CRWG

Because we analysed a wide variety of antipsychotics, CRWG per antipsychotic can be assessed. However, with the current methods it was impossible to compare CRWG between different antipsychotics. The reader should keep this in mind when reading different percentages for antipsychotics below. Network meta-analysis using the present data-set can enable those conclusions in the future (also see the Methodological issues section below). CRWG was severe for clozapine and olanzapine, with respectively 76.3% and 36.9% of patients gaining ≥7% body weight after 38 weeks of use. After prolonged use, paliperidone (18.3%), quetiapine (17.0%) and risperidone (23.0%) showed moderate percentages of CRWG, as did so-called metabolically friendly antipsychotics: aripiprazole (17.2%), amisulpride (20.6%), asenapine (16.4%) and haloperidol (22.8%). This may seem counterintuitive, as most studies and systematic reviews report the average weight gain in a study population, which may obscure the true magnitude of antipsychotic-induced weight gain. An average weight change is calculated by averaging weight gain in some patients and weight loss in others and may also be distorted by outliers in a small proportion of patients. When focusing on average weight change, some antipsychotics may appear metabolically friendly, i.e. on average do not lead to much weight gain, but this average does not apply to all patients. Thus, even if an antipsychotic is generally considered metabolically friendly and associated with limited weight gain or even CRWL in some patients, other patients using it may still experience CRWG. Proportions showing CRWG were relatively low for lurasidone (7.4%) and ziprasidone (7.6%) after 38 weeks of use. Proportions showing CRWG were similar to placebo (6.7%), but available data for lurasidone and ziprasidone were limited. Of the newer antipsychotics, brexpiprazole and cariprazine were promising for the short term, but little or no data were available for the long term (Table 1).

CRWG and duration of antipsychotic use

Visual inspection of Fig. 1 shows that CRWG continues to increase with longer antipsychotic use, except for ziprasidone and brexpiprazole. In a subset of antipsychotics with sufficient data, meta-regression analyses showed that a longer duration of use was associated with more CRWG for most antipsychotics (Table 2). This is also the case for so-called metabolically friendly antipsychotics such as aripiprazole, asenapine and haloperidol, as well as the newer compound cariprazine. The result for cariprazine should be interpreted with caution as it was based on a single study. However, placebo was also associated with CRWG in studies exceeding 16 weeks.

Previous systematic reviews and meta-analyses focused mainly on short-term weight gain or did not distinguish between short-term and long-term studies.^{Reference Huhn, Nikolakopoulou and Schneider-Thoma24,Reference Pillinger, McCutcheon, Vano, Mizuno, Arumuham and Hindley25,Reference Barton, Segger, Fischer, Obermeier and Musil28–Reference Musil, Obermeier, Russ and Hamerle32} In contrast, our findings suggest that time is a relevant factor in antipsychotic-induced weight gain. Unfortunately, a majority of studies included in this meta-analysis focused on the short term (<6 weeks; 6–16 weeks), and only about 15% of the studies focused on the long-term. The availability of long-term data is limited and suggests that the true impact of long-term antipsychotic use on weight gain remains hidden. Conducting long-term studies or longitudinal studies in this patient population presents methodological and other challenges but is essential to obtain a complete picture of antipsychotic-induced weight gain. We believe that non-randomised studies will better answer this question. We plan to conduct a systematic review and meta-analysis on such studies in the near future. However, non-randomised studies also have methodological shortcomings.

Our findings suggest that the duration of antipsychotic use is an important determinant of weight gain, highlighting the importance of monitoring weight gain and weight management strategies from the start and throughout antipsychotic treatment.^{Reference Bak, Drukker, Cortenraad, Vandenberk and Guloksuz17,Reference Barton, Segger, Fischer, Obermeier and Musil28,Reference Musil, Obermeier, Russ and Hamerle32}

CRWL after antipsychotic switch

CRWL was noticeable for aripiprazole (9.1%), lurasidone (12.6%) and ziprasidone (28.6%), but also olanzapine (10.8%) after 38 weeks of treatment. Except for ziprasidone, CRWL for these antipsychotic was similar to CRWL for placebo (12.0%). Data, however, are too limited to draw firm conclusions. For lurasidone and ziprasidone, long-term results were based on a single study (Table 3). The effect of treatment duration on weight loss could be tested for only a limited subset of antipsychotics: aripiprazole, asenapine, olanzapine and paliperidone. For olanzapine and paliperidone, a longer duration of antipsychotic use was associated with more CRWL (Table 4).

