Fluoxetine for adults who are overweight or obese

Aurora E Serralde-Zúñiga; Alejandro G Gonzalez Garay; Yanelli Rodríguez-Carmona; Guillermo Melendez

doi:10.1002/14651858.CD011688.pub2

. 2019 Oct 15;2019(10):CD011688. doi: 10.1002/14651858.CD011688.pub2

Fluoxetine for adults who are overweight or obese

Aurora E Serralde-Zúñiga ¹, Alejandro G Gonzalez Garay ^2,^✉, Yanelli Rodríguez-Carmona ³, Guillermo Melendez ⁴

Editor: Cochrane Metabolic and Endocrine Disorders Group

PMCID: PMC6792438 PMID: 31613390

Abstract

Background

Fluoxetine is a serotonin reuptake inhibitor indicated for major depression. It is also thought to affect weight control: this seems to happen through appetite changes resulting in decreased food intake and normalisation of unusual eating behaviours. However, the benefit‐risk ratio of this off‐label medication is unclear.

Objectives

To assess the effects of fluoxetine for overweight or obese adults.

Search methods

We searched the Cochrane Library, MEDLINE, Embase, LILACS, the ICTRP Search Portal and ClinicalTrials.gov and World Health Organization (WHO) ICTRP Search Portal. The last date of the search was December 2018 for all databases, to which we applied no language restrictions .

Selection criteria

We included randomised controlled trials (RCTs) comparing the administration of fluoxetine versus placebo, other anti‐obesity agents, non‐pharmacological therapy or no treatment in overweight or obese adults without depression, mental illness or abnormal eating patterns.

Data collection and analysis

Two review authors independently screened abstracts and titles for relevance. Screening for inclusion, data extraction and risk of bias assessment was performed by one author and checked by the second. We assessed trials for the overall certainty of the evidence using the GRADE instrument. For additional information we contacted trial authors by email. We performed random‐effects meta‐analyses and calculated the risk ratio (RR) with 95% confidence intervals (95% CI) for dichotomous outcomes and the mean difference (MD) with 95% CI for continuous outcomes.

Main results

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).

Authors' conclusions

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

Fluoxetine for overweight or obese adults

Review question What are the effects of fluoxetine treatment in overweight or obese adults?

Background Fluoxetine is a medicine used for the treatment of depression, which reduces appetite as a side effect. Therefore, it is suspected that fluoxetine could be used as a treatment for overweight or obese people. In this group of people administration of fluoxetine means an off‐label treatment which means it is not licensed for treating obesity.

Study characteristics 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.

Key results 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.

Certainty of the evidence 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.

Summary of findings

Summary of findings 1. Summary of findings: fluoxetine compared with placebo.

Fluoxetine compared with placebo
Population: overweight or obese adults Settings: outpatients Intervention: fluoxetine Comparison: placebo
Outcomes	Placebo	Fluoxetine	Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
Weight loss (kg) (a) All fluoxetine dosages (b) Fluoxetine 60 mg/d (c) Fluoxetine 40 mg/d (d) Fluoxetine 20 mg/d Follow‐up: (a) 11 days to 52 weeks (b) 11 days to 52 weeks (c) 8 & 12 weeks (d) 8 weeks to 52 weeks	(a) The mean weight loss ranged across placebo groups from −4.9 kg to 0.3 kg (b) The mean weight loss ranged across placebo groups from −4.9 kg to 0.3 kg (c) The mean weight loss ranged across placebo groups from −1.7 kg to −0.5 kg (d) The mean weight loss ranged across placebo groups from −3.1 kg to −0.5 kg	(a) The mean weight loss in the fluoxetine groups was 2.7 kg higher (4 kg higher to 1.4 kg higher) (b) The mean weight loss in the fluoxetine groups was 2.5 kg higher (3.8 kg higher to 1.2 kg higher) (c) The mean weight loss in the fluoxetine groups was 4 kg higher (8.8 kg higher to 0.8 kg lower) (d) The mean weight loss in the fluoxetine groups was 1.5 kg higher (3.5 kg higher to 0.5 kg lower)	—	(a) 956 (10) (b) 819 (7) (c) 182 (2) (d) 279 (3)	(a) & (b) ⊕⊝⊝⊝ low^a (c) & (d) ⊝⊝⊝⊝ verylow^b	(a) The 95% prediction interval ranged between −7.1 kg and 1.7 kg (b) The 95% prediction interval ranged between −6.4 kg and 1.4 kg
Health‐related quality of life	Not reported
Any adverse event (N) Follow‐up: median 3 months, maximum 12 months	562 per 1000	664 per 1000 (557 to 798)	RR 1.18 (0.99 to 1.42)	1253 (9)	⊕⊝⊝⊝ low^c	Only 9/19 trials reported on the outcome 'any adverse event' Adverse events dizziness, drowsiness, fatigue, insomnia and nausea were observed approximately twice as often following fluoxetine treatment
Anthropometric measurements other than weight loss in kg (BMI reduction measured inkg/m²) Follow‐up: median 3 months, maximum 12 months	The mean BMI ranged across placebo groups from −0.4 kg/m² to −1.2 kg/m²	The mean BMI reduction in the fluoxetine groups was 1.1 kg/m² higher (3.7 kg/m² higher to 1.4 kg/m² lower)	—	97 (3)	⊕⊝⊝⊝ very low^d
Morbidity: depression (N) Follow‐up: median 9.2 months	61 per 1000	73 per 1000 (35 to 154)	RR 1.20 (0.57 to 2.52)	393 (3)	⊕⊝⊝⊝ very low^e
All‐cause mortality	Not reported
Socioeconomic effects	Not reported
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMI: boy mass index; CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

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^aDowngraded by 1 level because of reporting bias and by 1 level because of imprecision (small median sample size) ‒ see Appendix 1 ^bDowngraded by 1 level because of reporting bias and attrition bias, by 1 level because of inconsistency (point estimates varied widely) and by 1 level because of imprecision (small median sample size, small number of trials) ‒ see Appendix 1 ^cDowngraded by 1 level because of reporting bias and attrition bias, and by 1 level because of imprecision (small median sample) ‒ see Appendix 1 ^dDowngraded by 1 level because of reporting bias and performance bias and by 2 levels because of imprecision (CI consistent with benefit and harm, small median sample size, small number of trials) ‒ see Appendix 1 ^eDowngraded by 1 level because of reporting bias, performance bias and attrition bias, and by 2 levels because of imprecision (CI consistent with benefit and harm, small median sample size, small number of trials) ‒ see Appendix 1

Background

Description of the condition

Excess body weight is the sixth most important risk factor contributing to the overall burden of non‐communicable diseases (NCDs) worldwide. Over the past 30 years, the prevalence of weight gain has considerably increased in high‐, low‐ and middle‐income countries. According to the latest available estimates and projections, the World Health Organization (WHO) indicated that approximately 1.9 billion adults aged 18 years and over were overweight and 600 million were obese in 2014 (WHO 2014). In addition, the projection for the next 15 years is not promising: if current secular trends continue at the same pace, by 2030 the estimated total numbers of overweight and obese people will be 2.16 billion and 1.12 billion, respectively (Kelly 2008), with most residing in low‐ and middle‐income countries.

It is well known that NCDs are the leading causes of death worldwide. Of the 57 million deaths that occurred in 2008, the majority (36 million) were attributed to cardiovascular diseases, diabetes, cancers and chronic respiratory diseases (WHO 2014).

Body mass index (BMI) is useful for identifying individuals who are overweight and obese in adult populations. BMI is calculated by dividing a person's weight (in kilograms) by the square of her/his height (in metres) (kg/m²). Individuals with a BMI ranging from 25 to 29.9 are classified as being overweight, and those with a BMI of 30 or more are considered obese. Weight gain is associated with NCDs, including cardiovascular diseases, stroke, hypertension, osteoarthritis, fatty liver, several types of cancers, metabolic syndrome, respiratory disorders and type 2 diabetes mellitus (Haslam 2005; WHO 2014).

Obesity has become a major public health concern, and it alone represents an independent risk factor for cardiovascular disease; therefore, the global state of this condition necessitates effective preventive and therapeutic strategies to reduce its prevalence and abate the costs of complications. The adverse health consequences of obesity are manifold, potentially involving all major organ systems and the detriment of health‐related quality of life (NTF 2000). It has been shown, moreover, that life expectancy is reduced by seven years in obese individuals aged 40 years and older (Peeters 2003).

Description of the intervention

Non‐pharmacological, pharmacological and surgical strategies to reduce weight and maintain weight loss over time should be made available to individuals with these conditions. Pharmacological therapy has been used for some people, in addition to behaviour‐changing interventions, to facilitate weight loss and prevent weight rebound for a certain period of time.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) with the capacity to enhance serotonin activity. Although it has not been approved for weight loss, it is being prescribed for this indication (Anelli 1992).

Approved indications for fluoxetine are major depression, obsessive behaviours, panic disorders and bulimia (Aigner 2011; Beasley 1990; Halpern 2003; Peeters 2003). However, physicians have used it off‐label to promote weight loss (Goldstein 1994; Reimherr 1998; Serretti 2010).

Adverse effects of the intervention

The adverse effects of fluoxetine with incidences of greater than 5% are headache, nausea, somnolence, asthenia, diarrhoea, insomnia, nervousness, sweating and tremor (Wise 1992). Additionally sexual dysfunction has been reported, including erectile dysfunction, anorgasmia and diminished libido, which have been well documented in 30% to 70% of people and frequently result in treatment non‐compliance (Colman 2012; Wenthur 2014).

How the intervention might work

As endogenous serotonin levels respond to both deprivation and energy excess, and reduced caloric intake lowers central nervous system serotonin levels and turnover, this neurotransmitter appears to operate on appetite. Fluoxetine acts specifically by blocking the reuptake of serotonin (5‐hydroxytryptamine (5‐HT)), which is a neurotransmitter shown to reduce food intake by preventing the membrane uptake carrier transport of serotonin from the extracellular space to the inside of serotonin nerve terminals (Leibowitz 1990). Fluoxetine increases extracellular concentrations of serotonin and amplifies signals sent by serotonin neurons. Because serotonin neurons are widespread in the central nervous system, the functional consequences of blocking its uptake are diverse and include symptoms such as decreased food intake; altered food selection; endocrine changes (increases in adrenocorticotropic hormone and corticosterone concentrations, potentiating a 5‐HT‐induced rise of corticosterone and prolactin concentrations) (Fuller 1991); and normalisation of unusual eating behaviours (such as the frequency and severity of binge eating episodes) (Halford 2008).

Additionally, the hypophagic effects of serotonergic drugs appear to be influenced by the anorexigenic melanocortin system. The hypothalamic serotonin satiety system is known to interact with orexigenic systems, a family of peptides that stimulate food consumption in the hypothalamus; major orexigenic representatives are orexin and neuropeptide Y (Gutiérrez 2002). In the case of serotonin, its potent anorexigenic effect can block hunger signals produced by neuropeptide Y (Dryden 1996; Ioannides‐Demos 2005). Furthermore, the hypophagic effects of serotonergic drugs appear to extend the effect to another anorexigenic system such as that driven by melanocortin. It has been postulated that fluoxetine can generate a reduction in body weight gain by inhibiting neuropeptide Y action in the paraventricular nucleus of the hypothalamus, a site where neuropeptide Y exerts its hyperphagic effects (Dryden 1996; Gutiérrez 2002). The neurons of the hypothalamic paraventricular nucleus contain moderate to abundant levels of serotonin receptor subtypes related to hypophagia (2A and 1B). The proximity of neuropeptide Y and 5‐HT neurons in the hypothalamus suggest that these two systems may interact on hyperphagia/hypophagia regulation but serotonin may also be responsible for altered appetite and feeding behaviours. In addition, these neurons contain corticotrophin‐releasing factor too, a neuropeptide that suppresses feeding behaviours (Boisvert 2011; Ioannides‐Demos 2005).

The effects of fluoxetine in reducing caloric intake by modifying appetite have been documented in both lean and obese humans. Specifically, this drug may reduce appetite before and after the consumption of fixed caloric loads, decreasing pre‐meal appetite and caloric intake during unrestricted meals (Halford 2007; McGuirk 1990). There are also some speculations that fluoxetine contributes to weight loss by increasing resting energy expenditure (Halford 2005; Suplicy 2013).

Why it is important to do this review

Fluoxetine is an SSRI that affects weight control, and can be used either alone or in combination with other behaviour‐changing or pharmacological interventions. The benefit‐risk ratio of this drug is, however, unclear. There has been no systematic review performed to date to evaluate the effects of fluoxetine in overweight or obese adult people. Given the prevalence of being overweight and obesity, it is important to establish the possible impact of fluoxetine on people affected by these conditions.

Objectives

To assess the effects of fluoxetine for overweight or obese adults.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCT) comparing the administration of fluoxetine versus another pharmacological therapy with anti‐obesity agents, no treatment or placebo for overweight or obese adults.

Types of participants

We included adults (aged 18 years and older) who were overweight or obese according to WHO 2000 criteria, with or without comorbidities, of any ethnicity, who received fluoxetine as treatment for this condition.

Diagnostic criteria for being overweight and obese

We calculated BMI by dividing a person's weight by the square of her/his height (kg/m²). We calculated a range of between 25 and 29.9 as overweight, and 30 or more as indicating obesity (WHO 2014).

Types of interventions

We planned to investigate the following comparisons of any treatment duration of fluoxetine versus a control/comparator.

Intervention

Fluoxetine

Comparator

Placebo
Another anti‐obesity agent (e.g. orlistat, metformin)
Non‐pharmacological therapy for overweight or obesity (e.g. diet, exercise)
No treatment

Concomitant interventions had to be identical in the intervention and comparator groups to establish fair comparisons.

If a trial included multiple arms, we included any arm that met our review inclusion criteria.

Minimum duration of intervention

Minimal duration of intervention was three days.

Summary of specific exclusion criteria

We excluded trials of the following categories of participants.

Children
Pregnant women
People with diabetes mellitus
People with polycystic ovary syndrome
People with schizophrenia
People with eating disorders
People with HIV infection
People with cancer

Types of outcome measures

Primary outcomes

Weight loss (kg)
Health‐related quality of life
Adverse events

Secondary outcomes

Anthropometric measurements other than weight loss in kg
Morbidity
All‐cause mortality
Socioeconomic effects

Method of outcome measurement

Weight loss: measured in kg.
Health‐related quality of life: evaluated by a validated instrument, such as the Short‐Form Health Survey (SF‐36) or the 12‐item Short‐Form Health Survey (SF‐12).
Adverse events: such as headache, nausea, somnolence, asthenia, diarrhoea, insomnia, nervousness, sweating, tremor.
Anthropometric measurements other than weight loss in kg: defined as BMI.
Morbidity: cardiovascular diseases and psychiatric disorders.
All‐cause mortality: defined as death from any cause.
Socioeconomic effects: such as costs of treatment, hospitalisation, resources lost due to illness by the participant or absence from work.

Timing of outcome measurement

For weight loss, health‐related quality of life and anthropometric measurements: at 3, 6 and 12 months.
For adverse events, morbidity and all‐cause mortality: at any time after the randomisation of participants to intervention/comparator groups.
Socioeconomic effects: measured for up to 12 months.

Search methods for identification of studies

Electronic searches

We searched the following sources from the inception of each database to the specified date and placed no restrictions on the language of publications.

Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO) (until 20 December 2018).
MEDLINE Ovid (Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R); from 1946 until 20 December 2018.
Embase Ovid (from 1974 until 25 December 2018).
LILACS (Latin American and Caribbean Health Science Information database; from 1982 until 28 December 2018).
ClinicalTrials.gov (www.clinicaltrials.gov) (until 31 December 2018).
World Health Organization International Clinical Trials Registry Platform (ICTRP) (www.who.int/trialsearch) (until 31 December 2018).

We continuously applied a MEDLINE (via Ovid SP) email alert service established by the Cochrane Metabolic and Endocrine Disorders (CMED) Group to identify newly published studies using the same search strategy as described for MEDLINE (for details on search strategies see Appendix 2). After supplying the final review draft for editorial approval, the CMED Group performed a complete updated search on all databases available at the editorial office and sent the results to the review authors. In case we detected new studies for inclusion, we evaluated these and incorporated findings in our review before submission of the final review draft.

Searching other resources

We planned to identify other potentially eligible trials or ancillary publications by searching the reference lists of retrieved included trials, systematic reviews, meta‐analyses and health technology assessment reports. In addition we contacted the authors of the included trials to identify any further studies we may have missed.

We defined grey literature as records detected in ClinicalTrials.gov or WHO ICTRP.

We did not use abstracts or conference proceedings for data extraction because this information source does not fulfil the CONSORT requirements which is "an evidence‐based, minimum set of recommendations for reporting randomized trials" (CONSORT; Scherer 2007). However, we planned to specify trial details in the table 'Characteristics of studies awaiting classification'.

Data collection and analysis

Selection of studies

Two review authors (AS and GM) independently scanned the title or abstract, or both, of every record retrieved, to determine which trials should be assessed further. We investigated the full text articles of all potentially relevant articles. We resolved any discrepancies through consensus or by recourse to a third review author (AGG). If we could not resolve a disagreement, we recorded the study in the 'Studies awaiting classification' section and contacted trial authors for clarification. We present an adapted PRISMA flow diagram to show the process of trial selection (Figure 1; Liberati 2009). We listed all articles excluded after full‐text assessment in the 'Characteristics of excluded studies' table and provided the reasons for exclusion.

Data extraction and management

For trials that fulfilled our inclusion criteria, two review authors (AS and YR) independently abstracted relevant key participant and intervention characteristics. We reported data on efficacy outcomes and adverse events using standard data extraction sheets from the CMED Group. We resolved any disagreements by discussion or, if required, by consultation with a third review author (AGG) (for details see Characteristics of included studies; Table 2; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6; Appendix 7; Appendix 8; Appendix 9; Appendix 10; Appendix 11; Appendix 12; Appendix 13; Appendix 14; Appendix 15; Appendix 1).

1. Overview of trial populations.

Trial ID (trial design)	Intervention(s) and comparator(s)	Description of power and sample size calculation	Screened/eligible (N)	Randomised (N)	ITT (N)	Analysed (N)	Finishing trial (N)	Randomised finishing trial (%)	Duration of intervention
Al‐Helli 2015 (parallel RCT)	I1: fluoxetine 20 mg	—	48/48	12	12	12	12	100	2 months
	I2: omega‐3 gel			12	12	12	12	100
	I3: fluoxetine 20 mg + omega‐3 gel			12	12	12	12	100
	C: placebo			12	12	12	12	100
	total:			48	48	48	48	100
Suplicy 2014 (parallel RCT)	I1: diethylpropion	"As we had calculated the day to day coefficient of variation of resting metabolic rate for this method to be less than 5% for a given subject, we calculated that it was necessary to study at least 26 subjects to have sufficient power"	507/180	30	28	28	23	76.7	52 weeks
	I2: fenproporex			31	29	29	23	74.2
	I3: mazindol			29	29	29	24	82.7
	I4: fluoxetine 20 mg			31	29	29	20	64.5
	I5: sibutramine			30	30	30	24	80
	C: placebo			29	29	29	15	51.7
	total:			180	174	174	129	71.7
Guimaraes 2006 (parallel RCT)	I1: sibutramine	—	35/35	8	8	8	8	100	90 days
	I2: metformin			8	8	8	8	100
	I3: fluoxetine 60 mg			9	9	9	9	100
	C: placebo			10	10	10	10	100
	total:			35	35	35	35	100
Bondi 2000 (parallel RCT)	I1: fluoxetine 40 mg	—	32/32	8	8	8	8	100	12 weeks
	I2: fluoxetine 60 mg			12	12	12	12	100
	C: placebo			12	12	12	12	100
	total:			32	32	32	32	100
Huang 1998 (parallel RCT)	I: fluoxetine 60 mg	—	60/60	30	—	28	28	93.3	12 weeks
	C: no treatment	—	60/60	30	—	22	22	73.3
	total:			60	—	50	50	83.3
Bross 1995 (parallel RCT)	I: fluoxetine 60 mg	—	20/20	10	10	10	10	100	3 weeks
	C: placebo	—	20/20	10	10	10	10	100
	total:			20	20	20	20	100
Fernández‐Soto 1995 (cross‐over RCT)	I: fluoxetine 60 mg	—	42 participants with full cross‐over	23	—	18	18	78.2	3 months
	C: placebo	—	42 participants with full cross‐over	19	—	15	15	78.9
	total:			42	—	33	33	78.5
Lawton 1995 (cross‐over RCT)	I: fluoxetine 60 mg	—	13 participants with full cross‐over	13	12	12	12	92.3	2 weeks
	C: placebo	—	13 participants with full cross‐over	13	12	12	12	92.3
	total:			13	12	12	12	92.3
Goldstein 1994 (parallel RCT)	I: fluoxetine 60 mg	—	458/458	230	217	217	99	43	52 weeks
	C: placebo	—	458/458	228	217	217	108	47.3
	total:			458	434	434	207	45.1
Goldstein 1993 (parallel RCT)^a	I1: fluoxetine 60 mg	—	458/450	106	61	61	60	56.6	40 weeks
	I2: fluoxetine 20 mg			104	72	72	70	67.3
	C: placebo			107	72	72	72	67.2
	total:			317	205	205	202	63.7
Pedrinola 1993 (parallel RCT)	I: fluoxetine 40 mg	—	20/20	10	—	10	10	100	12 weeks
	C: placebo	—	20/20	10	—	8	8	80
	total:			20	—	18	18	90
Visser 1993 (parallel RCT)	I: fluoxetine 60 mg	"Based on earlier studies at our department 40 men in total were selected for detecting a 10% improvement in body weight, fat‐free mass and abdominal fat areas, with 80% probability"	132/40	20	—	18	18	90	12 weeks
	C: placebo		132/40	20	—	20	20	100
	total:			40	—	38	38	95
Wurtman 1993 (parallel RCT)	I1: dexfenfluramine	—	87/87	28	28	28	21	75	12 weeks
	I2: fluoxetine 20 mg			30	30	30	18	60
	C: placebo			29	29	29	25	86.2
	total:			87	87	87	64	73.5
Kopelman 1992 (cross‐over RCT)	I: fluoxetine 60 mg	—	11 participants with full cross‐over	11	11	11	11	100	3 days
	C: placebo	—	11 participants with full cross‐over	11	11	11	11	100
	total:			11	11	11	11	100
Stinson 1992 (cross‐over RCT)	I: fluoxetine 60 mg	"A 12‐wk placebo‐subtracted total weight loss of at least 5% was considered. It was assumed that roughly 10% of participants in the placebo group would have a weight loss of 5% at the end of the study and the magnitude of the effect (the minimum difference between treatment arms to be considered clinically relevant) was assumed to be 40%. "Power was set as 0.8 with an alpha level of 0.05, resulting in an estimate minimum sample size of 26 participants per group"	30 participants with full cross‐over	13	13	13	13	100	2 weeks
	C: placebo		30 participants with full cross‐over	17	17	17	17	100
	total:			30	30	30	30	100
Bagiella 1991 (parallel RCT)	I1: fenfluramine	—	60/60	—	—	—	—	—	12 weeks
	I2: 5‐hydroxy‐tryptophan			—	—	—	—	—
	I3: d‐fenfluramine			—	—	—	—	—
	I4: fluoxetine 20 mg			—	—	—	—	—
	I5: fluvoxamine			—	—	—	—	—
	C: placebo			—	—	—	—	—
	total:			60	60	60	60	100
Pijl 1991 (parallel RCT)	I: fluoxetine 60 mg	—	24/24	12	—	11	11	91.6	6 weeks
	C: placebo	—	24/24	12	—	12	12	100
	total:			24	—	23	23	95.8
Levine 1989 (parallel RCT)	I1: fluoxetine 10 mg	—	655/655	131	131	131	80	61	8 weeks
	I2: fluoxetine 20 mg			131	131	131	86	65.6
	I3: fluoxetine 40 mg			131	131	131	90	68.7
	I4: fluoxetine 60 mg			131	131	131	87	66.4
	C: placebo			131	131	131	74	56.4
	total:			655	655	655	417	63.6
Levine 1987 (parallel RCT)	I: fluoxetine 60 mg	—	120/120	60	59	48	48	80	11 days
	C: placebo	—	120/120	60	59	52	52	86.6
	total:			120	118	100	100	83.3
Grand total^b	All interventions			1280			842
	All comparators			936			761
	All interventions and comparators			2216			1603

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— denotes not reported

^aObese outpatients were randomised who had lost 23.6 kg after 8 weeks of single‐blind fluoxetine 60 mg/d in the "qualification phase" ^bNumbers do not add up correctly because Bagiella 1991 did not provide the numbers of randomised participants per intervention and comparator group; Fernández‐Soto 1995, Kopelman 1992, Lawton 1995 and Stinson 1992 were cross‐over trials and were subsumed under all interventions only

C: comparator; I: Intervention; ITT: intention‐to‐treat; RCT: randomised controlled trial; wk: week.

We planned to provide information including the trial identifier for potentially relevant ongoing studies in the 'Characteristics of ongoing studies' table and in Appendix 8 'Matrix of trial endpoints (publications and trial documents)'. We tried to find the protocol of each included trial and reported primary, secondary and other outcomes measured by the study personnel (objectively) in comparison with the data from the publications in Appendix 8.

We planned to analyse clinical study reports from manufacturers, provided they were willing to share the information. We also planned to collect these clinical study reports from the regulatory agencies. We sent an email request to the authors of the included trials to enquire whether they were willing to answer questions regarding their trials: Appendix 14 shows the results of this survey. Thereafter, we sought relevant missing information on the trial from the primary author(s) of the article, if required.

Dealing with duplicate and companion publications

In the event of duplicate publications, companion documents or multiple reports of a primary trial, we planned to maximise the information yield by collating all available data and use the most complete data set aggregated across all known publications. We listed duplicate publications, companion documents, multiple reports of a primary trial and trial documents of included trials (such as trial registry information) as secondary references under the study identifier (ID) of the included trial. Furthermore, we listed duplicate publications, companion documents, multiple reports of a trial and trial documents of excluded trials (such as trial registry information) as secondary references under the study ID of the excluded trial.

Data from clinical trial registers

If data from included trials were available as study results in clinical trial registries such as ClinicalTrials.gov or similar sources, we planned to make full use of this information and to extract the data. If there was also a full publication of the trial, we collected and critically appraised all available data. If an included trial was marked as a completed study in a clinical trials registry but no additional information (study results, publication or both) was available, we planned to add this trial to the table 'Characteristics of studies awaiting classification'.

Assessment of risk of bias in included studies

Two review authors (AS and YR) independently assessed the 'Risk of bias' of each included trial. We resolved disagreements by consensus or by consulting a third review author (AGG). In case of disagreement, we consulted the rest of the review author team and we made a judgement based on consensus. If adequate information was unavailable from the trials or trial protocols, we contacted the trial authors to recover missing data on 'Risk of bias' items.

We used the Cochrane 'Risk of bias' assessment tool (Higgins 2011a; Higgins 2017), assigning assessments of low, high, or unclear risk of bias (for details, see Appendix 3; Appendix 4). We evaluated individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions according to the criteria and associated categorisations contained therein (Higgins 2017).

Summary assessment of risk of bias

We present a 'Risk of bias' graph (Figure 2) and a 'Risk of bias' summary figure (Figure 3).

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials (blank cells indicate that the particular outcome was not measured in some trials).

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial ((blank cells indicate that the particular outcome was not measured in some trials).

We distinguished between self‐reported, investigator‐assessed and adjudicated outcome measures.

We accepted the following outcomes as self‐reported.

Health‐related quality of life.
Adverse events, if measured by participants.
Weight loss and other anthropometric measures, if measured by participants.

We required the following outcomes to be investigator‐assessed.

Weight loss and other anthropometric measures, if measured by study personnel.
Adverse events, if measured by study personnel.
All‐cause mortality.
Morbidity.
Socioeconomic effects.

Risk of bias for a trial across outcomes

Some 'Risk of bias' domains, such as selection bias (sequence generation and allocation sequence concealment), affect the risk of bias across all outcome measures in a trial. In case of high risk of selection bias, all endpoints investigated in the associated trial were marked as high risk. Otherwise, we did not perform a summary assessment of the risk of bias across all outcomes for a trial.

Risk of bias for an outcome within a trial and across domains

We assessed the risk of bias for an outcome measure by including all entries relevant to that outcome (i.e. both trial‐level entries and outcome‐specific entries). We considered low risk of bias to denote a low risk of bias for all key domains; unclear risk to denote an unclear risk of bias for one or more key domains; and high risk to denote a high risk of bias for one or more key domains.

Risk of bias for an outcome across trials and across domains

These are the main summary assessments that we incorporated into our judgements about the quality of the certainty of the 'Summary of findings' tables. We defined outcomes as at low risk of bias when most information came from trials at low risk of bias; unclear risk when most information came from trials at low or unclear risk of bias; and high risk when a sufficient proportion of information came from trials at high risk of bias.

Measures of treatment effect

When at least two included trials were available for a comparison of a given outcome, we planned to express dichotomous data as a risk ratio (RR) or an odds ratio (OR) with 95% confidence intervals (CIs). For continuous outcomes measured on the same scale (e.g. weight loss in kg) we planned to estimate the intervention effect using the mean difference (MD) with 95% CIs. For continuous outcomes that measured the same underlying concept (e.g. health‐related quality of life) but used different measurement scales, we planned to calculate the standardised mean difference (SMD). We wanted to express time‐to‐event data as a hazard ratio (HR) with 95% CIs.

Unit of analysis issues

We took into account the level at which randomisation occurred, such as cross‐over trials, cluster‐randomised trials and multiple observations for the same outcome. If more than one comparison from the same trial was eligible for inclusion in the same meta‐analysis, we either combined groups to create a single pair‐wise comparison or appropriately reduced the sample size so that the same participants did not contribute more than once (splitting the 'shared' group into two or more groups). While the latter approach offers some solution to adjusting the precision of the comparison, it does not account for correlation arising from inclusion of the same set of participants in multiple comparisons (Higgins 2011b).

