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Cited by 44Schizophrenia research and treatmentPharmacology and Obesity TreatmentEating Disorders and Behaviors

Reversibility of Antipsychotic-Induced Weight Gain: A Systematic Review and Meta-Analysis

Open access
Speyer, Helene, Westergaard, Casper, Albert, Nikolai, Karlsen, Mette, Stürup, Anne Emilie, Nordentoft, Merete, Krogh, Jesper·2021·Frontiers in Endocrinology
DOI 10.3389/fendo.2021.577919PMC PMC8355990
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Abstract

Background and Aims: Weight gain is a major adverse effect of antipsychotic medication, negatively affecting physical and mental well-being. The objective of this study was to explore if dose reduction, discontinuation, switch to a partial agonist, or switch from polypharmacy to monotherapy will lead to weight loss. Methods: Controlled and uncontrolled studies reporting the effects of discontinuation, dose reduction, switch to a partial agonist, or switch from polypharmacy to monotherapy on weight were included. Primary outcome was difference in weight compared to maintenance groups based on controlled studies. Secondary outcome was change in weight from initiation of one of the included interventions until follow-up in a pre-post analysis. Results: We identified 40 randomized controlled trials and 15 uncontrolled studies including 12,279 individuals. The effect of the interventions, i.e. dose reduction, drug discontinuation, or switch to a partial agonis, reduced the weight with 1.5 kg (95% CI −2.03 to −0.98; P < 0.001) compared to maintenance treatment. The weight change from pre to post was a reduction of 1.13 kg (95% CI −1.36 to −0.90; P < 0.001). Conclusion: We found a significant but small reduction in weight, suggesting that antipsychotic-induced weight gain can be reversed to some degree. Only a few studies were designed to address the question as primary outcome, which limits the generalizability of our findings.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review and meta-analysis found that discontinuing, dose-reducing, or switching to a partial agonist antipsychotic produced a small but statistically significant weight reduction compared with maintenance treatment. However, few included trials were designed primarily to test reversibility of antipsychotic-induced weight gain, and no studies examined switching from polypharmacy to monotherapy.

Key findings

  • In the primary analysis of 40 randomized trials, pooled weight change versus maintenance treatment was −1.51 kg (95% CI −1.95 to −1.06; P < 0.001), with a 95% prediction interval of −4.71 to 1.61. Subgroup effects were −1.60 kg for discontinuation (N = 31; 95% CI −2.25 to −0.95), −0.46 kg for dose reduction (N = 7; 95% CI −2.00 to 1.07; P = 0.56), and −3.19 kg for switch to partial agonist (N = 2; 95% CI −3.43 to −2.96).
  • In the secondary pre-post analysis of 55 studies reporting 58 groups, pooled weight reduction from baseline to follow-up was −1.13 kg (95% CI −1.36 to −0.90; P < 0.001). Subgroup effects were −0.86 kg for discontinuation (N = 33), −1.25 kg for dose reduction (N = 7; P = 0.084), and −1.57 kg for switch to partial agonist (N = 18).
  • No included studies evaluated switching from antipsychotic polypharmacy to monotherapy. Heterogeneity was substantial (I² = 90.7% for the primary outcome; text reports 97.8% for the secondary outcome). Risk of bias was low in 26 trials and raised some concerns in 14 trials.

Methods

  • Systematic review and meta-analysis searching PubMed, Scopus, Lilac, Embase, and Web of Science on 18 February 2021. Eligible studies included adults over 17 years with major depression, schizophrenia, psychosis, bipolar disorder, or schizoaffective psychosis, and evaluated dose reduction, discontinuation, switch to a partial dopamine agonist, or switch from polypharmacy to monotherapy, with weight reported in kg or lbs.
  • Primary outcome was mean difference in weight between intervention and maintenance treatment from controlled studies; secondary outcome was pre-post weight change from intervention initiation to follow-up. Random-effects meta-analysis pooled end scores and change scores, reported 95% CIs and prediction intervals, and explored heterogeneity with subgroup analyses and meta-regressions using Comprehensive Meta-Analysis v3.11.
  • The review included 55 studies: 40 randomized controlled trials and 15 uncontrolled studies, totaling 12,279 participants (mean age 40 years; mean baseline weight 69.6 kg). Of these, 33 reported discontinuation, 7 dose reduction, 18 switch to a partial agonist, and none switch from polypharmacy to monotherapy.

