NetCE 4 Hour Course #95420 • Antipsychotic Medications: Principles of Safe and Effective Use
Author: Gina Corley, PharmD; www.netce.com
Date: 2026-10-01
Keywords: Pharmacology
Description: Antipsychotic medications are essential to the treatment of schizophrenia, bipolar disorder, and other conditions associated with psychosis, but their safe use requires careful medication selection, monitoring, and patient counseling. This course compares first- and second-generation antipsychotics, reviews their mechanisms, indications, adverse effects, and clinically important drug interactions, and examines strategies for improving adherence. Participants will also explore metabolic, cardiovascular, hematologic, and movement-disorder monitoring; risk-mitigation approaches; off-label use; an
Publisher: NetCE
Rights: Copyright © 2026 NetCE, All rights reserved.

95420 • Antipsychotic Medications: Principles of Safe and Effective Use

Table of Contents

95420 • Antipsychotic Medications: Principles of Safe and Effective Use

How to Receive Credit
Course Overview
Audience
Accreditations & Approvals
Designations of Credit
Individual State Nursing Approvals
Special Approvals
Course Objective
Learning Objectives
Faculty
Faculty Disclosure
Division Planners
Division Planners Disclosure
Director of Development and Academic Affairs
Director Disclosure Statement
About the Sponsor
Disclosure Statement
Implicit Bias in Health Care

1. INTRODUCTION

2. MEDICAL CONDITIONS REQUIRING ANTIPSYCHOTIC THERAPY

SCHIZOPHRENIA

BIPOLAR DISORDER

3. FIRST-GENERATION ANTIPSYCHOTICS
4. SECOND-GENERATION ANTIPSYCHOTICS
5. ADHERENCE
6. ADVERSE EFFECTS

AKATHISIA
ANTICHOLINERGIC EFFECTS
DYSTONIA

CARDIOVASCULAR EFFECTS AND ELECTROCARDIOGRAM (ECG) CHANGES

HYPERPROLACTINEMIA
LIPID ABNORMALITIES
NEUROLEPTIC MALIGNANT SYNDROME
PSEUDOPARKINSONISM
SEDATION
SEIZURES
SUDDEN CARDIAC DEATH
TARDIVE DYSKINESIA
WEIGHT GAIN
CLOZAPINE: NEUTROPENIA AND AGRANULOCYTOSIS

7. DRUG INTERACTIONS
8. ANTIPSYCHOTIC SELECTION
9. MONITORING

CARDIAC MONITORING
METABOLIC MONITORING
MOVEMENT DISORDERS

10. RISK MITIGATION STRATEGIES

11. OFF-LABEL ANTIPSYCHOTIC USE

ANXIETY
DEMENTIA
DEPRESSION
EATING DISORDERS
INSOMNIA
OBSESSIVE-COMPULSIVE DISORDER (OCD)
POST-TRAUMATIC STRESS DISORDER (PTSD)
SUBSTANCE USE DISORDER

12. USE OF LONG-ACTING ANTIPSYCHOTICS
13. CASE STUDY
14. CONCLUSION
Works Cited

Evidence-Based Practice Recommendations Citations

95420 • Antipsychotic Medications: Principles of Safe and Effective Use

Gina Corley, PharmD

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

Antipsychotic medications are essential to the treatment of schizophrenia, bipolar disorder, and other conditions associated with psychosis, but their safe use requires careful medication selection, monitoring, and patient counseling. This course compares first- and second-generation antipsychotics, reviews their mechanisms, indications, adverse effects, and clinically important drug interactions, and examines strategies for improving adherence. Participants will also explore metabolic, cardiovascular, hematologic, and movement-disorder monitoring; risk-mitigation approaches; off-label use; and the advantages and limitations of long-acting injectable formulations. Clinical examples demonstrate how patient preferences, comorbidities, treatment response, and tolerability can guide individualized antipsychotic therapy.

95420 • Antipsychotic Medications: Principles of Safe and Effective Use

Education Category. Pharmacology

Release Date. 10/01/2026

Expiration Date. 09/30/2029

How to Receive Credit

To complete this course for continuing education credit please go to http://www.netce.com/course/3690 in your browser.

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

Course Overview

Antipsychotic medications are essential to the treatment of schizophrenia, bipolar disorder, and other conditions associated with psychosis, but their safe use requires careful medication selection, monitoring, and patient counseling. This course compares first- and second-generation antipsychotics, reviews their mechanisms, indications, adverse effects, and clinically important drug interactions, and examines strategies for improving adherence. Participants will also explore metabolic, cardiovascular, hematologic, and movement-disorder monitoring; risk-mitigation approaches; off-label use; and the advantages and limitations of long-acting injectable formulations. Clinical examples demonstrate how patient preferences, comorbidities, treatment response, and tolerability can guide individualized antipsychotic therapy.

Audience

This course is designed for physicians, physician assistants, and nurses involved in the care of patients who are prescribed antipsychotics.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 4 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 4 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 4 ANCC contact hour(s). NetCE designates this continuing education activity for 4 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 4.8 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 4 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 4 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This activity has been designated for 4 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 0.4 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 30, 2029); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2027; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide healthcare professionals with practical knowledge for selecting, monitoring, and managing antipsychotic medications safely and effectively, resulting in improved patient care and outcomes.

Learning Objectives

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

1. Discuss conditions that commonly require antipsychotic therapy.

2. Identify key differences between first- and second-generation antipsychotics, including their efficacy profiles.

3. Identify key approaches to assess and improve patient adherence to antipsychotic therapy.

4. Describe the adverse effects of antipsychotics.

5. Explain common drug interactions with antipsychotics.

6. Outline appropriate drug selection and monitoring of antipsychotic therapy.

7. Discuss long-acting injectable antipsychotics.

Faculty

Gina Corley, PharmD, is an Assistant Editor at TRC Healthcare. She earned her Doctor of Pharmacy degree from West Virginia University in 2013. Before joining TRC in 2024, Gina worked as an inpatient operations floater pharmacist at WVU Medicine’s J.W. Ruby Memorial Hospital, gaining experience in central pharmacy operations, IV room/sterile products, peri-op/OR, psychiatry, and the cancer center. She also spent 6 years as a retail pharmacist at CVS Health, including two years as a pharmacy manager. Gina’s professional interests include women’s health, mentoring residents, and fostering professional networking relationships with other providers.

Faculty Disclosure

Contributing faculty, Gina Corley, PharmD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Mary Franks, MSN, APRN, FNP-C

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

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

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

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.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Antipsychotics have historically been classified as first generation, or "typical," and second generation, or "atypical." Chlorpromazine, a first-generation phenothiazine antipsychotic, was the first drug to introduce the psychopharmacological era and replace other practices such as electroconvulsive therapy and frontal lobotomy [1]. Discovery of the psychiatric effects of the phenothiazines was accidental but led to the development of the first-generation antipsychotic medications as early as the 1940s and 1950s [1]. The second-generation antipsychotics became a growing class of medications in the 1990s. Antipsychotics are most commonly used to treat mental health conditions associated with psychosis, a term used to describe a loss of contact with reality which often includes delusions (false fixed beliefs) or hallucinations (seeing or hearing things that are not there) [2]. Mental health conditions associated with psychosis can include schizophrenia or bipolar disorder [2]. You may also see antipsychotics used in combination with other medications to treat conditions such as severe depression or behavioral or psychological symptoms of dementia [3].

