SEARCHSYSTEMATIC_REVIEWpsychiatry, addiction medicine

systematic_review·psychiatry, addiction medicine, primary care, pulmonology, cardiology, oncology, public health·PMC10207863

Antidepressants for smoking cessation

The Cochrane Database of Systematic Reviews · 7 authors, 2 centres

AI SUMMARY

FIDELITY 100%

POPULATIONpeople who smoke tobacco cigarettes (adults and adolescents aged 12–21; with and without mental health conditions)

INTERVENTIONantidepressant medications (bupropion, nortriptyline, SSRIs, MAOIs, venlafaxine, St John's wort, SAMe) alone or in combination with NRT or varenicline

COMPARISONplacebo, no pharmacological treatment, alternative pharmacotherapy (NRT, varenicline), or different doses/durations of the same antidepressant

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AGENT 01 · STRUCTURED SUMMARY

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TL;DR

This Cochrane review of 124 RCTs (48,832 participants) found high-certainty evidence that bupropion increases long-term smoking cessation rates by 60% compared to placebo (RR 1.60, 95% CI 1.49 to 1.72). Nortriptyline also showed benefit (RR 2.03 vs placebo), but bupropion was less effective than varenicline and combination NRT. Clinically, bupropion remains a valid first-line option, though varenicline and combination NRT appear more effective, and bupropion increases adverse events and treatment dropouts.

Full summary

3,619 CHARS

**Background:** Tobacco use causes over 7 million deaths annually. Antidepressants may aid smoking cessation by relieving nicotine withdrawal-induced low mood or by acting on neural pathways underlying nicotine addiction. This is the fifth update of a Cochrane review first published in 2003.

**Methods:** The authors searched the Cochrane Tobacco Addiction Group Specialised Register (most recently 29 April 2022) for RCTs comparing antidepressant medications with placebo, no treatment, alternative pharmacotherapy, or different regimens. Included trials had at least 6 months' follow-up for efficacy; any follow-up was accepted for harms. The primary outcome was smoking cessation at ≥6 months using the strictest available abstinence definition, biochemically validated where possible. Secondary outcomes included adverse events (AEs), serious adverse events (SAEs), psychiatric AEs, seizures, overdoses, suicide attempts, death by suicide, all-cause mortality, and dropouts due to treatment. Meta-analyses used Mantel-Haenszel fixed-effect methods; GRADE assessed certainty.

**Key Results:** 124 studies (48,832 participants) were included; 10 were new to this update. 34 studies were at high risk of bias, but sensitivity analyses did not change clinical interpretation.

- **Bupropion vs placebo/no treatment:** High-certainty evidence from 50 trials (18,577 participants) showed bupropion increased cessation (RR 1.60, 95% CI 1.49 to 1.72; I²=16%). Moderate-certainty evidence suggested a possible increase in SAEs (RR 1.16, 95% CI 0.90 to 1.48; 23 studies, 10,958 participants). High-certainty evidence showed more dropouts due to AEs with bupropion (RR 1.44, 95% CI 1.27 to 1.65; 25 studies, 12,346 participants). Bupropion increased AEs (RR 1.14, 95% CI 1.11 to 1.18), psychiatric AEs (RR 1.25, 95% CI 1.15 to 1.36), anxiety (RR 1.42, 95% CI 1.21 to 1.67), and insomnia (RR 1.78, 95% CI 1.62 to 1.96). - **Bupropion + NRT vs NRT alone:** Low-certainty evidence from 15 studies (4117 participants) showed no clear benefit (RR 1.17, 95% CI 0.95 to 1.44; I²=43%). SAEs and dropouts were imprecise. - **Bupropion + varenicline vs varenicline alone:** Moderate-certainty evidence from 3 studies (1057 participants) suggested possible benefit (RR 1.21, 95% CI 0.95 to 1.55; I²=15%). SAEs and dropouts were imprecise (low certainty). - **Bupropion vs varenicline:** Bupropion was inferior (RR 0.73, 95% CI 0.67 to 0.80; 9 studies, 7564 participants). - **Bupropion vs combination NRT:** Bupropion was inferior (RR 0.74, 95% CI 0.55 to 0.98; 2 studies, 720 participants). - **Bupropion vs single-form NRT:** No clear difference (RR 1.03, 95% CI 0.93 to 1.13; 10 studies, 7613 participants). - **Nortriptyline vs placebo:** Moderate-certainty evidence from 6 studies (975 participants) showed benefit (RR 2.03, 95% CI 1.48 to 2.78; I²=16%). Dropouts due to treatment were increased (RR 1.99, 95% CI 1.18 to 3.36). - **SSRIs, MAOIs, venlafaxine, St John's wort, SAMe:** No clear evidence of efficacy for smoking cessation. - **Depression as moderator:** Findings were sparse and inconsistent; most studies found no interaction between depression history and bupropion efficacy.