Limitations

  • The authors state that the protocol was not pre-registered at PROSPERO; studies reporting only >7% weight gain were excluded, possibly introducing selection bias; adverse events such as relapse were not assessed; and lack of individual participant data precluded subgroup analyses by magnitude of weight gain or antipsychotic type.
  • The authors state that most included trials were designed to evaluate relapse prevention rather than weight reversibility, often with short stabilization phases and low mean baseline weight, limiting generalizability. Weight was usually reported as an adverse event with unclear handling of missing data, many trials were industry sponsored, and placebo exposure was often shortened by relapse. Pre-post analyses may overestimate effects due to regression to the mean, skewed loss to follow-up, or confounding.
  • Evident from the text: heterogeneity was high, the prediction interval for the primary outcome included the possibility of no effect in future trials, the primary switch-to-partial-agonist subgroup included only 2 randomized trials, and no studies addressed polypharmacy-to-monotherapy switching.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fendo.2021.577919

Cites

99 of 100 references verified0 citation errors · 1 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

14 of 35 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The magnitude of weight reduction is similar to the magnitude of weight lost from lifestyle interventions and by adding topiramate or metformin to current antipsychotic medication.

    “On the other hand, the magnitude is similar to the magnitude of weight lost from lifestyle interventions (79, 80) and by adding topiramate or metformin to current antipsychotic medication, all being recommended in clinical guidelines (81).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [79] Speyer, 2019, Lifestyle Interventions for Weight Management in People With Serious Mental Illness: A Systematic Review With Meta-Analysis, Trial Sequential Analysis, and Meta-Regression Analysis Exploring the Mediators and Moderators of Treatment Effects, Psychother Psychosom source
    • cites [80] Speyer, 2016, The CHANGE Trial: No Superiority of Lifestyle Coaching Plus Care Coordination Plus Treatment as Usual Compared to Treatment as Usual Alone in Reducing Risk of Cardiovascular Disease in Adults With Schizophrenia Spectrum Disorders and Abdominal Obesity, World Psychiatry source

      The Discussion (page unavailable) says prior behavioural-intervention trials generally reported favourable weight-reduction results. But the CHANGE trial’s Results (page unavailable) found no significant difference in weight between its lifestyle-coaching and comparison groups, and the paper provides no basis for the claimed similarity in magnitude. The topiramate/metformin clause is attached to a different citation, not this source. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [81] Cooper, 2016, BAP Guidelines on the Management of Weight Gain , Metabolic Disturbances and Cardiovascular Risk Associated With Psychosis and Antipsychotic Drug Treatment, J Psychopharmacol source
  • Premisecitation

    Prior case reports and a few studies suggest that at least some weight can be lost after discontinuation of antipsychotic medication.

    “Peculiarly, little research has been focusing on the potential reversibility of weight gain if the antipsychotic drug is reduced, discontinued, or switched to an agent with lower obesogenic properties, but case reports (13, 14) and a few studies of patients with intellectual disabilities and children with bipolar disorder (15) suggest that at least some weight can be lost after discontinuation.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [13] Dibben, 2005, Diabetes Associated With Atypical Antipsychotic Treatment may Be Severe But Reversible: Case Report, Int J Psychiatry Med source
    • cites [14] Sahoo, 2007, Dose-Dependent Acute Excessive Weight Gain and Metabolic Changes in a Drug-Naive Patient on Risperidone are Reversible With Discontinuation: A Case Report [4], Br J Clin Pharmacol source
    • cites [15] Upadhyay, 2019, Reversibility of Psychotropic Medication Induced Weight Gain Among Children and Adolescents With Bipolar Disorders, Psychiatry Res source
  • Premisecitation

    Case reports confirm reversibility of severe weight gain and metabolic disturbances, at least to some degree.

    “Finally, case reports describing severe cases of rapid weight gain and metabolic disturbances confirm reversibility, at least to some degree (14, 84).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [14] Sahoo, 2007, Dose-Dependent Acute Excessive Weight Gain and Metabolic Changes in a Drug-Naive Patient on Risperidone are Reversible With Discontinuation: A Case Report [4], Br J Clin Pharmacol source
    • cites [84] Wysokiński, 2016, Improvements in Body Composition, Anthropometric Measurements and Lipid Profile Following Discontinuation of Clozapine, Nord J Psychiatry source
  • Premisecitation

    Based on very few trials, switch to monotherapy does not seem to increase relapse rates.