We planned to re‐analyse cluster‐RCTs that had not appropriately adjusted for potential clustering of participants within clusters in their analyses. Variance of the intervention effects would have been inflated by a design effect. Calculation of a design effect involves estimation of an intra‐cluster correlation (ICC). We planned to obtain estimates of ICCs through contact with the trial authors, or by imputing ICC values using either estimates from other included trials that reported ICCs, or external estimates from empirical research (e.g. Bell 2013). We planned to examine the impact of clustering by performing sensitivity analyses.

Dealing with missing data

If possible, we obtained missing data from the authors of included trials. We carefully evaluated important numerical data such as screened, randomly assigned participants, as well as intention‐to‐treat and as‐treated and per‐protocol populations. We investigated attrition rates (e.g. dropouts, losses to follow‐up, withdrawals), and we critically appraised issues concerning missing data and use of imputation methods (e.g. last observation carried forward).

For trials in which the standard deviation (SD) of the outcome was not available at follow‐up or could not be re‐created, we planned to standardise by the average of the pooled baseline SD from those trials that reported this information.

When included trials did not report means and SDs for outcomes, and we did not receive requested information from trial authors, we planned to impute these values by estimating the mean and the variance from the median, the range, and the size of the sample (Hozo 2005).

We planned to investigate the impact of imputation on meta‐analyses by performing sensitivity analyses and we reported per outcome which trials were included with imputed SDs.

Assessment of heterogeneity

In the event of substantial clinical or methodological heterogeneity, we did not report trial results as the pooled effect estimate in a meta‐analysis.

We identified heterogeneity (inconsistency) by visually inspecting the forest plots and by using a standard Chi² test with a significance level of α = 0.1 (Deeks 2017). In view of the low power of this test, we also considered the I² statistic, which quantifies inconsistency across trials to assess the impact of heterogeneity on the meta‐analysis (Higgins 2002; Higgins 2003).

When we found heterogeneity, we attempted to determine possible reasons for this by examining individual trial and subgroup characteristics.

Assessment of reporting biases

If we included 10 or more studies in a meta‐analysis investigating a particular outcome, we used funnel plots to assess small‐study effects. Several explanations might account for funnel plot asymmetry, including true heterogeneity of effect with respect to trial size, poor methodological design (and hence bias of small trials), and publication bias (Sterne 2017). Therefore we interpreted results carefully (Sterne 2011).

Data synthesis

We planned to undertake (or display) a meta‐analysis only if we judged participants, interventions, comparisons, and outcomes to be sufficiently similar to ensure an answer that was clinically meaningful. Unless good evidence showed homogeneous effects across trials of different methodological quality, we primarily summarised low risk of bias data using a random‐effects model (Wood 2008). We interpreted random‐effects meta‐analyses with due consideration for the whole distribution of effects and presented a prediction interval (Borenstein 2017a; Borenstein 2017b; Higgins 2009). A prediction interval needs at least three trials to be calculated and specifies a predicted range for the true treatment effect in an individual trial (Riley 2011; Riley 2013). For rare events such as event rates below 1%, we planned to use the Peto's odds ratio method, provided that there was no substantial imbalance between intervention and comparator group sizes, and intervention effects were not exceptionally large. In addition, we performed statistical analyses according to the statistical guidelines presented in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017).

Subgroup analysis and investigation of heterogeneity

We expected the following characteristics to introduce clinical heterogeneity, and we planned to carry out the following subgroup analyses including investigation of interactions (Altman 2003).

Magnitude of obesity
Overweight versus obesity
Gender
Ethnicity
Age
Different comparison interventions
Fluoxetine dosage
Duration of intervention
Treatment compliance
Socioeconomic status

Sensitivity analysis

We planned to perform sensitivity analyses to explore the influence of the following factors (when applicable) on effect sizes by restricting analysis to the following.

Published trials
The effect of risk of bias, as specified in the Assessment of risk of bias in included studies section
Very long or large trials to establish the extent to which they dominated the results
Use of the following filters: diagnostic criteria, imputation, language of publication, source of funding (industry versus other), or country

We also tested the robustness of the results by repeating the analysis using different measures of effect size (RR, OR, etc.) and different statistical models (fixed‐effect and random‐effects models).

Summary of findings and assessment of the certainty of the evidence

Certainty of the evidence

We present the overall certainty of the evidence for each outcome specified below according to the GRADE approach, which takes into account issues related not only to internal validity (risk of bias, inconsistency, imprecision, publication bias) but also to external validity, such as directness of results. Two review authors (AS and YR) independently rated the certainty of the evidence for each outcome. We resolved disagreements by consensus or by consulting a third review author (AGG). In case of disagreement, we consulted the rest of the review author team and we made a judgement based on consensus.

We include an appendix entitled 'Checklist to aid consistency and reproducibility of GRADE assessments' (Appendix 1), to help with standardisation of the 'Summary of findings' tables (Meader 2014). Alternatively, we planned to use the GRADEpro Guideline Development Tool (GDT) software and planned to present evidence profile tables as an appendix (GRADEproGDT 2015). We present results for outcomes as described in the Types of outcome measures section. If meta‐analysis was not possible, we planned to present the results in a narrative format in the 'Table 1'. We justify all decisions to downgrade the quality of trials by using footnotes, and add comments to aid the reader's understanding of this Cochrane Review when necessary.

'Summary of findings' table

We present a summary of the evidence in the Table 1. This provides key information about the best estimate of the magnitude of effect, in relative terms and as absolute differences, for each relevant comparison of alternative management strategies, numbers of participants and trials addressing each important outcome and a rating of overall confidence in effect estimates for each outcome. We created the 'Summary of findings table' using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2017), along with Review Manager 5 table editor (Review Manager 2014). Intervention presented in the 'Summary of findings' table was fluoxetine and comparator was placebo.

We reported the following outcomes, listed according to priority. 

Weight loss (kg)
Health‐related quality of life
Any adverse event
Anthropometric measurements other than weight loss in kg
Morbidity
All‐cause mortality
Socioeconomic effects

Results

Description of studies

For a detailed description of trials, see Table 2, 'Characteristics of included studies' and 'Characteristics of excluded studies' sections.

Results of the search

From the last updated search performed in December 2018, we screened 1036 bibliographic records after removing duplicates. Of these we excluded 984 records on the basis of their abstracts because they were not relevant for this review. We retrieved 52 full‐text publications and conference abstracts for detailed examination. Of the 52 articles examined in detail, we excluded 34; one trial is awaiting classification. Nineteen trials met our inclusion criteria. There were 15 parallel clinical trials (Al‐Helli 2015; Bagiella 1991; Bondi 2000; Bross 1995; Goldstein 1993; Goldstein 1994; Guimaraes 2006; Huang 1998; Levine 1987; Levine 1989; Pedrinola 1993; Pijl 1991; Suplicy 2014; Visser 1993; Wurtman 1993); and four cross‐over clinical trials (Fernández‐Soto 1995; Kopelman 1992; Lawton 1995; Stinson 1992) (see Figure 1).

Included studies

Details of the characteristics of included trials are presented in the Characteristics of included studies table and the following appendices: Appendix 5; Appendix 6; Appendix 7; Appendix 8; Appendix 9; Appendix 10; Appendix 11; Appendix 12; Appendix 13; Appendix 14; Appendix 15. The following is a brief overview.

Source of data

We obtained data from published literature. We did not find data from trial registries, web‐based data repositories or correspondence with authors (Appendix 14).

Comparisons

We identified a great variety of interventions in our 19 included trials, which we grouped into five main comparisons with overall 56 trial arms.

A) Eighteen trials compared fluoxetine with placebo (Al‐Helli 2015; Bagiella 1991; Bondi 2000; Bross 1995; Fernández‐Soto 1995; Goldstein 1993; Goldstein 1994; Guimaraes 2006; Kopelman 1992; Lawton 1995; Levine 1987; Levine 1989; Pedrinola 1993; Pijl 1991; Stinson 1992; Suplicy 2014; Visser 1993; Wurtman 1993).

B) Four trials compared fluoxetine with another anti‐obesity agent (Bagiella 1991; Guimaraes 2006; Suplicy 2014; Wurtman 1993).

C) One trial compared fluoxetine with no treatment (Huang 1998).

D) One trial compared fluoxetine with a non‐pharmacological treatment (Al‐Helli 2015).

E) Three trials compared fluoxetine 60 mg/d with fluoxetine at smaller doses (10, 20 and 40 mg/d) (Bondi 2000; Goldstein 1993; Levine 1989).

Overview of trial populations

There were a total of 2216 participants in 19 trials, including one trial with 60 participants which did not specify how many participants constituted each arm of the study (Bagiella 1991). A total of 1280 participants without depression, mental illness or abnormal eating patterns were randomly assigned to the fluoxetine groups (680 participants received 60 mg/d, 149 received 40 mg/d, 320 received 20 mg/d and 131 received 10 mg/d). The comparator groups of interest for this review had 936 participants with 730 on placebo, 164 using other anti‐obesity agents, 12 being treated non‐pharmacologically and 30 who received no treatment.

The proportion of participants in the intervention groups who finished the trials was lowest in Goldstein 1993 with 43% at 52 weeks of follow‐up, and ranged from 56.6% to 82.7% in five other trials (Fernández‐Soto 1995; Goldstein 1994; Levine 1989; Suplicy 2014; Wurtman 1993). The 12 trials with highest proportion of participants in the intervention groups who finished the trials were Al‐Helli 2015, Bondi 2000, Bross 1995, Guimaraes 2006, Huang 1998, Kopelman 1992, Lawton 1995, Levine 1987, Pedrinola 1993, Pijl 1991, Stinson 1992and Visser 1993, with proportions of 80% to 100%. In the comparator groups, the proportion of participants who finished the trials was lowest in Goldstein 1994, Levine 1989 and Suplicy 2014 with 47.3% to 56.4% of participants. In four other trials, the proportion who finished ranged from 67.3% to 80% (Fernández‐Soto 1995; Goldstein 1993; Huang 1998; Pedrinola 1993). The 11 trials with the highest proportion of participants in the comparator groups who finished the trial were Al‐Helli 2015, Bondi 2000, Bross 1995, Guimaraes 2006, Kopelman 1992, Lawton 1995, Levine 1987, Pijl 1991, Stinson 1992, Visser 1993 and Wurtman 1993, with proportions ranging from 86.2% to 100%. The sample size ranged from 20 in Bross 1995 and Pedrinola 1993 to 655 in Levine 1989. See Table 2 for details.

Trial design

Of the 19 trials included in this review, 15 were parallel comparisons with individual randomisation (Al‐Helli 2015; Bagiella 1991; Bondi 2000; Bross 1995; Goldstein 1993; Goldstein 1994; Guimaraes 2006; Huang 1998; Levine 1987; Levine 1989; Pedrinola 1993; Pijl 1991; Suplicy 2014; Visser 1993; Wurtman 1993); and four trials were cross‐over comparisons (Fernández‐Soto 1995; Kopelman 1992; Lawton 1995; Stinson 1992).

Fifteen trials were performed with a parallel group superiority design and used a placebo as comparator (Al‐Helli 2015; Bagiella 1991; Bross 1995; Fernández‐Soto 1995; Goldstein 1994; Guimaraes 2006; Kopelman 1992; Lawton 1995; Levine 1987; Pedrinola 1993; Pijl 1991; Stinson 1992; Suplicy 2014; Visser 1993; Wurtman 1993), and only one trial used no treatment as the comparator (Huang 1998). Three trials used an equivalence design (Bondi 2000; Goldstein 1993; Levine 1989).

Of the 19 trials, one trial had six comparisons (five intervention groups and one placebo group) (Suplicy 2014); one trial had five arms (four fluoxetine groups and one placebo group) (Levine 1989); two trials had four arms (three intervention groups and one placebo arm) (Al‐Helli 2015; Guimaraes 2006); three trials had three arms (two intervention groups and one placebo group) (Bondi 2000; Goldstein 1993; Wurtman 1993); 11 trials had two arms (one intervention group and one placebo group) (Bagiella 1991; Bross 1995; Fernández‐Soto 1995; Goldstein 1994; Kopelman 1992; Lawton 1995; Levine 1987; Pedrinola 1993; Pijl 1991; Stinson 1992; Visser 1993); and one trial had two arms with a no‐treatment group used as the comparator group (Huang 1998).

Sixteen trials were performed in a single centre (Al‐Helli 2015; Bagiella 1991; Bondi 2000; Bross 1995; Fernández‐Soto 1995; Guimaraes 2006; Huang 1998; Kopelman 1992; Lawton 1995; Levine 1987; Pedrinola 1993; Pijl 1991; Stinson 1992; Suplicy 2014; Visser 1993; Wurtman 1993); and three trials were performed in multiple centres ranging from 6 to 10 centres (Goldstein 1993; Goldstein 1994; Levine 1989).

Twelve trials were reported as double‐blinded for participants and personnel (Bondi 2000; Bross 1995; Fernández‐Soto 1995; Goldstein 1993; Kopelman 1992; Lawton 1995; Levine 1989; Pedrinola 1993; Pijl 1991; Stinson 1992; Visser 1993; Wurtman 1993). Two trials were reported as single‐blinded for participants (Stinson 1992; Visser 1993); and two trials did not state whether they were blinded as to participants, personnel or assessors (Al‐Helli 2015; Bagiella 1991).

The trials were performed between 1987 and 2015. The duration of the interventions ranged from three days (Kopelman 1992) to 52 weeks (Goldstein 1994; Suplicy 2014), with a median of duration of 12 weeks. The duration of follow‐up ranged from three weeks (Bross 1995) to 52 weeks (Suplicy 2014; Goldstein 1994), with a median duration of 12 weeks. Eight trials reported a run‐in period of between four days and nine weeks (Bross 1995; Goldstein 1993). No trials were terminated before their prespecified end.

Settings

The interventions were performed in an outpatient setting in eight trials (Bagiella 1991; Fernández‐Soto 1995; Goldstein 1993; Goldstein 1994; Guimaraes 2006; Levine 1987; Levine 1989; Visser 1993); in an outpatient obesity or research clinic in nine trials (Al‐Helli 2015; Bondi 2000; Huang 1998; Lawton 1995; Pedrinola 1993; Pijl 1991; Stinson 1992; Suplicy 2014; Wurtman 1993); and on hospitalised participants during intervention or outcomes assessment in two trials (Bross 1995; Kopelman 1992). Five trials were performed in the USA (Goldstein 1994; Goldstein 1993; Wurtman 1993; Levine 1989; Levine 1987); three in Brazil (Guimaraes 2006; Pedrinola 1993; Suplicy 2014); two in the UK (Kopelman 1992; Lawton 1995); two in Italy (Bagiella 1991; Bondi 2000); two in the Netherlands (Pijl 1991; Visser 1993); and one each in Canada (Bross 1995), Spain (Fernández‐Soto 1995), Ireland (Stinson 1992), Iraq (Al‐Helli 2015) and the Republic of China (Huang 1998).

Participants

Three trials were performed on participants from low‐ to middle‐income countries (Brazil, Iraq and the Republic of China), and the remaining 16 trials were performed on participants from high‐income countries (Ireland, Italy, Canada, Spain, the UK, the USA and the Netherlands), according to definitions from the World Bank.

Only four trials reported ethnicities, being white participants in all four trials (Goldstein 1993; Goldstein 1994; Levine 1987; Levine 1989). No trial reported the duration of overweight or obesity.

Of the all trials reporting gender in our review, which involved 2216 participants, the majority of participants (from 80% to 100%) were female (see Appendix 7). In three trials, however, women constituted less than 62% of participants (Huang 1998, 46%; Kopelman 1992, 9%; and Stinson 1992, 61%), one trial included exclusively men (Visser 1993) and three trials did not report the sex of the participants (Al‐Helli 2015; Bagiella 1991; Pedrinola 1993). The mean age of the participants ranged from 30 years in Guimaraes 2006 to 51 years in Bondi 2000.

Baseline characteristics were similar between treatment groups in most of the trials. In one trial there was a difference in weight between the groups (84.9 kg in the fluoxetine group versus 89.2 kg in the placebo group) (Goldstein 1993). Mean BMI at baseline in 15 trials ranged from 27.9 kg/m² (Visser 1993) to 44 kg/m² (Kopelman 1992). However, two trials reported a mean BMI of 25 kg/m² or more (Levine 1987; Levine 1989), one trial reported a mean BMI of 30 kg/m² or more (Al‐Helli 2015), and one trial reported a mean BMI ranging from 30 kg/m² to 40 kg/m² (Bagiella 1991). Except for this last trial, all the trials reported the mean body weight of the participants at baseline, which ranged from 84.9 kg (Goldstein 1993) to 129 Kg (Kopelman 1992). No trial reported glycosylated haemoglobin A1c (HbA1c) values.

Of the 19 trials, only Wurtman 1993 reported comorbidities in the participants. No trials reported that participants used co‐medications.

The main inclusion criteria in the trials were adult participants (16 years or older) who were overweight (BMI 25 kg/m² to 29.9 kg/m²) or obese (BMI ≥ 30 kg/m²), with stable body weight before trial entry. The main exclusion criteria were pregnant or lactating women, previous bariatric surgery, use of appetite suppressants, antidepressants or medicines that could affect body weight, alcohol or drug abuse and serious medical conditions (e.g. hypertension, diabetes, viral infections).

Diagnosis

The diagnostic criteria for overweight and obese participants differed between the trials. Fifteen trials used BMI greater than 25 kg/m² (overweight) or greater than 30 kg/m² (obesity) as criteria (Bagiella 1991; Bondi 2000; Bross 1995; Fernández‐Soto 1995; Goldstein 1993; Goldstein 1994; Guimaraes 2006; Kopelman 1992; Lawton 1995; Levine 1987; Pedrinola 1993; Pijl 1991; Stinson 1992; Suplicy 2014; Visser 1993). One trial used more than 30% of ideal body weight according to Huang's formula (Huang 1998), another trial used more than 20% to 100% of ideal body weight (Levine 1989), and another trial used 40 lb to 60 lb above ideal body weight according to the Metropolitan Life Insurance Height and Weight Table (Wurtman 1993).

Interventions

Some of the included trials were performed with several arms. Of 19 trials, two had six arms (Suplicy 2014; Bagiella 1991), one had five arms (Levine 1989), two had four arms (Al‐Helli 2015; Guimaraes 2006), three had three arms (Bondi 2000; Goldstein 1993; Wurtman 1993), and 11 had two arms (Bross 1995; Fernández‐Soto 1995; Goldstein 1994; Huang 1998; Kopelman 1992; Lawton 1995; Levine 1987; Pedrinola 1993; Pijl 1991; Stinson 1992; Visser 1993).

Two trials reported that participants received treatment before starting the trial. In Goldstein 1993, the participants received fluoxetine 60 mg/d for eight weeks during qualification phase; in Guimaraes 2006, the participants received dietary re‐education for six months.

In all trials, the intervention was administered by the oral route. The doses differed between trials. In 14 trials, at least one group received 60 mg of fluoxetine once daily (Bondi 2000; Bross 1995; Fernández‐Soto 1995; Goldstein 1993; Goldstein 1994; Guimaraes 2006; Huang 1998; Kopelman 1992; Lawton 1995; Levine 1987; Levine 1989; Pijl 1991; Stinson 1992; Visser 1993); in two trials, at least one group received 40 mg of fluoxetine once daily (Pedrinola 1993; Levine 1989); in five trials, at least one group received 20 mg of fluoxetine once daily (Bagiella 1991; Goldstein 1993; Levine 1989; Suplicy 2014; Wurtman 1993); and in one trial, one group received 10 mg of fluoxetine once daily (Levine 1987). The average daily dose of fluoxetine was 55 mg.

A wide variety of interventions was performed. Eleven trials compared fluoxetine with placebo (Bondi 2000; Bross 1995; Fernández‐Soto 1995; Goldstein 1994; Kopelman 1992; Lawton 1995; Levine 1987; Pedrinola 1993; Pijl 1991; Stinson 1992; Visser 1993). Four trials compared fluoxetine with at least one anti‐obesity agent (diethylpropion, fenproporex, mazindol, sibutramine, metformin, fenfluramine, dexfenfluramine, fluvoxamine or 5‐hydroxy‐tryptophan) (Bagiella 1991; Guimaraes 2006; Suplicy 2014; Wurtman 1993) (see Appendix 5). One trial compared fluoxetine with omega‐3 gel intake (Al‐Helli 2015). One trial compared fluoxetine with no treatment (Huang 1998); and two trials compared 60 mg fluoxetine with smaller doses of fluoxetine (10, 20 and 40 mg/d) (Goldstein 1993; Levine 1989).

Of 19 trials included in our review, 15 used adequate interventions and comparators. However, four trials included at least one intervention (sibutramine and dexfenfluramine) with harmful effects on the cardiovascular system according to the Food and Drug Administration (FDA) (Bagiella 1991; Guimaraes 2006; Suplicy 2014; Wurtman 1993).

Outcomes

Twelve of nineteen included trials explicitly stated primary or secondary outcomes (Suplicy 2014; Guimaraes 2006; Bondi 2000; Lawton 1995; Goldstein 1993; Visser 1993; Wurtman 1993; Kopelman 1992; Stinson 1992; Bagiella 1991; Pijl 1991; Levine 1989). The most common outcome was a weight loss in kilograms (Suplicy 2014; Guimaraes 2006; Bondi 2000; Goldstein 1993; Wurtman 1993; Levine 1989).

Fifteen trials had a median of six outcomes (Al‐Helli 2015; Suplicy 2014; Guimaraes 2006; Bondi 2000; Huang 1998; Bross 1995; Fernández‐Soto 1995; Lawton 1995; Goldstein 1994; Goldstein 1993; Wurtman 1993; Kopelman 1992; Stinson 1992; Pijl 1991; Levine 1987), with a range of six (Bondi 2000; Goldstein 1993; Kopelman 1992; Stinson 1992; Pijl 1991; Levine 1987) to 26 outcomes (Wurtman 1993). See Appendix 8 for details.

Fourteen trials reported adverse events (Fernández‐Soto 1995; Goldstein 1993; Goldstein 1994; Guimaraes 2006; Huang 1998; Kopelman 1992; Lawton 1995; Levine 1987; Levine 1989; Pedrinola 1993; Pijl 1991; Suplicy 2014; Visser 1993; Wurtman 1993). One trial investigated health‐related quality of life but did not report results (Suplicy 2014); nine trials evaluated anthropometric measurements other than weight loss in kilograms (Al‐Helli 2015; Goldstein 1994; Guimaraes 2006; Huang 1998; Kopelman 1992; Levine 1987; Levine 1989; Pedrinola 1993; Suplicy 2014) (see Appendix 8 for detail). Three trials investigated morbidity (depression as psychiatric disorder) (Suplicy 2014; Goldstein 1993; Levine 1987); 13 trials investigated laboratory parameters (Bagiella 1991; Bondi 2000; Fernández‐Soto 1995; Goldstein 1993; Goldstein 1994; Guimaraes 2006; Huang 1998; Levine 1987; Levine 1989; Pedrinola 1993; Stinson 1992; Suplicy 2014; Wurtman 1993). No trial investigated all‐cause mortality or socioeconomic effects.

Excluded studies

After examination of 52 full‐text studies and records, we excluded 34 records. The reasons for exclusion were that the trial design was not a clinical trial (seven publications), participants did not meet the specified inclusion criteria (23 publications) and the participants did not receive the right intervention or comparator (four publications). For further details see Characteristics of excluded studies.

Risk of bias in included studies

For details on the risk of bias of the included trials see Characteristics of included studies. For an overview of the review authors' judgments about the risk of bias for individual trials and across all studies see Figure 2 and Figure 3.

Allocation

Only Pijl 1991 and Suplicy 2014 reported the method used for random sequence generation and described details of allocation concealment; hence we judged these studies at low risk of selection bias. We considered the risk of selection bias uncertain for all other trials.

Blinding

We judged four trials to be at high risk of performance bias for most of the reported outcomes (Guimaraes 2006; Huang 1998; Levine 1987; Suplicy 2014). The remaining trials reported sufficient information on how the blinding was performed, with the exception of two trials which described blinding methods in little detail, so we judged them as unclear risk of bias (Goldstein 1994; Pedrinola 1993). See Characteristics of included studies for details.

All included trials did not provide adequate information to evaluate blinding of outcome assessment for any outcome measure, with the exception of Pedrinola 1993 who reported that there was no blinding of outcome assessment.

Incomplete outcome data

For the outcome measure 'weight loss', 12 of 17 trials investigating this outcome reported attrition rates from 4.2% to 22% during the follow‐up; hence we judged these at low risk of selection bias (Bondi 2000; Bross 1995; Fernández‐Soto 1995; Guimaraes 2006; Huang 1998; Kopelman 1992; Lawton 1995; Levine 1987; Pedrinola 1993; Pijl 1991; Stinson 1992; Visser 1993). We identified a high risk of attrition bias in five trials, with attrition rates ranging from 26.5% to 55% (Goldstein 1993; Goldstein 1994; Levine 1989; Suplicy 2014; Wurtman 1993). We judged the only trial evaluating health‐related quality of life with an attrition rate of 28.3% to be at high risk of attrition bias (Suplicy 2014). We judged five out of 14 trials investigating adverse events to be at high risk of attrition bias (Goldstein 1993; Goldstein 1994; Levine 1989; Suplicy 2014; Wurtman 1993). We judged three out of nine trials investigating anthropometric measurements other than weight loss with attrition rates of 26.5% to 43.4% to be at high risk of attrition bias (Goldstein 1994; Levine 1989; Suplicy 2014). Three trials reported on morbidity and we judged two of them with attrition rates of 28.3% to 36.3% to be at high risk of attrition bias (Goldstein 1993; Suplicy 2014).

Selective reporting

With respect to the Outcome Reporting Bias in Trials classification (ORBIT), we judged nine trials to have a high risk of selection bias because their outcomes were incompletely reported or not reported at all: for weight loss two trials (Goldstein 1993; Levine 1989), for adverse events three trials (Guimaraes 2006; Kopelman 1992; Pedrinola 1993), for anthropometric measurements other than weight loss in kilograms three trials (Al‐Helli 2015; Goldstein 1994; Levine 1987), and for health‐related quality of life one trial (Suplicy 2014). The remaining 10 trials were judged to have low risk of reporting bias. For details see Appendix 9.

Other potential sources of bias

We judged six trials to have an unclear risk of other bias, mainly because of possible sponsor bias (Bross 1995; Goldstein 1994; Lawton 1995; Levine 1987; Stinson 1992; Suplicy 2014).

Effects of interventions

See: Table 1

Because there were very limited data comparing fluoxetine with other anti‐obesity drugs we only established a 'Summary of findings' table for the comparison 'fluoxetine with placebo'.

Baseline characteristics

For details of baseline characteristics, see Appendix 6 and Appendix 7. Only three trials included non‐obese participants (Levine 1987; Levine 1989; Visser 1993).

Fluoxetine versus placebo

For a summary of findings see Table 1.

Primary outcomes

Weight loss (kg)

Ten trials with extractable data compared fluoxetine with placebo (Figure 4). Seven trials used a dose of 60 mg/d (Bondi 2000; Goldstein 1994; Guimaraes 2006; Levine 1987; Levine 1989; Pijl 1991; Visser 1993), two trials used a dose of 40 mg/d (Levine 1989; Pedrinola 1993) and three trials used a dose of 20 mg/d (Levine 1989; Suplicy 2014; Wurtman 1993).

Forest plot of comparison: Fluoxetine versus placebo (parallel RCTs), outcome: 1.1 Weight loss, end of trial weight [kg].

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 (without Levine 1989 and fluoxetine 20 mg/d and 40 mg/d to avoid a unit of analysis error), 956 participants; low certainty evidence in favour of fluoxetine; Analysis 1.1). The 95% prediction interval ranged between −7.1 kg and 1.7 kg.

1.1 — Comparison 1: Fluoxetine versus placebo, Outcome 1: Weight loss (end of trial weight)

The different fluoxetine dosages showed the following results (Analysis 1.1).

For fluoxetine 60 mg/d, the MD was −2.5 kg (95% CI −3.8 to −1.2; P < 0.001; 7 trials, 819 participants; low certainty evidence in favour of fluoxetine; Analysis 1.1). The 95% prediction interval ranged between −6.4 kg and 1.4 kg.
For fluoxetine 40 mg/d, the MD was −4 kg (95% CI −8.8 to 0.8; P = 0.10; 2 trials, 182 participants; very low certainty; Analysis 1.1). Fixed‐effect meta‐analysis performed because of the low number of trials showed a MD of −2.3 kg (95% CI −3 to −1.6; P < 0.001 in favour of fluoxetine).
For fluoxetine 20 mg/d, the MD was −1.5 kg (95% CI −3.5 to 0.5; P = 0.15; 3 trials, 279 participants; very low certainty evidence; Analysis 1.1). Fixed‐effect meta‐analysis performed because of the low number of trials showed an MD of −1.4 kg (95% CI −2.1 to −0.6; P < 0.001 in favour of fluoxetine). The 95% prediction interval did not provide a meaningful estimate.

Of the seven trials that administered fluoxetine 60 mg/d, five trials reported weight loss from zero to three months (Bondi 2000; Levine 1987; Levine 1989; Pijl 1991; Visser 1993); and two reported weight loss from four to six months (Goldstein 1994; Guimaraes 2006) (Analysis 1.2). The test for subgroup differences did not indicate a statistically significant difference (P = 0.62).

1.2 — Comparison 1: Fluoxetine versus placebo, Outcome 2: Weight loss (duration of intervention)

The two trials with the longest duration of follow‐up (52 weeks) did not show a clear difference between fluoxetine and placebo (Goldstein 1993; Goldstein 1994).