**Clinical Implications:** High-certainty evidence supports bupropion as an effective smoking cessation aid, but it is less effective than varenicline and combination NRT. Nortriptyline is also effective but less studied. Bupropion increases AEs, psychiatric AEs, and treatment dropouts. Given the superior efficacy of varenicline and combination NRT, these may be preferred options. Further research on harms and tolerability is needed.

PICO

PPOPULATION

people who smoke tobacco cigarettes (adults and adolescents aged 12–21; with and without mental health conditions)

IINTERVENTION

antidepressant medications (bupropion, nortriptyline, SSRIs, MAOIs, venlafaxine, St John's wort, SAMe) alone or in combination with NRT or varenicline

OOUTCOME

smoking cessation after at least 6 months (primary); adverse events, serious adverse events, psychiatric AEs, seizures, overdoses, suicide attempts, death by suicide, all-cause mortality, and dropouts due to treatment (secondary)

STUDY TYPE

systematic_review

SPECIALTY

psychiatry

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10207863

Antidepressants for smoking cessation

The Cochrane Database of Systematic Reviews

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ABSTRACT

Abstract Background 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. Objectives 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. Search methods We searched the Cochrane Tobacco Addiction Group Specialised Register, most recently on 29 April 2022. Selection criteria 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. Data collection and analysis 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. Main results 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; I 2 = 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; I 2 = 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; I 2 = 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; I 2 = 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; I 2 = 0%; 4 studies, 657 participants) and randomised to bupropion plus varenicline versus varenicline alone (RR 1.23, 95% CI 0.63 to 2.42; I 2 = 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; I 2 = 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; I 2 = 0%; 3 studies, 737 participants) or bupropion combined with varenicline versus varenicline alone (RR 0.80, 95% CI 0.45 to 1.45; I 2 = 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; I 2 = 0%; 9 studies, 7564 participants), and to combination NRT (RR 0.74, 95% CI 0.55 to 0.98; I 2 = 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; I 2 = 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; I 2 = 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; I 2 = 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. Authors' conclusions 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. Keywords: Adolescent, Adult, Child, Humans, Young Adult, Antidepressive Agents, Antidepressive Agents/adverse effects, Bupropion, Bupropion/adverse effects, Nicotinic Agonists, Nicotinic Agonists/adverse effects, Nortriptyline, Nortriptyline/adverse effects, Smoking Cessation, Smoking Cessation/methods, Varenicline, Varenicline/adverse effects

CITATION EXPORT

Anisa Hajizadeh, Seth Howes, Annika Theodoulou et al.. Antidepressants for smoking cessation. The Cochrane Database of Systematic Reviews. (2023). https://doi.org/10.1002/14651858.CD000031.pub6

AUTHORS

7 · 2 CENTRES

Anisa Hajizadeh, Seth Howes, Annika Theodoulou, Elias Klemperer, Jamie Hartmann-Boyce, Jonathan Livingstone-Banks, Nicola Lindson

1Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
2Departments of Psychological Sciences & Psychiatry, University of Vermont, Burlington, VT, USA