Avoiding Antipsychotic Polypharmacy in Schizophrenia

Antipsychotic polypharmacy, defined as attempting to augment one antipsychotic with another antipsychotic, is often tried in cases of refractory schizophrenia, despite a lack of evidence regarding the benefit of this strategy.1

Under certain circumstances, using an antipsychotic to augment another class of psychotropic, such as adding lurasidone (Latuda) to lithium for refractory bipolar depression, or adding extended-release quetiapine (Seroquel XR) to an antidepressant for refractory major depressive disorder, has garnered enough evidence to reach FDA approval.

On the contrary, there is good evidence that antipsychotic polypharmacy increases the rate of certain side effects. For patients with schizophrenia who are taking multiple antipsychotics, a trial of clozapine (Clozaril, Novartis) monotherapy, or a trial of a simplified regimen, may be beneficial.  

Antipsychotic polypharmacy, when compared to monotherapy, increases the risk of extra-pyramidal symptoms,2 yields higher rates of the antipsychotic-associated metabolic syndrome,3  compounds the risk of diabetes,4 and lowers HDL levels. Even when controlling for many other factors, antipsychotic polypharmacy is associated with increased mortality5.

For patients with schizophrenia refractory to a trial of a second-generation antipsychotic (SGA), the data continues to support a trial of clozapine monotherapy. For example, clozapine was more efficacious than switching to another SGA in the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) schizophrenia trial.6

Although providers appropriately associate clozapine with its serious risks of, amongst other things, agranulocytosis, diabetes, weight gain, seizures, and myocarditis, clozapine is routinely recommended ahead of antipsychotic polypharmacy in consensus guidelines.1,7

Beyond the adverse side effects, regulatory and monitoring requirements may be additional barriers to clozapine use. Regardless, providers appear to delay clozapine trials for years, often attempting antipsychotic polypharmacy instead of adhering to treatment guidelines.8

There are several reasons why patients get stuck on a regimen of antipsychotic polypharmacy. Sometimes, in the middle of a cross titration from one antipsychotic to another, the patient demonstrates improvement. Rather than assuming the benefit is from the new medication or other factors, the cross-titration is halted.9

Or a patient may have a partial response to a partial dose of an antipsychotic, but develops intolerable side effects on a higher dose. Despite treatment guidelines that would recommend switching to another, single agent,1,7 providers may try to use half-doses of multiple medications in an attempt to minimize the side effects of each.

Although there is a relative dearth of prospective, antipsychotic polypharmacy trials (other than those that seek to augment clozapine in hyper-refractory cases), there was a 2011 study that approached the issue from the other direction. In a trial by Essock, et al,10 outpatients who had a diagnosis of schizophrenia and who were on two antipsychotics concurrently were randomized to continue on polypharmacy or taper down to monotherapy.

At six months, two-thirds of the patients assigned to simplified regimens had successfully made the transition with no differences in psychopathology and hospitalization rates. Patients switched to monotherapy also showed a significant benefit in body mass index.

Schizophrenia is a heterogeneous disorder and there exists a cohort of patients who are hyper-refractory, even to clozapine. However, in some clinical reviews, antipsychotic polypharmacy is used in as many as 46% of the patients with schizophrenia.11

The data suggest that many patients on antipsychotic polypharmacy could experience better efficacy and/or fewer side effects if clozapine or a simplified antipsychotic regimen is used instead. 

Ryan Kimmel, MD, is Assistant Professor in the Department of Psychiatry & Behavioral Sciences at the University of Washington School of Medicine.


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