2. MEDICAL CONDITIONS REQUIRING ANTIPSYCHOTIC THERAPY

SCHIZOPHRENIA

Schizophrenia is a disabling, chronic, and severe mental health disorder, affecting around 1% of the population in the United States or Canada [4,5]. Schizophrenia has three main categories of symptoms: positive, negative, and cognitive.

Positive symptoms may include [6,7]:

- Delusions
- Disorganized speech and behavior
- Hallucinations
- Suspiciousness
- Thought disorders

Evidence Based Practice Recommendation

The American Psychiatric Association recommends that patients with schizophrenia be treated with an antipsychotic medication and monitored for effectiveness and side effects. This guideline statement should be implemented in the context of a person-centered treatment plan that includes evidence-based nonpharmacological and pharmacological treatments for schizophrenia.

https://psychiatryonline.org/doi/full/10.1176/appi.books.9780890424841.Schizophrenia02

Last Accessed: September 18, 2026

Strength of Recommendation/Level of Evidence: IA (High confidence that the evidence reflects the true effect)

Negative symptoms may include [6,7]:

- Difficulty beginning or maintaining activities

- Flat or blunted affect (e.g., reduced emotion)

- Reduced pleasure from everyday activities

- Social withdrawal

Cognitive symptoms may include [6,7]:

- Difficulty focusing or an inability to pay attention

- Difficulty with memory (e.g., unable to use information after learning)

- Impaired executive functioning (e.g., ability to make decisions)

- Impaired verbal fluency

Antipsychotics remain first-line medication therapy for schizophrenia. Medications are more effective at alleviating positive symptoms (e.g., delusions, hallucinations) compared with negative symptoms or cognitive symptoms [8,9,10]. Drug selection is based on symptoms, patient comorbidities, and adverse effect profiles [10].

BIPOLAR DISORDER

Bipolar disorder is a mental health disorder characterized by large shifts in mood, energy, activity levels, and the ability to complete everyday tasks, affecting about 1% to 2.8% of U.S. or Canadian populations [5,11,12]. Symptoms of bipolar disorder fall into two main categories: mania and depression [11,13].

Symptoms of mania may include [11,13]:

- Abnormally upbeat, "jumpy," "wired"
- Agitation or irritability
- Decreased need for or trouble sleeping
- Exaggerated sense of well-being
- Increased energy levels

- Poor decision making (e.g., spending sprees, sexual risk-taking)

- Racing thoughts

- Unusually talkative

Symptoms of depression may include [11,13]:

- Appetite changes (e.g., eat too much or not enough)

- Depressed mood (e.g., sad, empty, hopeless)
- Fatigue
- Inability to think or concentrate
- Loss of interest in activities

- Sleep disturbances (e.g., sleeping too much, sleeping too little)

- Suicidal thoughts

- Weight gain or weight loss

Bipolar I disorder typically involves primarily manic episodes that either last at least seven days or require hospitalization [11]. Some patients with bipolar I disorder also experience depressive episodes, lasting at least two weeks [11]. Bipolar II disorder typically involves more depressive episodes with some hypomania, but not true manic episodes [11]. In addition, there are other categories including cyclothymic disorder (where patients have multiple episodes of hypomania and depressive symptoms over at least two years) and other specified or unspecified bipolar disorders that do not fit into the previously defined categories [11].

Antipsychotics are recommended as one of the first-line medication options in the management of bipolar disorder [14]. Second-generation antipsychotics are preferred and much more commonly used for bipolar disorder due to their adverse effect profile compared to first-generation antipsychotics [15,16].

3. FIRST-GENERATION ANTIPSYCHOTICS

First-generation antipsychotics are dopamine-2 receptor antagonists. They decrease dopaminergic transmission in several areas within the brain, including the mesocortical, mesolimbic, nigrostriatal, and tuberoinfundibular pathways [17]. These agents are generally approved for the treatment of schizophrenia but may have additional approved uses for other conditions as well (Table 1).

Table 1: FIRST-GENERATION ANTIPSYCHOTIC LABELED INDICATIONS

Medication | Schizophrenia | Other FDA-Approved Mental Health-Related Indications

Chlorpromazine

Yes

Acute psychosis

ADHD in pediatric patients who show excessive motor activity along with conduct disorders

Severe behavioral problems (e.g., combativeness, aggression) associated with oppositional defiant disorder or other disruptive behavioral disorders

Fluphenazine | Yes | Acute agitation associated with psychotic disorders

Haloperidol

Yes

Acute agitation associated with psychotic disorders

ADHD in pediatric patients who show excessive motor activity along with conduct disorders

Severe behavioral problems (e.g., combativeness, aggression) associated with oppositional defiant disorder or other disruptive behavioral disorders

Loxapine | Yes | Acute agitation associated with schizophrenia or bipolar I disorder
Molindone | Yes | None

Perphenazine

Yes

None (but does have FDA approval for nausea/vomiting [chlorpromazine and prochlorperazine also have a nausea/vomiting indication])

Pimozide | No | None (but does have FDA approval for Tourette syndrome)
Prochlorperazine | Yes | Anxiety
Thioridazine | Yesa | None
Thiothixene | Yes | None
Trifluoperazine | Yes | Generalized anxiety disorder
aUsually reserved for patients that fail other antipsychotics, due to risk of arrhythmias

Source: [3]

Blocking dopamine-2 receptors is responsible for the following within each of these areas [17]:

- Mesocortical: Secondary negative symptoms and cognitive effects

- Mesolimbic: Possible antipsychotic mechanism of action in schizophrenia

- Nigrostriatal: Increased risk of extrapyramidal side effects (e.g., akathisia, dystonic reactions, rigidity, tremor)

- Tuberoinfundibular: Increased prolactin levels

Dopamine-2 antagonism is believed to be the mechanism for the relief of acute mania when used to treat bipolar disorder [18].

As a general rule with first-generation antipsychotics, lower potency agents are dosed in 100s of milligrams while higher potency agents are dosed in 1 to 10s of milligrams (Table 2). Low-potency antipsychotics are typically associated with higher rates of sedation and anticholinergic effects. High-potency antipsychotics are typically associated with higher rates of extrapyramidal side effects [17].

Table 2: EXAMPLES OF FIRST-GENERATION ANTIPSYCHOTIC POTENCY AND DOSING

Drug | Potency | Typical Daily Maintenance Dose
Chlorpromazine | Low | 200–600 mg
Thioridazine | Low | 200–800 mg
Loxapine (oral) | Medium | 60–100 mg
Perphenazine | Medium | 16–32 mg
Thiothixene | Medium | 20–30 mg
Fluphenazine | High | 1–5 mg
Haloperidol | High | 1–30 mg
Pimozide | High | 2–4 mg
Trifluoperazine | High | 15–20 mg

Source: [19,20]

4. SECOND-GENERATION ANTIPSYCHOTICS

Second-generation antipsychotics are dopamine-2 and serotonin-2 (5HT-2) receptor antagonists. The antagonism of serotonin receptors increases the release of endogenous dopamine [21]. This increase in dopamine is the reason second-generation antipsychotics are less likely to cause extrapyramidal side effects and increased prolactin levels without compromising the beneficial effects against positive symptoms of psychosis [7]. They still maintain dopamine-2 receptor antagonism to combat mania [18]. In addition, the blocking of serotonin receptors is responsible for their antidepressant activity, and relief of depressed mood in patients with bipolar disorder (Table 3).

