A self-adhesive electrode transmits electrical impulses to specific areas of the trigeminal nerve, generating an analgesic effect. The Cefaly device is used 20 minutes daily at a frequency of 60 Hz to prevent migraine or can be used for acute treatment during migraine with or without aura at a frequency of 100 Hz [183].

Results of a trial published in 2019 showed that patients using Cefaly as a preventive treatment for three months experienced a 16.21% reduction in headache days and a 30.81% decrease in acute medication intake compared with a group assigned to a sham device. Minor adverse events included skin irritation under the electrode and headache worsening with vertigo [184]. Another study published in 2019 examined the efficacy in acute treatment of migraine with or without aura. One hour after beginning the Cefaly treatment, 79% of patients achieved significant pain relief and 29% reported being pain free [185]. According to results of these and other studies, the Cefaly device is considered safe and effective for both prevention and acute treatment of migraine. In 2020, Cefaly was made available over-the-counter without the need for a prescription [194].

gammaCore

In 2017, the gammaCore device was cleared by the FDA for the acute treatment of migraine and cluster headache, and as a preventive treatment for cluster headache. This device is a handheld, non-invasive vagus nerve stimulator (nVNS) that produces mild electrical stimulation to the vagus nerve through the neck, thereby reducing and preventing pain [186]. Stimulation is controlled by the user, and treatment sessions consist of 2 to 3 two-minute stimulations. Patients that have a metallic device (e.g., a stent, bone plate, or bone screw) implanted at or near their neck should not use gammaCore.

A four-week study published in 2018 examined the effects of nVNS using the gammaCore device on episodic migraine headache with or without aura. Researchers found 12.7% of patients were pain free after 30 minutes of initiation of treatment (vs. 4.2% in the sham group) and 21% after 60 minutes (vs. 10%). The only adverse event was vertigo, seen in 1% of patients. Researchers indicate that nVNS is a safe treatment that may possibly decrease the risk of medication overuse in some patients [187].

Another study published in 2018 examined the effects of nVNS on episodic and chronic cluster headache over the course of two weeks. Compared with the sham group, 16.7% of patients with episodic cluster headaches achieved pain-free status at 15 minutes for greater than 50% of their attacks (vs. 6.8%), and 64.3% of patients reported significant improvement (vs. 15.4%). Comparison of patients with chronic cluster headaches were insignificant, with patients reporting free of pain at 8.8% (vs. 6.5% in the sham group) and patients with significant improvement at 29.4% (vs. 12.9%) [188].

Clinical trials for prophylactic treatment of cluster headaches using nVNS showed that there was a significantly greater reduction in the number of cluster attacks per week versus the control (5.9 vs 2.1, respectively). Forty percent of patients reported pain relief of 50% or greater, compared with 8.3% of the control group. nVNS also led to a reduction in the use of abortive medications. There was no change in cluster headache duration or severity of acute attacks reported in this trial [186].

Nerivio Migra

Nerivio Migra received FDA de novo clearance in 2019 for acute treatment of migraine with or without aura. It is a prescription trunk and limb electrical stimulator that is used on the upper arm. Electrical pulses are controlled through a smartphone for 30 to 45 minutes. This device is expected to be available in the United States in late 2019 [189].

A study of the efficacy of Nerivio Migra was published in 2019 and included patients who experience two to eight migraines per month. Two hours post-treatment with active stimulation, Nerivio Migra provided complete pain relief to 37.4% of patients (vs. 18.4% of sham participants), significant pain relief in 66.7% of patients (vs. 38.8%), and relief of most bothersome symptoms in 46.3% of patients (vs. 22.2%). For many, pain relief was sustained 48 hours post-therapy [190].

Relivion

In 2021, the FDA cleared Relivion, a transcutaneous electrical nerve stimulator that can be self-applied at home [195]. This device consists of a headset controlled by a smartphone app and delivers stimualtion to to six branches of the occipital and trigeminal nerves. It is is indicated for the treatment of migraine with or without aura in patients 12 years of age or older.

Preventive Therapies

The initiation of a preventive agent is a decision that can be made only when a variety of factors have been considered. For example, if an individual is using abortive medications more than two times per week with only moderate success, if there are more than two seriously disabling attacks per month, if there is failure of or contraindication to abortive treatments, if there is occurrence of uncommon features, or if there is a pattern being established of medication overuse, physicians should consider the initiation of a preventive medication [38,113]. Additional factors that should be considered include the patient's preference, adverse events associated with treatments for acute migraine attacks, and how much treatment costs for acute attacks and migraine prevention [54]. Most treatment is effective within the first month.

Although the precise mechanism of action is unknown, it is believed that preventive therapies act on the CNS by raising the threshold of a migraine headache, producing "resistance" for the system to develop headaches. They also work by inhibiting the propagation of the migraine process early on.

When considering preventive agents, keep in mind the following points [98,113]:

- Start with the lowest possible dose.

- Give the medication an adequate trial, which typically is two to three months.

- Increase the dose slowly until either benefits or unacceptable adverse reactions are observed.

- Try to use long-acting formulations; these may help improve patient compliance.

- Choose an agent that may treat co- existing conditions, such as depression or hypertension.

- Encourage the patient to use a headache diary for better evaluation of effectiveness.

The proven and/or well-accepted drugs used for prevention of migraines include beta blockers (e.g., propranolol, metoprolol), tricyclic antidepressants, triptans, and antiepileptics (Table 9) [98,113]. When antiepileptic drugs are used to treat or prevent migraine, the dose is typically much lower than the dose used to treat seizures. Also, divalproex sodium and topiramate are the only antiepileptic drugs approved by the FDA for migraine prevention [73]. Antiepileptic drugs have been shown to be effective in reducing the frequency of migraine attacks by 38% to 50% or more with antiepileptics than with an inactive placebo [99,100,101]. It should be noted that, although the drug may be beneficial, the FDA has issued a warning regarding the risk of metabolic acidosis in patients receiving topiramate as well as a warning of increased risk of development of oral clefts in infants born to women treated with the drug during pregnancy [76,102].

Table 9: MEDICATIONS AND STANDARD DOSES FOR MIGRAINE PREVENTION

Medication/Therapy

Standard Dose

Beta Blockers

Propranolola

160–240 mg daily

Timolola

10–30 mg daily

Metoprolol

25–100 mg daily

Tricyclic Antidepressants

Amitriptyline

10–150 mg daily

Antiepileptics

Divalproex sodiuma

250–1,000 mg daily

Topiramatea

25–100 mg daily

CGRP Antagonists

Erenumab-aooea

70 mg monthly

Fremanezumab-vfrma

225 mg monthly

Galcanezumab-gnlma

120 mg monthly

Neuromodulation Devices

Cefalya

100 Hz, for 20 minutes daily

gammaCorea

50–60 Hz, for 4 to 6 minutes daily

aFDA-approved for migraine prevention

Source: [73,98,178,179,180,113]

Gabapentin has demonstrated some effectiveness in the prevention of migraine; however, more research is needed to determine long-term effectiveness [98,101,103,104]. The preventive treatments are often helpful but will not eradicate headaches altogether. Preventive therapy may reduce the frequency of migraines by 38% or more; such improvement is considered successful [36,99,100,101,105].

In 2018, the FDA approved three once-monthly medications for migraine prevention—erenumab-aooe, fremanezumab-vfrm, and galcanezumab-gnlm [178,179,180]. These CGRP antagonists are self-administered once per month with an autoinjector.

Physicians and other clinicians should also be cognizant that migraine sufferers often must try as many as five different medications (both acute and preventive) before they find one that is effective for their symptoms. It is important to be patient and not become frustrated during these trial periods.

CLUSTER HEADACHES

Cluster headaches are one of several types of trigeminal autonomic cephalalgias, primary headaches characterized by unilateral pain in the trigeminal nerve region. As defined by the IHS, cluster headaches are attacks of severe unilateral pain in the orbit and/or the surrounding region of the eye that last 15 to 180 minutes [43,53]. The term "cluster" refers to the headache attacks occurring in daily episodes. The patient is headache-free in between the clusters.

The attacks may occur anywhere from every other day to eight times per day and are accompanied by one or more of the following symptoms: ipsilateral conjunctival injection and/or lacrimation, nasal congestion and/or rhinorrhea, ptosis and/or miosis, eyelid edema, forehead/facial sweating, forehead/facial flushing, or sensation of fullness in the ear (Table 10). Attacks occur in series lasting for weeks or months separated by remissions lasting for months to years [43].

