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.

Education Category: Psychiatric / Mental Health
Release Date: 08/01/2014
Expiration Date: 07/31/2017


This intermediate course is designed for psychologists in any setting who may identify and treat depressed and suicidal patients.

Accreditations & Approvals

NetCE is approved by the American Psychological Association to sponsor continuing education for psychologists. NetCE maintains responsibility for this program and its content.

Designations of Credit

NetCE designates this continuing education activity for 15 credit(s).

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 psychologists 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 specific modified types.
  6. Assess patients for depressive signs and symptoms, with particular attention to unique features in special populations.
  7. Identify other conditions that may 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. Outline key components of an effective suicide prevention plan.
  16. Evaluate tools available for the assessment and evaluation of suicide risk.


Mark Rose, BS, MA, is a licensed psychologist and researcher in the field of alcoholism and drug addiction based in Minnesota. He has written or contributed to the authorship of numerous papers on addiction and other medical disorders 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 various law firms on matters related to substance abuse, is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine, and is a member of several professional organizations.

James Trent, PhD, earned his doctorate in clinical psychology from the University of Mississippi in 1977. He has worked in rural community mental health, where psychiatric emergencies were managed without the benefit of adjacent inpatient psychiatric facilities. He has managed an independent practice of psychology since 1979, a practice that has included managing patients presenting with psychiatric emergencies. Dr. Trent taught at Middle Tennessee State University and Capella University, lecturing graduate students on psychopathology and psychotherapy. He supervised practicum students and interns at the VAMC Nashville, Tennessee, and at the Vanderbilt University Psychological and Counseling Center. He is currently the staff psychologist for the Charleston, South Carolina, VAMC Home Based Primary Care program, providing psychological services to elderly veterans who have chronic, comorbid illnesses that preclude their ability to receive primary care at the hospital and manages psychiatric emergencies among elderly veterans. Dr. Trent also acts as the Psychology Division Planner at CME Resource.

Faculty Disclosure

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

Contributing faculty, James Trent, PhD, 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.

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.

Table of Contents

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#66401: Depression and Suicide

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Depression is a common, debilitating mood disorder. It is highly prevalent in medically ill populations, and many persons with depression are either unaware that they need professional help or are reluctant to seek it. Although contact in 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 clinicians, with one study showing inadequate assessment and diagnosis even after training [1,2].

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 [3]. Provider competence and confidence related to the diagnosis and treatment of depression is one factor; another factor 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 [4,5]. These widespread shortcomings in the proper diagnosis, treatment, and implementation of treatment adherence strategies among primary care professionals, including physicians, nurses, and behavioral health professionals, represent an opportunity to improve patient health through increased education and appreciation of depression's impact on public health.



Depressive disorders afflict approximately 17.6 million, or 1 in 6, Americans each year [6,7,8]. Major depressive disorder (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 meeting diagnostic criteria for MDD [9,10,11,12].

In 2011, there were 39,518 reported suicide deaths in the United States [13]. Suicide is the tenth leading cause of death among persons 10 to 65 years of age (36,891 suicides) and the 10th leading overall cause of mortality [13,14]. Every day, approximately 90 Americans take their own life, and 1 person dies by suicide every 13.3 minutes. An estimated 90% of persons who complete suicide have a diagnosable psychiatric disorder at the time of death [13,14].

For the approximately 39,000 suicide deaths each year, an estimated 200,000 additional individuals are affected by the loss of a loved one or acquaintance by suicide [15,16]. This figure does not take into account the physical and emotional pain and trauma endured by persons who have made unsuccessful suicide attempts [16].


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 2 weeks) diagnosable depression [17]. 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 (7% in men; 12% in women). The lifetime incidence of depression in the United States is 20% in women and 12% in men [18]. 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 [17]. Persons living below the poverty level are five times more likely to have current depression than those living at or above the poverty line [19].

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 [20]. 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 [21]. The recurrence rate of MDD in the elderly is also extremely high, at 40% [22]. Chronic health conditions contribute to an increased risk of depression in the elderly [21].

Postpartum Women

The postpartum 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 [23,24,25].

Persistent Depressive Disorder (Dysthymia)

Persistent depressive disorder (dysthymia) as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (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 [26].


Major depression exacts an enormous toll on the afflicted person. Recurrent major depression affects approximately 35% of patients and is associated with numerous chronic medical comorbidities and complications from acute medical illness, such as myocardial infarction [26]. Marital, parental, social, and occupational functioning is degraded, and every interpersonal connection of the depressed individual is adversely affected. 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 Americans as a whole [26].

MDD is among the most costly illnesses in the world. The cost of depression in the United States was estimated to exceed $83.1 billion in 2000, accounted for by workplace costs (62%), direct costs (31.4%), and suicide-related costs (6.6%) [27]. Even minor levels of depression have been associated with decreased work productivity [28]. A study in 2002 estimated the economic burden of depression to represent a 30% to 75% increase in healthcare costs after controlling for differences in medical comorbidities [29,30]. Patients who fail to achieve adequate treatment response use twice as many healthcare services and cost employers almost 4 times as much as patients achieving remission [31]. 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 [32]. The total economic burden of suicide is estimated to be $34 billion annually, with the costs falling most heavily on adults of working age [33]. Depression causes an estimated 200 million lost workdays each year at a cost to employers of $17 to $44 billion [34]. However, the accuracy of attempts to quantify such costs on a national scale are hampered by incomplete data, such as the underreporting of suicides and an absence of reliable data on suicide attempts [16].



Several risk factors are associated with a heightened risk for the development of depression, including demographic/socioeconomic, psychosocial, familial, medical, and psychological factors.

Women are at increased risk of depression, with a lifetime prevalence almost twice that of men [35]. Among women, severe obesity (body mass index greater than 40) is strongly associated with depression [36]. Lower socioeconomic status and being single are also risk factors for both genders [37].

Stressful life events in childhood, such as significant loss, parental divorce, and emotional trauma or physical abuse, are risk factors for the development of depression. In adulthood, recent loss (e.g., death, divorce), domestic abuse/violence, traumatic events (e.g., a serious car accident), and major life changes (e.g., job change, financial difficulties) are all potential red flags for depression [25,37].

Family history of psychopathology, affective disorders in general, and major depression are particularly robust risk factors. MDD is 2 to 4 times more common among persons with an afflicted first-degree biological relative (e.g., a parent) 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 [38].

There are several psychological conditions that can predispose an individual to depression, including [9,35]:

  • Excessive anxiety

  • Impulsive and obsessional personalities

  • Negative cognitive styles

  • High levels of neuroticism

Certain neurological illnesses are greater risk factors, such as Parkinson's 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 an episode of MDD [26]. Chronic pain, medical illness, and persistent or severe psychosocial stress elevate the risk of major depression, possibly explained by the negative impact of cortisol and other stress hormones on the neuronal substrate of mood in the central nervous system (CNS) [37].

Disorders related to cardiovascular disease that originate from endothelial dysfunction are risk factors, as are comorbid illnesses such as stroke, cancer, dementia, or disabilities. Risk factors for late-onset depression include widowhood, physical illness, educational attainment less than high school, impaired functional status, and heavy alcohol consumption [25,39].

As noted, postpartum women are particularly vulnerable to depression. Risk factors for the development of postpartum depression include [25]:

  • Depression or anxiety during pregnancy

  • Previous history of a mood disorder

  • Low levels of social support

  • Stressful life events

  • Pre-pregnancy and gestational diabetes

  • Fragmented or poor sleep

  • Substance abuse

  • Current or past experiences of abuse

  • Difficulty breastfeeding in the first two months postpartum


Research indicates that a major life event precedes the first episode of major depression in 40% to 60% of patients [40]. Symptoms of MDD may develop over a period of days or weeks or appear suddenly in response to a serious psychosocial stressor. A prodromal syndrome of anxiety or milder depression symptoms may persist for several months before the full onset of a major depressive episode. Major depression has a variable age of onset, with the average age of onset in the mid-20s [9,26].

Although the duration of an episode varies greatly, the mean duration among untreated persons is often 6 months or longer. At one year following the onset of a major depressive episode, 40% of persons will experience a level of symptom severity sufficient to continue meeting the diagnostic criteria for MDD [26]. Some individuals rarely, if ever, experience remission (i.e., 2 or more months with no symptoms or only one or two symptoms to no more than a mild degree), while others experience many years with few or no symptoms between episodes. Individuals with chronic depressive illness are more likely to have underlying personality, anxiety and substance use disorders than individuals with recent onset of symptoms and are less likely to experience full symptom resolution [9]. Recovery typically begins within 3 months of onset for 40% of individuals with MDD and within 1 year of onset for 80% of individuals. Persons with recent-onset MDD are more likely to experience near-term recovery, and many individuals who have been depressed only for several months can be expected to recover spontaneously. 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].

Substantial differences in the alteration of disease course and recurrence are found among persons with treated versus untreated depression. Recurrence rates are reduced by approximately 70% by maintenance on antidepressant medication for three years following the most recent episode, with an average recurrence on placebo of 41% versus 18% on active treatment [41,42]. Premature discontinuation of antidepressant treatment is associated with a 77% increase in the risk of relapse/recurrence of symptoms [43]. Prevention of recurrence is vitally important. Research has shown that the use of a collaborative care model that includes continuous use of antidepressants and regular follow-up can help with medication compliance and reduce the risk of relapse/recurrence of depression [25,44]. 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 [45]. Research has shown that the number of depressive episodes predicts an inadequate treatment response or treatment nonresponse [26].

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 3 months is the period of highest risk for a first attempt, with the 3 months following the first attempt being the highest risk period for a second attempt [30].


There are several similar terms used when describing depressed mood. An understanding of these terms is vital to understanding and addressing the problem in patients. According to the DSM-5, the common feature of all 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 (involving chronic, severe, persistent irritability), is included in the DSM-5 to address concerns about the potential overdiagnosis of and treatment for bipolar disorder in children up to 12 years of age [9]. MDD, formerly called major depression or clinical depression, is the classic condition in this group of disorders and is characterized by discrete episodes of at least 2 weeks' duration involving clear-cut changes in affect, cognition, and functioning, with interepisode 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 2 years (or at least 1 year for children and adolescents) is the essential feature of this disorder [9].



Although scientists have sought to elucidate the neurobiological bases of depression for decades, the exact underlying pathophysiology of MDD remains unknown [46]. Earlier theories attempting to account for the underlying basis of depression, including the monoamine-deficiency hypothesis and the hypothalamic-pituitary-adrenal (HPA) axis theory of depression, have been dismissed in light of subsequent research findings [26,47]. However, one consistent observation is that stress or emotional trauma, especially when experienced earlier in life, is associated with increased risk of developing depression [48]. It is believed that 40% to 50% of the risk for developing depression is due to genetic factors, and that the interactions between genetic and environmental factors across the lifespan underlie depressive vulnerability in most patients [49]. Early-life stress is likely to account for much of the environmental contribution to depression. This is supported by evidence that early-life stress can result in persistent neuroendocrine, physiological, behavioral, and psychological changes that negatively affect the development of brain systems involved in learning, motivation, and stress response, and that may also reflect a biological priming for the development of depression, especially with additional stress exposure [46,50]. Additionally, a chaotic, unstable caregiving environment during infancy may create a chronically over-reactive stress response system, resulting in subsequent impairments in stress response, emotional regulation, and impulse control [51,52,53]. Childhood sexual abuse also increases the overall risk for the development of numerous psychiatric disorders, including depression [53,54,55].

Until recently, explanations of the pathophysiology of depression have focused on imbalance among specific neurotransmitter systems, most prominently serotonin, norepinephrine, and dopamine. Considerable evidence does support the notion that major depression involves an alteration in the balance of neurotransmitters and/or their function, as manifested by impaired neurotransmitter synthesis, increased breakdown or metabolism of neurotransmitters, and increased pump uptake of neurotransmitters. A decrease in the functional balance of specific neurotransmitters has been hypothesized to cause certain types of depression; decreased norepinephrine would cause dullness and lethargy, while decreased serotonin would result in irritability, hostility, and suicidal ideation [56].

Depression is now realized to be a heterogeneous disorder in which different biologic abnormalities contribute to the disruptions in sleeping, eating, energy, and emotional reactions [57]. The four domains of cognitive function that are disturbed in persons with depression are executive control, memory, affective processing, and feedback sensitivity. Converging evidence from neuroimaging, lesion analysis, and postmortem studies now suggest that these disturbances in cognitive function, and the other signs and symptoms of depression, reflect dysfunction within an extended visceromotor network that interferes with the ability to modulate emotional behavior [58]. The medial prefrontal cortex and related limbic and striato-pallido-thalamic structures organize emotional expression and are part of a larger "default system" of cortical regions that include the dorsal prefrontal cortex, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex. Dysregulation within and between structures in this circuit, and with their interactions with subcortical regions (striatum, thalamus) and temporal lobe structures (amygdala, hippocampus), is believed to underlie the disturbances of emotional processing, cognitive performance, neurotransmission, autonomic regulation, and neuroendocrine responses associated with mood disorders such as major depression [59].

Although enormous gaps remain in understanding the neurobiology and heterogeneity of depression and its treatment, the increasing focus on dysregulated neural circuitry as the underlying pathophysiology of depression, with a corresponding de-emphasis on specific neurotransmitter system dysfunction, represents a critical new dimension for the development of fundamentally novel and more effective antidepressant treatments [56].


Although suicide is a potential complication of all psychiatric disorders, serious suicidal actions have a neurobiological basis that is distinct from the psychiatric illnesses with which they are associated [60].

Alterations in several neurobiological systems are associated with suicidal behavior, most prominently hyperactivity of the HPA axis, serotonergic system dysfunction, and excessive activity of the noradrenergic system. While the first and the last system appear to be involved in the response to stressful events, serotonergic dysfunction is thought to be trait-dependent and associated with disturbances in the regulation of anxiety, impulsivity, and aggression [61,62]. Altered functioning of these systems may stem from both genetic and developmental causes. Exposure to extreme or chronic stress during childhood has developmental consequences on these systems that persist into adulthood. Genetic differences may also contribute to alterations in the functioning of these neurobiological systems, and the interactive effect of adverse childhood experiences, such as physical abuse, sexual abuse, or caregiver abandonment, with genetic vulnerability is increasingly believed to play a role in suicidal behavior [61,63].

Neurobiological and psychological perspectives have converged to identify the most prominent risk factors for suicidal behavior: dysregulated impulse control and propensity to intense psychological pain that includes hopelessness, often in the context of a mood disorder. These factors are believed to largely reflect serotonergic system dysregulation [64]. Investigation into the role played by serotonergic dysfunction in suicidal behavior has identified two prominent regions: the dorsal and median raphe nuclei in the midbrain, which host the main serotonergic cell bodies, and the prefrontal cortex, particularly the ventral prefrontal cortex, which is innervated by the serotonergic system. In vivo and postmortem examinations have revealed serotonergic hypofunction in these two brain systems in persons who have died by suicide or made serious suicide attempts. The deficient serotonergic input in the ventral prefrontal cortex stemming from this serotonin hypofunction can result in a breakdown in inhibitory function leading to a predisposition to impulsive and aggressive behavior. This vulnerability to deficient impulse control coupled with the development of psychiatric illness or other life stressors elevates the risk of acting on suicidal thoughts [65].


As noted, depression is a disorder of mood involving disturbances in emotional, cognitive, behavioral, and somatic regulation. The mood disorder is considered secondary if it occurs in association with substance abuse or withdrawal, other psychiatric illnesses, certain medical illnesses, 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, dysthymic disorder, and depression NOS [25].

As no quantifiable measures of depression are currently used in clinical medicine, diagnosis is made through psychometric findings, fulfillment of diagnostic criteria, patient history, and clinical impression [66].


Depression is often difficult to diagnose because it can manifest in many different ways, some of which are not the obvious manifestations of a mood disorder. Many patients with MDD may not initially seek help for depressed mood, but instead may exhibit non-mood-behavior patterns that suggest depression and further investigation by the clinician [9,25]. This includes:

  • More than 5 medical visits per year

  • Weight gain or loss

  • Multiple unexplained symptoms

  • Sleep disturbance

  • Work or relationship dysfunction

  • Fatigue

  • Changes in interpersonal relationships

  • Dementia

  • Dampened affect

  • Irritable bowel syndrome

  • Poor behavioral follow-through with activities of daily living or prior treatment recommendations

Assessment of the presence of depression can also be made through signs and symptoms of the following cognitive, affective, and behavioral domains [9,25,26].

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 [9,25,26].

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 typically 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 [9,26].

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 [25,26].


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 [9,25,26].

Thought Content, Suicidality, and Homicidality

The thought content of depressed patients 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 [25].


If depression is suspected, a screening instrument can be administered. Depression screening tests are used to identify patients who should undergo a full psychological assessment that uses DSM-5 diagnostic criteria to determine the presence or absence of specific depressive disorders, the severity of depression, and the presence or absence of comorbid psychiatric conditions such as panic attacks or substance abuse [67]. Many formal screening tools are available, and with little evidence to recommend one screening method over another, clinician selection is guided by personal preference, the patient population served, and the practice setting [67]. The following are widely used depression screening instruments [68,69]:

  • Patient Health Questionnaire-9 (PHQ-9): The PHQ-9 is a 9-item instrument that uses a Likert scale.

  • General Health Questionnaire (GHQ): The 28-item GHQ was developed as a general screen of psychiatric distress and measures a variety of constructs, such as depression and anxiety.

  • Zung Self-Rating Depression Scale: The Zung is a widely used depression screen that was developed in 1965 and is also used to measure treatment progress and outcome.

  • Beck Depression Inventory II (BDI-II): In addition to its use as a depression screen, this 21-item scale has been widely used as a depression outcome measure and to provide information on the severity of depression.

  • Criteria for Epidemiologic Studies-Depression (CES-D): The CES-D has 20 items and is also used as a treatment outcome measure.

  • Geriatric Depression Scale (GDS): The GDS was developed to assess depression in older adults.

  • Hamilton Rating Scale for Depression (HAM-D or HDRS): The HAM-D is used to help identify symptom severity of MDD and is clinician-rated. The questionnaire is one of the most commonly used scales for rating depression in clinical research.

  • Montgomery-Åsberg Depression Rating Scale (MADRS): The MADRS is a 10-item questionnaire used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders. It was developed as an adjunct to the HAM-D, but provides greater sensitivity to medication or other treatment response.

Other screening instruments can assist in the assessment of comorbidity or differential diagnosis. These include [25,68,69,70]:

  • Mood Disorder Questionnaire (MDQ): The MDQ is a screening instrument to help identify patients with bipolar-spectrum conditions and can help in differential diagnosis.

  • Young Mania Rating Scale (YMRS): The YMRS is a clinician-administered instrument for mania.

  • Edinburgh Postnatal Depression Scale (EPDS): The 10-item EDPS is the most widely used assessment instrument for postpartum depression. It is administered to patients 6 weeks after delivery.

  • CAGE Questionnaire: Due to the very high rates of substance abuse with depression, the CAGE should also be given as a screen to patients undergoing further evaluation. Although the original CAGE questionnaire focused on drinking, there is an adapted version that includes drug use (CAGE-AID). To administer the CAGE-AID, ask the patient if he or she has 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: The Distress Thermometer can be used in patients with significant language or communication difficulties, and consists of a 1-question screen that identifies distress from any source. The person places a mark on 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 a significant level of distress that should be investigated further.


A positive depression screen indicates the presence of depression but does not provide information as to whether the depression is attributable to a primary depressive disorder or is secondary to another psychiatric disorder. Additional psychological testing with the Millon Clinical Multiaxial Inventory-III (MCMI-III) or Minnesota Multiphasic Personality Inventory-2 (MMPI-2) can be used to help determine diagnosis or differential diagnoses [71]. Both instruments can only be interpreted by a licensed psychologist with training in psychological 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. Survivors of suicide attempts often experience continued depression and other mental health problems [72,73].


The American Psychiatric Association (APA) published their most recently revised diagnostic criteria for depression and other psychiatric illness in 2013, 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 2 consecutive years (at least 1 year in children and adolescents), and must include the presence (while depressed) of 2 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 5 of the following symptoms for at least 2 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 MDD patient 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 physiological 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 2 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: 2 symptoms

  • Moderate: 3 symptoms

  • Moderate-to-severe: 4 or 5 symptoms

  • Severe: 4 or 5 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 3 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 2 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 [26].

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 4 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 2 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.


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 2 months and 7 months following the loss [74]. 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 [9,26].


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 [76,77]. 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 [78].

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 white women [79].

African Americans

In general, African Americans are more likely than whites to seek help for psychological 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 [80]. They tend to seek services later and, therefore, face worse outcomes [81]. When they perceive they need help for an emotional problem, African American women tend to prefer individual or group therapy over medication [79].

Latino/Hispanic Americans

Latino/Hispanic Americans often show psychological distress differently, and assessment for depressive symptoms alone may not adequately capture their psychological distress [82]. 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 [80,83]. Latina women are more likely to express distress via depressive symptoms while Latino men are more likely to externalize distress [82]. When they perceive they need help for an emotional problem, Latina women tend to prefer individual or group therapy over medication [79].


Asian immigrants, especially Chinese Americans, are less likely to use mental health services than other ethnic groups [84]. The discrepancy between aspiration and achievement may better predict psychiatric illness and emotional disturbance than socioeconomic status [85].

Elderly Patients

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 [86]. 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 [25].

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 [25]. 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 [86,87].

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 [25]. Stigma also contributes to the denial among elderly patients of the psychological 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 [86,88].

Provider-Related Factors

Provider-specific factors contributing to underdetection and undertreatment 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 [89]. 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 [89,90,91].


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 [89,92,93,94]. Suicidal thoughts may also be considered age-appropriate in the elderly [91]. 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 [93,94]. 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 [89,91].

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 [95].


First-episode depression in elderly patients may have an undiagnosed neurological 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 [26].


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 somatic reasons (e.g., respiratory infection), giving practitioners clues as to their mental state that were not often explored [96]. 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 [23]. 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) [97].


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 [97]. There are several inherent barriers in the accurate assessment of younger children, including limited cognitive, language, and reading abilities [98]. 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 [99,100].

Gay, Lesbian, and Bisexual Individuals

Some depression risk factors occur with greater frequency in the gay, lesbian, and bisexual communities, including family rejection, ostracization, peer victimization, and negative self-image, and depression is more common in this group than in the general population [101,102]. However, there is some evidence that available screening tools may overestimate the incidence of mental disorders among gay, lesbian, and bisexual patients [103]. Because the risk of suicide is high in this population, any possible depressive signs or symptoms should be fully explored.


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 biological 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 [9,26,104].

CNS Conditions

A broad range of CNS processes and conditions can produce changes in mood, cognition, and behavior that resemble MDD. These include Alzheimer's disease, Parkinson's disease, Huntington's 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's disease, Cushing's 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 1 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, 3 (or more) of the following symptoms have persisted (4 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 is 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 physiological 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.