Three cross‐over trials compared fluoxetine 60 mg/d with placebo (Fernández‐Soto 1995; Lawton 1995; Stinson 1992). Only Lawton 1995 provided adequate information to calculate a weight loss of 1.9 kg (95% CI 0.6 to 3.2; P = 0.004; 24 participants in favour of fluoxetine) (Analysis 1.3).

1.3 — Comparison 1: Fluoxetine versus placebo, Outcome 3: Weight loss (cross‐over trial)

Health‐related quality of life

Only Suplicy 2014 planned to assess health‐related quality of life but did not report findings.

Adverse events

Nine trials reported adverse events in the comparison of fluoxetine with placebo (Goldstein 1993; Goldstein 1994; Guimaraes 2006; Levine 1987; Levine 1989; Pijl 1991; Suplicy 2014; Visser 1993; Wurtman 1993). The types of events and the fluoxetine dose differed between trials. 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. Pooling the trials in a 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; Analysis 1.4. The 95% prediction interval ranged between 0.74 and 1.88.

1.4 — Comparison 1: Fluoxetine versus placebo, Outcome 4: Any adverse event

The most frequently reported adverse events comparing fluoxetine with placebo were the following (see Analysis 1.5).

1.5 — Comparison 1: Fluoxetine versus placebo, Outcome 5: Specific adverse events

Abdominal pain: RR 1.51, 95% CI 0.58 to 3.90; P = 0.40; 5 trials, 504 participants.
Allergy: RR 0.17, 95% CI 0.03 to 0.98; P = 0.05; 3 trials, 780 participants.
Amnesia: RR 12.89, 95% CI 0.73 to 227.44; P = 0.08; 1 trial, 458 participants.
Anorexia: RR 8.89, 95% CI 1.36 to 57.89; P = 0.02; 1 trial, 19 participants in favour of placebo.
Anxiety: RR 1.07, 95% CI 0.56 to 2.03; P = 0.83; 7 trials, 1210 participants.
Constipation: RR 2.83, 95% CI 0.58 to 13.90; P = 0.20; 3 trials, 381 participants.
Diarrhoea: RR 1.44, 95% CI 0.97 to 2.13; P = 0.07; 7 trials, 1191 participants.
Dizziness: RR 2.40, 95% CI 1.03 to 5.60; P = 0.04; 5 trials, 693 participants in favour of placebo.
Drowsiness: RR 2.67, 95% CI 1.68 to 4.24; P < 0.001; 9 trials, 1253 participants in favour of placebo.
Dry mouth: RR 1.23, 95% CI 0.66 to 2.30; P = 0.52; 6 trials, 896 participants.
Dyspepsia: RR 1.99, 95% CI 0.71 to 5.55; P = 0.19; 4 trials, 501 participants.
Fatigue: RR 2.50, 95% CI 1.62 to 3.85; P < 0.001; 5 trials, 1112 participants in favour of placebo.
Headache: RR 1.17, 95% CI 0.94 to 1.47; P = 0.16; 8 trials, 1234 participants.
Insomnia: RR 2.23, 95% CI 1.22 to 4.08; P = 0.009; 7 trials, 1191 participants in favour of placebo.
Irritability: RR 1.41, 95% CI 0.63 to 3.15; P = 0.40; 3 trials, 442 participants.
Malaise: RR 0.60, 95% CI 0.15 to 2.46; P = 0.48; 2 trials, 322 participants.
Nausea: RR 1.99, 95% CI 1.35 to 2.91; P < 0.001; 7 trials, 1016 participants in favour of placebo.
Palpitations: RR 2.81, 95% CI 0.12 to 66.40; P = 0.52; 1 trial, 60 participants.
Rhinitis: RR 0.99, 95% CI 0.75 to 1.30; P = 0.94; 3 trials, 933 participants.

The adverse events dizziness, drowsiness, fatigue, insomnia and nausea were observed approximately twice as often following fluoxetine treatment.

Across all fluoxetine dosages and durations of treatment the RR for the outcome 'any adverse event' was 1.18 (95% CI 0.99 to 1.42; P = 0.07; 9 trials (without Levine 1989 and fluoxetine 20 mg/d and 40 mg/d, and Goldstein 1993 and fluoxetine 20 mg/d to avoid a unit of analysis error), 1253 participants; low certainty evidence; Analysis 1.6).

1.6 — Comparison 1: Fluoxetine versus placebo, Outcome 6: Participants with any adverse event (per dose)

Subgroup analyses of different fluoxetine doses for adverse events did not show statistically significant subgroup differences (Analysis 1.6).

For fluoxetine 60 mg/d the RR was 1.16, 95% CI 0.93 to 1.44; P = 0.18; 7 trials, 1134 participants.
For fluoxetine 40 mg/d the RR was 1.07, 95% CI 0.93 to 1.24; P = 0.32; 1 trial, 262 participants.
For fluoxetine 20 mg/d, the RR was 1.10, 95% CI 0.92 to 1.31; P = 0.30; 4 trials, 592 participants.
For fluoxetine 10 mg/d, the RR was 0.96, 95% CI 0.82 to 1.12; P = 0.59; 1 trial, 262 participants.

Of the seven trials administering fluoxetine 60 mg/d, four trials reported the outcome 'any adverse event' from zero to three months (Levine 1987; Levine 1989; Pijl 1991; Visser 1993); two reported 'any adverse event' from four to six months (Goldstein 1994; Guimaraes 2006); and one reported 'any adverse event' from 7 to 12 months (Goldstein 1993) (Analysis 1.7). The test for subgroup differences did not indicate a statistical significant difference.

1.7 — Comparison 1: Fluoxetine versus placebo, Outcome 7: Participants with any adverse event (duration of intervention)

Two cross‐over trials reported adverse events in the comparison of fluoxetine 60 mg/d with placebo (Fernández‐Soto 1995; Lawton 1995). Adverse events were comparable between intervention and control groups. For further details see Appendix 11; Appendix 12; Appendix 13.

Discontinuation of the trial due to an adverse event comparing fluoxetine therapy with placebo had an RR of 1.88 (95% CI 0.87 to 4.06; P = 0.11; 8 trials, 1188 participants; Analysis 1.8). The 95% prediction interval ranged between 0.26 and 13.61.

1.8 — Comparison 1: Fluoxetine versus placebo, Outcome 8: Participants discontinuing due to adverse events

Secondary outcomes

Anthropometric measurements other than weight loss in kilograms (reduction in BMI)

Three trials compared fluoxetine with placebo. The MD in BMI reduction across all fluoxetine doses compared with placebo was −1.1 kg/m² (95% CI −3.7 to 1.4; 3 trials, 97 participants; very low certainty evidence; Analysis 1.9). Calculation of the 95% prediction interval did not provide a meaningful estimate.

1.9 — Comparison 1: Fluoxetine versus placebo, Outcome 9: Anthropometric measurements other than weight loss (BMI)

Subgroup analyses of different fluoxetine doses did not show statistically significant subgroup differences; Analysis 1.9.

For fluoxetine 60 mg/d the MD was −3.3 kg/m² (95% CI −7.3 to 0.7; P = 0.10; 1 trial, 19 participants (Guimaraes 2006)).
For fluoxetine 40 mg/d the MD was −2.8 kg/m² (95% CI −8.7 to 3.1; P = 0.35; 1 trial, 18 participants (Pedrinola 1993)).
For fluoxetine 20 mg/d the MD was 0.2 kg/m² (95% CI −0.6 to 1; P = 0.62; 1 trial, 60 participants (Suplicy 2014)).

Morbidity (depression)

Three trials compared fluoxetine with placebo on the incidence of depression (Goldstein 1993; Levine 1987; Suplicy 2014). 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 risk ratio 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; Analysis 1.10). Calculation of the 95% prediction interval did not provide a meaningful estimate.

1.10 — Comparison 1: Fluoxetine versus placebo, Outcome 10: Morbidity (depression)

Three trials with four trial arms provided data for different doses of fluoxetine (Analysis 1.11). Subgroup analysis did not show a statistically significant subgroup difference.

1.11 — Comparison 1: Fluoxetine versus placebo, Outcome 11: Morbidity (depression per dose)

For fluoxetine 60 mg/d, the RR was 1.41 (95% CI 0.53 to 3.79; P = 0.49; 2 trials, 333 participants) (Goldstein 1993; Levine 1987).
For fluoxetine 20 mg/d, the RR was 0.58 (95% CI 0.23 to 1.48; P = 0.25; 2 trials, 271 participants) (Goldstein 1993; Suplicy 2014).

All‐cause mortality

None of the trials reported on all‐cause mortality.

Socioeconomic effects

None of the trials reported on socioeconomic effects.

Fluoxetine compared with another anti‐obesity agent

The certainty of the evidence for all outcomes was very low because of high risk of performance bias, attrition bias and selective reporting, and very serious imprecision (CI consistent with benefit and harm, small number of trials and small number of participants).

Primary outcomes

Weight loss (kg)

Three trials (234 participants) compared different doses of fluoxetine with six types of anti‐obesity agents (sibutramine, metformin, dexfenfluramine, diethylpropion, fenproporex and mazindol) (Analysis 2.1).

2.1 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 1: Weight loss, end of trial weight

For fluoxetine 60 mg/d versus sibutramine the MD was 4.3 kg (95% CI −3.2 to 11.8; P = 0.26; 1 trial, 17 participants) (Guimaraes 2006).
For fluoxetine 60 mg/d versus metformin the MD was −8.9 kg (95% CI −19.9 to 2.1; P = 0.11; 1 trial, 17 participants) (Guimaraes 2006).
For fluoxetine 20 mg/d versus sibutramine the MD was 7 kg (95% CI 4.4 to 9.6; P < 0.001; 1 trial, 61 participants) (Suplicy 2014).
For fluoxetine 20 mg/d versus dexfenfluramine the MD was −0.5 kg (95% CI −3.4 to 2.4; P = 0.73; 1 trial, 58 participants) (Wurtman 1993).
For fluoxetine 20 mg/d versus diethylpropion the MD was 7.5 kg (95% CI 4.7 to 10.3; P < 0.001; 1 trial, 61 participants) (Suplicy 2014).
For fluoxetine 20 mg/d versus fenproporex the MD was 5.3 kg (95% CI 2.4 to 8.2; P < 0.001; 1 trial, 62 participants) (Suplicy 2014).
For fluoxetine 20 mg/d versus mazindol the MD was 4.9 kg, 95% CI 2.6 to 7.3; P < 0.001; 1 trial; 60 participants (Suplicy 2014).

Health‐related quality of life

None of the trials assessed health‐related quality of life.

Adverse events

Three trials compared different doses of fluoxetine with six anti‐obesity agents (sibutramine, metformin, dexfenfluramine, diethylpropion, fenproporex and mazindol) for any adverse event (Analysis 2.2).

2.2 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 2: Any adverse event

For fluoxetine 60 mg/d versus sibutramine the RR was 1.19 (95% CI 0.75 to 1.88; P = 0.47; 1 trial, 17 participants) (Guimaraes 2006).
For fluoxetine 60 mg/d versus metformin the RR was 1.78 (95% CI 0.86 to 3.69; P = 0.12; 1 trial, 17 participants) (Guimaraes 2006).
For fluoxetine 20 mg/d versus sibutramine the RR was 1.58 (95% CI 0.91 to 2.77; P = 0.11; 1 trial, 61 participants) (Suplicy 2014).
For fluoxetine 20 mg/d versus dexfenfluramine the RR was 1.09 (95% CI 0.89 to 1.33; P = 0.42; 1 trial, 59 participants) (Wurtman 1993).
For fluoxetine 20 mg/d versus diethylpropion the RR was 1.58 (95% CI 0.91 to 2.77; P = 0.11; 1 trial, 61 participants) (Suplicy 2014).
For fluoxetine 20 mg/d versus fenproporex the RR was 1.20 (95% CI 0.75 to 1.92; P = 0.45; 1 trial, 62 participants) (Suplicy 2014).
For fluoxetine 20 mg/d versus mazindol the RR was 1.05 (95% CI 0.68 to 1.64; P = 0.82; 1 trial, 60 participants) (Suplicy 2014).

The comparisons of the various anti‐obesity agents with fluoxetine with regard to specific adverse events showed inconclusive findings (Analysis 2.3; Analysis 2.4; Analysis 2.5; Analysis 2.6; Analysis 2.7; Analysis 2.8; Analysis 2.9; Analysis 2.10; Analysis 2.11; Analysis 2.12; Analysis 2.13; Analysis 2.14; Analysis 2.15; Analysis 2.16; Analysis 2.17; Analysis 2.18; Analysis 2.19; Analysis 2.20; Analysis 2.21).

2.3 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 3: Adverse events (abdominal pain)

2.4 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 4: Adverse events (allergy)

2.5 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 5: Adverse events (anorexia)

2.6 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 6: Adverse events (anxiety)

2.7 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 7: Adverse events (constipation)

2.8 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 8: Adverse events (diarrhoea)

2.9 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 9: Adverse events (dizziness)

2.10 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 10: Adverse events (drowsiness)

2.11 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 11: Adverse events (dry mouth)

2.12 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 12: Adverse events (dyspepsia)

2.13 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 13: Adverse events (fatigue)

2.14 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 14: Adverse events (headache)

2.15 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 15: Adverse events (insomnia)

2.16 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 16: Adverse events (irritability)

2.17 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 17: Adverse events (malaise)

2.18 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 18: Adverse events (nausea)

2.19 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 19: Adverse events (palpitation)

2.20 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 20: Adverse events (sweating)

2.21 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 21: Adverse events (tremor)

Secondary outcomes

Anthropometric measurements other than weight loss in kilograms (reduction in BMI)

Two trials compared different dose of fluoxetine with five types of anti‐obesity agents (sibutramine, metformin, diethylpropion, fenproporex and mazindol); Analysis 2.22.

2.22 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 22: Anthropometric measurements other than weight loss in kg (BMI)

For fluoxetine 60 mg/d versus sibutramine the MD was −1.5 kg/m² (95% CI −5.2 to 2.2; P = 0.42; 1 trial, 17 participants) (Guimaraes 2006).
For fluoxetine 60 mg/d versus metformin the MD was −2.2 kg/m² (95% CI −8.4 to 4; P = 0.48; 1 trial, 17 participants) (Guimaraes 2006).
For fluoxetine 20 mg/d versus sibutramine the MD was 2.4 kg/m² (95% CI 1.4 to 3.4; P < 0.001; 1 trial, 61 participants) (Suplicy 2014).
For fluoxetine 20 mg/d versus diethylpropion the MD was 2.9 kg/m² (95% CI 1.8 to 4; P < 0.001; 1 trial, 61 participants) (Suplicy 2014).
For fluoxetine 20 mg/d versus fenproporex the MD was 2 kg/m² (95% CI 0.9 to 3.1; P < 0.001; 1 trial, 62 participants) (Suplicy 2014).
For fluoxetine 20 mg/d versus mazindol the MD was 2 kg/m² (95% CI 1.1 to 2.9; P < 0.001; 1 trial, 60 participants) (Suplicy 2014).

Morbidity (depression)

Only Suplicy 2014 compared fluoxetine 20 mg/d with four types of anti‐obesity agents (sibutramine, diethylpropion, fenproporex and mazindol). Two comparisons provided data for the outcome depression (Analysis 2.23).

2.23 — Comparison 2: Fluoxetine versus another anti‐obesity agent, Outcome 23: Morbidity (depression)

For fluoxetine versus sibutramine the RR was 0.32 (95% CI 0.01 to 7.63; P = 0.48; 1 trial, 61 participants).
For fluoxetine versus diethylpropion the RR was 0.19 (95% CI 0.01 to 3.88; P = 0.28; 1 trial, 61 participants).

All‐cause mortality

None of the trials reported on all‐cause mortality.

Socioeconomic effects

None of the trials reported on socioeconomic effects.

Fluoxetine versus non‐pharmacological therapy

One trial (48 participants) consisting of four trial arms included omega‐3 gel as monotherapy and in combination with fluoxetine (Al‐Helli 2015). None of the primary or secondary outcomes were reported.

Fluoxetine versus no treatment

The certainty of the evidence for all outcomes was very low because of high risk of performance bias and very serious imprecision (one trial only with 60 participants).

Primary outcomes

Weight loss (kg)

One trial compared fluoxetine 60 mg/d with no treatment (Huang 1998). The treatment showed a weight loss from 0 to 3 months with an MD of −2.7 kg in favour of fluoxetine (95% CI −3 to −2.4; P < 0.001; 60 participants, 1 trial) (Analysis 3.1).

3.1 — Comparison 3: Fluoxetine versus no treatment, Outcome 1: Weight loss

Health‐related quality of life

This outcome was not reported.

Adverse events

There was an increase in the risk of at least one adverse event in the fluoxetine 60 mg/d group compared with the no‐treatment group (RR 8.67, 95% CI 2.94 to 25.59; P < 0.001; 60 participants, 1 trial) (Analysis 3.2).

3.2 — Comparison 3: Fluoxetine versus no treatment, Outcome 2: Adverse events

Comparisons for allergy, diarrhoea, headache, insomnia, malaise and drowsiness showed inconclusive results. Fluoxetine was associated with increased anorexia (RR 26.00, 95% CI 3.77 to 179.51; P < 0.001; 1 trial, 60 participants) and nausea (RR 8.00, 95% CI 1.07 to 60.09; P = 0.04; 1 trial, 60 participants) (Analysis 3.2).

Secondary outcomes

Morbidity, all‐cause mortality or socioeconomic effects were not reported.

Anthropometric measurements other than weight loss in kilograms (reduction in BMI)

The MD was −0.5 kg/m² in favour of fluoxetine (95% CI −0.6 to −0.3; P < 0.001; 1 trial, 60 participants) (Analysis 3.3).

3.3 — Comparison 3: Fluoxetine versus no treatment, Outcome 3: Anthropometric measurements other than weight loss in kg (BMI)

Subgroup analyses

We only performed subgroup analyses for fluoxetine doses and duration of intervention for the outcome measures 'weight loss and adverse events' for fluoxetine versus placebo, because there were not enough trials to estimate effects for the other subgroups.

Sensitivity analyses

We did not perform sensitivity analyses because we could not include enough trials.

Assessment of reporting bias

We did not draw funnel plots because of the limited number of trials for a particular outcome.

Ongoing trials

We did not find ongoing trials.

Discussion

Summary of main results

We included 19 published trials in this review (one record is awaiting assessment), out of which 15 were parallel trials, and four had a cross‐over design. There were a total of 2216 overweight or obese participants without depression, mental illness or abnormal eating patterns who were followed up for between three weeks and one year. In 16 trials BMI was the diagnostic criterion.

The 19 included trials in the review had a great variety of interventions with overall 56 trial arms. Out of the total number of participants entered in completed studies, 1280 were assigned to four fluoxetine groups according to the dose administered (60 mg/d, 40 mg/d, 20 mg/d and 10 mg/d) and 936 participants were randomly assigned to 12 comparison groups: A) placebo, our main comparison, in 18 trials; B) anti‐obesity agents (diethylpropion, fenproporex, mazindol, sibutramine, metformin, fenfluramine, dexfenfluramine, fluvoxamine and 5‐hydroxy‐tryptophan) in four trials; C) no treatment in one trial; and D) non‐pharmacological treatment (omega‐3 gel) in another trial.

The outcomes assessed also varied among the included trials as: biochemical parameters (glucose, urea, uric acid, serum lipids, cholesterol, triglycerides, fasting glucose, fasting insulin, glycated haemoglobin, insulin resistance, HOMA, glucose‐induced thermogenesis, nitrogen balance, resting energy expenditure); anthropometric measurements (waist circumference, abdominal circumference, fatty tissue); cardiovascular parameters (blood pressure, heart rate, oxygen consumption, arterial oxygen saturation, changes in the electrocardiogram); and others composite outcomes (appetite, energy intake, macronutrient intake, resting metabolic rate, satiety, resting respiratory quotient, sleep‐breathing patterns).

Overall, the results of this systematic review suggest that 60 mg/d fluoxetine compared with placebo decreased weight by 2.5 kg; however the 95% prediction interval ranged between a 6.4 kg weight loss and a 1.4 kg weight increase. The adverse events of dizziness, drowsiness, fatigue, insomnia and nausea were observed approximately twice as often following treatment. There were no clear differences between fluoxetine and placebo with regard to morbidity (depression). 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).

Overall completeness and applicability of evidence

This review included 19 trials with the main comparison being fluoxetine versus placebo. Our included trials did not report on 'all‐cause mortality', 'health‐related quality of life' and 'socioeconomic effects' and there is a high degree of uncertainty regarding these outcome measures. Also, limited data were available for depression as a morbidity outcome.

Quality of the evidence

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 attrition rates of up 20% of their participants and almost half of the trials had a high risk of reporting bias.

The certainty of the evidence for all outcomes was overall low or very low, mainly because of risk of bias and serious imprecision due to low number of trials and participants, and CIs being consistent with benefit and harm.

Potential biases in the review process

This review was performed using standard Cochrane methodology and without any restrictions regarding the language or date of publication. All included trials were selected and assessed, and data were extracted by three review authors to minimise biases in the process of the review. When we identified substantial heterogeneity, we tried to reduce it by data stratification. When data were missing, we attempted to contact the trial authors. However, most of the trials were conducted in the late 1980s and early 1990s and information obtained from trial authors was very limited.

Agreements and disagreements with other studies or reviews

The finding of our review are consistent with those of previous systematic reviews conducted in other populations, which demonstrated a weight loss of 5.1 kg (95% CI 3.4 to 6.83; 4 trials, 97 participants) compared with placebo in participants with type 2 diabetes who received fluoxetine for 24 weeks to 26 weeks (Norris 2005); and 4.3 kg (95% CI 2.6 to 6; 5 trials, 213 participants) compared with placebo in participants who received fluoxetine for up to 12 months (Ye 2011). Another systematic review reported a weight loss of 1.3 kg (95% CI 0.2 to 2.4; 19 trials) in overweight or obese adults (BMI of 26 kg/m² to 39 kg/m²) treated with fluoxetine between 4 and 12 months compared with placebo (Domecq 2015).

Authors' conclusions

Implications for practice.

Approved indications for use of fluoxetine are major depression, obsessive behaviours, panic disorders and bulimia. 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, there were limited data from other comparator anti‐obesity agents and non‐pharmacological therapies were scarce.

Implications for research.

Further research is required to determine whether the administration of fluoxetine has any effect on morbidity, socioeconomic effects and health‐related quality of life in overweight and obese people, as well as whether this intervention might be useful in combination with other anti‐obesity agents or with non‐pharmacological interventions to reduce weight. To ensure the efficacy and safety of fluoxetine in overweight or obese adults high‐certainty evidence is needed to analyse the effects of long‐term use of fluoxetine to promote weight loss and to determine the severity of adverse events. On the other hand, researchers should improve their efforts to reduce high attrition rates in these types of long‐term therapies.

What's new

Date	Event	Description
29 July 2022	Amended	Data was added on the co‐publication of the review.

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History

Protocol first published: Issue 5, 2015 Review first published: Issue 10, 2019

Notes

Portions of the background and Methods sections, the appendices, additional tables and figures 1 to 3 of this review are based on a standard template established by the Cochrane Metabolic and Endocrine Disorders Group.

An abridged version of this review was co‐published in the journal Obesity Facts in 2022 (Serralde‐Zuñiga 2022).

Acknowledgements

We thank the CMED Group for their assistance. We acknowledge the CMED Group Information Specialist, Maria‐Inti Metzendorf, for developing the search strategy and the Assistant Director of Scientific Information and Documentation of National Institute of Pediatrics, Cecilia Solis‐Galicia, for acquiring study reports.

The review authors, and the CMED editorial base, 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.

Appendices

Appendix 1. Checklist to aid consistency and reproducibility of GRADE assessments: fluoxetine versus placebo

Items		(1) Weight loss (kg)	(2) Health‐related quality of life	(3) Any adverse event	(4) Anthropometric measurements other than weight loss in kg (BMI)	(5) Morbidity: depression	(6) All‐cause mortality	(7) Socioeconomic effects
Trial limitations (risk of bias)^a	Was random sequence generation used (i.e. no potential for selection bias)?	Unclear	Not reported	Unclear	Unclear	Unclear	Not reported	Not reported
	Was allocation concealment used (i.e. no potential for selection bias)?	Unclear		Unclear	Unclear	Unclear
	Was there blinding of participants and personnel (i.e. no potential for performance bias) or outcome not likely to be influenced by lack of blinding?	Yes		Yes	No (↓)	No (↓)
	Was there blinding of outcome assessment (i.e. no potential for detection bias) or was outcome measurement not likely to be influenced by lack of blinding?	Unclear		Unclear	Unclear	Unclear
	Were more than 80% of participants enrolled in trials included in the analysis (i.e. no potential reporting bias)?^e	60 mg/d: unclear 40 mg/d: no (↓) 20 mg/d: no (↓)		No (↓)	Unclear	No (↓)
	Were data reported consistently for the outcome of interest (i.e. no potential selective reporting)?	No (↓)		No (↓)	No (↓)	No (↓)
	No other biases reported (i.e. no potential of other bias)?	Yes		Yes	Yes	Yes
Inconsistency^b	Point estimates did not vary widely?	60 mg/d: yes 40 mg/d: no (↓) 20 mg/d: no (↓)		Yes	Yes	Yes
	To what extent did confidence intervals overlap (substantial: all confidence intervals overlap at least one of the included studies point estimate;some: confidence intervals overlap but not all overlap at least one point estimate; no: at least one outlier: where the confidence interval of some of the studies do not overlap with those of most included studies)?	60 mg/d: substantial 40 mg/d: no (↓) 20 mg/d: some		Substantial	Substantial	Substantial
	Was the direction of effect consistent?	Yes		Yes	Yes	Yes
	What was the magnitude of statistical heterogeneity (as measured by I²) ‐ low (I²<40%), moderate (I² 40%‐60%), high I²>60%)?	High (↓)		High (↓)	Moderate	Low
	Was the test for heterogeneity statistically significant (P < 0.1)?	Statistically significant (↓)		Statistically significant (↓)	Not statistically significant	Not statistically significant
Indirectness	Were the populations in included studies applicable to the decision context?	Highly applicable		Highly applicable	Highly applicable	Highly applicable
	Were the interventions in the included studies applicable to the decision context?	Highly applicable		Highly applicable	Highly applicable	Highly applicable
	Was the included outcome not a surrogate outcome?	Yes		Yes	Yes	Yes
	Were the conclusions based on direct comparisons?	Yes		Yes	Yes	Yes
Imprecision^c	Was the confidence interval for the pooled estimate not consistent with benefit and harm?	60 mg/d: yes 40 mg/d: unclear 20 mg/d: unclear		Yes	No (↓)	No (↓)
	What is the magnitude of the median sample size (high: 300 participants, intermediate: 100‐300 participants, low: <100 participants)?^e	Low (↓)		Low (↓)	Low (↓)	Low (↓)
	What was the magnitude of the number of included studies (large: >10 studies, moderate: 5‐10 studies, small: <5 studies)?^e	60 mg/d: moderate 40 mg/d: small (↓) 20 mg/d: small (↓)		Moderate	Small (↓)	Small (↓)
	Was the outcome a common event (e.g. occurs more than 1/100)?	NA		Yes	NA	NA
Publication bias^d	Was a comprehensive search conducted?	Yes		Yes	Yes	Yes
	Was grey literature searched?	Yes		Yes	Yes	Yes
	Were no restrictions applied to study selection on the basis of language?	Yes		Yes	Yes	Yes
	There was no industry influence on studies included in the review?	Yes		Yes	Yes	Yes
	There was no evidence of funnel plot asymmetry?	NA		NA	NA	NA
	There was no discrepancy in findings between published and unpublished trials?	NA		NA	NA	NA
^aQuestions on risk of bias are answered in relation to the majority of the aggregated evidence in the meta‐analysis rather than to individual trials ^bQuestions on inconsistency are primarily based on visual assessment of forest plots and the statistical quantification of heterogeneity based on I² ^cWhen judging the width of the confidence interval it is recommended to use a clinical decision threshold to assess whether the imprecision is clinically meaningful ^dQuestions address comprehensiveness of the search strategy, industry influence, funnel plot asymmetry and discrepancies between published and unpublished trials ^eDepends on the context of the systematic review area (↓): key item for potential downgrading the quality of the evidence (GRADE) as shown in the footnotes of the 'Summary of finding' table(s); BMI: body mass index; GRADE: Grading of Recommendations Assessment, Development and Evaluation; NA: not applicable.