Table 10: DIAGNOSTIC CRITERIA FOR CLUSTER HEADACHES

At least five attacks with the following characteristics:

1. Severe or very severe unilateral pain in the orbit, surrounding area, or both, lasting 15 to 180 minutes untreated

2. Either or both of the following:

- At least one of the following signs on the side of the pain

- Conjunctival injection and/or lacrimation

- Sensation of fullness in the ear

- Nasal congestion and/or rhinorrhea

- Facial and forehead sweating

- Miosis and/or ptosis

- Facial and forehead flushing

- Eyelid edema

- A sense of restlessness or agitation

3. Frequency of attacks from every other day to eight times a day

4. Not better accounted for by another diagnosis

Source: [43]

Cluster headaches are divided into two subclasses: episodic and chronic [43]. The episodic cluster occurs at a rate six times higher than chronic cluster [106]. Episodic cluster headache attacks occur in periods lasting seven days to one year, separated by pain-free periods lasting one month or longer [43]. The chronic cluster headache occurs for more than one year without remission or with remissions lasting less than one month. Chronic cluster headache may arise de novo or evolve from the episodic subtype. Some patients may switch from chronic to episodic cluster headache [43].

Cluster headaches are typically described as an excruciating burning or piercing pain. The pain comes on quickly and reaches its peak quickly. The location is typically retro-orbital and unilateral. Although people do not experience an aura, per se, some individuals report brief warning signs prior to the headache such as a "fuzzy" feeling in the head, spasm of the neck muscles, or a general feeling of discomfort. Interestingly, when a patient is in the throes of a headache, rather than resting and remaining still (as is the characteristic "migraine" behavior) the individual will likely be seen rocking, pacing, or even banging his or her head against a wall in an attempt to somehow divert the pain. The pain is often so excruciating that it has been called the "suicide headache." Each episode lasts from 15 minutes to three hours. Nausea and vomiting are rarely present [43,107].

Prevalence varies by gender. Men are more likely to get this type of headache than women with an approximate 3:1 ratio [43]. Cluster headaches tend to start in individuals 20 to 40 years of age and often remit by 55 years of age. They may be inherited in about 5% of cases [43]. Attacks often begin during sleep, implicating a disorder of circadian rhythm. An increased incidence of sleep apnea in patients with cluster headache suggests that periods of reduced oxygenation of key tissues may trigger an attack [106].

Although the symptoms for cluster headache are quite dramatic and for the most part pathognomonic, tumors in the vicinity of the internal carotid artery may induce symptoms that mimic those seen in cluster headaches. For this reason, some clinicians advocate a CT scan or MRI for patients who are initially presenting with this type of headache [108].

Cluster headaches are quite rare, affecting only 0.1% of adults [107]. Interestingly, there are some associated risk factors. Most individuals with cluster headaches are smokers, yet smoking cessation rarely, if ever, brings relief. A history of head trauma also seems to convey an increased risk of developing cluster headaches. Headache triggers include smoking, alcohol consumption, changes in temperature, breezes on the face, and changes in physical, emotional, or mental activity [43,107].

PET scanning and functional MRI are helping to clarify the poorly understood etiology of cluster headaches. It is thought to be multifactorial and likely involves alterations in the hypothalamus [107]. It is generally believed that the trigeminal system is involved in these headaches [107].

Treatment of cluster headache involves a dual strategy of abortion (during the acute stage) and concurrent prophylaxis, which is initiated to suppress the expected recurrent headaches [109]. Patients with chronic cluster headache require long-term prophylaxis (Table 11). Patients with intractable headaches may require more aggressive intervention, including combination therapy or surgery [107,110].

Table 11: TREATMENT OF CHRONIC CLUSTER HEADACHE

Therapy

Dosage and Route

Comments

Verapamil

120 mg PO three times/day

—

Lithium

Start at 300 mg PO three times/day; use blood levels to achieve therapeutic dose

Need close monitoring of lithium levels; test 12 hours after last dose. Side effects include tremor and dysuria. Check thyroid and renal function before and during treatment.

Microvascular decompression

NA

Only used for intractable cases

Source: [73,107,109,181]

Evidence Based Practice Recommendation

According to the Institute for Clinical Systems Improvement, oxygen inhalation is a highly effective treatment for cluster headaches when delivered at the beginning of an attack with a non-rebreathing facial mask (7–15 L/min). Most patients will obtain relief within 15 minutes.

https://www.icsi.org/wp-content/uploads/2019/01/HeadacheRR.pdf

Last Accessed: April 5, 2022

Level of Evidence: Expert Opinion/Consensus Statement

The treatments of choice for acute cluster headache are oxygen, a triptan, or a combination of the two (Table 12). There has been some data suggesting the use of melatonin in patients who suffer from cluster headaches, especially those who have concomitant sleep disorders; however, the effectiveness of melatonin remains unclear because of conflicting studies [107,108].

Table 12: TREATMENT OF ACUTE CLUSTER HEADACHE

Therapy/Drug

Dosage and Route

Reported Adverse Effects

Oxygen

100% oxygen at least 7 L/min over 15 minutes

None

gammaCore (non-invasive vagus nerve stimulator)

Stimulation level between 1–40 using device on side of neck over vagus nerve at maximum level tolerable for a treatment consisting of 3 two-minute stimulations applied consecutively at the onset symptoms; additional treatment may be administered if symptoms are not aborted; use for up to four attacks (or eight separate treatments) per day (for a total of up to 24 stimulations per day).

Local skin reactions, muscle contractions, dizziness

Triptans

Sumatriptan

Up to 6 mg subcutaneously; may repeat in 24 hours OR 25–100 mg PO; repeat after two hours if significant relief not attained

Maximum: 200 mg/day

Local skin reactions, fatigue, nausea, vomiting, dizziness, burning sensations, paresthesias

20 mg nasal spray

None

Zolmitriptan

2.5 mg PO at onset (includes orally disintegrating wafer)

Maximum: 10 mg/day

Chest pain, palpitation, dizziness, somnolence, vertigo, nausea, paresthesia, warm/cold sensation

One nasal spray (5 mg) at onset

None reported

Intranasal dihydroergotamine

0.5 mg nasal spray bilaterally

Abuse potential; contraindicated in patients with cardiovascular disease

Intranasal lidocaine

1 mL of 4% lidocaine placed with a cotton swab bilaterally for 5 minutes

Unpleasant taste

Source: [73,76,107,108,111,112,188]

Preventive therapies are usually initiated when the cluster headache series begins. Preventive medications include antidepressants, antiepileptics, ergotamine, and calcium channel blockers (Table 13).

Table 13: PROPHYLAXIS OF EPISODIC CLUSTER HEADACHE

Drug/Therapy

Dosage and Route

Reported Adverse Effects

Comments

gammaCore (non-invasive vagus nerve stimulator)

Stimulation level between 1–40 using device on side of neck over vagus nerve at maximum level tolerable for a prophylaxis treatment consisting of 2 two-minute stimulations; first daily treatment should be applied within 1 hour of waking; second treatment should be applied at least 7 to 10 hours later; additional treatment may be administered if symptoms are not aborted; use for up to four attacks (or eight separate treatments) per day (for a total of up to 24 stimulations per day).

Local skin reactions, muscle contractions, dizziness

Intended to be used as an adjunctive therapy; first FDA-cleared device

Galcanezumab-gnlm

Loading dose of 240 mg subcutaneous (SQ) injection, followed by 120 mg SQ monthly

Antibody development, injection site reaction

Given by patient self-injection, FDA-approved

Verapamil

120–160 mg PO three times/day

Hypotension, bradycardia, atrioventricular block, dizziness, fatigue, nausea, constipation

In doses of 360–480 mg/ day, has been found to be effective in reducing attack frequency

Prednisone

100 mg PO/day, up to 500 mg IV (methylprednisolone or equivalent corticosteroid) titrated over five days

Increased appetite, insomnia, nervousness, hyperglycemia, dizziness, headache

Recurrences frequent toward the end of the taper; take concurrently with another prophylactic medication

Divalproex sodium

600–2,000 mg/day

Nausea, somnolence, dizziness, insomnia, anorexia, weakness, thrombocytopenia, alopecia, weight gain

Small studies indicate efficacy; use with caution in patients with renal or hepatic insufficiency; contraindicated in pregnant women

Topiramate

25 mg PO/day for seven days, then increase by 25 mg/day every week to maximum dosage of 200 mg/day

Paresthesias, cognitive effects, drowsiness, dizziness

Small studies indicate efficacy

Ergotamine

2–4 mg/day in divided doses

Vertigo, pruritus, nausea, paresthesias, weakness, cardiac valvular fibrosis, retroperitoneal or pleuropulmonary fibrosis, angina, myocardial infarction

Best for nocturnal attacks; should not be taken concurrently with sumatriptan

May cause withdrawal symptoms if suddenly discontinued

Melatonin

10 mg PO at bedtime

None reported

May be useful in some patients; drug of third choice

Source: [107,111,186]

TENSION HEADACHES

Tension headaches are among the most common headache type seen in practice today; however, it is the least studied of the primary headache disorders, despite the fact that it has the highest socioeconomic impact. The lifetime prevalence ranges from 30% to 78%, with a rate of 63% seen in men and 86% in women [21,43].

