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Clozapine: The Safest Antipsychotic?

22 July 2009. The road to needless deaths in schizophrenia may be paved with good intentions, hints a new study based on the entire population of Finland. Published online in Lancet on July 13, it suggests that the restrictions on clozapine use, spurred by safety concerns, do more harm than good. The researchers involved, led by Jari Tiihonen of the University of Kuopio, Finland, report that clozapine showed the lowest mortality rate of the seven antipsychotic drugs that they studied. They also tie long-term use of any antipsychotic to lower mortality.

When clozapine emerged as the first atypical, or second-generation antipsychotic (see, however, SRF related news story and commentary by H. Meltzer on these terms), it offered the advantage of causing fewer movement disorders than the existing alternatives did (Crilly, 2007). Just as its long struggle for acceptance into the treatment mainstream began to succeed, another Lancet report from Finland (Idänpään-Heikkilä et al., 1975) warned that 16 patients who had been taking it developed agranulocytosis, a blood disease that hampers the ability to fight infection. Half of them died.

The drug’s superior efficacy (see SRF related news story; see SRF news story) kept it from fading into obscurity, but its availability came with restrictions. In the United States, for instance, a black-box warning tells prescribers to use it only for patients whose severe schizophrenia has not responded to other antipsychotic drugs and for those with schizophrenia or schizoaffective disorder who are prone to repeated suicide attempts. In addition, clozapine users must undergo frequent blood testing, particularly early in treatment.

Second-generation antipsychotics can also cause weight gain, diabetes, and death from cardiovascular disease (see SRF related news story; see SRF news story), although first-generation ones may do so, too (see SRF related news story; see SRF news story). Tiihonen and colleagues wondered whether the growing use of the newer class of drugs could have contributed to the widening mortality gap between the general population and people with schizophrenia (see SRF related news story). The latter tend to die about 25 years earlier.

Keeping patients alive
To examine deaths in relation to antipsychotic drug use, the new study compared the 11-year mortality rate of the 66,881 patients with schizophrenia in Finland with that of the nation’s entire population of 5.2 million. The researchers linked data from three nationwide registries: A hospital discharge registry enabled them to identify subjects who had received inpatient treatment for schizophrenia; the national sickness insurance program provided data on filled prescriptions for antipsychotic drugs; and the government agency Statistics Finland supplied information about deaths and their causes. To compare the utilization of different drugs, the study used the defined daily dose (Wertheimer, 1986).

The results suggest that while the use of second-generation antipsychotics jumped from 13 percent of defined daily doses in 1996 to 64 percent in 2006, no widening of the life expectancy difference between subjects with and without schizophrenia occurred. Rather, patients’ life expectancy at age 20 rose by 4.9 years, twice the increase seen in the general Finnish population. This did not eliminate patients’ mortality disadvantage, however. That seemed to stem from deaths at an early age in that the life expectancy gap at age 20 exceeded that at age 40.

Despite fears about fatal side effects, the findings indicate that taking antipsychotic drugs might actually delay death. Patients who had received at least seven years of antipsychotic treatment were less likely to die during the 11-year follow-up than patients who had not filled any prescriptions for them (adjusted HR 0.81, 95 percent CI 0.77 – 0.84). Furthermore, in patients who had filled at least one antipsychotic prescription, the longer the use, the lower the mortality risk (HR for trend per exposure year 0.991, 95 percent CI 0.985 – 0.997). “Tiihonen and colleagues’ study is an important reminder that the adverse effects of drugs are not the only factor contributing to excess mortality,” write Lydia Chwastiak and Cenk Tek, both of Yale University, New Haven, Connecticut, in their commentary in the same issue of Lancet.

The risks of clozapine restrictions may exceed the benefits
These findings may reassure patients and clinicians that necessary treatment need not cost patients years of life. However, as two meta-analyses revealed in 2008, individual drugs differ widely, even within the "classes" of first-generation or second-generation antipsychotics (see SRF related news story). Fortunately, Tiihonen and colleagues examined the mortality profiles of six of the most widely used antipsychotic drugs: thioridazine, oral haloperidol, and oral perphenazine from the first generation, and clozapine, olanzapine, oral risperidone, and quetiapine from the second. They compared each of the other drugs against perphenazine, while controlling for sex, age, and several indicators of physical and mental health.

During the 11-year follow-up, patients with schizophrenia who were currently taking clozapine showed, by far, the lowest risk of all-cause mortality (adjusted HR 0.74, 95 percent CI 0.60 – 0.91); those on quetiapine showed the highest (adjusted HR 1.41, 95 percent CI 1.09 -1.82). Besides quetiapine, analyses also tied risperidone (adjusted HR 1.34, 95 percent CI 1.12 – 1.62) and haloperidol (adjusted HR 1.37, 95 percent CI 1.10 – 1.72) to a heightened death risk. Notably, they did not implicate olanzapine, despite its link to greater metabolic side effects (see SRF related news story; see SRF news story).

As for causes of death, the researchers looked at suicide and ischemic heart disease. They found a much lower risk of death by suicide in clozapine users than in patients who were taking another antipsychotic medication (adjusted HR in comparison with perphenazine 0.34, 95 percent CI 0.20 – 0.57). Clozapine stood alone in this regard; no other drug showed a lower risk of death from suicide than perphenazine did. Mortality from heart disease, on the other hand, did not differ among drugs in analyses that controlled for potential confounding variables.

Tiihonen and colleagues warn that many premature deaths may have resulted from patients being prescribed other antipsychotics with worse safety profiles than clozapine. “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.” As Chwastiak and Tek note, “Even though people with clinically significant medical comorbidities might be excluded from clozapine treatment and the eventual burden of cardiovascular mortality could take decades to emerge fully, this finding is still striking.”—Victoria L. Wilcox.

Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, Haukka J. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009 July 13. Abstract

Chwastiak LA, Tek C. The unchanging mortality gap for people with schizophrenia. Lancet. 2009 July 13. Abstract

Comments on News and Primary Papers
Comment by:  John McGrath, SRF Advisor
Submitted 23 July 2009 Posted 23 July 2009
  I recommend the Primary Papers

The results of this study are surprising. In those with...  Read more

View all comments by John McGrath

Comment by:  Francine Benes, SRF Advisor
Submitted 4 November 2009 Posted 4 November 2009

Clozapine: A First-Line Antipsychotic?
Tiihonen...  Read more

View all comments by Francine Benes

Comment by:  Edward Orton (Disclosure)
Submitted 18 November 2009 Posted 18 November 2009
  I recommend the Primary Papers

Dr. Benes notes that clozapine is "...a very effective...  Read more

View all comments by Edward Orton
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