Varenicline successfully promoted durable smoking cessation without exacerbating depression or anxiety in a randomized, phase IV, industry-funded study of patients with stably treated major depressive disorder.

Smoking cessation, defined as carbon monoxide–confirmed continuous abstinence, was higher at weeks 9-12 among 256 subjects in the double-blind study who were randomized to receive varenicline, compared with 269 who received placebo (35.9% vs. 15.6%; odds ratio, 3.35), Dr. Robert M. Anthenelli of the University of California, San Diego, and his colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The differences between the groups were also significant for weeks 9-24 (20.3% vs. 10.4%; OR, 2.36) and for weeks 9-52 (25% vs. 12.3%; OR, 2.36), the investigators said (Ann. Intern. Med. 2013;159:390-400).*

A new study suggests varenicline may help patients quit smoking without exacerbating depression or anxiety.

No clinically relevant differences were seen between the groups in suicidal ideation or behavior as captured by the Columbia Suicide Severity Rating Scale. Furthermore, no overall worsening of depression or anxiety occurred in either group. In fact, trajectories of mood and anxiety rating trended slightly toward improvement in both groups, they said.

Participants in the multicenter study were adults aged 19-73 years who had no recent cardiovascular events, who smoked at least 10 cigarettes daily, and who had current or past stably treated unipolar major depressive disorder without psychotic features. They were recruited from 38 centers in 8 countries between March 2010 and June 2012. Randomization was stratified by antidepressant use at baseline (any vs. none) and by baseline depression score (Montgomery-Asberg Depression Rating Scale score 11 or less vs. greater than 11). Patients received either placebo or varenicline titrated to a dose of 1 mg twice daily for 12 weeks, with a 40-week nontreatment follow-up phase.

Treatment was relatively safe; although 72.3% and 66.9% of the treatment and placebo groups, respectively, experienced treatment-emergent adverse events, most were mild or moderate. The most frequent adverse events in the treatment vs. placebo groups were nausea (27.0% vs. 10.4%, respectively), headaches (16.8% vs. 11.2%), abnormal dreams (11.3% vs. 8.2%), irritability (10.9% vs. 8.2%), and insomnia (10.9% vs. 4.8%). Two patients in the treatment group died during the nontreatment phase, but neither death was considered to be related to treatment, the investigators said.

The findings suggest that varenicline, like other FDA-approved smoking cessation aids effective in non–psychiatrically ill smokers, are similarly effective in smokers with a history of depression – without increasing depressive symptoms; in the case of varenicline, as demonstrated in this study, this also applies to patients with depression who are using antidepressant medications.

"Varenicline is a partial agonist of brain alpha4beta 2 nicotinic acetylcholine receptors and is believed to alleviate nicotine withdrawal while simultaneously blocking its rewarding effects. Because depressed smokers are prone to more severe nicotine withdrawal than nonpsychiatric smokers, mitigating withdrawal symptoms may be important in this population," the investigators said. Depressed smokers who lapse into smoking while attempting to regulate mood may find cigarettes less reinforcing while taking varenicline, thus facilitating prolonged abstinence, they noted.

Although the findings may not extrapolate to untreated or actively depressed smokers and those with other psychiatric conditions, since only stably treated patients without psychotic features and other disorders frequently associated with major depressive disorder (such as bipolar disorder and current substance use disorders) were included, the findings nevertheless suggest an important role for varenicline in smokers with a history of stably treated depression.

"With 350 million individuals having the disease worldwide and because a large proportion of smokers that seeks treatment has a lifetime history of MDD, these results have the potential to reduce morbidity and mortality in many smokers," they concluded.

The researchers noted several study limitations, including their selection of "a population of smokers who were stably treated for or remitted from depression." Thus, they wrote, "our findings may not extrapolate to untreated or actively depressed smokers, whom many consider to be poor candidates for smoking cessation until their condition stabilizes." They also excluded individuals with "with psychotic features, bipolar disorder, current substance use disorders, and other conditions frequently associated with major depressive disorder; patients receiving medication for mania or psychosis were also excluded. Missing data resulting from attrition in both treatment groups may have affected the outcomes, the authors further noted.

This study was funded by Pfizer. Individual authors reported receiving support from the Department of Veterans Affairs; the National Institute on Alcohol Abuse and Alcoholism; the University of California, San Francisco; the Smoking Cessation Leadership Center; and/or the Colorado Department of Public Health and Environment. Detailed disclosures are available at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0777.

*CORRECTION, 10/10/13: An earlier version of this article misstated the citation for the journal article referenced in the story.

Varenicline helps smokers with stably treated depression