Abstract: We identified 1036 records, scrutinized 52 full-text articles and included 19 completed RCTs (one trial is awaiting assessment). A total of 2216 participants entered the trials, 1280 participants were randomly assigned to fluoxetine (60 mg/d, 40 mg/d, 20 mg/d and 10 mg/d) and 936 participants were randomly assigned to various comparison groups (placebo; the anti-obesity agents diethylpropion, fenproporex, mazindol, sibutramine, metformin, fenfluramine, dexfenfluramine, fluvoxamine, 5-hydroxy-tryptophan; no treatment; and omega-3 gel). Within the 19 RCTs there were 56 trial arms. Fifteen trials were parallel RCTs and four were cross-over RCTs. The participants in the included trials were followed up for periods between three weeks and one year. The certainty of the evidence was low or very low: the majority of trials had a high risk of bias in one or more of the risk of bias domains. For our main comparison group — fluoxetine versus placebo — and across all fluoxetine dosages and durations of treatment, the MD was −2.7 kg (95% CI −4 to −1.4; P < 0.001; 10 trials, 956 participants; low-certainty evidence). The 95% prediction interval ranged between −7.1 kg and 1.7 kg. The MD in body mass index (BMI) reduction across all fluoxetine dosages compared with placebo was −1.1 kg/m² (95% CI −3.7 to 1.4; 3 trials, 97 participants; very low certainty evidence). Only nine placebo-controlled trials reported adverse events. A total of 399 out of 627 participants (63.6%) receiving fluoxetine compared with 352 out of 626 participants (56.2%) receiving placebo experienced an adverse event. Random-effects meta-analysis showed an increase in the risk of having at least one adverse event of any type in the fluoxetine groups compared with placebo (RR 1.18, 95% CI 0.99 to 1.42; P = 0.07; 9 trials, 1253 participants; low-certainty evidence). The 95% prediction interval ranged between 0.74 and 1.88. Following fluoxetine treatment the adverse events of dizziness, drowsiness, fatigue, insomnia and nausea were observed approximately twice as often compared to placebo. A total of 15 out of 197 participants (7.6%) receiving fluoxetine compared with 12 out of 196 participants (6.1%) receiving placebo experienced depression. The RR across all fluoxetine doses compared with placebo was 1.20 (95% CI 0.57 to 2.52; P = 0.62; 3 trials, 393 participants; very low certainty evidence). All-cause mortality, health-related quality of life and socioeconomic effects were not reported. The comparisons of fluoxetine with other anti-obesity agents (3 trials, 234 participants), omega-3 gel (1 trial, 48 participants) and no treatment (1 trial, 60 participants) showed inconclusive results (very low certainty evidence). Low-certainty evidence suggests that off-label fluoxetine may decrease weight compared with placebo. However, low-certainty evidence suggests an increase in the risk for dizziness, drowsiness, fatigue, insomnia and nausea following fluoxetine treatment.

Plain-language summary: We found 19 randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) evaluating mainly women receiving different doses of fluoxetine. A total of 1280 overweight or obese participants received fluoxetine and 936 participants received mainly placebo or another anti-obesity medication. The participants in the included studies were followed up for periods varying between three weeks and one year. For our main comparison group — fluoxetine compared with placebo — and for all fluoxetine doses there was a 2.7 kg weight loss in favour of fluoxetine. We are uncertain, however, if an additional study would again show a benefit for fluoxetine. A total of 399 out of 627 participants (63.6%) receiving fluoxetine compared with 352 out of 626 participants (56.2%) receiving placebo experienced a side effect. Dizziness, drowsiness, fatigue, insomnia and nausea were observed approximately twice as often after fluoxetine compared to placebo. A total of 15 out of 197 participants (7.6%) receiving fluoxetine compared with 12 out of 196 participants (6.1%) receiving placebo experienced depression. The studies did not report on death from any cause, health-related quality of life and socioeconomic effects. This evidence is up to date as of December 2018. The overall certainty of the evidence was low or very low, mainly because of the small number of studies per outcome measurement and the small number of participants.