Additional psychiatric disorders are present in many patients with MDD. The rates of comorbidity vary according to whether the results were based on community or clinical sampling. However, the most commonly occurring psychiatric comorbidities and their rates of occurrence in persons with MDD are [26,105,106,107,108]:

  • Generalized anxiety disorder (62%)

  • Social phobia (52%)

  • Post-traumatic stress disorder (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's disease, and cardiovascular disease [109]. 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's disease (40%), and Alzheimer's disease (20% to 40%). The recurrence rate of MDD in the elderly is also extremely high, at roughly 40% [22].


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 [26].


Although the DSM-5 criteria require the presence of 5 of 9 symptoms for MDD diagnosis, significant impairment in functioning can occur with as few as 2 symptoms [9,110]. 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 [25,111].

Although primary care providers write 60% to 70% of all antidepressant prescriptions in the United States, evidence suggests that nonpsychiatric practitioners underdiagnose and/or undertreat depressive illness [30,112]. When a patient with major depression is identified and considered for treatment in the primary care setting, several challenges in achieving remission in the patient have been identified. These include time constraints on the treatment of a time-intensive disorder; potential of multiple 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, psychological care; and patient expectation of a "quick fix" [30].


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. In addition to serving as the initial basis of engagement, patient education is important to help counter the negative effects of pessimism, low motivation, low energy, social isolation, and guilt regarding lack of treatment adherence [25,26].

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 illness, not a character defect, and recovery is the rule, not the exception [25,26]. Treatment is effective for most patients, and it is important to stress that the aim of treatment 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 [45]. Clinicians should include the following topics related to treatment and follow-up in discussions with the patient before directly addressing specific therapy options [25,26]:

  • 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

The importance of assuming some responsibility for self-care should be communicated to the patient. This can range from simply taking medications reliably and notifying the provider about side effects to agreeing to participate in sessions, or journaling and completing homework for cognitive behavioral therapies. Written materials can help reinforce the information regarding self-care, and bibliotherapy, whereby the patient reads self-help books and other materials related to depression, has modest empirical validation [113,114].

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 [115]. 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 [25,116,117]. 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 [118].

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, 3 to 5 days a week [25].


The two initial treatment options for most patients with MDD are psychotherapy and/or pharmacotherapy. A third option, electroconvulsive therapy (ECT), should only be considered in highly selected patients as first-line therapy [111]. 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 [119]. 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 [26].

Pharmacologic and psychological interventions are both effective in treating depression. General factors to consider in making treatment recommendations include symptom severity, presence of psychosocial stressors, presence of comorbid conditions, chronicity of symptoms, and patient preference. If the initial presentation is mild-to-moderate, either an antidepressant or psychotherapy is indicated. If the presenting symptoms of depression are severe or chronic, the initial recommendation is to treat with antidepressants and psychotherapy [25]. Patients with MDD with psychotic features should receive an antipsychotic and an antidepressant medication or ECT. Lithium can be added in patients unresponsive to antipsychotic/antidepressant therapy [26]. 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 [26].

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 [26].

Specific Features

As discussed, patients with MDD may present with features that specify the current episode as catatonic, melancholic, or atypical. These specifiers can help guide treatment decisions.

Rapid alleviation of potentially life-threatening catatonia in MDD patients 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 [26].

For patients with melancholic features, serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) may have an advantage over selective serotonin reuptake inhibitors (SSRIs) [26]. MDD with atypical features may respond better to treatment with MAOIs than TCAs. However, the use of SSRIs, bupropion, and cognitive-behavioral therapy (CBT) is supported by some data, and ECT is also effective [26].

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 [26].

Patients with MDD and borderline personality disorder may respond to SSRIs or SNRIs and to low-dose antipsychotics or lithium. Some antiepileptic medications can help manage behavioral impulsivity and dyscontrol. MAOIs should be avoided due to side effects and dietary compliance issues [26]. MDD patients with comorbid personality disorders show a less satisfactory antidepressant response in terms of social functioning and residual symptom reduction. 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 [26]. Other evidence suggests that, among depressed patients, comorbid personality disorders interfere with treatment response to interpersonal psychotherapy but not CBT [120].

Eating disorders may also 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 increased seizure potential, and ECT has not been shown to be effective [26].

Finally, if a patient's depression is determined to be seasonal affective disorder, bright-light therapy is recommended as first-line therapy and can be used adjunctively with antidepressants in severe cases. The entire range of treatments for MDD may also be used to treat seasonal affective disorder, either in combination with or as an alternative to bright-light therapy [26].

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 [7,68]. For patients with persistent subthreshold depressive symptoms or depression of mild-to-moderate severity, consider an antidepressant or CBT, interpersonal therapy, or behavioral activation [68].

The cognitive impairment in pseudodementia, unlike true dementia, is secondary to MDD and should resolve with adequate antidepressant or ECT response [26].

Demographic and Psychosocial Factors Influencing the Treatment Plan

Female Gender

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 [26].

Major Psychosocial Stressors

MDD may follow a substantially adverse life event, typically involving the loss of an important relationship or life role. Although major depression precipitated by such events is equal to other depressive episodes in terms of requirement and response to antidepressants, the treatment approach should consider the relationship of both prior and concurrent life events to the onset, worsening, or maintenance of major depressive symptoms, and a psychotherapeutic intervention coupled with medication may be particularly useful [26]. Antidepressant medications or psychotherapy should be used in cases with prolonged reaction to relationship loss with significant functional impairment, and some patients may benefit from bereavement support groups [26].

Another psychosocial stressor that should be considered in treatment selection is a history of early life trauma, such as physical/sexual abuse or parental loss or abandonment. A study involving 681 patients with chronic major depression found that among patients with childhood trauma, CBT was consistently more effective than antidepressant medication monotherapy, and that combining both therapies did not offer a significant advantage over CBT monotherapy [121]. However, remission was estimated to be twice as likely with psychotherapy than with antidepressant therapy among patients with chronic major depression and early life trauma, especially among those with early parental loss. These results suggest a central role for psychotherapy in the treatment of patients with chronic major depression and a history of childhood trauma [121].

An ongoing family stressor can interfere with treatment response, with ambivalent, abusive, rejecting, or highly dependent family relationships predisposing an individual to MDD. Such families should be evaluated for family therapy, which may be used in conjunction with individual and pharmacologic therapies [26].

Other Psychosocial Factors

Psychosocial stressors such as housing, food, child care, transportation, employment, immigration status, and financial stability may be more prevalent with certain populations and should be considered during treatment planning [122]. 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 [25,123].

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 experience a number of barriers to accessing mental health services, including stigma, deficits in knowledge/understanding, economic hardship, and language barriers [75]. 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) [75].

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 [26]. 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 [26]. Weight loss may be a concern for some older patients, who may benefit from medication that promotes weight gain [25].

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 [124]. Collaborative care has demonstrated considerably greater and more sustained improvement of depressive symptoms in the elderly than usual care [125].

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 for maintenance treatment, while a family history of positive treatment response to a particular antidepressant may be used in the selection process of an antidepressant for the patient [26].

Comorbid Medical Conditions

As with psychiatric conditions, comorbid medical conditions will impact the treatment plan for depressed patients. Pharmacologic agents should be chosen carefully in these patients due to the increased risk for adverse events and drug-drug interactions. In particular, the following considerations should be made [26]:

  • 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's 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's 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.


In mild-to-moderate depression, psychotherapy can be equally as effective as medication, although with severe depression, antidepressant medication is usually necessary [126,127]. Psychotherapy can significantly reduce symptoms, restore psychosocial and occupational functioning, and prevent relapse in patients with major depression [128]. It is especially useful in addressing the psychosocial stressors and psychological factors that impact the development or maintenance of depressive symptoms [26]. 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 [26]. 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 psychological or psychosocial issues are prominent or if the patient requests it [129,130,131].

Phases of Treatment

Initiation/Acute Phase

The initiation or acute phase of treatment consists of two subphases in the first 8 to 16 weeks of treatment. The initial 4 to 8 weeks is the beginning of the treatment plan, while the second 4 to 8 weeks involves a reassessment of response adequacy. During this period, the patient is monitored for the degree of response, side effects, functional status, adherence, any residual risk of harm to self or others, and co-occurring psychiatric and medical comorbidities [30]. Remission is the goal and is defined as minimal residual symptoms [25,132].

Continuation Phase

Defined as the 4 to 9 months following remission, during the continuation phase the patient is maintained on the same dose of antidepressant medication as the initiation phase to prevent relapse. Specific psychotherapies may be used during this phase to maintain remission and prevent relapse. The patient is reassessed every 8 to 12 weeks [26,30,132]. Relapse is defined as the return of depressive symptoms during the initiation or continuation phases and is considered part of the same depressive episode.

Maintenance Phase

Following the continuation phase, the maintenance phase of treatment should consist of the same antidepressant medication dose used in previous treatment phases. A reduced frequency of visits with CBT and interpersonal therapy usually occurs during this phase [26,132].

Recurrence is defined as the return of depressive symptoms during the maintenance phase and is considered a new, distinct depressive episode [7].

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 [133,134]. Two issues should be considered when deciding the duration of medication treatment: maintenance of current therapeutic response and prevention of additional episodes. Patients who require several medication changes to achieve remission have higher rates of relapse and a shorter duration of remission until relapse compared with patients who require fewer medication changes to achieve remission [135]. Substantial evidence validates the effectiveness of antidepressants in preventing the recurrence of a major depressive episode. Patients with the greatest risk of future episodes include those with multiple prior episodes and patients who were older at the age of onset [136]. These patients are candidates for long-term or lifetime prophylactic treatment. In determining the duration of antidepressant medication, consider the following recommendations [25,137]:

  • 1st episode: Continue medication treatment a minimum of 6 to 12 months after remission (including acute and continuation therapy).

  • 2nd episode: Continue medication treatment for 3 to 5 years.

  • 3+ episodes or 2 episodes with complicating factors (e.g., rapid recurrence of episodes, age of onset older than 60 years, severe episodes, family history) or persistent depressive disorder: Continue medication treatment indefinitely.

When antidepressants drugs are discontinued, a contingency plan should be in place for prompt intervention if relapse occurs [41]. Factors that contribute to premature discontinuation of medication include inadequate education about the illness, physician or patient failure to establish goals for follow-up, psychosocial factors, and side effects. Ongoing collaborative care for depression between providers and patients can increase remission rates as much as 76% by 24 months [138,139].


The objective of psychotherapy (sometimes referred to as psychosocial therapy) is to change thinking and behavior patterns in an effort to modulate limbic-cortical pathways in regions of the prefrontal cortex, hippocampus, and cingulate that are associated with normal emotions and behavior [140]. There are a variety of psychotherapy options available to the depressed patient.

Cognitive-Behavioral Therapy

CBT is a structured, circumscribed psychological 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 [26]. 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. The therapist helps the patient develop the skills to identify, monitor, and then counteract problematic thoughts, beliefs, and interpretations that are related to the target symptoms or problems. The therapist also provides the patient with a repertoire of coping skills that are appropriate to the target thoughts, beliefs, and/or problem areas [68]. Most trials of CBT involve 16 to 20 therapy sessions for treatment and relapse prevention work, and several variants of CBT have been developed and used in patients with depression, including group and mindfulness-based modalities [68,141].

Group CBT

Group CBT utilizes psychoeducation to teach participants techniques and strategies to cope with the problems believed to underlie their depression. These strategies include improving social skills, addressing negative thinking, increasing pleasant activities, and engaging in relaxation training. Group CBT typically involves 12 sessions of 2 hours' duration for 8 weeks; groups often meet twice weekly for the first 4 weeks [142,143]. One- and 6-month follow-up sessions are also held, and booster sessions can be used to help prevent relapse [68].

Mindfulness-Based Cognitive Therapy

Mindfulness-based cognitive therapy originated as an intervention for stress reduction in patients with chronic medical illness and was modified for use in depressed patients with the objective of preventing relapse and recurrence [144]. The goal of mindfulness-based cognitive therapy is to facilitate patient learning and awareness of the bodily sensations, thoughts, and feelings associated with depressive relapse, and to relate constructively to these experiences [145]. Patients are taught to recognize these "automatic pilot" modes, step back, and counter them by detaching from the negative thoughts and feelings (for example, by learning that feelings are not facts), accepting difficulties by embracing self-compassion, and using bodily awareness to ground and transform experience. In the latter stages of the therapy, patients develop a contingency plan that outlines response strategies when they become aware of early warning signs of relapse/recurrence [146].

Interpersonal Therapy

Originally developed by Klerman and Weissman for depression, interpersonal therapy has now been adapted for use with other disorders [147,148]. Interpersonal therapy focuses on current relationships and interpersonal processes rather than past relationships and intrapsychic processes and conflicts. It is time-limited and identifies and helps resolve relationship problems occurring during major depression episodes [68].

Patients are taught to associate their mood with their interpersonal connections and to recognize that relationships and depressive symptoms can be improved through addressing relationship problems. A focal point is agreed on at the beginning of treatment; focal points can include interpersonal role transitions, interpersonal roles or conflicts, grief, or interpersonal deficits. Interpersonal therapy is appropriate for addressing specific areas of interpersonal difficulty and can be delivered as individual or group therapy [149]. "Homework" is not explicitly assigned, but patients are expected to apply to their relationships what they are learning in therapy between sessions.

Short-Term Psychodynamic Psychotherapy

Psychodynamic psychotherapy is a psychological intervention derived from the psychodynamic/psychoanalytic model, whereby therapist and patient identify and further define conflicts and their manifestation in current situations and relationships, including the therapeutic relationship (e.g., transference and countertransference). This is intended to provide the patient with the opportunity to explore feelings and conscious and unconscious conflicts originating in the past, allowing therapists to interpret and help patients to work through the conflicts. The therapy session is non-directive, and patients are not taught specific skills (e.g., thought monitoring, re-evaluating, problem solving) [68].

Marital/Family Therapy

Marital and family problems are common in the course of mood disorders and may either predate, help perpetuate, or be a consequence of the mood disorder. Several marital/family therapy approaches are effective in the treatment of depression, including behavioral approaches, problem-focused approaches, and strategic marital therapy. Marital/family therapy is a useful adjunct to medications and hospitalization in severely ill patients [26].

Problem-Solving Therapy

Problem-solving therapy is a time-limited, structured psychological intervention that involves therapist-patient collaboration in identifying and prioritizing key problems; breaking problems down into specific, manageable tasks; problem solving; and developing appropriate coping behaviors for problem resolution or management. Problem-solving therapy was developed from the association of depression with deficits in social problem solving originating from the effects of the depressed state, lack of knowledge, and excessive rumination [150,151]. Problem-solving therapy was developed to be used in the primary care setting [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 [68].

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 3 or more previous episodes of depression [68].


Successful treatment with antidepressant medications often involves dosage adjustments and/or trials of a different medication at some point in order to maximize response and minimize side effects [26]. Because patient adherence to the medication regimen is essential in achieving the maximum clinical benefit, there are several messages that should be communicated to the patient to encourage and support ongoing medication adherence [25]. First, side effects from medication often precede therapeutic benefit and typically recede over time. It is important to expect some discomfort prior to the benefit. Dosage adjustments and/or trials of different medications are often necessary for successful treatment. Most people should continue on one medication for at least 6 to 12 months after adequate response to symptoms, and patients may show improvement at 2 weeks but need a longer length of time to really see response and remission. Also, medications must be taken as prescribed, even after one feels better, because early discontinuation is associated with substantially elevated rates of relapse/recurrence. Patients should be advised to not stop taking the medication without calling their provider. Side effects often can be managed by changes in the dosage or dosage schedule. Consider increasing support and reassurance, education, engagement, and follow-up for patients who are at higher risk for poor treatment adherence, in patients with an initial depression diagnosis, patients in the middle of their first depression episode, and patients who have lapsed in the middle of a previous course of treatment [25,154].

Providers should carefully evaluate patients in whom depression persistently worsens or in whom emergent suicidality is severe, abrupt in onset, or was not part of the presenting symptoms, in order to determine what intervention is needed, including discontinuing or modifying the current drug therapy [25]. Providers should also instruct the patient and the patient's caregiver(s) to be alert for the emergence of agitation, irritability, and other symptoms. The emergence of suicidality and worsening depression should be closely monitored and reported immediately to a healthcare provider [25].

Because the overall efficacy of antidepressants in the treatment of major depression is comparable between classes and within classes of medications, other factors are considered in the medication selection process, including patient or family history of previous response to antidepressant medications (if any); positive or negative impact of the antidepressant on comorbid psychiatric or medical conditions; clinician familiarity; patient preference; safety in overdose; availability and cost; and drug-drug interactions [25]. The second-generation antidepressant drugs, which include the SSRIs, venlafaxine, duloxetine, desvenlafaxine, mirtazapine, and bupropion, are usually recommended for first-line treatment due to the quality of published data, side effect tolerability, and safety in overdose relative to TCAs and MAOIs [25,26,155].

The three most distressing side effects for patients being treated with antidepressant medications 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].

Selective Serotonin Reuptake Inhibitors

As a class, SSRIs are believed to act by inhibiting the reuptake of the neurotransmitter serotonin (5-HT) into the presynaptic cell, increasing levels of 5-HT within the synaptic cleft. SSRIs have the advantage of ease of dosing and low toxicity in overdose, and compliance is promoted due to a less prominent side effect profile than other classes of antidepressants. They are particularly effective in patients with obsessive-compulsive symptoms, but may initially worsen anxiety or panic symptoms [7,25,26]. This class includes the agents fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), escitalopram (Lexapro), and vortioxetine (Brintellix).

Escitalopram has been shown to have superior efficacy to other antidepressants in the treatment of more severe depression, being at least as effective as SNRIs and better tolerated, even in severe depression [158,159]. Escitalopram may lead to earlier depression relief than most other antidepressants, with an onset of action of 1 to 2 weeks in many cases. For patients with melancholia and psychomotor agitation, sertraline appears superior. 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 [7,25,26].

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 (loss of erectile or ejaculatory function in men, loss of libido and anorgasmia in both sexes), headache, fatigue, and weight gain [7,25,26]. Many of these side effects dissipate over time. Sertraline is particularly associated with diarrhea, and paroxetine with weight gain [7,26].

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 [7,25,26]. Most SNRIs, including venlafaxine (Effexor), desvenlafaxine (Pristiq), levomilnacipran (Fetzima), and duloxetine (Cymbalta), are several fold more selective for serotonin over norepinephrine.

Safety, tolerability, and side effect profiles of SNRIs are similar to 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 pain syndromes associated with the episode of depression. The SNRIs also have an important role as second-line agents in patients who have not responded to SSRIs [7,25,26].

Venlafaxine is especially beneficial in treating anxiety in depressed patients. At lower doses (75 mg/day), venlafaxine acts much like an SSRI; SSRI-like side effects such as gastrointestinal upset often improve at higher doses (150–300 mg/day) [7,25,26]. Discontinuation syndrome has been reported to be markedly worse for venlafaxine when compared to other SNRIs.

Common Side Effects

SNRIs are associated with greater likelihood of increased pulse rate, dilated pupils, dry mouth, excessive sweating, and constipation [25]. Venlafaxine has a greater incidence of nausea and vomiting than SSRIs and may be associated with an increased risk for cardiovascular events [7,26].

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. The 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 [160].

The TCAs are classified by the nature of the final amine group on the side chain as tertiary amines, which include amitriptyline (Elavil), clomipramine (Anafranil), doxepin (Sinequan), trimipramine (Surmontil), imipramine (Tofranil), and lofepramine (Lomont); secondary amines, such as nortriptyline (Pamelor), desipramine (Norpramin), and protriptyline (Vivactil); and the tetracyclic antidepressants, amoxapine (Asendin) and maprotiline (Ludiomil). TCAs are sometimes referred to as first-generation antidepressants.

The literature clearly supports the treatment effectiveness of TCAs, but despite this and their advantage of low cost, TCAs are infrequently used as first-line therapy due to associated side effects [7,25,26]. TCAs may initially worsen anxiety or panic symptoms. Due to the potential side effect of cardiac arrhythmia, TCAs should be monitored cautiously in patients with heart problems or in patients with potential for drug interactions. Monitoring blood levels and electrocardiogram may be advised. Secondary amine TCAs cause less orthostatic hypotension and sedation than tertiary amine TCAs. Tertiary amine TCAs should generally be avoided in elderly patients because of the high incidence of orthostatic hypotension, sedation, cognitive problems, and cardiac effects. Nortriptyline, a secondary amine TCA, is regarded as one of the most effective medications for elderly patients with moderate-to-severe depression. Clomipramine is particularly effective in patients with obsessive-compulsive symptoms [7,25,26].

Common Side Effects

The antimuscarinic and antihistamine receptor affinity of TCAs accounts for many of their side effects, including dry mouth or nose, blurred vision, reduced gastrointestinal motility or constipation, urinary retention, cognitive and/or memory impairment, and increased body temperature [7,25,26]. 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 then gradually increased [160,161].

Monoamine Oxidase Inhibitors

MAOIs act by inhibiting the activity of the enzyme monoamine oxidase, blocking the breakdown of monoamine neurotransmitters including epinephrine, norepinephrine, dopamine, and serotonin and increasing their availability. The earlier MAOIs inhibited monoamine oxidase irreversibly by permanently deactivating it until the enzyme was replaced by the body over a 2-week period. A few newer MAOIs, such as moclobemide, are reversible in that they detach from the enzyme to facilitate catabolism of the substrate [162,163]. This class of antidepressants includes phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), linezolid (Zyvox, Zyvoxam, Zyvoxid), moclobemide (Aurorix, Manerix), pirlindole (Pirazidol), and selegiline (Deprenyl, Eldepryl, Emsam).

There do not appear to be significant differences in efficacy between MAOIs. They are widely effective in a broad range of affective and anxiety disorders and may be more effective than other classes of antidepressants in major depression patients with anxiety or panic symptoms [7,25,26]. Patients with MDD with atypical features may preferentially respond to MAOIs over other antidepressant classes. Although effective, MAOIs are seldom used as first-line treatment due to the potential for serious side effects and dietary restriction. However, the selegiline transdermal patch (Emsam), when used at the lowest strength (6 mg delivered over 24 hours), may be used without the dietary restrictions required for oral MAOIs [164]. The most significant risk associated with the use of MAOIs is the potential for seriously adverse interactions with over-the-counter and prescription medicines, illicit drugs, and some nutritional supplements, including St. John's wort [7,25,26].

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 1) [162]. 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.


None to LittleModerateSevere
Fresh cheeses
Fresh meats
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

MAOIs should not be combined with other psychotropic drugs or with any other psychoactive substance except under expert care. Common side effects include orthostatic hypotension, weight gain, sexual dysfunction, sedation, headache, and insomnia [162].

Atypical Antidepressants

The atypical antidepressants are a diverse group of agents with actions that do not fit into other categories, including 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 is a norepinephrine and dopamine reuptake inhibitor, which 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 [7,25,26].