Recently, much research has been done on strategies to prevent or counteract antipsychotic-induced weight gain. Behavioural therapies, exercise programmes, dietary counselling and pharmacological interventions such as metformin and topiramate may have a moderate effect on reducing weight gain.^{Reference Firth, Siddiqi, Koyanagi, Siskind, Rosenbaum and Galletly2,Reference Dayabandara, Hanwella, Ratnatunga, Seneviratne, Suraweera and de Silva7,Reference Vancampfort, Firth, Correll, Solmi, Siskind and De Hert54–Reference Hiluy, Nazar, Goncalves, Coutinho and Appolinario56} A switch to so-called metabolically friendly antipsychotics (amisulpride, aripiprazole, haloperidol, lurasidone, ziprasidone) might also result in weight loss.^{Reference Dayabandara, Hanwella, Ratnatunga, Seneviratne, Suraweera and de Silva7,Reference Rummel-Kluge, Komossa, Schwarz, Hunger, Schmid and Lobos23–Reference Pillinger, McCutcheon, Vano, Mizuno, Arumuham and Hindley25} In a recent meta-analysis of antipsychotic-switch studies, switching to aripiprazole and ziprasidone was associated with weight loss, but a switch to amisulpride, paliperidone, risperidone, quetiapine or lurasidone was not.^{Reference Siskind, Gallagher, Winckel, Hollingworth, Kisely and Firth57} However, switching to a metabolically friendly antipsychotic should be done with caution and always involves uncertainties, for instance about the effect on symptoms and side-effects. In addition, there is evidence that weight gain and other metabolic side-effects appear to be associated with more clinical improvement.^{Reference Pillinger, McCutcheon, Vano, Mizuno, Arumuham and Hindley25,Reference Garcia-Rizo58} Our meta-analysis shows modest CRWL for aripiprazole, lurasidone and olanzapine, comparable with placebo. Surprisingly, although olanzapine is known to be associated with weight gain, and the present data showed that the proportion of patients showing CRWG increased, in other patients CRWL increased over time. However, this result was strongly influenced by one long-term study with a 2-year follow-up, comparing long-acting injection and oral administration, but with no significant differences between both groups.^{Reference Detke, Weiden, Llorca, Choukour, Watson and Brunner59} Ziprasidone appears promising for long-term CRWL, but these results were based on one study^{Reference Chen, Bobo, Watts, Jayathilake, Tang and Meltzer46} and need replication in larger patient populations to draw firm conclusions. Based on these results, there is insufficient evidence to recommend switching antipsychotic as a weight management strategy.

In contrast to current guidelines that recommend switching to a metabolically friendly antipsychotic as the first step in controlling antipsychotic-induced weight gain, we strongly recommend considering alternative strategies for losing body weight. Focus first on individual lifestyle counselling and exercise interventions, possibly supplemented with metformin, topiramate or bupropion, before switching to another antipsychotic.^{Reference Marteene, Winckel, Hollingworth, Kisely, Gallagher and Hahn15,Reference Vancampfort, Firth, Correll, Solmi, Siskind and De Hert54–Reference Hiluy, Nazar, Goncalves, Coutinho and Appolinario56}

