Background: The introduction of second-generation antipsychotic drugs during the 1990s is widely believed to have adversely affected mortality of patients with schizophrenia. Our aim was to establish the long-term contribution of antipsychotic drugs to mortality in such patients.
Methods: Nationwide registers in Finland were used to compare the cause-specific mortality in 66 881 patients versus the total population (5.2 million) between 1996, and 2006, and to link these data with the use of antipsychotic drugs. We 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.
Findings: Although the proportional use of second-generation antipsychotic drugs rose from 13% to 64% during follow-up, the gap in life expectancy 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 (adjusted hazard ratio [HR] 1.41, 95% CI 1.09-1.82), and the lowest risk for clozapine (0.74, 0.60-0.91; p=0.0045 for the difference between clozapine vs perphenazine, and p<0.0001 for all other antipsychotic drugs). Long-term cumulative exposure (7-11 years) to any antipsychotic treatment was associated with lower mortality than was no drug use (0.81, 0.77-0.84). In patients with one or more filled prescription for an antipsychotic drug, an inverse relation between mortality and duration of cumulative use was noted (HR for trend per exposure year 0.991; 0.985-0.997).
Interpretation: Long-term treatment with antipsychotic drugs is associated with lower mortality compared with no antipsychotic use. Second-generation drugs are a highly heterogeneous group, and clozapine seems to be associated with a substantially lower mortality than any other antipsychotics. Restrictions on the use of clozapine should be reassessed.
Funding: Annual EVO Financing (Special government subsidies from the Ministry of Health and Welfare, Finland).