As with other antidepressant classes, each agent has apparent benefits and drawbacks, with some being 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 [7,25,26]. 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 advantageous. 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 [7,25,26].

Common Side Effects

The side effects of atypical antidepressants vary considerably according to the specific agent. 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 [26]. Sedation is the most common side effect associated with trazodone, followed by cardiovascular side effects (such as orthostasis) and sexual side effects [26]. Finally, nefazodone is associated with sedation, dry mouth, nausea, constipation, orthostasis, visual alterations, and possible increased risk of hepatotoxicity [7].

Dopamine Agonists

Although the role of stimulants for antidepressant monotherapy is very limited, dopamine agonists 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 monoamine reuptake inhibitors (SSRIs and TCAs), in terminally ill and medically ill patients with depression, and in elderly patients with complicating medical conditions [9,165,166,167].

This class of antidepressants includes amphetamine derivatives such as dextroamphetamine (Dexedrine) and methylphenidate (Ritalin). Methylphenidate inhibits the dopamine transporter and, to a lesser degree, the norepinephrine transporter. Dextroamphetamine increases cytosolic dopamine and norepinephrine by blocking vesicular sequestration of dopamine and norepinephrine through inhibition of vesicular monoamine transporter-2 activity [7,25,26].

Common Side Effects

In general, stimulants are associated with side effects related to hyperactivity (e.g., agitation, aggression, tachycardia, restlessness, insomnia). Other potential side effects include headache, anorexia, nausea, and irritability [168].

Dopamine agonists are contraindicated in patients with a history of drug abuse, with agitated states, and with moderate-to-severe hypertension [168]. In addition, patients who have initiated MAOIs within the last 14 days should not begin therapy with a dopamine agonist.

Pharmacotherapy to Reduce Suicide Risk

Abundant evidence has demonstrated that lithium reduces the rate of suicidal behavior in patients with bipolar disorder and recurrent major depression and that clozapine reduces suicidal behavior in schizophrenia [169,170,171,172,173,174,175]. Both drugs reduce suicide risk independently of their effect on the primary psychiatric disorder. Although the exact anti-suicide mechanism of both drugs has yet to be identified, lithium enhances serotonergic activity and clozapine is a potent 5-HT2A antagonist. Serotonergic modulation is a likely explanation of the suicide-reducing effects of both medications, because aggression levels and suicide are correlated with prefrontal cortical 5-HT2A binding [176,177,178].

Potential Complications with All Antidepressants

Sexual Dysfunction

Sexual dysfunction is a relatively common side effect with any antidepressant therapy. Bupropion has a significantly lower rate of sexual side effects than fluoxetine or sertraline, and paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline [7].

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 [179,180].

Discontinuation Symptoms

Discontinuation symptoms are placed into six groups: affective (e.g., irritability), gastrointestinal (e.g., nausea), neuromotor (e.g., ataxia), vasomotor (e.g., sweating), neurosensory (e.g., paresthesia), and other neurological (e.g., intense dreaming) [181]. These symptoms are experienced by at least one-third of patients and occur to some extent with all antidepressants [182,183,184]. Among commonly used antidepressants, the risk of discontinuation symptoms is greatest with paroxetine, venlafaxine, and amitriptyline and the lowest with fluoxetine [184].

Symptoms usually begin within 5 days of treatment cessation or occasionally during taper or after missed doses [185,186]. 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 [182,187]. Risk factors include taking antidepressants longer than 8 weeks, the development of anxiety symptoms at the beginning of antidepressant treatment (particularly with SSRIs), the use of other medications with CNS activity (e.g., antihypertensives, antihistamines, antipsychotics), and a history of previous discontinuation symptoms [187,188].

Symptoms may be severe enough to interfere with daily functioning, and although a 4-week taper is usually suggested, some patients may require longer periods, particularly with drugs with shorter half-lives such as paroxetine and venlafaxine [189]. 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 [68]. An alternate approach involves switching to a brief course of fluoxetine, such as 10 mg for 1 to 2 weeks, which is then tapered and discontinued [26].

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 [190]. 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 2) [26].


Side EffectTreatment
Orthostatic hypotension
Add salt to diet
Dry mouth
Pilocarpine oral rinse
Gum and/or hard candy
Bulk laxatives
Urinary hesitancyBethanechol
Visual changesPilocarpine eye drops
Bedtime dosing
Modafinil or methylphenidate
Morning dosing
Trazodone or melatonin at bedtime
SeizuresAntiepileptic medication
Impaired sexual arousal, erectile dysfunction, orgasm dysfunction
HyperlipidemiaStatin medication
Weight gain
Other antidepressant with less weight promotion, if necessary


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 a behavioral healthcare provider when caring for the depressed patient. It is specifically recommended in the following situations [25]:

  • 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

The use of psychometric instruments may enhance the quality of care and improve clinical outcomes. Clinician-rated and/or self-rated scales can help determine the trajectory of disease course and treatment response, and 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 Beck Depression Inventory (BDI) [26].


With a response/remission rate of 70% to 90%, ECT produces the highest response rate of any antidepressant treatment, and positive treatment response to ECT is associated with significantly improved health-related quality of life. Although ECT is generally reserved for use in patients who do not respond to medication, it should be considered as first-line therapy in severe MDD with psychotic features, catatonia, or heightened suicide risk; depression-associated anorexia that results in nutritional compromise; cases in which a rapid antidepressant effect is essential; and in patients with previous positive response or preference for ECT. ECT is very safe due to substantial modifications since its introduction; side effects can include confusion, anterograde amnesia, and retrograde amnesia [26].


The extensive use of complementary medicines in patients suffering from chronic illnesses, including depression, is widely documented, and the use of complementary medicines may exceed 40% among patients suffering from severe depression [191]. 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 who are ambivalent about taking psychiatric medication are also likely to gravitate to these therapy approaches [192].

All patients should be asked if they are taking over-the-counter dietary supplements or herbal medications to avoid adverse drug-drug interactions. Additionally, it is important to note that the safety, efficacy, and purity of herbal products and nutritional supplements are not evaluated or regulated by the U.S. Food and Drug Administration (FDA) [25]. Because patients will use complementary/alternative therapies, healthcare professionals should have a clear understanding of the most common modalities and their potential impact on treatment course and outcomes.


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. However, 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 [25].

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 HIV-positive patients [26].

Hypericum perforatum (St. John's Wort)

St. John's wort possesses a mechanism of action similar to SSRIs, 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. Because of the numerous potential drug interactions, St. John's wort cannot be considered a benign agent; further studies are needed [168,193,194,195,196,197,198].


Myo-inositol is an isomer of glucose and an essential component of the phosphatidylinositol second messenger system, which is critically linked to several CNS receptor signaling systems [199,200,201,202]. Randomized placebo-controlled trials have found the efficacy of inositol to be superior to placebo in the treatment of depression, panic disorder, and obsessive-compulsive disorder, and equivalent to fluvoxamine 150 mg/day in panic disorder [199,203,204,205]. The effective daily dose is 12 to 18 grams, and inositol at 18 g/day is free of side effects other than loose stools and drowsiness [206]. The published research needs replication in larger trials but is intriguing in light of a 2010 study in which patients with severe depression receiving treatment with repetitive transcranial magnetic stimulation showed significantly elevated prefrontal cortex myo-inositol levels [207]. This elevation correlated with the extent of clinical improvement.


The use of folate in non-folate-deficient patients with MDD may be most effective as augmentation to SSRI antidepressants such as fluoxetine. Persons receiving fluoxetine and folate may actually have fewer side effects from the SSRI than those receiving fluoxetine monotherapy [26].

Saffron (Crocus sativus L.)

Saffron is a spice that has been used for the treatment of depression in Persian traditional medicine. Its proposed mechanism includes inhibited reuptake of dopamine, norepinephrine, and serotonin [208]. Saffron has shown antidepressant effects comparable to fluoxetine and may be a promising antidepressant therapy, although additional research is necessary [192]. Several well-designed clinical trials have evaluated the efficacy of saffron 30 mg daily over 6 to 8 weeks in mild-to-moderate depression. Results indicate that saffron is more effective than placebo and at least equivalent to therapeutic doses of imipramine and fluoxetine, using the Hamilton Depression Rating Scale, with no significant differences in adverse events in any of the studies. However, the studies involved small sample sizes (40 patients) and were conducted by the same group of researchers with a non-Western population [209,210,211,212,213].

Omega-3 Fatty Acids

The overall research results suggest that omega-3 fatty acids are beneficial in mood disorders. Although efficacy in the treatment of MDD cannot be determined, subgroups such as children and pregnant women may show meaningful clinical response. Side effects are minimal [26].

Sleep Deprivation

Sleep deprivation therapy involves staying awake for one whole night and the following day, without any sleeping. 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 [192].

Bright-Light Therapy

Bright-light therapy is very effective in patients with seasonal affective disorder and may also be efficacious as monotherapy treatment of MDD without a 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 [26].


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 assessing compliance with the prescribed therapy. If the patient remains unresponsive to treatment, referral to a psychiatrist may be indicated.


Increase the Dose of the Initial Antidepressant

Although signs of positive response can occasionally occur within the first week, 4 to 6 weeks may be required for a full response. Adequate treatment for 6 to 8 weeks is necessary before concluding that a patient is not responsive to a particular medication [25,111].

A 25% or greater reduction in baseline symptom severity after 6 weeks of a therapeutic dose and good tolerability of the medication are reasonable grounds to continue prescribing an antidepressant [109]. Also during the initial 6 to 8 weeks, consider increasing the dose if side effects are tolerable, or reducing the dose if the patient is experiencing some symptom reduction but side effects are interfering with treatment [25,111].

If there is less than 25% symptom reduction (i.e., partial response) after 6 weeks at therapeutic dose, add, switch, or substitute another treatment modality. A standardized assessment tool will serve to quantify therapeutic response and progress [25].

Switch to Another Antidepressant

Lack of response to a drug in one class does not preclude potential benefits from other drugs in the same class, especially with SSRIs. If a patient does not adequately respond to a particular SSRI or has intolerable side effects, then a trial of a different SSRI often yields positive results. Other medication alternatives include selecting an antidepressant from a different class, combining antidepressants, or adding augmentation medications such as lithium or low-dose thyroid hormone [25,111].

Subtype-Treatment Matching

Matching treatment to subtype and comorbidity may lead to greater symptom reduction and higher remission rates of depressive and comorbid symptoms. However, this requires accurate assessment and differential diagnosis.

Combining or Switching Antidepressants and Psychotherapy

Switching from an antidepressant to psychotherapy or vice versa appears useful for non-responders to initial treatment [214]. The addition of CBT or another medication such as buspirone or bupropion can result in similar rates of improvement, although the addition of medication results in a more rapid response [215].

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 [216].

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 [25,217]. If a patient has received psychotherapy and not responded, evaluate the treatment and consider another type.


Most patients with MDD have comorbid conditions that can contribute to disease burden and may prevent a full response to treatment [218]. Undiagnosed psychiatric comorbidity, such as panic disorder and obsessive-compulsive disorder, can lead to poor medication response, and patients with significant anxiety are more likely to be susceptible to side effects, resulting in treatment discontinuation. Patients with anxious depression and a variety of concurrent anxiety disorders have significantly lower remission rates. Comorbid social anxiety disorder has been associated with a more malignant course of depression. Alcohol and substance abuse can contribute to poor treatment response; in these cases, involve addiction specialists as needed [219]. A behavioral health provider should be involved if a personality disorder is present [220]. Consider the possible presence of bipolar disorder. Bipolar patients require a different treatment approach, and hypomanic, mixed, or manic histories may not be apparent during the initial evaluation [25].

Patients with chronic subtypes of depression (i.e., chronic MDD, double depression, recurrent MDD) may take longer to respond to treatment, contributing to treatment failure by causing clinicians or patients to discontinue treatment prematurely. Additionally, different subtypes of depression respond preferentially to antidepressants [221].


Patient nonadherence can result in nonresponse to the optimal antidepressant regimen, and intolerance of side effects strongly influences therapy nonadherence [219]. 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 [222,223]. In an evaluation of patient adherence to antidepressant medications, Lin et al. found 28% had discontinued treatment within the first month and 51.2% had stopped their antidepressant medication by the fourth month [224]. At all time points, roughly 64% of patients cited side effects as the reason for stopping their medication.

Compared with standard care models, 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 3) [225,226]. Other research has shown that patients receiving five specific instructions were significantly more likely to continue their medication through the first month of therapy [157,224]. These five instructions were:

  • Take the antidepressant daily.

  • Antidepressants must be taken for at least 2 to 4 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.


Patient educationInform patient of the causes and course of depression, and the effects, duration, and side effects of treatment.
Patient-provider empathy/allianceEstablish a good relationship between patient and provider, with an emphasis on communication, consensus, and understanding.
Clinical management strategiesProvide 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 treatmentMinimize the number and doses per day of medication.
Active management of side effectsInform patient about side effects, monitor their occurrence, provide reassurance, and adjust the treatment if needed.
Behavioral feedbackHelp 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 SSRIsWhen possible, use SSRIs due to greater tolerability relative to TCAs.
Physician trainingImprove skills on caring for depressed patients and patient adherence to treatment.


Most definitions of treatment response to therapy for depression involve comparing the extent that scores obtained from rating scales change over time. Standardized rating scales such as the Clinical Global Impressions (CGI) scale, the Montgomery-Asberg Depression Rating Scale (MADRS), and the HAM-D are the most widely used instruments to quantify treatment response [221]. As discussed, the definition of antidepressant response falls into 4 categories [25,111]:

  • Remission: The absence of depressive symptoms or minimal symptoms (e.g., a HAM-D score less than 7)

  • Response: At least a 50% symptom reduction, as measured by a standardized rating scale

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

  • Nonresponse: The absence of any clinically meaningful response

Nonremitted responders remain partially ill [227]. Although remission should be the treatment objective, because it is associated with lower rates of disability, dysfunction, relapse, and recurrence than response without remission, roughly 30% to 45% of MDD patients do not adequately respond to initial antidepressant therapy, with 12% to 15% showing a partial response and 19% to 34% showing nonresponse [105,228].

Treatment-resistant depression is a growing problem increasingly encountered by primary care and mental health providers. A 2008 meta-analysis estimated the prevalence of treatment-resistant depression to be as high as 40%, compared with a decade ago when treatment-resistant depression occurred in 10% to 15% of cases [229]. Risk factors associated with treatment resistance include psychosocial stressors, neurotic personality traits, female sex, longer previous depressive episode, family history of MDD, persistence of dysthymic symptoms after recovery from a major depressive episode, additional nonaffective psychiatric comorbidity, presence of a chronic general medical disorder, and premature discontinuation of antidepressant therapy [230]. The greatest risk factors are the negative impact of unresolved depressive symptoms following acute phase therapy and the extent of previous treatment resistance [230,231].

Treatment-resistant depression exists along a continuum, from early-stage treatment-resistant depression (nonresponse to initial antidepressant treatment) to advanced-stage treatment-resistant depression (nonresponse to 3 or more prior treatment attempts that included combinations and augmentations of medications, psychotherapy, and/or ECT) [162,232]. A classification scheme has been devised to stage the severity of treatment-resistant depression and reflects the continuum of treatment-resistant depression [221,233]:

  • Stage I: Failure of 1 or more adequate trials of antidepressant monotherapy

  • Stage II: Stage I plus failure of an adequate trial of a different antidepressant class

  • Stage III: Stage II plus failure of adequate trial of TCA

  • Stage IV: Stage III plus failure of adequate trial of MAOI

  • Stage V: Stage IV plus failure of ECT

Patients in stages III, IV, and V are considered treatment refractory [221].


The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study was a landmark study that identified optimal treatment approaches after the failure of initial antidepressant monotherapy [234]. Patients nonresponsive to treatment at each of four sequential treatment levels proceeded to the next treatment option. Results from this study have provided valuable information regarding the management of treatment-resistant depression.

The STAR*D study identified a sequential treatment approach as the best strategy to optimize response in patients with treatment-resistant depression. The results showed that among patients failing to achieve remission with initial therapy, approximately 33% achieved remission with augmentation involving a second agent and roughly 25% achieved remission by switching to a different antidepressant [135].

The results of the STAR*D study, additional published evidence, and clinical experience suggest following an algorithm for treatment-unresponsive patients with MDD. If a patient does not respond to SSRI monotherapy, switching to another SSRI is the preferred option. If response is limited but treatment is well tolerated, augmentation should follow. If SSRI treatment is poorly tolerated, switching to venlafaxine is the preferred treatment option. If the patient does not respond to venlafaxine, augment with bupropion, followed by a mood stabilizer. Treatment with an MAOI, either alone or in combination with lithium, should be considered before ECT, and assessing the degree of previous response can help determine whether treatment should be augmented or switched [110].

Therapy Augmentation

Augmentation approaches are used in patients whose depression is either resistant or partially responsive to treatment. This involves the addition of another non-antidepressant medication with the purpose of enhancing the effects of the current antidepressant drug [219].

There are several options for augmenting initial therapy, and the choice is generally dependent on the agent already in use. Augmentation of bupropion or buspirone with citalopram after a trial of non-remission with citalopram alone yielded a remission rate of 29.7% and 30.1%, respectively, in one trial [109]. Several open series have described beneficial results with this approach [25]. The addition of mirtazapine to an existing SSRI may lead to more rapid onset of symptom relief but is associated with higher rates of weight gain than comparative drugs [235,236,237,238]. Augmentation of TCA therapy with the thyroid hormone triiodothyronine led to a remission rate of 24.7% in one study [218]. Stimulants may be added to TCA or SSRI therapy to improve results. Open-label studies have supported the benefits of modafinil augmentation of SSRI, but methylphenidate- or amphetamine-based augmentation requires further evaluation in well-designed clinical trials [25,239,240]. Augmenting TCA or SSRI therapy with lithium yielded a remission rate of 15.9% in the STAR*D study [218].

Although a combination of a TCA and an SSRI has been found more rapidly effective and remission more likely, in these cases the dose of TCA should be adjusted, because SSRIs may increase TCA levels [241,242]. It is important to monitor side effects and consider checking blood levels when using this combination [25].

A meta-analysis of 16 trials involving 3,480 patients with treatment-resistant, nonpsychotic, unipolar MDD found augmentation with atypical antipsychotics was significantly more effective than placebo on measures of both response and remission. The antipsychotics evaluated were risperidone, olanzapine, quetiapine, and aripiprazole, and no significant differences in efficacy were noted between the antipsychotics. Discontinuation due to adverse events was higher in patients receiving augmentation than with placebo [243].

Switching Therapies

Switching antidepressant therapies can involve either switching to another agent within the same class or to a different class [25,219,244]. When initial therapy is a TCA, switch to either another TCA, a second-generation heterocyclic, an SSRI, or an MAOI. When initial therapy is an SSRI, switch to venlafaxine, a TCA, bupropion, another SSRI, mirtazapine, or an MAOI.

Bright-Light Therapy

As mentioned, advanced treatment-resistant depression is the failure to achieve remission with adequate trials of three different classes of antidepressants [25,219,221,245]. Patients for whom depressive symptoms persist despite attempts to utilize different antidepressants are candidates for additional therapeutic options, such as bright-light therapy.

Use of bright-light therapy for treatment of major depression with a seasonal specifier (seasonal affective disorder) is well established [246,247]. 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 [248,249,250,251]. Bright-light therapy may also quicken and enhance the effects of antidepressant medication [252]. Although the light exposure dosage (typically 3,000 to 10,000 lux) and exposure length (typically 30 to 60 minutes) have become the standard of care for seasonal affective disorder treatment, research on bright-light therapy for other types of depression has not necessarily utilized standard dosages and exposure times. It is important that any light therapy treatment utilize equipment that eliminates ultraviolet frequencies and produces bright light of known spectrum and intensity.

Neurostimulation Therapies

Although much progress has been made over the past two decades in the development of safe and efficacious antidepressant drugs, truly novel therapies with mechanisms differing from MAO reuptake inhibition are years away from becoming clinically available. Unfortunately, up to 50% of patients with major depression do not achieve remission with currently available treatments as measured by short-term (i.e., 6 to 8 weeks), double-blind, placebo-controlled trials [253,254].

Treatment-resistant depression is unlikely to be a disease involving a specific brain region or the result of a single neurotransmitter deficit. Several lines of evidence suggest that specific neural circuits within the limbic-cortical system mediate stress response, mood, and emotional regulation, and the underlying neurobiology of major depression is thought to be a "systems-level" or circuitry disorder affecting cortical, subcortical, and limbic brain regions. New neurostimulatory therapies based on progress in understanding this emotional circuitry are likely to provide more rapid and robust approaches for treating debilitating and complex conditions such as treatment-resistant depression [255].

Interest in the use of brain stimulation techniques for treatment-resistant depression emerged in recent years for a number of reasons: as part of a general re-evaluation of both noninvasive and invasive brain stimulation techniques, in response to the efficacy of brain stimulation in neurological disorders, and as a logical consequence of studies defining the functional neurocircuitry of several psychiatric disorders [256]. ECT is the prototype in this field, and several other approaches have been developed and are under investigation.

Electroconvulsive Therapy

ECT involves the application of brief electrical pulses to the scalp to induce depolarization of cortical neurons and resultant brain seizures. It is among the most effective treatments in psychiatry for refractory depression, yet its mechanism of action remains unclear. Furthermore, although it is now a largely safe and effective treatment approach, there are numerous disadvantages, such as anesthesia exposure, postseizure amnesia, and a high rate of depressive relapse within 6 months after treatment [255].

ECT is indicated in several conditions, including [25]:

  • Geriatric depression

  • When antidepressant medications cannot be tolerated or pose a significant medical risk

  • When antidepressant medication trials have been unsuccessful

  • If ECT has been successful in previous episodes

  • The presence of catatonia

  • When a rapid response is needed because of severe suicide risk or because the patient's health has been significantly compromised by the depression

  • Depression with psychotic features or predominant melancholic symptoms

  • Comorbid depression and Parkinsonism

ECT is also effective for treating major mental illness during pregnancy. The risks of adverse events with ECT are low, and it should be strongly considered in pregnant women with psychotic symptoms, catatonia, or intense suicidal urges [257].

ECT is usually reserved for patients whose depression is refractory to any kind of treatment. Although its antidepressant efficacy achieves a high remission rate, ECT is invasive, and the need for repeated treatments to maintain efficacy preclude the use of ECT as a long-term treatment option [258,259].

Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) uses an implantable device to provide intermittent stimulation to the left vagus nerve (80% afferent to the CNS). It is used as an adjunctive treatment along with other treatment modalities and has been studied only in refractory or treatment-resistant depression [25]. The VNS Therapy System received expedited FDA approval for treatment-resistant depression in July 2005 due to the lack of approved drug treatments for treatment-resistant depression and concerns over the long-term efficacy and safety of ECT [259].

