Mechanism of Action of Antipsychotic Medications

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The Journal of Clinical Psychiatry
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A variety of antipsychotic medications exist for treating patients with schizophrenia. Knowledge of pharmacokinetics (the body’s effect on the drug) and pharmacodynamics (the drug’s effect on the body) can help clinicians select antipsychotics and make timely dose adjustments to improve patient outcomes. Currently, the only known effective mechanism to reduce positive psychotic symptoms is dopamine D2 blockade. However, several relevant dopamine pathways exist, and increasingly sophisticated insight into the role of subsections of the striatum has helped link dopamine D2 blockade in specific pathways to the beneficial and adverse effects of antipsychotics, including extrapyramidal side effects (EPS) and secondary negative or cognitive effects. Antipsychotics with low D2 affinity (partial D2 agonism) that modulate dopamine transmission via blockade of histamine or cholinergic receptors or that bind more tightly to serotonin 5-HT2A receptors than D2 receptors generally have less risk for EPS. However, some of the mechanisms that balance dopamine tone can be associated with sedation, central and peripheral anticholinergic effects, weight gain and metabolic abnormalities. Thus, treatment selection needs to be individualized based on the pharmacokinetic and pharmacodynamic profiles of available antipsychotics as well as their effects in a given patient with past treatment response patterns, comorbidities, and preferences. Importantly, new medications with either additional or exclusive nondopaminergic pharmacologic mechanisms need to be developed that can address not only positive symptoms of schizophrenia but also negative and cognitive symptoms, which do not appear to be primarily related to dopamine dysfunction.