By Joanna Lyford, Senior medwireNews Reporter

The relationship between antipsychotic use and mortality in people with schizophrenia shows a clear U-shape curve, with the highest risk of death seen in those with no antipsychotic exposure, a Swedish cohort study has found.

A similar pattern was apparent for cardiovascular-specific mortality, leading the study authors to conclude that excess deaths in people with schizophrenia “are attributable to other factors than antipsychotic treatment when used at adequate doses.”

Patients with schizophrenia have a shorter life expectancy than the general population and recent studies have suggested that exposure to antipsychotic drugs may be associated with increased mortality.

To investigate this hypothesis in a rigorous, prospective setting, Jari Tiihonen (Karolinska Institute, Stockholm) and colleagues undertook a population-based cohort study of all 21,492 people aged 17–65 years in Sweden diagnosed with schizophrenia before 2006.

In order to avoid survival bias, they also conducted an analysis in a separate cohort of 1230 patients with first-episode schizophrenia during the period 2006–2010. A total of 214,670 age- and gender-matched individuals from the general population served as controls.

The schizophrenia patients were assessed for cumulative exposure to antipsychotic drugs by defined daily dose (DDD) and categorised into four groups: no antipsychotics; small doses or occasional use (0–0.5 DDD/day); moderate doses (0.5–1.5 DDD); and high doses (>1.5 DDD/day).

In total, 1591 (7%) people in the main cohort died during 5 years of follow-up while 45 (4%) of those with first-episode schizophrenia died.

Mortality rates differed among the four antipsychotic exposure groups and displayed a U-shape curve, Tiihonen and co-workers report in Schizophrenia Bulletin. Compared with the general population, hazard ratios (HRs) for overall mortality were 6.3 for no antipsychotic use, 5.7 for high antipsychotic use, and 4.1 and 4.0 for low and moderate antipsychotic use, respectively.

Analyses of cardiovascular- and cancer-specific mortality showed similar U-shaped curves, with low and moderate antipsychotic exposure being associated with substantially lower mortality than either no or high exposure.

Respiratory disease followed a different pattern, in which high-dose exposure had the highest mortality and no exposure had the lowest mortality; the reverse was true for suicide, whereby the higher the antipsychotic exposure the lower the suicide risk.

In a further analysis controlled for age and gender, first-episode schizophrenia patients who had not used antipsychotics had higher mortality when compared with those with moderate antipsychotic use (HR=3.60). Low or high exposure were not significantly associated with mortality.

Noting that this is the first study to investigate how cumulative antipsychotic exposure may affect the excess mortality seen in schizophrenia, the authors say their study “clearly indicates that both excess overall and cardiovascular mortality in schizophrenia is attributable to other factors than long-term antipsychotic treatment when used in adequate dosages.”

They add: “An alarmingly high excess mortality among first-episode patients who do not use any antipsychotics deserves more attention, in order to increase adherence to their prescribed pharmacological treatment.”

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