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Appendix 2. Search strategies

CENTRAL (Cochrane Library)

1. [mh ^Obesity] 2. [mh ^"Obesity, Abdominal"] 3. [mh ^"Obesity, Morbid"] 4. [mh ^Adiposity] 5. [mh ^"Body Weight Changes"] 6. [mh ^"Body Weight"] 7. [mh ^"Weight Loss"] 8. [mh ^Overweight] 9. ("over weight*" or overweight*):ti,ab 10. adipos*:ti,ab 11. obes*:ti,ab 12. (weight near/4 (cyc* or reduc* or los* or maint* or decreas* or control* or gain* or chang* or improv* or modif* or exessiv*)):ti,ab 13. "fat":ti,ab 14. {or #1‐#13} 15. [mh Fluoxetine] 16. fluoxetin*:ti,ab 17. ("prozac" or "sarafem"):ti,ab 18. {or #15‐#17} 19. #14 and #18

MEDLINE (Ovid SP)

1. Obesity/ 2. Obesity, Abdominal/ 3. Obesity, Morbid/ 4. Adiposity/ 5. Body Weight Changes/ 6. Body Weight/ 7. Weight Loss/ 8. Overweight/ 9. (overweight* or over weight*).tw. 10. adipos*.tw. 11. obes*.tw. 12. (weight adj3 (cyc* or reduc* or los* or maint* or decreas* or control* or gain* or chang* or improv* or modif* or exessiv*)).tw. 13. fat.tw. 14. or/1‐13 15. Fluoxetine/ 16. fluoxetin*.tw. 17. (prozac or sarafem).tw. 18. or/15‐17 19. 14 and 18 [20‐30: Cochrane Handbook 2008 RCT filter ‐ sensitivity maximizing version] 20. randomized controlled trial.pt. 21. controlled clinical trial.pt. 22. randomized.ab. 23. placebo.ab. 24. drug therapy.fs. 25. randomly.ab. 26. trial.ab. 27. groups.ab. 28. or/20‐27 29. exp animals/ not humans/ 30. 28 not 29 31. 19 and 30

Embase (Ovid SP)

1. obesity/ 2. abdominal obesity/ 3. morbid obesity/ 4. weight control/ 5. weight reduction/ 6. (overweight* or over weight*).tw. 7. adipos*.tw. 8. obes*.tw. 9. (weight adj (reduc* or los* or control* or gain*)).tw. 10. or/1‐9 11. (fluoxetin* or prozac or sarafem).tw. 12. 10 and 11 [13 Wong et al. 2006 "sound treatment studies" filter – BS version]  13. random*.tw. or clinical trial*.mp. or exp health care quality/ 14. 12 and 13 [15‐18 TSC Portal filter for exclusion of animal references] 15. exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/ 16. human/ or normal human/ or human cell/ 17. 15 and 16 18. 15 not 17 19. 14 not 18

LILACS (iAHx)

(MH:"Obesity" OR MH:"Obesity, Morbid" OR MH:"Obesity, Abdominal" OR MH:"Pediatric Obesity" OR MH:"Overweight" OR MH:"Weight Loss" OR adipos$ OR obes$ OR overweight$ OR "over weight" OR sobrepes$ OR "exceso de peso" OR "excesso de peso" OR "weight reduction" OR "weight loss" OR "weight control") AND (MH:"Fluoxetine" OR fluoxetin$ OR prozac OR sarafem) + Filter "Controlled Clinical Trial"

ClinicalTrials.gov (Advanced search)

Conditions: obesity OR obese OR adiposity OR adipose OR overweight OR "over weight" OR "weight reduction" OR "weight loss" OR "weight control" Interventions: fluoxetin OR fluoxetine OR prozac OR sarafem Age Group: Adult (18‐65), Senior (66+)

WHO ICTRP Search Portal (Standard search)

obes* AND fluoxetin* OR adipos* AND fluoxetin* OR overweight* AND fluoxetin* OR weight AND fluoxetin* OR obes* AND fluoxetine OR adipos* AND fluoxetine OR overweight* AND fluoxetine OR weight AND fluoxetine OR obes* AND prozac OR adipos* AND prozac OR overweight* AND prozac OR weight AND prozac OR obes* AND sarafem OR adipos* AND sarafem OR overweight* AND sarafem OR weight AND sarafem

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Appendix 3. 'Risk of bias' assessment

'Risk of bias' domains

Random sequence generation (selection bias due to inadequate generation of a randomised sequence)
For each included trial, we described the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

Low risk of bias: trial authors achieved sequence generation using computer‐generated random numbers or a random numbers table. Drawing of lots, tossing a coin, shuffling cards or envelopes, and throwing dice are adequate if an independent person performed this who was not otherwise involved in the trial. We considered the use of the minimisation technique as equivalent to being random.
Unclear risk of bias: insufficient information about the sequence generation process.
High risk of bias: the sequence generation method was non‐random or quasi‐random (e.g. sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number; allocation by judgment of the clinician; allocation by preference of the participant; allocation based on the results of a laboratory test or a series of tests; or allocation by availability of the intervention).

Allocation concealment (selection bias due to inadequate concealment of allocation prior to assignment)
We described for each included trial the method used to conceal allocation to interventions prior to assignment and we assessed whether intervention allocation could have been foreseen in advance of or during recruitment or changed after assignment.

Low risk of bias: central allocation (including telephone, interactive voice‐recorder, Internet‐based and pharmacy‐controlled randomisation); sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes.
Unclear risk of bias: insufficient information about the allocation concealment.
High risk of bias: used an open random allocation schedule (e.g. a list of random numbers); assignment envelopes used without appropriate safeguards; alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

We also evaluated trial baseline data to incorporate assessment of baseline imbalance into the 'Risk of bias' judgement for selection bias (Corbett 2014).
Chance imbalances may also affect judgements on the risk of attrition bias. In the case of unadjusted analyses, we distinguished between trials that we rate as being at low risk of bias on the basis of both randomisation methods and baseline similarity, and trials that we judge as being at low risk of bias on the basis of baseline similarity alone (Corbett 2014). We reclassified judgements of unclear, low, or high risk of selection bias as specified in Appendix 4.
Blinding of participants and study personnel (performance bias due to knowledge of the allocated interventions by participants and personnel during the trial)
We evaluated the risk of detection bias separately for each outcome (Hróbjartsson 2013). We noted whether endpoints were self‐reported, investigator‐assessed, or adjudicated outcome measures (see below).

Low risk of bias: blinding of participants and key study personnel was ensured, and it was unlikely that the blinding could have been broken; no blinding or incomplete blinding, but we judge that the outcome is unlikely to have been influenced by lack of blinding.
Unclear risk of bias: insufficient information about the blinding of participants and study personnel; the trial does not address this outcome.
High risk of bias: no blinding or incomplete blinding, and the outcome is likely to have been influenced by lack of blinding; blinding of trial participants and key personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias due to knowledge of the allocated interventions by outcome assessment)
We evaluated the risk of detection bias separately for each outcome (Hróbjartsson 2013). We noted whether endpoints were self‐reported, investigator‐assessed, or adjudicated outcome measures (see below).

Low risk of bias: blinding of outcome assessment is ensured, and it is unlikely that the blinding could have been broken; no blinding of outcome assessment, but we judge that the outcome measurement is unlikely to have been influenced by lack of blinding.
Unclear risk of bias: insufficient information about the blinding of outcome assessors; the trial did not address this outcome.
High risk of bias: no blinding of outcome assessment, and the outcome measurement was likely to have been influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement was likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias due to quantity, nature or handling of incomplete outcome data)
For each included trial or each outcome, or both, we described the completeness of data, including attrition and exclusions from the analyses. We stated whether the trial reported attrition and exclusions, and we reported the number of participants included in the analysis at each stage (compared with the number of randomised participants per intervention/comparator groups). We also noted if the trial reported the reasons for attrition or exclusion, and whether missing data were balanced across groups or were related to outcomes. We considered the implications of missing outcome data per outcome such as high dropout rates (e.g. above 15%) or disparate attrition rates (e.g. difference of 10% or more between trial arms).

Low risk of bias: no missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to introduce bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (mean difference or standardised mean difference) among missing outcomes was not enough to have a clinically relevant impact on observed effect size; appropriate methods, such as multiple imputation, were used to handle missing data.
Unclear risk of bias: insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias; the trial did not address this outcome.
High risk of bias: reason for missing outcome data was likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in the intervention effect estimate; for continuous outcome data, plausible effect size (mean difference or standardised mean difference) among missing outcomes enough to induce clinically relevant bias in observed effect size; 'as‐treated' or similar analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.

Selective reporting (reporting bias due to selective outcome reporting)
We assessed outcome reporting bias by integrating the results of the appendix 'Matrix of trial endpoints (publications and trial documents)' (Boutron 2014; Jones 2015; Mathieu 2009), with those of the appendix 'High risk of outcome reporting bias according to the Outcome Reporting Bias In Trials (ORBIT) classification' (Kirkham 2010). This analysis formed the basis for the judgement of selective reporting.

Low risk of bias: the trial protocol was available and all the trial's prespecified (primary and secondary) outcomes that were of interest to this review were reported in the prespecified way; the study protocol was unavailable, but it was clear that the published reports included all expected outcomes (ORBIT classification).
Unclear risk of bias: insufficient information about selective reporting.
High risk of bias: not all the trial's prespecified primary outcomes were reported; one or more primary outcomes were reported using measurements, analysis methods, or subsets of the data (e.g. subscales) that were not prespecified; one or more reported primary outcomes were not prespecified (unless clear justification for their reporting was provided, such as an unexpected adverse effect); one or more outcomes of interest in the Cochrane Review were reported incompletely so that we cannot enter them into a meta‐analysis; the trial report failed to include results for a key outcome that we would expect to have been reported for such a trial (ORBIT classification).

Other bias

Low risk of bias: the trial appears to be free from other sources of bias.
Unclear risk of bias: information was insufficient to assess whether an important risk of bias existed; insufficient rationale or evidence that an identified problem introduced bias.
High risk of bias: the trial had a potential source of bias related to the specific trial design used; the trial was claimed to be fraudulent; or the trial had some other serious problem.

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Appendix 4. Selection bias decisions

Selection bias decisions for trials that reported unadjusted analyses: comparison of results obtained using method details alone versus results obtained using method details and trial baseline information^a
Reported randomisation and allocation concealment methods	Risk of bias judgement using methods reporting	Information gained from study characteristics data	Risk of bias using baseline information and methods reporting
Unclear methods	Unclear risk	Baseline imbalances present for important prognostic variable(s)	High risk
		Groups appear similar at baseline for all important prognostic variables	Low risk
		Limited or no baseline details	Unclear risk
Would generate a truly random sample, with robust allocation concealment	Low risk	Baseline imbalances present for important prognostic variable(s)	Unclear risk^b
		Groups appear similar at baseline for all important prognostic variables	Low risk
		Limited baseline details, showing balance in some important prognostic variables^c	Low risk
		No baseline details	Unclear risk
Sequence is not truly randomised or allocation concealment is inadequate	High risk	Baseline imbalances present for important prognostic variable(s)	High risk
		Groups appear similar at baseline for all important prognostic variables	Low risk
		Limited baseline details, showing balance in some important prognostic variables^c	Unclear risk
		No baseline details	High risk
^aTaken from Corbett 2014; judgements highlighted in bold indicate situations in which the addition of baseline assessments would change the judgement about risk of selection bias compared with using methods reporting alone. ^bImbalance was identified that appears likely to be due to chance. ^cDetails for the remaining important prognostic variables are not reported.

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Appendix 5. Description of interventions

Trial ID	Intervention(s) (route, frequency, total dose/day)	Comparator(s) (route, frequency, total dose/day)
Al‐Helli 2015	I1: fluoxetine (oral, once per day for 2 months, 20 mg/day)	Placebo (oral, once per day for 2 months)
	I2: omega‐3 gel (oral, twice per day for 2 months, 1000 mg)
	I3: fluoxetine + omega‐3 gel (oral, once per day for 2 months, 20 mg/day + 1000 mg)
Suplicy 2014	I1: diethylpropion (oral, once per day for 52 weeks, 75 mg/day)	Placebo (oral,once per day for 52 weeks)
	I2: fenproporex (oral, once per day for 52 weeks, 25 mg/day)
	I3: mazindol (oral, once per day for 52 weeks, 2 mg/day)
	I4: fluoxetine (oral, once per day for 52 weeks, 20 mg/day)
	I5: sibutramine (oral, once per day for 52 weeks, 15 mg/day)
Guimaraes 2006	I1: sibutramine (oral, once per day for 90 days, 15 mg/day)	Placebo (oral, once per day for 90 days)
	I2: metformin (oral, once per day for 90 days, 1700 mg/day)
	I3: fluoxetine (oral, once per day for 90 days, 60 mg/day)
Bondi 2000	I1: fluoxetine (oral, single dose, 40 mg)	Placebo (oral, once per day for 12 weeks)
Bondi 2000	I2: fluoxetine (oral, once per day before breakfast for 12 weeks, 40 mg/day and once per day before lunch for 12 weeks, 20 mg/day)	Placebo (oral, once per day for 12 weeks)
Huang 1998	Fluoxetine (oral, once per day for 12 weeks, 60 mg/day)	No treatment
Bross 1995	Fluoxetine (oral, once per day for 3 weeks, 60 mg/day)	Placebo (oral, once per day for 3 weeks)
Fernández‐Soto 1995	Fluoxetine (oral, once per day for 3 months, 60 mg/day)	Placebo (oral, once per day for 3 months)
Lawton 1995	Fluoxetine (oral, once per day for 2 weeks, 60 mg/day)	Placebo (oral, once per day for 2 weeks)
Goldstein 1994	Fluoxetine (oral, once per day for 52 weeks, 60 mg/day)	Placebo (oral, once per day for 52 weeks)
Goldstein 1993	I1: fluoxetine (oral, once per day for 40 weeks, 60 mg/day)	Placebo (oral, once per day for 40 weeks)
Goldstein 1993	I2: fluoxetine (oral, once per day for 40 weeks, 20 mg/day)	Placebo (oral, once per day for 40 weeks)
Pedrinola 1993	Fluoxetine (oral, twice per day for 12 weeks, 40 mg/day)	Placebo (oral, twice per day for 12 weeks)
Visser 1993	Fluoxetine (oral, once per day for 12 weeks, 60 mg/day)	Placebo (oral, once per day for 12 weeks)
Wurtman 1993	I1: dexfenfluramine (oral, once per day for 12 weeks, 15 mg/day)	Placebo (oral, once per day for 12 weeks)
Wurtman 1993	I2: fluoxetine (oral, once per day for 12 weeks, 20 mg/day)	Placebo (oral, once per day for 12 weeks)
Kopelman 1992	Fluoxetine (oral, once per day for 3 days, 60 mg/day)	Placebo (oral, daily for 3 days)
Stinson 1992	Fluoxetine (oral, once per day for 2 weeks, 60 mg/day)	Placebo (oral, once per day for 2 weeks)
Bagiella 1991	I1: fenfluramine (oral, every 8 hours for 12 weeks, 20 mg/day)	Placebo (oral, every 8 or 12 hours for 12 weeks)
	I2: 5‐hydroxy‐tryptophan (oral, every 8 hours for 12 weeks, 300 mg/day)
	I3: d‐fenfluramine (oral, twice per day for 12 weeks, 15 mg/day)
	I4: fluoxetine (oral, every 8 hours for 12 weeks, 20 mg/day)
	I5: fluvoxamine (oral, every 8 hours for 12 weeks, 50 mg/day)
Pijl 1991	Fluoxetine (oral, once per day for 6 weeks, 60 mg/day)	Placebo (oral, once per day for 6 weeks)
Levine 1989	I1: fluoxetine (oral, once per day for 8 weeks, 10 mg/day)	Placebo (oral, once per day for 8 weeks)
	I2: fluoxetine (oral, once per day for 8 weeks, 20 mg/day)
	I3: fluoxetine (oral, once per day for 8 weeks, 40 mg/day)
	I4: fluoxetine (oral, once per day for 8 weeks, 60 mg/day)
Levine 1987	Fluoxetine (oral, once per day, 20 mg day 1; 40 mg days 2‐3; 60 mg days 4‐14; 40‐80 mg/day at the discretion of the investigator based on weight loss and adverse events to 8 weeks)	Placebo (oral, once per day for 8 weeks)
C: comparator; FDA: Food and Drug Administration I: intervention; NA: not applicable.

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Appendix 6. Baseline characteristics (I)

Trial ID	Intervention(s) and comparator(s)	Duration of intervention	Description of participants	Trial period (year to year)	Country	Setting	Ethnic groups (%)	Duration of being overweight or obese
Al‐Helli 2015	I1: fluoxetine 20 mg	2 months	Age 18 to 40 years, either sex with BMI > 30 kg/m²	—	Iraq	Obesity research and treatment centre/Al‐Kindy medical college, Iraq	—	—
	I2: omega‐3 gel
	I3: fluoxetine 20 mg + omega‐3 gel
	C: placebo						—	—
Suplicy 2014	I1: diethylpropion	52 weeks	Premenopausal women between 18 and 50 years old with BMI 30 to 39.9 kg/m² who were weight stable within the previous 3 months (< 3 kg)	—	Brazil	Obesity Outpatient Clinic of the Endocrine Division (SEMPR) of the Parana Federal University Hospital, Curitiba, Brazil	—	—
	I2: fenproporex
	I3: mazindol
	I4: fluoxetine 20 mg
	I5: sibutramine
	C: placebo						—	—
Guimaraes 2006	I1: sibutramine	90 days	Age 30 to 38 years, either sex with BMI > 30 kg/m²	—	Brazil	University of Riberao Preto	—	—
	I2: metformin
	I3: fluoxetine 60 mg
	C: placebo						—	—
Bondi 2000	I1: fluoxetine 40 mg	12 weeks	Obese women between 48 and 51 years old with BMI 38 to 43 kg/m² who did not achieve a significant weight change during previous 6 months with diet.	—	Italy	Centro di Nutrizione Clinica, Università di Modena	—	—
	I2: fluoxetine 60 mg
	C: placebo						—	—
Huang 1998	I: fluoxetine 60 mg	12 weeks	Either sex, between 17 and 65 years old, who no clinical problems other than moderate obesity (30% over ideal body weight)	1994 to 1995	Republic of China	Departament of Internal Medicine and Nutrition, Memorial Hospital, Taipei	—	—
	C: no treatment						—	—
Bross 1995	I: fluoxetine 60 mg	3 weeks	Nondepressed healthy women between 32 and 33 years old, who maintained their body weight at 91 to 93 kg and BMI at 34 to 35 kg/m² for several months	—	Canada	Clinical Investigation Unit of the Royal Victoria Hospital	—	—
	C: placebo						—	—
Fernández‐Soto 1995	I: fluoxetine 60 mg	3 months	Obese women with mean age of 39 years and BMI 35 to 37 kg/m²	—	Spain	Endocrine and Metabolic Unit. Department of Internal Medicine, University Hospital, Granada	—	—
	C: placebo						—	—
Lawton 1995	I: fluoxetine 60 mg	2 weeks	Women with mean age of 32 years, BMI > 30 kg/m² and intention to diet or to restrict food intake	—	United Kingdom	Obesity Clinic of the General Infirmary, Leeds	—	—
	C: placebo						—	—
Goldstein 1994	I: fluoxetine 60 mg	52 weeks	Either sex, at least 18 years old with BMI > 25 kg/m²	—	USA	Multi‐centre (10 sites)	White	—
	C: placebo						White	—
Goldstein 1993	I1: fluoxetine 60 mg	40 weeks	Either sex, older than 18 years, BMI 30 to 39 kg/m² and not using an appetite suppressant within 2 weeks before trial	—	USA	—	White	—
	I2: fluoxetine 20 mg
	C: placebo						White	—
Pedrinola 1993	I: fluoxetine 40 mg	12 weeks	Obese participants (> 80 kg) of either sex, between 20 and 50 years old with BMI 33 to 36 kg/m²	—	Brazil	Outpatient Endocrinology Clinic of the Clinical Hospital of the University of Sao Paulo	—	—
	C: placebo						—	—
Visser 1993	I: fluoxetine 60 mg	12 weeks	Obese men (87 to 90 kg) between 38 and 43 years old with stable body weight for the last 2 months of trial	—	The Netherlands	University Hospital Utrecht	—	—
	C: placebo						—	—
Wurtman 1993	I1: dexfenfluramine	12 weeks	Women between 39 and 42 years old, weight 85 to 91 kg with BMI 32 to 34 kg/m²	—	USA	Massachusetts Institute of Technology, Clinical Research Center, Cambridge MA	—	—
	I2: fluoxetine 20 mg
	C: placebo						—	—
Kopelman 1992	I: fluoxetine 60 mg	3 days	Either sex, extremely obese (mean weight 131 kg) between 25 and 53 years old with normal thyroid function	—	United Kingdom	Royal London Hospital Obesity Clinic	—	—
	C: placebo						—	—
Stinson 1992	I: fluoxetine 60 mg	2 weeks	Healthy men and women < 65 years old, weight 97 kg to 99 kg, mean BMI 36.7 kg/m² without history of depression	—	Ireland	Departament of Metabolic Medicine, Adelaide Hospital, Dublin	—	—
	C: placebo						—	—
Bagiella 1991	I1: fenfluramine	12 weeks	Men and women between 16 and 57 years old with BMI 30 to 40 kg/m²	—	Italy	Istituto di Terapia Medica Sistematica Univeristà "La Sapienza"	—	—
	I2: 5‐hydroxy‐tryptophan
	I3: d‐fenfluramine
	I4: fluoxetine 20 mg
	I5: fluvoxamine
	C: placebo						—	—
Pijl 1991	I: fluoxetine 60 mg	6 weeks	Women between 37 to 39 years old with BMI > 30 kg/m²	—	The Netherlands	Clinic of Internal Medicine for Obesity, University Hospital, Leiden	—	—
	C: placebo						—	—
Levine 1989	I1: fluoxetine 10 mg	8 weeks	Nondepressed participants weighing 20% to 100% in excess of ideal body weight, either sex, 18 to 65 years old and not pregnant or lactating	—	USA	—	White	—
	I2: fluoxetine 20 mg
	I3: fluoxetine 40 mg
	I4: fluoxetine 60 mg
	C: placebo						White	—
Levine 1987	I: fluoxetine 60 mg	11 days	Nondepressed participants of either sex, between 18 and 65 years old and mean weight 93 kg who had not taken an appetite suppressant within 2 weeks before trial	—	USA	—	White	—
	C: placebo						White	—
— denotes not reported BMI: body mass index; C: comparator; I: intervention; SD: standard deviation.

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Appendix 7. Baseline characteristics (II)

Trial ID	Intervention(s) and comparator(s)	Sex (female %)	Age (mean/range years (SD), or as reported)	BMI (mean kg/m² (SD))	Comedications/Cointerventions (% of participants)	Comorbidities (% of participants)
Al‐Helli 2015	I1: fluoxetine 20 mg	—	18 to 40	≥ 30	—	—
	I2: omega‐3 gel
	I3: fluoxetine 20 mg + omega‐3 gel
	C: placebo
Suplicy 2014	I1: diethylpropion	100	36.1 (33.1 to 39.0)	34.6 (33.6 to 35.6)	Balanced hypocaloric diet and encouraged to maintain at least 150 min per week of moderate physical activity	—
	I2: fenproporex		35.6 (33.1 to 38.1)	34.0 (33.1 to 34.8)
	I3: mazindol		37.0 (34.5 to 39.6)	34.8 (33.8 to 35.9)
	I4: fluoxetine 20 mg		38.5 (35.7 to 41.2)	34.7 (33.8 to 35.6)
	I5: sibutramine		35.4 (32.8 to 38.0)	34.9 (33.8 to 35.9)
	C: placebo	100	37.1 (34.4 to 39.8)	34.9 (33.9 to 35.9)
Guimaraes 2006	I1: sibutramine	88.5	30.2 (—)	32.0 (2.4)	Dietary reeducation containing on average 1500 kcal/d	—
	I2: metformin		38.9 (—)	37.2 (5.8)
	I3: fluoxetine 60 mg		30.9 (—)	36.1 (3.2)
	C: placebo		31.4 (—)	32.2 (3.2)
Bondi 2000	I1: fluoxetine 40 mg	100	51.4 (2.6)	42.8 (1.9)	Diet (55% carbohydrates, 20% protein, 25% fat), caloric deficit of 500 kcal/d of 70% energy expenditure by indirect calorimetry	—
	I2: fluoxetine 60 mg		48.2 (5.2)	38.8 (2.9)
	C: placebo	100	47.8 (3.6)	39.7 (2.4)
Huang 1998	I: fluoxetine 60 mg	54	41.2 (10.9)	33.5 (4.2)	Participants were instructed to follow a weight‐reducing low calorie diet ([25‐35 kcal/d adjusted to work load * ideal body weight ‐ 500 kcal]. The energy distribution of the diet consisted of 50% carbohydrates, 20% protein and 30% fat.	—
	C: no treatment	41	44.5 (13.6)	32.6 (3.9)
Bross 1995	I: fluoxetine 60 mg	100	32.0 (3.2)	34.0 (1.3)	Formula diet (420 kcal including 70 g protein/d and ≥ 100% RDA vitamins and minerals). Treatment duration: 3 weeks	—
	C: placebo	100	33.0 (3.9)	34.1 (1.3)
Fernández‐Soto 1995	I: fluoxetine 60 mg	100	39.0 (16)	35.1 (6.0)	Diet 1200 kcal maintained throughout the trial; 2 to 3 L/d, no caloric liquids, vitamins, minerals and trace elements FDA requirements; psychotherapy	—
	C: placebo	100	39.0 (16)	36.8 (4.6)
Lawton 1995	I: fluoxetine 60 mg	100	32.8 (—)	39.9 (—)	Diet: each treatment phase incorporated 2 separate test days on which the participants response to either a high‐carbohydrate or a high‐fat meal was assessed (days 7 and 14)	—
	C: placebo	100	32.8 (—)	39.9 (—)
Goldstein 1994	I: fluoxetine 60 mg	81	43 (12)	36.2 (6.5)	Diet with caloric intake designed to produce a weight loss of 0.45 kg per week	—
	C: placebo	79	43 (12)	35.8 (6.7)
Goldstein 1993	I1: fluoxetine 60 mg	87	44.9 (10.9)	31.6 (3.0)	Advised to reduce overall caloric consumption and offered a diet to lose 0.45 kg per week	—
	I2: fluoxetine 20 mg	78	43.4 (10.3)	31.8 (3.1)
	C: placebo	73	42.6 (11.9)	31.9 (2.9)
Pedrinola 1993	I: fluoxetine 40 mg	—	20 to 50	35.1 (5.1)	Counselled by a dietician to follow a standard 1000 kcal diet	—
	C: placebo			33.6 (4.0)
Visser 1993	I: fluoxetine 60 mg	0	42.6 (5.6)	27.9 (1.0)	Received dietary advice on healthy nutrition and means to lose weight	—
	C: placebo	0	38.8 (7.7)	27.9 (1.3)
Wurtman 1993	I1: dexfenfluramine	100	41.2 (1.7)	32.0 (0.5)	—	Seasonal affective disorders
	I2: fluoxetine 20 mg		41.0 (1.9)	33.1 (0.6)
	C: placebo	100	39.5 (1.7)	32.8 (0.5)
Kopelman 1992	I: fluoxetine 60 mg	9	Men: 40 (25 to 53) Women: 47 (—)	44 (6)	—	—
	C: placebo
Stinson 1992	I: fluoxetine 60 mg	61.7	< 65	36.7 (0.8)	—	—
	C: placebo
Bagiella 1991	I1: fenfluramine	—	16 to 57	30 to 40	—	—
	I2: 5‐hydroxy‐tryptophan
	I3: d‐fenfluramine
	I4: fluoxetine 20 mg
	I5: fluvoxamine
	C: placebo
Pijl 1991	I: fluoxetine 60 mg	100	38.1 (2.9)	35.2 (0.8)	—	—
	C: placebo	100	37.3 (2.7)	36.4 (1.3)
Levine 1989	I1: fluoxetine 10 mg	85	40 (11)	≥ 25	—	—
	I2: fluoxetine 20 mg	85	41 (11)
	I3: fluoxetine 40 mg	85	39 (10)
	I4: fluoxetine 60 mg	80	39 (10)
	C: placebo	81	39 (10)	≥ 25
Levine 1987	I: fluoxetine 60 mg	88	43 (12)	≥ 25	Advised to reduce overall calorie consumption by 20%	—
	C: placebo	88	46 (11)	≥ 25
— denotes not reported BMI: body mass index; C: comparator; FDA: Food and Drug Administration; I: intervention; RDA: recommended dietary allowances; SD: standard deviation.

