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Smokers with psychiatric disorders who took the stop-smoking drug varenicline (Chantix) or the antidepressant bupropion (Wellbutrin) in an effort to kick the habit were no more likely to experience serious neuropsychiatric side effects than those who used nicotine patches or placebo, researchers reported.

Findings from the randomized, double-blind, multinational -- and manufacturer-funded -- , which included more than 8,000 participants, were reported April 22 online in .

No significant increase in psychiatric events was seen with varenicline or bupropion use, relative to nicotine patch or placebo use, and varenicline was found to be somewhat more effective for smoking cessation than the other interventions, researcher of the University of California San Diego, and colleagues wrote.

Smokers in the study with psychiatric disorders were more likely than those without them to experience moderate to severe neuropsychiatric adverse events during the study, but the event rate was similar for all treatments, including placebo.

"This is the largest randomized, controlled trial to date comparing these smoking-cessation medications directly and comparing them with placebo," Anthenelli told 乌鸦传媒. "We are hoping that the recognition that these medications are safe for smokers with and without psychiatric disorders will encourage people to try and quit and feel comfortable that they can use any of the available medications."

Study Requested by FDA

The randomized trial was requested by the FDA. In 2009, the agency ordered varenicline's manufacturer, Pfizer, to add black box labeling to the drug, which was approved for smoking cessation in 2006, warning of a potential increased risk for depressive behavior or suicidal ideation in users.

Pfizer appealed to the FDA to have the warning removed in 2014, citing new data indicating little risk of suicidality and other psychiatric risk, but an advisory committee recommended that the warning stay at least until data from the large, randomized trial were available.

In an editorial published with the study, addiction and mental health researcher of the University of Toronto wrote that "although the incidence of neuropsychiatric adverse events during smoking cessation is not zero, the risk of such an event occurring is not significantly increased by smoking-cessation medications."

"It will be of interest to see if the U.S. Food and Drug Administration (and their counterparts in other countries) will remove the black box warning for varenicline and bupropion in light of these findings," she added.

The study included 8,144 smokers attending 140 academic centers, clinical trial centers, and outpatient clinics in 16 countries who were randomized to 12 weeks of treatment with placebo, nicotine patch (21 mg per day with taper), varenicline (1 mg twice a day), or bupropion (150 mg twice a day), followed by 12 weeks of follow-up.

"Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit," the researchers wrote, adding that randomization was computer generated (in a 1:1:1:1 ratio) and participants, investigators, and research personnel were masked to the treatment assignments.

The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for 9 to 12 weeks.

Psychiatric Events Similar for All Treatments

A total of 4,116 participants were assigned to the psychiatric cohort and 4,028 to the nonpsychiatric cohort. All participants smoked, on average, more than 10 cigarettes a day at enrollment, and about half of those in the psychiatric cohort were taking psychotropic medications.

Among the study findings:

• In the nonpsychiatric cohort, moderate to severe neuropsychiatric adverse events occurred in 1.3%, 2.2%, 2.5%, and 2.4% of the varenicline, bupropion, nicotine patch, and placebo users, respectively.
• The varenicline-placebo and bupropion-placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were 1.28 (95% CI −2.40 to −0.15) and −0.08 (95% CI −1.37 to 1.21), respectively; the RDs for comparisons with nicotine patch were −1.07 (95% CI −2.21 to 0.08) and 0.13 (95% CI −1.19 to 1.45), respectively.
• In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 6.5%, 6.7%, 5.2%, and 4.9% of varenicline, bupropion, nicotine patch, and placebo users, respectively. The varenicline-placebo and bupropion-placebo RDs were 1.59 (95% CI −0.42 to 3.59) and 1.78 (95% CI −0.24 to 3.81), respectively; the RDs versus nicotine patch were 1.22 (95% CI −0.81 to 3.25) and 1.42 (95% CI −0.63 to 3.46), respectively.

Smokers who took varenicline achieved higher smoking-cessation rates at follow-up than those in the placebo group (odds ratio [OR] 3.61, 95% CI 3.07-4.24), nicotine patch (OR 1.68, 95% CI 1.46-1.93), and bupropion (OR 1.75, 95% CI 1.52-2.01), while bupropion and nicotine patch users were roughly twice as likely as placebo users to be smoking abstinent at follow-up.

In her editorial, Zawertailo noted that the exclusion from the trial of patients with substance abuse issues greatly limited the generalizability of the findings to this very high-risk population.

"Considering the extremely high prevalence of substance use among psychiatric populations, this exclusion is extremely disappointing," she wrote.

In a written statement, Pfizer chief medical officer and executive vice president noted that the newly published EAGLES trial findings add to the growing evidence supporting the safety of varenicline for smoking cessation.

"Smoking is one of the leading preventable causes of death worldwide, and the benefits of quitting are immediate and substantial," she noted. "These data from the EAGLES study build on the large body of clinical evidence characterizing the neuropsychiatric safety and efficacy of Chantix, which supports Chantix as an important treatment option for people who want to quit smoking."

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