The etiology of tension headaches is multifactorial. Although once thought to be simply secondary to muscle spasm, it is now felt that other factors play important roles. In fact, although tension headaches may arise from sustained contraction of pericranial muscles, no correlation exists between muscle contraction and the presence of a tension headache. It seems that, just as in migraine headaches, tension headaches arise in part from centrally mediated neural dysfunction. This abnormality may in part be due to central sensitization in the trigeminal area [43,67].

The IHS has categorized tension headaches into two categories: episodic and chronic (Table 14). Episodic tension-type headache is further divided into infrequent (i.e., episodes that occur less than once per month) and frequent subtypes. The infrequent subtype has little impact on the individual. Frequent sufferers, however, may encounter considerable disability that requires the use of expensive drugs and prophylactic medications. The chronic subtype is always associated with disability and high personal and socioeconomic costs [43].

Table 14: DIAGNOSTIC CRITERIA FOR TENSION HEADACHE

A. Infrequent Episodic Tension Headache

1. At least 10 episodes occurring less than 1 day per month on average or less than 12 days per year

2. Duration from 30 minutes to seven days

3. At least two of the following pain characteristics:

- Pressing or tightening (non-pulsating) sensation around the head

- Mild-to-moderate severity

- Bilateral location

- No aggravation by walking, climbing stairs, or similar physical activity

4. No nausea/vomiting and no more than one photophobia or phonophobia

5. Not better accounted for by another diagnosis

B. Frequent Episodic Tension Headache

1. At least 10 episodes of headache occurring on 1 to 14 days per month on average for more than three months (≥12 and <180 days per year)

2. Duration from 30 minutes to seven days

3. At least two of the following pain characteristics:

- Bilateral location

- Pressing or tightening (non-pulsating) quality

- Mild-to-moderate severity

- No aggravation by routine physical activity such as walking or climbing stairs

4. No nausea/vomiting and no more than one of photophobia or phonophobia

5. Not better accounted for by another diagnosis

C. Chronic Tension Headache

1. More than 180 days of headache in a given year or at least 15 headaches per month for an average of greater than three months

2. Duration may be from hours or it may be continuous

3. At least two of the following pain characteristics:

- Pressing or tightening sensation around the head

- Mild-to-moderate severity

- Bilateral location

- No aggravation by walking stairs or similar physical activity

- May include one of the following: nausea, photophobia, or phonophobia

4. No evidence of organic disease

Source: [43]

Episodic tension headaches are usually associated with a stressful event. They are of moderate intensity, typically are self-limited, and usually respond well to over-the-counter headache treatments. They are usually described as soreness, tightness, or a band-like pressure around the entire head. They are often accompanied by stiffness in the neck and shoulders [114].

IHS diagnostic criteria for infrequent episodic tension-type headache include at least ten episodes occurring on less than 1 day per month on average (i.e., less than 12 days per year), lasting from 30 minutes to 7 days, with at least two of the following characteristics: a pressing or tightening (non-pulsating) sensation around the head, mild-to-moderate severity, bilateral location, and no aggravation by walking stairs or similar routine physical activity. There is no nausea, but either photophobia or phonophobia may be present [43].

Chronic tension headaches generally have the same pain characteristics as episodic tension headaches, including phonophobia or photophobia. They occur more frequently, with an incidence of at least 15 headaches per month on average for greater than three months, or greater than 180 days in a given year. The headache may last hours, or it may be continuous [43,53].

As with migraines, there are both nonpharmacologic and pharmacologic treatments. Nonpharmacologic measures tend to be more effective for tension headaches than for migraines or clusters. These measures include the use of hot or cold packs, ultrasound, electrical stimulation, improvement of posture, trigger point injections, regular exercise, and consistent sleep schedules [114]. Forward head posture and neck mobility have been associated with tension-type headache [115].

Tension headaches also tend to respond well to medications. Some commonly used medications that are effective include aspirin, acetaminophen, and NSAIDs in the standard prescribed doses [114]. Combination treatments with the above medications and caffeine, butalbital, and muscle relaxants are also effective. However, overuse of these medications, especially those containing caffeine, may lead to rebound headaches. The use of butalbital also may result in dependency, and for this reason, it is not recommended for prolonged use [53,73]. In general, narcotics should be avoided because tension headaches are typically mild-to-moderate in pain intensity. Botulinum has also been suggested for the treatment of tension headaches; however, not all researchers agree that it should be used for chronic tension-type headache [11,116]. As discussed, however, more study regarding efficacy and safety is required.

Some chronic tension headaches may not respond as well to the above modalities and may require preventive medication. Before preventive medication is initiated, it is important, as in the case with migraine headaches, to have the individual keep a headache diary to determine what factors, if any, are triggering the headache [114]. Use of nonpharmacologic measures may also be initiated. Some clinicians may try a drug-free holiday, whereby all headache drugs are stopped for at least two weeks. If none of these modalities prove effective, preventive medications may be helpful. The same preventive medications used for migraine are used for chronic tension headache. These tend to be helpful especially if the patient experiences both migraine and tension headaches.

OTHER PRIMARY HEADACHES

Primary Exercise Headache

As the name implies, primary exercise headache (formerly referred to as a primary exertional headache) is a headache that occurs with exertion, is benign in nature, and is unassociated with any structural lesions. On first occurrence of this headache type, it is mandatory to exclude subarachnoid hemorrhage (SAH) and arterial dissection [43,117].

The headache is typically described as a diffuse, bilateral pain, throbbing in quality and acute in onset. It is precipitated by strenuous physical exercise. The headache lasts from five minutes to 48 hours and occurs particularly in hot weather or at high altitude [43,117].

Primary exercise headache is believed to be vascular in origin. Strenuous physical activity increases intracranial venous sinus pressure, which leads to an increase in intracranial pressure and decreases blood flow. This results in the occurrence of the headache. Effective treatment includes ergotamines and NSAIDs. Indomethacin has been found effective in the majority of cases [43,117].

Hypnic Headache

Hypnic headaches are relatively brief in duration (15 to 240 minutes), mild-to-moderate (severe pain is reported in 20% of patients), usually dull in quality, and bilateral in about two-thirds of cases. Hypnic headaches occur during sleep and are related to the REM stage. The headaches typically awaken patients from sleep, but there are few other associated symptoms [43]. They usually occur almost every night and may last for months until patients ultimately present for evaluation. These types of headaches primarily affect the elderly [118].

The etiology is considered idiopathic, and thus, the diagnosis is primarily one of exclusion. Other causes of headache associated with sleep, such as sleep apnea and drug withdrawal, should be excluded.

One of the most effective treatments for hypnic headaches includes the use of lithium; however, it is often limited by side effects and interactions and requires monitoring of plasma concentrations to avoid toxicity. Indomethacin, atenolol, prednisone, and caffeine have also been shown to be useful [43,118].

Headache Associated with Sexual Activity

These headaches have been previously referred to as benign sex headaches, coital cephalalgias, benign vascular sexual headaches, or benign orgasmic headaches. They may be provoked by activities besides coitus and not necessarily with orgasm. Headache associated with sexual activity affects men more than women [119,120].

Two subforms (preorgasmic headache and orgasmic headache) were previously described, but further research was unable to clearly delineate the two separate entities [43]. Therefore, headache associated with sexual activity is now a single diagnosis with variable presentation. The condition is characterized by at least two episodes of pain in the head and/or neck brought on by and occurring only during sexual activity [43]. The pain becomes more severe with increasing sexual excitement and/or may be experienced as abrupt explosive intensity just before or with orgasm. The duration of severe pain is from 1 minute to 24 hours; more mild presentations may last up to 72 hours [43].

Diagnosis cannot be made until secondary causes (e.g., SAH or arterial dissection) have been excluded. For most patients, these are self-limited disorders. Patients often can lessen the severity of an impending attack by ceasing the sexual activity. Frequent, recurrent episodes may require preventive strategies, such as propranolol or indomethacin [119].

6. SECONDARY HEADACHES

As noted, it is helpful to think of secondary headaches in terms of etiologic categories, such as vascular, traumatic, neoplastic, infectious, pressure, metabolic/toxic ingestions, and medication overuse. A secondary headache may be diagnosed when another disorder known to cause headache has been demonstrated; headache occurs in close temporal relation to the other disorder and/or there is other evidence of a causal relationship; and headache is greatly reduced or resolves within three months (this may be shorter for some disorders) after successful treatment or spontaneous remission of the causative disorder. The IHS has divided secondary headaches into subtypes attributed to specific causes [43]. Table 15 shows a summary of several causes of secondary headache.