Table 3: SECOND-GENERATION ANTIPSYCHOTIC FDA-LABELED USES

Medication | Bipolar Disorder | Schizophrenia | Other FDA-Approved Mental Health-Related Indications
Aripiprazole (Abilify, Abilify Maintena, Abilify MyCite, Abilify Asimtufii, Aristada, Aristada Initio, Opipza, generics) | Yesa,b,c,h | Yesh | Major depression (adjunct)
Asenapine (Saphris, Secuado) | Yesa,b,c | Yes | None
Brexpiprazole (Rexulti) | No | Yes | Major depression (adjunct)
Cariprazine (Vraylar) | Yesa,e | Yes | None

Clozapine (Clozaril, Fazaclo, Versacloz, generics)

No (but may be used off-label)

Yesd

Reduce suicide risk in schizophrenia or schizoaffective disorder (mental health illness marked by a combination of schizophrenia symptoms [hallucinations or delusions], and mood disorder symptoms [depression or mania])

Iloperidone (Fanapt) | No | Yes | None
Lumateperone (Caplyta) | Yes | Yes | None
Lurasidone (Latuda, generics) | Yesb,c,e | Yes | None
Milsaperidone(Bysanti) | Yesa | Yes | None
Olanzapine (Zyprexa, Zyprexa Relprevv, Zyprexa Zydis, generics) | Yesa,b,c,h | Yesh | Treatment-resistant depression or bipolar depression (in combination with fluoxetine)
Paliperidone (Erzofri, Invega, Invega Hafyerai, Invega Sustenna, Invega Trinzaf, generics) | No (but is sometimes used off-labelg) | Yes | Schizoaffective disorder

Pimavanserin (Nuplazid)

No

No

Parkinson disease psychosis (for treatment of hallucinations and delusions)

Note – only available as Nuplazid

Quetiapine (Seroquel, Seroquel XR, generics) | Yesa,b,c,e,g | Yes | Major depression (adjunct)
Risperidone (Risperdal, Risperdal Consta, Perseris, Uzedy, generics) | Yesa,b,c | Yes | None
Ziprasidone (Geodon, generics) | Yesa,b,c | Yesh | None

aAcute treatment of manic and mixed episodes associated with bipolar I disorder
bAdjunct treatment to lithium or valproate
cMonotherapy
dTreatment resistant
eDepressive episodes with bipolar I disorder
fIndicated after four or more months of adequate treatment with Invega Sustenna
gManic episodes
hAgitation associated with schizophrenia or bipolar mania
iIndicated after four or more months of adequate treatment with Invega Sustenna OR adequate treatment with Invega Trinza for at least one three-month cycle

Source: [3,22]

Of note, some antipsychotics in this list (aripiprazole, brexpiprazole, cariprazine, iloperidone, lumateperone, lurasidone, and pimavanserin) are classified in some references as third-generation antipsychotics. Unlike first- and second-generation agents, which primarily act as dopamine D2 receptor antagonists (with or without serotonin antagonism), third-generation antipsychotics are distinguished by their dopamine D2/D3 receptor partial agonism (along with some serotonin receptor activity). This mechanism allows them to act as dopamine system stabilizers. Despite these differences, it is important to note that this nomenclature is not often widely used in clinical practice. Many clinical guidelines and regulatory bodies continue to classify these agents as second-generation antipsychotics, and the terminology remains a subject of ongoing debate in the literature [23,24].

Additionally, another medication, xanomeline/trospium chloride (Cobenfy), is the first in a new class of drugs approved to treat schizophrenia in decades. Given its novel mechanism of action, it has been described in some publications as the "first fourth-generation antipsychotic." This drug is an oral agonist/antagonist combo that works by selectively activating muscarinic M1 and M4 cholinergic receptors in the CNS. The starting dose is 50 mg/20 mg twice daily for two days, then titrate to 100 mg/20 mg twice daily for at least five days. Doses can be increased to a max of 125 mg/30 mg twice daily, depending on tolerability and response. Patients should take xanomeline/trospium one hour before or two hours after meals to lessen GI side effects [25,26].

5. ADHERENCE

Adherence to antipsychotic therapy is a critical determinant of treatment effectiveness and should be assessed routinely throughout treatment. Nonadherence may be partial or complete and can include missed doses, irregular medication use, premature discontinuation, or inconsistent follow-up. Poor adherence is associated with an increased risk of symptom recurrence or relapse, psychiatric hospitalization, emergency care utilization, and functional decline. Prescribers should avoid assuming that recurrent symptoms represent medication failure without first assessing whether the medication has been taken as prescribed.

Adherence is influenced by multiple patient-, treatment-, and system-related factors. Common barriers include adverse effects, lack of perceived benefit or limited insight into illness, concerns about long-term medication use, complex dosing schedules, cognitive impairment, substance use, cost, inadequate access to medications or follow-up care, and stigma. Adverse effects are particularly important contributors to intentional nonadherence and may include extrapyramidal symptoms, sedation, weight gain and other metabolic effects, sexual dysfunction, hyperprolactinemia, and anticholinergic effects. The likelihood and severity of adverse effects should be discussed proactively, and patients should be encouraged to report concerns rather than independently reducing the dose or discontinuing treatment.

A collaborative, patient-centered approach can support adherence. Prescribers should use shared decision-making when selecting an antipsychotic, taking into account the patient's treatment goals, prior treatment experience, preferences regarding route and frequency of administration, anticipated adverse effects, comorbidities, lifestyle, and practical considerations. Providing clear education about the expected benefits of treatment, the anticipated time course of response, potential adverse effects, and the risks associated with abrupt discontinuation can help establish realistic expectations. When possible, simplifying the treatment regimen and minimizing unnecessary polypharmacy may also reduce the burden of treatment.

Adherence should be assessed in a nonjudgmental manner. Open-ended questions, such as "Many people find it difficult to take medication every day. How has it been for you?", may facilitate a more accurate discussion of medication use than simply asking whether the patient is taking the medication as prescribed. Pharmacy refill history, collateral information, and other objective measures may provide additional information when appropriate, but should supplement rather than replace direct discussion with the patient.

For patients with recurrent or persistent difficulty adhering to oral therapy, a long-acting injectable antipsychotic may be an appropriate option. Long-acting injectables can reduce the need for daily medication administration and allow clinicians to more readily identify missed doses. Selection of a long-acting injectable should nevertheless involve shared decision-making and consideration of the patient's prior response to and tolerability of the corresponding medication, dosing interval, need for oral supplementation or overlap, administration requirements, access, and patient preference. Long-acting injectables should not be viewed solely as an intervention for patients perceived as "noncompliant;" they may be considered whenever a patient prefers an injectable formulation or when the characteristics of a long-acting injectable are consistent with the individual's treatment needs and goals.