Antipsychotic-naive versus antipsychotic-switch populations

Recent network meta-analyses did not distinguish between antipsychotic-naive patients and antipsychotic-switch patients.^{Reference Huhn, Nikolakopoulou and Schneider-Thoma24,Reference Pillinger, McCutcheon, Vano, Mizuno, Arumuham and Hindley25} However, this distinction is relevant because antipsychotic-naive patients are more likely to develop antipsychotic-induced weight gain, as previous meta-analyses^{Reference Bak, Fransen, Janssen, van Os and Drukker20,Reference Tek, Kucukgoncu, Guloksuz, Woods, Srihari and Annamalai31} have shown. Moreover, weight gain in antipsychotic-naive patients is much more indicative of the effect of a specific antipsychotic on weight, whereas in switch studies the effect of a previous antipsychotic can certainly not be excluded for the short term and therefore leads to bias.^{Reference Strassnig, Miewald, Keshavan and Ganguli60} We could include only a few studies that assessed CRWG and no studies that assessed CRWL in an antipsychotic-naive population. We excluded multiple studies that had data on 7% weight change but were either not randomised, used a per-protocol analysis or included patients younger than 15 years. Antipsychotic-naive patients taking aripiprazole, olanzapine and quetiapine showed significantly more CRWG than switch patients (Table 3). Results for haloperidol, risperidone and ziprasidone were not statistically significant. These results are consistent with previous findings indicating that antipsychotic-naive patients are particularly vulnerable to excessive weight gain.^{Reference Bak, Fransen, Janssen, van Os and Drukker20,Reference Tek, Kucukgoncu, Guloksuz, Woods, Srihari and Annamalai31} This is probably because the antipsychotic-naive patients were not overweight at baseline as there is no effect of prior antipsychotic use on body weight, and because they are younger.^{Reference Tarricone, Gozzi and Berardi33,Reference Manu, Dima, Shulman, Vancampfort, De Hert and Correll61–Reference Verma, Liew, Subramaniam and Poon63}

Because weight gain is a predictor of non-adherence as well as metabolic and cardiovascular dysregulation,^{Reference De Hert, Dekker, Wood, Kahl, Holt and Möller5,Reference Eckel, Li, Kuxhaus, Stefan, Hu and Schulze64} assessment of the effect of antipsychotics on weight gain is necessary and requires long-term RCTs and prospective studies. Until recently, few pharmacological studies had investigated the efficacy and side-effects of antipsychotics exclusively in populations with first-episode psychosis.^{Reference Strassnig, Miewald, Keshavan and Ganguli60} In addition, many people with first-episode psychosis struggle with substance misuse or depression or use co-medications such as benzodiazepines or antidepressants, which often exclude them from participation in an RCT.^{Reference Foley and Morley62,Reference Verma, Liew, Subramaniam and Poon63} A recent analysis of two national patient registries estimated that only about 20% of patients with schizophrenia spectrum disorders may be represented in RCTs.^{Reference Taipale, Schneider-Thoma, Pinzon-Espinosa, Radua, Efthimiou and Vinkers65} Studies with a naturalistic design then have the advantage of investigating antipsychotic-induced weight gain in a realistic setting and may help us to explain underlying mechanisms that influence it.^{Reference Strassnig, Miewald, Keshavan and Ganguli60}

Diagnosis

We found some evidence that diagnosis moderates CRWG (Table 4). People with bipolar disorder taking aripiprazole, cariprazine, lurasidone or olanzapine showed less CRWG compared with those with schizophrenia (<6 weeks). People with major depressive disorder, generalised anxiety disorder or borderline personality disorder treated with quetiapine showed less CRWG than whose with schizophrenia (<16 weeks). People with dementia taking olanzapine or risperidone also showed less CRWG (6–16 weeks). These differences in CRWG between schizophrenia and other diagnoses were visible only in the short term.

