Varenicline's Neuropsychiatric Safety Concerns Allayed

Megan Brooks

September 17, 2013

The smoking-cessation drug varenicline (Chantix, Pfizer Inc) can help patients with stably treated current or past depression quit smoking without worsening their depression, results of a randomized, controlled, phase 4 postmarketing surveillance study funded by Pfizer suggests.

"These findings are reassuring from a neuropsychiatric safety perspective because varenicline did not worsen overall measures of depression, anxiety, or suicidal thinking or behavior," study leader Robert Anthenelli, MD, associate chief of staff for mental health at the Veterans Affairs San Diego Healthcare System and professor of psychiatry at the University of California, San Diego, School of Medicine, told Medscape Medical News.

The study was published online September 17 in Annals of Internal Medicine.

Black Box Warning

Roughly half of smokers who seek help quitting have a history of depression, and they have greater difficulty quitting than their nondepressed peers.

Studies have shown that varenicline boosts quit rates among smokers without depression, but case reports and postmarketing adverse event reports have raised concerns about the drug's neuropsychiatric safety profile in psychiatric patients, a group generally excluded from pivotal phase 3 trials that led to the drug's approval in 2006.

In 2009, a black box warning was added to the drug stating that it has been associated with serious mental health events, as reported by Medscape Medical News. Reported symptoms include changes in behavior, hostility, agitation, depressed mood, suicidality, and attempted suicide.

"By conducting a randomized, placebo-controlled trial and by using rigorous methods to probe and assess changes in mood, anxiety levels, and suicidal thinking, we think our results help place the surveillance reports in better perspective," Dr. Anthenelli said.

A total of 525 adults from 38 centers in 8 countries who smoked at least 10 cigarettes per day and were motivated to stop smoking participated in the study. All of the participants had stably treated current or past major depression and no recent cardiovascular events.

Nearly three quarters were taking selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, benzodiazepines, or nonbenzodiazepine sedative hypnotics. Adults taking medications prescribed for mania or psychosis were excluded from the study.

No Difference in Safety

Participants were randomly allocated to varenicline 1 mg twice daily or placebo for 12 weeks and were then followed for 40 weeks. Overall, 68% of the varenicline group and 67% of the placebo group completed the study.

During the last 4 weeks of treatment (weeks 9 to 12), varenicline-treated patients were about twice as likely to quit as placebo-treated patients (35.9% vs 15.6%; odds ratio [OR], 3.35).

At the end of the 40-week follow-up, 20.3% of participants in the varenicline group continued to abstain from smoking compared with 10.4% in the placebo group (OR, 2.36).

Importantly, the researchers note, there were "no clinically relevant" between-group differences in mood, anxiety, or thoughts about suicide, and no overall worsening of depression or anxiety in either group.

Suicidal ideation or behavior, as captured by the Columbia Suicide Severity Rating Scale during study treatment, occurred in 6.0% of the varenicline group vs 7.5% of the placebo group.

Varenicline was generally well tolerated, with common adverse events similar to those of smokers without psychiatric disorders. The most common adverse event was nausea, which occurred in 27.0% of those taking varenicline and 10.4% of those taking placebo. Two patients in the varenicline group died during the nontreatment phase; neither death was judged by the study investigators to be related to the drug.

The researchers caution, however, that about one third of the participants did not complete the study, and the missing data could have affected the findings. The researchers also say that the study was not adequately powered to detect differences in rare events. The results may not apply to patients with untreated or active depression or co-occurring psychiatric conditions or to those taking mood stabilizers and antipsychotics.

Despite these limitations, the researchers believe the data suggest that varenicline "may be suitable for smoking cessation in smokers with stably treated current or past depression.... However, clinicians should remain vigilant when treating depressed smokers with more complex psychiatric presentations for smoking cessation," they write.

"Reassuring" Data

In an interview with Medscape Medical News, Charles Cutler, MD, chair of the American College of Physicians' Board of Regents and a practicing internist, said that because the researchers started with a population at risk, the data are "very reassuring" and will "help doctors help patients end their tobacco use and their addiction to tobacco."

"There simply are not enough tools for patients to successfully end their use of and dependence on tobacco products. Some postmarketing studies have raised some issues about safety. I think this study will lessen physician fears; certainly, it will lessen mine about use of this product," Dr. Cutler said.

The study was funded by Pfizer Inc. Dr. Anthenelli is a scientific advisor to Pfizer. He receives no personal income from Pfizer and his services have been contracted by the Regents to Pfizer. As a result of this contractual arrangement, Dr. Anthenelli receives funding to support research and other university activities. A complete list of disclosures for authors is available online. Dr. Cutler reports no relevant financial relationships.

Ann Intern Med. Published online September 17, 2013. Full article

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