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Appendix 8. Matrix of trial endpoints (publications and trial documents)

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Appendix 9. High risk of outcome reporting bias according to Outcome Reporting Bias In Trials (ORBIT) classification

Trial ID	Outcome	High risk of bias (category A)^a	High risk of bias (category D)^b	High risk of bias (category E)^c	High risk of bias (category G)^d
Al‐Helli 2015	Anthropometric measurements other than weight loss in kilograms	Yes	No	No	No
Suplicy 2014	Health‐related quality of life	No	Yes	No	No
Guimaraes 2006	Adverse events	No	Yes	No	No
Goldstein 1994	Anthropometric measurements other than weight loss in kilograms	Yes	No	No	No
Goldstein 1993	Weight loss (kg)	No	Yes	No	No
Pedrinola 1993	Adverse events	Yes	No	No	No
Kopelman 1992	Adverse events	Yes	No	No	No
Levine 1989	Weight loss (kg)	No	Yes	No	No
Levine 1987	Anthropometric measurements other than weight loss in kilograms	No	No	Yes	No
^aClear that outcome was measured and analysed; trial report states that outcome was analysed but reports only that result was not significant (Classification 'A', table 2, Kirkham 2010) ^bClear that outcome was measured and analysed; trial report states that outcome was analysed but reports no results (Classification 'D', table 2, Kirkham 2010) ^cClear that outcome was measured but was not necessarily analysed; judgement says likely to have been analysed but not reported because of non‐significant results (Classification 'E', table 2, Kirkham 2010) ^dUnclear whether outcome was measured; not mentioned, but clinical judgement says likely to have been measured and analysed but not reported on the basis of non‐significant results (Classification 'G', table 2, Kirkham 2010)

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Appendix 10. Definition of endpoint measurement^a

Trial ID	Weight (kg)	Health‐related quality of life	Patient satisfaction	Anthropometric measurements other than weight loss	Socioeconomic effects	Severe/serious adverse events	Cardiovascular parameters	Metabolic parameters
Al‐Helli 2015	NR	NR	NR	ND	NR	NR	NR	ND
Suplicy 2014	ND	Assessed by Short‐Form Health Survey (SF‐36), a general health questionnaire and the Impact of Weight on Quality of Life (IWQOL‐LITE) with higher scores indicating a better quality of life (IO)	NR	ND	NR	Assessed by reports of adverse events in the follow‐up visits (SO)	Measured with electrocardiogram and transthoracic echocardiography, with the participant in the left lateral decubitus position, using Sonos 5500, Hewlett‐Packard with an electronic multifrequential transducer of 2 to 4 MHz (IO)	ND
Guimaraes 2006	Assessed by Filizola anthropometric scale while participant is wearing only a hospital gown (IO)	NR	NR	Height: measured with Filizola anthropometric scale BMI: Ratio of weight (kg) to height (m) squared Abdominal circumference: measured half way between the last rib and the iliac crest in the position of inspiration using a measuring tape % Fatty tissue: assessed by bioelectric impedance using a model 101‐A RJL Prizum apparatus with electrodes (IO)	NR	Assessed by reports of adverse events at follow‐up visits (SO)	Blood pressure: measured with an Oxigel sphygmomanometer, always at the same time of the day (IO)	ND
Bondi 2000	ND	NR	NR	NR	NR	NR	Oxygen concentration: measured by a paramagnetic differential oxygen sensor and expired carbon dioxide concentration continuously with an infrared sensor (IO)	Resting energy expenditure: measured by indirect calorimetry (Datex Instrumentarium) with a constant flow rate of 40 L/min through a transparent canopy over the participant´s head to the Deltatrac metabolic monitor (IO) Plasma glucose: measured by glucose oxidase colorimetric method (Glucofix, by Menarini Diagnostics) (AO) Serum insulin: measured in duplicate by immunoradiometric assays (Sorin Biomedica) (IO)
Huang 1998	ND	NR	NR	Ideal body weight: calculated by Huang´s formula: body height (cm) — 80 * 0.7 in men body height (cm) — 70 * 0.6 in women (IO)	NR	Assessed by self‐reported by direct questionnaire recorded at each visit (SO)	ND	ND
Bross 1995	Assessed each morning with the participants wearing light bedclothes, after voiding and before breakfast, with a high‐precision digital platform scale (Scale‐Tronix)(IO)	NR	NR	NR	NR	NR	ND	Resting energy expenditure: measured by ventilated‐hood indirect calorimetry (Deltatrac; SensorMedics) (IO) Thermic effect: measured by subtracting the contribution due to resting energy expenditure from total energy expenditure (IO) Serum thyroxine and triiodothyronine: measured by automated radioimmunoassay (ARIA II; Becton Dickinson Immunodiagnostics) Urine samples: collected in serial 24‐h aliquots in bottles containing 15 mL of 12 mol HCl/L, then analysed daily for (IO) Creatinine, sodium and potassium (Beckman Syncron CX4 and CX5 Systems) (IO) Norepinephrine and normetanephrine: measured by an automated HLPC system (Bio Rad, Richmond) Urine total nitrogen: determined by colorimetrically after Kjeldahl digestion by Technicon Autoanalyzer II (Chauncey) (IO) Nitrogen balance: calculated as nitrogen intake minus the sum of urinary and estimated fecal (0.6 g/d) and losses (8 mg * kg^‐1 * d^‐1) (IO)
Fernández‐Soto 1995	ND	NR	NR	NR	NR	Assessed by participants' report of medical problems since their last visit (SO)	ND	ND
Lawton 1995	ND	NR	NR	NR	NR	Assessed by reports of adverse events at follow‐up visits (SO)	ND	NR
Goldstein 1994	ND	NR	NR	BMI: ratio of weight (kg) to height (m) squared (IO)	NR	Assessed by treatment‐emergent adverse event reports (SO)	ND	ND
Goldstein 1993	ND	NR	NR	NR	NR	All adverse events were elicited by non‐probing inquiry (SO)	Measured by scalar electrocardiogram (IO)	ND
Pedrinola 1993	ND	NR	NR	ND	NR	Assessed by treatment‐emergent adverse event reports (SO)	ND	Haematology and biochemical profile: assessed by automated methods in the University Hospital clinical laboratories (IO)
Visser 1993	Measured with the participants wearing indoor clothing without shoes with a scale (Berkel ED‐60T) minus a correction of 1.2 kg for the clothes (IO)	NR	NR	Height: measured to the nearest 1 mm by a microtoise (IO) Body composition: measured by hydro‐densitometry; participants were weighed underwater with simultaneous assessment of the residual lung volume by a helium dilution technique. Underwater weight was measured to the nearest 0.05 kg (Sartorius 3826PM 81) Body fat percentage: calculated from body density using Siri´s formula (IO) Body circumferences: measured to the nearest 1 mm with a plastic tape at the levels of the waist and hip with the participant standing (IO) Waist‐hip circumference ratio: calculated by dividing waist circumference by hip circumference (IO) Abdominal fat: assessed by magnetic resonance imaging with the participant in the supine position (GYROSCAN S15, Philips Medical Systems) with a 1.5 T magnetic field (64 MHz) by use of a body coil with a diameter of 56 cm. An inversion recovery sequence was used: inversion time 300 ms, repetition time 820 mg and echo time 20 ms (IO)	NR	Assessed by reports of adverse events at follow‐up visits (SO)	NR	NR
Wurtman 1993	ND	NR	Assessed by log book (SO)	NR	NR	Monitored by recording spontaneous descriptions of mood and physical status during the previous week (SO)	Assessed by electrocardiogram (IO)	ND
Kopelman 1992	ND	NR	NR	NR	NR	ND	Arterial oxygen saturation: measured with an earlobe probe with a BIOX III pulse oximeter (Ohmeda Ltd) (IO) Electroencephalogram: Obtained with conventional surface electrodes with Nikon‐Kohden amplifiers Air flow: Measured at the nose and mouth with thermistors (Comark Ltd). (IO)	Pulmonary function: assessed with a Wright peak flow meter and a Vitalograph dry spirometer (IO) Apnoea: Calculated from the number of recorded episodes divided by the length of rapid eye movements (IO)
Stinson 1992	Participant was weighed wearing light summer clothing on the same weighing balance at the same time of day with the participant fasting and having micturated and defaecated before the recordings (IO)	NR	NR	NR	NR	NR	ND	Metabolic rate: measured by indirect open circuit calorimetry with a transparent ventilated hood over the participant´s head. Air was drawn through at a rate of 100 L/min, and inspired and expired air were analysed by a Taylor Servomex OA 272 oxygen analyser (IO) Resting metabolic rate: recorded by estimating the resting oxygen consumption over a 30‐min period after consumption of a glucose load drink (1 g/kg body weight, dissolved in water and lemon juice) (IO)
Bagiella 1991	NR	NR	NR	NR	NR	NR	ND	NR
Pijl 1991	ND	NR	NR	NR	NR	Assessed by reports of adverse events at follow‐up visits (SO)	NR	ND
Levine 1989	ND	NR	NR	ND	NR	At each visit, participants were questioned in a open‐ended manner about adverse events based on the 1200 FDA COSTART terms (SO)	Measured by 12‐lead scalar electrocardiogram (IO)	NR
Levine 1987	ND	NR	NR	ND	NR	Elicited by non‐probing inquiry at each follow‐up visit (SO)	Measured by scalar electrocardiogram (IO)	NR
^aIn addition to definition of endpoint measurement, description who measured the outcome (AO: adjudicated outcome measurement; IO: investigator‐assessed outcome measurement; SO: self‐reported outcome measurement) BMI: body mass index; ND: not defined; NR: not reported.

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Appendix 11. Adverse events (I)

Trial ID	Intervention(s) and comparator(s)	Participants included in analysis (N)	Deaths (N)	Deaths (% of participants)	Participants with at least one adverse event (N)	Participants with at least one adverse event (%)	Participants with at least one severe/serious adverse event (N)	Participants with at least one severe/serious adverse event (%)
Al‐Helli 2015	I1: fluoxetine 20 mg	12	—	—	—	—	—	—
	I2: omega‐3 gel	12
	I3: fluoxetine 20 mg + omega‐3 gel	12
	C: placebo	12
Suplicy 2014	I1: diethylpropion	28	—	—	11	39.3	0	0
	I2: fenproporex	29			15	51.7	0	0
	I3: mazindol	29			16	55.2	0	0
	I4: fluoxetine 20 mg	29			18	60	0	0
	I5: sibutramine	30			11	35.5	0	0
	C: placebo	29			8	27.5	0	0
Guimaraes 2006	I1: sibutramine	8	—	—	6	79.2	0	0
	I2: metformin	8			4	45.6	0	0
	I3: fluoxetine 60 mg	9			8	92.6	0	0
	C: placebo	10			1	10	0	0
Bondi 2000	I1: fluoxetine 40 mg	8	—	—	—	—	—	—
	I2: fluoxetine 60 mg	12			—	—	—	—
	C: placebo	12			—	—	—	—
Huang 1998	I: fluoxetine 60 mg	28	—	—	26	92.8	0	0
Huang 1998	C: no treatment	22	—	—	3	13.6	0	0
Bross 1995	I: fluoxetine 60 mg	I: 10	0	0	0	0	0	0
Bross 1995	C: placebo	C: 10	0	0	0	0	0	0
Fernández‐Soto 1995	I: fluoxetine 60 mg	18	—	—	4	22.2	—	—
Fernández‐Soto 1995	C: placebo	15	—	—	4	26.6	—	—
Lawton 1995	I: fluoxetine 60 mg	12	—	—	9	75	0	0
Lawton 1995	C: placebo	12	—	—	6	50	0	0
Goldstein 1994	I: fluoxetine 60 mg	230	—	—	200	86.9	0	0
Goldstein 1994	C: placebo	228	—	—	194	85.1	0	0
Goldstein 1993	I1: fluoxetine 60 mg	106	—	—	19	17.9	0	0
	I2: fluoxetine 20 mg	104			16	15.4	0	0
	C: placebo	107			20	18.7	0	0
Pedrinola 1993	I: fluoxetine 40 mg	10	—	—	—	—	0	0
Pedrinola 1993	C: placebo	8	—	—	—	—	0	0
Visser 1993	I: fluoxetine 60 mg	18	—	—	7	38.8	0	0
Visser 1993	C: placebo	20	—	—	2	10	0	0
Wurtman 1993	I1: dexfenfluramine	28	—	—	23	82.1	0	0
	I2: fluoxetine 20 mg	30			27	90	0	0
	C: placebo	29			24	82.7	0	0
Kopelman 1992	I: fluoxetine 60 mg	11	0	0	0	0	0	0
Kopelman 1992	C: placebo	11	0	0	0	0	0	0
Stinson 1992	I: fluoxetine 60 mg	13	—	—	—	—	—	—
Stinson 1992	C: placebo	17	—	—	—	—	—	—
Bagiella 1991	I1: fenfluramine	60	—	—	—	—	—	—
	I2: 5‐hydroxy‐tryptophan
	I3: d‐fenfluramine
	I4: fluoxetine 20 mg
	I5: fluvoxamine
	C: placebo
Pijl 1991	I: fluoxetine 60 mg	11	—	—	4	36.4	0	0
Pijl 1991	C: placebo	12	—	—	2	16.7	0	0
Levine 1989	I1: fluoxetine 10 mg	131	—	—	90	68.7	0	0
	I2: fluoxetine 20 mg	131			100	76.3
	I3: fluoxetine 40 mg	131			101	77.1
	I4: fluoxetine 60 mg	131			101	77.1
	C: placebo	131			94	71.7	0	0
Levine 1987	I: fluoxetine 60 mg	60	—	—	15	25	0	0
Levine 1987	C: placebo	60	—	—	7	11.6	0	0
— denotes not reported C: comparator; I: intervention.

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Appendix 12. Adverse events (II)

Trial ID	Intervention(s) and comparator(s)	Participants included in analysis (N)	Participants discontinuing trial due to an adverse event (N)	Participants discontinuing trial due to an adverse event (%)	Participants with at least one hospitalisation (N)	Participants with at least one hospitalisation (%)	Participants with at least one outpatient treatment (N)	Participants with at least one outpatient treatment (%)
Al‐Helli 2015	I1: fluoxetine 20 mg	12	—	—	—	—	—	—
	I2: omega‐3 gel	12
	I3: fluoxetine 20 mg + omega‐3 gel	12
	C: placebo	12
Suplicy 2014	I1: diethylpropion	28	2	7.1	—	—	—	—
	I2: fenproporex	29	2	6.8
	I3: mazindol	29	1	3.4
	I4: fluoxetine 20 mg	29	3	10.3
	I5: sibutramine	30	2	6.6
	C: placebo	29	3	10.3
Guimaraes 2006	I1: sibutramine	8	0	0	—	—	—	—
	I2: metformin	8
	I3: fluoxetine 60 mg	9
	C: placebo	10	0	0
Bondi 2000	I1: fluoxetine 40 mg	8	—	—	—	—	—	—
	I2: fluoxetine 60 mg	12
	C: placebo	12
Huang 1998	I: fluoxetine 60 mg	28	1	3.5	—	—	1	3.5
	C: no treatment	22	0	0			0	0
Bross 1995	I: fluoxetine 60 mg	10	—	—	—	—	—	—
	C: placebo	10
Fernández‐Soto 1995	I: fluoxetine 60 mg	18	—	—	—	—	—	—
	C: placebo	15
Lawton 1995	I: fluoxetine 60 mg	12	—	—	2	8.3	—	—
	C: placebo	12
Goldstein 1994	I: fluoxetine 60 mg	230	41	17.8	—	—	—	—
	C: placebo	228	19	8.3
Goldstein 1993	I1: fluoxetine 60 mg	106	14	13.2	—	—	—	—
	I2: fluoxetine 20 mg	104	2	1.9
	C: placebo	107	6	5.6
Pedrinola 1993	I: fluoxetine 40 mg	10	0	0	—	—	—	—
	C: placebo	8	0	0
Visser 1993	I: fluoxetine 60 mg	18	—	—	—	—	—	—
	C: placebo	20
Wurtman 1993	I1: dexfenfluramine	21	1	4.7	—	—	—	—
	I2: fluoxetine 20 mg	18	7	38.8
	C: placebo	25	2	8
Kopelman 1992	I: fluoxetine 60 mg	11	—	—	—	—	—	—
	C: placebo	11
Stinson 1992	I: fluoxetine 60 mg	13	—	—	—	—	—	—
	C: placebo	17
Bagiella 1991	I1: fenfluramine	60	—	—	—	—	—	—
	I2: 5‐hydroxy‐tryptophan
	I3: d‐fenfluramine
	I4: fluoxetine 20 mg
	I5: fluvoxamine
	C: placebo
Pijl 1991	I: fluoxetine 60 mg	11	—	—	—	—	—	—
	C: placebo	12
Levine 1989	I1: fluoxetine 10 mg	131	10	7.6	—	—	—	—
	I2: fluoxetine 20 mg	131	10	7.6
	I3: fluoxetine 40 mg	131	10	7.6
	I4: fluoxetine 60 mg	131	8	6.1
	C: placebo	131	11	8.3
Levine 1987	I: fluoxetine 60 mg	60	6	10	—	—	—	—
	C: placebo	60	1	1.7
— denotes not reported C: comparator; I: intervention.

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Appendix 13. Adverse events (III)

Trial ID	Intervention(s) and comparator(s)	Participants included in analysis (N)	Participants with a specific adverse event (description)	Participants with at least one specific adverse events (N)	Participants with at least one specific adverse event (%)
Al‐Helli 2015	I1: fluoxetine 20 mg	12	—	—	—
	I2: omega‐3 gel	12
	I3: fluoxetine 20 mg + omega‐3 gel	12
	C: placebo	12
Suplicy 2014	I1: diethylpropion	28	(1) dry mouth (2) constipation (3) insomnia (4) anxiety (5) headache (6) irritability (7) nausea (8) somnolence (9) dizziness (10) tremor (11) palpitation	(1) 11 (2) 6 (3) 2 (4) 9 (5) 3 (6) 6 (7) 2 (8) 2 (9) 2 (10) 1 (11) 1	(1) 39.3 (2) 21.4 (3) 7.1 (4) 32.1 (5) 10.7 (6) 28.6 (7) 7.1 (8) 7.1 (9) 7.1 (10) 3.6 (11) 3.6
	I2: fenproporex	29	(1) dry mouth (2) constipation (3) insomnia (4) anxiety (5) headache (6) irritability (7) nausea (8) somnolence (9) dizziness (10) tremor (11) diarrhoea (12) hair loss (13) fatigue	(1) 15 (2) 5 (3) 7 (4) 6 (5) 3 (6) 7 (7) 1 (8) 2 (9) 1 (10) 1 (11) 2 (12) 2 (13) 1	(1) 51.7 (2) 17.2 (3) 24.1 (4) 20.7 (5) 10.3 (6) 33.3 (7) 3.4 (8) 6.9 (9) 3.4 (10) 3.4 (11) 6.9 (12) 6.9 (13) 3.4
	I3: mazindol	29	(1) dry mouth (2) constipation (3) insomnia (4) anxiety (5) headache (6) irritability (7) nausea (8) somnolence (9) dizziness (10) dyspepsia (11) malaise	(1) 16 (2) 7 (3) 7 (4) 1 (5) 4 (6) 4 (7) 6 (8) 1 (9) 3 (10) 3 (11) 2	(1) 55.2 (2) 24.1 (3) 24.1 (4) 3.4 (5) 13.8 (6) 19.0 (7) 20.7 (8) 3.5 (9) 10.3 (10) 10.3 (11) 6.9
	I4: fluoxetine 20 mg	29	(1) dry mouth (2) constipation (3) insomnia (4) anxiety (5) headache (6) irritability (7) nausea (8) somnolence (9) dizziness (10) dyspepsia (11) malaise	(1) 18 (2) 3 (3) 7 (4) 1 (5) 5 (6) 3 (7) 2 (8) 2 (9) 1 (10) 2 (11) 1	(1) 60 (2) 43.3 (3) 23.3 (4) 3.3 (5) 16.7 (6) 14.3 (7) 6.7 (8) 6.7 (9) 3.3 (10) 6.7 (11) 3.3
	I5: sibutramine	30	(1) dry mouth (2) constipation (3) insomnia (4) anxiety (5) headache (6) nausea (7) somnolence (8) dizziness (9) diarrhoea (10) palpitation (11) polyuria (12) sweating (13) cramps (14) abdominal pain	(1) 11 (2) 4 (3) 7 (4) 4 (5) 4 (6) 7 (7) 7 (8) 5 (9) 1 (10) 1 (11) 2 (12) 1 (13) 1 (14) 1	(1) 35.5 (2) 12.9 (3) 22.6 (4) 12.9 (5) 12.9 (6) 22.6 (7) 22.6 (8) 16.1 (9) 3.2 (10) 3.2 (11) 6.4 (12) 3.2 (13) 3.2 (14) 3.2
	C: placebo	29	(1) dry mouth (2) constipation (3) insomnia (4) anxiety (5) headache (6) irritability (7) nausea (8) somnolence (9) dyspepsia (10) tremor (11) urticaria (12) edema	(1) 8 (2) 1 (3) 1 (4) 2 (5) 3 (6) 1 (7) 2 (8) 4 (9) 1 (10) 1 (11) 1 (12) 1	(1) 27.5 (2) 3.4 (3) 3.4 (4) 6.8 (5) 10.3 (6) 3.4 (7) 6.8 (8) 13.7 (9) 3.4 (10) 3.4 (11) 3.4 (12) 3.4
Guimaraes 2006	I1: sibutramine	8	(1) mouth dryness (2) sudoresis (3) constipation (4) insomnia (5) headache	(1) 6 (2) 4 (3) 3 (4) 2 (5) 1	(1) 79.2 (2) 45.8 (3) 41.7 (4) 20.8 (5) 16.7
	I2: metformin	8	(1) mouth dryness (2) sudoresis (3) diarrhoea (4) vertigo (5) nausea	(1) 3 (2) 2 (3) 4 (4) 2 (5) 2	(1) 37.5 (2) 29.2 (3) 45.8 (4) 29.2 (5) 20.8
	I3: fluoxetine 60 mg	9	(1) insomnia (2) sleepiness (3) anorexia	(1) 3 (2) 3 (3) 8	(1) 29.6 (2) 29.6 (3) 92.6
	C: placebo	10	(1) anorexia (2) thirst (3) diarrhoea	(1) 1 (2) 1 (3) 1	(1) 10 (2) 10 (3) 10
Bondi 2000	I1: fluoxetine 40 mg	8	—	—	—
	I2: fluoxetine 60 mg	12
	C: placebo	12
Huang 1998	I: fluoxetine 60 mg	28	(1) anorexia (2) nausea (3) malaise (4) diarrhoea (5) lethargy	(1) 26 (2) 8 (3) 5 (4) 4 (5) 4	(1) 92.8 (2) 28.5 (3) 17.8 (4) 14.2 (5) 14.2
Huang 1998	C: no treatment	22	(1) anorexia (2) nausea (3) malaise (4) diarrhoea (5) lethargy	(1) 1 (2) 1 (3) 3 (4) 1 (5) 2	(1) 4.5 (2) 4.5 (3) 13.6 (4) 4.5 (5) 9
Bross 1995	I: fluoxetine 60 mg	10	—	—	—
Bross 1995	C: placebo	10	—	—	—
Fernández‐Soto 1995	I: fluoxetine 60 mg	18	(1) cephalalgia (2) drowsiness (3) insomnia (4) fatigue (5) dryness of mouth	(1) 2 (2) 2 (3) 3 (4) 4 (5) 1	(1) 11.1 (2) 11.1 (3) 16.6 (4) 22.2 (5) 11.1
Fernández‐Soto 1995	C: placebo	15	(1) cephalalgia (2) drowsiness (3) insomnia (4) fatigue (5) dryness of mouth	(1) 1 (2) 1 (3) 1 (4) 4 (5) 1	(1) 6.6 (2) 6.6 (3) 6.6 (4) 26.6 (5) 6.6
Lawton 1995	I: fluoxetine 60 mg	12	(1) nausea (2) dizziness (3) indigestion (4) heartburn (5) insomnia (6) migraine (7) headache (8) tiredness (9) drowsiness (10) lightheadedness (11) vomiting (12) breathlessness (13) flushes (14) constipation (15) osteomyelitis (16) cough (17) hay fever	(1) 6 (2) 1 (3) 1 (4) 1 (5) 2 (6) 1 (7) 2 (8) 4 (9) 1 (10) 2 (11) 1 (12) 1 (13) 1 (14) 1 (15) 1 (16) 1 (17) 1	(1) 50 (2) 8.3 (3) 8.3 (4) 8.3 (5) 16.6 (6) 8.3 (7) 16.6 (8) 33.3 (9) 8.3 (10) 16.6 (11) 8.3 (12) 8.3 (13) 8.3 (14) 8.3 (15) 8.3 (16) 8.3 (17) 8.3
Lawton 1995	C: placebo	12	(1) nausea (2) diarrhoea (3) stomach discomfort (4) sore throat (5) common cold (6) inflamed tendon (7) hay fever	(1) 1 (2) 1 (3) 1 (4) 1 (5) 1 (6) 1 (7) 1	(1) 8.3 (2) 8.3 (3) 8.3 (4) 8.3 (5) 8.3 (6) 8.3 (7) 8.3
Goldstein 1994	I: fluoxetine 60 mg	230	(1) headache (2) rhinitis (3) asthenia (4) diarrhoea (5) nausea (6) sweating (7) insomnia (8) somnolence (9) bronchitis (10) nervousness (11) nausea and vomiting (12) tremor (13) amnesia (14) thirst	(1) 62 (2) 55 (3) 41 (4) 33 (5) 31 (6) 25 (7) 23 (8) 21 (9) 20 (10) 16 (11) 12 (12) 10 (13) 6 (14) 4	(1) 26.9 (2) 23.9 (3) 17.8 (4) 14.3 (5) 13.5 (6) 10.9 (7) 10 (8) 9.1 (9) 8.7 (10) 7 (11) 5.2 (12) 4.3 (13) 2.6 (14) 1.7
Goldstein 1994	C: placebo	228	(1) headache (2) rhinitis (3) asthenia (4) diarrhoea (5) nausea (6) sweating (7) insomnia (8) somnolence (9) bronchitis (10) nervousness (11) nausea and vomiting (12) allergic reaction	(1) 50 (2) 52 (3) 18 (4) 19 (5) 14 (6) 2 (7) 11 (8) 7 (9) 4 (10) 5 (11) 4 (12) 5	(1) 21.9 (2) 22.8 (3) 7.9 (4) 8.3 (5) 6.1 (6) 0.9 (7) 4.8 (8) 3.1 (9) 1.8 (10) 2.2 (11) 1.8 (12) 2.2
Goldstein 1993	I1: fluoxetine 60 mg	106	(1) headache (2) rhinitis (3) asthenia (4) insomnia (5) diarrhoea (6) infection (7) pain (8) dizziness (9) increased appetite (10) pharyngitis (11) sinusitis (12) somnolence (13) anxiety (14) back pain	(1) 19 (2) 18 (3) 17 (4) 11 (5) 10 (6) 9 (7) 8 (8) 7 (9) 7 (10) 7 (11) 6 (12) 6 (13) 3 (14) 1	(1) 17.9 (2) 17 (3) 16 (4) 10.2 (5) 9.4 (6) 8.5 (7) 7.5 (8) 6.6 (9) 6.6 (10) 6.6 (11) 5.7 (12) 5.7 (13) 2.8 (14) 0.9
	I2: fluoxetine 20 mg	104	(1) headache (2) rhinitis (3) asthenia (4) insomnia (5) diarrhoea (6) infection (7) pain (8) dizziness (9) increased appetite (10) pharyngitis (11) sinusitis (12) somnolence (13) anxiety (14) back pain	(1) 13 (2) 16 (3) 8 (4) 3 (5) 10 (6) 11 (7) 7 (8) 4 (9) 5 (10) 3 (11) 4 (12) 3 (13) 8 (14) 10	(1) 12.5 (2) 15.4 (3) 7.7 (4) 2.9 (5) 9.6 (6) 10.6 (7) 6.7 (8) 3.8 (9) 4.8 (10) 2.9 (11) 3.8 (12) 2.9 (13) 7.7 (14) 9.6
	C: placebo	107	(1) headache (2) rhinitis (3) asthenia (4) insomnia (5) diarrhoea (6) infection (7) pain (8) dizziness (9) increased appetite (10) pharyngitis (11) sinusitis (12) somnolence (13) anxiety (14) back pain	(1) 10 (2) 20 (3) 5 (4) 10 (5) 7 (6) 14 (7) 10 (8) 2 (9) 15 (10) 8 (11) 5 (12) 4 (13) 7 (14) 10	(1) 9.3 (2) 18.7 (3) 4.7 (4) 9.3 (5) 6.5 (6) 13.1 (7) 9.3 (8) 1.9 (9) 14 (10) 7.5 (11) 4.7 (12) 3.7 (13) 6.5 (14) 9.3
Pedrinola 1993	I: fluoxetine 40 mg	10	(1) headache (2) decreased libido (3) diarrhoea (4) dizziness	—	—
Pedrinola 1993	C: placebo	8	(1) headache (2) decreased libido (3) diarrhoea (4) dizziness	—	—
Visser 1993	I: fluoxetine 60 mg	18	(1) somnolence (2) dry mouth (3) decreased libido (4) tremor (5) nausea (6) sweating (7) intestinal discomfort (8) nervousness (9) dizziness	(1) 7 (2) 4 (3) 4 (4) 2 (5) 2 (6) 1 (7) 1 (8) 1 (9) 1	(1) 38.8 (2) 22.2 (3) 22.2 (4) 11.1 (5) 11.1 (6) 5.5 (7) 5.5 (8) 5.5 (9) 5.5
Visser 1993	C: placebo	20	(1) intestinal discomfort (2) nervousness (3) dizziness	(1) 2 (2) 1 (3) 1	(1) 10 (2) 5 (3) 5
Wurtman 1993	I1: dexfenfluramine	28	(1) headache (2) fatigue (3) insomnia (4) drowsiness (5) anxiety (6) dry mouth (7) diarrhoea (8) nausea (9) upper gastrointestinal distress (10) constipation (11) polyuria (12) menstrual disturbances	(1) 21 (2) 14 (3) 6 (4) 4 (5) 3 (6) 25 (7) 10 (8) 1 (9) 4 (10) 3 (11) 3 (12) 7	(1) 75 (2) 50 (3) 21.4 (4) 14.2 (5) 10.7 (6) 89.2 (7) 35.7 (8) 3.5 (9) 14.2 (10) 10.7 (11) 10.7 (12) 25
	I2: fluoxetine 20 mg	30	(1) headache (2) fatigue (3) insomnia (4) drowsiness (5) anxiety (6) dry mouth (7) diarrhoea (8) nausea (9) upper gastrointestinal distress (10) constipation (11) polyuria (12) menstrual disturbances	(1) 17 (2) 16 (3) 16 (4) 9 (5) 4 (6) 12 (7) 1 (8) 7 (9) 3 (10) 5 (11) 1 (12) 4	(1) 62.9 (2) 59.2 (3) 59.2 (4) 33.3 (5) 14.8 (6) 44.4 (7) 3.7 (8) 25.9 (9) 11.1 (10) 18.5 (11) 3.7 (12) 14.8
	C: placebo	29	(1) headache (2) fatigue (3) insomnia (4) drowsiness (5) anxiety (6) dry mouth (7) diarrhoea (8) nausea (9) upper gastrointestinal distress (10) constipation (11) polyuria	(1) 15 (2) 6 (3) 4 (4) 1 (5) 3 (6) 9 (7) 1 (8) 3 (9) 4 (10) 1 (11) 1	(1) 51.7 (2) 20.6 (3) 13.7 (4) 3.4 (5) 10.3 (6) 31 (7) 3.4 (8) 10.3 (9) 13.7 (10) 3.4 (11) 3.4
Kopelman 1992	I: fluoxetine 60 mg	11	—	—	—
Kopelman 1992	C: placebo	11	—	—	—
Stinson 1992	I: fluoxetine 60 mg	13	—	—	—
Stinson 1992	C: placebo	17	—	—	—
Bagiella 1991	I1: fenfluramine	60	—	—	—
	I2: 5‐hydroxy‐tryptophan
	I3: d‐fenfluramine
	I4: fluoxetine 20 mg
	I5: fluvoxamine
	C: placebo
Pijl 1991	I: fluoxetine 60 mg	11	(1) drowsiness (2) stomach discomfort (3) sweating (4) tremor (5) headache	(1) 4 (2) 4 (3) 3 (4) 3 (5) 2	(1) 36.3 (2) 36.3 (3) 27.2 (4) 27.2 (5) 18.1
Pijl 1991	C: placebo	12	(1) drowsiness (2) stomach discomfort (3) sweating (4) tremor (5) headache	(1) 1 (2) 1 (3) 2 (4) 1 (5) 1	(1) 8.3 (2) 8.3 (3) 16.6 (4) 8.3 (5) 8.3
Levine 1989	I1: fluoxetine 10 mg	131	(1) headache (2) nervousness (3) diarrhoea (4) nausea (5) asthenia (6) rhinitis (7) somnolence (8) dry mouth (9) insomnia (10) injection (11) anxiety (12) dyspepsia (13) dysmenorrhoea (14) sweating (15) abdominal pain (16) pain (17) dizziness (18) pharyngitis (19) rash (20) back pain (21) sinusitis (22) myalgia (23) flu syndrome (24) constipation (25) decreased libido	(1) 35 (2) 13 (3) 15 (4) 8 (5) 7 (6) 9 (7) 5 (8) 8 (9) 4 (10) 6 (11) 7 (12) 5 (13) 5 (14) 5 (15) 5 (16) 5 (17) 4 (18) 3 (19) 5 (20) 5 (21) 2 (22) 5 (23) 2 (24) 3 (25) 2	(1) 26.7 (2) 9.9 (3) 11.4 (4) 6.1 (5) 5.3 (6) 6.8 (7) 3.8 (8) 6.1 (9) 3 (10) 4.5 (11) 5.3 (12) 3.8 (13) 3.8 (14) 3.8 (15) 3.8 (16) 3.8 (17) 3 (18) 2.2 (19) 3.8 (20) 3.8 (21) 1.5 (22) 3.8 (23) 1.5 (24) 2.2 (25) 1.5
	I2: fluoxetine 20 mg	131	(1) headache (2) nervousness (3) diarrhoea (4) nausea (5) asthenia (6) rhinitis (7) somnolence (8) dry mouth (9) insomnia (10) injection (11) anxiety (12) dyspepsia (13) dysmenorrhoea (14) sweating (15) abdominal pain (16) pain (17) dizziness (18) pharyngitis (19) rash (20) back pain (21) sinusitis (22) myalgia (23) flu syndrome (24) constipation (25) decreased libido (26) allergic reaction	(1) 37 (2) 15 (3) 17 (4) 15 (5) 6 (6) 15 (7) 8 (8) 9 (9) 5 (10) 6 (11) 5 (12) 8 (13) 6 (14) 5 (15) 6 (16) 5 (17) 2 (18) 5 (19) 5 (20) 5 (21) 3 (22) 3 (23) 4 (24) 3 (25) 5 (26) 8	(1) 28.2 (2) 11.4 (3) 12.9 (4) 11.4 (5) 4.5 (6) 11.4 (7) 6.1 (8) 6.8 (9) 3.8 (10) 4.5 (11) 3.8 (12) 6.1 (13) 4.5 (14) 3.8 (15) 4.5 (16) 3.8 (17) 1.5 (18) 3.8 (19) 3.8 (20) 3.8 (21) 2.2 (22) 2.2 (23) 3 (24) 2.2 (25) 3.8 (26) 6.1
	I3: fluoxetine 40 mg	131	(1) headache (2) nervousness (3) diarrhoea (4) nausea (5) asthenia (6) rhinitis (7) somnolence (8) dry mouth (9) insomnia (10) injection (11) anxiety (12) dyspepsia (13) dysmenorrhoea (14) sweating (15) abdominal pain (16) pain (17) dizziness (18) pharyngitis (19) rash (20) back pain (21) sinusitis (22) myalgia (23) flu syndrome (24) constipation (25) decreased libido (26) allergic reaction	(1) 34 (2) 15 (3) 15 (4) 15 (5) 17 (6) 9 (7) 9 (8) 8 (9) 8 (10) 9 (11) 5 (12) 6 (13) 5 (14) 5 (15) 4 (16) 2 (17) 4 (18) 6 (19) 2 (20) 1 (21) 4 (22) 1 (23) 5 (24) 5 (25) 4 (26) 2	(1) 25.9 (2) 11.4 (3) 11.4 (4) 11.4 (5) 12.9 (6) 6.8 (7) 6.8 (8) 6.1 (9) 6.1 (10) 6.8 (11) 3.8 (12) 4.5 (13) 3.8 (14) 3.8 (15) 3.0 (16) 1.5 (17) 3 (18) 4.5 (19) 1.5 (20) 0.7 (21) 3 (22) 0.7 (23) 3.8 (24) 3.8 (25) 3 (26) 1.5
	I4: fluoxetine 60 mg	131	(1) headache (2) nervousness (3) diarrhoea (4) nausea (5) asthenia (6) rhinitis (7) somnolence (8) dry mouth (9) insomnia (10) injection (11) anxiety (12) dyspepsia (13) dysmenorrhoea (14) sweating (15) abdominal pain (16) pain (17) dizziness (18) pharyngitis (19) rash (20) back pain (21) sinusitis (22) myalgia (23) flu syndrome (24) constipation (25) decreased libido	(1) 34 (2) 18 (3) 13 (4) 15 (5) 15 (6) 7 (7) 12 (8) 6 (9) 8 (10) 2 (11) 5 (12) 6 (13) 3 (14) 8 (15) 5 (16) 3 (17) 5 (18) 2 (19) 4 (20) 3 (21) 3 (22) 4 (23) 4 (24) 2 (25) 4	(1) 25.9 (2) 13.7 (3) 9.9 (4) 11.4 (5) 11.4 (6) 5.3 (7) 9.1 (8) 4.5 (9) 6.1 (10) 1.5 (11) 3.8 (12) 4.5 (13) 2.2 (14) 6.1 (15) 3.8 (16) 2.2 (17) 3.8 (18) 1.5 (19) 3 (20) 2.2 (21) 2.2 (22) 3 (23) 3 (24) 1.5 (25) 3
	C: placebo	131	(1) headache (2) nervousness (3) diarrhoea (4) nausea (5) asthenia (6) rhinitis (7) somnolence (8) dry mouth (9) insomnia (10) injection (11) anxiety (12) dyspepsia (13) dysmenorrhoea (14) sweating (15) abdominal pain (16) pain (17) dizziness (18) pharyngitis (19) rash (20) back pain (21) sinusitis (22) myalgia (23) flu syndrome (24) constipation (25) allergic reaction	(1) 32 (2) 15 (3) 9 (4) 11 (5) 6 (6) 9 (7) 5 (8) 5 (9) 5 (10) 8 (11) 7 (12) 3 (13) 5 (14) 3 (15) 2 (16) 5 (17) 4 (18) 2 (19) 3 (20) 3 (21) 6 (22) 4 (23) 1 (24) 1 (25) 2	(1) 24.4 (2) 11.4 (3) 6.8 (4) 8.3 (5) 4.5 (6) 6.8 (7) 3.8 (8) 3.8 (9) 3.8 (10) 6.1 (11) 5.3 (12) 2.2 (13) 3.8 (14) 2.2 (15) 1.5 (16) 3.8 (17) 3 (18) 1.5 (19) 2.2 (20) 2.2 (21) 4.5 (22) 3 (23) 0.7 (24) 0.7 (25) 1.5
Levine 1987	I: fluoxetine 60 mg	60	(1) nausea (2) asthenia (3) nervousness (4) excessive sweating (5) drowsiness (6) sinusitis (7) upper respiratory infection (8) headache (9) anxiety (10) dizziness/lightheadedness (11) insomnia (12) arthritis (13) dyspepsia (14) viral infection (15) tremor (16) diarrhoea (17) gastroenteritis (18) abdominal pain	(1) 15 (2) 14 (3) 7 (4) 7 (5) 6 (6) 6 (7) 6 (8) 5 (9) 4 (10) 4 (11) 4 (12) 3 (13) 3 (14) 3 (15) 3 (16) 1 (17) 1 (18) 1	(1) 25 (2) 23.3 (3) 11.6 (4) 11.6 (5) 10 (6) 10 (7) 10 (8) 8.3 (9) 6.6 (10) 6.6 (11) 6.6 (12) 5 (13) 5 (14) 5 (15) 5 (16) 1.6 (17) 1.6 (18) 1.6
Levine 1987	C: placebo	60	(1) nausea (2) asthenia (3) nervousness (4) excessive sweating (5) drowsiness (6) sinusitis (7) upper respiratory infection (8) headache (9) anxiety (10) dyspepsia (11) viral infection (12) diarrhoea (13) gastroenteritis (14) abdominal pain	(1) 7 (2) 2 (3) 2 (4) 5 (5) 1 (6) 2 (7) 6 (8) 4 (9) 5 (10) 1 (11) 2 (12) 5 (13) 7 (14) 3	(1) 11.6 (2) 3.3 (3) 3.3 (4) 8.3 (5) 1.6 (6) 3.3 (7) 10 (8) 6.6 (9) 8.3 (10) 1.6 (11) 3.3 (12) 8.3 (13) 11.6 (14) 5
— denotes not reported C: comparator; I: intervention.

