In this review we used a predefined strategy to search for the available evidence on the ability of psychotropics to induce changes in body weight. The articles were selected based on a hierarchical level of evidence and were subsequently evaluated using AMSTAR for systematic reviews and SIGN 50 for controlled trials. The best evidence available was presented. We restricted our search to subjects with psychiatric disease since this review is intended as a resource to help choose psychotropics for psychiatric illness according to risk of weight gain.
Although most antipsychotics were found to be associated with weight gain, there are inherent difficulties in quantifying this weight. Many trials did not account for weight gain among the reported side-effects, some reported change in mean body weight, and some reported the percentage who gained more than 7% of their initial body weight. Many studies did not consider drug dosages or parameters for drug adherence, gender, and pharmacogenetics. Most studies had high dropout rates. There are factors that would result in significant underestimations of weight gain potential. These include studies of short duration, the use of last observation carried forward to handle data from study dropouts, previous drug use that would cause weight gain, and industry sponsorship.
Since the treatment of psychiatric illness often takes months or years, and because it takes time for weight gain to develop, we selected articles with study duration of 12 weeks or longer. Unfortunately, many of the randomized clinical trials were of short duration and thus were not able to provide sufficient information about the full impact of the drug on body weight. Kinon 
and Tran 
reported on the time course of weight gain with olanzapine; they showed continued weight gain up to 39 and 22 weeks.
Recovery from the psychiatric illness itself may influence study outcome. This may be a more important factor in the treatment of depression than of other psychiatric disorders 
. Also, measures that patients take to offset weight gain are rarely discussed but may influence the degree to which a patient gains weight.
The effect of drug dosage on weight gain has been reviewed 
, but it is rarely discussed in reviews. We minimized this effect by verifying that all studies and reviews also had efficacy as an outcome measure.
We found only two studies that addressed the issue of drug adherence by determining plasma drug levels in the study subjects 
. Genetic and gender differences may also be significant factors affecting a patient’s side-effect response to these drugs 
. Pharmacogenetics approaches may offer the possibility of identifying patient-specific biomarkers for predicting the risk of these side effects 
. A retrospective chart review 
indicates that women and those with a greater initial BMI are more susceptible to weight gain 
, for example, obese patients given lithium gained more weight on lithium compared with lean patients 
. There were high drop-out rates in many of the studies. In one study 74% of the patients discontinued the study medication within 18 months. The Last Observation Carried Forward (LOCF) method used in many studies for dealing with dropouts is likely to underestimate drug-associated weight gain 
Many studies have confounding variables that have contributed to the underestimation of drug-induced weight gain. Weight gain differs between those with previous psychotropic treatments and those previously unexposed to psychotropics. In patients who are not drug-naïve, weight gain can be affected by the previous drug as well as the study drug. For example, studying the weight gains with long-acting risperidone in patients who had been switched from other antipsychotics, Lindenmayer 
found an overall mean weight gain of 0.4 kg over 12 weeks. The same study found a gain of 1.4 kg in patients who had been on haloperidol and of 0.3 kg in those who had been on quetiapine, and a loss of 0.5 kg in those on olanzapine. This shows that absolute weight gain is underestimated in studies that include patients who are not drug-naïve. Weight gain was three to four times greater in studies that included individuals with limited previous exposure to antipsychotic drugs 
Approximately one third of the studies presented in the tables were directly funded by pharmaceutical manufacturers. This number may be underestimated because many of the studies did not declare their source of funding. Two systematic reviews, Sismondo, and Ahmer conclude that pharmaceutical company sponsorship is strongly associated with results that favour the sponsors’ interests 
. In studying “wish bias” in antidepressant drug trials, Barbui found that fluoxetine was favoured in clinical trials when fluoxetine was the experimental agent, and that comparator antidepressants were favoured in trials using fluoxetine as the reference agent 
. In a report with a noteworthy title (“Why Olanzapine beats Risperidone, Risperidone beats Quetiapine and Quetiapine beats Olanzapine”) Heres et al come to the same conclusion and suggest ways in which potential sources of bias can be addressed by study initiators, peer reviewers and readers 
. However, in a secondary analysis of a systematic review, Gartelhner found that the effect of study sponsorship on a systematically evaluated body of evidence of head-to-head trials was modest and perhaps not clinically significant 
We saw an urgent need for a clinical tool to allow choice of psychotropic drugs with respect to weight change. A full systematic review was beyond the scope of our resources, we therefore developed this hierarchical approach. The biggest challenge in conducting this systematic synthesis was the analysis of very heterogeneous study designs. While we have done our best to summarize the extremely large amount of published literature, we caution the user about the limitations of this analysis. These limitations include drug dosage, variation in reporting of weight gains, use of drug naïve versus non-drug naïve patients, mono-therapy vs. combination therapy, duration of treatment, psychiatric diagnosis, baseline patient characteristics such as age, gender, BMI, genetic factors, recovery from the underlying condition and concurrent weight treatments during the study.
The findings of this review highlight the need for the development of psychotropics that are not associated with weight gain. As well, a better understanding of the pharmacogenetics of psychotropic drug response might help select psychotropics for individuals so that weight gain is minimized. It is important to consider methods for minimizing the impact of weight gain induced by psychotropic drugs. Choices must be made on a case-by-case basis, with careful consideration of issues of weight, therapeutic efficacy, and other relevant factors discussed in this paper in order to minimize the impact of weight gain with psychotropic medications.
Further research is needed to determine actual weight gain for all psychotropics in drug naïve patients for sufficient lengths of time to determine the full impact of the weight gain and co-morbidities of this weight gain. These studies should be done at arms-length from industry funding and reported in both mean weight change and percent who gain more than 7% of initial body weight.