San Diego—Neuropsychiatric adverse events weren’t elevated in patients using smoking-cessation aids varenicline and bupropion compared to those using nicotine patches or placebo, according to an international study.

The research, published online by The Lancet, was in response to an FDA mandate following postmarketing reports suggesting that varenicline and bupropion could cause adverse neuropsychiatric events, such as increased agitation, depression, hostility, or suicidal behavior.

Boxed warnings to that effect have limited usage, according to a University of California San Diego press release which notes that the “EAGLES” study was funded by Pfizer and GlaxoSmithKline, makers of varenicline and bupropion, respectively, and designed in consultation with the FDA.

“There are 1 billion smokers in the world and nearly 6 million smoking-related deaths each year, but there are only three approved medication treatments for quitting: nicotine replacement therapies like the patch and the two non-nicotine medications, bupropion and varenicline,” said first author Robert Anthenelli, MD, professor of psychiatry and director of the Pacific Treatment and Research Center at UC San Diego School of Medicine.

For the study, researchers sought to directly assess the safety and efficacy of varenicline and bupropion compared to the nicotine patch and to a placebo in smokers with and without psychiatric disorders. More than 8,000 smokers seeking to quit in 16 countries were involved in the randomized, controlled double-blind trial from November 2011 to January 2015.

Participants were adults aged 18 to 75 years who smoked on average more than 10 cigarettes a day and were motivated to stop smoking, with 82% having made at least one attempt to quit. Half of them had a history of a past or current stable psychiatric condition including a mood, anxiety, psychotic, or borderline personality disorder, and about half of that group was taking psychotropic medications.

Anthenelli noted that no other study has looked at “smokers with current or past psychiatric disorders who consume roughly 45% of the cigarettes sold in the U.S.”

Results indicate that an average 2% of nonpsychiatric participants reported moderate or severe adverse neuropsychiatric events for any of the treatments—1.3% for varenicline, 2.2% for bupropion, 2.5% for the nicotine patch, and 2.4% for placebo.

Among those with psychiatric disorders, meanwhile, moderate and severe adverse neuropsychiatric events were slightly higher across the board, including 6.5% for varenicline, 6.7% for bupropion, 5.3% for the nicotine patch, and 4.9% for placebo.

“The findings from this study, together with data from previous trials and large observational studies, make it highly unlikely that varenicline and bupropion increase the risk of moderate-to-severe neuropsychiatric side effects in smokers without psychiatric disorders,” Anthenelli said.

The study found varenicline to be the most effective for smoking cessation, with bupropion determined to be about as effective as nicotine patches. All were more effective than placebo, according to the research.

Study authors warn that, since the participants had a stable psychiatric disorder and were being treated, the findings might not apply to those with untreated or unstable psychiatric illness.

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