Are Your Patients Receiving Unnecessary Antipsychotic Polypharmacy?

The recently published randomized, placebo-controlled trial (RCT) by my colleagues and me confirms what guidelines have been telling us for some time now—that the evidence does not support the use of antipsychotic polypharmacy. Yet the practice continues in about 1 in 4 patients. Are clinicians that indifferent to evidence-based medicine or do these figures reflect the fact that the issue is not so straightforward? I suggest the latter.

Such categorical positions rarely hold up in medicine; our own study reminds us of this. Indeed, a fellow clinical researcher at my center recently recalled aloud that one of his patients who participated in this trial experienced clinical worsening when the second antipsychotic was withdrawn. I could conjecture reasons for this; for example, in our study, discontinuation of the second antipsychotic was abrupt rather than gradual. It remains, though, that some individuals do seem to worsen when polypharmacy is changed to monotherapy, and unfortunately we have no way of accurately predicting who these individuals are (just as we have no clearly established rationale for why or how a change to monotherapy might benefit other patients). The net result is that we have many patients who are unnecessarily receiving combined antipsychotic therapy. This situation is not unlike the high-dose antipsychotic story. Almost every clinician working with patients who have schizophrenia can identify someone who has required high doses to maintain response, but this group of patients is far outweighed by those who fail to benefit from such a strategy.

That there are some individuals who might benefit from antipsychotic polypharmacy is less troublesome to me than how this practice plays out clinically. Evidence and my own clinical experience indicate that polypharmacy is routinely used before clozapine and, on occasion, clozapine is not even offered or only after endless trials and combinations to avoid its use. In addition, antipsychotic polypharmacy often seems to be implemented without a clear framework. What are the target symptoms, how will change be monitored, and when will the trial be terminated in the absence of clear improvement? As someone who deals predominantly with treatment resistance, I am taken aback by how often I see treatment combinations continued in the absence of any clear benefits. And, of course, these same issues exist after clozapine is tried.

In fairness, it is important to also view this process through the eyes of busy clinicians who are under pressure from a variety of sources, themselves included, to get people “better.” In a field in which our available treatments, including clozapine, demonstrate limited success, we still feel a need to be seen as “doing something.” Arguably, there are occasions when combined antipsychotics and/or high doses do work, but the evidence would indicate that these instances are, at best, infrequent. When using what can be considered desperate measures, the treatment plan needs to be held to the same (or even higher) standards as the previous, simpler strategies.

Financial disclosure:Dr Remington is a consultant for Neurocrine and Synchroneuron and is a member of the speakers/advisory board for Novartis. ​