John M. KANE

Clozapine is underutilized

John M. KANE

I read the piece by Wang and Li[1]with great interest. The issues surrounding the use of clozapine in China and the United States provide an interesting contrast. Wang and Li suggest that clozapine is over-utilized in China both as a first-line treatment and (in low doses) to augment other antipsychotic agents. The situation in the United States is that clozapine is grossly underutilized as a treatment for patients with refractory schizophrenia and clinically significant suicidality. Despite the evidence that 25-40% of patients with schizophrenia would be candidates for clozapine based on labeled indications, approximately 5% of patients with schizophrenia are receiving it.

Clozapine was approved by the Food and Drug Administration in the United States in 1989 following a large-scale clinical trial we conducted in 1988[2]demonstrating clozapine’s superiority over chlorpromazine in carefully selected treatment refractory patients who had undergone a prospective trial of high dose haloperidol in order to confirm their lack of response. Over the subsequent two decades clozapine’s superiority has been confirmed in several governmentfunded studies.[3-5]Despite the introduction of other so called 'atypical' or second generation antipsychotics, no other compound—even those with similar chemical structures—has consistently replicated clozapine’s effects.

Although clozapine has been shown to be superior in patients who have failed on other medications, there is no evidence that clozapine is superior as a first-line medication. At the same time, however, it is possible that waiting until a patient fails adequate trials of three different medications is too conservative an approach; these patients may be waiting too long to try an effective treatment. Unfortunately, there is insufficient research to establish the optimum point in an individual’s treatment history to introduce clozapine. It is certainly possible that the introduction of clozapine after one fully adequate failed trial of an antipsychotic medication (with confirmed adherence and therapeutic blood levels) would be sufficient. If this proved true it would be particularly valuable in the first episode of illness or in the first years after onset of illness as it would increase the likelihood of a timely treatment response.

Clozapine’s use has been somewhat constrained by the requirement for weekly blood monitoring in order to detect the presence of agranulocytosis. The risk of true agranulocytosis appears to have declined since the early years of clozapine use, and new methods for managing this condition has reduced fatality rates enormously. Nevertheless, the management of clozapine’s side effects continues to be a challenge. Though progress is being made in identifying individuals at high risk for agranulocytosis[6]this still remains an obstacle for some physicians and patients. The risk of metabolic side effects is also very real and needs to be considered in any management plan.

The appropriate or optimum dosing of clozapine also remains a challenge. Dosage patterns vary considerably from country to country. Though some studies provide guidance regarding therapeutic blood levels it is likely that there are ethnic differences in these relationships as well. Clearly, as suggested by Wang and Li,[1]more research is necessary to achieve the goals of personalized medicine in the use of a drug like clozapine, where both the potential rewards and risks are higher than usual.

Some clinicians and policy makers attribute the underutilization of clozapine to its side effect profile and, therefore, patient resistance to its use. However, it is often the case that physicians project their own concerns about the possible serious side effects of clozapine onto patients and make assumptions about patients’ desires without an appropriate process of shared decision-making. Moreover, many physicians in the United States and in China appear more comfortable with antipsychotic drug polypharmacy than with clozapine monotherapy, despite the fact that polypharmacy has not been adequately established as an appropriate strategy for the treatment of refractory patients.

The fact that clozapine utilization varies as much asit does from country to country underscores the variety of factors that contribute to its use. Many clinicians are inadequately informed about the evidence base for the use of clozapine and about the strategies necessary for managing its potential adverse effects. Further training about clozapine is necessary. But there is also a need for research on implementation. How can the field of psychiatry better succeed at promulgating the use of evidence-based practices?

Conflict of interest

The author reports no conflict of interest related to this manuscript. Dr. Kane has been a consultant, served on an advisory board and/or received honoraria for lecturing from the following companies:

Amgen, BMS, Eli Lilly, Intracellular Therapeutics, Janssen, Jazz Pharmaceuticals, Johnson and Johnson, Lundbeck, Merck, Novartis, Otsuka, Pierre-Fabre, Roche, Sunovion.

1. Wang CY, Li LL. Proper use of clozapine; experiences in China. Shanghai Archives of Psychiatry, 2012;24(2): 108-109.

2. Kane JM, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1998; 45(9): 789-796.

3. Kane JM, Marder SR, Schooler NR, Wirshing WC, Umbricht D, Baker RW, et al. Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and doubleblind comparison. Arch Gen Psychiatry 2001;58(10):965-972.

4. Kumra S, Kranzler H, Gerbino-Rosen G, Kester HM, DeThomas C, Kafantaris V, et al. Clozapine and “high dose” olanzapine in refractory early-onset schizophrenia: a 12 week randomized and double-blind comparison. Biol Psychiatry 2008;63(5):524-529.

5. McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006;163(10):600-610.

6. Athanasiou MC, Dettling M, Cascorbi I, Mosyagin I, Salisbury BA, Pierz KA, et al. Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis. J Clin Psychiatry 2011;72(4):458-463.

10.3969/j.issn.1002-0829.2012.02.008

Department of Psychiatry, The Zucker Hillside Hospital and Department of Psychiatry, Hofstra North Shore-LIJ School of Medicine

Correspondence: psychiatry@nshs.edu