Previously, we found no evidence that diagnosis moderates weight gain.^{Reference Bak, Drukker, Cortenraad, Vandenberk and Guloksuz17} However, in this study, there is weak evidence that diagnosis is of influence. This may be explained by the fact that only the extremes of a spectrum, i.e. individuals who gain or lose ≥7% of their body weight, were examined here. Even if an antipsychotic is, on average, associated with no or minimal weight gain, some individuals may still experience CRWG. For example, a subgroup of individuals with schizophrenia may experience more short-term CRWG than individuals with other psychiatric diagnoses, despite the fact that there was no significant difference in weight gain as a continuous measure between diagnoses.^{Reference Bak, Drukker, Cortenraad, Vandenberk and Guloksuz17}

Previous research has been inconclusive about the role of diagnosis in antipsychotic-induced weight gain. Some studies concluded that people with schizophrenia were at greater risk of developing metabolic syndrome or diabetes mellitus than people with bipolar disorder.^{Reference van Winkel, van Os, Celic, Van Eyck, Wampers and Scheen66} Other studies found no differences in weight gain between the diagnoses.^{Reference Correll, Frederickson, Kane and Manu67–Reference van der Heijden, Steylen, Hoogenbosch, Slaar, Kok and Hendrikx69} Several studies have investigated the possibility of a shared genetic predisposition between schizophrenia and weight gain, but the results are still inconclusive.^{Reference Grajales, Ferreira and Valverde70}

Regardless of the influence of diagnosis on antipsychotic-induced weight gain, the results of our meta-analysis indicate that a substantial proportion of patients will experience CRWG with all antipsychotics.

Methodological issues

Our comprehensive meta-analysis included 202 papers addressing the use of antipsychotics and clinically relevant weight change. Another strength is that all RCTs irrespective of study duration or psychiatric diagnosis were included. However, several limitations should be kept in mind when interpreting the results of this meta-analysis.

First, our meta-analysis focused exclusively on CRWG or CRWL, but relevant studies did not systematically report CRWG and CRWL. Therefore, we excluded multiple studies that met all other inclusion criteria. Nevertheless, we consider this meta-analysis to be a useful and valuable addition to previous analyses as it provides information on the severe body weight changes associated with antipsychotic use and as such may guide clinical decision-making. Despite the representation problems in RCTs,^{Reference Taipale, Schneider-Thoma, Pinzon-Espinosa, Radua, Efthimiou and Vinkers65} we assume that the studies that reported CRWG and CRWL are sufficiently representative and generalisable to real-world patient populations.

Second, this meta-analysis was intended to give an overview of individual antipsychotic drugs, not to compare them. With the analysis method we used, comparisons between interventions (including placebo) were not possible. Direct comparison of weight change between antipsychotics would require novel analysis methods such as a network meta-analysis. Given the stratified structure of the data, i.e. studies were included with multiple time points and multiple antipsychotics, and the heterogeneity of the included studies and patient groups, this was not possible within the scope of the current meta-analysis.^{Reference Tonin, Rotta, Mendes and Pontarolo71} Previous network meta-analyses examining CRWG included only short-term studies (≤13 weeks)^{Reference Huhn, Nikolakopoulou and Schneider-Thoma24} or analysed data at the individual patient level.^{Reference Spertus, Horvitz-Lennon, Abing and Normand30}

Third, we included only randomised studies in this meta-analysis because this design has the lowest risk of bias and the highest methodological quality at the expense of ecological validity. We excluded multiple cohort studies, which often follow large study populations for a prolonged period. The majority of studies included in this meta-analysis were of relatively short duration, whereas our results clearly showed that weight change continues even after 38 weeks of treatment. Cohort studies also include patients with comorbidities and co-medication often excluded in RCTs.^{Reference Barton, Segger, Fischer, Obermeier and Musil28} A systematic review or meta-analysis based on cohort studies could therefore provide a better understanding of the long-term effects of antipsychotics on weight gain in large study populations. Meta-analyses such as the present one including only RCTs and meta-analyses including observational studies both have their own merits. Since both types of meta-analysis are needed to obtain a complete overview, a meta-analysis including observational studies is needed in the near future.