Controlled studies with follow-up of 6 months or longer have found significant improvements in depressive symptoms among patients receiving active VNS that were often sustained over time, with relapse rates relatively low [260]. Chronic VNS can lead to significant side effects, including decreases in airway flow and respiratory effort and laryngopharyngeal dysfunction [261]. Although several aspects of VNS therapy have yet to be standardized, given the profound negative impact of treatment-resistant depression and the durable response rates among many VNS patients, it may be a useful option in treatment-resistant depression [262].

Deep Brain Stimulation

Deep brain stimulation is the process of implanting an electrode to stimulate the subgenual cingulated gyrus with high-frequency impulses to diminish depression in patients with treatment-resistant depression [25]. Surgical implantation of deep brain stimulation is invasive and carries the risk of infection, hemorrhage, and other common 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 [263].

Although some therapeutic benefit from deep brain stimulation has been observed shortly after treatment, a substantial proportion of symptom improvement occurs only after months of long-term stimulation. A study involving 15 treatment-resistant depression patients found remission rates of 27%, 24%, and 37% at 3-month, 6-month, and 2-year follow-up, respectively [264]. Deep brain stimulation can increase the risk of suicide ideation, attempts, and completions, strongly indicating that patients should be pre-screened for suicide risk before deep brain stimulation surgery and monitored closely for suicidal behavior postoperatively [265]. Deep brain stimulation for treatment-resistant depression is considered investigational [263]. Deep brain stimulation cannot be considered as therapy for treatment-resistant depression until additional double-blind studies with sufficient follow-up durations are performed.

Transcranial Magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that stimulates the brain in vivo using high-intensity, pulsed electromagnetic fields. The procedure involves a handheld stimulating coil applied directly to the patient's head to deliver a magnetic pulse to the cortex [258,266].

The body of clinical research on rTMS for treatment-resistant depression treatment has shown larger effect sizes in more recent studies [267]. The FDA approved rTMS in October 2008. As of October 2009, Canadian guidelines on neurostimulation therapies support the use of rTMS as a second-line treatment [268]. It appears there probably is enough evidence to consider rTMS (using a 6-week standardized protocol) as evidence-based treatment for treatment-resistant depression in adults. It is not a first-line treatment, and there is ongoing lack of clarity about which patient populations should be targeted [269].

Magnetic Seizure Therapy

Magnetic seizure therapy uses focused stimulation of the brain (generally of the right frontal area) to induce a focal seizure. This is designed to obtain efficacy of ECT without the cognitive side effects that generally occur when seizures spread to the hippocampus [25].

A meta-analysis of 1092 patients with treatment-resistant depression found aggregate response and remission rates for active versus sham magnetic seizure therapy of 25% and 17% versus 9% and 6%, respectively [270]. Active magnetic seizure therapy augmentation of SSRI treatment for treatment-resistant depression has been shown to significantly improve clinical outcomes over sham magnetic seizure therapy [271]. The relatively low response and remission rates, the short treatment duration, and the relative lack of follow-up suggest the need for additional efficacy data before magnetic seizure therapy can be considered as a first-line monotherapy treatment for treatment-resistant depression [270,271].


Although opioids were used to treat major depression until the late 1950s, research evaluating their antidepressant potential has been very rare in the past 60 years. The synthetic opioid buprenorphine is a partial mu receptor agonist and kappa receptor antagonist. It is exceptionally safe in overdose and produces substantially less euphoria than pure mu receptor agonists such as morphine and oxycodone. A small study published in 1995 hints that buprenorphine may provide greater benefit in the treatment of treatment-resistant depression than other pharmaceutical agents [272]. The 10 participants averaged 20.7 years of unipolar major depression duration, 7.6 previous antidepressant trials, and a HAM-D score of 28.1. Buprenorphine was initiated in an open-label manner at 0.15 mg/day with maximum upward titration to 1.80 mg/day over the 4 to 6 week trial (final mean dose: 1.26 mg/day). Three subjects dropped out due to side effects of malaise, nausea, and dysphoria. Of the remaining 7 subjects, 6 achieved marked clinical improvement and 1 deteriorated. The mean endpoint HAM-D score was 10.7, a 60.7% reduction from baseline, and 4 patients achieved complete symptom remission. The mean overall level of functioning increased 45.5%, and the mean reduction in depression was 50%. Significant improvement on all outcome parameters was apparent at the end of the first week [272].

The authors concluded that the results were remarkable and that the number of previous treatment failures, the level of disease severity, and the duration of improvement argue against a placebo response as the basis of improvement. Patients did not report euphoria or intoxication but instead felt "more normal," which together with the 33% drop-out rate suggests a limited abuse liability [272]. These preliminary results are begging for replication in larger studies, but despite researcher awareness of these outcomes, follow-up studies have not been conducted due to the stigma surrounding opioid drugs and their association with addiction.


The potential efficacy of ketamine in treatment-resistant depression was evaluated in a double-blind, placebo-controlled study involving 18 subjects whose mean duration of current episode, lifetime duration of depression, and previous antidepressant trials were 33.6 months, 23.7 years, and 5.7, respectively. Among subjects receiving a single intravenous infusion of ketamine (0.5 mg/kg), 71% met response criteria and 29% met remission criteria the day following ketamine administration, with 35% maintaining treatment response for at least 1 week. Most adverse events occurred during the first 80 minutes of treatment and included perceptual disturbances, confusion, elevated blood pressure, euphoria, dizziness, and increased libido. These results suggest a rapid antidepressant effect of single-dose infused ketamine that is mostly sustainable for more than 1 week [273]. However, due to insufficient numbers of randomized controlled trials and limited data on long-term outcomes and potential risks, ketamine administration is not recommended outside the hospital setting [274].


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 [275,276]. 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% [277]. 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 [278].


Several nonpharmacologic treatments with demonstrated efficacy for mild-to-moderate depression are available for pregnant and breastfeeding women, including interpersonal psychotherapy, bright-light therapy, and CBT [251,279,280]. Interpersonal therapy is efficacious in postpartum depression and can improve functioning for 6 months postpartum [280]. While these interventions are more efficacious than routine care for postpartum depression, there is little indication of superiority for any one intervention [280]. Other nonpharmacologic treatments that may be effective include acupuncture, progressive relaxation, music therapy, sleep deprivation, and exercise [278]. Empirical support for nutritional or supplemental omega-3 fatty acids is lacking, although they pose little to no risk of adverse effects [281]. Progesterone is ineffective in postpartum depression and may intensify depressive symptoms in some patients [278].


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 .


The largest amount of reproductive safety information is available for TCAs and SSRIs (Table 4). 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 [168,283,284].


RatingDefinition and Examples
ANo 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.
BMaprotiline—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.
CAmitriptyline, 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.
DImipramine, 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.
XNo 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.

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 [285,286,287]. 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 [275,285,288,289]. There is a lack of evidence suggesting that reducing or discontinuing antidepressants in late pregnancy will reduce adverse neonatal effects [285].

Women with a history of depression who are planning to become pregnant should carefully consider the choice and timing of an antidepressant [288]. 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 [285]. Women who discontinue medication relapse significantly more frequently over the course of their pregnancy compared with women who maintain their medication [290]. 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 [25].


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 [291]. Also, the mother-infant pair should be monitored for the emergence of adverse effects or complications [292]. Regarding the use of specific medications during lactation, several observations and recommendations have been made [25,282,293]. 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 [168]. The TCA doxepin should be avoided due to a case report of infant respiratory distress [168]. Data on citalopram, fluvoxamine, bupropion, and venlafaxine are more limited and their use cannot be recommended during breastfeeding [168]. 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 [25].


Every year, close to 1 million people around the world complete suicide, representing a worldwide mortality rate of 16 per 100,000, or 1 death every 40 seconds. This suicide rate has increased by 60% in the past 45 years, with suicide rates among young people increasing at alarming rates in both developed and developing countries [294].

Suicide rates vary according to race, ethnicity, sex, and many other factors, including age [294]. In almost every country, suicide is predominated by male victims, with the exception of China, which is the only country in which the female suicide rate (14.8 per 100,000) exceeds the male rate (13 per 100,000) [294]. In the United States, the suicide rate is nearly four times greater among men (20.7 per 100,000) than among women (5.8 per 100,000). Overall, suicide accounts for 12.3% of all deaths in the United States [6,14,295,296,367].

From the mid-1950s to late 1970s, the suicide rate tripled among men 15 to 24 years of age and doubled among women 15 to 24 years of age. The suicide rate reached a plateau during the 1980s and early 1990s and began decreasing during the mid-1990s [295]. However, the age-adjusted suicide rate has increased 24% between 1999 and 2014, with increases in all age groups younger than 75 years of age [367]. Among the elderly, the suicide rate peaked in 1987, at 21.8 per 100,000 people, and has since declined 28% (to 14.9 per 100,000 in 2010), the largest decline among the elderly since the 1930s [296,297]. Despite the growing recognition of suicide as a problem demanding public health attention, the overall rates of suicide in the United States have remained static over the last half-century [73].

Although official national statistics are not compiled on attempted suicide (e.g., nonfatal actions), an estimated 1 million adults (18 years of age and older) attempted suicide in 2012 [298]. Overall, there are roughly 25 attempts for every death by suicide; this ratio changes to 100 to 200:1 for the young and 4:1 for the elderly [298]. The risk of attempted (nonfatal) suicide is greatest among women and the young, and the ratio of female-to-male non-fatal suicide attempts is 3:1 [33,295].


There is broad agreement that not all suicide deaths are accurately recorded and reported. Reasons for under-reporting include [16,299,300,301,302]:

  • Families or family physicians may hide evidence due to the stigma of suicide.

  • The determination of death is judged by local standards, which can vary widely.

  • Ambiguous cases involving suicide may end up classified as "accidental" or "undetermined."

  • Compared with the "accidental" or "undetermined" motive categories, a larger number of deaths are officially classified as "ill-defined and unknown causes of mortality," in which even the actual cause of death is uncertain, and some of which are undoubtedly suicides.

  • The frequency of physician-assisted suicide for the terminally ill is unknown but is probably both substantial and increasing.

In contrast, some ambiguous cases are classified as suicides, often in institutions such as prisons, hospitals, religious orders, and the military, where the verdict of suicide is likely to be less embarrassing than homicide. Other motivations for declaring a death a suicide, despite much doubt surrounding a case, are that homicides must be investigated and a murderer sought and accidental death may be the basis of negligence lawsuits [16].


Suicide rates may temporarily spike with intense media coverage of a suicide, especially among youth, and both news reports and fictional accounts of suicide in movies and television can produce this effect [303,304,305]. Imitation is often the key factor and is most powerful with the highly publicized suicides of entertainment celebrities [16,306].

Media coverage of suicide can lead to misinformation, as when suicide is attributed to a single event, such as the loss of a job or a relationship, without mention of a broader context involving ongoing problems with depression, substance abuse, or lack of access to treatment for these conditions. On the other hand, responsible coverage of suicide can educate audiences about the causes, warning signs, and treatment advances and prevention of suicide [16].



A woman takes her own life every 90 minutes in the United States [13]. Suicide is more common among women who are single, recently separated, divorced, or widowed, and the suicide rates for women peak between the ages of 45 to 54 years, and again after 75 years of age. Precipitating life events for women who attempt suicide often involve interpersonal losses or crises in significant social or family relationships. As noted, more women attempt suicide than men, and there is a 3:1 ratio of women versus men with a history of attempted suicide. The higher rates of attempted suicide among women are likely due to the higher rates of mood disorders such as major depression, persistent depressive disorder (dysthymia), and seasonal affective disorder. Factors that may contribute to the lower rates of completed suicide in women relative to men include stronger social supports, feeling that their relationships are a deterrent to suicide, differences in preferred suicide method, and greater willingness in seeking psychiatric and medical intervention [13].


In 2010, suicide was the third leading cause of death for young people 15 to 24 years of age, exceeded only by accidents and homicides. As noted, an estimated 100 to 200 attempts are made for every suicide completion in this age group. Risk factors for suicide among the young include suicidal thoughts, psychiatric disorders (e.g., depression, impulsive aggressive behavior, bipolar disorder, panic disorder), drug and/or alcohol abuse, and previous suicide attempts. The risk is further elevated with situational stress or access to firearms [13,297].

Children 10 to 14 Years of Age

In 2010, 1.29 per 100,000 children died of suicide in the United States. Suicide rates were highest among Native American/Alaska Native youth, with 20.89 suicides per 100,000. White youth were next highest with 11.30 deaths per 100,000, and black youth had 6.59 deaths by suicide per 100,000 [13,297].

College Students

More than 1,000 suicides occur each year on college campuses, and 1 in 12 college students have made a suicide plan [297]. A 2011 survey of 27,774 college students from 44 campuses found that 6.6% had seriously contemplated suicide and 1.1% had attempted suicide [298]. In the 12 months before the survey, 60.5% reported feeling very sad, 45.2% reported feeling hopeless, and 30.3% reported feeling so depressed they were unable to function [298]. More than 45% reported feelings of hopelessness; however, only 6.7% of men and 13.1% of women reported a diagnosis of depression, suggesting that many students are not receiving adequate diagnosis and/or treatment [298].

Students with a pre-existing mental health condition and students who develop mental health conditions in college are at highest risk of suicide. Risk factors for suicide among college students include depression, sadness, hopelessness, and stress [297].

Other Considerations in Youth Suicide

Most adolescent suicides occur at home after school hours. Adolescent nonfatal suicide attempters are typically girls who ingest pills, while suicide completers are typically boys who die from gunshot wounds. Deliberate self-harm should be considered serious and in need of further evaluation because not all adolescent attempters admit their intent. Most adolescent suicide attempts are triggered by interpersonal conflicts and are motivated by the desire to change the behavior or attitude of others. Repeat attempters may use this behavior as a coping mechanism for stress and tend to exhibit more chronic symptomatology, worse coping histories, and higher rates of suicidal and substance abuse behaviors in their family histories [297]. The presence of multiple emotional, behavioral, and/or cognitive problems may be a more important predictor of suicide behavior risk than a specific type of problem (e.g., an addictive behavior or an emotional problem) [297,307]. The presence of acne is associated with social and psychological problems, and certain acne medications have been linked with an increased risk of suicidal ideation [308].


The elderly account for roughly 15.6% of suicides but only 13% of the population [297]. Suicide rates rise with age for men, especially after age 65, and the suicide rate in elderly men is 5.25 times that of same-aged women; 84% of elderly suicides are among men [297]. The overall rate of elderly suicide is 14.89 per 100,000. However, the rate is 29.0 per 100,000 among elderly white men and 47.33 per 100,000 among white men older than 85 years of age, a rate that is more than 2 times the rate for men of all ages. In contrast, the suicide rate of women declines after age 60 years [297].

Although undiagnosed and/or untreated depression is the primary cause of suicide in the elderly, suicide completion is rarely preceded by only one factor. Risk factors for suicide in this population include a previous suicide attempt; mental illness; physical illness or uncontrollable pain; fear of a prolonged illness; major changes in social roles, such as retirement; loneliness and social isolation (especially in older men who have recently lost a loved one); and access to means, such as firearms in the home [297].


Although the true incidence of suicide among military war veterans is unknown due to the lack of national suicide surveillance data, veterans often possess many risk factors for attempting or completing suicide. This includes combat exposure, combat wounds, post-traumatic stress disorder and other mental health problems, comorbid MDD, traumatic brain injury, poor social support, feelings of not belonging or of being a burden to others or society, acquired ability to inflict lethal self-injury, and access to lethal means [309,310,311,312].

Despite preventive measures taken by the military, the number of suicides in this population continues to increase [313,314,315,316,317]. Although the majority of military suicides occur among young men shortly after their discharge from military service, military women 18 to 35 years of age commit suicide nearly three times more frequently than nonveteran women of the same age group [310,318].


The true incidence of suicide among lesbian, gay, bisexual, and transgender (LGBT) youth is unknown, but research indicates higher rates of suicidal behavior among LGBT youth (15 to 24 years of age) compared with heterosexual youth [101,319]. Among adolescents and young adults, the lifetime prevalence of suicide attempts range from 20.5% to 52.4% among LGBs versus 4.2% to 24.8% among same-aged heterosexuals [320,321,322,323]. Among adolescents and young adults, past-year suicide attempts are 2 to 4 times higher among LGB youth than same-aged heterosexual youth [297,324,325,326,327]. Several other studies not using comparison groups found lifetime suicide attempt rates of 30% to 40.3% among LGB persons 14 to 25 years of age [101].

Little research has been done regarding depression in transgender individuals. One study of 182 transgender adults reported that 30.1% of individuals surveyed reported having ever attempted suicide [297,328].

The effect of race/ethnicity and other demographic characteristics on suicidal behavior in the LGB population has also been studied little, but reports suggest high suicide attempt rates among African American LGB men, among gay/bisexual men of lower socioeconomic status, and among LGB Latinos [329,330,331].

LGBT youth generally have more risk factors, more severe risk factors, and fewer protective factors, such as family support and safe schools, than heterosexual youth. There are also risks unique to this population related to sexual orientation, such as disclosure to family or friends [297]. The impact of stigma and discrimination against LGBT individuals is enormous and is directly tied to risk factors for suicide such as isolation, alienation and rejection from family, and lack of access to culturally competent care [101]. Family connectedness, perceived caring from other adults, and feeling safe at school were reported as significant protective factors in a survey of 6th-, 9th-, and 12th-grade LGBT students [332].


Suicide is now understood to be a multidimensional disorder stemming from a complex interaction of biological, genetic, psychological, sociological, and environmental factors [333,334]. One of the first social scientists to empirically investigate contributing factors to suicide was Emile Durkheim. Instead of focusing only on shared traits among persons who had completed suicide, Durkheim compared one group with another and originated the scientific study of suicide risk factors [16,335]. Protective factors reduce suicide risk by enhancing resilience and counterbalancing risk factors, while risk factors increase the potential for suicidal behavior. Both protective and risk factors may be biopsychosocial, environmental, or sociocultural in nature [16].


Several protective factors against suicide behavior have been identified [16,336]. These include:

  • Access to effective clinical care for mental, physical, and substance use disorders, and support for help-seeking

  • Restricted access to highly lethal means of suicide

  • Strong connections to family and community support

  • Emotionally supportive connections with medical and mental health providers

  • Effective problem solving and conflict resolution skills

  • Cultural and religious beliefs that discourage suicide and support self-preservation

  • Reality testing ability

  • Pregnancy, children in the home, or sense of family responsibility

  • Life satisfaction


In addition to risk factors specific to special populations, there are many general risk factors common among most populations. General biopsychosocial risk factors include [13,16,336]:

  • Psychiatric disorders

  • Alcohol and other substance use disorders

  • Hopelessness

  • Impulsive and/or aggressive tendencies

  • History of physical or sexual trauma or abuse, especially in childhood

  • Medical illness involving the brain or CNS

  • Family history of suicide

  • Suicidal ideas, plans, or attempts (current or previous)

  • Lethality of suicidal plans or attempts

In addition, environmental factors can impact an individual's suicide risk. Attention to the presence of job or financial loss, relationship or social loss, easy access to lethal means, and local clusters of suicide (due to contagious influence) is necessary.

Lack of social support and sense of isolation are risk factors for suicide, along with cultural factors. Some cultural practices and/or beliefs can predispose an individual to suicide, such as stigma associated with help-seeking behavior; barriers to accessing mental health care and substance abuse treatment; certain cultural and religious beliefs (e.g., suicide as an honorable act); and media exposure to and the influence of others who have died by suicide [13,16,336].

Psychiatric Disorders

At least 90% of people who complete suicide have diagnosable psychiatric illness [13,86]. The psychiatric conditions with the greatest association with suicidal behavior are depression, bipolar disorder, substance abuse, schizophrenia, and personality disorders.


Major depression is the psychiatric diagnosis most commonly associated with suicide. The lifetime risk of suicide among patients with untreated and treated depressive disorder is nearly 20% and 141 per 100,000, respectively [98,297,337]. About 30% of all patients with major depression attempt suicide, half of whom ultimately take their own lives. More than 60% of persons who complete suicide are clinically depressed at the time of their deaths, although this climbs to 75% when alcoholics with depression are added. Seven of every 100 men and 1 of every 100 women diagnosed with depression will complete suicide [297]. Among persons 18 years of age and older who experienced depression in the previous year, 56.3% thought it would be better if they were dead during their worst or most recent episode, 40.3% contemplated suicide, 14.5% made a suicide plan, and 10.4% attempted suicide [338].

The risk of suicide in persons with major depression is roughly 20 times that of the general population [297]. Among persons with depression, those with a history of multiple episodes of depression and those with an alcohol or other substance use disorder are at greatest risk [13]. Persons with depression who exhibit the following symptoms are at heightened risk for suicide [13,297]:

  • Extreme hopelessness or desperation

  • A lack of interest in previously pleasurable activities

  • Intense anxiety and/or panic attacks

  • Insomnia

  • Talk of suicide or history of attempts

  • Irritability, agitation, or enraged behavior

  • Isolation

Feelings of hopelessness (e.g., belief that there is no solution) are more predictive of suicide risk than a diagnosis of depression per se. It is also important to remember that patients who desire an early death during a serious or terminal illness are usually suffering from treatable depressive illness [13].

Bipolar Disorder

Between 5 and 10 million Americans currently suffer from bipolar disorder. Of these, as many as 1 in 5 will die by suicide [86,339]. Like depression, bipolar disorder is treatable, and effective treatment decreases the risk of suicide.

Alcohol and Substance Abuse

Alcohol and drug abuse are second only to depression and other mood disorders as conditions most associated with suicide. The suicide risk among alcoholics is 50% to 70% higher than the general population. Alcohol abuse is a factor in roughly 30% of suicides, and about 7% of persons with alcohol dependence die by suicide [13,297,340].

In 2011, an estimated 228,366 emergency department admissions were made for alcohol- or drug-related suicide attempts. Almost all (94.7%) involved either a prescription drug or an over-the-counter medication [341]. Approximately 64.4% involved multiple drugs, and 29% involved alcohol [341].

As mentioned, comorbid psychiatric and substance use disorders substantially increase the risk of suicide behavior. Combined data from 2004 and 2005 indicated that 16.4 million adults 18 years of age and older experienced a major depressive episode in the previous year. Of these persons, more than 10% attempted suicide. But when alcohol abuse or illicit drug use occurred with major depression, the proportion of suicide attempts rose to nearly 14% for alcohol abuse and close to 20% for illicit drug use [73,338].

There are several possible explanations for the association between alcohol/drug use and suicide. Alcoholism can cause loss of friends, family, or job, leading to social isolation; however, the reverse is equally plausible. Alcohol abuse and suicide may also both represent attempts to deal with depression and misery. Alcohol increases the sedating effects of some drugs that are frequently used in suicide attempts and may increase impulsive actions, making suicide attempts and completions more common [76,299]. To claim that alcoholism "causes" suicide is simplistic; while the association of alcohol and suicide is clear, a causal relationship is not. Both alcoholism and suicide may be responses to the same pain [299].


