Positive symptoms may include [6,7]:

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 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].

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]:

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).

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 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.

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].

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].

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].

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].

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].

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].

Individualize medication selection, taking into account the following:

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].

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].