Large Population Study Does Not Link Varenicline With Suicide, Psychosis, or Traffic Incidents

Varenicline is emerging as a promising smoking cessation agent. This medication has been found to be more effective than nicotine replacement strategies like the patch, and it even works well for people who want to quit smoking gradually instead of abruptly (Psychiatric News, March 20). Research highlighted at APA’s 2015 annual meeting even suggests that varenicline may be used to treat alcohol use disorder (Psychiatric News, June 19).

Despite the results of these trials, there continue to be concerns that varenicline increases the risk of depression, suicide, or psychosis—factors that in 2009 led the Food and Drug Administration (FDA) to issue a black-box warning for the drug. Additionally, varenicline use has been reported to increase the risk of traffic accidents. As a result, several transportation-industry professions have restricted or prohibited its use.

While the psychiatric side effects and increased risk of traffic accidents were first identified during postmarketing surveillance of varenicline users, several clinical studies since have found no association between varenicline and these problems, except possibly in people with pre-existing mental health conditions.

“Such controlled clinical trials are a gold standard in identifying reactions or effects of a medication,” said Robert Gibbons, Ph.D., director of the Center for Health Statistics at the University of Chicago and an expert in pharmacological epidemiology. “However, they typically involve smaller groups so they may not be generalizable to the broad population or catch rare events.”

Seena Fazel, M.D., a professor of forensic psychiatry at the University of Oxford, along with colleagues at Sweden’s Karolinska Institute, has now published a large, population-level study using Swedish registry data, providing more evidence that the psychiatric concerns linked with varenicline may be unfounded.

The study, which was published last month in the British Medical Journal, also offered a new twist in methodology.

“In a traditional comparison study, you would look at people on varenicline versus people not on varenicline,” Fazel told Psychiatric News. “In this study, we compared the same person at times when they were taking the medication or not taking the medication; so everyone was basically his or her own control.”

One advantage of this method, known as within-person analysis, is that several factors that can influence a study—such as genetics or childhood experiences—are constant, which reduces the amount of statistical adjustments that need to be made to account for the natural variability of a large group.

Indeed, when Fazel and his team compared the roughly 70,000 people in Sweden who took varenicline between 2006 and 2009 with the country’s population at large, they found that the varenicline users had higher rates of seven adverse outcomes: diagnosis of a new psychiatric condition, suicidal behavior, suspected or convicted of a crime, suspected or convicted of a traffic offense, and transportation accidents. However, such an analysis did not factor in that people on varenicline are all smokers and have inherently different behaviors and health risks than nonsmokers.

When the team carried out a within-person analysis of these same 70,000 people, they found no differences in the rates of these events in relation to varenicline use, except that individuals taking varenicline had a slight increase in depression and anxiety; as in other studies, these risks were confined to people with an existing psychiatric disorder.

However, the researchers found that smokers on the cessation drug buproprion also had slightly elevated risks of mood and anxiety disorders. “So this phenomenon may be a general consequence of nicotine withdrawal and not related to the medication,” Fazel said.

“With any drug safety issue, you want multiple lines of evidence pointing in the same direction,” Gibbons said. “Varenicline is becoming an important drug, and while patient safety is paramount, we do not want to deny people treatment based on consequences that are not valid.”

Gibbons noted that Pfizer, the manufacturer of varenicline, is currently carrying out its own large clinical study assessing neuropsychiatric side effects, and the FDA estimates the results will be available by the end of 2015.

This study was funded by the Wellcome Trust, the Swedish Research Council, and the Swedish Research Council for Health, Working Life, and Welfare. ■

“Varenicline and Risk of Psychiatric Conditions, Suicidal Behaviour, Criminal Offending, and Transport Accidents and Offences: Population Based Cohort Study” can be accessed here.