The use of two antipsychotics simultaneously, sometimes called antipsychotic polypharmacy, is a debatable contemporary practice in psychiatry, based more upon experience than evidence (1, 2). Whereas antipsychotic monotherapies are well accepted for the treatment of psychosis because of compelling evidence from numerous large randomized controlled trials and meta-analyses (3, 4), antipsychotic polypharmacy is a growing practice that is derived from clinical experience, small trials and case reports (2, 5). Should treatment decisions with these important drugs be based upon evidence, experience or both (3, 6, 7)? Some argue that the practice of medicine is an art, and clinical trial evidence needs to be balanced with descriptive experiences from cases (6). Others worry that too much faith in clinical experience is nothing more than ‘eminence-based medicine’ (7) that can lead to ‘making the same mistakes with increasing confidence over an impressive number of years’ (8). The case of antipsychotic polypharmacy is especially problematic in terms of the evidence versus the experience and also the costs of this practice.

The new generation antipsychotics, known as ‘atypical antipsychotics’, and exemplified by risperidone, olanzapine, quetiapine and ziprasidone, are rapidly replacing early generation ‘conventional antipsychotics’ in clinical practice because their incremental benefits are well documented in numerous evidence-based studies that compare monotherapies to each other and/or to placebo (3, 4). This evidence is good as far as it goes, but often fails to address certain patients of great concern to clinicians, namely those who do not respond to antipsychotic monotherapies and those for whom a greater than median improvement of psychosis (usually defined as >30% reduction of symptoms in randomized controlled trials) is sought. For these patients, there is a growing body of experience that antipsychotic polypharmacy may be useful. Freudenreich and Goff (2) in this issue present a much needed review of the evidence that does exist for the risks and benefits of this practice and propose testable hypotheses that might provide a rationale for prescribers to use antipsychotic polypharmacy. There is good news and bad news to this approach. The good news is that symptom-focused studies can be designed with adequate power and sample sizes to determine whether antipsychotic polypharmacy is useful and safe. The bad news is that ‘antipsychotic combination treatment clearly requires further studies before clinical recommendations can be made’ (2).

This leaves the prescriber in a dilemma: what do you do now when there is no compelling evidence on which to base a clinical decision to use antipsychotic polypharmacy? Freudenreich and Goff (2) propose some useful clinical tips and also point out some potential pitfalls for how to deal with the complex issue of antipsychotic polypharmacy while compelling evidence for or against this practice is being generated. First, prescribers must optimize monotherapies prior to attempting polypharmacy. Too often monotherapies are tried for only 4–8 weeks, but the evidence suggests that it can take 16 weeks or longer for the majority of patients to improve symptoms by 30% (9) and up to a year for some patients to improve by 60% (10). Secondly, a pitfall to avoid is the common fallacy that improvement after adding drug B to drug A is because of synergy between them. It is also possible that the improvement is because of drug B alone, and that drug A should be discontinued. It is even possible that the improvement is because of more time on drug A alone, and that drug B should be discontinued.

Another issue of growing concern is how much of our limited resources to allocate to polypharmacy. A recent study of polypharmacy within the California Medicaid program showed that 11% of patients received two antipsychotics for more than 60 consecutive days (5) and about half of these, orapproximately 5000 patients, received two of the first-line agents risperidone, olanzapine or quetiapine, which are the first, second and eighth most expensive among the 1750 drugs covered by the program, respectively. Drug costs for polypharmacy patients were three times greater than for patients who received just one drug. What is the evidence to support this practice of atypical polypharmacy with expensive first-line agents? There are no randomized controlled trials, and only nine case reports of risperidone–olanzapine, two case reports of risperidone–quetiapine and one case report of olanzapine–quetiapine polypharmacy in the published literature (2, 5). Payors such as California Medicaid are currently looking to reduce the very high overall costs of these drugs by curtailing some high cost–low evidence practices such as atypical antipsychotic polypharmacy rather than complete removal of the availability of some members of this class (5).

For now, a sensible recommendation appears to be that combining antipsychotics should be done only following truly adequate trials of multiple monotherapies, and then with close monitoring in a time-limited trial and continued only when clear therapeutic benefits result. In the meantime, we eagerly await the results of adequate trials to help us determine the costs versus the benefits of antipsychotic polypharmacy.

Acta Psychiatrica Scandinavica

Stephen M. Stahl

Invited Guest Editor


  1. Top of page
  2. References
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    Freudenreich O, Goff DC. Antipsychotic combination therapy in schizophrenia. A review of efficacy and risk of current combinations. Acta Psychiatr Scand 2002;106: 323330.
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    Stahl SM. Selecting an atypical antipsychotic by combining clinical experience with guidelines from clinical trials. J Clin Psychiatry 1999;60 ( Suppl. 10 ):3141.
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