#95420: Antipsychotic Medications: Principles of Safe and Effective Use

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].

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).

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

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].

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).

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].

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.

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].

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:

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].

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:

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].

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.

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

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].

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.

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

Potential Disadvantages

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.

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.

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.