What are antidepressants?
Antidepressants are medicines and supplements used to treat depression. Some have also been tested to see whether they can help people to stop smoking. Two of these treatments – bupropion (sometimes called Zyban) and nortriptyline – are sometimes given to help people quit smoking.
Why we did this Cochrane Review
Smoking tobacco is extremely bad for people’s health. For people who smoke, quitting is the best thing they can do to improve their health. Many people find it difficult to quit smoking. We wanted to find out whether using antidepressants helps people to stop smoking (for six months or longer), and what potential harms might come from using these medicines.
We were interested in finding out:
- how many people stopped smoking for at least six months; and
- how many people had unwanted effects.
What did we do?
We searched for studies that looked at the use of antidepressants to help people quit smoking.
We looked for randomised controlled trials, in which the treatments people received were decided at random. This type of study usually gives the most reliable evidence about the effects of treatment. We included studies of any length when looking at evidence of harms, but studies needed to be at least six months long when assessing whether people had managed to quit smoking.
What we found
This review includes 124 studies, including 48,832 participants, looking at how helpful and safe different antidepressants are when used to quit smoking. Most studies were conducted in adults who smoked tobacco, with and without a history of mental illness. Four studies recruited young people aged 12 to 21 years. Most participants were motivated to quit smoking.
What are the results of our review?
Compared to not using any medication, using the antidepressant bupropion makes it 49% to 72% more likely that a person will successfully stop smoking, which is equal to six to eight more people successfully quitting for six months or more for every one hundred people who try to quit. There is evidence that people who use the antidepressant nortriptyline to quit smoking also improve their chances of success (48% to 178% more likely).
Bupropion may increase serious unwanted effects (such as death, hospitalisation, or life-threatening events). Unwanted effects may increase the chance that people stop using the medicine. There is not enough information to draw clear conclusions about the harms of nortriptyline for stopping smoking.
The evidence suggests that taking bupropion at the same time as other stop-smoking medicines – varenicline (a drug sometimes known as Champix or Chantix which is not an antidepressant) and combination nicotine replacement therapy (a patch plus another form) – may make people more likely to quit smoking than if they use nicotine replacement therapy or varenicline on their own. However, further evidence may change our findings. The evidence does not suggest a benefit of using bupropion at the same time as a single form of nicotine replacement therapy; for example, a patch, gum, or lozenge alone. People may be more likely to quit smoking when using bupropion compared with nortriptyline, but more likely to quit when using varenicline than bupropion.
How reliable are these results?
There is high-certainty evidence that bupropion helps people to quit smoking, meaning further research is very unlikely to change this conclusion. However, there is also high-certainty evidence to suggest that people using bupropion are more likely to stop taking the medicine because of unpleasant effects than those taking a pill without medication (a placebo) or no medication. The certainty of the evidence was moderate or low for the other key questions we looked at. This means that the findings of those questions may change when more research is carried out. In most cases, this was because there were not enough studies or studies were too small.
How up to date is this evidence?
This review updates our previous review. The evidence is up to date to April 2022.
- Bupropion can help people to quit smoking but may make people more likely to experience serious unwanted effects that could result in people stopping taking it or having to go to the hospital.
- Nortriptyline also appears to help people to quit smoking, but bupropion may be more effective.
- Bupropion may be as helpful as a single form of nicotine replacement therapy in helping people to quit smoking, but less so than combination nicotine replacement therapy (that is, a patch plus another form) and varenicline.
There is high-certainty evidence that bupropion can aid long-term smoking cessation. However, bupropion may increase SAEs (moderate-certainty evidence when compared to placebo/no pharmacological treatment). There is high-certainty evidence that people taking bupropion are more likely to discontinue treatment compared with people receiving placebo or no pharmacological treatment. Nortriptyline also appears to have a beneficial effect on smoking quit rates relative to placebo, although bupropion may be more effective. Evidence also suggests that bupropion may be as successful as single-form NRT in helping people to quit smoking, but less effective than combination NRT and varenicline. In most cases, a paucity of data made it difficult to draw conclusions regarding harms and tolerability.
Further studies investigating the efficacy of bupropion versus placebo are unlikely to change our interpretation of the effect, providing no clear justification for pursuing bupropion for smoking cessation over other licensed smoking cessation treatments; namely, NRT and varenicline. However, it is important that future studies of antidepressants for smoking cessation measure and report on harms and tolerability.
The pharmacological profiles and mechanisms of antidepressants are varied. However, there are common reasons why they might help people to stop smoking tobacco: nicotine withdrawal can produce short-term low mood that antidepressants may relieve; and some antidepressants may have a specific effect on neural pathways or receptors that underlie nicotine addiction.
