Long-term benzodiazepine use is associated with increased mortality in people with schizophrenia

Randall F. White, MD, FRCPC (biography and disclosures) Disclosures: Honoraria from MedscapeCME.com, Otsuka-Lundbeck, UBC CPD. Mitigation: The practice and research discussed has no direct relevance to my activities with the organizations listed above; only published trial data is discussed.

What I did before

When psychiatric patients are treated in an emergency department, they are often hypervigilant, manic, or otherwise in an excited, agitated state. The current standard of care to manage acute agitation in adults is using an antipsychotic medication and a benzodiazepine, often loxapine or haloperidol and lorazepam (1). All three medications are available as tablets and intramuscular injections; oral medication is preferred. In many cases, patients remain on such a medication combination when they are admitted to the inpatient psychiatry service, and often the benzodiazepine is continued during the hospitalization for comorbid anxiety or insomnia. For patients who have schizophrenia, antipsychotic medication alone often treats such symptoms in the longer term, yet many patients are discharged with a benzodiazepine prescription continue long-term benzodiazepine treatment possibly because the community clinician hopes to avoid triggering a relapse in discontinuing the medication. As a psychiatrist who has worked on acute and tertiary inpatient units, I have discharged patients on benzodiazepines with the expectation it would eventually be discontinued, but I have also seen many patients for whom it never was.

What changed my practice

In 2013, Dr. Jari Tiihonen of the Karolinska Institute in Stockholm visited Vancouver for the 7th Annual  Pacific Psychopharmacology Conference. In his presentation (http://bcpsychosis.org/2013/09/25/benzoate-and-not-benzodiazepines-for-antipsychotic-augmentation/) he mentioned his research showing that people with schizophrenia on chronic benzodiazepine therapy have an increased risk for suicide and all-cause mortality. These findings came from a cohort of about 2,600 Finnish patients observed during a 7-year interval; the hazard ratio was 1.91 (2). An earlier study from Denmark had found an odds ratio of 1.78 for death in schizophrenia patients taking long-acting benzodiazepines (3).  I kept these observations in the back of my mind and was further alarmed in 2016 when Dr. Tiihonen and his group published an article from a Swedish cohort that replicated his first study just after release of a different team’s findings from a US cohort (http://bcpsychosis.org/2016/10/22/benzodiazepines-may-increase-the-risk-of-death-in-people-with-schizophrenia/) (4,5).

The Swedish cohort comprised 21,492 people with schizophrenia, mean age of 45.5 years, of whom 1,591 (7.4%) died during a 5-year interval, a rate 4.8 times that of 214,670 matched controls from the general population. More than 19,000 of the cohort were on antipsychotic medication whereas nearly 14,600 were on a benzodiazepine, usually in combination with an antipsychotic and sometimes an antidepressant. Antipsychotic treatment protected against all-cause mortality and suicide, but benzodiazepine use increased both in a somewhat dose-dependent fashion. High-dose benzodiazepine use, but not lesser doses, was associated with increased suicide and cardiovascular mortality. Antidepressant use tended to decrease all-cause mortality, but its effects were relatively small and in fact nil for death by suicide.

The causality and mechanisms of benzodiazepine-associated mortality in schizophrenia require further investigation. The Finnish/Swedish team mentions hypotheses such as:

• Patients with the most severe illness are prescribed high-dose benzodiazepines
• Benzodiazepines increase the risk for unintentional injuries and death
• Benzodiazepines increase impulsiveness that facilitates self-harm and suicide
• In a population prone to substance use disorders, benzodiazepines may be combined with alcohol or opioids leading to fatal unintentional overdoses

What I do now

Based upon these studies from populations in four countries that comprise 70,000 people with schizophrenia, I find the evidence compelling that benzodiazepines are contraindicated for long-term use in people with schizophrenia. This chronic mental illness is associated with premature death apart from medication effects; most of this mortality is due to suicide and cardiovascular disease (6). I continue to use lorazepam for acute agitation as it is effective in sedation and reduction of anxiety, and it allows lower doses of antipsychotics and their uncomfortable side effects such as dystonia. However, I attempt to discontinue them in all patients with chronic psychotic disorders as soon as possible, or to at least minimize the dose. When appropriate, I also educate patients about the risk of long-term use, including dependence and cognitive impairment in addition to mortality.

To raise awareness of this issue among my colleagues, I mention the rationale and include recommendations for tapering benzodiazepines in consultation reports and discharge summaries. If a patient has been on low-dose benzodiazepines for a brief time, such as during a month-long inpatient stay, tapering is typically not difficult and may be done in a matter of weeks. After months or years of benzodiazepine use, or if a sedative use disorder or concurrent addiction is present, a residential detoxification may be justified. Some general guidelines for benzodiazepine weaning are available here (http://nationalpaincentre.mcmaster.ca/opioid/cgop_b_app_b06.html), but each patient requires an individualized approach.

References

1. Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. American Journal of Emergency Medicine. 1997;15:335-340. (View with CPSBC or UBC) DOI: 10.1016/S0735-6757(97)90119-4
2. Tiihonen J, Suokas JT, Suvisaari JM, Haukka J, Korhonen P. Polypharmacy With Antipsychotics, Antidepressants, or Benzodiazepines and Mortality in Schizophrenia. Archives of General Psychiatry. 2012;69:476-483. (Request with CPSBC or view UBC) DOI: 10.1001/archgenpsychiatry.2011.1532
3. Baandrup L, Gasse C, Jensen V, et al. Antipsychotic Polypharmacy and Risk of Death From Natural Causes in Patients With Schizophrenia: A Population-Based Nested Case-Control Study. Journal of Clinical Psychiatry. 2010;71:103-108. (View with CPSBC or UBC) DOI: 10.4088/JCP.08m04818yel
4. Tiihonen J, Mittendorfer-Rutz E, Torniainen M, Alexanderson K, Tanskanen A. Mortality and Cumulative Exposure to Antipsychotics, Antidepressants, and Benzodiazepines in Patients With Schizophrenia: An Observational Follow-Up Study. American Journal of Psychiatry. 2016;173:600-606. (View with CPSBC or UBC) DOI: 10.1176/appi.ajp.2015.15050618
5. Fontanella C, Campo J, Phillips G, et al. Benzodiazepine Use and Risk of Mortality Among Patients With Schizophrenia: A Retrospective Longitudinal Study. Journal of Clinical Psychiatry. 2016;77:E661-E667. (Request with CPSBC or view UBC) DOI: 10.4088/JCP.15m10271
6. Walker ER, McGee RE, Druss BG. Mortality in Mental Disorders and Global Disease Burden Implications: A Systematic Review and Meta-analysis. Journal of the American Medical Association Psychiatry. 2015;72:334-341. (Request with CPSBC or view UBC) DOI: 10.1001/jamapsychiatry.2014.2502

Resource:

Ashton H. Benzodiazepines: How They Work & How to Withdraw. Benzo.org.uk. Published 1999. Accessed February 20, 2017. (View)

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