Table 15: CHARACTERISTICS OF SECONDARY HEADACHES

Type of Headache

Position

Quality

Radiation

Duration

Therapy

Subarachnoid hemorrhage

Diffuse

Sharp

Neck, back

Several days

Surgery, hypertension management, volume expansion

Giant cell arteritis

Temporal area, unilateral or bilateral

Soreness/ burning

No

Days to weeks

High-dose steroids

Arterial dissection

One-sided, nonthrobbing pain in the eye

Pounding

Neck

Days

Anticoagulants, stenting, surgery

Stroke

Diffuse

Dull

No

Hours

Supportive

Epidural hematoma

Diffuse

Severe

No

Hours to days

Surgery

Dental

Occipital, temporal

Squeezing

No

Varies

Dental referral for care

Subdural hematoma

Diffuse

Mild

No

—

Diuretics, anticonvulsants, surgical evacuation

Brain tumor

Diffuse or unilateral

Mild ache

No

—

Surgery, radiation, chemotherapy

Meningitis

Diffuse

Mild to moderate

Neck

—

Rest, fluids, electrolyte balance, antibiotics

Encephalitis

Diffuse

Dull

No

—

Rest, fluids, electrolyte balance, antiretrovirals

Sinusitis

Sinus area

Heavy fullness

No

Duration of illness

Antibiotics

Abscess

Hemicrania

Moderate to severe

Neck

—

Evacuation, antibiotics

Source: [43]

TRAUMATIC CAUSES OF HEADACHES

Epidural Hematoma

Epidural hematomas occur between the dura and skull, and thus separate the dura from the skull. In the majority of cases, there is an associated skull fracture. Typically, there is a history of head trauma, although an epidural hematoma occurs in less than 2% of all serious head injuries. Epidural hematomas are not a frequent occurrence in the elderly, partly because as one ages, the dura becomes more firmly attached to the inner part of the skull [121].

Classically, there is a brief period of unconsciousness and then a return to a normal mental status. This is known as the "lucid interval." Roughly 10% to 33% of patients demonstrate the classic presentation of a lucid interval, and alterations in the level of consciousness may have a variable presentation. After a period of hours, the hematoma expands and pushes the dura inward. Signs of rising intracranial pressure manifest as a severe, diffuse, constant headache, which develops within minutes to 24 hours after development of the hematoma [121]. Other symptoms may include papillary dilatation, hemiplegia, and eventually obtundation. Often there is weakness on the side of the body opposite the hematoma [121].

Hemorrhages usually occur in the temporal fossa from middle meningeal artery tears; they may also occur in the posterior fossa as a result of a transverse sinus tear. Posterior fossa epidural hematoma may exhibit a rapid and delayed progression from minimal symptoms to even death within minutes. Overall mortality has been estimated to be as high as 50%, so prompt evaluation and treatment is critical [43].

With respect to diagnosis through neuroimaging, in the acute setting, unenhanced CT scan is more useful than MRI imaging. Epidural hematomas have a characteristic white lenticular shape adjacent to the bone, while focal hypodense or isodense areas on CT indicate active bleeding. Because the temporal fossa is often involved, one must be careful that bony artifacts do not obscure a hemorrhage [121].

Subdural Hematoma

As the name implies, subdural hematomas occur between the surface of the brain and the dura. The source of bleeding is the venous system (i.e., bridging veins) as opposed to the arterial system. Because the subdural space is continuous, these types of hemorrhage may have significant mass effect. Subdural hematomas are more common than epidural hematomas. They tend to evolve more slowly based on the slower rate of venous bleeding compared to arterial hemorrhage. As a result, there may be a progression of symptoms over two to four weeks; the rate of progression depends upon the severity of the injury [122].

Patients often present with a mild persistent headache. There may be drowsiness and confusion, although focal neurologic signs are often absent. Symptoms may be followed by a brief lucid interval with subsequent deterioration. Subdural hematomas are seen in approximately 15% of all head traumas. Automobile accidents are a typical cause of subdural hematomas [122].

Different types of subdural hematomas should be differentiated according to their temporal profile. In acute and subacute hematomas, which usually occur after obvious head trauma, headache is frequent (11% to 53% of cases) but commonly overshadowed by focal signs and disorders of consciousness. In chronic subdural hematomas, headache is more frequent still (up to 90%) and, though moderate, may be the leading symptom [122]. The diagnosis can be difficult because the causative head trauma is often trivial and may have been forgotten by the patient [43].

Subdural hematomas are more common in the elderly than epidural hematomas, and patients on anticoagulants are at increased risk of developing a subdural hematoma. Chronic subdural hematoma should always be considered in an elderly patient with a progressive headache, particularly if there is some cognitive impairment and/or mild focal signs [43,122,123].

Patients with suspected subdural hematoma should undergo CT scanning. CT scan findings depend on the age of the hemorrhage but typically demonstrate an abnormality in the entire hemisphere, causing a shift of the midline structures. Early on, there are hyperdense areas demonstrated on CT, followed by isodense areas after a week and hypodense areas after a month [122,123].

Prompt treatment is critical because mortality can reach 60%. Treatment may include diuretics to reduce swelling. Because there is a high frequency of seizures, antiepileptics are frequently used to either control or prevent seizures. For more serious hematomas, surgical evacuation may be necessary. The long-term prognosis is actually worse than that for epidural hematomas [122,123,124].

Upon further history taking, it becomes clear that Mrs. T did experience a significant fall a few weeks ago, even though she minimized it when mentioning it. Sequelae are present. Therefore, a contrast-enhanced CT should be ordered.

The CT scan demonstrated hypodense areas in both hemispheres, consistent with subdural hematoma. There was no evidence of mass effect. The subdural hematoma is likely a result of the fall approximately one month earlier. Mrs. T was admitted to the hospital for observation and given diuretics and anticonvulsants. Her clinical course was good with resolution of the hematoma without the need for surgery.

VASCULAR HEADACHES

Subarachnoid Hemorrhage

Typically, headache due to an SAH is described as a sharp pain that usually involves the entire head. Patients classically describe it as the "worst headache of their life." It often radiates into the neck and even into the back. There is usually nausea and vomiting. In general, there are no focal neurologic deficits early on, but as it progresses, there may be loss of consciousness and altered mental state. Seizures during the acute phase occur in 10% to 25% of patients [125].

The course of this headache is abrupt in its onset and maximum intensity at its origin; it is typically incapacitating in its severity. It is exacerbated by neck and head movements. It usually remains severe for several days and then gradually diminishes [43]. An often overlooked aspect is that the acute headache may be preceded days to weeks earlier by a similar but less severe headache due to slow bleeding. Therefore, a high index of suspicion is necessary for accurate diagnosis [125].

The headache results most often (approximately 80% of cases) from rupture of an aneurysm, although this condition may also result from trauma, arteriovenous malformations, venous thrombosis, blood dyscrasias, cocaine use, amphetamine use, and a variety of metabolic conditions [43,125]. Types of aneurysms include berry aneurysms, fusiform aneurysms, atherosclerotic lesions, and mycotic aneurysms from septic emboli. Approximately 80% of nontraumatic SAHs are due to a ruptured berry aneurysm; rupture of arteriovenous malformations is the second most identifiable cause (10%) [126]. The initial pain is actually produced by tearing and distortion of the blood vessel and its adjacent arachnoid membrane. The incidence of headache in ruptured aneurysms is 90% [122].

The prevalence of SAH increases with age in a linear relationship. The mean age is 50 years [125,126,127]. On physical examination, the patient is typically in severe pain. The pain is sometimes referred to as a "thunderclap" headache [126]. Symptoms of meningeal irritation, such as nuchal rigidity and pain, back pain, and bilateral leg pain, occur in as many as 80% of patients with SAH but may take several hours to manifest [126]. Focal neurologic deficits, such as facial droop or weakness in a specific extremity, are present in 25% of patients. However, if the hemorrhage is associated with infarction it will likely involve the brain parenchyma, which may lead to hemiparesis, aphasia, or visual field abnormalities. Loss of consciousness is transient [43,125].

Patients with suspected SAH should undergo CT scanning without contrast or MRI (flair sequences) [43,122]. The CT typically demonstrates blood localized to the basal cisterns or extended into the ventricles [122]. Unenhanced CT detects SAH in about 90% of cases; however, sensitivity drops to 80% after three days. As a result, a normal CT does not exclude a small SAH [125].