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Appendix 14. Survey of trial investigators providing information on included trials

Trial ID	Date trial author contacted	Date trial author replied	Date trial author was asked for additional information (short summary)	Date trial author provided data (short summary)
Al‐Helli 2015	19 July 2018	No answer	NA	NA
Suplicy 2014	04 September 2017	18 September 2017	02 August 2016 and 03 September 2017 (How was the randomisation technique performed for participants?	04 September 2017 (Patients were consecutively randomized by choosing a paper identified with the number of each study group)
Guimaraes 2006	13 May 2017	No answer	NA	NA
Bondi 2000	09 May 2017	No answer	NA	NA
Huang 1998	03 September 2017	No answer	NA	NA
Bross 1995	13 May 2017	No answer	NA	NA
Fernández‐Soto 1995	13 May 2017	No answer	NA	NA
Lawton 1995	03 September 2017	No answer	NA	NA
Goldstein 1994	13 May 2017	No answer	NA	NA
Goldstein 1993	13 May 2017	No answer	NA	NA
Pedrinola 1993	03 August 2016 and 03 September 2017	05 September 2017	03 August 2016 and 03 September 2017 (How was the randomisation and blindness performed for participants?)	05 September 2017 (both groups included patients randomly selected from out outpatient clinic; patients were allocated to each group without previous selection; the personnel of the hospital were blind and there was no blinding of outcome of assessment)
Visser 1993	03 September 2017	04 September	03 September 2017 (How was the randomisation and blindness performed for participants?)	04 September 2017 (the randomisation was performed by a third party, but I believe that participants were given a number in the order of the date and time of their baseline assessment. That number corresponded with a code which was indicated on the pill bottles; participants and researchers were blinded for all outcomes)
Wurtman 1993	03 September 2017	No answer	NA	NA
Kopelman 1992	03 August 2016 and 03 September 2017	No answer	NA	NA
Stinson 1992	03 September 2017	No answer	NA	NA
Bagiella 1991	09 May 2017	No answer	NA	NA
Pijl 1991	03 September 2017	06 September 2017	03 September 2017 (How was the randomisation technique of the participants and how was the allocation concealment performed?)	06 September 2017 (the randomisation was performed by a computer random sequence generator; treatments were allocated in order of inclusion/study number; which were provided by the pharmacy to the study staff in similar capsules)
Levine 1989	05 August 2016	No answer	NA	NA
Levine 1987	05 August 2016	No answer	NA	NA
C: comparator; I: intervention; NA: not applicable.

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Appendix 15. Health‐related quality of life: instruments

Instrument	Dimensions (subscales) (no. of items)	Validated instrument	Answer options	Scores	Minimum score Maximum score	Weighting of scores	Direction of scales	Minimal important difference
Short‐Form Health Survey (SF‐36) Employed in: Suplicy 2014	Physical functioning (10 items) Role limitations due to physical problems (4 items) Social functioning (2 items) Bodily pain (2 items) General mental health (5 items) Role limitations due to emotional problems (3 items) Vitality (4 items) General health perceptions (5 items)	Yes	1, 3, 6‐11 items Likert scale	Scores for dimensions: Physical component summary (PCS) Mental component summary (MCS)	Minimum scores: Scores for dimensions/PCS/MCS: norm‐based scale Maximum scores: scores for dimensions/PCS/MCS: norm‐based scale	No	Higher values mean better assessment	PCS: 2 to 3 points MCS: 3 points Dimensions: PF/BT/VT: 2 points, if score < 40; 3 points, if score ≥ 40 RP: 2 points SF/MH: 3 points RE: 4 points
Impact of Weight on Quality of Life (IWQOL‐LITE) Employed in: Suplicy 2014	Health (14 items) Social/interpersonal (11 items) Work (7 items) Mobility (10 items) Self‐esteem (10 items) Sexual life (6 items) Activities of daily living (7 items) Comfort with food (9 items)	Yes	Likert scale	Health Social/interpersonal Work Mobility Self‐esteem Sexual life Activities of daily living Comfort with food	Health (14 to 70) Social/interpersonal (11 to 55) Work (7 to 35) Mobility (10 to 50) Self‐esteem (10 to 50) Sexual life (6 to 30) Activities of daily living (7 to 35) Comfort with food (9 to 45)	No	Higher values mean better quality of life	—
G: generic; S: specific; SF: short‐form health survey.

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Data and analyses

Comparison 1. Fluoxetine versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Weight loss (end of trial weight)	10		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.1.1 Fluoxetine 60 mg/d	7	819	Mean Difference (IV, Random, 95% CI)	‐2.50 [‐3.78, ‐1.22]
1.1.2 Fluoxetine 40 mg/d	2	182	Mean Difference (IV, Random, 95% CI)	‐3.97 [‐8.75, 0.81]
1.1.3 Fluoxetine 20 mg/d	3	279	Mean Difference (IV, Random, 95% CI)	‐1.50 [‐3.53, 0.54]
1.2 Weight loss (duration of intervention)	8	1466	Mean Difference (IV, Random, 95% CI)	‐2.72 [‐3.73, ‐1.71]
1.2.1 0 to 3 months	5	366	Mean Difference (IV, Random, 95% CI)	‐3.34 [‐3.93, ‐2.76]
1.2.2 4 to 6 months	2	453	Mean Difference (IV, Random, 95% CI)	‐2.75 [‐3.91, ‐1.59]
1.2.3 7 to 12 months	2	647	Mean Difference (IV, Random, 95% CI)	‐1.34 [‐5.71, 3.03]
1.3 Weight loss (cross‐over trial)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.4 Any adverse event	9	1253	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.99, 1.42]
1.5 Specific adverse events	9		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.5.1 Abdominal pain	5	504	Risk Ratio (M‐H, Random, 95% CI)	1.51 [0.58, 3.90]
1.5.2 Allergy	3	780	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.03, 0.98]
1.5.3 Amnesia	1	458	Risk Ratio (M‐H, Random, 95% CI)	12.89 [0.73, 227.44]
1.5.4 Anorexia	1	19	Risk Ratio (M‐H, Random, 95% CI)	8.89 [1.36, 57.89]
1.5.5 Anxiety	7	1210	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.56, 2.03]
1.5.6 Constipation	3	381	Risk Ratio (M‐H, Random, 95% CI)	2.83 [0.58, 13.90]
1.5.7 Diarrhoea	7	1191	Risk Ratio (M‐H, Random, 95% CI)	1.44 [0.97, 2.13]
1.5.8 Dizziness	5	693	Risk Ratio (M‐H, Random, 95% CI)	2.40 [1.03, 5.60]
1.5.9 Drowsiness	9	1253	Risk Ratio (M‐H, Random, 95% CI)	2.67 [1.68, 4.24]
1.5.10 Dry mouth	6	896	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.66, 2.30]
1.5.11 Dyspepsia	4	501	Risk Ratio (M‐H, Random, 95% CI)	1.99 [0.71, 5.55]
1.5.12 Fatigue	5	1112	Risk Ratio (M‐H, Random, 95% CI)	2.50 [1.62, 3.85]
1.5.13 Headache	8	1234	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.94, 1.47]
1.5.14 Insomnia	7	1191	Risk Ratio (M‐H, Random, 95% CI)	2.23 [1.22, 4.08]
1.5.15 Irritability	3	442	Risk Ratio (M‐H, Random, 95% CI)	1.41 [0.63, 3.15]
1.5.16 Malaise	2	322	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.15, 2.46]
1.5.17 Nausea	7	1016	Risk Ratio (M‐H, Random, 95% CI)	1.99 [1.35, 2.91]
1.5.18 Palpitation	1	60	Risk Ratio (M‐H, Random, 95% CI)	2.81 [0.12, 66.40]
1.5.19 Rhinitis	3	933	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.75, 1.30]
1.6 Participants with any adverse event (per dose)	9		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.6.1 Fluoxetine 60 mg/d	7	1134	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.93, 1.44]
1.6.2 Fluoxetine 40 mg/d	1	262	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.93, 1.24]
1.6.3 Fluoxetine 20 mg/d	4	592	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.92, 1.31]
1.6.4 Fluoxetine 10 mg/d	1	262	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.82, 1.12]
1.7 Participants with any adverse event (duration of intervention)	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.7.1 0 to 3 months	4	444	Risk Ratio (M‐H, Random, 95% CI)	1.71 [0.87, 3.33]
1.7.2 4 to 6 months	2	477	Risk Ratio (M‐H, Random, 95% CI)	2.51 [0.27, 23.63]
1.7.3 7 to 12 months	1	213	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.54, 1.69]
1.8 Participants discontinuing due to adverse events	8	1188	Risk Ratio (M‐H, Random, 95% CI)	1.88 [0.87, 4.06]
1.9 Anthropometric measurements other than weight loss (BMI)	3	97	Mean Difference (IV, Random, 95% CI)	‐1.11 [‐3.66, 1.43]
1.9.1 Fluoxetine 60 mg/d	1	19	Mean Difference (IV, Random, 95% CI)	‐3.30 [‐7.25, 0.65]
1.9.2 Fluoxetine 40 mg/d	1	18	Mean Difference (IV, Random, 95% CI)	‐2.80 [‐8.71, 3.11]
1.9.3 Fluoxetine 20 mg/d	1	60	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.60, 1.00]
1.10 Morbidity (depression)	3	393	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.57, 2.52]
1.11 Morbidity (depression per dose)	3	604	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.52, 1.73]
1.11.1 Fluoxetine 60 mg/d	2	333	Risk Ratio (M‐H, Random, 95% CI)	1.41 [0.53, 3.79]
1.11.2 Fluoxetine 20 mg/d	2	271	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.23, 1.48]

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Comparison 2. Fluoxetine versus another anti‐obesity agent.

Outcome or subgroup title	No. of studies	Statistical method	Effect size
2.1 Weight loss, end of trial weight	3	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.1.1 Fluoxetine 60 mg/d vs. sibutramine	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.1.2 Fluoxetine 60 mg/d vs. metformin	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.1.3 Fluoxetine 20 mg/d vs. sibutramine	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.1.4 Fluoxetine 20 mg/d vs. dexfenfluramine	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.1.5 Fluoxetine 20 mg/d vs. diethylpropion	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.1.6 Fluoxetine 20 mg/d vs. fenproporex	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.1.7 Fluoxetine 20 mg/d vs. mazindol	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.2 Any adverse event	3	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.2.1 Fluoxetine 60 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.2.2 Fluoxetine 60 mg/d vs. metformin	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.2.3 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.2.4 Fluoxetine 20 mg/d vs. dexfenfluramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.2.5 Fluoxetine 20 mg/d vs diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.2.6 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.2.7 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3 Adverse events (abdominal pain)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.1 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.2 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.3 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.4 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4 Adverse events (allergy)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.1 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.2 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.3 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.4 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.5 Adverse events (anorexia)	2	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.5.1 Fluoxetine 60 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.5.2 Fluoxetine 60 mg/d vs. metformin	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.5.3 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.5.4 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.5.5 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.5.6 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.6 Adverse events (anxiety)	2	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.6.1 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.6.2 Fluoxetine 20 mg/d vs. dexfenfluramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.6.3 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.6.4 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.6.5 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.7 Adverse events (constipation)	3	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.7.1 Fluoxetine 60 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.7.2 Fluoxetine 60 mg/d vs. metformin	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.7.3 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.7.4 Fluoxetine 20 mg/d vs. dexfenfluramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.7.5 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.7.6 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.7.7 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.8 Adverse events (diarrhoea)	3	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.8.1 Fluoxetine 60 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.8.2 Fluoxetine 60 mg/d vs. metformin	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.8.3 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.8.4 Fluoxetine 20 mg/d vs. dexfenfluramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.8.5 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.8.6 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.8.7 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.9 Adverse events (dizziness)	2	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.9.1 Fluoxetine 60 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.9.2 Fluoxetine 60 mg/d vs. metformin	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.9.3 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.9.4 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.9.5 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.9.6 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.10 Adverse events (drowsiness)	3	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.10.1 Fluoxetine 60 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.10.2 Fluoxetine 60 mg/d vs. metformin	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.10.3 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.10.4 Fluoxetine 20 mg/d vs. dexfenfluramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.10.5 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.10.6 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.10.7 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.11 Adverse events (dry mouth)	3	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.11.1 Fluoxetine 60 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.11.2 Fluoxetine 60 mg/d vs. metformin	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.11.3 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.11.4 Fluoxetine 20 mg/d vs. dexfenfluramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.11.5 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.11.6 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.11.7 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.12 Adverse events (dyspepsia)	2	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.12.1 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.12.2 Fluoxetine 20 mg/d vs. dexfenfluramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.12.3 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.12.4 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.12.5 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.13 Adverse events (fatigue)	2	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.13.1 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.13.2 Fluoxetine 20 mg/d vs. dexfenfluramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.13.3 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.13.4 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.13.5 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.14 Adverse events (headache)	3	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.14.1 Fluoxetine 60 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.14.2 Fluoxetine 60 mg/d vs. metformin	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.14.3 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.14.4 Fluoxetine 20 mg/d vs. dexfenfluramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.14.5 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.14.6 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.14.7 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.15 Adverse events (insomnia)	3	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.15.1 Fluoxetine 60 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.15.2 Fluoxetine 60 mg/d vs. metformin	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.15.3 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.15.4 Fluoxetine 20 mg/d vs. dexfenfluramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.15.5 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.15.6 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.15.7 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.16 Adverse events (irritability)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.16.1 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.16.2 Fluoxetine 20 mg/d vs diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.16.3 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.16.4 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17 Adverse events (malaise)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.1 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.2 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.3 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.4 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.18 Adverse events (nausea)	3	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.18.1 Fluoxetine 60 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.18.2 Fluoxetine 60 mg/d vs. metformin	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.18.3 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.18.4 Fluoxetine 20 mg/d vs. dexfenfluramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.18.5 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.18.6 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.18.7 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.19 Adverse events (palpitation)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.19.1 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.19.2 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.19.3 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.19.4 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.20 Adverse events (sweating)	2	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.20.1 Fluoxetine 60 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.20.2 Fluoxetine 60 mg/d vs. metformin	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.20.3 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.20.4 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.20.5 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.20.6 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.21 Adverse events (tremor)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.21.1 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.21.2 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.21.3 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.21.4 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.22 Anthropometric measurements other than weight loss in kg (BMI)	2	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.22.1 Fluoxetine 60 mg/d vs. sibutramine	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.22.2 Fluoxetine 60 mg/d vs. metformin	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.22.3 Fluoxetine 20 mg/d vs. sibutramine	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.22.4 Fluoxetine 20 mg/d vs. diethylpropion	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.22.5 Fluoxetine 20 mg/d vs. fenproporex	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.22.6 Fluoxetine 20 mg/d vs. mazindol	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.23 Morbidity (depression)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.23.1 Fluoxetine 20 mg/d vs. sibutramine	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.23.2 Fluoxetine 20 mg/d vs. diethylpropion	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.23.3 Fluoxetine 20 mg/d vs. fenproporex	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.23.4 Fluoxetine 20 mg/d vs. mazindol	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

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Comparison 3. Fluoxetine versus no treatment.

Outcome or subgroup title	No. of studies	Statistical method	Effect size
3.1 Weight loss	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.2 Adverse events	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.2.1 Any event	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.2.2 Allergy	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.2.3 Anorexia	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.2.4 Diarrhoea	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.2.5 Headache	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.2.6 Insomnia	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.2.7 Malaise	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.2.8 Nauseas	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.2.9 Drowsiness	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.3 Anthropometric measurements other than weight loss in kg (BMI)	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Al‐Helli 2015.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1:1:1)
Participants	Inclusion criteria: obese subjects (males & females) 18 to 40 years old with BMI ≥ 30 kg/m² Exclusion criteria: not reported Diagnostic criteria: BMI Setting: obesity research and treatment centre/Al‐Kindy medical college Gender distribution: females & males Country/countries where trial was performed: Iraq
Interventions	Interventions: I1: experimental group A (EGA): fluoxetine 20 mg orally, once a day for 2 months I2: experimental group B (EGB): omega‐3 gel (1000 mg) orally twice a day for 2 months I3: experimental group C (EGC): fluoxetine 20 mg plus omega‐3 gel (1000 mg) orally daily for 2 months Comparator: 4. Control group (CG): placebo orally once daily for 2 months Cointervention: not reported Duration of intervention: 2 months Duration of follow‐up: 2 months Run‐in period: no Number of study centres: 1 Treatment before study: no Titration period: no Treatment duration: 2 months
Outcomes	BMI, serum lipids: total cholesterol, low‐density‐lipoprotein cholesterol, high‐density‐lipoprotein cholesterol, triglycerides, fasting blood glucose, malondialdehyde, leptin
Study registration	Trial identifier: — Trial terminated early (for benefit/because of adverse events): no
Publication details	Language of publication: English Commercial funding: not reported Publication status: full article
Stated aim for study	Quote from publication: "… study the effects of fluoxetine and omega3 drugs alone or their combination on BMI, casting blood glucose, lipid profile, liver enzymes (ALT, AST), Malondiadehyde (MDA), and leptin”
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "… they were randomly allocated" (page 91) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "… they were randomly allocated" (page 91) Comment: insufficient information
Blinding of participants and personnel (performance bias) anthropometric measurements other than weight loss	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) anthropometric measurements other than weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) anthropometric measurements other than weight loss	Low risk	Comment: no missing data for primary outcome
Selective reporting (reporting bias)	High risk	Comment: anthropometric measurements other than weight loss (BMI) were analysed but only reports that results were not significant (see Appendix 9)
Other bias	Low risk	Comment: no other potential source of bias.