Suicide is the largest cause of premature death among individuals with schizophrenia, and young, unemployed men are at highest risk. Other risk factors include recurrent relapses; fear of deterioration, especially among persons with high intellectual ability; positive symptoms of suspiciousness and delusions; and depressive symptoms [333,334]. The suicide risk is highest during early stages of the illness, early relapse, and early recovery. The risk decreases with prolonging illness duration [333,334].

Personality Disorders

An estimated 20% to 50% of young people who complete suicide have a diagnosable personality disorder, with borderline personality and antisocial personality disorders being most frequently associated with suicide. Histrionic and narcissistic personality disorders and certain psychological traits, such as impulsivity and aggression, are also associated with suicide [333,334].

Deliberate Self-Harm

Deliberate self-harm is behavior related to but distinct from suicide behavior and includes suicide attempts and self-mutilation, such as burning, cutting, and hair pulling, that does not have fatal intent [342]. Self-mutilation behavior falls into three categories [342]:

  • Major self-mutilation: Infrequent, usually associated with psychosis or intoxication

  • Stereotypic self-mutilation: Repetitive and reflects a biological drive of self-harm

  • Superficial-to-moderate self-mutilation: The most common form and is used by self-mutilators to relieve tension, release anger, regain self-control, escape from misery, or terminate a state of depersonalization

Patients with a history of deliberate and repetitive self-harm are likely to be highly impulsive with a diagnosis of borderline personality disorder, and distress over their inability to curtail the behavior may heighten suicide risk [342,343,344]. It is essential to recognize that previous nonlethal self-harm does not preclude the development of suicidal ideation or plans with serious intent and lethality [336].

Medical Disorders

Illnesses affecting the brain and CNS have a greater effect on suicide risk compared with other medical conditions. These conditions include epilepsy, AIDS, Huntington's disease, traumatic head injury, and cerebrovascular accidents. In contrast, cancer and other potentially fatal conditions carry a more modest suicide risk [178].

Sociodemographic Factors

Suicide is an individual act that also occurs in the context of a broader culture, and specific sociodemographic factors are associated with suicide risk, including marital status, occupation, and previous suicide attempt(s) [333,334].

Marital Status

Divorced, widowed, and single people have a higher suicide risk. Marriage appears to be protective for men, but not so for women. Marital separation also increases the risk of suicide [333,334].


Certain occupational groups, such as veterinary surgeons, pharmacists, dentists, farmers, and medical practitioners, have higher rates of suicide. Although obvious explanations are lacking, access to lethal means, work pressure, social isolation, and financial difficulties may account for the heightened risk [333,334].

Unemployment and suicide are also correlated, although the nature of the association is complex. Poverty, social deprivation, domestic difficulties, and hopelessness likely mediate the effect of unemployment, but persons with psychiatric illness and personality disorders are also more likely to be unemployed. Recent job loss is a greater risk factor than long-term unemployment.

Previous Suicide Attempt

Approximately 20% of people who kill themselves had made a previous attempt, making previous serious suicide attempts a very high risk factor for future attempts [13].


Suicide is often the single most common cause of death in correctional settings, and collectively, inmates have higher suicide rates than their community counterparts. In pretrial facilities housing short-term inmates and in facilities housing sentenced prisoners, suicide rates are 10 times and 3 times that of the outside community, respectively. Also, for every completed suicide there are many more suicide attempts [345].

Inmates at highest risk of suicide include young men, the mentally ill, the socially disenfranchised and socially isolated, substance abusers, previous suicide attempters, and juveniles placed in adult correctional facilities. Factors that increase the likelihood of suicidal behavior include the psychological impact of arrest and incarceration; the stresses of prison life, including physical and sexual predation and assault from other inmates; and the absence of formal policies regarding managing suicidal patients, staff training, or access to mental health care [345].

Creative Personalities

Anecdotes of famous painters, writers, and musicians who were depressed and completed suicide have occurred for centuries, but only recently has science been able to identify the underlying basis of vulnerability to depression and suicide among creative people. Treatment of major depressive or bipolar illness in artists presents unique problems, one of which is the concern that creativity and the disorder are so intertwined that treatment might suppress the artist's unique talent [346,347,348,349].

Holiday Suicide Myth

The idea that suicide occurs more frequently during the holiday season is a myth perpetuated in part by the media and has been debunked [13]. The National Center for Health Statistics of the Centers for Disease Control and Prevention (CDC) reports that the suicide rate is actually lowest in December, with peak rates in the spring and the fall. This pattern has remained constant for many years [350]. The holiday suicide myth has been considered important to counter because it provides misinformation about suicide that might ultimately hamper prevention efforts [351].


While risk factors for suicide represent broader, durable, and ongoing factors, a suicide crisis is a time-limited event that signals an immediate danger of suicide. A suicide crisis can be triggered by a particularly distressing event, such as loss of a loved one or career failure, and involve an intense emotional state in addition to depression, such as desperation (anguish plus urgent need for relief), rage, psychic pain or inner tension, anxiety, guilt, hopelessness, or acute sense of abandonment. Changes in behavior or speech can suggest that suicide is imminent; speech may be indirect, with statements such as, "My family would be better off without me." Persons contemplating suicide may also talk as if they are saying goodbye or going away, exhibit actions ranging from buying a gun to suddenly putting one's affairs in order, or deterioration in social or occupational functioning, increasing use of alcohol, other self-destructive behavior, loss of control, or rage explosions [13].


Most people who are suicidal exhibit warning signs, whether or not they are in an acute suicide crisis. These warning signs should be taken seriously and include observable signs of serious depression, such as unrelenting low mood, pessimism, hopelessness, desperation, anxiety, psychic pain and inner tension; withdrawal from friends and/or social activities; sleep problems; and loss of interest in personal appearance, hobbies, work, and/or school [13,297]. Other signs include:

  • Increased alcohol and/or other drug use

  • Recent impulsiveness and taking unnecessary risks

  • Talk about suicide, death, and/or no reason to live

  • Making a plan (e.g., giving away prized possessions, sudden or impulsive purchase of a firearm, or obtaining other means of killing oneself, such as poisons or medications)

  • Unexpected rage, anger, or other drastic behavior change

  • Recent humiliation, failure, or severe loss (especially a relationship)

  • Unwillingness to "connect" with potential helpers.

The following expressions of thoughts, feelings, or behaviors may also be warning signs of suicidal behavior [297]:

  • Can't stop the pain

  • Can't think clearly

  • Can't make decisions

  • Can't see any way out

  • Can't sleep, eat, or work

  • Can't get out of the depression

  • Can't make the sadness go away

  • Can't see the possibility of change

  • Can't see themselves as worthwhile

  • Can't get someone's attention

  • Can't seem to get control

A mnemonic device, IS PATH WARM, has been developed for use in identifying suicide risk [352]. This mnemonic device was derived from the consensus of internationally renowned clinical researchers held under the auspices of the American Association of Suicidology in November 2003. It consists of the following [352]:

  • Ideation

  • Substance abuse

  • Purposelessness

  • Anxiety

  • Trapped

  • Hopelessness

  • Withdrawal

  • Anger

  • Recklessness

  • Mood change



Use of a firearm is the cause of death in 56% of suicides and is the number one method among adults 35 years of age and older. Gun use is also the most common suicide method among youth, accounting for 44.5% of all suicide deaths. The most common method of suicide among women in all age brackets is poisoning (37.4%), surpassing firearms every year since 2001. Firearms are also the most common means (71.3%) among the elderly [297,353].

The suicide rates among youths 15 to 19 years of age by firearm decreased from 7.3 per 100,000 in 1992 to 3.5 per 100,000 in 2011, while the suicide rates by suffocation (e.g., hanging) increased from 1.9 per 100,000 in 1992 to 3.68 per 100,000 in 2011. This trend among older teens has been mirrored by children 10 to 14 years of age, who since 1993 have increasingly used suffocation and decreasingly used guns to complete suicide. In this group, suicides by suffocation have occurred more frequently than those by firearms since 1999 [351].

Although most gun owners report keeping a firearm in their home for the purpose of protection or self-defense, 83% of gun-related deaths in these homes are the result of a suicide, usually by someone other than the gun owner. Guns are involved in more deaths by suicide than by homicide, and overall, death by firearm is the most common suicide method [296].


Although thousands of books have explored the question of why people kill themselves, in most cases the answer can be summed up in three words: to stop pain. The pain may be physical, as in chronic or terminal illness, but is usually emotional. However, Stone has delineated a more elaborate description of the motivations for suicide, including [299]:

  • Altruistic/heroic suicide: Occurs when someone (more or less) voluntarily dies for the benefit of the group. Examples include the Japanese Kamikaze pilots in WWII and the Buddhist monks who burned themselves to death protesting the Vietnam war.

  • Philosophical suicide: Various philosophical schools, such as the stoics and existentialists, have advocated suicide under some circumstances.

  • Religious suicide: Often as martyrdom, this type of suicide has a long history that spans from early Christianity to the Branch Davidians in Waco, Texas, and some members at Jonestown, Guyana.

  • Escape: This type of suicide represents an escape from an unbearable situation, such as persecution, a terminal illness, or chronic misery.

  • Excess alcohol and other drug use

  • Romantic suicide: This includes suicide pacts (dual suicide), which constitute about 1% of suicides in Western Europe. Participants are usually older than 51 years of age, except in Japan, where 75% of dual suicides are "lovers' pacts."

  • "Anniversary" suicide: Suicide involving the same method or date as a deceased loved one.

  • "Contagion" suicide: Occurs when one suicide appears to trigger others (e.g., "cluster" and "copycat" suicides), most often among adolescents.

  • Manipulation: Usually involving the theme "If you don't do what I want, I'll kill myself." The word "manipulative" does not imply a lack of seriousness, as fatal suicide attempts can be made by people hoping to influence or manipulate the feelings of others even though they will not be around to witness the outcome. However, the intent of manipulative attempts is to produce guilt in the other person, and a nonfatal result is usually intended.

  • Call for help: An expression of unbearable pain and misery that is more frequent in the young.

  • "Magical thinking" and vengeance: Associated with a feeling of power and complete control. This motivation to complete suicide is driven by a "you'll be really sorry when I'm dead" fantasy. A fatal outcome is intended, and this is sometimes called "aggressive suicide."

  • Cultural approval: In some cultures, such as Japanese culture, society has traditionally accepted or encouraged suicide when matters of honor were concerned.

  • Lack of an outside source to blame for one's misery: Evidence exists that rage and homicide is the extreme response when an external cause of one's unhappiness can be identified, and depression and suicide is the extreme response in the absence of a perceived or identifiable external source.


Understanding the interactive relationship between risk and protective factors in suicidal behavior and how this interaction can be modified forms the basis of suicide prevention [16,354]. The characteristics shared by effective suicide prevention programs include clear identification of the intended population, definition of desired outcomes, use of interventions known to effect a particular outcome, and use of community coordination and organization to achieve an objective. Prevention efforts are based on a clear plan with goals, objectives, and implementation steps [16].


In the United States, large-scale suicide prevention efforts began in 1958. Funding from the U.S. Public Health Service established the first suicide prevention center in Los Angeles, and other crisis intervention centers replicating this model were opened across the country [16]. The risk factor approach to suicide prevention was first implemented in 1966, and the American Association of Suicidology and the American Foundation for Suicide Prevention were established over the next two decades. Their activities included increasing the scientific understanding of suicide as the basis for effective prevention activities [16]. In 1983, the CDC established a violence prevention division that alerted the public to the disturbing increase in youth suicide rates.

In 1996, survivors of suicide loss mobilized to form the Suicide Prevention Advocacy Network USA (SPAN USA) and launched a campaign to advocate for the development of a national suicide prevention strategy [355]. The National Strategy for Suicide Prevention (NSSP) was released by the Surgeon General of the United States in 2001 and described a series of goals and objectives designed to reduce the incidence of suicide behaviors in the United States. Although activity in the field of suicide prevention has increased exponentially since publication of the NSSP, the overall rate of suicide since 2000 remains essentially unchanged [355].


College Students

Colleges and universities are increasingly challenged to identify and manage mental health and substance use problems in students. Because many of the risk and protective factors for suicide among young adults include substance abuse and interpersonal violence, suicide prevention may best be integrated within broader prevention efforts [16,356,357].

Inmates in Jails and Correctional Settings

Jails and juvenile justice facilities have exceptionally high suicide rates, and the highest rates of jail suicide occur within the first 24 to 48 hours of arrest, suggesting an important role of medical assessment of substance abuse and suicide proneness. Comprehensive prevention programs targeting inmate suicide include training, screening, effective communication methods, intervention, use of reporting protocols, and mortality review [16,358].

Elderly Persons

Almost 70% of elderly patients who take their own lives see their primary care physician within a few months of their death. This represents an absolutely vital, yet narrow, window for accurate screening and assessment of suicide risk [33].

Because the elderly have the highest overall suicide rate of all age groups, organizations with special access to older persons have an important role in suicide prevention. State aging networks exist in every state, and these networks develop and fund a variety of in-home and community-based services. States organize the provision of such services through area agencies on aging, which coordinate a broad range of services for older people [16].

Bipolar Disorder Patients

Although 20% of bipolar disorder patients have their first episode during adolescence, diagnosis is often delayed for years, which can result in problems such as substance abuse and suicidal behaviors. Thus, early recognition and aggressive treatment may prevent years of needless suffering and death by suicide. In particular, lithium is effective in preventing suicidal behavior in bipolar patients. Maintaining treatment is essential in preventing suicide, and the suicide rate in the first year of discontinuation of lithium treatment is 20 times higher than during lithium treatment [13].

Schizophrenia Patients

Of the 3 million people in the United States with schizophrenia, an estimated 20% to 40% have made a suicide attempt and more than 10% will eventually die of suicide. Depression is the most important risk factor for suicide in schizophrenic patients; only 4% of patients with schizophrenia who exhibit suicidal behavior do so in response to instructions from "command" voices. Clozapine is effective in reducing suicide and attempted suicide in schizophrenic patients, and effective suicide prevention involves the early recognition and prompt treatment of schizophrenia and all comorbid conditions [13].


The stigma of mental illness and substance abuse, both of which are closely linked to suicide, prevents many persons from seeking help out of a fear of prejudice and discrimination [359]. People who have a substance use disorder face additional stigma because many people believe that abuse and addiction are moral failings and that individuals are fully capable of controlling these behaviors if they want to [16,360]. The stigma of suicide, while deterring some from attempting suicide, is also a barrier to treatment for many persons who have suicidal thoughts or have attempted suicide. Family members of suicide attempters often hide the behavior from friends and relatives, because they may believe that it reflects badly on their own relationship with the suicide attempter or that suicidal behavior itself is shameful or sinful. Persons who attempt suicide may have many of these same feelings [16].

On a systems level, the stigma surrounding mental illness, substance use disorders, and suicide has contributed to inadequate funding for preventive services and inadequate insurance reimbursement for treatments. Substance use and mental health conditions, including those associated with suicide, will remain undertreated and services tailored to persons in crisis will remain limited as long as stigma persists, resulting in an unnecessarily high rate of suicidal behavior and suicide [16]. Additionally, the stigma associated with mental illness and substance abuse has led to separate systems for physical health and mental health care, a consequence being that preventive and treatment services for mental illness and substance abuse are much less available than for other health problems. This separation has also led to bureaucratic and institutional barriers between the two systems that impede and complicate access to care and service implementation [16].


Many persons who complete suicide have contact with healthcare providers in the time preceding their deaths. Roughly 45% of all persons who complete suicide have contact with a mental health professional in the year before their deaths, and 75% of elderly suicide completers had visited their physician in the month before their death [16,33]. Although close to 90% of these cases had diagnosable psychiatric illness at the time of death, only 30% reported suicidal ideation or intent to a health professional before their suicide attempt [33]. These figures suggest a widespread inadequacy in identifying and assessing at-risk persons by healthcare professionals, and numerous studies have concluded that health professionals often lack sufficient training in the proper assessment, treatment, management, or referral of suicidal patients [16,33]. Many health professionals also lack training in identifying grieving family members of loved ones who have died by suicide [16]. Primary care providers occupy a niche in the healthcare system and have perhaps the greatest opportunity to impact suicidal persons through educational means [16,333,334,361].


Many organizations have issued consensus statements regarding screening for suicide risk in the primary care setting. The U.S. Preventive Services Task Force states that although suicide screening is of high national importance, it is very difficult to predict who will die from suicide and has found insufficient evidence for routine screening by primary care clinicians to detect suicide risk and limited evidence of the accuracy of screening tools to identify suicide risk in the primary care setting [362]. The Canadian Task Force on the Preventive Health Care found insufficient evidence for routine screening by primary care clinicians to detect depression and suicide risk [363].

However, the American Academy of Pediatrics recommends asking about depression, substance abuse, suicidal thoughts, sexual abuse, and other suicide risk factors during the routine history in all ages throughout adolescence [364]. The American Academy of Child and Adolescent Psychiatry recommends clinician awareness of patients at high risk for suicide (i.e., older male adolescents and all adolescents with current psychiatric illness or disordered mental state), especially when complicated by comorbid substance abuse, irritability, agitation, or psychosis [365]. Finally, the American Medical Association recommends that all adolescents be asked annually about behaviors or emotions that indicate risk for suicide [366].


Initial Inquiry

Physicians and other healthcare providers may encounter a patient they suspect is suicidal. This suspicion may be prompted by the presence of one or more of the risk factors for suicide described previously, patient history, a statement expressed by the patient, or by their intuition. This scenario may present a dilemma of how to proceed. Although some healthcare professionals are uncomfortable with suicidal patients, it is essential not to ignore or deny the suspicion of suicide risk. The first and most immediate step is to allocate adequate time to the patient, even though many others may be scheduled. Showing a willingness to help begins the process of establishing a positive rapport with the patient. Closed-ended and direct questions at the beginning of the interview are not very helpful; instead, use open-ended questions such as, "You look very upset; tell me more about it." Listening with empathy is in itself a major step in reducing the level of suicidal despair and overall distress [333,334]. It is helpful to lead into the topic gradually with a sequence of useful questions, such as [333,334]:

  • Do you feel unhappy and helpless?

  • Do you feel desperate?

  • Do you feel unable to face each day?

  • Do you feel life is a burden?

  • Do you feel life is not worth living?

  • Do you feel like committing suicide?

It is important to ask these questions after a rapport has been established, when the patient feels comfortable about expressing his or her feelings, and when the patient is in the process of expressing negative feelings [333,334].

After the patient confirms an initial suspicion of suicidal ideation, the next step is to assess the frequency and severity of the ideation and the possibility of suicide. It is important to ask the patient about whether a method has been developed and planned, the accessibility to the means to complete suicide, and the magnitude of lethal intent in a manner that is not demanding or coercive, but is asked in a warm and caring way that demonstrates empathy with the patient. Such general questions might include [333,334]:

  • Have you made any plans for ending your life?

  • How are you planning to do it?

  • Do you have in your possession [pills/guns/other means]?

  • Have you considered when to do it?

In general, the more an individual has thought about suicide, made specific plans, and intends to act on those plans, the greater the suicide risk. Thus, as part of the assessment of suicide risk it is essential to inquire specifically about the patient's suicidal thoughts, plans, behaviors, and intent. Such questions may often flow naturally from discussion of the patient's current situation, but in other cases they should be explicitly asked [336].

Other questions may help further elucidate suicidal thoughts, plans, or behaviors, including [336]:

Patient's Feelings about Living

  • Have you ever felt that life was not worth living?

  • Did you ever wish you could go to sleep and just not wake up?

Thoughts of Death, Self-Harm, or Suicide

  • Is death something you've thought about recently?

  • Have things ever reached the point that you've thought of harming yourself?

Follow-Up Questions

  • When did you first notice such thoughts?

  • What led up to the thoughts (e.g., interpersonal and psychosocial precipitants, including real or imagined losses; specific symptoms such as mood changes, anhedonia, hopelessness, anxiety, agitation, psychosis)?

  • How often have those thoughts occurred (including frequency, obsessional quality, controllability)?

  • How close have you come to acting on those thoughts?

  • How likely do you think it is that you will act on them in the future?

  • Have you ever started to harm (or kill) yourself but stopped before doing something (e.g., holding knife or gun to your body but stopping before acting, going to edge of bridge but not jumping)?

  • What do you envision happening if you actually killed yourself (e.g., escape, reunion with significant other, rebirth, reactions of others)?

  • Have you made a specific plan to harm or kill yourself? If so, what does the plan include?

  • Do you have guns or other weapons available to you?

  • Have you made any particular preparations (e.g., purchasing specific items, writing a note or a will, making financial arrangements, taking steps to avoid discovery, rehearsing the plan)?

  • Have you spoken to anyone about your plans?

  • How does the future look to you?

  • What things would lead you to feel more (or less) hopeful about the future (e.g., treatment, reconciliation of relationship, resolution of stressors)?

  • What things would make it more (or less) likely that you would try to kill yourself?

  • What things in your life would lead you to want to escape from life or be dead?

  • What things in your life make you want to go on living?

  • If you began to have thoughts of harming or killing yourself again, what would you do?

For persons with previous suicidal or self-harm behavior, the following questions address the antecedents, methods, and aftermath [336]:

  • Can you describe what happened (e.g., circumstances, precipitants, view of future, use of alcohol or other substances, method, intent, seriousness of injury)?

  • What thoughts were you having beforehand that led up to the attempt?

  • What did you think would happen (e.g., going to sleep versus injury versus dying, getting a reaction out of a particular person)?

  • Were other people present at the time?

  • Did you seek help afterward yourself, or did someone get help for you?

  • Had you planned to be discovered, or were you found accidentally?

  • How did you feel afterward (e.g., relief versus regret at being alive)?

  • Did you receive treatment afterward (e.g., medical versus psychiatric, emergency department versus inpatient versus outpatient)?

  • Has your view of things changed, or is anything different for you since the attempt?

  • Are there other times in the past when you've tried to harm (or kill) yourself?

  • Repeated Suicidal Thoughts or Attempts

  • About how often have you tried to harm (or kill) yourself?

  • When was the most recent time?

  • Can you describe your thoughts at the time that you were thinking most seriously about suicide?

  • When was your most serious attempt at harming or killing yourself?

  • What led up to it, and what happened afterward?

Persons with Psychosis, Hallucinations, and Delusions

  • Can you describe the voices (e.g., single versus multiple, male versus female, internal versus external, recognizable versus nonrecognizable)?

  • What do the voices say (e.g., positive remarks versus negative remarks versus threats)? If the remarks are commands, determine if they are for harmless versus harmful acts; ask for examples.

  • How do you cope with (or respond to) the voices?

  • Have you ever done what the voices ask you to do? What led you to obey the voices? If you tried to resist them, what made it difficult?

  • Have there been times when the voices told you to hurt or kill yourself? How often? What happened?

  • Are you worried about having a serious illness or that your body is rotting?

