Primary Care Corner with Geoffrey Modest MD: Smoking Cessation Meds in Pts with Psych Disorders

By Dr. Geoffrey Modest

A couple of recent articles dealt with issues of smoking cessation:

  1. The lancet had a study finding no significant increase in psychiatric risk with any of the smoking cessation medications (see ). The FDA had issued an early warning on neuropsych concerns with varenicline, later extended to bupropion, based on case reports, and issued a post-marketing requirement for makers of both drugs to do RCTs to assess these risks. Hence this drug-company sponsored study.


  • 8144 smokers smoking at least 10 cigarettes/d in the past year, 4116 having underlying psych disorders/4028 in the non-psych cohort. In terms of the cohorts:
  • Nonpsych cohort: mean age 46, 50% female, 83% white/13% black, wt 80 kg, 47% US/33% Western Europe/11% Eastern Europe/10% Central/South America, Fagertstrom Test for Cigarette Dependence (FTCD) score 5.5 [a score signifying moderate dependence], 13 years duration of smoking, 21 cigs/day in past month, 3.3 prior quit attempts
  • Psych cohort: mean age 47, 62% female, 80% white/16% black, wt 80 kg, 58% US/29% Western Europe/9% Eastern Europe/4% Central/South America, Fagertstrom Test for Cigarette Dependence (FTCD) score 6.0, 12 years duration of smoking, 21 cigs/day in past month, 3.5 prior quit attempts. 70% with unipolar or bipolar depression, 20% anxiety disorder, 9% psychotic. 33% on antidepressants, 15% anxiolytics, 16% antipsychotics [of note: all had to be stable for the prior 6 months and not at risk for self-injury]
  • Randomized to nicotine patch 21 mg/d with taper, varenicline 1mg bid, or bupropion SR 150mg bid for 12 weeks with 12 week non-treatment follow-up. Done in 14 centers in 16 countries between 2011-2015 (this was a double-blind, triple dummy, placebo controlled trial – i.e. everyone took pills from 2 different unmarked bottles and used a patch)
  • All had brief smoking cessation counseling (no more than 10 minutes, at each clinic visit)
  • Quit date was 1 week after randomization, coinciding with end of uptitration of bupropion and varenicline and initiation of patch
  • Main outcomes: composite measure of moderate and severe neuropsych events; and biochemically confirmed continuous abstinence from smoking for weeks 9-12.


  • The same percent (78%) of each group completed the study
  • In the non-psychiatric cohort: moderate-to-severe neuropsych adverse events occurred in
    • Varenicline: 13 of 990 people (1.3%)
    • Bupropion: 22 of 989 (2.2%)
    • Patch: 25 of 1006 (2.5%)
    • Placebo: 24 of 999 (2.4%)
    • The only significant difference between active drug and placebo: varenicline-placebo risk difference was 1.28. Of note, there were essentially zero patients with psychosis, panic, mania, suicidal ideation or behavior, anxiety, or depression.
  • In the psychiatric cohort:
    • Varenicline: 67 of 1026 people (6.5%)
    • Bupropion 68 of 1017 (6.7%)
    • Patch: 53 of 1016 (5.2%)
    • Placebo: 50 of 1015 (4.9%)
    • No significant risk differences between active drug and placebo, though there were 14 of patients (2%) in the psych group who developed suicidal ideation
  • Quit rates at 9-12 weeks, vs placebo (documented by exhaled carbon monoxide measurements):
    • Varenicline (statistically significantly better than the other 2 active treatments), with OR 3.61 (3.07-4.24); most frequent adverse effect: 25% nausea
    • Bupropion: OR 2.07 (1.75-2.45); most frequent adverse effect: insomnia 12%
    • Patch: OR 2.15 (1.82-2.54); most frequent adverse effect: abnormal dreams 12%
    • Placebo: headache in 10%
    • Quit rates looking at weeks 9-24 showed some deterioration over those from weeks 9-12, but the order and significance of efficacy remained as above

So, this study adds a few things to the literature:

  • As a large study, it showed that neither varenicline nor bupropion posed a significant risk to smokers with or without a psych history.
  • The odds ratios for efficacy in smoking cessation did not vary by initial psych status: those with underlying psych issues had similar abstinence rates to those without
  • And, this is pretty important since the likelihood of smoking is 2-3x higher in those with underlying psych disorders (perhaps as self-medication with nicotine, a pretty potent psychoactive drug/anxiolytic: evidence shows improved vigilance, attention and cognition; decreased perceived stress, embarrassment, irritability, or depression; nicotine can be both a stimulant and relaxant, with initial epinephrine release causing stimulation but increasing dosages causing sedation)
  • A few caveats:
    • As per prior blog ( there might have been more success if the patch had been started earlier than 1 week before the quit date
    • I would still be concerned about using varenicline in those with psychotic disorders, since these were pretty underrepresented in the psych cohort (as were those with personality disorders, <1% of the cohort). But importantly, a large % (34%) had a history of suicidal ideation and 13% had a history of suicidal behavior. Also of importance, this study did not include patients with underlying with substance use disorders, including alcohol, in the past 12 months.
    • Although varenicline outshined the others, this trial only looked at monotherapy, and there are many studies showing the superior efficacy of multi-therapies
    • The evaluation of smoking cessation at 12 weeks should be viewed with some caution, since this may not reflect long-term abstinence
  • So, bottom line, varenicline, as a single agent, seemed to be the most effective in smoking cessation and did not seem to have any real increased neuropsych risk, even in those with underlying psych disorders (i.e.: assessing the confidence intervals above, it did not appear that there could be more than a 1.5 percentage point increase in neuropsych events by either varenicline or bupropion in those without psych disorders, or more than 4 percentage points in those with psych disorder). For patients with underlying psych disorders who meet the above criteria (including being stable psychiatrically and non-other-substance using), any of these methods seemed to work well and be well-tolerated, though I would really follow them more closely.

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