If the CT is negative, equivocal, or technically inadequate, a lumbar puncture should be performed [43]. Most cases not detected on CT are identified on lumbar puncture by red blood cells (RBCs) that do not clear in three samples of CSF. A decrease in RBCs from the first to the last tube represents an artificially bloody tap, whereas an increase count in RBCs suggests SAH. The fluid is then centrifuged and examined for xanthochromia. Xanthochromia is often characterized as a yellow-tinged supernatant, although it may also be pink or orange. It represents enzymatically derived breakdown products, oxyhemoglobin, methemoglobin, and bilirubin, of in vivo red blood cells. It is always seen within 12 hours of SAH but is absent after a traumatic tap. Its presence may be helpful in the diagnosis [43]. Of note, blood in the CSF after a traumatic tap will also result in an artificial increase in white blood cells (WBCs). WBCs will increase by one for every 500 to 1,000 RBCs in the CSF. This assumes a normal WBC count, which is typically the case in SAH [126]. Ultimately, angiography may be necessary to determine aneurysm size and location, as well as to determine surgical or medical management. Treatment options include a surgical clip, management of hypertension, and volume expansion [124,126]. In 2013, the FDA approved a new oral nimodipine solution for the treatment of patients with SAH from ruptured intracranial berry aneurysms. The solution is administered enterally (e.g., oral, nasogastric tube, gastric tube route) within 96 hours of the SAH at a starting dose of 20 mL every four hours for 21 consecutive days [73,128].

SAH is a serious condition. Prompt diagnosis of SAH is critical because 50% of patients die following SAH, often before arriving at hospital, and 50% of survivors are left disabled [43,125].

Giant Cell Arteritis

Giant cell (temporal) arteritis is systemic large and medium-sized vessel vasculitis. Most often, it involves the external carotid arteries [43,129]. This headache typically begins as an intermittent soreness or burning discomfort and steadily escalates over several weeks or months to become a constant, well-localized pain. On rare occasions, it can be explosive. Many patients report that the pain is worse at night. Although the pain is usually unilateral, it may also be bilateral. Pain is classically confined to the temples. Between 70% to 90% of patients with giant cell (temporal) arteritis complain of headache [53,129].

The typical presentation is a new-onset headache in patients older than 50 years of age. Incidence is higher in females than males (ratio 3.7:1), as well as in persons of northern European descent. It represents the most common vasculitis in adults. Nearly 50% of patients with polymyalgia rheumatica also have giant cell arteritis [129].

On exam, the affected scalp artery is sometimes prominent. It may be tender and is often pulseless. The scalp itself is usually tender as well. Depending upon the progression, visual field defects and decreased acuity may be noted, although the patient does not usually exhibit focal neurologic deficits. Typically, the headache occurs in someone who is febrile, has malaise, and feels aches in the back and shoulders. Claudication of the jaw occurs commonly and is virtually pathognomonic for this condition when present during talking or chewing [129].

Giant cell arteritis involves not only the arteries of the scalp causing headache, but also other vessels, including those supplying the eye and occasionally the brain. Nearly half of patients with giant cell arteritis develop blindness, if untreated, due to ischemia of the optic nerve or retina. Because blindness can be prevented by immediate steroid treatment, prompt and accurate diagnosis is critical [43,129].

Laboratory studies often show patients to have an elevated erythrocyte sedimentation rate (ESR), typically >80 mm/hour. (In general, a normal rate would be less than or equal to the patient's age, divided by two.) Given the lack of sensitivity and specificity of this test, however, a normal ESR does not exclude the diagnosis [129]. Platelets may also be elevated, as well as liver function tests (especially alkaline phosphatase). These are nonspecific but may provide more information to make a clinical diagnosis [129].

Diagnosis is confirmed by biopsy of the temporal artery, which should be performed as an outpatient procedure within one week after the initiation of corticosteroid therapy [129]. The biopsy demonstrates skip lesions, which are due to the disease's segmental process. When ocular symptoms exist, emergency medical treatment is necessary. High-dose corticosteroids are an effective treatment. Headache usually resolves or greatly improves within three days of high-dose steroid treatment [43,129]. A maintenance dose of prednisone may be required to be administered for one to two years in some patients [129].

Arterial Dissection

Arterial dissection may cause headache. Dissection of the cervical carotid or vertebral artery typically causes sudden, nonthrobbing pain around the eye, piercing pain in the neck, and a "pounding" one-sided headache. Headache with or without neck pain may be the only manifestation of cervical artery dissection. It is by far the most frequent symptom (55% to 100% of cases), and it is also the most frequent inaugural symptom (33% to 86% of cases). Headache and facial and neck pain are usually unilateral, severe, and persistent, averaging four days in duration. However, it has no constant specific pattern and may sometimes be misleading [43]. The headache is often mistaken to be due to migraine or tension. However, the time, course, and associated symptoms are considerably different.

The cause of arterial dissection is multifactorial and may involve some sudden neck movement, causing hyperextension or significant pressure in the area. This may be a result of trauma; however, cases of dissection have been reported after patients cough or sneeze, undergo spinal manipulation, shave a beard, or place their necks in the sink at beauty salons. Underlying arteriopathies, alone or in combination with the mechanical forces, account for most of the pathophysiology [130]. Therefore, it is important to determine what a patient was doing when the headache occurred.

The dissection may begin when the rotation/hyperextension of the neck causes a small lesion in the lining of an artery. This causes bleeding, which then leads to the formation of a clot. Over time, the clot expands restricting blood flow to the brain [130].

Dissection is more common in patients younger than 50 years of age. It accounts for nearly a quarter of all strokes in that age range [130]. Diagnosis is confirmed by Duplex scanning, MRI, MRA, and/or helical CT and, ultimately, arteriography. Several of these investigations are commonly needed as any of them may be normal. Once detected, the majority of patients survive, and most dissections heal without surgery. Treatment includes the use of anticoagulants (heparin followed by warfarin for three to six months), stenting, and bypass surgery on rare occasion [43].

Stroke

Headache, migraine, and stroke are common and can be temporally related, but a direct causal association has not been definitively proven in clinical studies. Headache may be coincidental with stroke (also referred to as cerebrovascular accident or stroke syndrome), including both ischemic and hemorrhagic stroke, or it may be a consequence of stroke. Headache or migraine may increase the risk of stroke [131]. Results of the Women's Health Study, presented at the 2013 International Headache Congress, reported that migraine with aura is a strong risk factor for any type of stroke [132,133,134]. Headaches associated with stroke are typically reported as dull but diffuse (35%) [135]. They are not localized to a particular side. In addition, headache presentation of a stroke is more common in patients younger than 40 years of age [135]. Headache is more likely to occur in combination with other signs and symptoms of stroke [132]. Depending upon the type of stroke, there may be a focal neurologic deficit, such as aphasia or dysarthria. Young patients should be evaluated carefully to avoid misclassification of stroke as a complicated migraine [135].

Diagnostic work-up necessitates a CT scan or MRI to identify the location of the stroke. Treatment focuses on preventing further ischemia and bleeding [132,135]. For ischemic strokes, recombinant tissue plasminogen activator may be given within 3 to 4.5 hours of symptoms. Aspirin and other antiplatelet medications are also frequently used. For hemorrhagic stroke, most care is supportive, unless there is a large hematoma, in which case surgery may be necessary [124].

NEOPLASTIC CAUSES OF HEADACHES

Brain tumors are either primary or metastatic, and both types may have headaches as a symptom. Primary brain tumors arise from CNS tissue and account for approximately 50% of all cases of intracranial neoplasms; most do not metastasize. The remainder of brain neoplasms are caused by metastatic lesions. Gliomas, meningiomas, acoustic neuromas, and pituitary adenomas account for 95% of all primary brain tumors [136].

Estimates of the annual incidence rate of primary brain tumors range from 7 to 19.1 cases per 100,000 population. Metastatic tumors to the brain are more common, affecting more than 200,000 patients per year in the United States. Brain tumors are the second most common cancer in children, comprising 15% to 25% of all pediatric malignancies [136]. The most common primary tumors that metastasize to the brain are lung, breast, melanoma, and kidney [137]. Although the overall incidence remains low, it is increasing. This increase appears to be independent of improved diagnostic capabilities. However, it could be due to the aging population; approximately 60% of brain tumor patients are 50 to 70 years of age. Men are slightly more affected than women [136,137].

Headache (42%) and seizure (21%) are the two most common presenting symptoms of brain tumors [137]. The headache is generally described as a dull ache and nonpulsating. It may be localized to one area early on, but often it is generalized. It tends to be mild and intermittent, but it is recurrent. Over a period of days, weeks, or months, it becomes more persistent and more intense. This is due to the fact that most brain tumors tend to grow slowly over time and cause progressive symptoms. Headache is often a late complaint, not an isolated finding, and the worst presenting symptom in only one-half of patients. Most headaches in patients with brain tumors are nonspecific and resemble tension-type headaches. New onset of headaches in middle-aged or older patients is cause for concern as is a change in any patient's headache pattern [136].