To assess the evidence for the efficacy, harms, and tolerability of medications with antidepressant properties in assisting long-term tobacco smoking cessation in people who smoke cigarettes.
We searched the Cochrane Tobacco Addiction Group Specialised Register, most recently on 29 April 2022.
We included randomised controlled trials (RCTs) in people who smoked, comparing antidepressant medications with placebo or no pharmacological treatment, an alternative pharmacotherapy, or the same medication used differently. We excluded trials with fewer than six months of follow-up from efficacy analyses. We included trials with any follow-up length for our analyses of harms.
We extracted data and assessed risk of bias using standard Cochrane methods.
Our primary outcome measure was smoking cessation after at least six months' follow-up. We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Our secondary outcomes were harms and tolerance outcomes, including adverse events (AEs), serious adverse events (SAEs), psychiatric AEs, seizures, overdoses, suicide attempts, death by suicide, all-cause mortality, and trial dropouts due to treatment. We carried out meta-analyses where appropriate.
We included a total of 124 studies (48,832 participants) in this review, with 10 new studies added to this update version. Most studies recruited adults from the community or from smoking cessation clinics; four studies focused on adolescents (with participants between 12 and 21 years old). We judged 34 studies to be at high risk of bias; however, restricting analyses only to studies at low or unclear risk of bias did not change clinical interpretation of the results.
There was high-certainty evidence that bupropion increased smoking cessation rates when compared to placebo or no pharmacological treatment (RR 1.60, 95% CI 1.49 to 1.72; I2 = 16%; 50 studies, 18,577 participants). There was moderate-certainty evidence that a combination of bupropion and varenicline may have resulted in superior quit rates to varenicline alone (RR 1.21, 95% CI 0.95 to 1.55; I2 = 15%; 3 studies, 1057 participants). However, there was insufficient evidence to establish whether a combination of bupropion and nicotine replacement therapy (NRT) resulted in superior quit rates to NRT alone (RR 1.17, 95% CI 0.95 to 1.44; I2 = 43%; 15 studies, 4117 participants; low-certainty evidence).
There was moderate-certainty evidence that participants taking bupropion were more likely to report SAEs than those taking placebo or no pharmacological treatment. However, results were imprecise and the CI also encompassed no difference (RR 1.16, 95% CI 0.90 to 1.48; I2 = 0%; 23 studies, 10,958 participants). Results were also imprecise when comparing SAEs between people randomised to a combination of bupropion and NRT versus NRT alone (RR 1.52, 95% CI 0.26 to 8.89; I2 = 0%; 4 studies, 657 participants) and randomised to bupropion plus varenicline versus varenicline alone (RR 1.23, 95% CI 0.63 to 2.42; I2 = 0%; 5 studies, 1268 participants). In both cases, we judged evidence to be of low certainty.
There was high-certainty evidence that bupropion resulted in more trial dropouts due to AEs than placebo or no pharmacological treatment (RR 1.44, 95% CI 1.27 to 1.65; I2 = 2%; 25 studies, 12,346 participants). However, there was insufficient evidence that bupropion combined with NRT versus NRT alone (RR 1.67, 95% CI 0.95 to 2.92; I2 = 0%; 3 studies, 737 participants) or bupropion combined with varenicline versus varenicline alone (RR 0.80, 95% CI 0.45 to 1.45; I2 = 0%; 4 studies, 1230 participants) had an impact on the number of dropouts due to treatment. In both cases, imprecision was substantial (we judged the evidence to be of low certainty for both comparisons).
Bupropion resulted in inferior smoking cessation rates to varenicline (RR 0.73, 95% CI 0.67 to 0.80; I2 = 0%; 9 studies, 7564 participants), and to combination NRT (RR 0.74, 95% CI 0.55 to 0.98; I2 = 0%; 2 studies; 720 participants). However, there was no clear evidence of a difference in efficacy between bupropion and single-form NRT (RR 1.03, 95% CI 0.93 to 1.13; I2 = 0%; 10 studies, 7613 participants). We also found evidence that nortriptyline aided smoking cessation when compared with placebo (RR 2.03, 95% CI 1.48 to 2.78; I2 = 16%; 6 studies, 975 participants), and some evidence that bupropion resulted in superior quit rates to nortriptyline (RR 1.30, 95% CI 0.93 to 1.82; I2 = 0%; 3 studies, 417 participants), although this result was subject to imprecision.
Findings were sparse and inconsistent as to whether antidepressants, primarily bupropion and nortriptyline, had a particular benefit for people with current or previous depression.