The risks of benzodiazepines, antidepressants and antipsychotics in adults with schizophrenia


Polypharmacy is the simultaneous use of two or more drugs to treat a single health condition.

Polypharmacy is often used in the treatment of schizophrenia where people are regularly prescribed two or more antipsychotics, as well as antidepressants and/or benzodiazepines, although there is little evidence to prove that these combinations are more effective than monotherapy. It is thought that these combinations of drugs may be harmful, but research investigating the long-term effects is fairly thin on the ground.

This registry-based retrospective cohort study has been conducted by a research team from the University of Eastern Finland. The researchers have followed a cohort of 2,588 patients with schizophrenia and linked their medical records to national databases of drug prescriptions and mortality.

The aim of the study was to find out if the use of benzodiazepines, antidepressants or multiple antipsychotics were associated with an increase in mortality for adults with schizophrenia. The primary outcome was all-cause mortality and the secondary outcome was suicide.

The mean follow-up period was just over 4 years and they used hazard ratios (PDF definition) to measure the likelihood of death.

Here’s what they found:

  • Compared with antipsychotic monotherapy, use of 2 or more antipsychotics was not associated with an increased risk of:
    • All-cause mortality (HR 0.86, 95% CI 0.51 to 1.44)
    • Suicide deaths (HR 0.87, 95% CI 0.32 to 2.34)
    • All other deaths (HR 0.88, 95% CI 0.48 to 1.63)
  • Compared with antipsychotic monotherapy, using no antipsychotics was associated with an increased risk of:
    • All-cause mortality (HR 2.09, 95% CI 1.34 to 3.26)
    • Compared with using no antipsychotics, using two or more antipsychotics was associated with a reduced risk of:
    • Mortality (HR 0.41, 95% CI 0.25 to 0.68)
  • Compared with no antidepressant use, using antidepressants was not associated with an increased risk of:
    • All-cause mortality (HR 0.57, 95% CI 0.28 to 1.16)
  • Compared with no antidepressant use, using antidepressants was associated with a decrease in:
    • Suicide deaths (HR 0.15, 95% CI 0.03 to 0.77)
  • Compared with no benzodiazepine use, using benzodiazepines was associated with a significant increase in:
    • All-cause mortality (HR 1.91, 95% CI 1.13 to 3.22)
    • Suicide deaths (HR 3.83, 95% CI 1.45 to 10.12)
  • Compared with no benzodiazepine use, using benzodiazepines was not associated with a significant increase in:
    • All other deaths (HR 1.60, 95% CI 0.86 to 2.97)

The authors concluded:

Benzodiazepine use was associated with a marked increase in mortality among patients with schizophrenia, whereas the use of an antidepressant or several concomitant antipsychotics was not. Antidepressant use was associated with decreased suicide deaths. The literature indicates that long-term use of benzodiazepines among patients with schizophrenia is more prevalent in other countries (e.g. the United States) compared with Finland, which suggests that benzodiazepine use may contribute to mortality among this patient population worldwide.

As always with this kind of observational research, there are inherent weaknesses in the study methodology:

  • The length of drug treatment and dosage were not considered
  • Deaths in hospital were not included
  • Hazard ratios do not show causality, but simply an association with prescriptions, which can be misleading

These prescription patterns are interesting, but it may be that the use of these drug treatments indicates the severity of the mental illness rather than leading directly to the cause of death.


Tiihonen J, Suokas JT, Suvisaari JM, et al. Polypharmacy with antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia. Arch Gen Psychiatry 2012;69:476–83. [PubMed abstract]

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Andre Tomlin

André Tomlin is an Information Scientist with 20 years experience working in evidence-based healthcare. He's worked in the NHS, for Oxford University and since 2002 as Managing Director of Minervation Ltd, a consultancy company who do clever digital stuff for charities, universities and the public sector. Most recently André has been the driving force behind the Mental Elf and the National Elf Service; an innovative digital platform that helps professionals keep up to date with simple, clear and engaging summaries of evidence-based research. André is a Trustee at the Centre for Mental Health and an Honorary Research Fellow at University College London Division of Psychiatry. He lives in Bristol, surrounded by dogs, elflings and lots of woodland!

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