The headache is typically associated with nausea. Depending upon the type, size, and location of the tumor, there may also be neurologic, visual, and/or hearing impairment. The location of the headache reliably indicates the side of the head affected, but it does not indicate the precise site of the tumor. The cause of the headache is a progressively enlarging mass causing displacement of, or traction on, pain-sensitive intracranial structures, producing a worsening headache [136,137].

Headaches are more common with posterior fossa tumors [136]. Colloid cysts of the third ventricle may produce explosive paroxysmal headaches that last minutes to several hours and may be brought on or alleviated by sudden changes in position. This occurs because they produce position-dependent intermittent obstruction.

Diagnosis is made by contrast-enhanced CT or MRI. MRI is most helpful for identifying tumors in the posterior fossa [136]. Scans should then be followed by histologic analysis (hence the phrase "tissue is the issue" in oncology). Depending upon several factors, including tumor type, degree of any metastasis, and comorbidities, treatment options include surgery, radiation, and/or chemotherapy.

INFECTIOUS CAUSES OF HEADACHES

In general, headaches related to infections tend to be painful, accompanied by nausea, and gradual in onset. Infections may be bacterial, viral, or fungal. The most common types of infections that cause headaches are meningitis, encephalitis, sinusitis, and brain abscess.

Meningitis

Meningitis is an inflammation of the meninges. The etiology of the meningitis may be bacterial, viral, or fungal.

Bacterial meningitis causes an abrupt diffuse headache associated with a high fever, altered consciousness (most commonly lethargy), focal neurologic deficits, and nuchal rigidity [43]. The severity of the headache and the acuteness of the infection are directly proportional. Focal neurologic deficits and papilledema are uncommon. Classically, a patient would show Kernig sign (i.e., resistance to knee extension following flexion of hips and knees) and Brudzinski sign (i.e., rapid flexion of the neck elicits involuntary flexing of the knees in a supine patient). However, a prospective study of 297 adults with suspected meningitis documented very low sensitivities for these signs (5% for Kernig sign; 5% for Brudzinski sign) indicating that their absence should not defer the performance of lumbar puncture [138]. In general, whenever the diagnosis of meningitis is strongly considered, a lumbar puncture should be promptly performed [139]. Laboratory studies reveal a CSF with more than 100 WBCs per mL and a protein level >100 mg/dL. CSF cell counts above 2,000/mL, a protein above 100 mg/dL, and a CSF-serum glucose ratio of <0.40 are all 99% specific for bacterial meningitis [139]. Treatment with antibiotics is usually empiric but may be modified by gram stain results. Typical organisms are Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae.

Viral meningitis causes a less severe headache that may develop over several days with a low-grade fever. The headache is usually frontal or retro-orbital. Other symptoms may include fever, irritability, nausea, vomiting, stiff neck, rash, or fatigue within the previous 18 to 36 hours. Meticulous history taking is essential and should include evaluation of exposure to ill contacts; mosquitoes, or ticks; outdoor activity in areas of endemic Lyme disease; travel history; history of medication use, including intravenous drug use; and risk of sexually transmitted disease [140]. Diagnosis may be made with the assistance of a CSF viral culture or the absence of a positive bacterial culture. Most cases of viral meningitis are caused by enteroviruses, such as coxsackieviruses and echoviruses. Herpes viruses and human immunodeficiency virus (HIV) may also cause viral meningitis. Therapy consists of bed rest, analgesics, fluids, and other conservative treatment [140].

Fungal meningitis gives a more chronic picture and may not be associated with fever or fever may be below normal. The headache is temporal, frontal, or retro-orbital. It becomes more frequent and severe over time and may be accompanied by irritability, nausea, vomiting, stiff neck, and hallucinations. Diagnosis is made by CSF analysis (fungal stain and culture, increased CSF pressure, elevated protein, decreased glucose [45% of blood glucose], and leukocytosis [40–400/mm^3—mostly mononuclear cells]). The most common organism is Cryptococcus neoformans [139]. Blastomyces and coccidioides may also cause fungal meningitis. The most common treatment is with amphotericin B, an intravenous therapy. Intrathecal medication is given to patients through the spinal cord who do not respond positively to IV therapy. Rarely, treatment may also consist of oral antifungal drug therapy [141].

Encephalitis

Encephalitis is an inflammation of the brain parenchyma. Encephalitis may be due to either infectious or noninfectious causes. Noninfectious causes include toxins, tumors, and connective tissue disorders.

Viral encephalitis is the most common infectious type. Examples include herpes, arboviruses, HIV, and cytomegalovirus. Typically, there is acute onset of low-grade fever, altered consciousness, vomiting, and sometimes seizures. There is often disorientation and some speech disturbances. Encephalitis may occur as a secondary complication after the administration of certain vaccines or during the course of an acute illness, such as measles. Dull, diffuse headache may also be present, although it is neither common nor prominent as a symptom. When present, the headache typically does not radiate. Headache is not as common a symptom as in meningitis [142].

Most cases of encephalitis are mild and benign in nature, with symptoms resolving over one to two weeks. When neurologic symptoms are present, it may take up to two months for symptoms to completely resolve. If associated with HIV, such infections may be life-threatening.

CSF examination is critical to establish the diagnosis and reveals moderate monocytosis and erythrocytosis with a variably elevated protein level. EEG is sensitive but not specific, and contrast CT is only 60% sensitive. It may be used, however, to evaluate acute disease progression and to follow up on complications. MRI is more sensitive than CT scan [142]. MRI with gadolinium enhancement is the preferred imaging study. One should keep in mind certain seasonal and geographic issues when differentiating specific etiologic agents.

Depending upon the etiology, treatment is mostly supportive (e.g., rest, fluid, electrolyte balance). For some conditions, antiretrovirals are available [142].

Sinusitis

Although the term "sinus headache" is widely used, sinus headaches are uncommon. Headaches due to sinusitis are confined to a small percentage of patients who have acute frontal sinusitis or sphenoiditis. Sinusitis rarely causes headache, let alone facial pain, except when there is an acute bacterial infection and the sinus in question cannot drain, and it is usually unilateral due to increased pressure and inflammation caused by pus trapped within the sinus cavity.

In acute rhinosinusitis, the patient may present with purulent nasal discharge, which is frequently associated with fever and leukocytosis [43]. The pain is felt as a deep, dull, heavy fullness that sometimes may be pulsatile. Shaking or flexion of the head, coughing, and sneezing exacerbate the pain. Sinus headache is seldom associated with nausea. In addition, it does not reach the same pain intensity of cluster headache or migraine. The vast majority of patients with acute sinusitis respond to antibiotics [143]. Plain radiography is generally obsolete, but exceptions include its use in confirming air-fluid levels in acute sinusitis [144]. MRI is generally reserved for the evaluation of any complications of local sinus infections, particularly suspected intracranial extension. A CT scan is highly sensitive and is the examination of choice in the evaluation of sinusitis, particularly in cases of chronic sinus disease [144]. However, it is usually not useful in acute sinusitis, as diagnosis in these cases is primarily based on clinical findings. Coronal CT imaging is the preferred initial procedure [144].

Diagnosis may be made by Gram stain of the discharge directly from the sinuses. This is a technique that is not commonly performed in the primary care office setting. The most common organism is Streptococcus. The treatment, therefore, is appropriate antibiotics, typically for 10 to 14 days. The use of local corticosteroids may offer the allergic individual added relief when nasal symptoms are prominent [145]. Decongestants are often added.

It is important to note that more than 90% of self- or physician-diagnosed sinus headaches meet the IHS criteria for migraine or probable migraine [145,146]. In those patients with migraine, the most common reasons for misdiagnosis include headache triggers, pain location, and associated features commonly attributed to sinus headache. The clinician should be aware of these unique presentations of migraine so that a correct diagnosis can be made and effective treatment instituted [145]. Additionally, a portion of patients with self-diagnosed sinus headache suffer from a headache type that is unclassifiable by the IHS criteria. These headaches are characterized by bilateral maxillary pressure, mild-to-moderate pain intensity, cranial autonomic symptoms, and the complete absence of migraine features [145].

Abscess

Brain abscesses are quite uncommon; however, when they do occur they are life-threatening. They may originate from a contiguous site of infection (e.g., sinusitis, dental infections, otitis media), hematogenous spread, or trauma. In at least 15% of cases, the source of the infection is unknown [43,146,147]. They occur usually in the first three decades of life. They are also more prevalent in immunocompromised patients [146].

A moderate-to-severe headache, frequently hemicranial, is a common complaint (70%) [147]. The level of pain remains constant and may be aggravated by straining [43]. Often, there is nuchal rigidity. Frontal lobe abscesses tend to present with headache more often than other regions. In more than half of the cases, patients present with fever, altered mental status, nausea, and vomiting. There may also be papilledema and seizures [146,147].

