Varenicline, Smoking Cessation, and Neuropsychiatric Adverse Events

Analysis of longitudinal neuropsychiatric event data across the 17 randomized placebo-controlled trials of varenicline revealed no evidence of an increased risk of suicidal ideation or behavior or of neuropsychiatric events (depression, aggression, and agitation potentially associated with a greater risk of suicidal behavior) with varenicline. Moreover, we did not detect an increased risk of depression-related events after treatment discontinuation. There is, however, clear evidence that varenicline can cause side effects such as nausea, illustrating our ability to detect adverse events when present. A further strength of our research synthesis of the randomized controlled trial data is that we included two new studies, conducted with patients with current diagnoses of depression or schizophrenia, and identified additional study subjects with a history of psychiatric illness from the other studies. Overall, 13% of the sample had a current or past psychiatric illness, allowing us to determine the extent to which current or past psychiatric illness moderated the effect of the drug on both efficacy and safety. No evidence of a moderator effect was found, indicating that patients with psychiatric illness (current or past) are not at increased risk of developing neuropsychiatric events when treated with varenicline.

In terms of efficacy, 12 weeks of treatment with varenicline produced a 124% increase in the rate of abstinence relative to placebo and 22% relative to bupropion. The number needed to treat based on the estimated abstinence rates at 12 weeks was 2.63. A similar conclusion was reached by the recent Cochrane Collaboration review of nicotine receptor partial agonists for smoking cessation (2). The researchers found that the chances of successful long-term smoking cessation were two to three times better for varenicline compared with pharmacologically unassisted smoking cessation attempts and that the main adverse event was nausea at mild to moderate levels, which tended to subside over time. With respect to neuropsychiatric events, the researchers concluded that “there is little evidence from controlled studies of any link between varenicline and psychiatric adverse events.” We reach the same conclusion based on a more complete analysis of the data. The DOD data showed that eight of the nine neuropsychiatric event types examined were less frequent in patients using varenicline than in those using nicotine patch. The only disorder more frequently observed in varenicline-treated patients was transient mental disorder; however, there were few of these events (0.05% for varenicline and 0.03% for nicotine patch), and the apparent difference was not statistically significant. Similar results were obtained when patients with a past-year psychiatric illness were included or excluded. These results are similar to recent FDA (12) and DOD (13) reports regarding the absence of risk for psychiatric hospitalizations in VA and DOD patients treated with varenicline relative to those treated with nicotine patch. We note that the original DOD investigators (13) focused on inpatient events because outpatient events “are more likely to suffer from misclassification and should be interpreted with caution” and that “in outpatient settings, codes may represent instances of routine psychiatric care rather than adverse neuropsychiatric events.” While we agree that the absence of an observed effect for neuropsychiatric hospitalizations is a critically important finding and stands on its own, our analysis of the combination of inpatient and outpatient events adds further to the finding by ruling out the possibility that important events such as suicide attempts that did not lead to hospitalization would be overlooked in such an analysis. Furthermore, we do not see why the concern that outpatient treatment may be for a psychiatric illness unrelated to the medication should not apply equally to inpatient treatment, and we believe that the outpatient reports of neuropsychiatric events provide comparably meaningful and useful data, with the advantage of greatly expanding the sample size and number of outcome events.

It is possible that the decreased risk of neuropsychiatric events seen in the outpatient data for varenicline relative to nicotine replacement therapy resulted from clinicians prescribing nicotine replacement therapy instead of varenicline for patients at higher risk of such events. This explanation is tempered by the fact that the DOD data were for a period before the FDA warning.

The other large-scale observational study, conducted by Gunnell et al. (8), also failed to identify any significant difference between varenicline and nicotine replacement therapy in rates of depression and suicidal events. These observational studies are important because they demonstrate that the results of the randomized controlled trials generalize to the clinical population of patients treated with smoking cessation products and are not limited by the inclusion and exclusion criteria of the specific randomized controlled trials.

Signals have been identified, however, in spontaneous reports of depression and suicidal events made to the FDA’s Adverse Event Reporting System/MedWatch program. As previously noted, a possible safety signal for varenicline (relative to bupropion and nicotine replacement therapy) has been reported (5) for depression and suicidal events. As noted by Cahill et al. (2), however, the limitations of this class of data include “confounding by indication, underreporting, double-counting from multiple sources, and lack of representativeness, which limits generalizability” (4). They also note that because of heightened media coverage and FDA warnings, neuropsychiatric events may be more likely to be reported to the FDA for varenicline than for nicotine replacement therapy. The FDA also cautioned (17) against drawing causal inferences from such data, noting that there is often insufficient information on the report forms to evaluate the event and that not all adverse events are reported to them; hence they “cannot be used to calculate the incidence of an adverse event … in the U.S. population.”

In an effort to shed further light on this question, we obtained the same FDA data analyzed by Moore et al. (5) and followed their methodology for including and excluding adverse event reports. We were able to obtain a reasonably similar total number of events for varenicline: 10,291, compared with 9,575 reported by Moore et al. for the period 1998–2010. Note that this time frame includes 8 years before varenicline’s entry into the market and extends through the period of media attention and FDA warnings. In our analysis, we restricted the time frame to the period during which varenicline was on the market and before the media attention and FDA warnings, which could have stimulated reporting (the second quarter of 2006 through the third quarter of 2007). We found no evidence of a safety signal for varenicline relative to nicotine replacement therapy during this period for suicidal events (odds ratio=0.69, 95% CI=0.40–1.26), an effect for depression events (odds ratio=1.72, 95% CI=1.08–2.84), and no effect for aggression events (odds ratio=0.58, 95% CI=0.27–1.37). By contrast, significant effects of a much greater magnitude for bupropion relative to nicotine replacement therapy were observed during this same period (suicidal events: odds ratio=6.85, 95% CI=3.18–14.77; depression events: odds ratio=5.17, 95% CI=2.44–10.82; aggression events: odds ratio=7.64, 95% CI=2.90–20.58). Given the limitations of these data, their interpretation remains difficult; however, these results at least offer the alternative explanation that the safety signals identified for varenicline regarding neuropsychiatric events may have been produced by stimulated reporting.

In summary, our synthesis and reanalysis of all sponsor-conducted randomized placebo-controlled trials and an original analysis of a large DOD observational data set revealed no evidence that varenicline is associated with adverse neuropsychiatric events and confirmed nausea as a side effect. These findings are generally consistent with the literature and other randomized controlled trials and large observational studies. Our analysis reveals evidence in support of the superior efficacy of varenicline relative to both placebo and bupropion, thus indicating considerable benefit without evidence of risk of serious neuropsychiatric adverse events. These findings generalize to patients with and without a recent history of a psychiatric disorder.