Which atypical antipsychotic least weight gain

Published studies including uncontrolled observations, large retrospective database analyses and controlled experimental studies, including randomised clinical trials, indicate that the different second-generation antipsychotics are associated with differing effects on glucose and lipid metabolism.

These studies offer generally consistent evidence that clozapine and olanzapine treatment are associated with an increased risk of diabetes mellitus and dyslipidaemia. Inconsistent results, and a generally smaller effect in studies where an effect is reported, suggest limited if any increased risk for treatment-induced diabetes mellitus and dyslipidaemia during risperidone treatment, despite a comparable volume of published data. A similarly smaller and inconsistent signal suggests limited if any increased risk of diabetes or dyslipidaemia during quetiapine treatment, but this is based on less published data than is available for risperidone.

The absence of retrospective database studies, and little or no relevant published data from clinical trials, makes it difficult to draw conclusions concerning risk for zotepine or amisulpride, although amisulpride appears to have less risk of treatment-emergent dyslipidaemia in comparison to olanzapine.

With increasing data from clinical trials but little or no currently published data from large retrospective database analyses, there is no evidence at this time to suggest that ziprasidone and aripiprazole treatment are associated with an increase in risk for diabetes, dyslipidaemia or other adverse effects on glucose or lipid metabolism.

Inspection of figure 1 to 8 suggests that other AP also display duration-response associations with weight gain. Although studies in AP-naive patients are more informative on weight gain induced by a specific AP, only one previous meta-analysis addressed the issue of weight change after start of an AP in AP-naive patients [26].

An increase in body weight and BMI for the combined group of all AP in AP-naive patients with schizophrenia over three duration categories of AP use was reported: 4—8 weeks, 10—12 weeks and 24—48 weeks [26].

This is in agreement with the present meta-analysis that showed that duration of AP use in AP naive patients resulted in weight gain. This result confirms also the direct impact of AP on weight gain. Switching to an AP like amisulpride, aripiprazole or ziprasidone may not result in weight loss in all cases, as the mean weight change post-baseline according to this meta-analysis is neutral. The consequence is that switching to another AP should be planned with care involving monitoring and evaluation of at least body weight and BMI, among other metabolic parameters [51].

It sheds light on the mean changes in body weight, as treatment with amisulpride, aripiprazole or ziprasidone resulted in a higher proportion of patients with clinically relevant weight loss, compared to other AP.

Combining mean weight change, the proportion of clinically relevant weight gain and weight loss, offers a more precise impact of AP on body weight. The same is seen for olanzapine.

Olanzapine shows a mean increase in body weight over the various duration categories, but even for this AP, a small proportion of patients showed clinically relevant weight loss. Previous systematic reviews and meta-analyses reported that clozapine and olanzapine induce most severe weight gain [19] , [20] , [24] , [26].

Amisulpride, aripiprazole and ziprasidone were weight neutral and may even result in some weight reduction [52]. A direct comparison between AP to calculate differences between the various AP was only presented by Rummel-Kluge, performing a head-to-head comparison [25] Leucht and colleagues [35] also showed that i all AP are associated with at least some weight gain compared with placebo and ii that olanzapine and clozapine have the most profound impact on weight gain.

These two studies uniquely allow for a direct comparison between AP. However, it should be kept in mind that the study by Leucht and colleagues was restricted to patients with a diagnosis of schizophrenia, with a follow-up time of 4—12 weeks, and only presenting a single weight related outcome measure mean body weight change. The short period of AP use and the diagnostic restrictions may explain some of the differences found between this study and the study by Leucht and colleagues [35].

The weight gain post-baseline for most AP in this study may not seem severe. Several factors may explain this finding. First, all diagnostic categories were included in the analyses. In most of the earlier meta-analyses, inclusion was restricted to severe mental illness, schizophrenia or bipolar disorders.

Patients with SMI have an increased risk for metabolic problems like obesity [9] , [53] , [54]. Within the group of SMI, the risk for weight gain is more enhanced for schizophrenia than for bipolar disorder [55] , [56]. Additionally, the level of weight change is predicted by baseline BMI. On the other hand, a continuous increase in body weight was observed over time, implying that switching from one AP to another AP has limited effect on body weight, even for AP like aripiprazole or amisulpride.

