Restrictions on the use of the second-generation antipsychotic drug clozapine because it caused depletion of white blood cells may have caused thousands of extra deaths worldwide, according to a new study.
Professor Jari Tiihonen, University of Kuopio and Niuvanniemi Hospital, Finland, and colleagues say that clozapine is associated with lower mortality (by 26%), when it and other antipsychotics are compared with the standard first generation antipsychotic perphenazine.
And long-term use of antipsychotics in general is associated with around 20% lower mortality compared with no antipsychotic use they conclude in a study published Online First today and in an upcoming edition of The Lancet.
The authors note their surprise that clozapine—the antipsychotic drug restricted by authorities in the late 1970s because of concerns that it caused agranulocytosis and only brought back into restricted use in USA in the late 1980s—was associated with the lowest mortality.
They say: “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. However, clozapine is inexpensive, and hence it is unprofitable for the pharmaceutical industry to market compared with other second-generation antipsychotic drugs.
“Additionally, (weekly blood) monitoring schedules are a drawback that would be encountered with heightened use of clozapine, and physicians and other hospital staff might therefore be reluctant to initiate clozapine treatment.”
And they conclude. “Restrictions on use of clozapine and thioridazine have not been based on any evidence for their overall ratio of risk to benefit. Our results suggest that these instructions and recommendations (except for blood monitoring) might have caused thousands of premature deaths worldwide in patients who have been exposed to other antipsychotic drugs, which might be associated with increased mortality.
“In our opinion, such restrictions and recommendations should be based on solid scientific evidence for the safety of drugs. This example underscores the need for large nationwide databases to be used for surveillance of drug safety.”
The introduction of several second-generation antipsychotic drugs during the 1990s is widely believed to have adversely affected mortality of patients with schizophrenia.
In this population-based study, the authors used national registers in Finland to compare the cause-specific mortality in some 67,000 patients versus the total population (5.2 million) between 1996 and 2006, and to link these data with use of antipsychotic drugs.
They measured the all-cause mortality of patients with schizophrenia in outpatient care during current and cumulative exposure to any antipsychotic drug versus no use of these drugs, and exposure to the six most frequently used antipsychotic drugs compared with perphenazine use.
Although the proportional use of second-generation antipsychotic drugs (from the total of all types of antipsychotic drugs combined) rose from 13% to 64% during follow-up, the gap in life expectancy from age 20 years between patients with schizophrenia and the general population did not widen between 1996 (25 years) and 2006 (22.5 years).
Compared with current use of perphenazine, the highest risk for overall mortality was recorded for quetiapine (41% increase) and the lowest for clozapine (26% decrease).
Long-term cumulative exposure (7-11 years) to any antipsychotic treatment was associated with around 20% lower mortality than was no drug use. In patients with one or more filled prescription for an antipsychotic drug, an inverse relation between mortality and duration of cumulative use was noted.