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Mortality with schizophrenia—effects of antipsychotic treatment
Despite the availability of effective antipsychotic therapy for treatment of schizophrenia, there remains an excess mortality associated with the disorder—a trend that has increased over recent time.^1,2 An increased risk of suicide has been identified as one contributing factor to this higher mortality. Studies have reported a 10- to 12-fold increase in the risk of suicide among patients with schizophrenia compared to the general population. However, as much as 60% of early deaths in patients with schizophrenia is attributed to natural causes, such as cardiovascular disease.³ The higher mortality seen from cardiovascular disease is likely secondary to a higher prevalence of modifiable cardiovascular risk factors—obesity, smoking, diabetes, hypertension, dyslipidemia, and metabolic syndrome—among these individuals.⁴ The contribution of newer atypical antipsychotics, which can cause weight gain and adverse metabolic effects, to the increased mortality with schizophrenia is unclear.¹

The FIN11 study
To further address the issue of mortality in patients with schizophrenia and to evaluate the role of antipsychotic therapy on mortality, Tiihonen and colleagues conducted a large population-based cohort study (the FIN11 study).³ Data for the study, conducted in Finland, were obtained from various health-related registries and databases, including the National Hospital Discharge Register, Statistics Finland, and the Social Insurance Institution. Data collected included duration of antipsychotic therapy and mortality. Current and cumulative use of antipsychotics was also determined. Antipsychotics used were primarily the first generation agents perphenazine, thioridazine, and haloperidol and second generation atypicals clozapine, olanzapine, risperidone, and quetiapine. Patients who received only 1 agent were classified as monotherapy, patients receiving multiple agents were considered as polypharmacy, and those taking antipsychotics other than those listed above were classified as other. Any cause mortality was the primary outcome, with secondary outcomes of mortality due to suicide and mortality due to ischemic heart disease. The study cohort included all patients in Finland with schizophrenia—66,881 patients—and data from 1996 through 2006 were analyzed.

During the 11-year study period, 156,456,368 purchased defined daily doses (average daily dose of the drug for its indication⁵) of medication were used.³ Use of second generation antipsychotics increased from 12.6% to 64.0% over the 11 years. Life expectancies for patients with schizophrenia were compared with that of the general population using data from the initial year of the study (1996) and at study end (2006). Based on 1996 data, the difference in life expectancy between patients with schizophrenia and the general population was 25 years (52.5 vs. 77.5 years). In 2006, the difference was similar—22.5 years (57.4 vs. 79.9 years).

Risk of any cause mortality was compared between no antipsychotic use and current use; current use was divided into specific time periods (e.g., ≥1 to 2 years, ≥2 years to 3 years, up to 11 years) and each time period compared to no use.³ Any cause mortality decreased significantly for current antipsychotic use beginning at ≥2 years and remained significant throughout the remaining time-cohorts, with hazard ratios (HRs) for mortality ranging from 0.89 to 0.73. Risk of mortality was also significantly lower within the first time period (0 to 0.5 years) with a HR of 0.49; no difference was seen for current use of ≥0.5 to 2 years versus no use. The authors looked at mortality for the specific antipsychotic agents taken, using perphenazine as the reference drug. For any cause death, only clozapine showed a significant reduction in the risk of mortality (5.69 vs. 10.77 deaths/1000 person-years for perphenazine; HR 0.74). No significant differences were seen with polypharmacy, olanzapine, or thioridazine in comparison with perphenazine, although the crude mortality rates were numerically higher (11.19 to 12.32 deaths/1000 person-years). However, risperidone, haloperidol, quetiapine, and other were all associated with a significant increase in any cause death (HRs 1.34, 1.37, 1.41, and 1.45, respectively). Clozapine was also the only antipsychotic to be associated with a significant reduction in death from suicide compared to perphenazine (0.84 vs. 1.84 deaths/1000 person-years; HR 0.34). Antipsychotics classified as other showed a significantly increased risk of suicide (2.75 deaths/1000 person-years; HR 1.55); the remaining agents had no effect. Finally, none of the antipsychotics showed any significant effect on the risk of death from ischemic heart disease in comparison to perphenazine, although clozapine again had the lowest crude mortality rate (1.31 deaths/1000 person-years). Based on cumulative use of an antipsychotic during the 11-year study, clozapine had the lowest relative risk (RR) of death compared with perphenazine. However, both quetiapine and risperidone had periods (at 2 to 4 years) of an increased RR of death during the 11 years.

The authors concluded that long-term use of antipsychotics is associated with a reduction in mortality among patients with schizophrenia in comparison to no or short-term use.³ Clozapine, usually reserved for severe or refractory cases, was the most effective in terms of preventing death among patients with schizophrenia. However, overall life expectancy for patients with schizophrenia was not shown to be further decreased with the increased use of atypical antipsychotics.

Summary
The study conducted by Tiihonen and colleagues is likely one of the largest to determine mortality among patients with schizophrenia, including over 66,000 patients. Clozapine was associated with the lowest any cause mortality as well as mortality due to suicide. None of the antipsychotics had an effect on mortality due to ischemic heart disease.

Clozapine was the first of the atypical antipsychotics to be made available, approved in 1989.⁶ Although it carries a boxed warning for significant adverse effects and requires regular monitoring, clozapine has been shown to be more effective than first generation antipsychotics and to result in lower discontinuation rates compared with other antipsychotics.^7-9 Available guidelines on the treatment of schizophrenia suggest a trial of 1 or 2 atypical antipsychotics (aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone) for initial therapy of schizophrenia.¹⁰ However, since only clozapine showed a reduction in mortality due to suicide, it may be the safest option for treatment of schizophrenia for some patients provided monitoring is appropriate.

References