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Fleischhacker, W. A randomized trial of paliperidone palmitate and risperidone long-acting injectable in schizophrenia. Hough, D. After qualitative assessment, papers were selected and used for data extraction.
During data extraction, papers that were extensions of a previous meta-analysis but with different baseline data or reporting a subgroup analysis were excluded See Fig 1 Prisma Checklist flow diagram. The aim of the search was to identify RCTs, controlled clinical trials, and randomised open label studies.
The identified outcome was absolute change in weight. Studies were included if they reported data of one or more AP, or AP versus placebo or healthy control people. There were no restrictions with regard to diagnosis, age, dosage of AP or duration of AP exposure. No specific study protocol was made. This study was an extension of a previous meta-analysis [ 11 ].
We checked whether studies had a focused research question, a randomised study design, adequate and unbiased patient recruitment, unbiased measurement of outcomes, identification and control of major confounding factors, completeness of follow-up and accuracy of estimates.
In the case of conflict between reviewing researchers, publications were discussed with MB, SC and EV until consensus was reached. In case of remaining doubt the publication was further discussed with MD. The detailed evaluation and data entry were performed by SC and EV separately. MB supervised the search and data management process. New publications were entered into the existing database that was prepared for the previous meta-analysis [ 11 ]. The non-ITT analysis publications were therefore not included.
Only publications that reported body weight change per individual AP were included. The main outcome was defined as the body weight change in kilograms kgs after the initiation in the AP naive group or after the switch of an AP in the AP-switch group.
Weight change was calculated by subtracting end of study body weight from baseline study body weight body weight baseline—end body weight. In the instances in which standard errors were not available, these were calculated using the formulas below: in which:.
The number of antipsychotics complicates a comprehensive statistical analyses. Therefore, the number of AP included in the meta-analysis was restricted to those AP that were reported in the figures, i.
All analyses were performed using Stata 16 [ 33 ]. Analyses were stratified by AP-switch and AP-naive. A meta-regression was performed to test whether weight gain was different in AP- naive patients than in AP-switch patients in each AP, separately.
The computation of summary effects was carried out under the random-effects model, in which Tau was estimated using the DerSimonian-Laird method. Heterogeneity analyses were carried out using the chi-square, I-square, and Tau-square statistics. Tau-square estimates the total amount of variability heterogeneity among the effect sizes but does not differentiate between sources. Heterogeneity may be due to random or systematic differences between the estimated effect sizes.
I-square estimates the proportion of the total variability in the effect size estimates that is due to heterogeneity among the true effects. We also presented figures per AP for each outcome measure. These figures were for descriptive purposes only. For the second and third aim, meta-regression analyses were performed. Finally, in 6 most frequently used AP and in the placebo groups, a meta-regression was performed with BMI at baseline as a modifier.
Funnel plots were obtained and Egger tests were performed Stata commands meta-funnel and meta-bias, respectively. Trim-and-fill analysis was performed to estimate effects of publication bias. After checking for duplicates in both records and identifying publications through cross-referencing, we included publications See Prisma flow diagram. As we built upon our previous meta-analysis, both papers included in the previous meta-analysis and papers obtained from the current Pubmed or Embase search were already in the database.
In total, we found publications outside search strategies based upon Pubmed and Embase. Record screening by inspecting title resulted in papers eligible for abstract screening. Two hundred and sixteen papers had no data on body weight change, which resulted in papers for further independent screening and check on full-text eligibility see Fig 1 PRISMA flow diagram. One publication was treated as two separate studies, as it presented two separate data sets in a single paper [ 35 ].
After checking for quantitative analysis, studies eligible for analysis were included in the data base. For a more detailed explanation of the reasons for exclusion of publications in the meta-analysis, see PRISMA flow diagram and S3 in S2 File : publication included in the study. Funnel plots and Egger tests showed some evidence for publication bias in some of the analyses S7 and S8 in S2 File. In AP-switch patients, trim-and fill added studies, only in Olanzapine 6—16 weeks.
