Benzodiazepines may increase the risk of death in people with schizophrenia

Patients with psychosis often accumulate medications during hospitalizations and changes in prescribers. The use of multiple medications, often with uncertain benefit, is called polypharmacy. The use of more than one antipsychotic is considered problematic and may increase the risk of adverse effects such as weight gain and diabetes, but other kinds of psychiatric medications often accumulate as well, including antidepressants and benzodiazepines. The latter are used for a variety of reasons, often for acute agitation in an emergency setting, but also for insomnia or chronic anxiety. They may be associated with tolerance, escalating dosage and dependence, although overall are considered safe medications.

Population-based studies from Finland and Denmark have revealed that patients with schizophrenia, however, may be at elevated risk for death when treated with a benzodiazepine.  Now the same has been found in a US cohort. Researchers from Ohio State University examined outpatients covered by US Medicaid, age 18 to 58 years old, who had received a diagnosis of schizophrenia during 2007 to 2009. They looked at prescription claims for benzodiazepines, antipsychotics, antidepressants and mood stabilizers from time of diagnosis through 2013. They then examined death certificate files for deaths among the 18,953 identified subjects and calculated hazard ratios for all-cause mortality, death from suicide and accidental poisoning, and death by natural causes.

Of 18,953 patients with schizophrenia, 3,476 received a benzodiazepine, and those subjects were more often Caucasian females who were separated or divorced. The top 3 benzodiazepines prescribed were, in order, lorazepam, clonazepam and alprazolam. In patients taking an antipsychotic, in comparison with those who had no added benzodiazepine, the adjusted hazard ratio after initiating a benzodiazepine was 1.48, i.e. a 48% increased risk of death during the time of cotreatment. For patients who received only a benzodiazepine and no antipsychotic or other medication, the adjusted hazard ratio was 3.08. The calculated mortality rate per 1000 person-years was significantly elevated in every examined combination of medications, e.g. for a mood stabilizer alone, or for an antidepressant plus an antipsychotic, when a benzodiazepine was added. Furthermore, the risks of death from suicide, accidental poisoning and natural causes were all elevated.

The investigators caution that this is an association, and that benzodiazepines cannot yet be implicated as a definite cause of premature mortality in people with schizophrenia. However, this evidence adds to existing epidemiologic findings to make the risk-benefit ratio of benzodiazepine prescription less favorable. The possible mechanisms behind the risk could be multiple, and the researchers mention lower mood and impulsiveness which may occur during benzodiazepine use along with withdrawal-related anxiety as factors that could elevate risk of suicide. As for natural causes, some evidence exists for heightened incidence of infectious diseases concomitant with benzodiazepine use. Prospective studies and larger epidemiologic investigations are required to understand this association, but prescribers should always keep in mind the maxim “do no harm” and attempt to eliminate unnecessary medications.

Reference

Fontanella CA, Campo JV, Phillips GS, Hiance-Steelesmith DL, Sweeney HA, Tam K, Lehrer D, Klein R, Hurst M. Benzodiazepine use and risk of mortality among patients with schizophrenia: a retrospective longitudinal study. J Clin Psychiatry. 2016;77(5):661-667. Abstract