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Progress Report - September 2009

State of play

 

The clozapine and myocarditis study now has:

·         85 confirmed cases

·         124 confirmed controls

·         13 samples for DNA extraction

 

We will shortly be submitting for publication two articles on:

·         The 9 fatal cases of myocarditis, in comparison with the non-fatal cases

·         Evidence-based monitoring guidelines

 

Clozapine the safest antipsychotic for mortality

An article published last month in the Lancet1 demonstrated that clozapine is associated with a significantly lower all-cause mortality than any other antipsychotic.

 

The study included all individuals in Finland admitted with a diagnosis of schizophrenia from 1973 to 2004 and followed up those living from 1996 to 2006.  Data on antipsychotic prescription and mortality were collected. The researchers found:

  • Antipsychotic drug use versus no use was protective against death.
  • Clozapine was way out in front for protection against all cause mortality compared with other antipsychotics in monotherapy - HR 0.74 (0.60-0.91) compared with perphenazine. All other antipsychotics were less protective than perphenazine.
  • For death from suicide, clozapine was again the most protective vs perphenazine: HR 0.34 (0.20-0.57).
  • For cardiovascular mortality, clozapine monotherapy was still the best (0.78; 0.54-1.12), but the differences between antipsychotics were not statistically significant. This suggests that the effects of clozapine on weight gain and glucose resistance do not offset other positive factors affecting cardiovascular mortality in patients taking clozapine.
  • The authors also plotted relative risk of death with cumulative antipsychotic use, and clozapine gave the most protection for durations of use from 1-7 years; only olanzapine improved on clozapine at 7-11 years (not significant).  As yet it is unknown whether clozapine may continue to be advantageous for mortality after 20 or 30 years of use.

The authors concluded that the restrictions placed on the use of clozapine might have caused thousands of premature deaths worldwide in patients exposed to other antipsychotics associated with higher mortality than clozapine.

This gives considerable impetus to the myocarditis study.  Since evidence indicates that clozapine is superior in efficacy2 and safety, as measured by mortality, to all other antipsychotics, it is essential to reduce the risk of myocarditis as a major cause of mortality and morbidity during clozapine initiation.

1.    Tiihonen J et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009;374:620-7.

2.      Leucht S, et al.  Second generation versus first generation antipsychotic drugs for schizophrenia: a meta-analysis.  Lancet 2009;373:31-41.