  • Are you concerned about your financial situation even when others tell you there is nothing to worry about?

  • Are there things that you have been feeling guilty about or blaming yourself for?

Potential to Harm Others

  • Are there others who you think may be responsible for what you are experiencing (e.g., persecutory ideas, passivity experiences)? Are you having any thoughts of harming them?

  • Are there other people you would want to die with you?

  • Are there others who you think would be unable to go on without you?

When assessing for suicide, it is important to be cautious of misleading information or false improvement [333,334]. When an agitated patient suddenly appears calm, he or she may have made the decision to complete suicide and feels calm after making the decision. Denial is another important consideration. Patients may deny harboring very serious intentions of killing themselves.


The opportunity for an emotionally disturbed patient with vague suicidal ideation to vent his or her thoughts and feelings to an understanding health or mental health provider may bring a degree of relief such that no further intervention is needed. However, in all cases the encouragement of further contact and follow-up should be conveyed to the patient, especially when inadequate social support is present. Independent of the actual catalyst, most suicidal persons possess feelings of helplessness, hopelessness, and despair and a triad of three cognitive/emotional conditions [333,334]:

  • Ambivalence: Most suicidal patients are ambivalent, with alternating wishes to die and to live. The healthcare provider can use patient ambivalence to increase the wish to live, thus reducing suicide risk.

  • Impulsivity: Suicide is usually an impulsive act, and impulse, by its nature, is transient. A suicide crisis can be defused if support is provided at the moment of impulse.

  • Rigidity: Suicidal people experience constricted thinking, mood, and action, and dichotomized black-and-white reasoning to their problems. The provider can help the patient understand alternative options to death through gentle reasoning.

Healthcare professionals should assess the strength and availability of emotional support to the patient, help the patient identify a relative, friend, acquaintance or other person who can provide emotional support, and solicit the person's help [333,334].


Entering the patient into a "no suicide" contract is a useful technique in suicide prevention but should only be used in patients with sufficient impulse control. Contracts should not be used in patients who are agitated, psychotic, impulsive, or intoxicated. The negotiation of the contract can promote discussion of relevant issues. Most patients respect the promises they give to physicians or healthcare professionals, and additional persons close to the patient can be involved in the contracting. The majority of suitable patients benefit from continuing contacts, which should be structured to meet individual needs. Few patients require support for longer than 2 to 3 months, and the focus of the support should be providing hope, encouraging independence, and helping the patient to learn different ways of coping with life stressors [333,334].


Depending on the level of suicide risk, referral to a psychiatrist or hospitalization may be warranted (Table 5). Suicidal patients should be referred to a psychiatrist when any of the following are present: psychiatric illness; previous suicide attempt; family history of suicide, alcoholism, and/or psychiatric disorder; physical illness; or absence of social support [333,334]. After deciding to refer a patient to a psychiatrist, the clinician should explain to the patient the reason for the referral and help alleviate patient anxiety over stigma and psychotropic medications. It is also important to help the patient understand that pharmacological and psychological therapies are both effective and to emphasize to the patient that referral does not mean "abandonment." The referring clinician should also arrange an appointment with the psychiatrist, allocate time for the patient following the initial appointment with the psychiatrist, and ensure the ongoing relationship with the patient [333,334].


Suicide Risk LevelSymptomsAssessmentAction
0No distress––––
1Emotionally disturbedInquire about suicidal thoughtsListen with empathy
2Vague ideas of deathInquire about suicidal thoughtsListen with empathy
3Vague suicidal thoughts
Assess the intent
(plan and method)
Explore possibilities
Identify support
Suicidal ideas
but no
psychiatric disorder
Assess the intent
(plan and method)
Explore possibilities
Identify support
Suicidal ideas
psychiatric disorder
severe life stressors
Assess the intent
(plan and method)
Make a contract
Refer to psychiatrist
Suicidal ideas
psychiatric disorder
severe life stressors
previous attempt
Remain with patient to prevent access to meansHospitalize


Some indications for immediate hospitalization include recurrent suicidal thoughts, high levels of intent of dying in the immediate future (the next few hours or days), the presence of agitation or panic, or the existence of a plan to use a violent and immediate suicide method [333,334]. When hospitalizing a patient, the patient should not be left alone; the hospitalization and transfer of the patient by ambulance or police should be arranged and the family and any appropriate authorities should be informed [333,334].


Family members and friends affected by the death of a loved one through suicide are referred to as "suicide survivors." Conservative estimates suggesting a ratio of 6 survivors for every completed suicide indicate that an estimated 4.73 million suicide survivors are living in the United States, based on 1983–2009 mortality data [297].

The death of a loved one by suicide can be shocking, painful, and unexpected for survivors. 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 [297].

Survivors often struggle with trying to comprehend why the suicide occurred and how they could have intervened. Feelings of guilt are likely when the survivor believes he or she could have prevented the suicide. The survivor may even experience relief at times, especially if the loved one had a psychiatric illness. The stigma and shame that surrounds suicide may cause difficulty among the family members and friends of survivors in knowing what to say and how to support the survivor and might prevent the survivor from reaching out for help. Ongoing support remains important to maintain family and other relationships during the grieving process [297].

Many survivors find that the best help comes from attending a support group for survivors of suicide in which they can openly share their own story and their feelings with fellow survivors without pressure or fear of judgment and shame. Support groups can be a helpful source of guidance, understanding, and support through the healing process [297]. The American Foundation for Suicide Prevention maintains an international directory of suicide bereavement support groups on their website, http://www.afsp.org.


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.

Works Cited

1. Cepoiu M, McCusker J, Cole MG, Sewitch M, Belzile E, Ciampi A. Recognition of depression by non-psychiatric physicians: a systematic literature review and meta-analysis. J Gen Int Med. 2007;23(1):25-36.

2. Lewy C, Sells CW, Gilhooly J, McKelvey R. Adolescent depression: evaluating pediatric residents' knowledge, confidence, and interpersonal skills using standardized patients. Acad Psychiatry. 2009;33(5):389-393.

3. Jameson JP, Blank MB. Diagnosis and treatment of depression and anxiety in rural and nonrural primary care: national survey results. Psychiatr Serv. 2010;61(6):624-627.

4. Raue PJ, Schulberg HC, Heo M, Klimstra S, Bruce ML. Patients' depression treatment preferences and initiation, adherence, and outcome: a randomized primary care study. Psychiatr Serv. 2009;60(3):337-343.

5. Young HN, Bell RA, Epstein RM, Feldman MD, Kravitz RL. Physicians' shared decision-making behaviors in depression care.Arch Intern Med. 2008;168(13):1404-1408.

6. National Institute of Mental Health. The Numbers Count: Mental Disorders in America. Available at http://www.nimh.nih.gov/health/publications/the-numbers-count-mental-disorders-in-america/index.shtml. Last accessed June 26, 2014.

7. Agency for Healthcare Research and Quality. Comparative Effectiveness of Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: Executive Summary. Available at http://www.effectivehealthcare.ahrq.gov/ehc/products/7/61/Antidepressants_Executive_Summary.pdf. Last accessed June 26, 2014.

8. Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC. Twelve-month use of mental health services in the United States: results from the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):629-640.

9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.

10. Mitchell AJ, Chan M, Bhatti H, et al. Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview-based studies. Lancet Oncol. 2011;12(2):160-174.

11. Strine TW, Mokdad AH, Balluz LS, et al. Depression and anxiety in the United States: findings from the 2006 Behavioral Risk Factor Surveillance System. Psychiatr Serv. 2008;59:1383-1390.

12. Chapman DP, Perry GS, Strine TW. The vital link between chronic disease and depressive disorders. Prev Chronic Dis. 2005;2:A14.

13. American Foundation for Suicide Prevention. Facts and Figures. Available at http://www.afsp.org/understanding-suicide/facts-and-figures. Last accessed June 26, 2014.

14. Centers for Disease Control and Prevention. National Suicide Statistics at a Glance. Available at http://www.cdc.gov/violenceprevention/suicide/statistics/aag.html. Last accessed June 26, 2014.

15. Palmer CS, Revicki DA, Halpern MT, Hatziandreu EJ. The cost of suicide and suicide attempts in the United States. Clin Neuropharmacol. 1995;18(suppl 3):S25-S33.

16. U.S. Department of Health and Human Services, Office of the Surgeon General, and National Action Alliance for Suicide Prevention. 2012 National Strategy for Suicide Prevention: Goals and Objectives for Action. Washington, DC: U.S. Department of Health and Human Services; 2012.

17. Centers for Disease Control and Prevention. QuickStats: prevalence of current depression among persons aged ≥12 years, by age group and sex—United States, National Health and Nutrition Examination Survey, 2007–2010. MMWR. 2012;60(51):1747.

18. Halverson JL, Bhalla RN, Moraille-Bhalla P, Andrew LB. Depression. Available at http://emedicine.medscape.com/article/286759-overview. Last accessed June 26, 2014.

19. National Center for Health Statistics. Health, United States, 2011: With Special Feature on Socioeconomic Status and Health. Hyattsville, MD: National Center for Health Statistics; 2012.

20. Pratt LA, Brody DJ. Depression in the United States household population, 2005–2006. NCHS Data Brief. 2008;7:1-8.

21. Centers for Disease Control and Prevention. Depression is Not a Normal Part of Growing Older. Available at http://www.cdc.gov/aging/mentalhealth/depression.htm. Last accessed June 26, 2014.

22. Birrer RB, Vemuri SP. Depression in later life: a diagnostic and therapeutic challenge. Am Fam Phys. 2004;69(10):2375-2382.

23. Gaynes BN, Gavin N, Meltzer-Brody S, et al. Perinatal depression: prevalence, screening accuracy, and screening outcomes.Evid Rep Technol Assess (Summ). 2005;(119):1-8.

24. Vesga-López O, Blanco C, Keyes K, Olfson M, Grant BF, Hasin DS. Psychiatric disorders in pregnant and postpartum women in the United States. Arch Gen Psychiatry. 2008;65(7):805-815.

25. Mitchell J, Trangle M, Degnan B, et al., for the Institute for Clinical Systems Improvement. Adult Depression in Primary Care. 16th ed. Available at https://www.icsi.org/guidelines__more/catalog_guidelines_and_more/catalog_guidelines/catalog_behavioral_health_guidelines/depression/. Last accessed June 26, 2014.

26. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, DC: American Psychiatric Publishing, Inc.; 2010.

27. Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64(12):1465-1475.

28. Beck A, Crain AL, Solberg LI, et al. Severity of depression and magnitude of productivity loss. Ann Fam Med. 2011;9:305-311.

29. Han D, Wang EC. Remission from depression: a review of venlafaxine clinical and economic evidence. Pharmacoeconomics. 2005;23(6):567-581.

30. Toney SD. Identifying and managing depression in women. J Manag Care Pharm. 2007;13(9 suppl A):S16-S22.

31. Greenberg P, Corey-Lisle PK, Birnbaum H, Marynchenko M, Claxton A. Economic implications of treatment-resistant depression among employees. Pharmacoeconomics. 2004;22(6):363-373.

32. Fletcher JM. Adolescent depression and educational attainment: results using sibling fixed effects. Health Econ. 2010;19(7):855-871.

33. American Foundation for Suicide Prevention. Suicide Deaths. Available at http://www.afsp.org/understanding-suicide/facts-and-figures. Last accessed June 26, 2014.

34. Centers for Disease Control and Prevention. Depression. Available at http://www.cdc.gov/workplacehealthpromotion/implementation/topics/depression.html. Last accessed June 26, 2014.

35. Mahendran R, Yap HL. Clinical practice guidelines for depression. Singapore Med J. 2005;46(11):610-615.

36. Onyike CU, Crum RM, Lee HB, Lyketsos CG, Eaton WW. Is obesity associated with major depression? Results from the third national health and nutrition examination survey. Am J Epidemiol. 2003;158(12):1139-1147.

37. Burcusa SL, Iacono WG. Risk for recurrence in depression. Clin Psychol Rev. 2007;27(8):959-985.

38. Belmaker RH, Agam G. Major depressive disorder. N Engl J Med. 2008;358(1):55-68.

39. Zemrak WR, Kenna GA. Association of antipsychotic and antidepressant drugs with Q-T interval prolongation. Am J Health Syst Pharm. 2008;65(11):1029-1038.

40. Mitchell J, Trangle M, Degnan B, et al. Adult Depression in Primary Care. Bloomington, MN: Institute for Clinical Systems Improvement; 2013.

41. Baldessarini RJ, Tondo L, Ghiani C, Lepri B. Illness risk following rapid versus gradual discontinuation of antidepressants. Am J Psychiatry. 2010;167(8):934-941.

42. Hirschfeld RMA. Clinical importance of long-term antidepressant treatment. Br J Psychiatry. 2001;179(suppl):S4-S8.

43. Melfi CA, Chawla AJ, Croghan TW, Hanna MP, Kennedy S, Sredl K. The effects of adherence to antidepressant treatment guidelines on relapse and recurrence of depression. Arch Gen Psychiatry. 1998;55(12):1128-1132.

44. Kim KH, Lee SM, Paik JW, Kim NS. The effects of continuous antidepressant treatment during the first 6 months on relapse or recurrence of depression. J Affect Disord. 2011;132(1-2):121-129.

45. NIMH/NIH Consensus Development Conference Statement. Mood disorders: pharmacologic prevention of recurrences. Am J Psychiatry. 1985;142(4):469-476.

46. Heim C, Plotsky PM, Nemeroff CB. Importance of studying the contributions of early adverse experience to neurobiological findings in depression. Neuropsychopharmacology. 2004;29(4):641-648.

47. Belmaker RH. The future of depression psychopharmacology. CNS Spectr. 2008;13(8):682-687.

48. Miniati M, Rucci P, Benvenuti A, et al. Clinical characteristics and treatment outcome of depression in patients with and without a history of emotional and physical abuse. J Psychiatr Res. 2010;44(5):302-309.

49. Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002;34(1):13-25.

50. Sinha R. Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci. 2008;1141:105-130.

51. Kalinichev M, Easterling KW, Holtzman SG. Long-lasting changes in morphine-induced locomotor sensitization and tolerance in Long-Evans mother rats as a result of periodic postpartum separation from the litter: a novel model of increased vulnerability to drug abuse? Neuropsychopharmacology. 2003;28(2):317-328.

52. Pryce CR, Feldon J. Long-term neurobehavioural impact of the postnatal environment in rats: manipulations, effects and mediating mechanisms. Neurosci Biobehav Rev. 2003;27(1-2):57-71.

53. Goodman A. The neurobiological development of addiction. Psychiatr Times. 2009;26(9):1-14.

54. Chen LP, Murad MH, Paras ML, et al. Sexual abuse and lifetime diagnosis of psychiatric disorders: systematic review and meta-analysis. Mayo Clin Proc. 2010;85(7):618-629.

55. Kendler KS, Aggen SH. Clarifying the causal relationship in women between childhood sexual abuse and lifetime major depression. Psychol Med. 2014;44(6):1213-1221.

56. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455(7215):894-902.

57. Gelenberg AJ, Thase ME. Performance improvement CME: improving outcomes in depression. J Clin Psychiatry. 2010;71(8):e19.

58. Clark L, Chamberlain SR, Sahakian BJ. Neurocognitive mechanisms in depression: implications for treatment. Annu Rev Neurosci. 2009;32:57-74.

59. Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct. 2008;213(1-2):93-118.

60. van Heeringen K, Mann JJ. The neurobiology of suicide. Lancet Psychiatry. 2014;1(1):63-72.

61. Mann JJ, Currier DM. Stress, genetics and epigenetic effects on the neurobiology of suicidal behavior and depression. Eur Psychiatry. 2010;25(5):268-271.

62. Costanza A, D’Orta I, Perroud N, et al. Neurobiology of suicide: do biomarkers exist? Int J Legal Med. 2014;128(1):73-82.

63. Fiori LM, Ernst C, Turecki G. Genetic and neurobiological approaches to understanding suicidal behaviors. In: Nock M (ed). The Oxford Handbook of Suicide and Self-Injury. Oxford: Oxford University Press; 2014: 155-182.

64. Joiner TE Jr, Brown JS, Wingate LR. The psychology and neurobiology of suicidal behavior. Annu Rev Psychol. 2005;56:287-314.

65. Ernst C, Mechawar N, Turecki G. Suicide neurobiology. Prog Neurobiol. 2009;89(4):315-333.

66. Mitchell AJ, Vaze A, Rao S. Clinical diagnosis of depression in primary care: a meta-analysis. Lancet. 2009;374(9690):609-619.

67. U.S. Preventive Services Task Force. Screening for depression in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;151(11):784-792.

68. National Institute for Health and Clinical Excellence. Depression: The Treatment and Management of Depression in Adults. London: The British Psychological Society and the Royal College of Psychiatrists; 2010.

69. Michigan Quality Improvement Consortium. Primary Care Diagnosis and Management of Adults with Depression. Southfield, MI: Michigan Quality Improvement Consortium; 2014.

70. Snowden A, White CA, Christie Z, Murray E, McGowan C, Scott R. The clinical utility of the distress thermometer: a review. Br J Nurs. 2011;20(4):220-227.

71. Bow JN, Flens JR, Gould JW. MMPI-2 and MCMI-III in forensic evaluations: a survey of psychologists. J Forensic Psychol Pract. 2010;10(1):37-52.

72. Centers for Disease Control and Prevention. Understanding Suicide: Fact Sheet. Available at http://www.cdc.gov/violenceprevention/pub/suicide_factsheet.html. Last accessed June 26, 2014.

73. Center for Substance Abuse Treatment. Substance Abuse and Suicide Prevention: Evidence and ImplicationsA White Paper. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2008.

74. Hensley PL, Clayton PJ. Bereavement-Related Depression. Available at http://www.psychiatrictimes.com/articles/bereavement-related-depression. Last accessed October 7, 2014.

75. Rothe EM, Pumariega AJ, Rogers KM. Cultural Aspects of the Pharmacological Treatment of Depression: Factors Affecting Minority and Youth. Available at http://www.psychiatrictimes.com/articles/cultural-aspects-pharmacological-treatment-depression-factors-affecting-minority-and-youth. Last accessed June 30, 2014.

76. Miranda J, Schoenbaum M, Sherbourne C, Duan N, Wells K. Effects of primary care depression treatment on minority patients' clinical status and employment. Arch Gen Psychiatry. 2004;61(8):827-834.

77. Muñoz RF, Mendelson T. Toward evidence-based interventions for diverse populations: the San Francisco General Hospital prevention and treatment manuals. J Consult Clin Psychol. 2005;73(5):790-799.

78. Karasz A. Cultural differences in conceptual models of depression. Soc Sci Med. 2005;60(7):1625-1635.

79. Nadeem E, Lange JM, Miranda J. Mental health care preferences among low-income and minority women. Arch Womens Ment Health. 2008;11(2):93-102.

80. Lesser IM, Castro DB, Gaynes BN, et al. Ethnicity/race and outcome in the treatment of depression: results from STAR*D. Med Care. 2007;45(11):1043-1051.

81. Anglin DM, Alberti PM, Link BG, Phelan JC. Racial differences in beliefs about the effectiveness and necessity of mental health treatment. Am J Comm Psychol. 2008;42(1-2):17-24.

82. Menselson T, Rehkopf DH, Kubzansky LD. Depression among Latinos in the United States: a meta-analytic review. J Consulting Clin Psychol. 2008;76(3):355-366.

83. Schmaling KB, Hernandez DV. Problem-solving treatment for depression among Mexican Americans in primary care. J Health Care Poor Underserved. 2008;19(2):466-477.

84. Tiwari SK, Wang JL. Ethnic differences in mental health service use among White, Chinese, South Asian and South East Asian populations living in Canada. Soc Psychiatry Psychiatr Epidemiol. 2008;43(11):866-871.

85. Ialongo N, McCreary BK, Pearson JL, et al. Major depression disorder in a population of urban, African-American young adults: prevalence, correlates, comorbidity and unmet mental health service need. J Affect Disord. 2004;79(1-3):127-136.

86. National Alliance on Mental Illness. What is Mental Illness? Available at http://www.nami.org/Template.cfm?Section=By_Illness. Last accessed June 26, 2014.

87. Kessler RC, Birnbaum H, Bromet E, Hwang I, Sampson N, Shahly V. Age differences in major depression: results from the National Comorbidity Survey Replication (NCS-R). Psychol Med. 2010;40(2):225-237.

88. Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital Stat Rep. 2013;61(4):1-118.

89. Substance Abuse and Mental Health Services Administration. The Treatment of Depression in Older Adults: Depression and Older Adults: Key Issues. Rockville, MD: Center for Mental Health Services, Substance Abuse and Mental Health Services Administration, US Department of Health and Human Services; 2011.

90. Bryant C. Anxiety and depression in old age: challenges in recognition and diagnosis. Int Psychogeriatr. 2010;22(4):511-513.

91. Fischer LR, Wei F, Solberg LI, Rush WA, Heinrich RL. Treatment of elderly and other adult patients for depression in primary care. J Am Geriatr Soc. 2003;51(11): 1554-1562.

92. Mitchell AJ, Rao S, Vaze A. Do primary care physicians have particular difficulty identifying late-life depression? A meta-analysis stratified by age. Psychother Psychosom. 2010;79(5):285-94.

93. Law J, Laidlaw K, Peck D. Is depression viewed as an inevitable consequence of age? The “understandability phenomenon” in older people. Clinical Gerontologist. 2010;33(3):194-209.

94. Uncapher H, Arean PA. Physicians are less willing to treat suicidal ideation in older patients. J Am Geriatr Soc. 2000;48:188-192.

95. Park M, Unützer J. Geriatric depression in primary care. Psychiatr Clin North Am. 2011;34(2):469-487.

96. Stromberg R, Wernering E, Aberg-Wistedt A, Furhoff A-K, Johansson S-E, Backlund LG. Screening and diagnosing depression in women visiting GPs' drop in clinic in primary health care. BMC Fam Pract. 2008;9:34-43.

97. Sharp LK, Lipsky MS. Screening for depression across the lifespan: a review of measures for use in primary care settings. Am Fam Phys. 2002;66(6):1001-1009.

98. Gotlib IH, Hammen CL (eds). Handbook of Depression. 2nd ed. New York, NY: Guilford Press; 2010.

99. Richardson LP, McCauley E, Grossman DC, et al. Evaluation of the Patient Health Questionnaire-9 Item for detecting major depression among adolescents. Pediatrics. 2010;126(6):1117-1123.

100. Kovacs M. Children's Depression Inventory. North Tonawanda, NY: Multi-Health System; 1992.

101. Suicide Prevention Resource Center. Suicide Risk and Prevention for Lesbian, Gay, Bisexual, and Transgender Youth. Available at http://www.sprc.org/library_resources/items/suicide-risk-and-prevention-lesbian-gay-bisexual-and-transgender-youth-1. Last accessed June 26, 2014.

