This article notes that the controversy over the safety of antidepressants has shaken public confidence and asks, “Were mistakes made and could they have been avoided?” The article is set out under the following headings:

• Regulatory problem
• Manipulation of data
• Interpretation of evidence
• Risk periods
• Confounding effect?
• Conclusions

The main summary points (taken directly from the article) are provided below:

• The case of selective serotonin reuptake inhibitors suggests that current regulatory practice overstates the benefits and underestimates the risks of drugs
• Manufacturers' inappropriate inclusion of suicidal acts in the placebo group biased estimates of suicide risk
• Regulators' rigid interpretation of confidence intervals may have delayed warnings of dangers of suicidal acts
• When individual drug trials are small regulators are in a unique position to analyse class effects but have rarely done so.

Link: http://bmj.bmjjournals.com/cgi/content/full/333/7558/92

Varenicline May Be More Effective Than Bupropion for Smoking Cessation 

Source: JAMA. 2006;296:47-71, 94-95

Varenicline is more effective than bupropion or placebo for smoking cessation, according to the results of 3 randomized studies reported in the July 5 issue of JAMA.

"The alpha-4-beta-2 nicotinic acetylcholine receptors (nAChRs) are linked to the reinforcing effects of nicotine and maintaining smoking behavior," write David Gonzales, PhD, from Oregon Health & Science University in Portland, and colleagues from the Varenicline Phase 3 Study Group. "Varenicline, a novel alpha-4-beta-2 nAChR partial agonist, may be beneficial for smoking cessation."

The first study was a double-blind, parallel-group, phase 3 clinical trial conducted at 19 US centers from June 19, 2003, to April 22, 2005. The investigators used advertising to recruit 1025 generally healthy smokers of at least 10 cigarettes per day, aged 18 to 75 years, with fewer than 3 months of smoking abstinence in the past year. These participants were randomized to receive brief counseling and varenicline titrated to 1 mg twice per day (n = 352), sustained-release bupropion (bupropion SR) titrated to 150 mg twice per day (n = 329), or placebo (n = 344) orally for 12 weeks, with 40 weeks of nondrug follow-up.

The main outcome measure was the 4-week rate of continuous abstinence from smoking for weeks 9 through 12, confirmed by exhaled carbon monoxide. Secondary outcomes included the rates of continuous abstinence for weeks 9 through 24 and weeks 9 through 52.

For weeks 9 through 12, the 4-week continuous abstinence rates were 44.0% for varenicline, 17.7% for placebo, and 29.5% for bupropion SR. Odds ratios [ORs] were 3.85 for varenicline vs placebo (95% confidence interval [CI], 2.70 - 5.50; P < .001); 1.93 for varenicline vs bupropion SR (95% CI, 1.40 - 2.68; P <.001); and 2.00 for bupropion SR vs placebo (95% CI, 1.38 - 2.89; P < .001).

For weeks 9 through 52, the continuous abstinence rates were 21.9% for varenicline vs 8.4% for placebo (OR, 3.09; 95% CI, 1.95 - 4.91; P < .001) and vs 16.1% for bupropion SR (OR, 1.46; 95% CI, 0.99 - 2.17; P = .057).

There were no sex differences in efficacy for varenicline. This drug reduced craving and withdrawal symptoms, and smoking satisfaction for those who smoked while receiving it. Varenicline was safe and generally well-tolerated, and study drug discontinuation rates were similar to those seen with placebo. The most common adverse events were nausea in 98 participants (28.1%) receiving varenicline and insomnia in 72 (21.9%) receiving bupropion SR.

"Varenicline was significantly more efficacious than placebo for smoking cessation at all time points and significantly more efficacious than bupropion SR at the end of 12 weeks of drug treatment and at 24 weeks," the authors write. "The hypothesis that a partial nAChR agonist would effectively reduce cravings and smoking satisfaction or reinforcement was supported and suggests a new direction for development of smoking cessation therapies."

Study limitations include inability to address the effects of varenicline on smokers with a history of bupropion use; and inclusion of generally healthy smokers, who may not be representative of smokers most likely to seek treatment.