What is the evidence regarding combining multiple antipsychotic medications?

Combining two or more antipsychotic agents is often discouraged; some quality metrics or policy efforts make this a stated goal. This has occurred in part because this quality metric is readily measured and because polypharmacy can increase pharmacy costs. There is modest evidence supporting these policies, and they have not been consistently supported by evidence. Research suggests that there may be greater effectiveness with multiple antipsychotic medications when this approach is used by psychiatrists in practice, presumably for patients who do not adequately improve with solo agents. At the same time, there is evidence that multiple medications can increase side effects, through interactions, increased cumulative antipsychotic dosage, or additive side effects. Overall, the evidence in this area is insufficient; there have been too few prospective trials.

The antipsychotic that has been most commonly studied in combination trials is clozapine. See the SMI Adviser Clozapine Center of Excellence or knowledge base entry on augmentation of clozapine. Another antipsychotic medication combination that has some theoretical basis is combining high potency first-generation antipsychotic agents with lower potency second-generation agents, if dosage of the second-generation agent is limited by side effects such as weight gain or sedation. Also, some have also added aripiprazole to antipsychotics that cause weight gain, in an effort to attenuate weight gain, or added aripiprazole to reduce hyperprolactinemia. Some have added agents such as quetiapine to other agents to help with sleep. However, there can be problems with combining antipsychotics. Combining aripiprazole with other agents has been associated with worsening of symptoms. Adding a second antipsychotic can add to side effects. And, if trials of combination antipsychotics mean that clozapine is not being tried in a patient with schizophrenia, this defers treatment with clozapine, which is clearly effective in many patients with refractory illness. The research support for clozapine in refractory schizophrenia is much stronger than the support for multiple antipsychotic medications.

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