102. Ryan C, Huebner D, Diaz RM, Sanchez J. Family rejection as a predictor of negative health outcomes in white and Latino lesbian, gay, and bisexual young adults. Pediatrics. 2009;123(1):346-352.

103. Mustanski BS, Garofalo R, Emerson EM. Mental health disorders, psychological distress, and suicidality in a diverse sample of lesbian, gay, bisexual, and transgender youths. Am J Pub Health. 2010;100(12):2426-2432.

104. Khouzam HR. Depression: guidelines for effective primary care. Part I: diagnosis. Psychiatr Times Consult. 2007;47(8):1-6.

105. Nierenberg AA, Trivedi MH, Fava M, et al. Family history of mood disorder and characteristics of major depressive disorder: a STAR*D (sequenced treatment alternatives to relieve depression) study. J Psychiatr Res. 2007;41(3-4):214-221.

106. Hasin DS, Goodwin RD, Stinson FS, Grant BF. Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch Gen Psychiatry. 2005;62(10):1097-1106.

107. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.

108. Nock MK, Hwang I, Sampson NA, Kessler RC. Mental disorders, comorbidity and suicidal behavior: results from the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15(8):868-876.

109. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40.

110. Nierenberg AA, Katz J, Fava M. A critical overview of the pharmacologic management of treatment-resistant depression. Psychiatr Clin North Am. 2007;30(1):13-29.

111. CareFirst Blue Cross Blue Shield. Clinical Practice Guidelines For Depression In Adults In The Primary Care Setting. Available at https://provider.carefirst.com/wcmwps/wcm/connect/9e9f3e00456e3cd8a7d2afed9a4bbc9e/BOK0023.pdf?MOD=AJPERES&CACHEID=9e9f3e00456e3cd8a7d2afed9a4bbc9e. Last accessed June 26, 2014.

112. Zimmerman M, Galione J. Psychiatrists' and nonpsychiatrist physicians' reported use of the DSM-IV criteria for major depressive disorder. J Clin Psychiatry. 2010;71(3):235-238.

113. Gregory RJ, Canning SS, Lee TW, Wise JC. Cognitive bibliotherapy for depression: a meta-analysis. Prof Psychol Res Pr. 2004;35(3):275-280.

114. Anderson L, Lewis G, Araya R, et al. Self-help books for depression: how can practitioners and patients make the right choice?Br J Gen Pract. 2005;55(514):387-392.

115. Dimidjian S, Barrera M Jr, Martell C, Muñoz RF, Lewinsohn PM. The origins and current status of behavioral activation treatments for depression. Annu Rev Clin Psychol. 2011;7:1-38.

116. Cuijpers P, van Straten A, Warmerdam L. Behavioral activation treatments of depression: a meta-analysis. Clin Psychol Rev. 2007;27(3):318-326.

117. Mazzucchelli T, Kane R, Rees C. Behavioral activation treatments for depression in adults: a meta-analysis and review. Cin Psychol Sci Prac. 2009;16(4):383-411.

118. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303(1):47-53.

119. O'Connor AM, Bennett C, Stacey D, et al. Do patient decision aids meet effectiveness criteria of the international patient decision aid standards collaboration? A systematic review and meta-analysis. Med Decis Making. 2007;27(5):554-574.

120. Joyce PR, McKenzie JM, Carter JD, et al. Temperament, character and personality disorders as predictors of response to interpersonal psychotherapy and cognitive behavioural therapy for depression. Br J Psychiatry. 2007;190:503-508.

121. Nemeroff CB, Heim CM, Thase ME, et al. Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc Natl Acad Sci U S A. 2003;100(24):14293-14296.

122. Ward EC. Examining differential treatment effects for depression in racial and ethnic minority women: a qualitative systematic review. J Natl Med Assoc. 2007;99(3):265-274.

123. Lanouette NM, Folsom DP, Sciolla A, Jeste DV. Psychotropic medication nonadherence among United States Latinos: a comprehensive literature review. Psychiatr Serv. 2009;60(2):157-174.

124. Unützer J, Katon W, Callahan CM, et al. Collaborative care management of late-life depression in the primary care setting: a randomized controlled trial. JAMA. 2002;288(22):2836-2845.

125. Areán PA, Ayalon L, Hunkeler E, et al. Improving depression care for older, minority patients in primary care. Med Care. 2005;43(4):381-390.

126. Williams JW Jr, Noël PH, Cordes JA, Ramirez G, Pignone M. Is this patient clinically depressed? JAMA. 2002;287(9):1160-1170.

127. Manber R, Arnow B, Blasey C, et al. Patient's therapeutic skill acquisition and response to psychotherapy, alone or in combination with medication. Psychol Med. 2003;33(4):693-702.

128. Leichsenring F, Rabung S, Leibing E. The efficacy of short-term psychodynamic psychotherapy in specific psychiatric disorders: a meta-analysis. Arch Gen Psychiatry. 2004;61(12):1208-1216.

129. de Jonghe F, Hendriksen M, Van Aalst G, et al. Psychotherapy alone and combined with pharmacotherapy in the treatment of depression. Brit J Psychiatry. 2004;185:37-45.

130. Dimidjian S, Hollon SD, Dobson KS, et al. Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the acute treatment of adults with major depression. J Consult Clin Psychol. 2006;74(4):658-670.

131. Kwan BM, Dimidjian S, Rizvi SL. Treatment preference, engagement, and clinical improvement in pharmacotherapy versus psychotherapy for depression. Behav Res Ther. 2010;48(8):799-804.

132. Qaseem A, Snow V, Denberg TD, Forciea MA, Owens DK, for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Using second-generation antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;149(10):725-733.

133. Bondolfi G, Jermann F, der Linden MV, et al. Depression relapse prophylaxis with Mindfulness-Based Cognitive Therapy: replication and extension in the Swiss health care system. J Affect Disord. 2010;122(3):224-231.

134. Sonawalla SB. Citalopram in the maintenance treatment of major depressive disorder. J Clin Psychiatry. 2001;62(12):993.

135. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.

136. Iovieno N, van Nieuwenhuizen A, Clain A, Baer L, Nierenberg AA. Residual symptoms after remission of major depressive disorder with fluoxetine and risk of relapse. Depress Anxiety. 2011;28(2):137-144.

137. Kaiser Permanente Care Management Institute. Diagnosis and Treatment of Depression in Adults: 2012 Clinical Practice Guideline. Oakland, CA: Kaiser Permanente Care Management Institute; 2012.

138. Rost K, Nutting P, Smith JL, Elliott CE, Dickinson M. Managing depression as a chronic disease: a randomised trial of ongoing treatment in primary care. BMJ. 2002;325(7370):934-937.

139. Schoenbaum M, Unützer J, McCaffrey D, Duan N, Sherbourne C, Wells KB. The effects of primary care depression treatment on patients' clinical status and employment. Health Serv Res. 2002;37(5):1145-1158.

140. Goldapple K, Segal Z, Garson C, et al. Modulation of cortical-limbic pathways in major depression: treatment specific effects of cognitive behavior therapy. Arch Gen Psychiatry. 2004;61(1):34-41.

141. Beck JS. Cognitive Behavior Therapy: Basics and Beyond. 2nd ed. New York, NY: Guilford Press; 2011.

142. Dobson KS (ed). Handbook of Cognitive-Behavioral Therapies. 3rd ed. New York, NY: Guilford Press; 2011.

143. Yoshimura S, Okamoto Y, Onoda K, et al. Cognitive behavioral therapy for depression changes medial prefrontal and ventral anterior cingulate cortex activity associated with self-referential processing. Soc Cogn Affect Neurosci. 2014;9(4):487-493.

144. Segal Z, Williams JMG, Teasdale JD. Mindfulness-Based Cognitive Therapy for Depression. 2nd ed. New York, NY: Guilford Press; 2012.

145. Lau MA, Segal ZV, Williams JMG. Teasdale's differential activation hypothesis: implications for mechanisms of depressive relapse and suicidal behaviour. Behav Res Ther. 2004;42(9):1001-1017.

146. Williams JM, Russell I, Russell D. Mindfulness-based cognitive therapy: further issues in current evidence and future research. J Consult Clin Psychol. 2008;76(3):524-529.

147. Klerman GL, Weissman MM, Rounsaville BJ, Chevron ES. Interpersonal Psychotherapy of Depression. New York, NY: Basic Books; 1984.

148. Weissman MM, Markowitz JC, Klerman GL. Comprehensive Guide to Interpersonal Psychotherapy. New York, NY: Basic Books; 2000.

149. Lemma A, Target M, Fonagy P. Brief Dynamic Interpersonal Therapy: A Clinician’s Guide. Oxford: Oxford University Press; 2011.

150. Bell AC, D’Zurilla TJ. Problem-solving therapy for depression: a meta-analysis. Clin Psychol Rev. 2009;29(4):348-353.

151. Nezu AM, Nezu CM, Perri MG. Problem-Solving Therapy for Depression: Theory Research and Clinical Guidelines. New York, NY: Wiley; 1989.

152. Areán PA, Raue P, Mackin RS, Kanellopoulos D, McCulloch C, Alexopoulos GS. Problem-solving therapy and supportive therapy in older adults with major depression and executive dysfunction. Am J Psychiatry. 2010;167:1391-1398.

153. Warmerdam L, van Straten A, Jongsma J, Twisk J, Cuijpers P. Online cognitive behavioral therapy and problem-solving therapy for depressive symptoms: exploring mechanisms of change. J Behav Ther Exp Psychiatry. 2010;41(1):64-70.

154. Vanelli M, Coca-Perraillon M. Role of patient experience in antidepressant adherence: a retrospective data analysis. Clin Ther. 2008;30(9):1737-1745.

155. Trivedi MH, Kleiber BA. Algorithm for the treatment of chronic depression. J Clin Psychiatry. 2001;62(suppl 6):22-29.

156. Bostwick JM. A generalist's guide to treating patients with depression with an emphasis on using side effects to tailor antidepressant therapy. Mayo Clin Proc. 2010;85(6):538-550.

157. U.S. Department of Veteran Affairs. Clinical Practice Guideline: Management of Major Depressive Disorder. Washington, DC: U.S. Department of Defense; 2009.

158. Kilts CD, Wade AG, Andersen HF, Schlaepfer TE. Baseline severity of depression predicts antidepressant drug response relative to escitalopram. Expert Opin Pharmacother. 2009;10(6):927-936.

159. Kornstein SG, Li D, Mao Y, Larsson S, Andersen HF, Papakostas GI. Escitalopram versus SNRI antidepressants in the acute treatment of major depressive disorder: integrative analysis of four double-blind, randomized clinical trials. CNS Spectr. 2009;14(6):326-333.

160. Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol. 2007;151(6):737-748.

161. Sinclair LI, Christmas DM, Hood SD, et al. Antidepressant-induced jitteriness/anxiety syndrome: systematic review. Br J Psychiatry. 2009;194(6):483-490.

162. Amsterdam JD. Monoamine oxidase inhibitor therapy in severe and resistant depression. Psychiatric Ann. 2006;36(9):607-613.

163. Fowler JS, Logan J, Azzaro AJ, et al. Reversible inhibitors of monoamine oxidase-A (RIMAs): robust, reversible inhibition of human brain MAO-A by CX157. Neuropsychopharmacology. 2010;35(3):623-631.

164. U.S. Food and Drug Administration website. FDA News Release: FDA Approves Emsam (Selegiline) as First Drug Patch for Depression. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108607.htm. Last accessed June 26, 2014.

165. Padala PR, Burke WJ, Bhatia SC, Petty F. Treatment of apathy with methylphenidate. J Neuropsychiatry Clin Neurosci. 2007;19:81-83.

166. Hardy SE. Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults. Am J Geriatr Pharmacother. 2009;7(1):34-59.

167. Ishizaki J, Mimura M. Dysthymia and apathy: diagnosis and treatment. Depression Res Treatment. 2011;893905.

168. LexiComp Online. Available at http://online.lexi.com. Last accessed June 26, 2014.

169. Baldessarini RJ, Tondo L. Suicidal risks during treatment of bipolar disorder patients with lithium versus anticonvulsants. Pharmacopsychiatry. 2009;42(2):72-75.

170. Tondo L, Baldessarini RJ. Long-term lithium treatment in the prevention of suicidal behavior in bipolar disorder patients. Epidemiol Psychiatr Soc. 2009;18(3):179-183.

171. Asenjo Lobos C, Komossa K, Rummel-Kluge C, et al. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010;(11):CD006633.

172. Kasckow J, Felmet K, Zisook S. Managing suicide risk in patients with schizophrenia. CNS Drugs. 2011;25(2):129-143.

173. Roy A, Pompili M. Management of schizophrenia with suicide risk. Psychiatr Clin North Am. 2009;32(4):863-883.

174. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646.

175. Baldessarini RJ, Tondo L, Hennen J. Lithium treatment and suicide risk in major affective disorders: update and new findings. J Clin Psychiatry. 2003;64(suppl 5):44-52.

176. Underwood MD, Kassir SA, Bakalian MJ, Galfalvy H, Mann JJ, Arango V. Neuron density and serotonin receptor binding in prefrontal cortex in suicide. Int J Neuropsychopharmacol. 2012;15(4):435-447.

177. Oquendo MA, Russob SA, Underwood MD, et al. Higher postmortem prefrontal 5-HT2A receptor binding correlates with lifetime aggression in suicide. Biol Psychiatry. 2006;59(3):235-243.

178. Mann JJ. Neurobiology of suicidal behavior. Nat Rev Neuroscienc. 2003;4(10):819-828.

179. Möller HJ, Baldwin DS, Goodwin G, et al. Do SSRIs or antidepressants in general increase suicidality? WPA Section on Pharmacopsychiatry: consensus statement. Eur Arch Psychiatry Clin Neurosci. 2008;258(suppl 3):3-23.

180. Leon AC, Solomon DA, Li C, et al. Antidepressants and risks of suicide and suicide attempts: a 27-year observational study.J Clin Psychiatry. 2011;72(5):580-586.

181. Delgado PL. Monoamine depletion studies: implications for antidepressant discontinuation syndrome. J Clin Psychiatry. 2006;67(suppl 4):22-26.

182. Narayan V, Haddad PM. Antidepressant discontinuation manic states: a critical review of the literature and suggested diagnostic criteria. J Psychopharmacol. 2011;25(3):306-313.

183. U.K. Medicines and Healthcare Products Regulatory Agency. Report of the CSM Expert Working Group on the Safety of Selective Serotonin Reuptake Inhibitor Antidepressants. Available at http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con019472.pdf. Last accessed June 26, 2014.

184. Taylor D, Stewart S, Connolly A. Antidepressant withdrawal symptoms: telephone calls to a national medication helpline.J Affect Disord. 2006;95(1):129-133.

185. Renoir T. Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved. Front Pharmacol. 2013;4:45.

186. Michelson D, Fava M, Amsterdam J, et al. Interruption of selective serotonin reuptake inhibitor treatment: double-blind, placebo-controlled trial. Br J Psychiatry. 2000;176:363-368.

187. Haddad PM. Antidepressant discontinuation syndromes. Drug Saf. 2001;24(3):183-197.

188. Valuck RJ, Orton HD, Libby AM. Antidepressant discontinuation and risk of suicide attempt: a retrospective, nested case-control study. J Clin Psychiatry. 2009;70(8):1069-1077.

189. Tint A, Haddad PM, Anderson IM. The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: a randomized study. J Psychopharmacol. 2008;22(3):330-332.

190. Hu XH, Bull SA, Hunkeler EM, et al. Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J Clin Psychiatry. 2004;65(7):959-965.

191. Werneke U. Risk management of nutritional supplements in chronic illness: the implications for the care of cancer and depression. Proc Nutr Soc. 2007;66(4):483-492.

192. Morgan AJ, Jorm AF. Self-help interventions for depressive disorders and depressive symptoms: a systematic review. Ann Gen Psychiatry. 2008;7:13-36.

193. Linde K, Mulrow CD. St. John's wort for depression. Cochrane Database Syst Rev. 2000;(2):CD000448.

194. Linde K, Berner M, Egger M, Mulrow C. St John's wort for depression: meta-analysis of randomised controlled trials. Br J Psychiatry. 2005;186:99-107.

195. Kasper S, Gastpar M, Müller WE, et al. Efficacy of St. John's wort extract WS 5570 in acute treatment of mild depression: a reanalysis of data from controlled clinical trials. Eur Arch Psychiatry Clin Neurosci. 2008;258(1):59-63.

196. Rahimi R, Nikfar S, Abdollahi M. Efficacy and tolerability of Hypericum perforatum in major depressive disorder in comparison with selective serotonin reuptake inhibitors: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(1):118-127.

197. Charrois TL, Sadler C, Vohra S; American Academy of Pediatrics Provisional Section on Complementary, Holistic, and Integrative Medicine. Complementary, holistic, and integrative medicine: St. John's wort. Pediatr Rev. 2007;28(2):69-72.

198. Sarris J. Herbal medicines in the treatment of psychiatric disorders: a systematic review. Phytother Res. 2007;21(8):703-716.

199. Freire RC, Hallak JE, Crippa JA, Nardi AE. New treatment options for panic disorder: clinical trials from 2000 to 2010. Expert Opin Pharmacother. 2011;12(9):1419-1428.

200. Zheng H, Zhang L, Li L, et al. High-frequency rTMS treatment increases left prefrontal myo-inositol in young patients with treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(7):1189-1195.

201. Karege F, Perroud N, Burkhardt S, et al. Alterations in phosphatidylinositol 3-kinase activity and PTEN phosphatase in the prefrontal cortex of depressed suicide victims. Neuropsychobiology. 2011;63(4):224-231.

202. Gianfranco C, Vittorio U, Silvia B, Francesco D. Myo-inositol in the treatment of premenstrual dysphoric disorder. Hum Psychopharmacol. 2011;26(7):526-530.

203. Levine J, Barak Y, Gonzalves M, et al. Double-blind, controlled trial of inositol treatment of depression. Am J Psychiatry. 1995;152(5):792-794.

204. Fux M, Levine J, Aviv A, Belmaker RH. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry. 1996;153(9):1219-1221.

205. Palatnik A, Frolov K, Fux M, Benjamin J. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol. 2001;21(3):335-339.

206. Levine J. Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol. 1997;7(2):147-155.

207. Zheng H, Zhang L, Li L, et al. High-frequency rTMS treatment increases left prefrontal myo-inositol in young patients with treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(7):1189-1195.

208. Akhondzadeh S, Fallah-Pour H, Afkham K, Jamshidi AH, Khalighi-Cigaroundi F. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial. BMC Complement Altern Med. 2004:4:12.

209. Akhondzadeh Basti A, Moshiri E, Noorbala AA, Jamshidi AH, Abbasi SH, Akhondzadeh S. Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients: a pilot double-blind randomized trial. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(2):439-442.

210. Akhondzadeh S, Fallah-Pour H, Afkham K, Jamshidi AH, Khalighi-Cigaroudi F. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial [ISRCTN45683816]. BMC Complement Altern Med. 2004;4:12.

211. Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, et al. Crocus sativus L. in the treatment of mild to moderate depression: a double-blind, randomized and placebo-controlled trial. Phytother Res. 2005;19(2):148-151.

212. Moshiri E, Basti AA, Noorbala AA, Jamshidi AH, Hesameddin Abbasi S, Akhondzadeh S. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression: a double-blind, randomized and placebo-controlled trial. Phytomedicine. 2006;13(9-10):607-611.

213. Noorbala AA, Akhondzadeh S, Tahmacebi-Pour N, Jamshidi AH. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: a double-blind, randomized pilot trial. J Ethnopharmacol. 2005;97(2):281-284.

214. Schatzberg AF, Rush AJ, Arnow BA, et al. Chronic depression: medication (nefazodone) or psychotherapy (CBASP) is effective when the other is not. Arch Gen Psychiatry. 2005;62(5):513-520.

215. Thase ME, Friedman ES, Biggs MM, et al. Cognitive therapy versus medication in augmentation and switch strategies as second-step treatments: a STAR*D report. Am J Psychiatry. 2007;164(5):739-752.

216. Taylor DJ, Walters HM, Vittengl JR, Krebaum S, Jarrett RB. Which depressive symptoms remain after response to cognitive therapy of depression and predict relapse and recurrence? J Affect Disord. 2010;123(1-3):181-187.

217. Schulberg HC, Katon W, Simon GE, Rush AJ. Treating major depression in primary care practice: an update of the agency for health care policy and research practice guidelines. Arch Gen Psychiatry. 1998;55(12):1121-1127.

218. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530.

219. Berlim MT, Fleck MP, Turecki G. Current trends in the assessment and somatic treatment of resistant/refractory major depression: an overview. Ann Med. 2008;40(2):149-159.

220. Sharma V, Khan M, Smith A. A closer look at treatment resistant depression: is it due to a bipolar diathesis? J Affect Disord. 2005;84(2-3):251-257.

221. Keller MB. Issues in treatment-resistant depression. J Clin Psychiatry. 2005;66(suppl 8):5-12.

222. Pampallona S, Bollini P, Tibaldi G, Kupelnick B, Munizza C. Patient adherence in the treatment of depression. Br J Psychiatry. 2002;180:104-109.

223. Bollini P, Pampallona S, Kupelnick B, Tibaldi G, Munizza C. Improving compliance in depression: a systematic review of narrative reviews. J Clin Pharm Ther. 2006;31(3):253-260.

224. Lin EH, Von Korff M, Katon W, et al. The role of the primary care physician in patients' adherence to antidepressant therapy.Med Care. 1995;33(1):67-74.

225. Tierney JG Jr. Treatment-resistant depression: managed care considerations. J Manag Care Pharm. 2007;13(6 Suppl a):S2-S7.

226. Vergouwen AC, Bakker A, Katon WJ, Verheij TJ, Koerselman F. Improving adherence to antidepressants: a systematic review of interventions. J Clin Psychiatry. 2003;64(12):1415-1420.

227. O'Reardon JP. Pharmacologic and therapeutic strategies in treatment-resistant depression: introduction and clinical presentations. CNS Spectr. 2009;14(3 Suppl 4):4-6.

228. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996;19(2):179-200.

229. Taylor SM. Electroconvulsive therapy, brain-derived neurotrophic factor, and possible neurorestorative benefit of the clinical application of electroconvulsive therapy. J ECT. 2008;24(2):160-165.

230. Kocsis JH. Recurrent depression: patient characteristics, clinical course, and current recommendations for management.CNS Spectr. 2006;11(12 suppl 15):6-11.

231. Mathew SJ. Treatment-resistant depression: recent developments and future directions. Depress Anxiety. 2008;25(12):989-992.

232. Greden JF. The burden of disease for treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 16):26-31.

233. Thase ME, Rush AJ. When at first you don't succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry. 1997;58(suppl 13):23-29.

234. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Psychiatr Clin North Am. 2003;26(2):457-494.

235. Blier P, Gobbi G, Turcotte JE, et al. Mirtazapine and paroxetine in major depression: a comparison of monotherapy versus their combination from treatment initiation. Eur Neuropsychopharmacol. 2009;19(7):457-465.

