High cumulative exposure to benzodiazepines is common in patients with schizophrenia and is associated with a significantly increased risk for premature death, according to new data from Sweden.

Treatment guidelines recommend that benzodiazepines not be used for longer than 1 month. "Therefore, it is alarming that one-third of the population of patients with psychosis in Sweden had used on average more than 0.5 defined daily dose per day of benzodiazepines, which is equal to more than 5 mg of diazepam or 25 mg of oxazepam every day during the 5-year follow-up," Jari Tiihonen, MD, PhD, of the Karolinska Institutet, Stockholm, and colleagues note.

"As common as long-term benzodiazepine use was in our study population, the literature indicates that it is probably more common among patients with schizophrenia in other developed countries, such as the United States," they add.

"When starting benzodiazepine treatment, it would be wise to try to limit the duration up to 1 month and to use antidepressants for long-term treatment of anxiety symptoms," Dr Tiihonen told Medscape Medical News.

The study was published online December 7 in the American Journal of Psychiatry.

Iatrogenic Cause of Early Death

The researchers investigated the association between mortality and cumulative exposure to antipsychotics, antidepressants, and benzodiazepines using two Swedish nationwide healthcare registers. Among roughly 7 million people aged 17 to 64 years, they identified 21,492 patients with schizophrenia, a prevalence of 0.34%.

Altogether, 1591 (7.4%) schizophrenia patients died during the 5-year follow-up period. Compared with 214,670 age- and sex-matched individuals from the general Swedish population, the mortality of the schizophrenia cohort was 4.8-fold higher. The most common specific cause of death was cardiovascular disease (32.7%), followed by neoplasms (16.5%), respiratory diseases (11.0%), and suicide (9.5%).

According to the researchers, any amount of antipsychotic and antidepressant use was associated with overall mortality rates 15% to 40% lower compared with no use of these medications. In contrast, benzodiazepine exposure was associated with a clear dose-response curve for mortality, with high exposure associated with a 70% higher risk for death compared with no exposure.

To date, two studies have assessed the relationship between benzodiazepine use and mortality in schizophrenia. In both studies, current benzodiazepine use was associated with an increase of 80% to 90% in mortality, Dr Tiihonen and colleagues note in their article.

"While it is probable that patients who need additional benzodiazepine treatment have more anxiety, insomnia, and depressive symptoms than other patients, it is also likely that high-dose chronic use of benzodiazepines, in violation of treatment guidelines, may have become an iatrogenic cause for excess mortality in this patient population," they point out. "On the other hand, patients who need add-on antidepressant treatment may also suffer from anxiety and depressive symptoms, which increase cardiovascular morbidity, suicidal behavior, and mortality."

"Physicians treating patients with schizophrenia should acknowledge the high mortality associated with chronic high-dose benzodiazepine use," the researchers conclude.

"It is important to realize that although monitoring of patients with moderate or high-dose antipsychotic treatment is relevant, it is essential to focus the preventive interventions on those patients who have an even higher risk of death, that is, patients not using antipsychotics and patients using high doses of benzodiazepines," said Dr Tiihonen.

Reached for comment, John Kane, MD, senior vice president, Behavioral Health Services, North Shore-LIJ Health System, Glen Oaks, New York, said that the study was important and provides "further evidence of an overall favorable benefit-to-risk ratio of antipsychotic medications in the treatment of individuals with a diagnosis of schizophrenia.

"In addition, antidepressant use was also associated with a reduction in overall mortality rates, whereas benzodiazepine use was associated with higher mortality. It is difficult to draw conclusions about the potential mechanism(s) of the benzodiazepine effect, but it should remind clinicians to be cautious in the long-term use of such agents in patients with schizophrenia," Dr Kane said.

The study was supported by the Karolinska Institutet (Stockholm); Niuvanniemi Hospital (Kuopio, Finland); and a grant from the Sigrid Juselius Foundation (Finland). Dr Tiihonen has served as a consultant, adviser, or speaker for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Hoffman-La Roche, Janssen-Cilag, Lundbeck, Novartis, Organon, Otsuka, and Pfizer and has received a grant from the Stanley Foundation. The other authors report no relevant financial relationships.

Am J Psychiatry. Published online December 7, 2015. Abstract