Use multiple strategies with your patients to help improve adherence. Technology (e.g., smartphone apps) may be helpful. Medisafe, Dosecast, and Everydose are popular reminder apps available for iPhone and Android [27]. New product formulations are also being developed to try to help with adherence. For example, Abilify MyCite is an aripiprazole formulation with a sensor built into each tablet. Once swallowed, the tablet sends a signal to a patch worn by the patient, which then connects to an app on their smartphone.

Finally, adherence should be understood as a dynamic process rather than a fixed patient characteristic. Changes in symptoms, adverse effects, life circumstances, financial or insurance status, housing stability, substance use, and therapeutic alliance may affect medication use over time. Regular reassessment of adherence and its barriers, combined with timely efforts to address modifiable factors, can help prescribers individualize treatment and reduce the risk of avoidable relapse.

6. ADVERSE EFFECTS

In general, typical (i.e., first-generation) antipsychotics are associated with adverse effects mostly involving movement disorders. These include extrapyramidal side effects, such as akathisia (inner restlessness or need to be in constant motion), dystonic reactions (involuntary contractions of muscles that may lead to abnormal movements or postures), rigidity, or tremors [19]. Atypical, or second-generation antipsychotics, are more commonly associated with endocrine or metabolic adverse reactions, including increasing lipid and glucose levels, along with weight gain. However, many side effects can be seen with both generations of antipsychotics (e.g., sedation, sexual dysfunction, orthostatic hypotension) [19].

AKATHISIA

Akathisia is a commonly occurring adverse effect associated with the first-generation antipsychotics. Patients will generally complain about an inability to sit still or restlessness such as shuffling, pacing, and foot tapping. Beta-blockers (e.g., propranolol) or benzodiazepines (e.g. lorazepam) may be effective in managing akathisia [20,28]. Dosage reductions are often used, but this must be balanced with the need for an effective dose to control symptoms. Though akathisia can also occur with the second-generation antipsychotics, it is less common. Recommend switching to a second-generation agent if dosage reductions are not appropriate based on the patient's symptoms. Though, keep in mind that of the second-generation antipsychotics, aripiprazole, lurasidone, and risperidone have the highest rates of akathisia, making medications such as iloperidone, quetiapine, and clozapine better choices [20,29].

ANTICHOLINERGIC EFFECTS

Anticholinergics effects (e.g., dry mouth, constipation, tachycardia, blurred vision, urinary retention) can be troubling with some of the antipsychotics. They are more common with the low-potency, first-generation anticholinergics (e.g., chlorpromazine, thioridazine). They can also be seen with some of the second-generation antipsychotics, especially clozapine and olanzapine. Anticholinergic effects can lead to additional problems, such as tooth decay, falls, or gastrointestinal obstruction [20].

DYSTONIA

Dystonia is a prolonged muscle contraction that occurs most commonly with the first-generation antipsychotics, especially high-potency medications or high doses. Dystonic reactions usually occur within just a few days of starting an antipsychotic or increasing the dose. Typical dystonias may present as torticollis (in the neck), protrusion of the tongue, or an oculogyric crisis (eyes rolling to the back of the head). Unless symptoms are very mild, these reactions should be taken seriously, especially with pharyngeal or laryngeal involvement [20,28].

Risk factors for dystonic reactions include [20,30]:

- First-generation antipsychotics, especially high-potency medications or high doses

- Male gender

- Young age

Severe symptoms are most often treated using intramuscular (IM) or intravenous (IV) anticholinergic medications (e.g., benztropine 2 mg or diphenhydramine 50 mg) [20]. Prophylactic use of anticholinergics or benzodiazepines is not routinely done in order to prevent dystonic reactions [19]. However, it can be considered for select patients. For example, it would not be unreasonable to use prophylactic oral doses of benztropine or diphenhydramine for a young male with a history of dystonic reactions that otherwise responds well to a first-generation antipsychotic (e.g., haloperidol, fluphenazine) [20].

CARDIOVASCULAR EFFECTS AND ELECTROCARDIOGRAM (ECG) CHANGES

Possible ECG changes seen with antipsychotics include tachycardia (increased heart rate) and prolonged QT intervals. The most significant of these is the prolonged QT interval, as this can be associated with potentially fatal cardiac arrhythmias (e.g., torsades de pointe). Of the available antipsychotics, ECG changes appear most commonly with thioridazine and ziprasidone but have also been observed with haloperidol. These medications should be used with caution with other drugs that prolong the QT interval [20,28].

Orthostatic hypotension can occur in up to 40% of patients treated with antipsychotic medications. It is more common in patients with existing cardiovascular disease and older patients. It occurs most commonly with medications that have high affinity for α1A-adrenoceptors relative to D2 receptors (e.g., clozapine and risperidone). Tolerance will usually develop within two to three weeks of antipsychotic initiation or dose increase. To minimize the risk of orthostatic hypotension, suggest starting with low doses and slowly titrating medications up over several days. To help patients minimize symptoms, counsel them to try rising slowly, staying hydrated, and using compression or support stockings [20].

Tachycardia may sometimes occur as a compensatory mechanism related to orthostatic hypotension. Patients taking clozapine may sometimes have a dose-related increase in heart rate of 20–25 bpm. Consider reducing the dose, using slower titration, or adding a low-dose cardioselective beta blocker (i.e., metoprolol) [20].

HYPERPROLACTINEMIA

Hyperprolactinemia may cause symptoms such as gynecomastia, galactorrhea (e.g., inappropriate milk production), irregular menses, reduced libido (sex drive), and sexual dysfunction. It most commonly occurs with medications such as paliperidone, risperidone, and haloperidol. For patients who experience elevated prolactin levels and associated symptoms, the best choice is to change them to an antipsychotic that is less likely to cause this. Consider switching these patients to a second-generation antipsychotic that has not been associated with elevated prolactin levels (e.g., aripiprazole or quetiapine). Alternatively, hyperprolactinemia may be treated with bromocriptine or cabergoline in some patients [20,28].

LIPID ABNORMALITIES

Increased risk of hypertriglyceridemia can occur with low-potency first generation antipsychotics and some of the second-generation agents (clozapine, olanzapine, and quetiapine) [20,28].

NEUROLEPTIC MALIGNANT SYNDROME

Neuroleptic malignant syndrome is a rare but potentially life-threatening reaction characterized by fever, altered mental status, muscle rigidity, and autonomic dysfunction (damage of the autonomic nervous system) [20,31]. It can occur because of treatment with any antipsychotic or abrupt cessation of a dopamine agonist. Treatment of neuroleptic malignant syndrome involves immediate discontinuation of the antipsychotic, supportive care, and the administration of medications such as dantrolene sodium, biperiden, or bromocriptine [20].

PSEUDOPARKINSONISM

Drug-induced parkinsonism is the most common reversible movement-related adverse effect of antipsychotics, presenting as rigidity, masked facies, slowed gait, and tremor, typically within the first three months of treatment. High-potency first-generation medications (e.g., fluphenazine, haloperidol) carry the greatest risk, particularly in medication-naive patients, females, and older adults. Second-generation agents are less likely to cause this effect, with clozapine and quetiapine posing the lowest risk. Management options include dose reduction, switching to quetiapine or clozapine, or adding antiparkinsonian agents such as anticholinergics (e.g., benztropine, trihexyphenidyl) or amantadine, though anticholinergics are generally only needed for the first three months and add to adverse effect burden.

