Objective: To evaluate the comparative effectiveness and safety of pharmacological and non-pharmacological smoking cessation interventions in people with severe mental illness.

Design: Systematic review and network meta-analysis.

Data sources: Medline, Embase, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, from inception to 19 September 2024.

Eligibility criteria for selecting studies: Trials enrolling adults who had established diagnoses of schizophrenia, bipolar disorder, recurrent or current severe major depressive disorder, or post-traumatic stress disorder, randomised to a smoking cessation intervention versus another active treatment, placebo, standard care, or no treatment.

Results: 74 randomised controlled trials (11 023 participants) evaluating nine smoking cessation interventions were included in the study. Compared with placebo or minimal care, varenicline (10 more per 100 achieving long term smoking abstinence, 95% confidence interval (CI) 5 to 16; high certainty evidence) and bupropion (5 more per 100, 1 to 10; moderate certainty evidence) increased long term abstinence. Effects on short term smoking abstinence were similar. Nicotine replacement therapy improved short term abstinence but with little or no long term abstinence benefit (moderate certainty evidence). Combination interventions (pharmacological with non-pharmacological interventions) may increase long term abstinence (6 more per 100, 95% CI 3 to 11; low certainty evidence). The certainty of evidence for other interventions was very low. Serious adverse event data were highly uncertain. Dropout from a trial because of harms was possibly no different for varenicline, bupropion, and nicotine replacement therapy compared with placebo or minimal care.

Conclusions: Varenicline, bupropion, and nicotine replacement therapy likely improved smoking abstinence in people with severe mental illness compared with placebo or minimal care (moderate to high certainty evidence). Combined pharmacological and non-pharmacological approaches may offer more benefit (low certainty evidence), but the risk of serious adverse events for all interventions was very uncertain.

Systematic review registration: PROSPERO CRD42022349498.