For this meta-analysis of pharmacologic interventions to attenuate antipsychotic-associated weight gain, we examined 32 placebo-controlled trials including 1482 subjects that tested 15 different interventions. Data were most consistently available for weight change, showing that, overall, pharmacologic interventions were associated with a weight change of −1.99
kg (CI:−2.77, −1.20) vs
placebo over a mean of 13 weeks. However, results were highly heterogeneous, suggesting significant differences across studies and individual agents. Metformin, having the largest database (25% of all patients with weight data), was most superior to placebo (−2.94
kg), yet results remained heterogeneous even in sensitivity analyses. Additional agents that were superior to placebo included fenfluramine (−2.60
kg), sibutramine (−2.56
kg), topiramate (−2.52
kg), and reboxetine (−1.90
kg). The nine remaining agents were not superior to placebo in attenuating weight gain, and one (fluvoxamine) did not have data for the primary outcome. In addition, metformin and rosiglitazone showed significant benefits for secondary outcomes, such as waist circumference, blood glucose, and insulin levels. There were no significant individual treatment–placebo differences regarding psychiatric psychopathology and premature dropouts. Regarding prevention of
7% weight gain, metformin and reboxetine had low and clinically relevant NNTs of 2.5 and 3.0, respectively, with NNTs <10 being considered clinically meaningful (Citrome, 2008
). Moreover, when reported, nausea, which could lead to weight decrease, occurred as frequently as with placebo for famotidine, fluvoxamine, metformin, sibutramine, and topiramate.
Sensitivity analyses revealed that metformin, given as an intervention after weight gain had occurred, yielded significantly greater weight loss than placebo, whereas preventive treatment started concomitantly with antipsychotic initiation did not separate from placebo. However, results for the intervention trials remained highly heterogeneous. The reduced weight loss effect in the prevention group could be due to the fact that intervention trials are enriched for patients sensitive to weight gain. In addition, in prevention trials, the early orexigenic antipsychotic effect may override the weight loss intervention at this generally more pronounced phase of weight gain (Alvarez-Jimenez et al, 2008
). The latter view is supported by data on absolute weight changes within group rather than relative weight differences between treatment and placebo. All nine prevention arms showed absolute weight gain compared with baseline in the treatment group, whereas 15 of the 20 intervention arms showed weight loss compared with baseline when given after weight gain had occurred.
Results remained heterogeneous in sensitivity analyses of youth or first episode patients vs chronically treated patients, likely reflecting the diversity of agents studied. However, younger, less chronic patients did somewhat better. This effect was largest with metformin in which individuals in early treatment lost three times the weight compared with older, more chronic patients. By contrast, inpatient or outpatient status and study duration had a negligible overall effect on weight loss efficacy or heterogeneity of the results, but larger studies are needed to more comprehensively assess these and additional moderator variables.
Although the observed weight loss and more isolated metabolic improvements with some agents reached statistical significance, the magnitude of these changes was modest. Even in studies with the most pronounced effects, subjects only lost part of the weight that they likely accrued during antipsychotic treatment. For example, although patients on amantadine lost −6.80
kg (CI:−5.67, −7.93) more than placebo (Atmaca et al, 2003
), the absolute weight loss in the treatment group was −4.6±2.2
kg, which was less than the amount that many individuals had gained in the 3 months before study entry (ie, 2.6–10.8
kg). Similarly, although patients on metformin lost −6.3
kg (CI:−5.32, −7.28) more than placebo (Wu et al, 2008b
), the absolute weight loss of −3.2±2
kg was clearly less than the minimum of 10% weight gain that was required for study inclusion. Furthermore, in the few medium-term studies, the weight loss signal did not seem to be amplified compared with shorter-term trials. Thus, although longer-term studies are needed, it seems that for many individuals the adjunctive pharmacological agents studied are unlikely to return their weight to baseline.