The time course of an abscess is reflected in the symptoms and usually progresses over one to two weeks [147]. Diagnosis is aided by CT, MRI, and nuclear medicine studies. In general, MRI provides better brain parenchymal differentiation than CT and shows the edema from the abscess in better detail [147]. The abscess is also better demonstrated because the routine brain MRI generally is multiplanar, as opposed to the routine CT, which is usually axial. However, MRI may not be useful in an acutely ill patient [146]. MR spectroscopy and some nuclear medicine studies may also be helpful to differentiate abscess from brain tumor [146]. Diffusion weighted MR may also give early indication of an infarction because this may be part of the sequelae of the abscess. Lumbar puncture is contraindicated due to its poor diagnostic yield and possible risk of herniation of the cerebellar tonsils [146,147].

The typical treatment is evacuation/drainage and an antibiotic regimen based on cultures. The most common organisms are Staphylococcus aureus, Streptococcus, Bacteroides species, and Enterobacter. Occasionally, intracranial tuberculosis or fungal infections may present as an abscess. Therefore, cultures for acid-fast bacilli and fungi should be done in all cases [43,146].

PRESSURE HEADACHES

Hypertension

High blood pressure is an infrequent cause of headaches. In general, it does not become a cause of headaches until diastolic blood pressure exceeds 120 mm Hg [43,148]. The association between blood pressure and headache is most clearly manifested in patients with systolic blood pressure greater than 200 mm Hg [148]. Whether moderate hypertension predisposes to headache at all remains controversial, but there is some evidence that it does [43].

Headaches associated with high blood pressure usually appear in the morning. Typically, the headache eases as the patient gets up and about [43,148]. It is usually dull, although sometimes throbbing, and is either diffuse or bioccipital in location. Infrequently, it is bifrontal in location. As blood pressure increases, there is often nausea, vomiting, and visual disturbances. As elevation of blood pressure progresses further, seizures and confusion may develop.

Malignant hypertension occurs when there is evidence of end-organ damage. On funduscopy, one will see papilledema and retinal hemorrhages. A diagnosis of malignant hypertension is based on the association of severely elevated blood pressure (e.g., >130 mm Hg) with severe hypertensive retinopathy [149]. The average age at diagnosis is 40 years, although a wide range of ages has been observed. Men are affected more often than women and black individuals more often than whites [150,151]. Despite progress in the overall management of hypertension, the prevalence of malignant hypertension has remained stable over the past 30 to 40 years [149].

Routine screening consists of a chest radiograph, which is useful for assessment of cardiac enlargement, pulmonary edema, or involvement of other thoracic structures. Other tests (e.g., head CT scan, transesophageal echocardiogram, renal angiography) may be indicated if directed by the initial workup. An EKG is an essential part of the evaluation to screen for ischemia, infarct, or evidence of electrolyte abnormalities or drug overdose [151]. Treatment consists of slowly reducing pressure. Too rapid a decline may cause cerebral hypoperfusion and coronary insufficiency. Recommendations advise reduction of mean arterial pressure by 25% over the first 24 to 48 hours [151]. Nitroprusside has been the drug of choice [151].

It is important not to misdiagnose the normal reactive hypertension that follows an ischemic stroke as hypertensive encephalopathy. In addition, a sudden increase in blood pressure may be the result of illicit drugs, such as cocaine or methamphetamine; this sudden increase may cause a headache [151]. Patients using MAOIs who ingest tyramine may also exhibit a precipitous rise in blood pressure that will cause a headache.

Idiopathic Intracranial Hypertension

Idiopathic intracranial hypertension (IIH) (formerly referred to as pseudotumor cerebri or benign intracranial hypertension) is characterized by increased intracranial pressure without evidence of a tumor, obstruction, infection, or encephalopathy [43,152]. The etiology is unknown [153]. Although benign, it is not without morbidity.

A majority of patients present with papilledema (although IIH without papilledema has been observed), progressive visual loss, sixth-nerve palsies (10% to 40%), and headache [43,152]. Headache is the most common symptom and is usually pulsatile and of mild severity. It is usually chronic in duration and can either be bilateral or unilateral; the most common presentation is bifrontotemporal. Overall, the patient appears in relatively reasonable health, although there may be some gastrointestinal upset [153,154].

Incidence is greatest in young obese females. Risk factors include corticosteroid use, pregnancy, large doses of vitamin A, adrenal and parathyroid disease, and venous sinus thrombosis [43,153].

The diagnosis is one of exclusion. Brain MRI with gadolinium enhancement is the study of choice for most patients with IIH because it provides sensitive screening for hydrocephalus, intracerebral masses, meningeal infiltrative or inflammatory disease, and dural venous sinus thrombosis. MR venography may be useful for patients who are at greater risk for dural venous sinus thrombosis. Brain CT scan is less expensive than MRI and is adequate to rule out larger tumors or lesions, but it is not as sensitive as MRI for meningeal infiltration and/or dural venous sinus thrombosis. On lumbar puncture, CSF pressure is elevated with a low protein level [153].

This condition may resolve spontaneously, although it may take several months to a year to completely resolve. Analgesics typically are given for the headache. Acetazolamide, or other diuretics, may be considered as well as serial lumbar punctures to drain fluid. Corticosteroids are sometimes used if there is impending visual loss. In rare circumstances, surgery consisting of lumboperitoneal shunting may be performed when the condition is refractory [153].

METABOLIC/TOXIC CAUSES OF HEADACHES

Carbon Monoxide

Numerous toxins may cause headache as a sequela. Carbon monoxide is one of the more common causes of poisoning and represents the most frequent cause of toxin-induced death. This poisoning most commonly occurs when there is inadequate or faulty ventilation. Examples of sources include car exhausts, propane heaters, and gasoline-powered generators [153,155,156,157].

Patients typically present with headache, altered mental status (most commonly confusion), nausea, chest pain, and dizziness. Cherry-red discoloration of the skin and lips has been described but is a rare manifestation. The acuity and time of exposure determine the degree of symptoms [43]. High levels may cause loss of consciousness and death [153,155,156].

High clinical suspicion is necessary as this condition mimics other illnesses with nonspecific symptoms, including significant myocardial damage. A complete blood count and arterial blood gas analysis are helpful in aiding the diagnosis. Often, there is a metabolic acidosis with an anion gap; in addition, there may be neutrophilia. Diagnosis is made through measuring venous or arterial carboxyhemoglobin, which will be elevated (>2% nonsmokers, >9% smokers). Treatment involves 100% oxygen. Some patients may need to undergo hyperbaric treatment. In severe cases of poisoning, there may be residual brain damage [158].

Lead Poisoning

Lead poisoning is fairly uncommon in adults. In general, it takes years of exposure before symptoms become apparent. Whereas children usually become exposed due to lead-based paint in old homes, adults can develop lead poisoning through occupational exposures [159].

Symptoms include headache, which generally is diffuse and nonspecific, irritability, confusion, mood disorders, and sleep problems. As levels become toxic, patients develop ataxia and convulsions [159].

Diagnosis is based on symptoms and blood or urine tests for lead. Treatment involves chelation therapy in severe cases, as well as removal of the source of exposure [159].

OTHER CAUSES OF SECONDARY HEADACHES

Syringomyelia

Syringomyelia is an uncommon presentation of headache. It is a condition in which a cyst forms within the spinal cord, either congenitally or due to trauma, malignancy, infection, or hemorrhage. In most cases, the disorder is related to a congenital abnormality of the brain called a Chiari malformation. This malformation occurs during the development of the fetus and causes the lower part of the cerebellum to protrude from its normal location in the back of the cranium into the cervical portion of the spinal canal [160].

The cyst, or syrinx, gradually expands and elongates over time, eventually resulting in destruction of the cord's center. As a result, patients may present with a variety of symptoms, although they typically present with headache, back pain and stiffness, and numbness of the extremities [160]. Symptoms usually begin between 25 and 40 years of age; they are more common in men than women and may worsen with straining (e.g., heavy lifting) or any activity that causes CSF pressure to fluctuate [160].

Signs of the disorder tend to develop slowly, although sudden onset may occur with coughing or straining. In addition, there are often long periods of stability. The preferred imaging modality is MRI, which shows dilation of the central canal and may reveal contributing factors (e.g., a tumor). The usual treatment when significant symptoms are present is surgery, which involves drainage of the syrinx. If not treated surgically, syringomyelia may lead to progressive weakness in the arms and legs, loss of hand sensation, and chronic, severe pain [160].

In the absence of symptoms, syringomyelia is usually followed by observation over time. Patients are advised to avoid activities that involve straining [160].

Dental and Myofascial Causes

There may be times when referral to a dentist is appropriate for headache management. Disorders of the teeth usually cause toothache and/or facial pain; those causing headache are rare. Pain from the teeth may be referred, however, and cause diffuse headache. The most common cause of headache is periodontitis or pericoronitis as the result of infection or traumatic irritation around a partially-erupted lower wisdom tooth [43].