SEDATION

Sedation is a possible adverse effect associated with several of the available antipsychotics. It may improve with continued administration. It occurs most commonly with low-potency first-generation antipsychotics, as well as clozapine [28]. Unfortunately, sedation can interfere with a patient's ability to function or be involved in social activities and may also keep patients from being adherent with their medication.

Consider the following options to address sedation associated with antipsychotics [20,28]:

- Administer total daily dose at bedtime

- Change to a less sedating antipsychotic (e.g., aripiprazole, paliperidone)

- Lower the dose

SEIZURES

Spontaneous seizures have been reported with antipsychotic use, since all antipsychotics can lower the seizure threshold. The highest risk is in patients with pre-existing seizure risk factors (e.g., previous head trauma, seizure disorder). When they occur, seizures tend to happen more often at the beginning of treatment or with rapid dose increases or high doses. Seizures are most commonly associated with sedating antipsychotics (low-potency first-generation agents and clozapine). There may be a lower seizure risk with fluphenazine, haloperidol, pimozide, trifluoperazine, and risperidone [28,32].

SUDDEN CARDIAC DEATH

Use of antipsychotics, especially at higher doses, has been associated with an increased risk of sudden cardiac death. This risk is rare. It is estimated that about 18 cases of sudden cardiac death may occur for every 10,000 years of antipsychotic exposure [33].

TARDIVE DYSKINESIA

Tardive dyskinesia is characterized as persistent, abnormal involuntary movements of the tongue, hands, feet, and (in severe cases) the trunk. Patients can experience difficulty swallowing, eyebrow arching, grimacing, lip smacking, and jerking movements. Symptoms typically occur much later into antipsychotic medication therapy but may begin within a few months [20,34].

Symptoms are more likely to be reversible if caught and medications are changed early in the course. However, tardive dyskinesia may become permanent even after stopping antipsychotic medication. Abnormal Involuntary Movement Scale (AIMS) and Dyskinesia Identification System: Condensed User Scale (DISCUS) are available rating scales that can be used to evaluate for abnormal involuntary movements [20,34].

Patients who develop tardive dyskinesia on a first-generation antipsychotic can be converted to a second-generation antipsychotic, as the risk appears to be lower [20]. There is a class of medications used to treat tardive dyskinesia, referred to as monoamine depleters, that work by depleting presynaptic dopamine [3,35]. This drug class includes the medications deutetrabenazine (Austedo) and valbenazine (Ingrezza) [3]. These medications may be an option for patients with moderate-to-severe tardive dyskinesia who are not candidates for dose reduction or change in antipsychotic therapy [36]. Of note, anticholinergics (e.g., diphenhydramine, benztropine) may worsen tardive dyskinesia and should typically be avoided [34].

WEIGHT GAIN

Second-generation antipsychotics such as clozapine, olanzapine, quetiapine, and risperidone are associated with significant weight gain, particularly in the early months of treatment, with some patients gaining more than 20 pounds. This weight gain is compounded by rises in serum triglycerides and glucose dysregulation, making it an especially serious concern for patients with schizophrenia, who already face elevated mortality risk due to sedentary lifestyles and poor physical health. Concomitant medications such as valproic acid, lithium, and mirtazapine can further exacerbate weight gain through synergistic pharmacological effects. Medications such as ziprasidone and aripiprazole are associated with less weight gain [20].

CLOZAPINE: NEUTROPENIA AND AGRANULOCYTOSIS

In addition to the other side effects discussed, clozapine is associated with the rare risk of neutropenia (an absolute neutrophil count [ANC] of less than 1,500 cells/mcL), and agranulocytosis (defined as an ANC of less than 500 cells/mcL) [3; 28]. Low neutrophil counts increase the risk of infection which can be dangerous and even life-threatening. Patients may be rechallenged on clozapine after experiencing neutropenia but should not be rechallenged after agranulocytosis. The risk of neutropenia usually occurs within the first few months of treatment but can occur at any time [20].

Previously, prescribers and pharmacies had to be enrolled in the Risk Evaluation and Mitigation Strategy (REMS) program in order to prescribe and dispense clozapine to patients. However, the FDA eliminated the clozapine REMS program in June 2025 after determining that it was no longer necessary to ensure the benefits of clozapine outweigh the risk of severe neutropenia. Despite this, patients should still have their neutrophil counts monitored before and after starting clozapine therapy in accordance with the prescribing information. Before starting therapy, a baseline ANC should be obtained. Clozapine initiation is not recommended if ANC counts are less than 1,500 cells/mm^3. ANC counts should be monitored weekly for the first six months of therapy, biweekly for the next six months, and then monthly for the duration of treatment. Recommend interrupting clozapine if ANC drops to less than 1,000 cells/mm^3 during treatment, and discontinue therapy if ANC is less than 500 cells/mm^3 [37,38].

7. DRUG INTERACTIONS

Drug interactions with antipsychotics involve additive pharmacodynamic interactions (e.g., sedation, urinary retention, anticholinergic effects) and cytochrome P450 interactions. Think of these examples of drugs or drug classes that you may see combined with antipsychotics, for additive pharmacodynamic effects:

- Anticholinergic effects: Benztropine, diphenhydramine, trihexyphenidyl

- Orthostatic hypotension: Alpha blockers, methyldopa, clonidine

- QT prolongation: Tricyclic antidepressants

- Sedation: Benzodiazepines, benztropine, diphenhydramine, tricyclic antidepressants

There are also some cytochrome P450 interactions to be aware of (Table 4). Stay alert for antipsychotics that are substrates, inhibitors, and/or inducers of CYP enzymes, since these interactions can alter medication levels in the body. Refer to the prescribing information for necessary dosage adjustments based on these interactions. There are a few drugs which are substrates of CYP1A2. CYP1A2 is induced by cigarette smoke. If a patient who is on one of these antipsychotics is a smoker and decides to quit, the patient may experience more adverse effects (e.g., sedation, extrapyramidal symptoms, confusion, weight gain) if their medication dose is not adjusted accordingly [39].

Table 4: EXAMPLES OF CYTOCHROME P450 INVOLVEMENT WITH ANTIPSYCHOTIC MEDICATIONS

Medication | CYP1A2 | CYP2D6 | CYP3A4
Aripiprazole | — | Substrate | Substrate
Asenapine | Substrate | Inhibitor and substrate | Substrate
Brexpiprazole | — | Substrate | Substrate
Cariprazine | — | Substrate | Substrate
Chlorpromazine | — | Inhibitor and substrate | —
Clozapine | Substrate | Inhibitor and substrate | Substrate
Fluphenazine | — | Inhibitor and substrate | —
Haloperidol | — | Inhibitor and substrate | Substrate
Iloperidone | — | Substrate | Substrate
Lumateperone | — | — | Substrate
Lurasidone | — | — | Substrate
Milsaperidone | — | Substrate | Substrate
Olanzapine | Substrate | — | —
Paliperidone | — | — | Substrate
Perphenazine | — | Inhibitor and substrate | —
Pimozide | — | Substrate | Substrate
Quetiapine | — | — | Substrate
Risperidone | — | Substrate | Substrate
Thioridazine | — | Inhibitor and substrate | Inducer
Xanomeline | — | Substrate | —
Ziprasidone | — | — | Substrate

Source: [3,25,39,40]

8. ANTIPSYCHOTIC SELECTION

Consider the case of Patient S, a newly diagnosed patient with schizophrenia. She has diabetes, hypertension, hyperlipidemia, and obesity. She currently has prescriptions for metformin, glipizide, lisinopril, and simvastatin. However, per her refill history, it does not appear that she is very adherent to her medications.