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Bagiella 1991.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: obese adult individuals (body mass index ranging between 30 kg/m² to 40 kg/m²) Exclusion criteria: no data Diagnostic criteria: BMI Setting: Istituto di Terapia Medica Sistematica Univeristà "La Sapienza" Gender distribution: females & males Country/countries where trial was performed: Italy
Interventions	Interventions: I1: experimental group A (EGA): fenfluramine 20 mg orally, every 8 hours for 12 weeks I2: experimental group B (EGB): 5‐hydroxy‐tryptophan 300 mg orally, every 8 hours for 12 weeks I3: experimental group C (EGC): d‐ fenfluramine 15 mg orally, twice per day for 12 weeks I4: experimental group D (EGD): fluoxetine 20 mg orally, every 8 hours for 12 weeks I5: experimental group E (EGE): fluvoxamine 50 mg orally, every 8 hours for 12 weeks Comparator: 6. Control group (CG): placebo 1 capsule orally, 2 or 3 times per day for 12 weeks Cointervention: 2 consecutive 6 week periods: during first period no diet restriction, whereas during second period a 5016 kJ diet was prescribed Duration of intervention: 12 weeks Duration of follow‐up: 12 weeks Run‐in period: 20 days Number of study centres: 1 Treatment before study: none Titration period: no Treatment duration: 12 weeks
Outcomes	Questionnaire, divided into 4 sections, intended to evaluate the cognitive and critical, behavioral, and cognitive aspects of the patient's dietary habits
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: non‐funding Publication status: full article
Stated aim for study	Quote from publication: “To evaluate the modifications in attitude toward food intake produced by treatment”
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: none specified 3. Outcome measures: changes in attitude toward food (questionnaires for dietary habits)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "… individuals were assigned at random to six treatment groups” (page 206) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "… individuals were assigned at random to six treatment groups” (page 206) Comment: insufficient information
Selective reporting (reporting bias)	Low risk	Comment: all the outcomes listed in the Method section described in results
Other bias	Low risk	Comment: no other potential source of bias

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Bondi 2000.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 2:3:3)
Participants	Inclusion criteria: obese but otherwise healthy menopausal women, did not achieve a significant weight change during previous 6 months with diet therapy alone, did not take appetite suppressant medications or drugs Exclusion criteria: diagnosis of depression or Beck inventory questionnaire score ≥ 18 Diagnostic criteria: BMI Setting: Università di Modena Gender distribution: females Country/countries where trial was performed: Italy
Interventions	Interventions: I1: experimental group A (EGA): fluoxetine 40 mg orally, single doses (acute study) I2: experimental group B (EGB): fluoxetine 40 mg (before breakfast) and 20 mg (before lunch), for 12 weeks (chronic study) Comparator: 3. Control group (CG): placebo orally for 12 weeks (chronic study) Cointervention: EGB and CG: Diet (55%‒20%‒25%), caloric deficit of 500 kcal/d of 70% energy expenditure by indirect calorimetry Duration of intervention: 12 weeks Duration of follow‐up: 12 weeks Run‐in period: 1 day Number of study centres: 1 Treatment before study: diet Titration period: no Treatment duration: 12 weeks
Outcomes	Compliance by pill count, resting respiratory quotient, resting energy expenditure, fasting blood glucose, plasma insulin
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: non funding Publication status: full article
Stated aim for study	Quote from publication: “Investigate the metabolic effects of fluoxetine both after acute administration and during chronic therapy on glucose‐induced thermogenesis and weight loss in obese individuals”
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: none specified
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "... participants were randomly assigned ..." (page 281) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "It was a double‐blind, placebo‐controlled design ..." (page 280) Comment: insufficient information
Blinding of participants and personnel (performance bias) weight loss	Low risk	Quote from publication: "It was a double‐blind, placebo‐controlled design ..." (page 280)
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) weight loss	Low risk	Comment: no missing data for primary outcome
Selective reporting (reporting bias)	Low risk	Comment: all the outcomes listed in the method section described in results
Other bias	Low risk	Comment: no other potential source of bias

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Bross 1995.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1)
Participants	Inclusion criteria: non‐depressed obese women, but otherwise healthy, non‐smokers who had maintained a stable body weight for several months and had taken no medication in recent weeks Exclusion criteria: hypertension, diabetes, or any other endocrine or significant medical condition Diagnostic criteria: BMI Setting: Clinical Investigation Unit of the Royal Victoria Hospital Gender distribution: females Country/countries where trial was performed: Canada
Interventions	Country centre: USA Interventions: 1. Experimental group (EG): fluoxetine 60 mg orally, once per day for 3 weeks Comparator: 2. Control group (CG): placebo orally, once per day for 3 weeks Cointervention: formula diet (420 kcal including 70 g protein/d and ≥ 100% RDA vitamins and minerals) Duration of intervention: 3 weeks Duration of follow‐up: 3 weeks Run‐in period: 4 to 5 days, liquid formula diet (Ensure with added polycose glucose polymer to provide 150% of basal energy expenditure and 80 g protein) Number of study centres: 1 Treatment before study: no Titration period: no Treatment duration: 3 weeks
Outcomes	Body weight, resting energy expenditure, O₂ consumption, CO₂ production, thermic effect, urinary norepinephrine excretion, normetanephrine excretion, serum triiodothyronine and thyroxine, nitrogen balance, urinary sodium and potassium, basal body temperature, adverse events
Study registration	Trial identifier:Scinet (Science and Technology Information web page) Trial terminated early: no
Publication details	Language of publication: English Commercial funding: grant from Lilly Research Laboratories. Authors received partial support from Fonds pour la Formation de chercheurs et l'aide à la recherche Publication status: full article
Stated aim for study	Quote from publication: "Determine whether increased energy expenditure contributes to this weight loss."
Notes	1. A priori sample size estimation: yes 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "... they were randomly assigned to …" (page 1020) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "... they were randomly assigned to …" (page 1020) Comment: insufficient information
Blinding of participants and personnel (performance bias) weight loss	Low risk	Quote from publication: "... in double blind fashion …" (page 1020)
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) weight loss	Low risk	Comment: no missing data for primary outcome
Selective reporting (reporting bias)	Low risk	Comment: all the outcomes listed in the method section described in results
Other bias	Unclear risk	Comment: this study was funding by Lilly Research Laboratories

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Fernández‐Soto 1995.

*Study characteristics*
Methods	Study design: cross‐over RCT (randomisation ratio 1:1)
Participants	Inclusion criteria: women with obesity Exclusion criteria: not reported Diagnostic criteria: BMI Setting: hospital Gender distribution: females Country/countries where trial was performed: Spain
Interventions	Interventions: 1. Experimental group (EG): fluoxetine 60 mg orally, once per day for 3 months Comparator: 2. Control group (CG): placebo orally, once per day for 3 months Cointervention: diet 1200 kcal which maintained throughout the study, 2‐3 L/d no caloric liquids, vitamins, minerals and trace elements covered the requirements FDA and psychotherapy Duration of intervention: 6 months Duration of follow‐up: 7 months Run‐in period: no Number of study centres: 1 Treatment before study: no Titration period: no Treatment duration: 3 months each and 4 weeks washout period
Outcomes	Weight, pulse, count of unused medication, patients' report of medical problems, adverse events, glucose, urea, uric acid, creatinine, ions, total cholesterol, triglycerides, HDL‐cholesterol
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: not reported Publication status: full article
Stated aim for study	Quote from publication: "Assesing the efficacy and safety of fluoxetine as compared with placebo in the treatment of obesity"
Notes	1. A priori sample size estimation: no 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: “The participants were randomly assigned to two groups …" (page 160) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: “The participants were randomly assigned to two groups …" (page 160) Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	Low risk	Quote from publication: "... using a double blind crossover study ..." (page 160)
Blinding of participants and personnel (performance bias) weight loss	Low risk	Quote from publication: "... using a double blind crossover study ..." (page 160)
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) adverse events	Low risk	Quote from publication: "By the end of the 7 months 5 participants in group A and 4 in group B had been withdrawn from the study" (page 161) Comment: data for primary outcome available for 78% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) weight loss	Low risk	Quote from publication: "By the end of the 7 months 5 participants in group A and 4 in group B had been withdrawn from the study" (page 161) Comment: data for primary outcome available for 78% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: all the outcomes listed in the Method section described in results
Other bias	Low risk	Comment: cross‐over design; appropriate design; order of receiving treatments randomised; no carry‐over effects; no unbiased data available

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Goldstein 1993.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1:1), superiority design
Participants	Inclusion criteria: individuals were at least 18 years, BMI 30 kg/m² to 39 kg/m², women were neither pregnant nor lactating, had not used an appetite suppressant nor monoamine oxidase inhibitor within 2 weeks of starting the study nor other antidepressant drugs or lithium within 1 week of starting the study Exclusion criteria: non‐responders in qualification phase Diagnostic criteria: BMI, responders in qualification phase Setting: — Gender distribution: females & males Country/countries where trial was performed: USA
Interventions	Interventions: I1. Experimental group A (EGA): fluoxetine 60 mg orally, once per day for 40 weeks I2. Experimental group B (EGB): fluoxetine 20 mg orally, once per day for 40 weeks Comparator: 3. Control group (CG): placebo orally, once per day for 40 weeks Cointervention: advised to reduce their overall caloric consumption and were offered a diet to lose 0.45 kg per week. Counselling about nutrition and behavior change varied among sites Duration of intervention: 40 weeks Duration of follow‐up: 40 weeks Run‐in period: 9 weeks (1 week with placebo + 8 weeks of qualification phase, single‐blind fluoxetine 60 mg/d) Number of study centres: 6 Treatment before study: fluoxetine 60 mg orally, once per day for 8 weeks (qualification phase) Titration period: no Treatment duration: 48 weeks
Outcomes	BP (sitting), pulse rate, oral temperature, carbohydrate craving scores, adverse events, urinalysis and blood chemistry, haematology
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: not reported Publication status: full article
Stated aim for study	Quote from publication: "Compare the effects of the specific serotonin uptake inhibitor, fluoxetine hydrochloride and placebo on maintenance of weight loss..."
Notes	1. A priori sample size estimation: no 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "… were randomly assigned to …" (page 94) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "… were randomly assigned to …" (page 94) Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	Low risk	Quote from publication: "… to double blind therapy ..." (page 94)
Blinding of participants and personnel (performance bias) morbidity	Low risk	Quote from publication: "… to double blind therapy ..." (page 94)
Blinding of participants and personnel (performance bias) weight loss	Low risk	Quote from publication: "… to double blind therapy ..." (page 94)
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) morbidity	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) adverse events	High risk	Quote from publication: "... 115 participants failed to complete the study" (page 95) Comment: data available for 56.6% group fluoxetine 60 mg, 67.3% fluoxetine 20 mg and 67.3% placebo group
Incomplete outcome data (attrition bias) morbidity	High risk	Quote from publication: "... 115 participants failed to complete the study" (page 95) Comment: data available for 56.6% group fluoxetine 60 mg, 67.3% fluoxetine 20 mg and 67.3% placebo group
Incomplete outcome data (attrition bias) weight loss	High risk	Quote from publication: "... 115 participants failed to complete the study". (page 95) Comment: data available for 56.6% group fluoxetine 60 mg, 67.3% fluoxetine 20 mg and 67.3% placebo group
Selective reporting (reporting bias)	High risk	Comment: weight loss and morbidity outcomes were analysed but their results were not reported
Other bias	Low risk	Comment: no other potential source of bias.

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Goldstein 1994.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1)
Participants	Inclusion criteria: at least 18 years of age and had a BMI of at least 25 kg/m² Exclusion criteria: women pregnant or lactating. Participants had used an appetite suppressant within 2 weeks of starting the study Diagnostic criteria: BMI Setting: multi‐centre Gender distribution: females & males Country/countries where trial was performed: USA
Interventions	Invervention: 1. Experimental group (EG): fluoxetine 60 mg orally, once per day for 52 weeks Comparator: 2. Control group (CG): placebo orally, once per day for 52 weeks Cointervention: diet with caloric intake designed to produce a weight loss of 0.45 kg per week Duration of intervention: 52 weeks Duration of follow‐up: 52 weeks Run‐in period: 1 week Number of study centres: 10 Treatment before study: no Titration period: no Treatment duration: 52 weeks
Outcomes	Weight loss, adverse events, BP (sitting), heart rate, oral temperature, blood chemistry, haematology and urinalysis, compliance (capsule record cards)
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: sponsored by Lilly Research Laboratories. Publication status: full article
Stated aim for study	Quote from publication: “... evaluate the effectiveness of fluoxetine in producing weight loss.”
Notes	1. A priori sample size estimation: no 2. Conflict of interest: not specified
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "… participants were randomly assigned ..." (page 130) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "… participants were randomly assigned ..." (page 130) Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	Unclear risk	Quote from publication: "The participants, observers, study personnel and sponsor were blinded to the treatment assignments" (page 130) Comment: insufficient information
Blinding of participants and personnel (performance bias) anthropometric measurements other than weight loss	Unclear risk	Quote from publication: "The participants, observers, study personnel and sponsor were blinded to the treatment assignments" (page 130) Comment: insufficient information
Blinding of participants and personnel (performance bias) weight loss	Unclear risk	Quote from publication: "The participants, observers, study personnel and sponsor were blinded to the treatment assignments" (page 130) Comment: insufficient information
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Quote from publication: "The participants, observers, study personnel and sponsor were blinded to the treatment assignments" (page 130) Comment: insufficient information
Blinding of outcome assessment (detection bias) anthropometric measurements other than weight loss	Unclear risk	Quote from publication: "The participants, observers, study personnel and sponsor were blinded to the treatment assignments" (page 130) Comment: insufficient information
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Quote from publication: "The participants, observers, study personnel and sponsor were blinded to the treatment assignments" (page 130) Comment: insufficient information
Incomplete outcome data (attrition bias) adverse events	High risk	Quote from publication: "... individuals who completed the study were similar for the fluoxetine (N = 99) and placebo (N = 108) ..." (page 132) Comment: data for primary outcome available for 50.7% of the randomised sample
Incomplete outcome data (attrition bias) anthropometric measurements other than weight loss	High risk	Quote from publication: "... participants who completed the study were similar for the fluoxetine (N = 99) and placebo (N = 108) ..." (page 132) Comment: data for primary outcome available for 50.7% of the randomised sample
Incomplete outcome data (attrition bias) weight loss	High risk	Quote from publication: "... participants who completed the study were similar for the fluoxetine (N = 99) and placebo (N = 108) ..." (page 132) Comment: data for primary outcome available for 50.7% of the randomised sample
Selective reporting (reporting bias)	High risk	Comment: anthropometric measurements other than weight loss outcomes were analysed but only reports that results were not significant (see Appendix 9)
Other bias	Unclear risk	Comment: this trial was sponsored by Lilly Research Laboratories

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Guimaraes 2006.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1:1:1)
Participants	Inclusion criteria: BMI > 30 kg/m² Exclusion criteria: alcoholic, diabetes, pregnant and nursing women, acquired immunodeficiency and those with viral liver infection Diagnostic criteria: BMI Setting: University of Riberao Preto Gender distribution: females & males Country/countries where trial was performed: Brazil
Interventions	Interventions: I1. Experimental group A (EGA): sibutramine 15 mg orally for 90 days I2. Experimental group B (EGB): metformin 1700 mg orally for 90 days I3. Experimental group C (EGC): fluoxetine 60 mg orally for 90 days Comparator: 4. Control group (CG): placebo orally for 90 days Cointervention: dietary re‐education containing on average 1500 kcal/d Duration of intervention: 90 days Duration of follow‐up: 90 days Run‐in period: 6 months Number of study centres: 1 Treatment before study: dietary reeducation for 6 months Titration period: no Treatment duration: 90 days
Outcomes	BMI, weight, abdominal circumference, % fatty tissue, HDL‐cholesterol, triglycerides, systolic and diastolic BP, adverse events, HOMA, insulin, glycaemia
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Other funding: Faculty of Pharmaceutical Sciences of Riberao Preto, University of Sao Paulo and CAPES Publication status: full article
Stated aim for study	Quote from publication: "Assess the effects of sibutramine, fluoxetine and metformin as an adjunct therapy to a 1500 kcal/d diet in reducing anthropometric and metabolic parameters"
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "This study was randomized ..." (page 1021) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "This study was randomized ..." (page 1021) Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	High risk	Quote from publication: "This study was randomized and single blind" (page 1021) Comment: outcome measure likely influenced by lack of blinding for either participant or study personnel
Blinding of participants and personnel (performance bias) anthropometric measurements other than weight loss	High risk	Quote from publication: "This study was randomized and single blind" (page 1021) Comment: outcome measure likely influenced by lack of blinding for either participant or study personnel
Blinding of participants and personnel (performance bias) weight loss	High risk	Quote from publication: "This study was randomized and single blind" (page 1021) Comment: outcome measure likely influenced by lack of blinding for either participant or study personnel
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) anthropometric measurements other than weight loss	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) adverse events	Low risk	Comment: no missing data for primary outcome
Incomplete outcome data (attrition bias) anthropometric measurements other than weight loss	Low risk	Comment: no missing data for primary outcome
Incomplete outcome data (attrition bias) weight loss	Low risk	Comment: no missing data for primary outcome
Selective reporting (reporting bias)	High risk	Comment: adverse events were analysed but no results reported (see Appendix 9)
Other bias	Low risk	Comment: no other potential source of bias

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Huang 1998.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1)
Participants	Inclusion criteria: either sex, between 17 and 65 years old, who demonstrated no significant clinical problems other than moderate obesity (30% over the ideal body weight according Huang's formula) Exclusion criteria: individuals using antidepressants, monoamine oxidase inhibitors, neuroleptics and anti epileptics, chronic alcoholism and individuals who were suspected to be non‐compliant with treatment Diagnostic criteria: obese moderate (130% of IBW) Setting: hospital Gender distribution: females & males Country/countries where trial was performed: Republic of China
Interventions	Interventions: 1. Experimental group (EG): fluoxetine 60 mg orally, once per day for 12 weeks Comparator: 2. Control group (CG): no treatment Cointervention: participants were instructed to follow a weight‐reducing low calorie diet ([25‐35 kcal/d adjusted to work load * ideal body weight ‐ 500 kcal]. The energy distribution of the diet consisted of 50% carbohydrates, 20% protein and 30% fat. Duration of intervention: 12 weeks Duration of follow‐up: 12 weeks Run‐in period: no Number of study centres: 1 Treatment before study: no Titration period: no Treatment duration: 12 weeks
Outcomes	Body weight, BMI, BP, fasting blood sugar, triglycerides, total cholesterol, uric acid, glutamic pyruvic transaminase (GPT), alkaline phosphatase (AP), adverse events
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: not reported Publication status: full article
Stated aim for study	Quote from publication: "Assess the possible weight‐reducing effects of fluoxetine in obese Taiwanese"
Notes	1. A priori sample size estimation: no reported 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "All participants were randomized to receive ...” (page 50) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "All participants were randomized to receive ...” (page 50) Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	High risk	Comment: the experimental group received the intervention, while the control group did not receive any intervention
Blinding of participants and personnel (performance bias) anthropometric measurements other than weight loss	High risk	Comment: the experimental group received the intervention, while the control group did not receive any intervention
Blinding of participants and personnel (performance bias) weight loss	High risk	Comment: the experimental group received the intervention, while the control group did not receive any intervention
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) anthropometric measurements other than weight loss	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) adverse events	Low risk	Quote from publication: "individuals who completed less than 4 weeks of the treatment were excluded from the efficacy analysis based on 50 participants" (page 51) Comment: data for primary outcome available for 83.3% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) anthropometric measurements other than weight loss	Low risk	Quote from publication: "individuals who completed less than 4 weeks of the treatment were excluded from the efficacy analysis based on 50 participants" (page 51) Comment: data for primary outcome available for 83.3% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) weight loss	Low risk	Quote from publication: "individuals who completed less than 4 weeks of the treatment were excluded from the efficacy analysis based on 50 participants" (page 51) Comment: data for primary outcome available for 83.3% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: all the outcomes listed in the Method section described in results
Other bias	Low risk	Comment: no other potential source of bias

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Kopelman 1992.

*Study characteristics*
Methods	Study design: cross‐over RCT
Participants	Inclusion criteria: extremely obese but asymptomatic, normal thyroid function and were not taking any regular medication at the time of the study Exclusion criteria: evidence on direct laryngoscopy of obstruction or narrowing of the pharynx or larynx. Diagnostic criteria: BMI Setting: hospital Gender distribution: females & males Country/countries where trial was performed: UK
Interventions	Intervention: 1. Experimental group (EG): fluoxetine 60 mg, orally per day for 3 days Comparator: 2. Control group (CG): placebo orally, once per day for 3 days Cointervention: none Duration of intervention: 3 days Duration of follow‐up: 5 weeks Run‐in period: no Number of study centres: 1 Treatment before study: no, for any of the groups Titration period: not reported Treatment duration: 3 days and 4 weeks washout period
Outcomes	Sleep‐breathing patterns, weight loss, adverse events, BP, haematology, nocturnal arterial oxygen saturation, apnoea/hypopnoea index, total sleep time, qualitative assessment of sleep
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: not reported Publication status: full article
Stated aim for study	Quote from publication: "… whether the compound may have a role in the management of the obese hypoventilation syndrome and investigated this by evaluating the effect of three days treatment with fluoxetine on the sleep‐breathing patterns in extremely obese, but asymptomatic individuals."
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "… participants were assigned at random to one of two treatment schedules …" (page 826) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "… participants were assigned at random to one of two treatment schedules …" (page 826) Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	Low risk	Quote from publication: "A double‐blind cross‐over placebo‐drug trial was used to …" (page 826)
Blinding of participants and personnel (performance bias) weight loss	Low risk	Quote from publication: "A double‐blind cross‐over placebo‐drug trial was used to …" (page 826)
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) adverse events	Low risk	Comment: no missing data for primary outcome
Incomplete outcome data (attrition bias) weight loss	Low risk	Comment: no missing data for primary outcome
Selective reporting (reporting bias)	High risk	Comment: adverse events were analysed but only reports that results were not significant (see Appendix 9)
Other bias	Low risk	Comment: cross‐over design; appropriate design; unclear randomised order of receiving treatments; no carry‐over effects; no unbiased data available

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Lawton 1995.

*Study characteristics*
Methods	Study design: cross‐over RCT
Participants	Inclusion criteria: females, BMI > 30 kg/m², intent to diet or to restrict food intake (score > 12) Exclusion criteria: none Diagnostic criteria: BMI and intention to diet or to restrict food intake Setting: obesity clinic of the general infirmary Gender distribution: females Country/countries where trial was performed: UK
Interventions	Intervention: 1. Experimental group (EG): fluoxetine 60 mg orally, once per day for 2 weeks Comparator: 2. Control group (CG): placebo orally, once per day for 2 weeks Cointervention: diet: each treatment phase incorporated 2 separate test days on which the participant response to either a high carbohydrates or a high‐fat meal was assessed (days 7 and 14). Participants received these meals in a counterbalanced order. The order of presentation of these meals in the first treatment phase was swapped in the second treatment phase Duration of intervention: 2 weeks Duration of follow‐up: 8 weeks Run‐in period: "A 3‐day placebo run‐in period preceded each 14‐day treatment phase " (page 346) Number of study centres: 1 Treatment before study: no Titration period: no Treatment duration: 2 weeks each and 6 weeks washout period
Outcomes	Satiety, weight loss, adverse events, appetite, energy intake, macronutrient intake, motivational ratings (hunger), food intake preferences, post‐lunch meal palatability rating, blood and urine analyses, check of concomitant medication, resting pulse, BP
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: Lilly Research Laboratories Publication status: full article
Stated aim for study	Quote from publication: “Investigate the effect of 5‐HT stimulation on the capacity of high CHO and high‐fat foods to control appetite in obese individuals”.
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: not specified
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "… randomized cross over design" (page 346) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "the study medication was administered in the form of a kit specific to each participant. The kit number determined which medication ... the individual was to receive in each treatment phase" (page 346) Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	Low risk	Quote from publication: "The study conformed to a 2‐week double blind randomized cross over design with a minimum 6‐week washout and crossover period" (page 346)
Blinding of participants and personnel (performance bias) weight loss	Low risk	Quote from publication: "The study conformed to a 2‐week double blind randomized cross over design with a minimum 6‐week washout and crossover period" (page 346)
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) adverse events	Low risk	Quote from publication: "One participant failed to return after the second visit and decided to withdraw. Twelve evaluable participants completed the study." (page 346) Comment: data for primary outcome available for 92% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) weight loss	Low risk	Quote from publication: "One participant failed to return after the second visit and decided to withdraw. Twelve evaluable participants completed the study." (page 346) Comment: data for primary outcome available for 92% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: all the outcomes listed in the method section described in results
Other bias	Unclear risk	Comment: the trial was sponsored by Lilly Research Laboratories Comment: carry‐over effects unclear

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Levine 1987.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1)
Participants	Inclusion criteria: non‐depressed of either sex, between 18 and 65 years, having no significant medical problems. Obesity. Individuals had not taken used an appetite suppressant or other psychotropic drug within 2 weeks of starting the study Exclusion criteria: women who were pregnant or lactating Diagnostic criteria: medical history, physical examination, scalar electrocardiogram, routine blood chemical and hematological test and urinalysis Setting: — Gender distribution: females & males Country/countries where trial was performed: USA
Interventions	Intervention: 1. Experimental group (EG): fluoxetine 20 mg single dose on day 1, 40 mg for the next 2 days, 60 mg for 11 days, 40 mg to 80 mg at the discretion of the investigator Comparator: 2. Control group (CG): placebo for 8 weeks Cointervention: individuals were advised to reduce overall calorie consumption by 20%, but were given no other dietary advice Duration of intervention: 11 days Duration of follow‐up: 8 weeks Run‐in period: no Number of study centres: 1 Treatment before study: no Titration period: no Treatment duration: 11 days
Outcomes	Weight loss (kg), anthropometric measurements other than weight loss in kilograms (BMI), adverse events, morbidity (blood pressure, heart rate, changes in the electrocardiogram)
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: none declared but the principal author works in Lilly Research Laboratories Publication status: full article
Stated aim for study	Quote from publication: "Each patient was given fluoxetine or placebo for 8 weeks in conjunction with minimal dietary advice, and body weight was determined weekly." (page 186)
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "Participants were randomly and blindly assigned to receive …" (page 186) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "Participants were randomly and blindly assigned to receive …" (page 186) Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	High risk	Quote from publication: "Participants were randomly and blindly assigned ..." (page 186) Comment: outcome likely influenced by lack of blinding of study personnel
Blinding of participants and personnel (performance bias) anthropometric measurements other than weight loss	High risk	Quote from publication: "Participants were randomly and blindly assigned ..." (page 186) Comment: outcome likely influenced by lack of blinding of study personnel
Blinding of participants and personnel (performance bias) morbidity	High risk	Quote from publication: "Participants were randomly and blindly assigned ..." (page 186) Comment: outcome likely influenced by lack of blinding of study personnel
Blinding of participants and personnel (performance bias) weight loss	High risk	Quote from publication: "Participants were randomly and blindly assigned ..." (page 186) Comment: outcome likely influenced by lack of blinding of study personnel
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) anthropometric measurements other than weight loss	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) morbidity	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) adverse events	Low risk	Quote from publication: "Only 100 participants (52 placebo and 48 in fluoxetine group) completing the study" (page 187) Comment: data for primary outcome available for 83% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) anthropometric measurements other than weight loss	Low risk	Quote from publication: "Only 100 participants (52 placebo and 48 in fluoxetine group) completing the study" (page 187) Comment: data for primary outcome available for 83% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) morbidity	Low risk	Quote from publication: "Only 100 participants (52 placebo and 48 in fluoxetine group) completing the study" (page 187) Comment: data for primary outcome available for 83% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) weight loss	Low risk	Quote from publication: "Only 100 participants (52 placebo and 48 in fluoxetine group) completing the study" (page 187) Comment: data for primary outcome available for 83% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Selective reporting (reporting bias)	High risk	Comment: anthropometric measurements other than weight loss were measured but not analysed (see Appendix 9)
Other bias	Unclear risk	Comment: the principal author worked in Lilly Research Laboratories but did not specify conflict of interest

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Levine 1989.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1:1:1:1)
Participants	Inclusion criteria: individuals weighed 20% to 100% in excess of ideal body weight, 18 to 65 years and were not pregnant or lactating Exclusion criteria: suspicion of clinical depression: Hopkins Symptom Checklist. Serious medical illness, use of an appetite suppressant within 2 weeks of starting the study; and use of diuretics, antidepressant or other drugs which could affect body weight Diagnostic criteria: ideal body weight Setting: — Gender distribution: females & males Country/countries where trial was performed: USA
Interventions	Interventions: I1. Experimental group A (EGA): fluoxetine 10 mg orally, once per day for 8 weeks I2. Experimental group B (EGB): fluoxetine 20 mg orally, once per day for 8 weeks I3. Experimental group C (EGC): fluoxetine 40 mg orally, once per day for 8 weeks I4. Experimental group D (EGD): fluoxetine 60 mg orally, once per day for 8 weeks Comparator: 5. Control group (CG): placebo once daily Cointervention: none Duration of intervention: 8 weeks Duration of follow‐up: 8 weeks Run‐in period: no Number of study centres: 8 Treatment before study: no Titration period: no Treatment duration: 8 weeks
Outcomes	Weight loss, BMI, adverse events, BP, heart rate
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: none declared but the principal author works in Lilly Research Laboratories Publication status: full article
Stated aim for study	Quote from publication: "Assess the dose‐response relationship of a fixed daily dose of this specific serotoninergic agent on weight loss of non depressed obese participants"
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "Participants were allocated randomly to one of the five treatment groups ..." (page 636) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "Participants, investigators and monitors were all blinded ..." (page 636) Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	Low risk	Quote from publication: "Participants, investigators and monitors were all blinded ..." (page 636)
Blinding of participants and personnel (performance bias) anthropometric measurements other than weight loss	Low risk	Quote from publication: "Participants, investigators and monitors were all blinded ..." (page 636)
Blinding of participants and personnel (performance bias) weight loss	Low risk	Quote from publication: "Participants, investigators and monitors were all blinded ..." (page 636)
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) anthropometric measurements other than weight loss	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) adverse events	High risk	Quote from publication: "417 participants remained in the study" (page 639) Comment: data for primary outcome available for 63.6% of the randomised sample
Incomplete outcome data (attrition bias) anthropometric measurements other than weight loss	High risk	Quote from publication: "417 participants remained in the study" (page 639) Comment: data for primary outcome available for 63.6% of the randomised sample
Incomplete outcome data (attrition bias) weight loss	High risk	Quote from publication: "417 participants remained in the study" (page 639) Comment: data for primary outcome available for 63.6% of the randomised sample
Selective reporting (reporting bias)	High risk	Comment: weight loss was analysed but their results were not reported (see Appendix 9)
Other bias	Low risk	Comment: none detected

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Pedrinola 1993.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1)
Participants	Inclusion criteria: adult male and female aged 20‐50 years with BMI > 30 kg/m² Exclusion criteria: pregnancy, hypertension, diabetes mellitus, lactation, use of depression suppressants, and serious medical illness Diagnostic criteria: BMI Setting: outpatient endocrinology clinic of the clinical hospital of the university of Sao Paulo Gender distribution: females & males Country/countries where trial was performed: Brazil
Interventions	Intervention: 1. Experimental group (EG): fluoxetine 20 mg orally, twice per day for 12 weeks Comparator: 2. Control group (CG): placebo orally, twice per day for 12 weeks Cointervention: individuals were counselled by a dietitian to follow a standard 1000 kcal Duration of intervention: 12 weeks Duration of follow‐up: 12 weeks Run‐in period: 2 weeks Number of study centres: 1 Treatment before study: no Titration period: no Treatment duration: 12 weeks
Outcomes	Weight loss, BMI, adverse events, cholesterol, triglycerides
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: donation of fluoxetine by Farmasa SA Publication status: full article
Stated aim for study	Quote from publication: "... investigate the effects of fluoxetine in a double ‐blind, placebo‐controlled randomized trial in non‐depressed obese individuals"
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "... the participants were randomized for …" (page 31); information by trial author: "both groups included patients randomly selected from our outpatient clinic" Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "… for a double‐blind, placebo controlled trial" (page 31); information by trial author: "patients were allocated to each group without previous selection" Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	Unclear risk	Quote from publication: "… for a double‐blind, placebo controlled trial" (page 31); information by trial author: "the personnel of the hospital were blind if the patients were from one or another group" Comment: insufficient information
Blinding of participants and personnel (performance bias) anthropometric measurements other than weight loss	Unclear risk	Quote from publication: "… for a double‐blind, placebo controlled trial" (page 31); information by trial author: "the personnel of the hospital were blind if the patients were from one or another group" Comment: insufficient information
Blinding of participants and personnel (performance bias) weight loss	Unclear risk	Quote from publication: "… for a double‐blind, placebo controlled trial" (page 31); information by trial author: "the personnel of the hospital were blind if the patients were from one or another group" Comment: insufficient information
Blinding of outcome assessment (detection bias) adverse events	High risk	Comment (information by trial author): "there was no blinding of outcome of assessment"
Blinding of outcome assessment (detection bias) anthropometric measurements other than weight loss	High risk	Comment (information by trial author): "there was no blinding of outcome of assessment"
Blinding of outcome assessment (detection bias) weight loss	High risk	Comment (information by trial author): "there was no blinding of outcome of assessment"
Incomplete outcome data (attrition bias) adverse events	Low risk	Quote from publication: "Two participants…dropped out" (page 32) Comment: data for primary outcome available for 90% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) anthropometric measurements other than weight loss	Low risk	Quote from publication: "Two participants…dropped out" (page 32) Comment: data for primary outcome available for 90% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) weight loss	Low risk	Quote from publication: "Two participants…dropped out" (page 32) Comment: data for primary outcome available for 90% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Selective reporting (reporting bias)	High risk	Comment: adverse events were analysed but only reports that results were not significant (see Appendix 9)
Other bias	Low risk	Comment: no other potential source of bias

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Pijl 1991.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1)
Participants	Inclusion criteria: BMI > 30 kg/m² Exclusion criteria: depression (Hamilton Depression Scale score > 10), pregnancy, use of an anorectic drug in a period of 2 months preceding and unstable body weight (± 2 kg) in the 2 weeks prior to the study Diagnostic criteria: BMI Setting: clinic of internal medicine for obesity, university hospital Gender distribution: females Country/countries where trial was performed: the Netherlands
Interventions	Intervention: 1. Experimental group (EG): fluoxetine 60 mg orally, once per day for 6 weeks Comparator: 2. Control group (CG): placebo orally, once per day for 6 weeks Cointervention: none Duration of intervention: 6 weeks Duration of follow‐up: 6 weeks Run‐in period: 1 week single blind placebo Number of study centres: 1 Treatment before study: no Titration period: no Treatment duration: 6 weeks
Outcomes	Body weight, total caloric intake, macronutrient selection, adverse events, spontaneous food choice
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: grant provided by Lilly Research Laboratories Publication status: full article
Stated aim for study	Quote from publication: “Determine the effect of serotonin re‐uptake inhibition on body weight, total caloric intake and macronutrient selection”
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from publication: "... participants received..in random order.." (page 238); information by trial author: "we used a computer random sequence generator for random sequence generation"
Allocation concealment (selection bias)	Low risk	Quote from publication: "... participants received..in random order.." (page 238); information by trial author: "treatments were allocated in order of inclusion/study number. The medication and placebo were provided by the pharmacy to the study staff in boxes labelled with study numbers of patients"
Blinding of participants and personnel (performance bias) adverse events	Low risk	Quote from publication: "... participants received..under double blind conditions" (page 238); information by trial author: "participants and study staff were not aware of treatment allocation (Prozac and placebo were provided in similar capsules and boxes which were provided by the pharmacy and labelled with study number)"
Blinding of participants and personnel (performance bias) weight loss	Low risk	Quote from publication: "... participants received..under double blind conditions" (page 238); information by trial author: "participants and study staff were not aware of treatment allocation (Prozac and placebo were provided in similar capsules and boxes which were provided by the pharmacy and labelled with study number)"
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Comment: insufficient information
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: insufficient information
Incomplete outcome data (attrition bias) adverse events	Low risk	Quote from publication: "Twenty‐three participants were evaluable at the end of the study" (page 239) Comment: data for primary outcome available for 95.3% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) weight loss	Low risk	Quote from publication: "Twenty‐three participants were evaluable at the end of the study" (page 239) Comment: data for primary outcome available for 95.3% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: all the outcomes listed in the Method section described in results
Other bias	Low risk	Comment: no other potential source of bias

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Stinson 1992.

