A user’ guide to clozapine

Abstract

In this issue of Acta Psychiatrica Scandinavica, Jimmi Nielsen et al. (1) provide a timely guide to optimizing clozapine treatment for the practicing psychiatrist. The review provides a summary of treatment recommendations as well as relevant strategies to reduce side effects and increase the likelihood of response. At the same time the authors emphasize the need to personalize treatment and engage in shared decision-making with the patient. The decision to use clozapine is not made lightly by either patient or physician, and it is particularly important that once this step is taken that everything possible be done to maximize the likelihood of its success. For the vast majority of appropriate patients it is their last hope for the kind of improvement that they and their loved ones hope for. Despite important advances in genetics and neuroscience the treatment of schizophrenia continues to rely very heavily on the use of antipsychotic drugs, hopefully combined with an appropriate array of psychosocial and vocational therapies. After a concerted effort on the part of the pharmaceutical industry drawing on years of basic research in industry and academia we are still relying on a paradigm that was developed decades ago. Clozapine remains the most efficacious antipsychotic drug when other medications produce partial or no response (2). It has also proven to be of value in reducing suicidality and aggressive behavior. Yet it is sobering to realize that clozapine was developed almost half a century ago. A number of so-called ‘atypical’ or second-generation antipsychotics were developed and modeled to some extent on what were thought to be neurochemical mechanisms which might account for clozapine’s unique properties. However, none of these medications have succeeded in replicating clozapine’s unique profile. Given this, it is imperative that we take full potential advantage of clozapine for the large population of patients who might benefit from it. Toward that end having a comprehensive understanding of how to best use clozapine is critical. Unfortunately, clozapine remains strikingly underutilized in many clinical settings across a broad range of countries around world. This has been particularly striking in the US. To some extent over the past fifteen years the introduction of other second-generation drugs gave practitioners some hope that alternatives which were easier to use might be equally efficacious. Unfortunately, that has not proven to be the case. Yet, many practitioners still do not turn to clozapine when they should. Hopefully, the availability of systematic reviews such as Nielsen’s will help by providing a readily, available resource for the busy clinician. At the same time, the review highlights areas where data are lacking and should help to stimulate further research to address unanswered questions. Examples of such questions would include: should clozapine be introduced after only one, or at most two, well-documented failures, rather than three; are there better predictors (e.g. pharmacogenetic, proteomic, neuroimaging) for who is most likely to benefit from a trial of clozapine and who is most likely to suffer from serious adverse effects; what strategies should be employed when clozapine fails; are there adjunctive pharmacotherapeutic strategies to enhance clozapine’s overall effectiveness. Although most treatment guidelines suggest that clozapine should be the preferred medication after inadequate response to two or three trials of antipsychotics Taylor et al. (3) found that patients who had been treated with clozapine had received an average of over five adequate trials (defined as treatment for at least 6 weeks with what would be considered a therapeutic dose). They also reported that the utilization of clozapine was delayed for an average of 5 years longer than should have been the case if the guidelines had been followed. Many clinicians site the inconvenience of the required blood monitoring due to the risk of agranulocytosis. Hodge and Jespersen (4) examined whether this posed as great a problem for patients as doctors thought it would. They reported that 19% of patients indicated that they felt inconvenienced by the blood monitoring, while in contrast 52% of the clinicians felt that their patients would be inconvenienced. There is no question that clozapine presents special challenges. It is associated with a significantly higher risk of agranulocytosis than other drugs and the risk of metabolic complications is also very high. There are other side effects as well. However, if an adequate therapeutic trial is given then an assessment can be made regarding benefits and risks. Until we and the patient have the opportunity to see how much benefit actually results from clozapine, it is difficult to make a personalized decision. One of the most important questions that remains for us is what can we do to increase the appropriate utilization of this treatment. The biggest obstacle appears not to be patient refusal, but physician reluctance. It is hoped that the work of Nielsen and others will help to remedy this situation.