However, although our findings had low-certainty evidence, we observed that off-label fluoxetine at any dose, especially 60 mg once a day, may cause moderate weight loss of approximately 2.7 kg and only with this dose generate a reduction of BMI of −1.1 kg/m2 compared with placebo in adults with overweight or obesity; ...
Introduction: Using fluoxetine is one of many weight loss strategies. A serotonin reuptake inhibitor indicated for depression believed to impact weight control by changing an individual’s appetite; however, its benefit-risk ratio is unclear. The aim of this review was to assess the efficacy and safety of fluoxetine in reducing weight in adults with overweight or obesity. Methods: We searched Cochrane Library, MEDLINE, Embase, and other databases without language restrictions. Cochrane Collaboration tool and GRADE instrument assessed the risk of bias of randomized controlled trials and certainty of their evidence. We conducted random-effects meta-analyses and calculated the risk ratio/mean difference with 95% confidence intervals for the outcomes. Results: We included 19 trials (2,216 adults) and found that fluoxetine may reduce weight by −2.7 kg (95% CI −4 to −1.4; p < 0.001) and body mass index by −1.1 kg/m2 (95% CI −3.7 to 1.4), compared with placebo; however, it would cause approximately twice as many adverse events, such as dizziness, drowsiness, fatigue, insomnia, or nausea. Conclusions: Although low-certainty evidence suggests that off-label fluoxetine may reduce weight, high-certainty research is needed to be conducted in the future to determine its effects exclusively as well as whether it is useful when combined with other agents. This article is based on a Cochrane Review published in the Cochrane Database of Systematic Reviews 2019, Issue 10, DOI: 10.1002/14651858.CD011688.pub2. Cochrane Reviews are regularly updated as new evidence emerges, and in response to feedback, it should be consulted for the most recent version of the review.
Excess body weight is the sixth most important risk factor that contributes to the overall burden of non-communicable diseases worldwide [1]. Over the past 30 years, the prevalence of weight gain has increased considerably to become an important public health issue as it has multiple consequences such as the risk of developing cardiovascular diseases (hazard ratio [HR] 1.27; 95% confidence interval [CI] 1.23–1.31), cerebrovascular accidents, hypertension, respiratory disorders (odds ratio [OR] 1.58; 95% CI 1.22–2.03; p < 0.001), osteoarthritis, metabolic syndrome, type 2 diabetes mellitus (HR 1.86; 95% CI 0.99–3.50; p = 0.053), and depression (OR 1.57; 95% CI 1.23–2.01; p < 0.001), which reduce the quality of life and increase the costs derived from their complications [2-6]. Therefore, different pharmacological strategies to reduce weight have been investigated to decrease the prevalence of obesity such as pancreatic lipase inhibitors (orlistat), GLP-1 analogues (liraglutide, semaglutide), MC4R agonists (setmelanotide), and appetite suppressants (phentermine-topiramate, naltrexone-bupropion), among others [7, 8].
Another pharmacological strategy is fluoxetine; it is a selective serotonin reuptake inhibitor with the capacity to treat major depression, obsessive behaviors, panic disorders, and bulimia, which also favors the hunger inhibition signals produced by the neuropeptide “Y” in the paraventricular hypothalamic nucleus, operating on appetite, altering food selection, and leading to a reduction in food intake [9-12]. Although fluoxetine has been documented to promote weight loss, currently, the only indications approved by the Food and Drug Administration are for the treatment of depression and obsessive behaviors, among others, as some studies have reported that its use may lead to adverse effects, such as headache, nausea, drowsiness, diarrhea, insomnia, sweating, and decreased libido in 5–30% of the users [13-15].
However, based on the evidence, it has been considered whether fluoxetine could be used alone or in combination with other pharmacological or behavioral changes interventions as a strategy to treat depression in adults with overweight or obesity who would also benefit from weight loss; however, the benefit-risk ratio (RR) of this drug is unclear in this regard, so we performed a systematic review to assess the efficacy and safety of fluoxetine in reducing weight in adults with overweight or obesity.
Methods
Search Strategy
Two reviewers conducted a search without language restriction up to January 2021 on the following databases: MEDLINE, Embase, LILACS, Cochrane CENTRAL, the ICTRP Search Portal, and ClinicalTrials.gov. The following MeSH terms were searched: (Obesity, Morbid OR Adiposity/OR Body Weight/OR Weight Loss/OR Overweight/OR fat) AND (Fluoxetine/AND (randomized controlled trial OR controlled clinical trial) AND (exp animal/not humans)).