Assuming that comparable populations were studied, and comparing our pooled results across all pharmacologic treatments (ie, −1.99
kg (CI: −1.20, −2.77)) with the pooled weight loss of −2.56
kg (CI: −1.92, −3.20) across all non-pharmacologic interventions from a recent meta-analysis of non-pharmacological interventions (Alvarez-Jimenez et al, 2008
), one could draw the conclusion that non-pharmacologic interventions are more effective. However, in the only randomized study in our meta-analysis in which these modalities were compared directly (Wu et al, 2008b
), the pharmacological intervention—metformin—performed significantly better than the non-pharmacological treatment (−3.2
kg (CI:−2.5, −3.9)) vs
kg (CI:−0.7, −2.0; p
<0.05). It is noteworthy that the most efficacious treatment in that study was the combined metformin and behavioral intervention (−4.7
kg (CI:−3.4, −5.7)). Thus, it appears that overall results across non-pharmacologic treatments are more consistent, whereas tested pharmacologic treatments included some that are clearly non-effective.
Although metformin outperformed other agents that have been studied against placebo, the current evidence is too limited to support its regular clinical use as an adjunctive medication. Data regarding the metformin related, rare, but potentially fatal side effect of lactic acidosis, particularly in elderly and those with compromised renal function (Chang et al, 2002
), and its new-found association with the accumulation of beta-amyloid, a factor in the pathogenesis of Alzheimer's disease (Chen et al, 2009
), alter the risk–benefit ratio in the elderly. However, the results do support further investigation of the risks and benefits of metformin in large, well-controlled trials in comparison with lower risk interventions such as switching to an antipsychotic medication with a lesser cardio metabolic burden, healthy lifestyle interventions and nutritional counseling.
The main limitation of this meta-analysis is the relative paucity of randomized controlled trials. As a result, there are too few studies for a number of medications, including orlistat and topiramate. Furthermore, there are no head-to-head studies of pharmacologic interventions, and only one study compared pharmacologic, nonpharmacologic, and combined pharmacologic plus non-pharmacologic interventions against placebo (Wu et al, 2008b
). Another related limitation is the heterogeneity of the results across individual studies that did not seem to be related to treatment setting, treatment duration, illness chronicity, and timing of the intervention, yet, our attempt to examine this heterogeneity through sensitivity analyses was hindered by a lack of statistical power. Thus, the variability of the effects may be explained by biological and/or environmental differences in patient cohorts and treatment environments, including studies that were performed in China and Venezuela, societies with different populations, weight norms and diets than in North America and Europe. Moreover, the heterogeneity of the results could also be due to different weight loss mechanisms of individual augmenting agents, and the strength of this effect could even differ based on which antipsychotic caused or maintains the weight gain and/or metabolic changes. It is noteworthy that we were not able to substantiate that metformin or other medications, for which information was available, were associated with greater rates of nausea that could be related to the observed weight loss. In spite of these limitations, this is the largest meta-analysis of pharmacologic weight loss interventions for antipsychotic weight gain. Compared with the previous meta-analysis on this topic (Faulkner et al, 2007b
), we included an additional 10 trials and 714 patients, allowing a more in-depth assessment of some individual agents and the added exploration of moderating variables.
The heterogeneous and relatively modest results of pharmacologic interventions for antipsychotic weight gain indicate the urgent need for more research in this area of high public health importance. Future research should consist of large studies that assess a wide array of body composition and metabolic parameters, document previous treatment history and weight change carefully, and focus on moderators and mediators of the response, ideally including a pharmacogenetic component (Correll and Malhotra, 2004
). Studies are also needed that document the time course and sustainability of weight loss over longer periods of time. Moreover, studies are needed in antipsychotic-naïve patients and in children and adolescents, who are at particular risk for weight gain and its long-term consequences (Alvarez-Jimenez et al, 2008
; Correll, 2008
). Furthermore, studies should be conducted in patients with disorders other than schizophrenia for which antipsychotics are endorsed (Suppes et al, 2005
) or prescribed frequently (Olfson et al, 2006
). Finally, studies are needed that examine the mechanisms of antipsychotic-induced weight gain and metabolic abnormalities to enable the development and testing of more targeted interventions that are hoped to be associated with greater weight loss efficacy and improved health outcomes in patients requiring antipsychotic treatment.