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How early should clozapine be used in the treatment of patients with schizophrenia?

Response From the Expert

John M. Kane, MD 
Professor of Psychiatry, Neurology, and Neuroscience, Albert Einstein College of Medicine; Chairman, Department of Psychiatry, The Zucker Hillside Hospital, New York, NY

Clozapine remains the only medication that has shown consistent superiority over other antipsychotic drugs in the management of patients who fail to benefit adequately from standard treatment.

Estimates are that at least one third of patients do not respond adequately to antipsychotic treatment. Of course, these estimates of response rates depend on how response is defined. The majority of patients will improve on antipsychotic medication; however, the definition of treatment resistance usually involves significant psychopathology, eg, ratings of moderate or greater on 2 psychotic symptoms. At the same time, it has been shown that even patients with only 1 psychotic symptom at a moderate or greater level who have failed to show further improvement after taking at least 2 different antipsychotic medications are more likely to benefit from clozapine than from other medications.

Clozapine is not an easy medication to use, and it is associated with a variety of side effects. Therefore, considerations around its use should be informed by a clear benefit-to-risk assessment and thorough discussion with the patients and their significant others.

Most experts agree that at least 2 antipsychotics should be tried before going on to clozapine. At present there is no real consensus as to whether one of those medications should be a conventional antipsychotic. Therefore, I do not believe that anyone would be faulted for only trying atypical medications prior to taking clozapine. On the basis of data from clinical trials and meta-analyses, olanzapine and risperidone are the 2 medications that have the most data suggesting some superiority over conventional medications, so it would make sense that at least 1 of those medications is prescribed in an adequate trial before considering clozapine.

The duration of an adequate trial is another component of this decision-making process. Most would agree that 6 weeks at an adequate dose is sufficient. Another caveat in this discussion is the issue of compliance. It is important that nonadherence be ruled out as a potential cause of poor treatment response. In addition, the diagnosis and the potential presence of comorbid medical or psychiatric conditions should be reevaluated before considering a patient to be treatment refractory. If the decision is made to institute a trial of clozapine, it is important to monitor for side effects but also to carefully evaluate treatment response. If no improvement is observed after 12 weeks despite an adequate dose of clozapine (500 mg if tolerated), further improvement is unlikely. If, on the other hand, some improvement is observed, further gradual improvement may occur. In those patients who have failed to respond despite an apparently adequate dose, a blood level should be obtained to determine whether or not it is in the therapeutic range.

Unfortunately, many patients who might benefit from clozapine are not given a trial — and even among those who are, it is often far later in the illness course than is appropriate.

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