Suicidal behavior and depression in smoking cessation treatments

Area of Science:

• Pharmacovigilance
• Clinical Safety
• Public Health

Background:

• Smoking cessation pharmacotherapies, including varenicline and bupropion, carry U.S. Food and Drug Administration (FDA) Boxed Warnings for suicidal behavior and depression.
• Epidemiological studies suggest potential risks associated with smoking cessation independent of specific treatments.
• Comparative safety data between varenicline and bupropion regarding these adverse events are limited.

Purpose of the Study:

• To compare the risk of suicidal/self-injurious behavior or depression associated with varenicline, bupropion, and nicotine replacement products.
• To analyze serious adverse event reports from the FDA's Adverse Event Reporting System (AERS) database.

Main Methods:

• Analysis of serious adverse event reports from the FDA AERS database (1998-2010) for varenicline, bupropion (for smoking cessation), and nicotine replacement products.
• Definition of a composite endpoint for suicidal/self-injurious behavior or depression using Standardized MedDRA Queries (SMQ).
• Calculation of disproportionality ratios (Odds Ratios) comparing event rates for each drug against all other serious events for that drug, using nicotine replacement as a reference.

Main Results:

• A total of 3,249 cases of suicidal/self-injurious behavior or depression were identified, with 90% linked to varenicline.
• Varenicline showed a significantly higher disproportionality (OR 8.4) for these events compared to nicotine replacement.
• Bupropion also demonstrated an increased disproportionality (OR 2.9) compared to nicotine replacement, though less pronounced than varenicline.

Conclusions:

• Varenicline is associated with a substantial and statistically significant increased risk of reported depression and suicidal/self-injurious behavior.
• Bupropion for smoking cessation presented smaller increased risks for these adverse events.
• The safety profile of varenicline, particularly its association with suicidal behavior and depression, suggests it may not be suitable as a first-line smoking cessation therapy.