236. Watanabe N, Omori IM, Nakagawa A, et al. Safety reporting and adverse-event profile of mirtazapine described in randomized controlled trials in comparison with other classes of antidepressants in the acute-phase treatment of adults with depression: systematic review and meta-analysis. CNS Drugs. 2010;24(1):35-53.

237. Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry. 2010;167(3):281-288.

238. Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Rockville, MD: Agency for Healthcare Research and Quality; 2011.

239. Schwartz TL, Azhar N, Cole K, et al. An open-label study of adjunctive modafinil in patients with sedation related to serotonergic antidepressant therapy. J Clin Psychiatry. 2004;65(9):1223-1227.

240. Ninan PT, Hassman HA, Glass SJ, McManus FC. Adjunctive modafinil at initiation of treatment with a selective serotonin reuptake inhibitor enhances the degree and onset of therapeutic effects in patients with major depressive disorder and fatigue. J Clin Psychiatry. 2004;65(3):414-420.

241. Nelson JC, Mazure CM, Bowers MB Jr, Jatlow PI. A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry. 1991;48(4):303-307.

242. Preskorn SH, Beber JH, Faul JC, Hirschfeld R. Serious adverse effects of combining fluoxetine and tricyclic antidepressants.Am J Psychiatry. 1990;147(4):532.

243. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166(9):980-991.

244. Nemeroff CB. Prevalence and management of treatment-resistant depression. J Clin Psychiatry. 2007;68(suppl 8):17-25.

245. Geddes JR, Carney SM, Davies C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet. 2003;361(9358):653-661.

246. Golden RN, Gaynes BN, Ekstrom RD, et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. Am J Psychiatry. 2005;162(4):656-662.

247. Leppämäki SJ, Partonen TT, Hurme J, Haukka JK, Lönnqvist JK. Randomized trial of the efficacy of bright-light exposure and aerobic exercise on depressive symptoms and serum lipids. J Clin Psychiatry. 2002;63(4):316-321.

248. Jorm AF, Christensen H, Griffiths KM, Rodgers B. Effectiveness of complementary and self-help treatments for depression.Med J Aust. 2002;176(10 suppl):S84-S95.

249. Prasko J, Horacek J, Klaschka J, Kosova J, Ondrackova I, Sipek J. Bright light therapy and/or imipramine for inpatients with recurrent non-seasonal depression. Neuro Endocrinol Lett. 2002;23(2):109-113.

250. Epperson CN, Terman M, Terman JS, et al. Randomized clinical trial of bright-light therapy for antepartum depression: preliminary findings. J Clin Psychiatry. 2004;65(3):421-425.

251. Oren DA, Wisner KL, Spinelli M, et al. An open trial of morning light therapy for treatment of antepartum depression.Am J Psychiatry. 2002;159(4):666-669.

252. Benedetti F, Colombo C, Pontiggia A, Bernasconi A, Florita M, Smeraldi E. Morning light treatment hastens the antidepressant effect of citalopram: a placebo-controlled trial. J Clin Psychiatry. 2003;64(6):648-653.

253. Barbui C, Cipriani A, Patel V, Ayuso-Mateos JL, van Ommeren M. Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis. Br J Psychiatry. 2011;198(1):11-16.

254. Rush AJ, Crismon ML, Toprac MG, et al. Consensus guidelines in the treatment of major depressive disorder. J Clin Psychiatry. 1998;59(suppl 20):73-84.

255. Ressler KJ, Mayberg HS. Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic.Nat Neurosci. 2007;10(9):1116-1124.

256. Giacobbe P, Kennedy SH. Deep brain stimulation for treatment-resistant depression: a psychiatric perspective. Curr Psychiatry Rep. 2006;8(6):437-444.

257. Anderson EL, Reti IM. ECT in pregnancy: a review of the literature from 1941 to 2007. Psychosom Med. 2009;71(2):235-242.

258. Schutter DJLG, van Honk J. A framework for targeting alternative brain regions with repetitive transcranial magnetic stimulation in the treatment of depression. J Psychiatry Neurosci. 2005;30(2):91-97.

259. Nemeroff CB, Mayberg HS, Krahl SE, et al. VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology. 2006;31(7):1345-1355.

260. Nahas Z, Teneback C, Chae JH, et al. Serial vagus nerve stimulation functional MRI in treatment-resistant depression. Neuropsychopharmacology. 2007;32(8):1649-1660.

261. Hatton KW, McLarney JT, Pittman T, Fahy BG. Vagal nerve stimulation: overview and implications for anesthesiologists.Anesth Analg. 2006;103(5):1241-1249.

262. Rush AJ, Siefert SE. Clinical issues in considering vagus nerve stimulation for treatment-resistant depression. Exp Neurol. 2009;219(1):36-43.

263. Rabins P, Appleby BS, Brandt J, et al. Scientific and ethical issues related to deep brain stimulation for disorders of mood, behavior, and thought. Arch Gen Psychiatry. 2009;66(9):931-937.

264. Malone DA Jr, Dougherty DD, Rezai AR, et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry. 2009;65(4):267-275.

265. Appleby BS, Duggan PS, Regenberg A, Rabins PV. Psychiatric and neuropsychiatric adverse events associated with deep brain stimulation: a meta-analysis of ten years' experience. Mov Disord. 2007;22(12):1722-1728.

266. Wassermann EM, Lisanby SH. Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin Neurophysiol. 2001;112(8):1367-1377.

267. Gross M, Nakamura L, Pascual-Leone A, Fregni F. Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and meta-analysis comparing the recent vs. the earlier rTMS studies. Acta Psychiatr Scand. 2007;116(3):165-173.

268. Kennedy SH, Milev R, Giacobbe P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. IV. Neurostimulation therapies. J Affect Disord. 2009;117(suppl 1):S44-S53.

269. Lisanby SH, Husain MM, Rosenquist PB, et al. Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: clinical predictors of outcome in a multisite, randomized controlled clinical trial. Neuropsychopharmacology. 2009;34(2):522-534.

270. Lam RW, Chan P, Wilkins-Ho M, Yatham LN. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and meta-analysis. Can J Psychiatry. 2008;53(9):621-631.

271. Bretlau LG, Lunde M, Lindberg L, Undén M, Dissing S, Bech P. Repetitive transcranial magnetic stimulation (rTMS) in combination with escitalopram in patients with treatment-resistant major depression: a double-blind, randomised, sham-controlled trial. Pharmacopsychiatry. 2008;41(2):41-47.

272. Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995;15(1):49-57.

273. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.

274. Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ. Ketamine for depression: where do we go from here? Biol Psychiatry. 2012;72(7):537-547.

275. Oberlander TF, Warburton W, Misri S, et al. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry. 2006;63(8):898-906.

276. Mian AI. Depression in pregnancy and the postpartum period: balancing adverse effects of untreated illness and treatment risks.J Psychiatr Pract. 2005;11(6):389-396.

277. Wisner KL, Sit DK, Hanusa BH, et al. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Am J Psychiatry. 2009;166(5):557-566.

278. Pearlstein T. Perinatal depression: treatment options and dilemmas. J Psychiatry Neurosci. 2008;33(4):302-318.

279. Nylen KJ, O’Hara MW, Brock R, Moel J, Gorman L, Stuart S. Predictors of the longitudinal course of postpartum depression following interpersonal psychotherapy. J Consult Clin Psychol. 2010;78(5):757-763.

280. O'Hara MW. Postpartum depression: what we know. J Clin Psychol. 2009;65(12):1258-1269.

281. Freeman MP, Davis M, Sinha P, Wisner KL, Hibbeln JR, Gelenberg AJ. Omega-3 fatty acids and supportive psychotherapy for perinatal depression: a randomized placebo-controlled study. J Affect Disord. 2008;110(1-2):142-148.

282. di Scalea TL, Wisner KL. Antidepressant medication use during breastfeeding. Clin Obstet Gynecol. 2009;52(3):483-497.

283. Bérard A, Ramos E, Rey E, Blais L, St-André M, Oraichi D. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol. 2007;80(1):18-27.

284. Thormahlen GM. Paroxetine use during pregnancy: is it safe? Ann Pharmacother. 2006;40(10):1834-1837.

285. Austin MP. To treat or not to treat: maternal depression, SSRI use in pregnancy and adverse neonatal effects. Psychol Med. 2006;36(12):1663-1670.

286. Bar-Oz B, Einarson T, Einarson A, et al. Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin Ther. 2007;29(5):918-926.

287. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354(6):579-587.

288. Ferreira E, Carceller AM, Agogué C, et al. Effects of selective serotonin reuptake inhibitors and venlafaxine during pregnancy in term and preterm neonates. Pediatrics. 2007;119(1):52-59.

289. Sivojelezova A, Shuhaiber S, Sarkissian L, Einarson A, Koren G. Citalopram use in pregnancy: prospective comparative evaluation of pregnancy and fetal outcome. Am J Obstet Gynecol. 2005;193(6):2004-2009.

290. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499-507.

291. Academy of Breastfeeding Medicine Protocol Committee. ABM clinical protocol #18: use of antidepressants in nursing mothers. Breastfeeding Med. 2008;3(1):44-52.

292. Eberhard-Gran M, Eskild A, Opjordsmoen S. Use of psychotropic medications in treating mood disorders during lactation: practical recommendations. CNS Drugs. 2006;20(3):187-198.

293. Weissman AM, Levy BT, Hartz AJ, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry. 2004;161(6):1066-1078.

294. World Health Organization. Suicide Prevention: The Problem. Available at http://www.who.int/mental_health/prevention/suicide/suicideprevent/en. Last accessed June 26, 2014.

295. Xu JQ, Kochanek KD, Murphy SL, Tejada-Vera B. Deaths: final data for 2007. Natl Vital Stat Rep. 2010;58(19):1-135.

296. Hoyert DL, Xu J. Deaths: preliminary data for 2011. Nat Vital Stat Rep. 2012;61(6):1-52.

297. American Association of Suicidology. Fact Sheets: Reliable Information about Suicide. Available at http://www.suicidology.org/resources/facts-statistics-current-research/fact-sheets. Last accessed June 26, 2014.

298. American College Health Association. American College Health Association-National College Health Assessment II: Reference Group Executive Summary Fall 2011. Hanover, MD: American College Health Association; 2012.

299. Stone G. Suicide and Attempted Suicide. New York, NY: Carroll & Graf; 2001.

300. Clark DC, Horton-Deutsch SL. Assessment in absentia: the value of the psychological autopsy method for studying antecedents of suicide and predicting future suicides. In: Maris RW, Berman AL, Maltsberger JT, Yufit RI (eds). Assessment and Prediction of Suicide. New York, NY: Guilford Press; 1992: 144-182.

301. Hawton K, Saunders KE, O’Connor RC. Self-harm and suicide in adolescents. Lancet. 2012;379(9834):2373-2382.

302. Bebbington PE, Minot S, Cooper C, et al. Suicidal ideation, self-harm and attempted suicide: results from the British psychiatric morbidity survey 2000. Eur Psychiatry. 2010;25(7):427-431.

303. Schmidtke A, Schaller S. The role of mass media in suicide prevention. In: Hawton K, van Heeringen K (eds). The International Handbook of Suicideand Attempted Suicide. New York, NY: Wiley; 2000: 675-697.

304. Velting DM, Gould MS. Suicide contagion. In: Maris RW, Silverman MM, Canetto SS (eds). Review of Suicidology. New York, NY: Guilford Press; 2000: 96-136.

305. Zenere EFJ. Suicide clusters and contagion. Principal Leadership. 2009;10(2):12-16.

306. Pirkis J. Suicide and the media. Psychiatry. 2009;8(7):269-271.

307. Garnefski N, Diekstra RFW. Suicidal behaviour and the co-occurrence of behavioural, emotional and cognitive problems among adolescents. Arch Suicide Res. 1995;1(4):243-260.

308. Halvorsen JA, Stern RS, Dalgard F, Thoresen M, Bjertness E, Lien L. Suicidal ideation, mental health problems, and social impairment are increased in adolescents with acne: a population-based study. J Invest Dermatol. 2011;131(2):363-370.

309. Sundararaman R, Panangala SV, Lister SA. CSR Report for Congress: Suicide Prevention Among Veterans. Washington, DC: Congressional Research Service; 2008.

310. Vsevolod R, Vladimir C. Suicide among war veterans. Int J Environ Res Public Health. 2012;9(7):2504-2519.

311. Selby EA, Anestis MD, Bender TW, et al. Overcoming the fear of lethal injury: evaluating suicidal behavior in the military through the lens of the Interpersonal-Psychological Theory of Suicide. Clin Psychol Rev. 2010; 30(3):298-307.

312. Boscarino J.A. Posttraumatic stress disorder and mortality among US Army veterans 30 years after military service. Ann Epidemiol. 2006;16:248-256.

313. Sundararman R, Panangala SV, Loster SA. CRS Report for Congress: Suicide Prevention Among Veterans. Available at http://assets.opencrs.com/rpts/RL34471_20080505.pdf. Last accessed June 26, 2014.

314. Department of Veterans Affairs Office of Inspector General. Healthcare Inspection. Evaluation of Suicide Prevention Program Implementation in Veterans Health Administration Facilities January–June, 2009. Washington, DC: VA Office of Inspector General; 2009.

315. Cogan J. US Military Suicide Rates at Record High. Available at http://www.wsws.org/articles/2009/feb2009/suic-f04.shtml. Last accessed June 26, 2014.

316. Airbus Defense and Space. U.S. Army Suicides Reach Record High. Available at http://www.defenceweb.co.za/index.php?option=com_content&view=article&id=18078:us-army-suicides-reach-record-high&catid=50:Land&Itemid=105. Last accessed June 26, 2014.

317. Sher L. Suicide in war veterans: the role of comorbidity of PTSD and depression. Expert Rev. Neurother. 2009;9:921-923.

318. McFarland B.H., Kaplan M.S., Huguet N. Datapoints: self-inflicted deaths among women with U.S. military service: a hidden epidemic? Psychiatr Serv. 2010;61(12):1177.

319. Haas AP, Eliason M, Mays VM, et al. Suicide and suicide risk in lesbian, gay, bisexual, and transgender populations: review and recommendations. J Homosex. 2011;58(1):10-51.

320. Hatzenbuehler ML. The social environment and suicide attempts in lesbian, gay, and bisexual youth. Pediatrics. 2011;127(5):896-903.

321. Haas AP, Eliason M, Mays VM, et al. Suicide and suicide risk in lesbian, gay, bisexual, and transgender populations: review and recommendations. J Homosex. 2011;58(1):10-51.

322. Eisenberg ME, Resnick MD. Suicidality among gay, lesbian and bisexual youth: the role of protective factors. J Adolesc Health. 2006;39(5):662-668.

323. Mustanski B, Liu RT. A longitudinal study of predictors of suicide attempts among lesbian, gay, bisexual, and transgender youth. Arch Sex Behav. 2013;42(3):437-448.

324. Massachusetts Department of Education. Child Nutrition Programs: 2005 Massachusetts Youth Risk Behavior Survey Results. Available at http://www.doe.mass.edu/cnp/hprograms/yrbs/05/default.html. Last accessed June 26, 2014.

325. Marshal MP, Dietz LJ, Friedman MS, et al. Suicidality and depression disparities between sexual minority and heterosexual youth: a meta-analytic review. J Adolesc Health. 2011;49(2):115-123.

326. Bolton SL, Sareen J. Sexual orientation and its relation to mental disorders and suicide attempts: findings from a nationally representative sample. Can J Psychiatry. 2011;56(1):35-43.

327. Russell ST, Joyner K. Adolescent sexual orientation and suicide risk: evidence from a national study. Am J Public Health. 2001;91(8):1276-1281.

328. Kenagy GP. Transgender health: findings from two needs assessment studies in Philadelphia. Health Soc Work. 2005;30(1):19-26.

329. Remafedi G. Suicidality in a venue-based sample of young men who have sex with men. J Adolesc Health. 2002;31(4):305-310.

330. Paul JP, Catania J, Pollack L, et al. Suicide attempts among gay and bisexual men: lifetime prevalence and antecedents. Am J Public Health. 2002;92(8):1338-1345.

331. Meyer I. H., Dietrich J., Schwartz S. Lifetime prevalence of mental disorders and suicide attempts in diverse lesbian, gay, and bisexual populations. Res Pract. 2007;97(11):9-11.

332. Eisenberg ME. Suicidality among gay, lesbian and bisexual youth: the role of protective factors. J Adolesc Health. 2006;39(5):662-668.

333. World Health Organization. Preventing Suicide: A Resource for General Physicians. Available at http://www.who.int/mental_health/media/en/56.pdf. Last accessed June 4, 2014.

334. World Health Organization. Preventing Suicide: A Resource for Primary Health Care Workers. Geneva: World Health Organization Department of Mental Health; 2000.

335. Durkheim E. Suicide: A Study in Sociology. New York, NY: Free Press; 1951.

336. American Psychiatric Association. Practice Guideline for the Assessment and Treatment of Patients with Suicidal Behaviors. Washington, DC: American Psychiatric Association; 2003.

337. Isacsson G. Suicide prevention: a medical breakthrough? Acta Psychiatrica Scandinavica. 2000;102(2):113-117.

338. Office of Applied Studies. The OAS Report: Suicidal Thoughts, Suicide Attempts, Major Depressive Episode and Substance Use Among Adults. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2006.

339. Depression and Bipolar Support Alliance. Bipolar Disorder Statistics. Available at http://www.dbsalliance.org/site/PageServer?pagename=education_statistics_bipolar_disorder. Last accessed June 26, 2014.

340. Goldsmith SK, Pellmar TC, Kleinman AM, Bunney WE (eds). Reducing Suicide: A National Imperative. Washington, DC: National Academy Press; 2002.

341. Substance Abuse and Mental Health Services Administration. Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2013.

342. Favazza A. Self-mutilation. In: Jacobs DG (ed). The Harvard Medical School Guide to Suicide Assessment and Intervention. San Francisco, CA: Jossey-Bass; 1999: 125-145.

343. Evans J, Platts H, Liebenau A. Impulsiveness and deliberate self-harm: a comparison of "first-timers" and "repeaters." Acta Psychiatr Scand. 1996;93(5):378-380.

344. Stanford S, Jones MP. Psychological subtyping finds pathological, impulsive, and “normal” groups among adolescents who self-harm. J Child Psychol Psychiatry. 2009;50(7):807-815.

345. World Health Organization. Preventing Suicide in Jails and Prisons. Available at http://www.who.int/mental_health/prevention/suicide/resource_jails_prisons.pdf. Last accessed June 26, 2014.

346. Tremblay CH, Grosskopf S, Yang K. Brainstorm: occupational choice, bipolar illness and creativity. Econ Human Biol. 2010;8(2):233-241.

347. Liu A, Werner K, Roy S, et al. A case study of an emerging visual artist with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurocase. 2009;15(3):235-247.

348. Gillett, G. The unwitting sacrifice problem. J Med Ethics. 2005;31(6):327-332.

349. Figueroa CG. Virginia Woolf as an example of a mental disorder and artistic creativity [article in Spanish]. Rev Med Chil. 2005;133(11):1381-1388.

350. Annenberg Public Policy Center. Holiday-Suicide Link: The Myth Persists. Available at http://www.annenbergpublicpolicycenter.org/holiday-suicide-link-the-myth-persists. Last accessed June 26, 2014.

351. Centers for Disease Control and Prevention. Injury Prevention and Control: Data and Statistics. Available at http://www.cdc.gov/injury/wisqars/index.html. Last accessed June 26, 2014.

352. Association of Suicidology. Know the Warning Signs of Suicide. Available at http://www.suicidology.org/resources/mutlimedia-resources/suicide-warning-signs. Last accessed June 20, 2014.

353. National Center for Injury Prevention and Control. Suicide: Facts at a Glance. Available at http://www.cdc.gov/violenceprevention/pdf/Suicide-DataSheet-a.pdf. Last accessed June 26, 2014.

354. Wasserman D, Wasserman C. Oxford Textbook of Suicidology and Suicide Prevention: A Global Perspective. Oxford: Oxford Universoty Press; 2009.

355. Suicide Prevention Resource Center and SPAN USA. Charting the Future of Suicide Prevention: A 2010 Progress Review of the National Strategy and Recommendations for the Decade Ahead. Washington, DC: Education Development Center, Inc.; 2010.

356. Brent DA, Johnson BA, Perper J, et al. Personality disorder, personality traits, impulsive violence, and completed suicide in adolescents. J Am Acad Child Adolesc Psychiatry. 1994;33(8):1080-1086.

357. Hunt J, Eisenberg D. Mental health problems and help-seeking behavior among college students. J Adolesc Health. 2010;46(1):3-10.

358. Pompili M, Lester D, Innamorati M, et al. Preventing suicide in jails and prisons: suggestions from experience with psychiatric inpatients. J Forensic Sci. 2009;54(5):1155-1162.

359. Najt P, Fusar-Poli P, Brambilla P. Co-occurring mental and substance abuse disorders: a review on the potential predictors and clinical outcomes. Psychiatry Res. 2011;186(2-3):159-164.

360. Murphy GE. Suicide in Alcoholism. New York, NY: Oxford University Press; 1992.

361. Kleespies PM (ed). Emergencies in Mental Health Practice: Evaluation and Management. New York, NY: Guilford Press; 2000.

362. U.S. Preventive Services Task Force. Screening for Suicide Risk in Primary Care: A Systematic Evidence Review for the U.S. Preventive Services Task Force: Evidence Syntheses, No. 103. Rockville, MD: Agency for Healthcare Research and Quality; 2013.

363. Canadian Task Force on Preventive Health Care. Recommendations on screening for depression in adults. CMAJ. 2013;185(9):775-782.

364. Shain BN, Committee on Adolescents. Suicide and suicide attempts in adolescents. Pediatrics. 2007;120(3):669-676.

365. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescents with suicidal behavior. J Am Acad Child Adolesc Psychiatry. 2001;40(7 suppl):24S-51S.

366. American Medical Association. Guidelines for Adolescent Preventive Services (GAPS): Recommendations Monograph. Chicago, IL: American Medical Association; 1997.

367. Curtin SC, Warner M, Hedegaard H. Increase in suicide in the United States, 1999–2014. NCHS Data Brief. 2016;241:1-7.

Evidence-Based Practice Recommendations Citations

1. Mitchell J, Trangle M, Degnan B, et al. Adult Depression in Primary Care. Bloomington, MN: Institute for Clinical Systems Improvement; 2013. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=47315. Last accessed July 9, 2014.

2. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Arlington, VA: American Psychiatric Association; 2010. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=24158. Last accessed July 9, 2014.

3. Scottish Intercollegiate Guidelines Network. Non-Pharmaceutical Management of Depression in Adults: A National Clinical Guideline. Edinburgh: Scottish Intercollegiate Guidelines Network; 2010. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=15596. Last accessed July 9, 2014.

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