Which Psychotropics Up Risk of Death?


Insights from the first study of mortality and cumulative psychotropic exposure in schizophrenia.

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Schizophrenia is associated with a dramatic increase in premature mortality. The potential impact of psychotropic medications on mortality risk in schizophrenia has been the subject of intense debate.

Previous studies of the relationship between risk of death and cumulative antipsychotic exposure in patients with schizophrenia did not control for effects of other psychotropic medications. Furthermore, few studies have explored relationships between current, but not cumulative, exposure to antidepressants and benzodiazepines in patients with schizophrenia, despite their frequent use in this population.

Tiihonen and colleagues1 studied the relationship between cumulative antipsychotic, antidepressant, or benzodiazepine exposure and mortality in Sweden. They used nationwide registry data (including information on inpatient care, specialized outpatient care, and disability pensions) to conduct a prospective, population-based cohort study of 21,492 patients with schizophrenia. Subjects were followed up from 2006 through 2010.

Information on prescribed and dispensed medications was obtained from the Prescribed Drug Register. Cumulative psychotropic exposure was estimated using the defined daily dose (DDD). Patients were categorized into 4 groups:

(1) no antipsychotic, antidepressants, or benzodiazepines during the follow-up period

(2) small doses or occasional use (0 to 0.5 DDD per day)

(3) moderate doses (0.5 to 1.5 DDD per day) and

(4) high doses (> 1.5 DDD per day). For reference, 1 DDD is equivalent to risperidone 5 mg, fluoxetine 20 mg, and diazepam 10 mg

This was the first study of the association between mortality and cumulative exposure to multiple classes of psychotropic medications in patients with schizophrenia.

Mortality data was obtained from the Causes of Death Register. The number of outpatient visits during 2001 to 2015 was used as a proxy marker for treatment adherence, and the number of hospital days during 1988 to 2005 was a proxy for illness severity. All-cause mortality and mortality due to cardiovascular disease and suicide were analyzed using Cox proportional hazards regression.

Subjects in the cohort had a mean age of 46 and mean duration of illness of approximately 6 years; 61% were male. During the 5-year follow-up, 1591 patients (7.4%) died, which was 4.8-fold higher than an age- and sex-matched cohort from the general population. The leading causes of death were cardiovascular disease (33%), neoplasms (17%), respiratory diseases (11%), and suicide (10%).

All levels of exposure to antipsychotics (adjusted hazard ratios [HRs], 0.59-0.75) or antidepressants (adjusted HRs, 0.60-0.85) were associated with a significantly lower overall mortality compared with no use. By contrast, exposure to benzodiazepines was associated with a significantly higher overall mortality, with a 74% higher risk of death in subjects with high exposure compared with no use.

Patients with high benzodiazepine exposure also had the most frequent visits to health care services. The pattern of results for death from cardiovascular disease was similar to that for overall mortality. Regarding suicide mortality, high benzodiazepine exposure was associated with a higher risk and high antipsychotic exposure was associated with a lower risk.

This was the first study of the association between mortality and cumulative exposure to multiple classes of psychotropic medications in patients with schizophrenia. Antipsychotics and antidepressants were associated with a significant reduction in mortality compared with no use, whereas there was a clear dose-response curve for benzodiazepine exposure and mortality. Potential mechanisms explaining the latter association include that long-term benzodiazepine use is a marker for illness severity and/or comorbid substance use disorder.

Tolerance may develop, and dose escalation could result in interactions with alcohol and illicit drugs, as well as accidents due to daytime sedation. The authors note that the findings regarding benzodiazepines could also be partly attributable to residual confounding because they were not able to fully control for illness severity and lifestyle factors (eg, smoking and diet).

The bottom line
Antipsychotics and antidepressants were associated with an approximately 15% to 40% reduction in overall mortality. In contrast, long-term, high-dose benzodiazepine use was associated with an up to 70% higher risk of mortality-compared with no use-in patients with schizophrenia.


Dr Miller is Associate Professor in the Department of Psychiatry at Augusta University in Augusta, GA, and Schizophrenia Section Editor for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.


1. Tiihonen J, Mittendorfer-Rutz E, Torniainen M, et al. Mortality and cumulative exposure to antipsychotics, antidepressants, and benzodiazepines in patients with schizophrenia: an observational follow-up study. Am J Psychiatry. 2016;173:600-606.

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