Prescription Medications for the Treatment of Insomnia and Risk of Suicide Attempt: a Comparative Safety Study

IMPORTANCE: Guidelines for the pharmacological treatment of chronic insomnia in adults recognize that trazodone and other off-label medications are commonly prescribed despite poor evidence. The Department of Veterans Health Affairs (VA) fills high volumes of inexpensive, over-the-counter sedating antihistamines and older antidepressants in addition to benzodiazepines and zolpidem. Yet little is known about the comparative safety of these agents with regard to suicidal behavior. OBJECTIVES: To assess the comparative effectiveness of the safety of medications routinely used to treat insomnia in VA. DESIGN: Comparative effectiveness using propensity score-matched samples. SETTING: VA. PARTICIPANTS: VA patients without any history of suicidal ideation or behavior 12 months prior to first exposure. Exposures: VA formularies and data were used to identify prescriptions for insomnia. Agents accounting for at least 1% of total insomnia fill volume were <200 mg trazodone, hydroxyzine, diphenhydramine, zolpidem, lorazepam, diazepam, and temazepam. Exposure was defined as an incident monotherapy exposure preceded by 12 months without any insomnia medications. Subjects with insomnia polypharmacy or cross-overs in the 12 months following first exposure were excluded. MAIN OUTCOMES AND MEASURES: Suicide attempts within 12 months of first exposure. RESULTS: Three hundred forty-eight thousand four hundred forty-nine subjects met criteria and three well-balanced cohorts by drug class matched to zolpidem were created. After adjusting for days' supply, mental health history, and pain and central nervous system medication history, hazard ratios (compared to zolpidem) were as follows: (<200 mg) trazodone (HR = 1.61, 95% CI 1.07-2.43); sedating antihistamines (HR = 1.37, 95% CI 0.90-2.07); and benzodiazepines (HR = 1.31, 95% CI 0.85-2.08). CONCLUSIONS AND RELEVANCE: Compared to zolpidem, hazard of suicide attempt was 61% higher with trazodone (<200 mg). No significant differences in suicide attempt risk were identified between benzodiazepines or sedating antihistamines and zolpidem, respectively. These findings provide the first comparative effectiveness evidence against the use of trazodone for insomnia.