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Second-generation antipsychotic medications: Pharmacology, administration, and side effects

Michael D Jibson, MD, PhD
Section Editor
Stephen Marder, MD
Deputy Editor
Richard Hermann, MD


Antipsychotic medications have unique efficacy in the treatment of acute psychosis from any cause and in the management of chronic psychotic disorders such as schizophrenia. As a class, they are also effective in the treatment of acute agitation, bipolar mania, and other psychiatric conditions.

Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, generally have lower risk of extrapyramidal side effects and tardive dyskinesia compared with first-generation antipsychotics (FGAs). First- and second-generation antipsychotic drugs are more comparable in their clinical efficacy, with the exception of clozapine, an SGA with unique efficacy in treatment-resistant schizophrenia. Antipsychotic drugs differ from one another in dosing, route of administration, pharmacokinetics, side effect profile, and cost, factors that influence the selection of an antipsychotic drug for individual patients.

The pharmacology, administration, and comparative side effects of SGAs available in the United States, including clozapine, are discussed here. The pharmacology, administration, and comparative side effects of FGAs are discussed separately, as is the use of antipsychotics in the treatment of schizophrenia, bipolar disorder, and acute agitation. Guidelines for the prescribing of clozapine are also discussed separately. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment" and "Pharmacotherapy for schizophrenia: Side effect management" and "Bipolar disorder in adults: Choosing pharmacotherapy for acute mania and hypomania" and "Assessment and emergency management of the acutely agitated or violent adult" and "Guidelines for prescribing clozapine in schizophrenia".)


The mechanism of action of most first- and second-generation antipsychotics (FGAs and SGAs) appears to be post-synaptic blockade of brain dopamine D2 receptors. Of the four exceptions, aripiprazole and brexpiprazole are D2 receptor partial agonists and cariprazine is a D3-preferring D3/D2 receptor partial agonist. Several lines of evidence support the role of these receptors in the activity of antipsychotics, most notably a strong correlation between D2 receptor binding and clinical potency [1] and a consistent requirement of 65 percent D2 receptor occupancy for antipsychotic efficacy in functional imaging studies [2]. The fourth exception, pimavanserin, is a serotonin 5HT2A inverse agonist and antagonist with no dopamine D2 affinity [3,4].  

Most SGAs differ from older medications pharmacologically in that serotonin 5HT2 receptor binding exceeds their affinity for dopamine D2 receptors, whereas in FGAs this is generally not the case. Largely for that reason, 5HT2 activity has been suggested as one basis for the lower overall risk of extrapyramidal side effects (EPS) with the atypical drugs compared with FGAs [5]. Other aspects of SGA pharmacology that correlate with reduced risk of EPS include "loose" D2 receptor binding with rapid dissociation rates [6] and preferential binding of drugs to receptors in limbic and cortical brain regions rather than striatal areas [7]. None of these hypotheses has been fully confirmed, and the most important message for the clinician is that the pharmacology of these drugs is complex and likely to result in some variability of side effect risk and pharmacokinetics from patient to patient.

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Literature review current through: Nov 2017. | This topic last updated: May 15, 2017.
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