Current use of antipsychotics
Antipsychotics are divided into 2 major classes—first-generation antipsychotics (FGAs) and SGAs—and principally are FDA-approved for treating schizophrenia. Some antipsychotics have received FDA approval for maintenance treatment of schizophrenia and bipolar disorder (BD), and others have been approved to treat tic disorders (haloperidol and pimozide).
To varying degrees, all antipsychotics block D2 receptors, which is thought to be necessary for treating psychosis. However, some SGAs have significant affinity at other receptors—such as 5-HT2A and 5-HT1A—that confer additional properties that are not fully understood (Table 3). For example, it is believed that 5-HT2A blockade in the striatum reduces the potential for extrapyramidal symptoms (EPS).
Each antipsychotic blocks a unique set of receptors in the brain, leading to a specific set of intended and potentially untoward effects. For example, olanzapine’s effect on psychosis largely stems from its action at the D2 receptor, whereas its sedative and anticholinergic properties are a result of activity at histamine (H1) receptors and muscarinic receptors, respectively. Clinicians can make rational use of unintended effects by carefully selecting a medication based on receptor binding profile (eg, using an antipsychotic with sedating properties in a patient who has psychosis and insomnia). This approach can limit use of multiple medications and maximize a medication’s known effects while attempting to minimize side effects.
Table 3
Antipsychotics: Receptor pharmacology and common side effects
| Antipsychotic | Pharmacology | Common side effectsa |
|---|---|---|
| Prochlorperazinea,b | D2 receptor antagonist and α-1 adrenergic receptor antagonism | EPS, akathisia, prolactinemia, orthostatic hypotension, altered cardiac conduction, agranulocytosis, sexual dysfunction |
| Chlorpromazinea,b | D2 receptor antagonist. Also binds to H1 and cholinergic M1 | EPS, akathisia, prolactinemia, orthostatic hypotension, urinary retention, non-specific QT changes, agranulocytosis, sexual dysfunction |
| Droperidola,b | D2 receptor antagonist and antagonist at peripheral α-1 activity | EPS, akathisia, prolactinemia, orthostatic hypotension, urinary retention, QT changes (dose dependent) |
| Haloperidola,b | D2 receptor antagonist. Also binds to D1, 5-HT2, H1, and α-2 adrenergic receptors | EPS, akathisia, prolactinemia, QT changes (dose dependent) |
| Aripiprazolea,c,d | D2 and 5-HT1A partial agonism, 5-HT2A antagonism | Akathisia, EPS, sedation, restlessness, insomnia, tremor, anxiety, nausea, vomiting, possible weight gain (20% to 30%) |
| Clozapinea,c,e | 5-HT2, D1, D2, D3, D4, M1, H1, α-1, and α-2 antagonism | Sedation, dizziness, tachycardia, weight gain, nausea, vomiting, constipation |
| Olanzapinea,c | 5-HT2A, 5-HT2C, D1, D2, D3, D4, M1-5, H1, and α1- antagonism | Sedation, EPS, prolactinemia, weight gain, constipation |
| Quetiapinea,c,d | D1, D2, 5-HT2A, 5-HT1A, H1, α-1, and α-2 antagonism | Sedation, orthostatic hypotension, weight gain, triglyceride abnormalities, hypertension (frequently diastolic), constipation |
| Risperidonea,c | 5-HT2, D2, H1, α-1, and α-2 antagonism | Sedation, akathisia, EPS, prolactinemia, weight gain, tremor |
| Ziprasidonea,c | D2, D3, 5-HT2A, 5-HT2C, 5-HT1D, and α-1 antagonism; moderate inhibition of 5-HT and NE reuptake; 5-HT1A agonism | EPS, sedation, headache, dizziness, nausea |
| aSide effects and their prominence usually are based on receptor binding profile. All antipsychotics to varying degrees share the following symptoms: EPS, neuroleptic malignant syndrome, QTc prolongation, anticholinergic side effects (urinary retention, decreased gastrointestinal motility, xerostomia), sedation, orthostatic hypotension, blood dyscrasias, and problems with temperature regulation. The class as a whole also carries a “black-box” warning regarding increased mortality when treating geriatric patients with psychosis related to dementia bNo frequencies were available cOnly side effects with frequency >10% listed d”Black-box” warning for suicidal ideation and behavior in children, adolescents, and young adults (age 18 to 24) with major depressive disorder and other psychiatric disorders e”Black-box” warnings for agranulocytosis, myocarditis, orthostatic hypotension, seizure risk EPS: extrapyramidal symptoms; H1: histamine; M1: muscarinic; NE: norepinephrine | ||
Insomnia
Clinicians use FGAs and SGAs to treat insomnia because of their sedating effects, although evidence supporting this use is questionable. Among the FGAs, chlorpromazine produces moderate to severe sedation, whereas haloperidol is only mildly sedating. Clozapine is believed to be the most sedating SGA, whereas quetiapine and olanzapine produce moderate sedation.7
Most data on antipsychotics’ sedating effects comes from studies completed for schizophrenia or BD. Few studies have evaluated using antipsychotics to treat primary insomnia or other sleep disorders in otherwise healthy patients.2 However, data from phase I studies of antipsychotics has shown that schizophrenia patients tolerate a higher maximum dose compared with healthy volunteers, who often experience more sedation.
An antipsychotic’s potential for sedation is directly related to its affinity at H1 receptors and total drug concentration at the H1 receptor binding site. Because drugs with lower affinity for D2 receptors typically are prescribed at higher doses when treating psychiatric illness, the corresponding concentration at H1 receptors can lead to greater sedation compared with equivalent doses of higher-potency agents.
The same phenomenon is seen with high-potency agents. Haloperidol has a relatively weak binding affinity to the H1 receptor,8 but causes more sedation at higher doses. Haloperidol, 20 mg/d, produces sedation in more patients than a moderate dose of risperidone, 2 to 10 mg/d.8 These observations correlate with “the high milligram-low-potency” spectrum seen with FGAs.7