A classification of clinically used antipsychotics is shown in Table 1. Typical antipsychotics are listed according to chemical structure, whereas atypical antipsychotics are classified according to their pharmacodynamic properties and affinity for receptors.
Table 1. Classification of Antipsychotics
Category | Examples of drugs |
Typical first-generation antipsychotics according to chemical structure |
Butyrophenones | benperidol, bromperidol, droperidol, haloperidol |
Diphenylbutylpiperidines | fluspirilene, pimozide |
Phenothiazenes | chlorpromazine, cyamemazine, fluphenazine, levomepromazine, perazine, perphenazine, pipotiazine, prochlorperazine, promethazine, trifluoperazine |
Thioxanthenes | chlorprothixene, clopenthixol, thiothixene |
Atypical second-generation antipsychotics according to affinities for specific receptors |
5-HT-dopamine antagonists: high selectivity for 5-HT2A and dopamine D2 receptors | brexpiprazole (successor to aripiprazole), iloperidone, lurasidone, risperidone and its metabolite paliperidone, ziprasidone |
Multi-action receptor-targeted: D2, D3, and receptors of other systems such as cholinergic, histaminergic (5-HT1A, 5-HT2A, 5-HT1C) | asenapine, cariprazine, clozapine, olanzapine, quetiapine |
Third-generation antipsychotics |
Partial dopamine receptor agonists | aripiprazole (currently the only approved drug in this category), brexpiprazole (in clinical trials) |
Designation as typical or atypical uncertain (according to chemical structure) |
Benzamides | sultopride |
Tricyclics | carpipramine, clocapramine, clorotepine, clotiapine, loxapine |
Other drugs with antipsychotic action |
5-HT2A receptor antagonists | pimavanserin for psychosis of Parkinson disease |
Antiepileptic drugs | valproic acid for bipolar disorder |
Herbal medicines | some Chinese and Ayurvedic herbs |
Miscellaneous drugs | lithium for bipolar disorder, alternative remedies |
Muscarinic receptor agonists | xanomeline has antipsychotic properties |
The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. It is combined with trospium, a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline.
Pharmacodynamics. Decreased dopamine release in the prefrontal cortex, and excess dopamine release in other pathways, are associated with psychotic episodes in schizophrenia and bipolar disorder. Typical antipsychotic drugs such as haloperidol and chlorpromazine block dopamine D2 receptors in the brain so that dopamine released in these pathways has less effect. They are not selective and block dopamine receptors in the mesocortical, tuberoinfundibular, and nigrostriatal pathways, which produces some unwanted side effects.
Typical antipsychotics were usually rated on a spectrum of low potency to high potency, based on the ability of the drug to bind to dopamine receptors and not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol usually require low doses and produce less sedation than low-potency antipsychotics such as chlorpromazine and thioridazine, which require high dosages with greater anticholinergic and antihistaminergic activity that can counteract dopamine-related side effects. Atypical antipsychotic drugs have a similar blocking effect on D2 receptors. However, most of them also act on serotonin receptors, especially 5-HT2A and 5-HT2C receptors. Both clozapine and quetiapine have a duration of binding to D2 receptors that suffices to elicit antipsychotic effects but is not long enough to induce extrapyramidal side effects and prolactin hypersecretion. 5-HT2A antagonism by atypical antipsychotics increases dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side effect liability, which is linked to the strong blockade of D2 receptors. A continuum spectrum of "atypia " has been proposed that begins with risperidone (the least atypical) to clozapine (the most atypical), whereas all the other atypical antipsychotics fall within the extremes of this spectrum (01).
A third-generation antipsychotic, aripiprazole (approved by the U.S. Food and Drug Administration), is the first “dopamine stabilizer” based on D2 partial agonist properties that does not induce D2 supersensitivity, but can reverse this supersensitivity when it has been induced by D2 antagonists (20). Aripiprazole competes with dopamine and causes partial antagonism offering clinical benefit in situations of high extracellular dopamine concentrations, but when extracellular dopamine concentrations are low, the drug can occupy additional receptors and cause partial activation (14). In clinical practice, this impacts the choice of treatment in first episode psychosis as well as in refractory schizophrenia.