In the rare case that trim-and-fill added studies, pooled estimate and p-value were rather similar to the original analysis see also S7 and S8 in S2 File. Despite only the most frequently included AP were presented in a funnel plot, funnel plots with low numbers of studies could not be interpreted. Only 72 publications reported data on AP naive patients Table 1.
All AP were associated with an increase in body weight since the start of AP treatment, with the only exception being paliperidone, which showed a weight gain over the shorter periods but no weight gain over the two longer periods. Placebo did not show any relevant weight change in all 4 periods. Only ziprasidone showed some weight gain in the longest period See Fig 2. In most meta-analyses, heterogeneity was large, when 2 or more studies were included the I-square estimates were between 63 and The antipsychotics per period.
Green indicates almost no weight gain or weight loss. After the antipsychotic between brackets is indicated period in weeks, number of studies N and number of patients n were reported. Inspecting the figures for all antipsychotics in the AP-naive group, it was visible that the longer the AP use, the more the weight gain was.
See the forest plots in supporting files for more detailed information per antipsychotic the forest plots in S4a in S2 File : Forest plots AP-naive studies on weight change. For some AP only 1 time period was identified. Switching to amisulpride, placebo and ziprasidone was associated with weight loss in the long term. Although switching to amisulpride was associated with a small increase in weight gain in the shorter terms, a decrease in body weight was observed in the longer period of 16—38 weeks: wks After switching to ziprasidone, body weight decreased, and this loss of body weight was statistically significant in studies with longer duration see Fig 3 and Table 2.
Switching to placebo resulted in no or a small decrease in body weight See also Fig 3. Heterogeneity was large the I-square was above 60 with the exceptions of 6 analyses. Black indicates placebo. After the antipsychotic between brackets is indicated period in weeks, number of studies N and number of patients n. All other antipsychotics were associated with body weight gain after AP-switch. Most APs were associated with a mild increase in body weight around 1—2 kgs at various time periods, but other antipsychotics resulted in more pronounced weight gain: chlorpromazine, FGA, SGA, and olanzapine see Fig 3 and Table 2.
See for more detailed information per antipsychotic the forest plots in S4b in S2 File : Forest plots AP-switch studies on weight change. In amisulpride, aripiprazole, haloperidol, perphenazine, olanzapine, quetiapine and ziprasidone, there was more weight gain in AP-naive patients than in switch patients see Table 3. The remaining APs could not be analysed.
Analyses of differences in weight gain per diagnosis could only be performed in AP-switch patients. The AP-naive studies included almost only patients with a diagnosis of schizophrenia. Table 4 shows the meta-regression data. There was no statistically significant evidence that AIWG was dependent of psychiatric diagnosis stratified by duration category, Table 4.
S5 in S2 File : All psychiatric diagnoses reported in the included papers. In AP switch patients, some but not all strata of aripiprazole, clozapine, haloperidol and olanzapine showed that a higher initial BMI was associated with less weight gain see S6 in S2 File.
In AP-naive patients and in patients randomised to risperidone or placebo, this was not the case see S6 in S2 File. This meta-analysis is an update of a previous meta-analysis [ 11 ] and covers a longer period 1-Jan till June Newer APs have been included as well and we have stratified by duration of AP treatment in studies using 4 time periods.
In this update, AP-naive patients and AP switch patients were analysed separately. The main finding was that all APs were associated with mean weight gain over time, with the exception of ziprasidone. Placebo a control compound showed a small weight loss over time. Meta-regression analysis showed that weight gain was larger in AP-naive patients in most APs except paliperidone.
Previous research also showed that the increase in body weight in the short term first few months was more noticeable in AP naive patients [ 36 ] than in AP switch patients. This finding is in line with the notion that the younger and more leaner patients are at risk the most [ 37 , 38 ].
Nevertheless, the comparison between AP-naive and AP-switch also captures the notion that the AP-switch group is essentially a heterogenous group, as the reasons for switching antipsychotics are pluriform. These reasons for switching APs may include: lack of effect, as a result of weight gain or other side effects, because of the research protocol patients participate in and various other reasons.