Only ziprasidone may result in some weight loss. This issues needs to be addressed in more detail given its clinical importance. A previous meta-analysis suggested that switching from higher to lower metabolic risk AP as a way of managing metabolic side should be conducted with care, considering the effect on psychopathology and other side effects [51].

Our findings also shed light on the effect of switching from so-called high to low metabolic risk AP. A proportion of patients may indeed benefit and lose weight.

However, prolonged duration of AP use, the mean weight did not change. The principal message is that switching to an AP with a different metabolic risk profile does not always result in losing body weight. Psychiatrists should keep in mind that switching antipsychotics requires monitoring and evaluation [51] and may benefit from concurrent non-pharmacological interventions [58] , [59].

In the present systematic review, only RCTs were included. In our view this is a legitimate choice because the RCT study design is generally accepted as gold standard [60].

In addition, the RCT design also has its drawbacks. The patient group in an RCT is kept artificially homogeneous; all patients with comorbidity, using other medications or presenting with substance use problems tend to be excluded. Drop-out due to probable weight problems may also bias the results.

Therefore, only ITT analyses were included, as a best possible correction procedure in the analyses. These factors impact on the generalizability of the results.

In real life clinical practice therapeutic effects of the tested medications may be different and side-effects like weight changes may also be different because of co-medication and other factors.

For these two reasons, future meta-analyses on various antipsychotics including and comparing, both RCTs and observational studies would be a welcome addition to the present meta-analysis. In addition, a follow-up meta-analysis, using the present data set, need to address direct comparison of weight change between AP and modifying factors, using modern analysis techniques like network analysis.

Despite the fact that various systematic reviews have been published before, this systematic review is the only meta-analysis that did not exclude any AP a priori. In addition, a clinically intuitive exposure period was used to assess the association between duration of AP intake and weight change. In spite of these advantages, several limitations apply. First, despite the inclusion of articles, the results for each AP separately were often based on very limited numbers of articles - one to three.

This was occasioned by grouping length of AP use in 4 exposure periods. Data thus were particularly sparse for AP-naive groups. This calls for a careful interpretation of results.

On the other hand, the results of various outcome measures all point in the same direction. Second, the aim of the present meta-analysis was to test whether weight changes are significantly different from the null for each AP across the 4 exposure periods.

Third, the definition of the 4 exposure categories is based on the average duration of exposure of the studies in the meta-analysis. Although the periods are chosen around the most common time frames presented in the studies, the demarcation is arbitrary. Most studies have fixed periods, however a substantial number of publications used average duration of study. This may have resulted in some measure of regression to the mean. Fourth, weight gain in groups treated with AP could be the result of other medications like antidepressants or mood stabilisers.

This problem is not present, as in studies that entered this meta-analysis, all other medications did not change during the study period, except the AP studied and control medication. Studies on weight change intervention were excluded. Fifth, not all AP were included. Publications on older AP rarely describe data on the adverse event of weight change.

Further, AP with a single reference, blonanserine, fluphenazine, levopromethazine, lurasidone, melperone, pimozide and zuclopentixol, similarly could not be included. Only papers published since were included, the year the meta-analysis by Allison [19] was published. This paper represented the start of a growing interest in metabolic side effects of AP, particularly weight gain. The current meta-analysis was originally designed as an extension of the Allison paper [19].

Unfortunately, first generation AP were mainly studied before and, therefore, information on weight is scarcer for some FGA. Furthermore, in a large number of studies neither standard deviation nor standard errors of the continuous outcomes weight change, BMI change were available and standard error, therefore, was estimated using a formula see methods section. Sensitivity analyses were performed to assess the impact of this on the final results weight change and BMI change , assuming a worst case scenario using the present data, it was possible to calculate the correlation between pre and post assessment if a study presented variances of both pre and post assessment as well as change score; in these studies the lowest correlation was 0.

Results of these sensitivity analyses were very similar to the original results results available upon request. Sensitivity analyses removing all estimated standard errors were not informative because too few studies remained results available upon request. Sixth, although only RCTs using the intention-to-treat principle were included, some of the included studies had a long-term follow-up after ending the study. Because these long-term results were very important for the research question, we did include these data, despite the fact that they were not per analysed intention-to-treat.

