'Weight loss drug increases chance of depression'

The weight-loss drug rimonabant increases the risk of anxiety and depression, reported four newspapers (16 November 2007). The reports were based on the findings of an analysis of four clinical trials that found rimonabant led to greater weight-loss than placebo, but was associated with a greater number of adverse events.

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Four newspapers (1-4) reported that the weight-loss drug rimonabant (sold as Acomplia) has been linked with an increase in the risk of anxiety and depression.
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The reports were based on the findings of a well-conducted meta-analysis of four clinical trials (5). This indicated that rimonabant led to significantly greater weight loss than placebo, but that a higher proportion of patients given rimonabant stopped treatment for reasons of depressive mood disorder or anxiety. Adverse events were significantly more common in the rimonabant group.
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All of the newspapers were generally accurate in their reporting of the authors' conclusions. However two newspapers (1,3) reported that participants given rimonabant were 40% more likely to become depressed or anxious, when the study actually reported a 40% increase in the reporting of adverse events. Three newspapers mention rimonabant and the risk of suicide (1-3), and two discuss the effectiveness of anti-obesity drugs more generally (2, 3), however these issues were not addressed by the research discussed here. Research on these issues is available elsewhere (6, 7).

Evaluation of the evidence base for the efficacy and safety of the weight-loss drug rimonabant
Where does the evidence come from?

The evidence comes from research conducted by Professor Arne Astrup and colleagues from Fredericksberg Hospital and the University of Copenhagen, Denmark. Funding was provided by grants from the Center for Pharmacogenomics, University of Copenhagen, The Oak Foundation, the H:S Research Foundation and Diabesity.
What were the authors' objectives?

To assess the safety and efficacy of the anti-obesity drug rimonabant.
What was the nature of the evidence?

This was a meta-analysis of four double-blind randomised controlled trials (RCTs), involving 4,105 participants, comparing rimonabant against placebo for the treatment of obesity. The majority of trial participants were women, with an average age of around 45 to 55 years. Average body mass index (BMI) at the beginning of the trials ranged from 33.9 to 37.3.

Outcomes of interest in the analysis were: mean weight change, proportion of patients achieving at least 10% weight loss, depression and anxiety scores on the Hospital Anxiety and Depression Scale (HADS), discontinuation of treatment dues to depressive mood disorders or anxiety, and adverse events. All of these outcomes were measured and analysed after one year of treatment.
What interventions were examined in the research?

In all four trials, participants who complied to a weight maintenance diet for four weeks were randomly assigned to receive either 5mg rimonabant, 20mg rimonabant or an apparently identical placebo daily. All participants were also required to follow a low calorie diet.
What were the findings?

The meta-analysis compared only the 20mg rimonabant treatment groups against the placebo groups.

Participants given rimonabant had a significantly greater reduction in weight after a year than those given placebo (4.7kg greater on average) and were around five times as likely to have achieved at least 10% weight loss.

There was no difference between the groups on the HADS depression score, but the average HADS anxiety score was significantly greater in participants receiving rimonabant. Participants given rimonabant were around 2.5 times more likely to discontinue treatment because of depressive mood disorders than those given placebo, and around 3 times more likely to discontinue because of anxiety.

Participants given rimonabant were 40% more likely to report adverse events or serious adverse events than patients given placebo.
What were the authors' conclusions?

20 mg per day rimonibant increases the risk of psychiatric adverse events - i.e. depressed mood disorders and anxiety - despite depressed mood being an exclusion criterion in these trials.
How reliable are the conclusions?

This was a well conducted meta-analysis in which the authors searched for and included all the relevant studies in the area and attempted to minimise bias in these processes. The included trials were assessed as good quality and all used a similar set of rules for the way in which participants were treated. Appropriate methods were used to analyse the study data, and the authors conclusions were in line with the findings of this analysis.

Though HADS anxiety scores were significantly higher for participants given rimonabant, average scores on this scale for both rimonabant and placebo groups appeared to be within the 'normal' range. Similarly, though significantly more participants given rimonabant discontinued treatment than those given placebo, in absolute terms, the proportions in each group were relatively small (3% vs. 1.4% due to depressive mood disorders; 1% vs. 0.3% due to anxiety).

Though rimonabant was associated with more serious adverse events, it is not clear what was considered a 'serious' adverse event.
Systematic reviews

Information staff at CRD searched for systematic reviews relevant to this topic. Systematic reviews are valuable sources of evidence as they locate, appraise and synthesize all available evidence on a particular topic.

There was one related systematic review identified on the Cochrane Database of Systematic Reviews (CDSR) (8). There were no related reviews on the Database of Abstracts of Reviews of Effects (DARE).
References and resources

1. Weight-loss drug increases chance of depression. The Guardian, 16 November 2007, p13.

2. Weight-loss pill taken by 40,000 'can lead to suicidal thoughts'. Daily Mail, 16 November 2007, p7.

3. Slimming drug 'linked to rise in depression'. The Daily Telegraph, 16 November 2007, p8.

4. Warning over weight-loss drug. The Independent, 16 November 2007, p6.

5. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 2007;370:1706–13.

6. Food and Drug Administration Endocrinologic and Metabolic Advisory. June 13th 2007. Briefing information, NDA 21-888 ZIMULTI (rimonabant) - Sanofi-Aventis. 2007.

7. Rucker D, Padwal R, Li SK, Curioni C, Lau DCW. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ, doi:10.1136/bmj.39385.413113.25 (online publication 15 November 2007).

8. Curioni C, André C. Rimonabant for overweight or obesity. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006162. DOI: 10.1002/14651858.CD006162.pub2