What specifics about Patient S are important in selecting an antipsychotic for her? What comorbid conditions could impact medication selection? What might be an appropriate antipsychotic for Patient S in light of her issues with medication adherence? How should Patient S be monitored when starting the chosen antipsychotic?

Many aspects need to be taken into consideration when selecting an antipsychotic. Both first- and second-generation antipsychotics are effective in treating the positive symptoms of schizophrenia. When the second-generation antipsychotics were developed, it was initially hoped that these would be more effective for the negative symptoms and/or have less adverse effects compared to the first-generation antipsychotics. Over time, we have learned that this is not exactly the case. Efficacy rates will vary from medication to medication and patient to patient, but in general the second-generation antipsychotics have not consistently been proven to be more effective than the first-generation agents in treating the negative symptoms and many drugs have never been directly compared in trials [42,43]. A systematic review including more than 50,000 patients and 32 different antipsychotics found that clozapine, olanzapine, and risperidone seemed to reduce overall symptoms of schizophrenia more than many other drugs [43]. Although the rates of some adverse effects may be lower with the second-generation antipsychotics (e.g., movement disorders, prolactin elevation), the rates of other adverse effects appear to be higher (e.g., metabolic disorders, weight gain, sedation) [43].

For patients with bipolar disorder, mood stabilizers such as lithium are typically used first to manage acute manic episodes [44]. Combining a mood stabilizer with an atypical antipsychotic may be preferred in patients with severe or psychotic mania [44]. For less severe manic episodes, monotherapy with either a mood stabilizer or atypical antipsychotic may be preferred [44,45].

Individualize medication selection, taking into account the following:

- Concomitant medical conditions and medications

- Cost of therapy
- Dosing schedule/frequency
- Potential for adverse effects

9. MONITORING

In addition to monitoring for effectiveness and asking patients and caregivers about adverse effects associated with therapy, patients taking antipsychotics should have baseline and periodic monitoring done throughout therapy. All patients should receive a lifestyle assessment at baseline and throughout each visit that includes smoking status, diet, exercise, and alcohol and drug use [46,47].

CARDIAC MONITORING

Assess baseline cardiac risk factors (e.g., history of heart disease, congenital long QT syndrome). Obtain a baseline EKG, potassium, and magnesium level before initiating an antipsychotic in high-risk patients, especially in elderly patients, or those taking medications that may prolong the QT interval [19]. In all patients, blood pressure and pulse should be taken at baseline, 12 weeks, and then at least annually [46,47,48].

METABOLIC MONITORING

Before initiating an antipsychotic, it is important to measure baseline laboratory values (e.g., fasting blood glucose, fasting lipid panel). In addition, body mass index, weight, and waist circumference should be documented to allow for future comparisons should metabolic abnormalities be a concern with medications [10]. Follow-up values should be obtained regularly during the course of therapy. Monitor weight more frequently (e.g., patients can monitor at home at least weekly for the first few weeks, providers can monitor at each visit), as this will be a more visible change week to week than lab values [10,48]. Recheck glucose and lipids at 12 weeks, and then every three to six months, and then annually [48,49].

Patients with existing diabetes should be monitored carefully with the initiation of an antipsychotic. Some antipsychotics are more likely to cause weight gain, worsen glucose control, and adversely affect lipid profiles (e.g., clozapine, olanzapine). However, when antipsychotics were compared using measures of efficacy, tolerability, patient choice, and emergence of medical problems, there was no conclusive agent to avoid or use. Choice of therapy must include all four of the above measures and then be followed up with appropriate, comprehensive metabolic monitoring [49].

MOVEMENT DISORDERS

Patients should be assessed for extrapyramidal symptoms at baseline and then at each subsequent visit. Additionally, patients at risk for tardive dyskinesia should also have an assessment using a structured instrument (e.g., AIMS) every 6 months (or every 12 months for all other patients) [50].

10. RISK MITIGATION STRATEGIES

As discussed, risk mitigation strategies should be initiated when prescribing any antipsychotics. Patients prescribed antipsychotics should receive education on the effects of the drugs, possible risks and benefits, and any recommended monitoring. However, this can be difficult if the patient has active psychosis or delusional paranoia. In these cases, caregivers and/or surrogate decision makers should be sought. All discussions should be fully documented. Patient education is an ongoing process (not a single event), and efficacy and adverse effects should be discussed regularly with patients as well as steps taken to treat or ameliorate adverse effects.

While monitoring presents an example of risk mitigation strategies for all antipsychotics, the actual strategies used should be specific to the patient and agent(s); abnormalities should generate a consult to appropriate medical team members. Aside from prevention and early detection of adverse effects, risk mitigation strategies should include a treatment plan for any possible adverse reactions. As discussed, there are several class-wide potential adverse effects, and these known risks should be reviewed and planned for.

11. OFF-LABEL ANTIPSYCHOTIC USE

In some cases, antipsychotics may be prescribed for off-label indications. The evidence supporting off-label use of antipsychotics varies by condition and agent.

ANXIETY

Antipsychotics are sometimes used off-label for the treatment of anxiety. Among the antipsychotics, quetiapine has the best evidence to support its use as monotherapy [51,52,53]. Aripiprazole, olanzapine, and risperidone can be considered as adjunctive therapy.

DEMENTIA

The use of antipsychotics to address agitation or psychosis in patients with dementia is complex. The risks associated with behaviors due to agitation and psychosis must be balanced with the risks associated with antipsychotic therapy [54]. Labeling for antipsychotics carries warnings about increased risk of death (boxed warning) and cerebrovascular events in patients with dementia-related psychosis [3].

If symptoms of agitation and psychosis are rare or attributable to specific factors, it may be best to educate caregivers and attempt targeted behavioral interventions. When symptoms are severe, persistent, or have significant negative consequences (e.g., pose a risk to the patient or those around them), antipsychotics may be considered [54].

There are very little data to support the use of antipsychotics for symptoms of dementia. The available data show only a small benefit to the patient and/or caregiver. Most of the data support the use of aripiprazole, brexpiprazole, or risperidone over other antipsychotics [52,54,55]. If antipsychotics are used, recommend starting at low doses, with slow titrations to minimize dose-related adverse effects [54]. Consider starting with about one-third to one-half of the typical starting dose [54].

DEPRESSION

Atypical antipsychotics may be used to augment an antidepressant in cases where patients have a partial response to a single antidepressant [56]. Aripiprazole, brexpiprazole, quetiapine, risperidone, and olanzapine have the best evidence of efficacy [56]. Aripiprazole, brexpiprazole, and quetiapine are FDA-approved for use as adjunct therapy in the treatment of depression [3].3 Olanzapine is approved for treatment-resistant depression in combination with the SSRI fluoxetine [3]. These should be your first choice antipsychotic for depression, after exhausting typical therapies. Lurasidone and cariprazine are approved for depressive episodes within bipolar I disorder, so they may be additional options if patients cannot take or have failed therapy with the other antipsychotics. Additionally, cariprazine and lumateperone are also approved for adjunctive treatment of major depressive disorder [3].