    “Based on very few trials, switch to monotherapy does not seem to increase relapse rates (78, 91).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [78] Baandrup, 2020, Polypharmacy in Schizophrenia, Basic Clin Pharmacol Toxicol source
    • cites [91] Matsui, 2019, Switching to Antipsychotic Monotherapy vs. Staying on Antipsychotic Polypharmacy in Schizophrenia: A Systematic Review and Meta-Analysis, Schizophr Res source
  • Premisecitation

    Off-label use of low-dose second-generation antipsychotics for indications like sleep and anxiety is increasingly being prescribed.

    “off-label use of low dose second generation antipsychotic for indications like sleep and anxiety, as this might create equally serious weight problems and is increasingly being prescribed (98).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [98] Sohn, 2016, National Trends in Off-Label Use of Atypical Antipsychotics in Children and Adolescents in the United States, Medicine (United States) source

      The Discussion (page not provided) reports increasing off-label prescribing of atypical antipsychotics in pediatric outpatient visits. The paper does not establish that the increase involved low-dose prescriptions specifically for sleep or anxiety; its Results instead identify ADHD as the most common primary diagnosis among visits without an FDA-approved indication. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 30
  • May combine two claims. 30
  • The quote only partly states this claim. 2

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Second-generation antipsychotic medication is the mainstay of treatment of psychotic disorders and is increasingly prescribed for other indications.

    “Second generation antipsychotic medication is the mainstay of treatment of psychotic disorders (1) and is increasingly prescribed for other indications like bipolar disorder and severe depression and off-label indications such as sleeplessness and anxiety (2, 3).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [1] Kuipers, 2014, Management of Psychosis and Schizophrenia in Adults: Summary of Updated NICE Guidance, BMJ source
    • cites [2] Taylor, 2014, Comparative Efficacy and Acceptability of Drug Treatments for Bipolar Depression: A Multiple-Treatments Meta-Analysis, Acta Psychiatr Scand source
    • cites [3] Højlund, 2021, Use of Antipsychotics in Denmark 1997–2018: A Nation-Wide Drug Utilisation Study With Focus on Off-Label Use and Associated Diagnoses, Epidemiol Psychiatr Sci source

      The Results (Diagnoses associated with antipsychotic use; page unavailable) report increasing use for affective and neurotic or stress-related disorders, and the Introduction identifies anxiety and insomnia as off-label uses. The study reports these trends for antipsychotics overall, not specifically second-generation drugs. The separate assertion that they are the mainstay of psychotic-disorder treatment is attached to citation (1), not this source. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Adverse effects of antipsychotic medication are not always reversible upon discontinuation, as exemplified by tardive dyskinesia.

    “Many may expect adverse effects to be reversible upon discontinuation, but this is not always the case with antipsychotic medication, as exemplified by tardive dyskinesia (7).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Stroup, 2018, Management of Common Adverse Effects of Antipsychotic Medications, World Psychiatry source

  • May combine two claims.

    Interpretationcitation

    Many of the studies reporting on the effect of switching to partial agonists were uncontrolled with metabolic disturbances being the primary outcome, which increases the risk that participants engaged in parallel weight reducing behaviors, which could inflate the effect.

    “Many of the studies reporting on the effect of switching to partial agonists were uncontrolled with metabolic disturbances being the primary outcome, which increases the risk that the participants engaged in parallel weight reducing behaviors, seen as a manualized co-treatment in one study (77), which could inflate the effect.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [77] Stroup, 2013, Effects of Switching From Olanzapine, Quetiapine, and Risperidone to Aripiprazole on 10-Year Coronary Heart Disease Risk and Metabolic Syndrome Status: Results From a Randomized Controlled Trial, Schizophr Res source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The effect of reducing or discontinuing antipsychotic medication on weight is likely mediated via neurotransmitter signaling involving histamine and serotonin.

    “The effect is likely mediated via neurotransmitter signaling involving histamine and serotonin (16), and some suggest that thyroid function is associated with antipsychotic medication (17).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Libowitz, 2021, The Burden of Antipsychotic-Induced Weight Gain and Metabolic Syndrome in Children, Front Psychiatry source

      The Histamine Signaling and Serotonin Signaling sections (page not provided) describe both pathways as possible mechanisms of antipsychotic-induced weight gain. The Risk for Antipsychotic-Related Metabolic Effects section reports some weight loss after discontinuation, but does not link that loss to histamine or serotonin signaling. The claimed mechanism for weight change after reducing or stopping medication is therefore an extension beyond what the source says. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    PRISMA reporting guidelines were followed.

