More Evidence Varenicline Helps Mentally Ill Quit Smoking

Fran Lowry

February 10, 2014

The antismoking drug varenicline (Chantix, Pfizer Inc) boosts quit rates in smokers with serious mental illness, new research shows. But at least 1 expert is still not entirely convinced of its safety in this patient population.

A randomized clinical trial conducted by investigators at Massachusetts General Hospital and Harvard Medical School in Boston showed that smokers with schizophrenia or bipolar disorder who received varenicline plus cognitive-behavioral therapy (CBT) were 3 times more likely to abstain from smoking at 1 year compared with those who received CBT alone.

Led by Anne Eden Evins, MD, MPH, the study is another to show that varenicline may be a useful therapy for this vulnerable patient population.

"People with schizophrenia suffer disproportionate morbidity and mortality from smoking-related illnesses," Dr. Evins told Medscape Medical News. "They die some 25 years younger than people in the general population from smoking-related diseases, so it's a true epidemic in this population, with disastrous effects on their health."

The study was published in the January 8 issue of JAMA.

Smoking Undertreated

A previous study published in May 2012 in the Journal of Clinical Psychiatry and reported by Medscape Medical News at that time showed that patients with schizophrenia or schizoaffective disorders who were randomly assigned to receive varenicline for 12 weeks had significantly higher smoking abstinence rates, as verified by carbon monoxide measurements, compared with their counterparts who received placebo.

At the time, principal investigator Jill M. Williams, MD, director of the Division of Addiction Psychiatry at the University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, in New Brunswick, told Medscape Medical News that smokers with psychotic disorders who want to quit smoking "should routinely be provided with smoking cessation treatment."

Dr. Williams added that pharmacotherapy should be used "more aggressively to help these smokers quit."

Dr. Anne Eden Evins

In the current study, Dr. Evins and colleagues sought to determine whether smokers diagnosed with schizophrenia and bipolar disorder would have higher rates of prolonged tobacco abstinence with maintenance pharmacotherapy than with standard treatment consisting of CBT.

The trial was conducted at 10 community mental health centers in the United States. The first phase of the study included 247 smokers who were recruited between March 2008 and April 2012. Of these, 203 received 12 weeks of varenicline and CBT.

Eighty-seven of these patients had 2 weeks or more of continuous abstinence at 12 weeks and so were eligible to go on to the relapse prevention phase of the trial.

These patients were randomly assigned to receive CBT and varenicline (1 mg twice daily) or placebo from weeks 12 to 52. After week 52, the patients discontinued study treatment and were followed for an additional 24 weeks.

The main outcome was the 7-day rate of continuous abstinence at week 52, as confirmed by exhaled carbon monoxide.

Secondary outcomes were continuous abstinence rates for weeks 12 through 64, determined on the basis of biochemically verified abstinence, and weeks 12 through 76, determined on the basis of self-reported smoking behavior.

No Psychiatric Side Effects

Sixty-one patients completed the relapse-prevention phase of the study. Twenty-six withdrew (7 varenicline, 19 placebo). Eighteen patients who withdrew from the relapse-prevention phase had relapsed prior to dropout.

"Relapse is a problem in the general population, estimated to be at about 50% at a year, but we had 75% relapse rates within 3 months in our mentally ill population, and most of it was within the first 3 weeks," Dr. Evins said.

After 52 weeks, the researchers found that patients who stayed on maintenance therapy with varenicline were 3 times more likely to be abstinent than those who had been switched to placebo.

In the varenicline group, the point-prevalence abstinence rate was 60% (24 of the 40 patients who were randomly assigned to receive varenicline in the relapse-prevention intervention phase of the study), compared with 19% (9 of 47) in the placebo group (odds ratio [OR], 6.2; 95% confidence interval [CI], 2.2 - 19.2; P<.001).

From weeks 12 through 64, 45% (18 of 40) of varenicline patients were continuously abstinent compared with 15% (7 of 47) of the placebo patients (OR, 4.6; 95% CI, 1.5 - 15.7; P = .004).

From weeks 12 through 76, 30% (12 of 40) of the varenicline patients were continuously abstinent compared with 11% (5 of 47) of the placebo patients (OR, 3.4; 95% CI, 1.02 - 13.6; P = .03).

The investigators found no significant treatment effects on psychiatric symptom ratings or psychiatric adverse events.

"In this study, the safety data were absolutely boring. There was no indication that varenicline worsened psychiatric symptoms of any kind, and this is consistent with every published placebo- controlled trial of varenicline in people with various mental illnesses," Dr. Evins said.

"And if you really want my opinion about this, the editor of the American Journal of Psychiatry asked me to write a commentary in December to accompany a large safety report by Gibbons and Mann. It's an enormous study of 35,000 veterans finding essentially that varenicline caused fewer problems than the nicotine patch," she said.

Medscape Medical News asked Robert D. Gibbons, PhD, from the University of Chicago, in Illinois, and J. John Mann, MD, from Columbia University in New York City, the authors of that of that article, to comment on the current study.

In e-mail correspondence, they told Medscape Medical News that these most recent findings "support the positive benefit-to-risk ratio of the smoking cessation drug varenicline. It indicates the generalizability of statistically significant benefit without significant risk in patients with psychiatric disorders."

Dr. Gibbons and Dr. Mann added that clinicians would be assisted if the US Food and Drug Administration (FDA) provided updated guidance on varenicline in light of these recent data.

"Taken as a whole, these findings indicate that varenicline is a highly effective smoking cessation treatment. The initial concern regarding increased risk of neuropsychiatric and suicidal events is not supported by these more recent studies, and their results appear to generalize to the population of real users of these medications, beyond those patients willing to participate in randomized clinical trials."

Safety Still a Concern?

But Sonal Singh, MD, MPH, from Johns Hopkins University, Baltimore, Maryland, is not entirely convinced of the safety of varenicline in patients with serious mental illness.

"This study demonstrates that varenicline is efficacious in helping those with schizophrenia and bipolar quit compared to behavior therapy," Dr. Singh, who was not part of the study, told Medscape Medical News.

"However, the study is too small and the follow-up too short to provide reassurance on the psychiatric safety of varenicline. Patients with bipolar disorder have 20 to 30 times the risk of suicide compared to the general population. A drug that has a black box warning about suicide, varenicline, is not my first choice for smoking cessation in patients with bipolar disorder," he said.

This study was initially funded by the National Institute on Drug Abuse (NIDA), the National Institutes of Health, and later supported by Pfizer, the makers of Chantix. Dr. Evins reports receiving product and financial support to her institution from EnVivo Pharmaceuticals for a NIDA-funded trial of an alpha-7 nicotinic agonist for smoking cessation in nonpsychiatrically ill smokers and from GSK (GlaxoSmithKline) to conduct phase II trials of novel compounds for a NIDA-funded Cooperative Drug Discovery Group for Nicotine Dependence. She also reports consulting for Pfizer. Dr. Gibbons reports that he has served as an expert witness for Pfizer in a case related to varenicline and neuropsychiatric adverse events, for the US Department of Justice, and for Wyeth on cases related to antidepressants and suicide, and for Pfizer on cases related to gabapentin and suicide. Dr. Mann reports that he has received research support from GlaxoSmithKline and Novartis, that he receives royalties for the Columbia Suicide Severity Rating Scale from the Foundation for Mental Health, and that he has stock options from Qualitas Health. Dr. Singh reports no relevant financial relationships.

JAMA. 2014;311:145-154. Abstract

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