EATING DISORDERS

You may see antipsychotics prescribed for patients with eating disorders. However, there is not enough evidence to say for sure that atypical antipsychotics are effective in the treatment of eating disorders [51]. Most studies have been with olanzapine, which has shown positive effects on weight gain and other psychological features associated with eating disorders, such as aggression, depression, and obsessive-compulsive symptoms [57]. There are also data available for aripiprazole which suggests it may be helpful for reducing purging episodes and eating preoccupations and rituals [57]. However, more evidence is needed before recommending atypical antipsychotics for eating disorders.

INSOMNIA

Antipsychotics have been prescribed for patients with insomnia to assist with sleep. However, there is not good evidence to justify antipsychotic use for this indication [51].

OBSESSIVE-COMPULSIVE DISORDER (OCD)

Among the atypical antipsychotics, risperidone and aripiprazole have the best evidence to support their use for OCD [58].

POST-TRAUMATIC STRESS DISORDER (PTSD)

There is insufficient evidence to support routine use of antipsychotics in the treatment of PTSD [59]. There is some mixed evidence for the use of risperidone as adjunctive therapy [51]. However, there is evidence to show that risperidone is not beneficial in the treatment of PTSD compared with placebo in patients with military-related PTSD. Thus, guidelines recommend against its use as monotherapy as well as adjunctive therapy [59,60]. Two small, separate studies also found no benefit from aripiprazole or olanzapine augmentation in patients with military-related PTSD. Overall, Veterans Affairs guidelines suggest against aripiprazole, asenapine, brexpiprazole, cariprazine, iloperidone, lumateperone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone for augmentation of medications for the treatment of PTSD in these patients [59]. Continue to recommend first-line options for PTSD, such as paroxetine, sertraline, or venlafaxine [61].

SUBSTANCE USE DISORDER

You may see antipsychotics used in patients with substance use disorders. However, evidence shows that atypical antipsychotics are not effective in the treatment of substance use disorders, especially in the absence of psychotic disorders [51,62]. Additionally, Veterans Affairs guidelines do not mention antipsychotics for substance use disorder and instead focus on more typical first-line therapies (e.g., buprenorphine/naloxone or methadone for opioid use disorder) [63]. Other guidelines suggest antipsychotics may be effective when used short-term for certain substance-induced psychotic symptoms (e.g., paranoia from stimulants or phencyclidine [PCP]), or during the acute stabilization phase of substance use treatment programs [62].

12. USE OF LONG-ACTING ANTIPSYCHOTICS

Long-acting injectable antipsychotics may be an option to consider in patients, especially when adherence is a concern. There are several long-acting formulations available in both the first- and second-generation classes of antipsychotics (Table 5 and Table 6). As with any therapeutic option, there are potential advantages and disadvantages associated with their use [64].

Table 5: TYPICAL DOSING FOR FIRST-GENERATION LONG-ACTING INJECTABLE ANTIPSYCHOTICS FOR SCHIZOPHRENIA

Drug | Initial Dose | Usual Maintenance Dose

Haloperidol decanoate IM

50 mga

Max: 100 mg

50–200 mg every three to four weeksa

Fluphenazine decanoate (IM or subcutaneous)

6.25–25 mg

6.25–25 mg every 2 weeks

Max: 100 mg/dose

aHaloperidol decanoate should only be used in patients with schizophrenia who have been stabilized on an immediate-release antipsychotic and who require prolonged parenteral therapy. Patients should be known to tolerate oral haloperidol prior to initiating haloperidol decanoate. Dosing conversion from an oral antipsychotic is based on the established dose (haloperidol or haloperidol equivalent dose).

Source: [3,64]

Table 6: TYPICAL DOSING FOR SECOND-GENERATION LONG-ACTING INJECTABLE ANTIPSYCHOTICS FOR SCHIZOPHRENIA

Drug | Available Forms | IM Dosinga,b | Comments/Considerations
Aripiprazole monohydrate (Abilify Maintena) | Vials and prefilled syringes (300 mg, 400 mg) | 400 mg once monthly | Requires overlap with oral aripiprazole for two weeks.

Aripiprazole monohydrate (Abilify Asimtufii)

Prefilled syringes (720 mg, 960 mg)

960 mg every two months

Requires overlap with oral aripiprazole (or other oral antipsychotic) for two weeks. Tolerability must be established with oral aripiprazole.

Aripiprazole lauroxil (Aristada, Aristada Initioc)

Prefilled syringes (Aristada) (441 mg, 662 mg, 882 mg, 1,064 mg)

Prefilled syringe (Aristada Initio) (675 mg)

441–882 mg once monthly
OR
882 mg every six weeks
OR
1,064 mg every two months

Two options for initiating Aristada:

Start with a single dose of Aristada Initio 675 mg along with one dose of 30 mg oral aripiprazole. Give the first dose of Aristada on the same day or up to 10 days later.

OR

Start with Aristada and overlap with oral aripiprazole for three weeks.

Olanzapine pamoate (Zyprexa Relprevv)

Vials (210 mg, 300 mg, 405 mg)

IM dose depends on previous amount of oral olanzapine

Can range from 150 mg every two weeks to 405 mg every four weeks

Oral overlap not required, but tolerability and target dose with oral olanzapine must be established first, before switching to Zyprexa Relprevv.

Available only through a restricted distribution program requiring all to enroll.

Monitor patients for three hours after injection due to risk of post-injection syndrome (e.g., sedation, confusion, agitation, dizziness).

Paliperidone palmitate (Invega Sustenna)

Prefilled syringes (39 mg, 78 mg, 117 mg, 156 mg, 234 mg)

Usually 117 mg once monthly, but can range from 39 mg to 234 mg once monthly

Oral overlap not required. Establish tolerability with oral paliperidone or risperidone before use.

Requires two separate loading dose injections during the first week: 234 mg injection on day 1, then 156 mg injection on day 8.

Paliperidone palmitate (Erzofri) | Prefilled syringes (39 mg, 78 mg, 117 mg, 156 mg, 234 mg, 351 mg) | 39–234 mg once monthly, starting four weeks after the first dose. | Initiate with 351 mg as a single dose.
Paliperidone palmitate (Invega Trinza) | Prefilled syringes (273 mg, 410 mg, 546 mg, 819 mg) | 273–819 mg every three months, based on previous Invega Sustenna dose | Use after patient is stabilized on Invega Sustenna (after at least four months).

Paliperidone palmitate (Invega Hafyera)

Prefilled syringes (1,092 mg, 1,560 mg)

1,092–1,560 mg every six months, based on previous Invega dose

Use after patient is stabilized on Invega Sustenna for at least 4 months, OR Invega Trinza for at least one 3-month cycle.

Longest dosing interval available.

Risperidone microspheres (Risperdal Consta)

Vials (12.5 mg, 25 mg, 37.5 mg, 50 mg)

25–50 mg every two weeks

12.5 mg may be needed for patients with hepatic or renal impairment

Requires overlap with oral risperidone for three weeks.