Fourth, in this meta-analysis we could include only a handful of studies that examined clinically relevant weight change in antipsychotic-naive patients. Studies in antipsychotic-naive patients were more often excluded. Therefore, results should be interpreted with caution. It is clear that more research is needed in the antipsychotic-naive population. Research on antipsychotic-induced weight gain in this population is highly relevant because, as first-time users, previous use of an antipsychotic does not affect weight gain. Moreover, they are more vulnerable to excessive weight gain because of their lower age and lower BMI.^{Reference Foley and Morley62}

Furthermore, a meta-analysis using data reported in original papers can assess only what the studies analysed. Results controlled for confounders (such as age and baseline BMI) and results stratified by a modifier (such as antipsychotic dose) can be extracted only when the original studies reported them. For example, antipsychotic dose differed within one arm of RCTs and therefore antipsychotic dose could not be analysed as a modifier. Only when the RCTs included study arms with different dosages or when the dosage differed between studies could this be analysed in our meta-analysis. For some antipsychotics (olanzapine, clozapine), preliminary evidence indicates a dose–response relationship between serum concentrations and metabolic outcomes; for other antipsychotics, the evidence for such a dose–response relationship is limited.^{Reference Simon, van Winkel and De Hert72} New original research could shed more light on this. We could not correct for antipsychotic drug use before participation in the trials. As most studies included here are antipsychotic-switch studies, a recording of the pre-switch antipsychotic would have been important. However, these pre-switch antipsychotics were not given or were listed as a percentage of which antipsychotic was previously prescribed. Except for a recent meta-analysis on antipsychotic switching,^{Reference Siskind, Gallagher, Winckel, Hollingworth, Kisely and Firth57} pre-switch medication is usually not included in meta-analyses. Interpreting the data is arduous^{Reference Musil, Obermeier, Russ and Hamerle32} and underscores the relevance of investigating antipsychotic-induced weight gain in an antipsychotic-naive population.

The present meta-analysis aimed to be comprehensive and thus to include all RCTs. The RCTs were not restricted to a specific diagnosis, age group or study duration. Despite the fact that all antipsychotics were analysed separately, the data showed a high degree of heterogeneity and results should therefore be interpreted with caution. However, because of the heterogeneity, the data were analysed using the random-effects option.

We included only articles written in English because it would be difficult to judge the methodological and outcome properties otherwise. A few studies from China or other Asian countries were therefore excluded. A meta-analysis found Asian patients to have a lower BMI and lower antipsychotic-induced weight gain than Western patients.^{Reference Tek, Kucukgoncu, Guloksuz, Woods, Srihari and Annamalai31} Another meta-analysis excluded Chinese studies because of a higher risk of methodological shortcomings.^{Reference Huhn, Nikolakopoulou and Schneider-Thoma24} We did include studies from China written in English. We did evaluate those articles as methodologically sound and they had all been published in peer-reviewed journals.

Finally, we did not include unpublished work in our meta-analysis, and studies with null findings tend to remain unpublished. We checked poster presentations and conference abstracts to partly overcome this. We found some evidence of publication bias, particularly for antipsychotics with few available studies. Where possible, post hoc trim-and-fill analyses were performed to control for this, but the pooled estimates and P-values were similar to the original analyses.

Clinical implications

Switching antipsychotics can lead to both clinically relevant weight gain and weight loss, although weight gain is more prominent. Switching to a metabolically friendly antipsychotic may help patients to lose some weight, but it does not appear to be very effective in substantially reducing body weight and carries the risk of worsening symptoms.^{Reference Marteene, Winckel, Hollingworth, Kisely, Gallagher and Hahn15,Reference Siskind, Gallagher, Winckel, Hollingworth, Kisely and Firth57} Clinically relevant weight gain is more pronounced in antipsychotic-naive patients, which emphasises the importance of immediate follow-up. Prevention of antipsychotic-induced weight gain and subsequent complications ultimately appears to be the best strategy and should be the focus of treatment. Careful consideration of possible side-effects of antipsychotics and individual risk factors for increased vulnerability to weight gain is crucial before initiating antipsychotic treatment.