    “Prisma reporting guidelines were followed (22).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] Page, 2021, The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews, BMJ source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Non-pharmacological interventions to reduce weight in a general population have shown only transient effect on obesity.

    “Non-pharmacological interventions to reduce weight in a general population have shown only transient effect on obesity (8).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [8] Hall, 2018, Maintenance of Lost Weight and Long-Term Management of Obesity, Med Clin North Am source

      The Introduction reports that weight regain is typical, and the section “Long term benefits require long term attention” says short-term interventions are unlikely to sustain benefits without ongoing support. But the paper also reports that continued behavioral support improves long-term weight maintenance, so “only transient effect” overstates its conclusion about non-pharmacological interventions. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Risk of bias was independently assessed by two authors using the Rob-2 tool.

    “HS and CW independently conducted risk of bias applying Rob-2 tool (19).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Sterne, 2019, RoB 2: A Revised Tool for Assessing Risk of Bias in Randomised Trials, BMJ source

  • May combine two claims.

    Premisecitation

    Weight gain is a major adverse effect of second-generation antipsychotics, affecting quality of life, personal recovery, and somatic morbidity.

    “Weight gain is a major adverse effect of second-generation antipsychotics, affecting quality of life (4), personal recovery, and somatic morbidity and is a common reason for antipsychotic discontinuation (5).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] Seeman, 2017, Obesity in Schizophrenia, J Obes Manag source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Among the included studies, 33 reported discontinuation, 7 reported dose reduction, 18 reported switch to a partial agonist, and none reported switch from polypharmacy to monotherapy.

    “Of these, 33 reported on the effect of discontinuation, seven on dose reduction, 18 on switch to a partial agonist, and no studies on switch from polypharmacy to monotherapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    The review identified 55 studies, comprising 40 randomized controlled trials and 15 uncontrolled studies, including 12,279 individuals.

    “We identified 40 randomized controlled trials and 15 uncontrolled studies including 12,279 individuals.”
    • Also stated in: § Results · plain
      “we identified 55 studies (23–76) fulfilling the inclusion criteria and none of the exclusion criteria (Table 1). Of these, 40 were RCTs and 15 were uncontrolled studies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 23–76

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingown data

    The I2 was 90.7% for the primary outcome and 97.8% for the secondary outcome, suggesting substantial heterogeneity.

    “The I2 was 90.7% for the primary outcome and 97.8% for the secondary outcome, suggesting substantial heterogeneity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the pooled pre-post analysis, we found a weight reduction of 1.13 kg (p < 0.001), with no substantial differences in subgroups.

    “In the pooled pre-post analysis, we found a weight reduction of 1.13 (p < 0.001), with no substantial differences in subgroups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The differences in exposure between active drug and placebo in the RCTs (N = 17) explained 9% of variation, but this was not significant (p = 0.27).

    “The differences in exposure between active drug and placebo in the RCTs (N = 17) explained 9% of variation, but this was not significant (p = 0.27).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The 95% CI interval was −2.08 to −1.2, allowing rejection of the null hypothesis.

    “The 95% CI interval was −2.08 to −1.2, allowing us to reject the null hypothesis”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The review found a significant but small reduction in weight, suggesting that antipsychotic-induced weight gain can be reversed to some degree.

    “We found a significant but small reduction in weight, suggesting that antipsychotic-induced weight gain can be reversed to some degree.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Two authors independently examined the full list, selected relevant abstracts, and examined relevant full texts for compliance with inclusion criteria using Covidence.

    “Two authors (HS, CW) independently examined the remaining full list, selected relevant abstracts and examined the relevant full text determining compliance with inclusion criteria using the software from Covidence.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Two authors independently extracted data using Covidence software.

    “Two authors (HS, CW) independently extracted data using Covidence software.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Only a few included studies were designed to address the question as primary outcome, which limits the generalizability of the findings.

    “Only a few studies were designed to address the question as primary outcome, which limits the generalizability of our findings.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    The secondary outcome addresses the question: Will I lose weight over time if I reduce dose/discontinue medication?

    “On the other hand, the secondary outcome, the change in weight form baseline to post intervention, addresses the question: Will I lose weight over time if I reduce dose/discontinue medication?”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The bibliographical search was performed on 18 February 2021 and included PubMed, Scopus, Lilac, Embase, and Web of Science.

