A successful antipsychotic combination trial. Quo Vadis?

Munro and colleagues (1) have made an important contribution with their naturalistic, 6-month trial of amisulpiride augmentation in clozapine non-responders. They demonstrated tolerability and provide preliminary evidence for persistent therapeutic benefit. We agree with the authors that this promising finding warrants randomized, controlled trials. We recently reviewed (2), editorialized (3) and debated the controversial issue of antipsychotic combination therapy in Acta Psychiatrica Scandanavica and elsewhere (4–12) and are pleased that the study by Munro and colleagues (1) published in this issue of ACP addresses several of the key issues we and others have raised. For example, we are concerned about the use of antipsychotic combinations in patients who do not receive adequate monotherapy trials (2, 3). The Munro et al. study targeted the most treatment resistant of patients with schizophrenia, namely those who not only failed trials of at least two antipsychotics from different classes, but also continued to exhibit significant psychotic symptoms following a minimum of 6 months on clozapine. This is the most appropriate population for studies of antipsychotic augmentation; the risks and high costs of polypharmacy are counterbalanced by the absence of any established intervention to alleviate the devastating effects of this illness. Too often antipsychotic combinations are prescribed long-term for patients prior to adequate trials of several monotherapies and prior to a trial of clozapine (2, 12). Indeed, it seems that the use of antipsychotic combinations reflects in large part the prescribing behaviors of a few clinicians who elect this treatment option frequently, whereas other prescribers will try iterative monotherapies (12). Due to the lack of safety and efficacy data for antipsychotic combinations and the high costs of this practice, combinations should be discouraged until more evidence for their utility is generated. We are also concerned that monotherapy trials are often of inadequate duration (<3 or 4 months) or use inadequate doses (12). A positive outcome following augmentation of inadequate monotherapy should not be interpreted as evidence for superiority of the combination. Munro and colleagues addressed this issue by optimizing clozapine doses and by requiring a minimum of 6 months of clozapine treatment prior to initiating augmentation. However, because this was a naturalistic trial design intended as a pilot trial to guide further controlled studies, we are limited in the conclusions that we can draw from these data. It is somewhat reassuring, however, that the response rate was similar to the response associated with sulpiride augmentation of clozapine in a randomized, placebo-controlled trial (13). Having emphasized the potential clinical value of this combination, we are nevertheless concerned that the results could be misinterpreted as proof of the efficacy of antipsychotic combination treatment in general. This trial exemplifies one particular augmenting strategy, namely the optimization of D2 receptor occupancy by adding an agent with greater affinity compared with clozapine. Alternatively, amisulpiride might enhance efficacy by broadening clozapine's receptor profile, in this case adding dopamine D3 antagonism. These two theories of action would not apply to most other antipsychotic drug combinations. Secondly, the response criterion of a 20% improvement of the PANSS score might be meaningful for some patients, but might not justify this approach for others. Finally, long-term complications require even longer follow-up periods. For many combinations the ultimate price from additive morbidities might be significant, but only manifest after long periods of treatment. In the final analysis, what does the Monro trial tell us? As was their intent, the authors developed preliminary evidence of efficacy of amisulpiride augmentation that can now be used to design a randomized controlled trial in schizophrenia patients resistant to clozapine. In the interim, clinicians should ensure that several adequate trials of monotherapy are offered to patients who remain symptomatic and should consider a carefully monitored time-limited trial of combination treatment only after clozapine has failed.