Study and Participant Selection Criteria
We included randomized controlled trials that examined the administration of fluoxetine for adults (>18 years) with overweight (body mass index [BMI] 25–29.9 kg/m2) or obesity (BMI ≥30 kg/m2) according to the WHO’s criteria compared with placebo, other anti-obesity agents, non-pharmacological therapy, and no treatment [1]. Trials in which participants presented with diabetes mellitus, polycystic ovary syndrome, eating disorders, schizophrenia, HIV infection, cancer, and pregnancy were excluded. Fluoxetine regimens were dose-adjusted to assess the following outcomes: (A) weight loss; (B) BMI reduction; (C) adverse events; (D) mortality; and (E) socioeconomic effects, with 12-month follow-up.
Assessment of Risk of Bias
Two independent reviewers used the Cochrane tool [16] and GRADE instrument [17] to assess the risk of bias of the randomized controlled trials and the certainty of their evidence. Disagreements were resolved by discussion and consultation with a third reviewer. For cases with unclear information, the authors were contacted through email.
Statistical Analysis
For dichotomous data, we obtained RRs; for continuous outcomes, we calculated the mean difference (MD) with 95% CI. Meta-analyses were performed using a random-effects model, with the inverse variance method. Heterogeneity was identified by visual inspection of forest plots and using a standard χ2 test with a significance level of 0.1 and I2 statistic using the Review Manager V5.4 software. For more details, see the Cochrane systematic review [18].
Results
Although we identified 1,036 potential studies for inclusion, 32 trials were excluded due to different reasons [41-72] (online suppl. Table 1; for all online suppl. material, see www.karger.com/doi/10.1159/000524995), and 19 trials were included with 2,216 participants with a mean age of 30–51 years, a wide variety of comparisons according to fluoxetine doses (10, 20, 40, and 60 mg once a day), and time of administration (from 3 days to 12 months) (Fig. 1; Table 1) [19-37].
Table 1.
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In most trials, the risk of selection bias was unclear because their reports provided no details of the methods of random sequence generation and blinding of outcome assessment. Approximately one-third of the trials had a high risk of bias due to an attrition rate of 20% (Fig. 2).
Fluoxetine versus Placebo
Weight Loss in Kilograms
Ten trials compared fluoxetine with placebo. Seven trials used a dose of 60 mg/day [21, 25, 26, 30, 31, 33, 36]; two trials used a dose of 40 mg/day [29, 30]; and three trials used a dose of 20 mg/day [31, 35, 37].
We identified a weight loss of −2.5 kg (95% CI −3.8 to −1.2; p = 0.0001; 7 trials) in 819 participants who received fluoxetine 60 mg/day, while for the adults who received fluoxetine 40 mg/day, the weight loss was −3.97 kg (95% CI −8.8 to 0.8; p = 0.10; 2 trials, 182 participants), and for individuals who received fluoxetine 20 mg/day, the weight loss was −1.5 kg (95% CI –3.5 to 0.5; p = 0.15; 3 trials, 279 participants). However, the test for subgroup differences did not indicate a statistically significant difference (p = 0.62). Overall, across all fluoxetine dosages and durations of treatment, the weight loss was −2.7 kg (95% CI −4 to −1.4; p = 0.0001; 10 trials, 956 participants; low-certainty evidence in favour of fluoxetine) [21, 25, 26, 30-33, 35-37]. The 95% prediction interval ranged between −7.1 kg and 1.7 kg (Fig. 3).
BMI Reduction
Three trials compared fluoxetine with placebo. We identified that 19 participants who received fluoxetine 60 mg/day showed a BMI reduction of −3.3 kg/m2 (95% CI −7.3 to 0.7; p = 0.10; 1 trial) and who received fluoxetine 40 mg/day showed −2.8 kg/m2 (95% CI −8.7 to 3.1; p = 0.35; 1 trial, 18 participants). On the other hand, we observed in one trial an increase in BMI of 0.2 kg/m2 in 60 individuals who received fluoxetine 20 mg/day. However, overall, we observed a BMI reduction across all fluoxetine doses compared with the placebo that was −1.1 kg/m2 (95% CI −3.7 to 1.4; 3 trials; 97 participants; very-low-certainty evidence) (Fig. 4) [26, 32, 35].