Risperidone for subcutaneous injection (Perseris) | Prefilled syringes (90 mg, 120 mg) | 90–120 mg subcutaneous once monthly | Oral overlap not required. Establish tolerability with oral risperidone before use.

Risperidone extended-release injectable suspension (Uzedy, Rykindo)

Prefilled syringes (Uzedy) (50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg)

Vials (Rykindo) (25 mg, 37.5 mg, 50 mg)

Uzedy: Dose is based on previous oral risperidone dose; can range from 50 mg subcutaneous once monthly to 250 mg every two months.

Rykindo: 25 mg every two weeks; may go up to 37.5–50 mg.

Supplement with oral risperidone during first seven days of Rykindo.

aAll listed injections are IM, except for risperidone (Perseris and Uzedy) injections, which are administered subcutaneously.

aSee product labeling for scheduling missed doses and appropriate time frames for administration.

aMay be used as a single loading dose when initiating Aristada (not for maintenance dosing)

Source: [3,64,65]

When prescribing a long-acting injectable antipsychotic, clinicians first initiate treatment with the oral form for a long enough period to demonstrate tolerance. The oral formulation should be continued until the long-acting therapy has been established. Both fluphenazine and haloperidol use sesame oil in their suspension, which may cause allergic reactions in patients sensitive to sesame.

Evidence Based Practice Recommendation

The American Psychiatric Association suggests that patients receive treatment with a long-acting injectable antipsychotic medication if they prefer such treatment or if they have a history of poor or uncertain adherence.

https://psychiatryonline.org/doi/full/10.1176/appi.books.9780890424841.Schizophrenia02

Last Accessed: September 18, 2026

Strength of Recommendation/Level of Evidence: 2B (Conditional recommendation based on low-quality evidence)

Potential Advantages

- Avoids first-pass metabolism (i.e., better correlation between dose and drug level)

- Decreased relapse frequency and rehospitalization rates

- Early identification of nonadherence

- Easier to distinguish between lack of response and non-adherence in cases of relapse or non-response

- Patients do not have to remember to take medication every day

- Provides mechanism to monitor adherence

- Reduced risk of overdose

- Reduced side effects due to lower and less frequent peak plasma level

- Regular interactions between patient and medical staff

Potential Disadvantages

- Delayed resolution of adverse effects

- Injection site pain

- Longer time to reach steady state concentrations

- Perception of stigma
- Reduced flexibility with dosage adjustments
- Slow dosage titrations
- Travel burden for injection clinic visits

Clinicians should consider using long-acting injectable antipsychotics in patients with recent-onset schizophrenia and in patients with a significant risk for nonadherence: patients with a history of nonadherence, severe symptoms, comorbid substance use, cognitive impairment, or negative attitudes about the need to take medication [64].

There are no randomized controlled trials showing superiority of decanoate injections over other formulations; however, some small studies have shown at least similar efficacy of long-acting injected and oral haloperidol [66]. Plasma serum concentrations with steady-state decanoate yield lower plasma drug concentrations than with oral administration. This suggests that decanoate forms are at least as effective as oral agents and that lower doses may be effectively used with this formulation [66].

The efficacy of long-acting injectable antipsychotics other than haloperidol is not clear [67]. Studies have found varying results for different antipsychotics, both in terms of efficacy and side effect profile [66,67]. The ultimate decision to select a long-acting injectable antipsychotic is complicated and typically driven by a need to improve compliance.

13. CASE STUDY

Patient A is 34 years of age with a history of schizoaffective bipolar disorder, first diagnosed at 18 years of age during his first year at college. His childhood was notable for several episodes of brief counseling for behavioral issues in school and at home, with a brief trial of methylphenidate (Ritalin) at 11 years of age. Patient A graduated from high school with his peers, but once at college, he developed delirious mania, paranoia, and psychosis. Treatment with olanzapine and valproic acid (Depakote) was initiated, but compliance has been an ongoing issue. During the past 16 years, the patient has had numerous episodes requiring hospitalization, one suicide attempt, and three arrests for breach of peace. He is now on probation and has been unable to maintain employment. He is living with his mother, who has communicated that he will have to leave the house if he does not take his medication. Patient A presents for medication management, stating that he does not like the weight gain he has experienced with many of the medications he has used in the past.

The nurse takes and documents a full history. On mental status exam, Patient A is alert and oriented. He scores 27 on a Mini-Mental State Exam (MMSE) and is mildly grandiose. His speech is slightly pressured but interruptible. At the time of presentation, Patient A is not taking any medications, having disagreed with his last provider's prescription of olanzapine, a drug that had been effective in the past.

Patient A is 6 feet 1 inch tall and weighs 235 pounds. His blood pressure is 124/86 mm Hg. Laboratory studies are requested, and all return normal. An EKG reveals a normal QTc and sinus rhythm.

The nurse asks Patient A what he wants to gain in his medication management, and his stated goals are to continue to live with his mother, to avoid future arrest, and to be able to maintain a job. The nurse discusses available typical and atypical oral and decanoate antipsychotics. After a long discussion, Patient A decides to try long-acting injection risperidone (Risperdal Consta). Patient education includes the risks of extrapyramidal reactions (e.g., movement disorders), weight gain, and prolactin elevation, which can lead to gynecomastia, as well as risk mitigation strategies if any of these develop.

A baseline AIMS test is conducted and is negative for any existing issues. The oral trial of risperidone is initiated, as required before using any long-acting injectable to demonstrate tolerance. The patient is titrated up to an oral dosage of 3 mg twice daily, which appears to resolve the patient's paranoia, pressured speech, and hypomania. Patient A reports that he is functioning better, but he reiterates that he does not think he will be able to comply with daily oral medication. The decision is made to progress to long-acting injected risperidone, which requires a three-week overlap with the oral medication.

While there is no exact dosage equivalency, the manufacturer recommends that a 6-mg total oral daily dose of risperidone should be converted to a bimonthly injectable dose of 37.5–50 mg long-acting risperidone. The patient is started at 37.5 mg IM every two weeks. After three weeks, the patient is stable and able to wean off the oral risperidone, decreasing to 4 mg in two divided doses for three days, then 2 mg in divided doses for three days, before total cessation. During this time, the nurse maintains frequent contact with Patient A to verify stability and compliance.

After six weeks, laboratory studies are ordered, including blood glucose level, lipids, and prolactin level, and a repeat EKG is done. All findings are normal. The nurse continues to administer the AIMS test every three months and to check weight and vital signs at every visit. While Patient A continues with this therapy, laboratory values are rechecked every three to six months.

Patient A responds well to treatment and is able to remain living with his mother. After six months, he has gained employment at a fast-food restaurant and has avoided any contact with law enforcement.

14. CONCLUSION

Antipsychotics are a complex group of medications, providing many opportunities for pharmacist involvement in their management. They can be used effectively to manage schizophrenia or bipolar disorder, as well as other indications. However, their use requires careful consideration to select the best medication for each individual patient, taking into account comorbid conditions, potential adverse effects, and drug interactions. In addition, medication monitoring and patient counseling can be valuable tools to improve adherence rates and optimize therapy.

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Evidence-Based Practice Recommendations Citations

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