It might be expected that patients who gained a significant amount of body weight as a result of an AP treatment e. Despite switch groups are heterogeneous, the comparison between AP-naive and AP-switch shows that the differences in results between those two types of patients are important.
Therefore it is necessary to analyse these groups of patients separately. We hypothesized that patients with higher BMI at baseline would gain less weight during the study period. This means that patients with higher BMI, including those who gained a significant amount of body weight by a previous AP, are more likely to show weight decrease. Whereas lower BMI may increase the risk for more substantial body weight gain. This might explain why in the AP-naive show relative more weight gain, as they are found to be younger and more lean, and therefore more at risk for AIWG [ 37 — 39 ].
In this meta-analysis this cannot be tested. The analyses are just explorative, because BMI at the subject level was not available. Future original studies should be performed to replicate this finding. In AP-naive patients, body weight increased clearly over time for all antipsychotics, except for paliperidone. A meta-analysis using data from first episode psychosis patients showed a similar result [ 40 ], which replicates our previous study [ 11 ].
These findings indicate that these medications do result in serious weight gain in most patients with clinical implications. Patients with a younger age and lower BMI are more vulnerable for excessive weight gain [ 38 , 39 ].
Earlier meta-analyses generally included shorter follow-up periods and predominantly AP-switch studies because of methodological pitfalls in studies with longer follow-up duration. The benefit in our current meta-analysis is that weight gain is examined across 4 stratified duration of AP use, which shows that body weight changes for a long time after the initiation or switch of an AP.
Recent meta-analyses did not stratify between AP-naive and AP switch patients, thereby underestimating the impact of antipsychotic medication on weight gain in AP-naive patients [ 9 , 13 , 17 , 18 ]. Future RCTs and naturalistic follow-up studies are needed to clarify the real impact of APs on body weight in AP-naive patients over time, as weight gain is a predictor of non-compliance and metabolic and cardiovascular dysregulations [ 3 , 22 ].
Previously, clozapine and olanzapine have been identified to be the two AP with most weight gain after AP-switch [ 9 , 11 , 17 , 18 , 41 ]. In this meta-analysis, these three APs were not associated with clinically relevant weight loss after switch. Whereas the body weight loss of aripiprazole was minimal to nothing.
Only ziprasidone showed a clear reduction in body weight after switching assessed at multiple time periods and weight loss was similar with placebo. The recently introduced APs, such as brexpiprazole and cariprazine, did not really differ from APs such as paliperidone or risperidone.
However, the number of studies and participants were limited. Recent network meta-analyses found that the impact of these AP on body weight were mild, with a modest body weight increase similar to aripiprazole after switching of an AP [ 17 , 18 ]. Using network analysis in the present data may help understand whether lurasidone in the long-run results in significantly less weight gain than older APs. The present meta-analysis did not provide evidence that diagnosis is a moderator.
This means that the AP related body weight changes are irrespective of the diagnosis. This seems counterintuitive. But the research literature is inconclusive. Some studies conclude that patients with schizophrenia appear more at risk for metabolic syndrome and diabetes mellitus compared with patient with bipolar disorder [ 42 ]. Whereas others reported no evidence for differences in body weight change depending on diagnosis [ 43 — 45 ].
The finding that diagnosis was not associated with AIWG emphasizes the impact of neurotransmitters involved, steering neurobiological experiences like feeling hungry related to 5HT2c or Histamine antagonism. Feeling hungry likely results in carbohydrate intake, especially if the reward system is blocked by the D2 antagonist. Similar to every healthy person, patients are very tempted to eat, especially hedonic foods like carbohydrates and fats [ 20 ].
When visually inspecting Fig 2 , it can be observed that the longer an AP is used, the more weight gain is noted. Hallmark meta-analyses did not control for the duration of an AP as a contributing factor for weight gain. Finally, we showed that treatment with the HTR2C-specific agonist lorcaserin suppressed olanzapine-induced hyperphagia and weight gain. Lorcaserin treatment also improved glucose tolerance in olanzapine-fed mice.