This means that for the long-term results bias, due to drop-out after weight gain is largest. In spite of this, weight gain in the long-term studies was largest.

Therefore, contrary to the expected direction of results with bias, we found that AP were associated with weight gain and that weight gain was larger over time.

Finally, this study did not address the issue of differences in weight change across various diagnostic groups. Indeed some reviews address this issue although restricted to only schizophrenia and bipolar disorder [27] , [61]. As mentioned in the introduction section, AP are more widely used and studied for various diagnoses other than schizophrenia of bipolar disorder.

In this meta-analysis, the number of studies that only include either schizophrenia or bipolar disorder is limited. The diagnostic categories included in studies mostly pertain to combinations of various psychiatric diagnoses of schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar disorder, or depression.

Given the complexity of the current study and the importance of the modifying factor diagnosis, a separate study to address this issue is required, but beyond the scope of the current analysis. Results reported in the present study provide a comprehensive overview of weight changes in all studies, but the reader has to keep in mind that associations may be stronger in specific diagnoses and weaker in others this meta-analysis.

Therefore, interpretation might be done with caution considering the potential influence of diagnosis or AP doses on weight change. All AP show weight gain over time. The increase in weight varies per AP and per duration of exposure category, both in switch studies and in studies of AP-naive patients. The vast majority of the studies included are switch studies. This analysis does not suggest that switching AP is likely to result in weight reduction in the long term. Additionally, in AP-naive patients the short term weight gain is substantial for all AP, although the number of studies with AP-naive patients was limited.

Apart from haloperidol and chlorpromazine, FGA are poorly studied with respect to their metabolic effects. Lastly, given that haloperidol is not weight neutral, it is questionable whether it can serve as a good comparator AP in studies. Forest plots S17—S Weight changes in AP naives per exposure category.

Forest Plots S36—S Forest plots S59a—S64c. Forest Plots S65—S72d. Number of studies reporting on each of the antipsychotics switch studies and drug naive separately. Conceived and designed the experiments: MB JvO. Supervised the process: JvO. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Introduction Antipsychotics AP induce weight gain.

Method A meta-analysis was conducted of clinical trials of AP that reported weight change. Results articles met inclusion criteria. Conclusion Given prolonged exposure, virtually all AP are associated with weight gain. Funding: These authors have no support or funding to report. Introduction Weight gain resulting in overweight and more particularly obesity is a growing problem worldwide.

Inclusion criteria and study evaluation The aim of the search was to identify randomised controlled studies RCT or controlled clinical trials where subjects were randomised into various AP intervention groups.

Age 18 years or older Minimum follow-up of one week Data available for AP treatment and weight change Randomised controlled trial, controlled clinical trial or clinical trial or phase IV clinical trial with adequate control group with intention to treat. Search strategy The PubMed search yielded citations. Download: PPT. Data extraction Data from RCT's were extracted if based on intention-to-treat analysis. Statistical analysis All analyses were performed using Stata 12 [39].

Results Weight change per type of antipsychotic for each duration of exposure category Of the included studies, a total of studies reported results on weight change records in the meta-analysis data. Figure 2. Weight change in kg per period per antipsychotic medication. Weight change in AP-naive patients for each duration of exposure category Weight change post-baseline in AP-naive patients was limited to 39 studies, yielding 90 records. Figure 3. Weight change kg per period only including AP-naive samples.

Table 2. Metaregression of weight changes per period in drug-naive patients. BMI change per duration of exposure category Ninety-one studies reported results on BMI change records in the meta-analysis data. Figure 6. Proportion of weight increase per antipsychotic per time period. Discussion Main findings This meta-analysis presents four outcome measures: i body weight change, ii BMI change, iii proportion of clinically relevant weight gain and iv proportion of clinically relevant weight loss for an extensive number of AP and within a subgroup of AP naive patients as well, simultaneously in one paper, The main result was that almost all AP showed a mean increase in body weight, BMI and a clinically relevant proportion of weight gain with increased duration of AP use, except for amisulpride, aripiprazole and ziprasidone which were weight neutral with duration of AP use.

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