Restrictions on the use of the second-generation antipsychotic drug clozapine* (due to safety concerns) may have caused thousands of extra deaths worldwide. This is because a new study has shown that use of clozapine is associated with lower mortality (by 26%), when it and other antipsychotics are compared with the standard first generation antipsychotic perphenazine. Furthermore, long-term use of antipsychotics in general is associated with around 20% lower mortality compared with no antipsychotic use. These are the conclusions of an Article published Online First and in an upcoming edition of The Lancet, written by Professor Jari Tiihonen, University of Kuopio and Niuvanniemi Hospital, Kuopio, Finland, and colleagues.
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.
The researchers found that 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.
The authors note their surprise that clozapine—the antipsychotic drug restricted by authorities because of safety concerns—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, 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."
In conclusion, the authors say that long-term treatment with antipsychotic drugs is associated with lower mortality compared with no antipsychotic use. They say: "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."
In an accompanying Comment, Dr Lydia A Chwastiak and Dr Cenk Tek, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA, say that 'these results mean that the reports of under-use of clozapine in African–American patients with schizophrenia are of even greater concern.'
They conclude: "The mortality gap in this study was largely attributed to deaths at an early age—the life-expectancy difference in people with schizophrenia compared with the general population was greater in those aged 20 years than in those aged 40 years. In the present crisis of health-care inequality, it seems that some disparities are more unequal than others."
Professor Jari Tiihonen, University of Kuopio and Niuvanniemi Hospital, Kuopio, Finland. T) +358 50 341 83 63 E) jari.tiihonen@niuva.fi
Dr Lydia A Chwastiak, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA. T) +1 203 974-7771 E) lydia.chwastiak@yale.edu
For full Article and Comment, see: http://press.thelancet.com/fin11.pdf
Notes to editors: *Clozapine was the first of the second-generation antipsychotics, discovered in the 1950s and brought into clinical practice in the 1970s.Its use was restricted due to safety issues (see below) and was only brought back into restricted use in the late 1980s (USA).
**Blood monitoring: (explained by Professor Tiihonen) The use of clozapine is restricted so that it can be used only after two unsuccessful trials with other antipsychotics—and currently, thioridazine is not used at all. Because clozapine is associated with lower mortality than other antipsychotics this restriction may have resulted into excess mortality. Clozapine can cause agranulocytosis, a condition in which white blood cells are depleted. Use of clozapine requires weekly blood monitoring for six months followed by monthly testing thereafter to look for signs of, and prevent, agranulocytosis.
Journal
The Lancet