    “The bibliographical search was performed on 18th of February 2021 and included a search of PUBMED, Scopus, Lilac, Embase, and Web of Science using medical subject headings (MESH or similar) when possible and text word terms:”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Risk of bias assessment found low risk of bias in 26 trials and some concerns in 14 trials.

    “We found a low risk of bias in 26 trials, and some concerns in 14 trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In youth with disruptive behavior, antipsychotic discontinuation was associated with improvement in metabolic factors and no psychiatric deterioration.

    “An improvement in metabolic factors and with no psychiatric deterioration, was reported by Hulvershorn et al. (83) who evaluated the effect of antipsychotic discontinuation in youth with disruptive behavior.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hulvershorn et al. [83] Hulvershorn, 2017, Improved Metabolic and Psychiatric Outcomes With Discontinuation of Atypical Antipsychotics in Youth Hospitalized in a State Psychiatric Facility, J Child Adolesc Psychopharmacol source

  • May combine two claims.

    Study design and conductown data

    Data on duration of exposure was available for 17 included trials and did not explain a significant proportion of the variance, although this could be a type II error.

    “Data on duration of exposure was available for 17 of the included trials and did not explain a significant proportion of the variance, although this could be a type II error.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    We did not assess potential adverse events associated with dose reduction, switch, or discontinuation.

    “Third, we did not assess potential adverse events associated with dose reduction, switch, or discontinuation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Missing measures of dispersion were imputed as recommended by Cochrane.

    “Missing measures of dispersion were imputed as recommended by Cochrane (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Higgins, 2011

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    It cannot be excluded that individuals with severe gain also have an equivalent weight loss, but that these are hidden in the mean.

    “Thus, it cannot be excluded that individuals with severe gain also have an equivalent weight loss, but that these are hidden in the mean.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Possible bias from industry sponsorship is likely to deflate effect size, as most sponsors would be interested in reporting a lower weight gain in the maintenance groups.

    “This possible bias is likely to deflate effect size, as most sponsors would be interested in reporting a lower weight gain in the maintenance groups.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Results from randomized clinical trials and uncontrolled studies were analyzed and reported separately.

    “Results from randomized clinical trials and uncontrolled studies were analyzed and reported separately.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The primary outcome does not inform about weight loss compared to baseline, as the observed difference may be explained by a larger weight increase in the maintenance group.

    “But the outcome does not inform about a weight loss compared to baseline, as the observed difference may be explained by a larger weight increase in the maintenance group.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The authors were not blinded to study results, authors, or institutions.

    “The authors were not blinded to study results, authors, or institutions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The 95% prediction interval of −4.71 to 1.61 does not exclude the probability of null effect in future trials, but results could be as high as −4.7 kg.

    “but the corresponding 95% prediction interval was −4.71 to 1.61, which does not exclude the probability of null effect in future trials, but the results could be as high as −4.7 kg.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    The largest weight loss was achieved by switching to partial agonists, which could be explained by longer duration of exposure to antipsychotic medication, making risk of relapse in this group lower compared to trials where an active treatment is compared to placebo.

    “The largest weight loss was achieved by switching to partial agonists, which could be explained by longer duration of exposure to antipsychotic medication, making risk of relapse in this group lower compared to trial where an active treatment is compared to placebo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The primary outcome, based on controlled trials, and secondary outcomes, based on uncontrolled trials, address two fundamentally different questions with different inherent methodological limitations.

    “The primary outcome, based on controlled trials, and secondary outcomes, based on uncontrolled trials, address two fundamentally different questions with different inherent methodological limitations to the answers.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    It may be easier to lose weight if the time being overweight is shorter, which could oppositely inflate effect size.

    “On the other hand, it may be easier to lose weight if the time being overweight is shorter, which could oppositely inflate effect size.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Analyses of publication bias did not confirm any concerns but cannot exclude selective reporting.

    “Analyses of publication bias did not confirm any concerns but cannot exclude selective reporting.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The subgroup results suggest that the effect of switch to partial agonists was larger than discontinuation and dose reduction, but this may reflect trial methodology rather than true differences.

    “The subgroup results suggest that the effect of switch to partial agonists was larger than discontinuation and dose reduction, but this may reflect trial methodology rather than true differences, as discussed beneath.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    It was difficult to assess if the way of reporting weight was pre-registered to avoid multiple possible methods, and this could be affected by financial conflicts of interest.

