BEHAVIOR
July 29, 2009

Clozapine Reconsidered

Clozapine, a highly effective anti-psychotic, is rarely prescribed because of its dangerous side-effects. But a new study finds...More

The average schizophrenia sufferer dies about 20 years sooner than a member of the general population. An 11−year Finnish study has found that the most effective drug at shrinking this gap is clozapine. Yet clozapine is rarely prescribed, particularly in the U.S., because of various health concerns surrounding its use. The new Finnish study authors are highly critical of this under−prescribing and claim that the benefits of clozapine treatment far outweigh its risks.

Nevertheless, the current study authors claim that not prescribing clozapine has led to thousands of needless deaths.

Clozapine was first introduced in Europe in 1971. It was voluntarily withdrawn from the market by the manufacturer in 1975 after it was shown to cause a condition called agranulocytosis in about 1% of all patients. Agranulocytosis is a drastic lowering of certain types of white blood cells and can be fatal. Clozapine has also been shown to increase the risk of myocarditis and other heart problems. Because of its effectiveness at treating schizophrenia, in 1989 the FDA approved clozapine for use in treating schizophrenia patients who were unresponsive to all other drugs. In 2002, the FDA widened availability to include schizophrenia patients thought to be at risk of suicide.

Despite its availability, physicians in the U.S. have been reluctant to prescribe clozapine. After all, the physician's credo is to first do no harm, and clozapine certainly has the potential to cause harmful side effects. Also, patients taking clozapine are required to have weekly blood cell counts to allow for early detection and treatment of any developing agranulocytosis for six months, and there is concern about schizophrenia patients following this routine.

Nevertheless, the current study authors claim that not prescribing clozapine has led to thousands of needless deaths. They suggest that the original restrictions on clozapine were arbitrary−not based on overall risk to benefit assessment. They also question the role of the drug companies in prescription practices; clozapine is inexpensive and unprofitable compared to most of the newer antipsychotics.

The study examined the cause of death in 67,000 Finnish schizophrenia patients between 1996 and 2006. Long term usage (7−11 years) of any antipsychotic lowered the death rate by about 20%. Clozapine was the most effective of the six most commonly prescribed antipsychotics at lowering the death rate.

The study was not originally focused on clozapine. It was undertaken because of concerns that some newer antipsychotics were actually increasing the death rate among schizophrenia patients. This was found not to be true. They all reduced the death rate, but varied greatly in effectiveness. When compared to the older antipsychotic perphenazine, the drug quetiapine was the least effective (a 41% higher death rate), while clozapine was the most effective (a 26% lower death rate). The effectiveness of clozapine caught the researchers by surprise.

Despite its potential for adverse side effects, those who took clozapine lived the longest. Jari Tiihonen, M.D., Ph.D, a co−author of the study and a professor in the department of forensic psychology at the University of Kuopio in Finland. Tiihonen sums up: "Our results raise the issue of whether clozapine should be used as a first−line treatment, because it seems to be the safest antipsychotic in terms of mortality and it is also the most effective."

The results of the study were published in an early, online version by The Lancet on July 13, 2009.

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