Long-term adjunctive benzodiazepines may not improve outcomes in bipolar disorder

In the late 1970s, benzodiazepines were among the most commonly prescribed drugs in the world. Today, they continue to be one of the most frequently prescribed classes of medications for patients with bipolar disorders. Evidence exists to support their use in bipolar patients in acute settings as adjuncts to core mood stabilizers for improving sleep and controlling mania or agitated and aggressive behavior. But there is less evidence supporting their adjunctive use in long-term treatment.

William V. Bobo, M.D., a psychiatrist specializing in the evaluation and treatment of depression at Mayo Clinic's campus in Rochester, Minnesota, says long-term benzodiazepine therapy in patients with bipolar disorder raises important safety concerns because of the potential for benzodiazepine abuse and the high prevalence of alcohol and substance use disorders in this population. Benzodiazepines may also be associated with a higher risk of mood episode recurrence.

"The concerning aspects of benzodiazepines create a dilemma for clinicians attempting to manage bipolar disorder — and coexisting anxiety disorders — over the long term," he says. "In addition, outpatient doctors often inherit patients discharged from the hospital on benzodiazepines, and there is no clear evidence to guide decisions about continuing or stopping these drugs."

To shed some light on the controversy, Dr. Bobo and colleagues looked at the effects of longer term adjunctive benzodiazepine therapy on core bipolar symptoms and associated anxiety and irritability using data from the Bipolar CHOICE study.

Bipolar CHOICE was a six-month randomized, multisite comparison of lithium and quetiapine-based treatment. Of the 482 patients with bipolar I or II disorder enrolled in the trial, 138 (28.6 percent) were considered benzodiazepine users at baseline or follow-up. The researchers then compared clinical measures, including the Bipolar Inventory of Signs and Symptoms (BISS) and Clinical Global Impressions-Bipolar (CGI-BP) scale, in benzodiazepine users and nonusers.

Although improvement was seen in both groups, benzodiazepine users experienced significantly less improvement in BISS total, BISS irritability and CGI-BP scores than nonusers did. Benzodiazepine use also did not affect any outcome measure in patients with comorbid anxiety or substance use disorders. Results of the study were published in 2014 in the Journal of Affective Disorders.

"What we found is that adjunctive benzodiazepine use may not significantly affect outcomes in patients with bipolar disorders over the long term," Dr. Bobo says. "We think this is an important finding given how frequently these drugs are prescribed for long periods and their potential for abuse and association with recurrences. The limitation is that this is only a secondary analysis of data from a trial not intended to address benzodiazepine use. Still, we think further study is warranted."

In a second study using Bipolar CHOICE data, the same research team looked at the characteristics of patients who were prescribed adjunctive benzodiazepines. They found that users were more likely to have bipolar I disorder with comorbid anxiety, had experienced more anxiety, depressive symptoms and suicidality, and were prescribed significantly more psychotropic medications than nonusers were. Having a comorbid substance use disorder did not seem to affect whether patients were benzodiazepine users. Results of the study were published in 2015 in the Journal of Clinical Psychopharmacology.

"Higher illness complexity appeared to be the major driver of benzodiazepine use in patients with bipolar I and II disorder, and using benzodiazepines with more established treatments may represent clinicians' best efforts to bring complex psychiatric symptoms under better control," Dr. Bobo says. "But that has to be weighed against the risks and limited evidence supporting long-term benzodiazepine treatment. My recommendation would be to exercise caution. Not every patient is guaranteed a worse or no outcome with these drugs, but we need to better understand for which patients they may be safe and effective."

For more information

Bobo WV, et al. Effect of adjunctive benzodiazepines on clinical outcomes in lithium- or quetiapine-treated outpatients with bipolar I or II disorder: Results from the Bipolar CHOICE trial. Journal of Affective Disorders. 2014;161:30.

Bobo WV, et al. Complexity of illness and adjunctive benzodiazepine use in outpatients with bipolar I or II disorder: Results from the Bipolar CHOICE study. Journal of Clinical Psychopharmacology. 2015;35:68.