Pharmacokinetics of antipsychotics. Common pharmacokinetic characteristics of most antipsychotic drugs include the following:
| • Good absorption from the gastrointestinal tract into the blood circulation reaching maximal concentrations within 1 to 6 hours. |
| • Pharmacokinetics is linear at therapeutic doses so that doubling the daily dose will result in doubling the drug concentration in blood. |
| • Systemic bioavailability is highly variable ranging from 5% to 100%. |
| • Blockade of D2 receptors by antipsychotic drugs reduces the binding of radioactive PET ligands, and PET has shown that receptor occupancy correlates better with concentrations of antipsychotic drugs in blood than with daily doses. |
| • Although ratios of brain to blood concentrations of the different antipsychotic drugs vary considerably, steady state concentrations in blood correlate well with concentrations. |
| • Elimination half-life is between 12 to 36 hours, eg, mean value is 14.2 hours for clozapine in steady state conditions. Exceptions include the shorter half-life of ziprasidone (about 2 to 10 hours) and longer elimination half-life of aripiprazole (72 hours). |
| • Elimination is mainly by hepatic metabolism. |
| • Differences in blood concentrations of antipsychotic drugs are due to variations in activities of drug-metabolizing enzymes such as cytochrome P450 and UDP-glucuronosyltransferases. |
Therapeutic drug monitoring. Because of individual variations in relation between dose and plasma concentration, therapeutic drug monitoring is recommended for maintaining the lowest possible dose of an antipsychotic that is effective. Therapeutic drug monitoring considers the interindividual variability of the pharmacokinetics of antipsychotics and, thus, enables personalized pharmacotherapy (11). Therapeutic drug monitoring has been recommended for the following atypical antipsychotics with desirable plasma concentration ranges (22).
| • Amisulpride 200-320 ng/ml
• Aripiprazole 150-210 ng/ml
• Clozapine 350-500 ng/ml
• Olanzapine 20-40 ng/ml
• Quetiapine 50-500 ng/ml
• Risperidone and paliperidone 20-60 ng/ml
• Sertindole 50-100 ng/ml
• Ziprasidone 50-130 ng/ml |
Pharmacogenetics of antipsychotics. Several antipsychotics are metabolized to a significant extent by the polymorphic cytochrome P450 (CYP) 2D6, which shows large interindividual variation in activity. Other CYPs, especially CYP1A2 and CYP3A4, also contribute to the interindividual variability in the kinetics of antipsychotics and the occurrence of drug interactions. Table 2 shows enzymes that metabolize antipsychotics.
Table 2. Enzymes That Metabolize Antipsychotics
Drug | CYP2D6 | CYP2C19 | CYP3A4 | CYP1A2 |
Chlorpromazine
Clozapine
Fluphenazine
Haloperidol
Olanzapine
Perphenazine
Risperidone
Sertindole
Thioridazine | +
+
+
+
+
+
+ |
+
+
|
+
+
+
|
+
+
+
+
|
Pharmacogenetic studies have identified genetic variants that affect response to antipsychotics, their serum levels, and adverse effects such as tardive dyskinesia, particularly associations between dopamine receptor polymorphisms and response. Two genes are associated with tardive dyskinesia as an adverse reaction to antipsychotic treatment in psychiatric patients: (1) dopamine D3 receptor, which involves the pharmacodynamics of antipsychotics, and (2) CYP1A2, which involves the pharmacokinetics of antipsychotics. These 2 polymorphisms have an additive effect for tardive dyskinesia and may be useful for predicting side effects of antipsychotics.
Properly designed studies with large sample sizes are still lacking. Although knowledge of pharmacogenetic status is useful in improving efficacy and safety as well as personalizing antipsychotic therapy, few tests are being used in practice. These are expensive and need improvement by covering more gene variants. Pharmacogenetic studies on the effects of antipsychotics on neurocognitive symptoms of schizophrenia are still in early stages, but findings indicate that these will help to identify factors that influence response to treatment (15).
