Clinical Inquiries

Does any antidepressant besides bupropion help smokers quit?

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Yes, nortriptyline approximately doubles smoking cessation rates, an effect comparable to bupropion. Adding nortriptyline to nicotine replacement therapy (NRT) doesn’t improve rates further (strength of recommendation [SOR]: A, systematic review of randomized controlled trials [RCTs]).

Selective serotonin reuptake inhibitors (SSRIs; fluoxetine, paroxetine, sertraline, citalopram), venlafaxine, monoamine oxidase inhibitors (MAOIs; moclobemide, selegiline), doxepin, and St. John’s wort don’t improve smoking cessation rates (SOR: A, systematic reviews and RCTs).


Bupropion is the only Food and Drug Administration (FDA)-approved antidepressant recommended as a first-line pharmacologic agent to assist with smoking cessation, based in part on a meta-analysis of 44 placebo-controlled RCTs (13,728 patients), which found that bupropion had a relative risk (RR) of 1.62 for smoking cessation compared with placebo (95% confidence interval [CI], 1.49-1.76). Bupropion produced quit rates that were approximately double those of placebo rates (18% [range 4%-43%] for bupropion vs 9% [range 0%-18%] for placebo).1

Nortriptyline is also effective, 
other antidepressants not so much

A Cochrane systematic review of 10 antidepressants used for smoking cessation included 64 placebo-controlled trials, measuring at least 6-month abstinence rates as primary outcomes, and monitoring biochemical markers (such as breath carbon monoxide and urinary cotinine) to verify abstinence. Some trials included participants with previous depressive episodes, but most didn’t enroll patients with active major depression.1 The TABLE1 gives an overview of the studies and outcomes.

Nortriptyline, which was evaluated in 6 trials, was the only antidepressant besides bupropion that was superior to placebo.1 Two of the nortriptyline trials included participants with active depression and the other trials had participants with a history of depression.Combining nortriptyline and nicotine replacement therapy (NRT) doesn’t increase quit rates compared with NRT alone. One trial found no difference in quit rates for patients taking nortriptyline with or without a history of major depression, although the subgroups were small. Two trials measured quit rates for 12 months whereas the other 4 trials used 6-month quit rates.

Four additional RCTs with 1644 patients that combined nortriptyline with NRT found no improvement in quit rates compared with NRT alone (RR=1.21; 95% CI, 0.94-1.55).1 Three RCTs with 417 patients compared bupropion with nortriptyline and found no difference (RR=1.3; 95% CI, 0.93-1.8).1

Evidence-based answers from the Family Physicians Inquiries Network

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