Review: Varenicline does not differ from placebo for adverse neuropsychiatric events

Question Is varenicline associated with an increased risk for neuropsychiatric events compared with placebo? Review scope Included studies compared maximum-dose varenicline (1 mg twice daily) for any duration, with placebo in smokers or nonsmokers. Primary outcomes were adverse neuropsychiatric events (depression, suicidal ideation, attempted suicide, and a composite of suicide or attempted suicide). Secondary outcomes included death, anxiety, fatigue, insomnia, and sleep disorders. Review methods MEDLINE, EMBASE/Excerpta Medica, PsycINFO, Cochrane Central Register of Controlled Trials, clinicaltrials.gov (all to May 2014), and reference lists were searched for randomized controlled trials (RCTs). 44 RCTs (n =11146, mean age range 15 to 73 y, 32% to 100% men, treatment duration 7 d to 52 wk) met selection criteria. Study populations included smokers in the general population (18 RCTs), smokers previously treated with varenicline (1 RCT), smokeless tobacco users (2 RCTs), people dependent on opioids or cocaine (3 RCTs), smokers with psychiatric illness (8 RCTs), adolescents (1 RCT), nonsmokers (2 RCTs), and patients with other conditions (9 RCTs). Risk for bias was low for randomization (38 RCTs), allocation concealment (37 RCTs), blinding of personnel or participants (42 RCTs), and blinded outcome assessments (38 RCTs). 5 RCTs were excluded from meta-analysis due to unclear risk for bias for 4 of 6 quality assessment criteria or lack of data. Main results Varenicline did not differ from placebo for depression, suicidal ideation, attempted suicide, suicide or attempted suicide, or death; it reduced anxiety and increased fatigue, insomnia, and sleep disorders (Table). Conclusion Varenicline does not differ from placebo for depression, suicidal ideation, attempted suicide, or suicide or attempted suicide. Adverse neuropsychiatric effects of varenicline (varen) vs placebo* Outcomes Number of trials (n) Weighted event rates At 8 d to 53 wk Varen Placebo RRR (95% CI) NNT (CI) Depression 31 (9843) 3.0% 3.1% 4% (21 to 24) Not significant Suicide ideation 20 (4990) 0.48% 0.82% 42% (20 to 72) Not significant Attempted suicide NR (6320) 0.08% 0.11% 25% (462 to 90) Not significant Anxiety 31 (10097) 3.9% 5.1% 24% (7 to 38) 83 (53 to 296) RRI (CI) NNH (CI) Suicide or attempted suicide 31 (9830) 0.07% 0.04% 67% (67 to 754) Not significant Death 36 (10647) 0.24% 0.23% 5% (53 to 137) Not significant Fatigue 31 (10203) 5.4% 4.3% 26% (6 to 51) 88 (46 to 407) Insomnia 10 (10383) 12% 8.0% 49% (32 to 68) 26 (19 to 40) Sleep disorders 28 (9365) 4.6% 2.9% 60% (28 to 101) 58 (35 to 125) *NR = not reported; other abbreviations defined in Glossary. Weighted event rates, RRR, RRI, NNT, NNH, and CI calculated from control event rates and Peto odds ratio in article using a fixed-effect model. Commentary RCTs have shown varenicline to be effective for smoking cessation (1), but any link with neuropsychiatric morbidity or mortality could limit its use. Accurate estimates of any excess risk for neuropsychiatric events associated with varenicline are needed. The review by Thomas and colleagues is the most comprehensive analysis to date and found no increase in suicide or attempted suicide, depression, or suicidal ideation with varenicline. However, the meta-analysis does not rule out clinically important increases in these adverse events (i.e., the 95% confidence interval for suicide or attempted suicide is wide and compatible with both a possible decrease or increase in risk). What should clinicians do in light of these results? One strategy would be to wait for the results of the industry-sponsored EAGLES trial, which is designed to assess the safety of varenicline and bupropion in participants with and without psychiatric disorders (expected enrollment n =8146) and measures neuropsychiatric adverse events as the primary outcome (2). Results are expected in late 2015. The addition of the EAGLES trial to trials analyzed by Thomas and colleagues will probably improve the precision of estimates for neuropsychiatric adverse events associated with varenicline. It should also address any concerns about reporting or publication bias in existing trials as a source of error. If the results of EAGLES are consistent with the current meta-analysis, concerns about neuropsychiatric risk of varenicline would be reduced. In the meantime, we recommend that clinicians continue to be cautious when considering varenicline for patients who wish to quit smoking and assess psychiatric symptoms and risk for suicide. Although varenicline probably won't induce serious neuropsychiatric events in most patients, clinicians should discuss the residual uncertainty with patients and come to a shared decision based on the risks and benefits for individual patients.