Collectively, our studies suggest that olanzapine exerts some of its untoward metabolic effects via antagonism of HTR2C. Atypical antipsychotics AATPs are second-generation antipsychotics that are currently used to treat a variety of psychiatric conditions, including schizophrenia, bipolar disorder, depression, and autism 1. Despite their documented efficacy and low risks for extrapyramidal symptoms, most AATPs have been linked to drug-induced metabolic side effects, including excessive weight gain, dyslipidemia, and type 2 diabetes 2.
Notably, schizophrenic patients have a reduced life span, with obesity-related metabolic syndrome being the leading cause of death 2. Moreover, the incidence of diabetes among AATP users is 4 times higher than in age-, race-, and sex-matched controls 3. While morbid obesity and type 2 diabetes typically take years to unfold in the general population, these conditions manifest acutely within months following AATP treatment 4. The rapid disease onset suggests a distinct etiology underlying AATP-induced metabolic syndrome that remains poorly understood.
AATPs bind to multiple monoamine receptors in the brain 5. The beneficial psychotropic effects are thought to be mediated primarily by a combinatorial blockade of serotonin 2a and dopamine D 2 receptors 6. Among them, Htr2c encodes the 5-HT 2C receptor, which acts in the brain to regulate food intake, body weight, and glucose metabolism 10 , However, previous efforts to test this hypothesis using genetic models have been hindered by the difficulty of replicating AATP-induced metabolic perturbations in mice Although it is one of the most commonly prescribed and effective AATPs, olanzapine causes the most weight gain and metabolic impairments in humans In the current study, we investigated the role of Htr2c in olazanpine-induced metabolic impairments in mice.
Nuclear magnetic resonance NMR analysis revealed an increase in fat mass, but not lean mass, in olanzapine-fed mice Figure 1B. In addition to causing obesity, chronic olanzapine treatment impaired glucose tolerance Figure 1C. Moreover, fasting plasma insulin levels were significantly higher in olanzapine-fed mice Figure 1D. Mice were fed a control diet D; Research Diets Inc.
Mice were then switched to the olanzapine diet 50 mg olanzapine compounded into 1 kg of the control diet, Research Diets Inc. Olanzapine is associated with food craving and binge eating in humans In addition to causing hyperphagia, olanzapine has a sedative effect that is thought to contribute to weight gain in humans We found a reduction in physical activity immediately following the dietary switch Figure 1F. Furthermore, indirect calorimetry analysis revealed an unexpected increase in parameters of energy expenditure, including heat production Figure 1G , oxygen O 2 consumption, and carbon dioxide CO 2 production following olanzapine exposure Supplemental Figure 1, B and C.
The respiratory exchange ratio remained constant before and after olanzapine treatment Supplemental Figure 1D. However, olanzapine-induced hyperphagia was less prominent in male compared with female mice. We tested whether hyperphagia was a primary contributor to weight gain using a pair-feeding paradigm. When fed ab libitum, mice on the olanzapine diet developed hyperphagia Figure 1E and gained significantly more weight than those fed the control diet during a 7-day period Supplemental Figure 1E.
In the pair-fed group, hyperphagia was prevented by restricting olanzapine-fed mice to the same amount of food consumed by those fed the control diet. We found that weight gain in the pair-fed olanzapine mice was similar to that in control mice during the same period, suggesting that hyperphagia is required for olanzapine-induced weight gain Figure 1H.
A Body weight. B Body composition. C GTT. D Plasma insulin levels. H Weight gain in ad libitum— and pair-fed mice. OLZ, olanzapine treated; Con, control. The olanzapine-induced hyperphagia and weight gain allowed us to use genetically modified mice to investigate candidate genes and pathways that underlie these metabolic perturbations.
In contrast with WT mice, olanzapine-fed Htr2c -null mice had body weight and body composition comparable to those fed the control diet Figure 2, A and B. Furthermore, olanzapine treatment did not significantly alter glucose tolerance or fasting plasma insulin levels in Htr2c -null mice Figure 2, C and D. We next repeated the metabolic cage analysis in Htr2c -null mice and found that hyperphagia did not develop in Htr2c -null mice following acute olanzapine exposure Figure 2E and Supplemental Figure 3A.
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