Myofascial pain dysfunction (MPD) syndrome (formerly called temporomandibular joint or TMJ syndrome) originates in the muscles that move the jaw. Symptoms include dull, aching pain in and around the ear, which may radiate to the side of the scalp, back of the head, or down into the neck. In the majority of instances, the source of pain is an overuse of the masticatory musculature through parafunction. The most common dental parafunctional habits are bruxism and clenching. The patient is often unaware of the habit, which may take place while asleep [161].

Initial therapy is directed at relief of muscle spasms and involves use of heat, massage, a soft and non-chewy diet, muscle relaxing, and pain-reducing medications. For many patients, one or two weeks of such treatment is sufficient to eliminate the symptoms. Early treatment is important to prevent shifting of the jaw and arthritic changes in the jaw joint [161].

Cervicogenic Headache

Cervicogenic headache is often a sequela of head or neck injury but may also occur in the absence of trauma [162]. With this type of headache, the pain is perceived to be in the head but is actually referred from the cervical spine. Typically, the pain may be characterized as insidious in nature and unilateral in position [163]. The parietal and occipital areas are most commonly affected. The pain is usually fairly constant and may last for days to weeks. It is aggravated by neck movements. On exam, there is usually cervical paraspinal tenderness. The source of pain is usually the cervical ligaments or intervertebral discs [162].

The mean age of patients with this condition is 43 years, and it is four times more prevalent in women than in men [162,163]. Diagnostic criteria have been established, but the presenting characteristics of cervicogenic headache are often difficult to distinguish from primary headaches disorders, such as tension-type headache [43,162]. Additionally, there are significant differences, especially with respect to quality of life. In a study comparing responses on a medical outcomes questionnaire for patients with cervicogenic headache, episodic tension-type headache, and patients with migraine without aura, domain scores for physical functioning for patients with cervicogenic headache were lower than the tension-type and migraine groups [164].

Diagnostic imaging cannot confirm the diagnosis of cervicogenic headache but may lend support to its diagnosis. Successful treatment requires a multifaceted approach, including using pharmacologic, nonpharmacologic, manipulative, anesthetic, and occasionally surgical interventions. Medications alone have proven to be ineffective or, at best, to provide only modest benefit [162,163].

Medication Overuse

Medication overuse headache, also known as rebound headache, results from misuse of drugs, most notably over-the-counter analgesics or migraine medications. It is most common in patients with frequent migraine attacks or tension-type headaches [165]. Chronic tension-type headache is less often associated with medication overuse; however, episodic tension-type headache has commonly become a chronic headache through overuse of analgesics [43]. The headache is caused by frequent use of anti-headache medications for more than 15 days per month. Evidence suggests that this occurs sooner with triptan overuse than with ergotamine overuse [43,166]. The mean period of time that elapses before this type of headache evolves ranges from one to two years for the triptans, three to five years for ergotamines, and up to 5 to 10 years for over-the-counter analgesics [167]. The pathophysiology of this syndrome remains unknown.

The diagnosis of medication-overuse headache is clinically extremely important because patients rarely respond to preventative medications while overusing acute medications [43]. Treatment is withdrawal from the medication. If tapered, this may take more than two weeks, depending on the medication. Improvement should occur within two months after cessation of overuse in order for the diagnosis to be definite [43]. This is followed by prophylactic treatment of the primary headache [165,166].

Herbal Medications

It is important to consider the use of herbal medications as a possible cause of headaches. Approximately 38% of adults in the United States use at least one herbal medicine [168]. Many patients do not admit use to physicians, either because they do not consider them to be a "medication," because they do not need a prescription to obtain them, or because they are embarrassed to admit they use a medication that most physicians do not consider scientific. Herbal medications that have been reported to cause headaches include valerian root, ginkgo biloba, and ginseng [169].

7. ACUTE VERSUS CHRONIC

Although chronic headache is a term often used by patients, as well as some clinicians, it is no longer a recognized diagnosis. Patients either have a chronic primary headache or a chronic secondary headache. Chronic daily headache occurs in approximately 4% to 5% of the population [170,171]. The overwhelming majority of chronic headaches are primary headaches, typically migraine or tension. Chronic headache is not a separate syndrome. The general time frame for chronic is when the headache occurs on more than 15 days of each month, whether or not the patient is taking any medication.

8. REFERRAL

Evidence Based Practice Recommendation

The decision to seek a specialty consultation will depend upon the practitioner's familiarity and comfort with headache and its management. The Institute for Clinical Systems Improvement recommends considering specialty consultation when:

- The diagnosis cannot be confirmed.

- Etiology cannot be diagnosed or warning signals are present.

- Headache attacks are occurring with a frequency or duration sufficient to impair the patient's quality of life despite treatment or the patient has failed to respond to acute remedies or is in status migrainosus.

https://www.icsi.org/wp-content/uploads/2019/01/HeadacheRR.pdf

Last Accessed: April 5, 2022

Level of Evidence: Expert Opinion/Consensus Statement

One of the most important decisions in managing patients with headaches, especially chronic headaches, is when to continue care and when to refer care. In general, most patients with benign headaches can be managed by primary care physicians and other clinicians. There are several factors involved when one should consider referral to a specialist. These include, but are not limited to:

- Minimal physician expertise in headache management

- Unable to determine diagnosis

- Failure of the patient to respond to appropriate treatment

- Worsening symptoms

- Development of rebound cycles

- Dependence on opioids

- Significant comorbidities

When one or more of these conditions exist, referral to a specialist should be considered. Specialists typically are neurologists, although some are internists and family practitioners who focus their clinical practice on headache management. Headaches represent the most common reason for neurology visits [172]. Therefore, physicians should not view referral as failure on their part.

9. MEDICO-LEGAL ISSUES

With rising malpractice premiums, the threat of malpractice remains high on the minds of many healthcare professionals. With respect to headaches, physicians are fearful of missing that rare brain tumor or other catastrophic cause of headache. When such a misdiagnosis occurs, a malpractice claim may ensue. Any malpractice action falls under tort law.

Tort law allows injured persons to recover damages through the civil (i.e., noncriminal) judicial system. It is important to note that injury is a necessary but not sufficient requirement for recovery and most injuries do not give rise to a legal action. In the context of medical malpractice suits, the most relevant aspect of tort law is negligence as that is the claim most plaintiffs raise. A common claim for headache management is "failure to diagnose."

Not all bad outcomes, however, support a claim for negligence. There are several necessary components to negligence, all of which must be present for a plaintiff to prevail. First, the defendant must have owed some duty to the plaintiff to adhere to a specific standard of conduct and protect the plaintiff from unreasonable risk of injury. In the context of the doctor-patient relationship, this duty is for the physician to meet the standard of care for his or her profession. Generally the standard of care is the knowledge and skill held by a member of the profession in the same community or a similar community. The standard of care for specialists is somewhat higher as it is based on the knowledge and skill held by specialists.

Second, the defendant must have breached this duty by deviating from the standard of care. Such a deviation may be either an act or an omission. Finally, this breach of duty must be the actual and proximate cause of the plaintiff's injury. This means that a physician might make a clear medical error but if that error proves harmless and does not actually cause any injury to the patient, there is no legitimate claim for negligence.

In order to minimize malpractice, physicians and other clinicians should document their actions and thought processes in the medical record. In addition, it is imperative that physicians keep up-to-date on the management of the conditions that they treat. If one has little expertise in headache management and the patient's condition is not improving, one should then consider referral.

10. CONCLUSION

Headaches represent one of the most common medical conditions and are a frequent reason for physician visits. They produce a significant socioeconomic cost in terms of lost work and decreased quality of life. In general, most headaches will be benign; however, there should be a thorough history and physical exam each time a patient presents with headaches. The majority of headaches will be primary in origin (i.e., migraine, tension, cluster), but secondary causes need to be excluded. Physicians should be aware of the warning signs that warrant an immediate and thorough work-up and realize that a patient may have more than one headache disorder. Various imaging modalities, such as CT, MRI, and PET, exist but should be used prudently, based on clinical presentation and clinical suspicion of disease.

Numerous treatment modalities exist to treat the various headache syndromes. Therapies for primary headaches include both pharmacologic and nonpharmacologic interventions. Preventive therapies also should be explored for patients with repeat headaches. Finally, primary care physicians and clinicians should know when to refer patients to a specialist.

11. ADDITIONAL SOURCES OF INFORMATION

American Migraine Foundation

https://americanmigrainefoundation.org

American Headache Society (AHS)

https://americanheadachesociety.org

Help for Headaches

http://www.headache-help.org

International Headache Society

https://ihs-headache.org

National Headache Foundation

https://headaches.org

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