The findings of this American study suggest that varenicline is associated with a significantly increased risk for suicidal behavior and depression. Bupropion, for smoking cessation, was found to be associated with smaller increased risks.

The researchers note that both varenicline and bupropion are treatments for smoking cessation and both carry Boxed Warnings from the United States Food and Drug Administration (U.S FDA) relating to suicidal/self-injurious behavior and depression. They examined the comparative neuropsychiatric safety profiles of varenicline and bupropion with regard to suicidal/self-injurious behavior and depression as reflected in adverse drug event data. Data for serious injury case reports between 1998 and September 2010 from the FDA's Adverse Event Reporting System AERS) database involving varenicline (n = 9575), bupropion (n = 1751), or nicotine replacement products (n = 1917) were examined. As comparison groups, the researchers selected case reports for all nicotine replacement products regardless of route of administration, and also the combined case reports for three frequently dispensed antibiotics, amoxicillin, amoxicillin-clavulanate, and azithromycin.

A composite endpoint of suicidal/self-injurious behavior or depression was defined as a case with one or more Preferred Terms in Standardised MedDRA Query (SMQ) for those adverse effects. MedDRA - or Medical Dictionary for Regulatory Activities - is a medical terminology used to classify adverse event information associated with the use of biopharmaceuticals and other medical products (e.g., medical devices and vaccines) in the U.S. (see link on SMQs below for further information). The main outcome measure considered was the ratio of reported suicide/self-injury or depression cases for each drug compared to all other serious events for that drug. The results found:

• Overall 3,249 reported cases of suicidal/self-injurious behavior or depression were identified -  2,925 (90%) for varenicline, 229 (7%) for bupropion, and 95 (3%) for nicotine replacement.

• Compared to nicotine replacement, the disproportionality results (OR (95% CI)) were varenicline 8.4 (6.8–10.4), and bupropion 2.9 (2.3–3.7).

• The disproportionality persisted after excluding reports indicating concomitant therapy with any of 58 drugs with suicidal behavior warnings or precautions in the prescribing information.

• An additional antibiotic comparison group showed that adverse event reports of suicidal/self-injurious behavior or depression were otherwise rare in a healthy population receiving short-term drug treatment.

The researchers note limitations of their study and conclude, “Varenicline shows a substantial, statistically significant increased risk of reported depression and suicidal/self-injurious behavior. The excess risk persisted even after adjusting for numbers of patients exposed, for the possibility of different reporting rates, and for concomitant therapy. Bupropion for smoking cessation had increased risks but less so than for varenicline. The findings for varenicline, combined with other problems with its safety profile, render it unsuitable for first-line use in smoking cessation.”

Editor’s note: NICE guidance on the use of varenicline in smoking cessation was published in 2007 and recommends varenicline as an option for smoking cessation. The MHRA has reviewed data on adverse psychiatric reactions linked to varenicline – see link below.