Nine trials reported adverse events in this comparison [24-26, 30, 31, 33, 35-37]. A total of 399 out of 627 participants (63.6%) who received fluoxetine experienced an adverse event (mainly dizziness with RR 2.40; 95% CI 1.03–5.60; p = 0.04; drowsiness with RR 2.67; 95% CI 1.68–4.24; p = 0.0001; fatigue RR 2.50; 95% CI 1.62–3.85; p = 0.0001; insomnia with RR 2.23; 95% CI 1.22–4.08; p = 0.009; and nausea RR 1.99; 95% CI 1.35–2.91; p = 0.0004), compared with 352 out of 626 participants (56.2%) who received placebo.
We observed an increase in the risk to develop at least one adverse event with RR 1.16 (95% CI 0.93–1.44; p = 0.18; 7 trials) in 1,134 participants who received fluoxetine 60 mg/day; same findings were identified in 262 adults who received fluoxetine 40 mg/day (RR 1.07; 95% CI 0.93–1.24; p = 0.32; 1 trial), fluoxetine 20 mg/day (RR 1.10; 95% CI 0.92–1.31; p = 0.30; 1 trial, 592 participants), and fluoxetine 10 mg/day (RR 0.96; 95% CI 0.82–1.12; p = 0.59; 1 trial, 262 participants) without significant subgroup differences (Fig. 5).
However, pooling the trials showed an increase in the risk of experiencing at least one adverse event in the fluoxetine groups, compared with the placebo with an RR of 1.18 (95% CI 0.99–1.42; p = 0.07; 9 trials, 1,253 participants; low-certainty evidence) [24-26, 30, 31, 33, 35-37]. The 95% prediction interval ranged between 0.74 and 1.88 (Table 2).
Table 2.
Fluoxetine versus Other Therapies and No Treatment
Weight Loss in Kilograms
Three trials (234 participants) compared different doses of fluoxetine with six types of anti-obesity agents (sibutramine, metformin, dexfenfluramine, diethylpropion, fenproporex, and mazindol) [26, 35, 37]; one trial (48 participants) used the omega-3 gel as monotherapy and in combination with fluoxetine [19]; and one trial compared with no treatment (60 participants) [27]; however, due to the great heterogeneity between the studies, it was not possible to generate the meta-analysis (Table 3).
Table 3.
BMI Reduction
Two trials compared fluoxetine with five types of anti-obesity agents (sibutramine, metformin, diethylpropion, fenproporex, and mazindol) [26, 35], and one trial compared with no treatment [27]. We identified that participants who received fluoxetine 60 mg/day showed a BMI reduction from −0.5 kg/m2 (95% CI –0.6 to −0.3; p = 0.0001, 60 adults) to −2.2 kg/m2 (95% CI –8.4 to 4; p = 0.48; 1 trial, 17 adults) compared to no treatment and metformin, respectively; however, on the other hand, we also observed an increase of BMI in participants who received fluoxetine 20 mg/day from 2 kg/m2 (95% CI 0.9–3.1; p = 0.0001; 1 trial, 62 adults) to 2.9 kg/m2 (95% CI 1.8–4; p = 0.0001; 1 trial 61 participants) compared to sibutramine, diethylpropion, fenproporex, and mazindol. As in the previous outcome analysis, we were unable to perform the meta-analysis due to the diversity of interventions and heterogeneity between the studies (Table 3).
Three trials reported the development of adverse events comparing fluoxetine with six anti-obesity agents [26, 35, and 37], and one trial compared with no treatment [27]. Overall, we observed an increase in the risk to develop at least one adverse event from an RR of 1.05 (95% CI 0.68–1.65; p = 0.82; 1 trial, 60 participants) to an RR of 1.58 (95% CI 0.91–2.77; p = 0.11; 1 trial) in participants who received fluoxetine at any dose; however, the meta-analysis could not be performed due to the heterogeneity between the trials (Table 3). For mortality and socioeconomic effects, none of the included trials reported these outcomes.