*Study characteristics*
Methods	Study design: cross‐over RCT
Participants	Inclusion criteria: healthy (normal ECG, haematological and biochemical screen) males < 65 years and post‐menopausal women attending the obesity clinic, no history of depression or medication known to interfere with metabolism Exclusion criteria: history of depression and medication known to interfere with metabolism; use of biguanides, bulking agents, thyroid hormones or beta blockers. Recent use of antidepressants or appetite suppressant drugs, weight loss greater than 2.5 kg in previous 2 months, any major illness in previous 6 months Setting: hospital Gender distribution: females & males Country/countries where trial was performed: Ireland
Interventions	Intervention: 1. Experimental group (EG): fluoxetine 60 mg orally, once per day for 2 weeks Comparator: 2. Control group (CG): placebo orally, once per day for 2 weeks Cointervention: no Duration of intervention: 2 weeks Duration of follow‐up: 10 weeks Run‐in period: 2 weeks placebo Number of study centres: 1 Treatment before study: none Titration period: no Treatment duration: 2 weeks for each intervention and 6 weeks of wash‐out period
Outcomes	Resting metabolic rate, diet induced thermogenesis, weight reduction, BP, serum urea and creatinine levels, hematocrit
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: Lilly Research Laboratories Publication status: full article
Stated aim for study	Quote from publication: "The aim of this study was to ascertain whether some of the weight reducing effect of fluoxetine is due to an increase in resting metabolic rate and/or an increase”
Notes	1. A priori sample size estimation: yes 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "… the study was randomized." (page 392) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "The study was randomized double blind …" (page 392) Comment: insufficient information
Blinding of participants and personnel (performance bias) weight loss	Low risk	Quote from publication: "The study was… double blind …" (page 392)
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) weight loss	Low risk	Comment: no missing data for primary outcome
Selective reporting (reporting bias)	Low risk	Comment: not detected
Other bias	Unclear risk	Comment: this study was supported by a grant from Lilly Research Laboratories Comment: no carry‐over effects

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Suplicy 2014.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1:1:1:1:1)
Participants	Inclusion criteria: premenopausal women, 18 to 50 years, BMI 30 kg/m² to 39.9 kg/m², weight stable within the previous 3 months (< 3 kg) Exclusion criteria: male, previous bariatric surgery, menopause, pregnancy or lactation, desire to become pregnant during the study, uncontrolled hypertension (160/100 mmHg at the time of enrolment), diabetes mellitus, clinically significant history diseases or drug/alcohol abuse, use of medications that could alter body weight Diagnostic criteria: BMI Setting: obesity outpatient clinic of the endocrine division (SEMPR) of the Clinical Hospital of the Federal University of Paraná Gender distribution: females Country/countries where trial was performed: Brazil
Interventions	Interventions: I1. Experimental group A (EGA): diethylpropion 75 mg orally, once per day for 52 weeks I2. Experimental group B (EGB): fenproporex 25 mg orally, once per day for 52 weeks I3. Experimental group C (EGC): mazindol 2 mg orally, once per day for 52 weeks I4. Experimental group D (EGD): sibutramine 15 mg orally, once per day for 52 weeks I5. Experimental group E (EGE): fluoxetine 20 mg orally, once per day for 52 weeks Comparator: 6. Control group (CG): placebo orally, once per day for 52 weeks Cointervention: balanced hypocaloric diet and were encouraged to maintain at least 150 minutes per week of moderate physical activity Duration of intervention: 52 weeks Duration of follow‐up: 52 weeks Run‐in period: 2 weeks Number of study centres: 1 Treatment before study: no Titration period: no Treatment duration: 52 weeks
Outcomes	Differences in weight loss, changes from the baseline values in anthropometric measures (waist circumference, BMI), safety was evaluated by reports of adverse events in the follow‐up visits, with an emphasis on serious events and events that led to the patient’s discontinuation. Key secondary safety endpoints included changes from the baseline in measures of blood pressure, heart rate, serum lipids (total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol and triglycerides, glycaemic variables (fasting glucose, fasting insulin, glycated haemoglobin and the HOMA assessment of insulin resistance) and quality of life
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: sibutramine and fluoxetine were provided by Medley Pharmaceuticals; fenproponex and diethylpropion by Aché Pharmaceuticals; mazindol and placebo were prepared by Apparenza Drugstore Publication status: full article
Stated aim for study	Quote from publication: "The main goal of the study was to compare, in a single‐blind, randomized, placebo‐controlled design, the efficacy and safety of a 52‐week (wk) therapeutic program with DEP, FEN, MZD, FXT or SIB for promoting weight loss in a group of obese premenopausal women." (page 1097)
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from publication: "... participants were randomly assigned in equal numbers to one of the six following treatment arms …" (page 1098); information by trial author: "participants were consecutively randomised by choosing a paper identified with the number of each study group" Comment: the randomisation was by a simple random method
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "... participants were randomly assigned in equal numbers to one of the six following treatment arms …" (page 1098); information by trial author: "participants were consecutively randomised by choosing a paper identified with the number of each study group" Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	High risk	Quote from publication: "The double design could not be employed, and uncoated capsules were utilized (the gel covered capsules have different pharmacokinetic pattern)" (page 1098)
Blinding of participants and personnel (performance bias) anthropometric measurements other than weight loss	High risk	Quote from publication: "The double design could not be employed, and uncoated capsules were utilized (the gel covered capsules have different pharmacokinetic pattern)" (page 1098)
Blinding of participants and personnel (performance bias) morbidity	High risk	Quote from publication: "The double design could not be employed, and uncoated capsules were utilized (the gel covered capsules have different pharmacokinetic pattern)" (page 1098)
Blinding of participants and personnel (performance bias) weight loss	High risk	Quote from publication: "The double design could not be employed, and uncoated capsules were utilized (the gel covered capsules have different pharmacokinetic pattern)" (page 1098)
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) anthropometric measurements other than weight loss	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) morbidity	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) adverse events	High risk	Quote from publication: "… with a dropout rate of 25.9%, mostly during the first 6 months of treatment" (page 1098) Comment: data for primary outcome available for 74% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) anthropometric measurements other than weight loss	High risk	Quote from publication: "… with a dropout rate of 25.9%, mostly during the first 6 months of treatment" (page 1098) Comment: data for primary outcome available for 74% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) morbidity	High risk	Quote from publication: "… with a dropout rate of 25.9%, mostly during the first 6 months of treatment" (page 1098) Comment: data for primary outcome available for 74% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) weight loss	High risk	Quote from publication: "… with a dropout rate of 25.9%, mostly during the first 6 months of treatment" (page 1098) Commennt: data for primary outcome available for 74% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Selective reporting (reporting bias)	High risk	Comment: trial report states that outcome was analysed but reports no results (see Appendix 9)
Other bias	Unclear risk	Comment: in this trial sibutramine and fluoxetine were provided by Medley and fenproporex and diethylpropion by Ache‐ Pharmaceuticals (page 1103)

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Visser 1993.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1)
Participants	Inclusion criteria: male 25 to 50 with stable body weight for the last 2 months, BMI 26 Kg/m² to 30 Kg/m² and a waist‒hip ratio > 0.97 Exclusion criteria: any medication, participation in other studies, previous treatment with fluoxetine, alcohol abuse or smoking Diagnostic criteria: BMI Setting: university hospital Utrecht Gender distribution: males Country/countries where trial was performed: the Netherlands
Interventions	Intervention: 1. Experimental group (EG): fluoxetine 60 mg orally, once per day for 12 weeks Comparator: 2. Control group (CG): placebo orally, once per day for 12 weeks Cointervention: diet advice Duration of intervention: 12 weeks Duration of follow‐up: 12 weeks Run‐in period: 2 weeks Number of study centres: 1 Treatment before study: none Titration period: no Treatment duration: 12 weeks
Outcomes	Body weight, body composition, anthropometry (waist‐hip ratio), abdominal fat areas, adverse events and illnesses, count of returned capsules
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: not reported Publication status: full article
Stated aim for study	Quote from publication: “Describe the effect of dietary advice with placebo or fluoxetine on body weight, body composition and abdominal fat accumulation”
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: "..participants were randomly assigned.." (page 248); answer of author: "the randomisation was performed by a third party. I do not know the details" Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: "..participants were randomly assigned.." (page 248); answer of author: "I do not recall exactly our procedure, but I believe that participants were given a number in the order of the date and time of their baseline assessment" Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	Unclear risk	Quote from publication: "….the double blind treatment period.." (page 248); answer of author: "both participants and researchers were blinded" Comment: self‐reported outcome measurement. Insufficient information
Blinding of participants and personnel (performance bias) anthropometric measurements other than weight loss	Unclear risk	Quote from publication: "….the double blind treatment period.." (page 248) Comment: insufficient information
Blinding of participants and personnel (performance bias) weight loss	Unclear risk	Quote from publication: "….the double blind treatment period.." (page 248) Comment: insufficient information
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Quote from publication: "….the double blind treatment period.." (page 248); answer of author: "both participants and researchers were blinded" Comment: insufficient information
Blinding of outcome assessment (detection bias) anthropometric measurements other than weight loss	Unclear risk	Quote from publication: "….the double blind treatment period.." (page 248) Comment: insufficient information
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Quote from publication: "….the double blind treatment period..". (page 248) Comment: insufficient information
Incomplete outcome data (attrition bias) adverse events	Low risk	Quote from publication: "38 individuals completed the study..." (page 248) Comment: data for primary outcome available for 95% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) anthropometric measurements other than weight loss	Low risk	Quote from publication: "38 individuals completed the study..." (page 248) Comment: data for primary outcome available for 95% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) weight loss	Low risk	Quote from publication: "38 individuals completed the study..." (page 248) Comment: data for primary outcome available for 95% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: all the outcomes listed in the method section described in results
Other bias	Low risk	Comment: no other potential source of bias

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Wurtman 1993.

*Study characteristics*
Methods	Study design: parallel RCT (randomisation ratio 1:1:1)
Participants	Inclusion criteria: women who were 40 lbs to 60 lbs above ideal body weight according to the Metropolitan Life Insurance Height and Weight table for midpoint frames and who perceived their obesity as being sustained by an excessive appetite for sweet and starchy snack foods. Good general health, a non‐smoker and least 3 months beyond the completion of any weight loss programme Exclusion criteria: moderate to severe premenstrual mood and appetite changes and/or a clear pattern of seasonal weight gain and loss Diagnostic criteria: 40 lbs to 60 lbs above ideal body weight Setting: clinical research centre Gender distribution: females Country/countries where trial was performed: USA
Interventions	Interventions: I1. Experimental group A (EGA): dexfenfluramine 15 mg orally, once per day for 12 weeks I2. Experimental group B (EGB): fluoxetine 20 mg orally, once per day for 12 weeks Comparator: 3. Control group (CG): placebo orally, once per day for 12 weeks Cointervention: no Duration of intervention: 12 weeks Duration of follow‐up: 12 weeks and 4 days Run‐in period: 4 days Number of study centres: 1 Treatment before study: 4 day outpatient measurement of their meal and snack intakes to identify those whose food intake reflected a consistent appetite for CHO‐rich snack foods Titration period: no Treatment duration: 12 weeks
Outcomes	Weight, carbohydrate intake, adverse events, glucose, triglycerides, urinalysis, thyroid profile, complete blood count, biochemical parameters, Hamilton Depression Rating Scale (HDRS), the self‐administered ProfIle of Mood States (POMS), the Center for Epidemiological Studies ‒ Depression (CESD) test, Stanford Sleepiness Scale (SSS) and the Menstrual Symptomatology Questionnaire (MSQ), drug levels
Study registration	Trial identifier: — Trial terminated early: no
Publication details	Language of publication: English Commercial funding: no Publication status: full article
Stated aim for study	Quote from publication: “Compare the effects of dexfenfluramine and fluoxetine treatment on calorie, macro nutriment intake, and weight loss among obese women”
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote from publication: “Participants … were randomly assigned to …" (page 203) Comment: insufficient information
Allocation concealment (selection bias)	Unclear risk	Quote from publication: “Participants … were randomly assigned to …" (page 203) Comment: insufficient information
Blinding of participants and personnel (performance bias) adverse events	Low risk	Quote from publication: "The study was conducted in double blind fashion" (page 203)
Blinding of participants and personnel (performance bias) weight loss	Low risk	Quote from publication: "The study was conducted in double blind fashion" (page 203)
Blinding of outcome assessment (detection bias) adverse events	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) weight loss	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) adverse events	High risk	Quote from publication: "64 individuals completed the study …" (page 204) Comment: data for primary outcome available for 73.5% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Incomplete outcome data (attrition bias) weight loss	High risk	Quote from publication: "64 individuals completed the study …" (page 204) Comment: data for primary outcome available for 73.5% of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: all the outcomes listed in the method section described in results
Other bias	Low risk	Comment: no other potential source of bias

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Note: where the judgement is 'Unclear' and the description is blank, the study did not report that particular outcome.

— denotes not reported

BMI: body mass index; BP: blood pressure; DSM III‐R: Diagnostic and Statistical Manual of Mental Disorders; RCT: randomised controlled trial.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Afkhami 2005	Quasi‐experimental trial, all participants received fluoxetine
Beyazyüz 2013	Included individuals with BMI < 25 kg/m²
Blondal 1999	Insufficient information about the weight of the participants
Borrelli 1999	Included obese and non‐obese participants
Bremner 1984	Insufficient information about the weight of the participants
Burns 1995	Included obese and non‐obese participants
Chojnacki 2015	Fluoxetine was a co‐intervention with melatonin
Cook 2004	Insufficient information about the weight of the participants
Dastjerdi 2007	Included participants under 14 years old
De Ronchi 1998	Included non‐obese participants
Falk 1989	Insufficient information about the weight of the participants
Folgelson 1991	Letter to the editor
Gendall 2000	Letter to the editor
Gilbert 2010	Not a clinical trial
Goldstein 1995	Included participants with diabetes mellitus
Goldstein 1997	Included obese and non‐obese participants
González 2017	Fluoxetine as co‐intervention with metformin
Harto 1998	Included obese and non‐obese participants
Keller 2007	Insufficient information about the weight of the participants
Macías‐Cortés 2017	Included obese and non‐obese participants
Maina 2004	Not a clinical trial
Mendoza 1995	Participants received fluoxetine or dexfenfluramine without distinction
Michelson 1999	Included obese and non‐obese participants
Newhouse 2000	Insufficient information about the weight of the participants
Niaura 2002	Insufficient information about the weight of the participants
Orzack 1990	Included adults who were overweight, underweight and of ideal weight
Papakostas 2005	Not a clinical trial
Pedrinola 1996	Compared fluoxetine alone versus dexfenfluramine plus fluoxetine for weight loss
Ravindran 2015	Not a clinical trial
Saules 2004	Insufficient information about the weight of the participants
Schweizer 1990	Insufficient information about the weight of the participants
Weng 2004	Insufficient information about the weight of the participants

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BMI: body mass index.

Characteristics of studies awaiting classification [ordered by study ID]

Krylov 1997.

Methods	Design: parallel RCT (randomisation ratio 1:1)
Participants	Inclusion criteria: obese women Exclusion criteria: not reported Diagnostic criteria: not reported
Interventions	Intervention: fluoxetine 60 mg orally, once per day for 26 weeks Comparator: placebo orally, once per day for 26 weeks Cointervention: none Duration of intervention: 26 weeks Duration of follow‐up: 26 weeks Run‐in period: none Number of study centres: not reported Treatment before study: none Titration period: none Treatment duration: 26 weeks
Outcomes	Weight loss
Study details	Trial identifier: not reported Trial terminated early: no
Publication details	Language of publication: English Commercial funding: not reported Publication status: congress report
Stated aim of study	Quote from publication: "Assess the efficacy and safety of fluoxetine as compared with placebo in the treatment of obesity."
Notes	1. A priori sample size estimation: not reported 2. Conflict of interest: not reported

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RCT: randomised controlled trial.

Differences between protocol and review

Due to change in author team and the long time between publication of the protocol (Melendez 2015) and the review, all parts of this review were adapted/changed according to the newest Cochrane Metabolic and Endocrine Disorders Group standards.

Parallel trials were analysed independently with respect to cross‐over trials, in order to reduce errors in the meta‐analysis.

Contributions of authors

All review authors read and approved the final review draft.

Aurora E Serralde‐Zuñiga (AS): protocol drafting, acquiring study reports, selecting studies for inclusion, data extraction, data interpretation, review of drafts, and future review updates.

Alejandro G Gonzalez‐Garay (AGG): protocol drafting, selecting studies for inclusion, data extraction, data analysis, data interpretation, review of drafts, and future review updates.

Yanelli Rodríguez‐Carmona (YR): protocol drafting, acquiring study reports, selecting studies for inclusion, data extraction, data interpretation, review of drafts, and future review updates.

Guillermo Melendez (GM): protocol drafting, acquiring study reports, selecting studies for inclusion, and review of drafts.

Sources of support

Internal sources

Library of the National Institute of Pediatrics, Mexico

The library will provide us with articles we require for review completion.

External sources

No sources of support provided

Declarations of interest

AS: none known.

AGG: none known.

YR: none known.

GM: has participated in an educational programme on Health Economics organised by Universidad Anahuac and only this programme was sponsored by Bayer, but did not receive any payment from the pharmaceutical company. Bayer company did not participate in the development of this systematic review, which was financed by the public budget of the institutions in which the authors work.

Edited (no change to conclusions)

References

References to studies included in this review

Al‐Helli 2015 {published data only}

Al-Helli A, Al-Abbassi M, Jasim G, Al-Bayaty M. Effects of fluoxetine, omega 3, or their combination on serum leptin in Iraqi obese subjects. International Journal of Pharmaceutical Sciences Review and Research 2015;35(1):90-5. [Google Scholar]

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Afkhami 2005 {published data only}

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Trial ID	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a	Endpoints quoted in publication(s)^b,c	Endpoints quoted in abstract of publication(s)^b,c
Al‐Helli 2015	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): BMI, serum lipids: total cholesterol, low‐density‐lipoprotein cholesterol, high‐density‐lipoprotein cholesterol, triglycerides, fasting blood glucose, malondialdehyde, leptin	Other outcome measure(s): BMI, fasting blood glucose, lipid profile, liver enzymes, malondialdehyde, leptin
Suplicy 2014	Source: NT	Primary outcome measure(s): "Efficacy was evaluated by the differences in weight loss promoted by medications and placebo and the proportion of patients in each arm who experienced a reduction in the baseline body weight of at least 5% or 10% after 52 wks"	Primary outcome measure(s): changes in body weight, % of women who achieved at least 5% weight loss by week 52 in the intent‐to‐treat population
		Secondary outcome measure(s): changes from the baseline values in anthropometric measures (waist circumference, BMI)	Secondary outcome measure(s): —
		Other outcome measure(s): safety was evaluated by reports of adverse events in the follow‐up visits, with an emphasis on serious events and events that led to the patient’s discontinuation. Key secondary safety endpoints included changes from the baseline in measures of blood pressure, heart rate, serum lipids (total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol and triglycerides, glycaemic variables (fasting glucose, fasting insulin, glycated haemoglobin and the HOMA assessment of insulin resistance) and quality of life	Other outcome measure(s): anthropometry, safety, metabolic and cardiovascular parameters
Guimaraes 2006	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): BMI, weight, abdominal circumference, % fatty tissue, HDL‐cholesterol, triglycerides, systolic and diastolic BP, adverse events, HOMA, insulin, glycaemia	Other outcome measure(s): BMI, weight, abdominal circumference, % fatty tissue, HDL‐cholesterol, triglycerides, systolic and diastolic BP, adverse events
Bondi 2000	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): compliance by pill count, resting respiratory quotient, resting energy expenditure, fasting blood glucose, plasma insulin	Other outcome measure(s): resting and glucose‐induced thermogenesis
Huang 1998	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): body weight, BMI, BP, fasting blood sugar, triglycerides, total cholesterol, uric acid, glutamic pyruvic transaminase (GPT), alkaline phosphatase (AP), adverse events	Other outcome measure(s): mean total body weight reduction, adverse events
Bross 1995	Source: NT	Primary outcome measure: —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): body weight, resting energy expenditure, oxygen consumption, carbon dioxide production, thermic effect, urinary norepinephrine excretion, normetanephrine excretion, serum triiodothyronine and thyroxine, nitrogen balance, urinary sodium and potassium, basal body temperature, adverse events	Other outcome measure(s): weight loss, resting energy expenditure, basal body temperature, urinary norepinephrine excretion, normetanephrine excretion, serum triiodothyronine
Fernández‐Soto 1995	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): weight, pulse, count of unused medication, patients' report of medical problems, adverse events, glucose, urea, uric acid, creatinine, ions, total cholesterol, triglycerides, HDL‐cholesterol	Other outcome measure(s): weight loss
Lawton 1995	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): satiety, weight loss, adverse events, appetite, energy intake, macronutrient intake, motivational ratings (hunger), food intake preferences, post‐lunch meal palatability rating, blood and urine analyses, check of concomitant medication, resting pulse, BP	Other outcome measure(s): satiety, weight loss, appetite, energy intake, macronutrient intake,
Goldstein 1994	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): weight loss, weight change, adverse events, BP (sitting), heart rate, oral temperature, blood chemistry, haematology and urinalysis, compliance (capsule record cards)	Other outcome measure(s): weight loss, adverse events
Goldstein 1993	Source: NT	Primary outcome measure(s): weight	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): BP (sitting), pulse rate, oral temperature, carbohydrate craving scores, adverse events, urinalysis and blood chemistry, haematology	Other outcome measure(s): weight loss, adverse events, discontinuation due to adverse events
Pedrinola 1993	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s):
		Other outcome measure(s): weight loss, BMI, adverse events, cholesterol, triglycerides	Other outcome measure(s): weight loss, BMI, adverse events, cholesterol, triglycerides
Visser 1993	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): body weight, body composition, anthropometry (waist‐hip ratio), abdominal fat areas, adverse events and illnesses, count of returned capsules	Other outcome measure(s): weight loss, body composition, abdominal fat
Wurtman 1993	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): weight, carbohydrate intake, adverse events, glucose, triglycerides, urinalysis, thyroid profile, complete blood count, biochemical parameters, Hamilton Depression Rating Scale (HDRS), the self‐administered ProfIle of Mood States (POMS), the Center for Epidemiological Studies‐Depression (CESD) test, Stanford Sleepiness Scale (SSS) and the Menstrual Symptomatology Questionnaire (MSQ), drug levels	Other outcome measure(s): weight loss, carbohydrate intake, discontinuation due to adverse effects, withdrawals
Kopelman 1992	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): sleep‐breathing patterns, weight loss, BMI, adverse events, BP, haematology, nocturnal arterial oxygen saturation, apnoea/hypopnoea index, total sleep time, qualitative assessment of sleep	Other outcome measure(s): nocturnal arterial oxygen saturation, apnoea/hypopnoea index, total sleep time, qualitative assessment of sleep
Stinson 1992	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): resting metabolic rate, diet‐induced thermogenesis, weight reduction, BP, serum urea and creatinine levels, hematocrit	Other outcome measure(s): resting metabolic rate, diet‐induced thermogenesis, weight reduction
Bagiella 1991	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): questionnaire, divided into 4 sections, intended to evaluate the cognitive and critical, behavioral, and cognitive aspects of the patient's dietary habits	Other outcome measure(s): questionnaire, divided into 4 sections, intended to evaluate the cognitive and critical, behavioral, and cognitive aspects of the patient's dietary habits
Pijl 1991	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): body weight, total caloric intake, macronutrient selection, adverse events, spontaneous food choice	Other outcome measure(s): weight loss, food intake, total caloric intake
Levine 1989	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): weight loss, BMI, adverse events, BP, heart rate	Other outcome measure(s): weight loss, BMI, adverse events
Levine 1987	Source: NT	Primary outcome measure(s): —	Primary outcome measure(s): —
		Secondary outcome measure(s): —	Secondary outcome measure(s): —
		Other outcome measure(s): weight loss (kg), anthropometric measurements other than weight loss in kilograms (BMI), adverse events, morbidity (blood pressure, heart rate, changes in the electrocardiogram)	Other outcome measure(s): weight loss (kg), adverse events
— denotes not reported ^a Trial document(s) refers to all available information from published design papers and sources other than regular publications (e.g. FDA/EMA documents, manufacturer's websites, trial registers) ^b Publication(s) refers to trial information published in scientific journals (primary reference, duplicate publications, companion documents or multiple reports of a primary trial) ^c Other outcome measures refer to all outcomes not specified as primary or secondary outcome measures BP: blood pressure; EMA: European Medicines Agency; FDA: Food and Drug Administration (US); HDL: high‐density lipoprotein; NT: no trial document available; BMI: body mass index; HOMA: homeostatic model assessment of insulin resistance.

PERMALINK

Fluoxetine for adults who are overweight or obese

Aurora E Serralde-Zúñiga

Alejandro G Gonzalez Garay

Yanelli Rodríguez-Carmona

Guillermo Melendez

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Summary of findings: fluoxetine compared with placebo.

Background

Description of the condition

Description of the intervention

Adverse effects of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Diagnostic criteria for being overweight and obese

Types of interventions

Intervention

Comparator

Minimum duration of intervention

Summary of specific exclusion criteria

Types of outcome measures

Primary outcomes

Secondary outcomes

Method of outcome measurement

Timing of outcome measurement

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

1.

Data extraction and management

1. Overview of trial populations.

Dealing with duplicate and companion publications

Data from clinical trial registers

Assessment of risk of bias in included studies

Summary assessment of risk of bias

2.

3.

Risk of bias for a trial across outcomes

Risk of bias for an outcome within a trial and across domains

Risk of bias for an outcome across trials and across domains

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Certainty of the evidence

'Summary of findings' table

Results

Description of studies

Results of the search

Included studies

Source of data

Comparisons

Overview of trial populations

Trial design

Settings

Participants

Diagnosis

Interventions

Outcomes