Discussion
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Overall, we identified a great variety of doses and durations of treatment in the intervention groups, many different groups of comparators, and variation in the diagnostic criteria and characteristics of the grade of obesity in the participants, which limited comparability and increased the heterogeneity between trials. In most trials, the risk of selection bias was unclear because their reports did not mention in detail the methods of random sequence generation and concealment of allocation. Blinding of outcome assessment was unclear in almost all trials. Approximately one-third of the trials had a high risk of bias due to an attrition rate of 20% of their participants, and almost half of the trials had a high risk of reporting bias.
However, although our findings had low-certainty evidence, we observed that off-label fluoxetine at any dose, especially 60 mg once a day, may cause moderate weight loss of approximately 2.7 kg and only with this dose generate a reduction of BMI of −1.1 kg/m2 compared with placebo in adults with overweight or obesity; however, it may lead to approximately twice as many adverse events, such as dizziness, drowsiness, fatigue, insomnia, or nausea. These findings are similar to other systematic reviews which reported that the participants who received fluoxetine at least for 4 months showed a weight loss from 1.3 kg in adults with overweight or obese (BMI of 26–39 kg/m2) to 5.1 kg in participants with type 2 diabetes compared with placebo [38-40].
Based on the above, although there are FDA-approved pharmacological therapies effective for weight reduction in adults with overweight or obesity, such as pancreatic lipase inhibitors, GLP-1 analogues, MC4R agonists, and appetite suppressants, the only therapeutic strategy that includes a weak antidepressant is the naltrexone-bupropion combination despite the reported association between obesity and the development of depression [4]; so, although the indication for fluoxetine is for the treatment of obsessive behaviors, depression, and anxiety crises, it could be considered as another strategy for weight loss in adults with this condition since it may produce a modest weight loss as a side effect compared to the annoying adverse effects of the administration of pancreatic lipase inhibitors such as the presence of steatorrhea, flatulence, and deficits in the absorption of vitamins A, D, E, and beta-carotene or those developed by the use of GLP-1 analogues and MC4R agonists, which in addition to injection site reactions and their high cost, also favor the appearance of headache, hypoglycemia, nausea, vomiting, and diarrhea [7, 8]. In this way, health decision makers can take into consideration another therapeutic option at a lower cost, which could be an alternative to be implemented, especially in overweight or obese adults in low- and middle-income countries.
Conclusions
We observed low-certainty evidence suggesting that off-label fluoxetine may produce a modest weight loss compared with placebo at any dose, especially when given at a dose of 60 mg/day. However, we found low-certainty evidence of a small increase in the risk for specific adverse events, such as dizziness, drowsiness, fatigue, insomnia, and nausea following fluoxetine consumption. With respect to other findings of our review, more high-certainty research is needed to exclusively determine the effects of fluoxetine at different doses and whether it is useful when combined with other anti-obesity agents and non-pharmacological interventions.
Acknowledgements
We thank the Cochrane Metabolic and Endocrine Disorders Group for their assistance and their Information Specialist; Maria-Inti Metzendorf for developing the search strategy; and the Assistant Director of Scientific Information and Documentation of the Instituto Nacional de Pediatría, Cecilia Solis-Galicia, for acquiring study reports. The review authors are grateful to the following peer reviewers for their time and comments: Dr. Emma Axon, Cochrane Systematic methodologist, Cochrane Skin Group, University of Nottingham, UK, and Ian Caterson, University of Sydney.
Statement of Ethics
This manuscript did not require ethical approval by the ethics committee of the Instituto Nacional de Pediatría and was reviewed, approved, and co-published by Cochrane Database of Systematic Reviews 2019, Issue 10. Art. No.: CD011688 titled Fluoxetine for adults who are overweight or obese [18].
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
This manuscript has been supported by the Instituto Nacional de Pediatría (2019/C-043 fiscal resources program E022) only for publication.
Author Contributions
A.E.S.-Z. contributed to conceptualization, investigation, supervision, validation, visualization, medical oversight, and preparing the original draft and final manuscript. A.G.G.-G. contributed to conceptualization, data curation, formal analysis, methodology, software, validation, visualization, and writing the final manuscript. Y.R.-C. contributed to investigation, conceptualization, data curation, visualization, and preparing the original draft. G.M.-M. contributed to conceptualization, supervision, validation, project administration, and critical revision of the draft and final manuscript. All the authors approved the final manuscript. Y.R.-C. and G.M.-M. contributed equally to this article and shared final authorship.
Data Availability Statement
All data generated or analyzed during this study are included in this manuscript. Further enquiries can be directed to the corresponding author.
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