    “if the way of reporting weight was pre-registered to avoid any multiple possible methods (continuous, dichotomized, BMI, 7% change) could be affected by financial conflicts of interest”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    High degrees of relapses are observed in real world data, and these findings therefore reflect effectiveness rather than efficacy, as complete adherence is often not realistic.

    “On the other hand, high degrees of relapses are observed in real world data, and these findings therefore reflect the effectiveness rather than efficacy, as complete adherence is often not realistic.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Study design and conductreasoning

    Excluding papers that only reported >7% weight gain and not 7% weight loss or mean weight change may have introduced a selection bias.

    “It is possible that excluding these papers has introduced a selection bias.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    We a-priori decided to measure weight change as a continuous variable, as dichotomizing continuous variables may inflate effect sizes and decrease power.

    “Second, we a-priori decided to measure weight change as continuous variable, as dichotomizing continuous variable may inflate effect sizes and decrease power (85).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Altman, 2006, The Cost of Dichotomising Continuous Variables, BMJ source

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Random effects were reported, assuming underlying heterogeneity of effects due to variations in the interventions.

    “Random effects were reported, assuming underlying heterogeneity of effects due to variations in the interventions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Results could overestimate the effect due to regression to the mean, skewed loss to follow-up, or confounding by lifestyle or other types of medication.

    “Results could overestimate the effect due to regression to the mean, skewed loss to follow-up; it could also be confounded by lifestyle or other types of medication.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Weight change was reported as an adverse event for the large majority of RCTs.

    “Weight change was reported as an adverse event for the large majority of RCTs”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The short period of weight gain allowed by the stabilization phase could deflate effect sizes compared to real-world populations.

    “This allows only a short period of weight gain, which could deflate effect sizes compared to real-world populations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    It is likely that individuals with severe weight gain were excluded in the stabilization phase due to adverse effects, which could explain the low mean baseline weight and affect generalizability to a real-world population.

    “It is likely that individuals with severe weight gain were excluded in the stabilization phase due to adverse effects, which could explain the low mean baseline weight, which again could affect the generalizability to a real-world population.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Weight was reported as adverse events, and methods to handle missing data were often not clearly described.

    “as weight was reported as adverse events, the methods to handle missing data were often not clearly described.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In children and adolescents with bipolar disorder who experienced weight gain while treated with psychotropic medication, weight loss was stabilized but never returned to baseline at 12 months follow-up after discontinuation.

    “Upadhyay et al. (15) followed a large sample of children and adolescents (N = 537) with bipolar disorder who had experienced weight gain while treated with psychotropic medication. At 12 months follow-up after discontinuation of psychotropic medication, weight loss was stabilized, but never returned to baseline”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Upadhyay et al. [15] Upadhyay, 2019, Reversibility of Psychotropic Medication Induced Weight Gain Among Children and Adolescents With Bipolar Disorders, Psychiatry Res source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    We did not pre-register the protocol at Prospero.

    “First, we did not pre-register the protocol at Prospero.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    It cannot be excluded that the weight loss could continue over time.

    “Thus, it cannot be excluded that the weight loss could continue over time.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    It was generally difficult to assess how missing data were handled.

    “it was generally difficult to assess how missing data were handled”
    Quote in the paperNot a substantial claim
50 of 50

  • The paper relies on this without support.

    Knowledge about the reversibility of antipsychotic-induced weight gain when medication is reduced or discontinued remains scarce.

    “However, knowledge about the reversibility of weight gain when the antipsychotic medication is reduced or discontinued remains scarce.”
    “Peculiarly, little research has been focusing on the potential reversibility of weight gain if the antipsychotic drug is reduced, discontinued, or switched to an agent with lower obesogenic properties, but case reports (13, 14) and a few studies of patients with intellectual disabilities and children with bipolar disorder (15) suggest that at least some weight can be lost after discontinuation.”

  • The paper relies on this without support.

    The pooled effect estimates from the meta-analysis are valid despite the substantial heterogeneity across included studies.

    “This was expected, as we pooled different diagnoses, different interventions, and different designs.”

  • The paper relies on this without support.

    The maintenance treatment groups in the included trials represent continued antipsychotic treatment at stable doses.

    “compared to control groups who continued maintenance treatment”

  • The paper relies on this without support.

    The weight change reported as adverse events in the included trials is a valid measure of antipsychotic-induced weight change.

    “Weight change was reported as an adverse event for the large majority of RCTs”

  • The paper relies on this without support.

    The risk of bias assessment using Table S1 adequately captures the risk of bias in the included trials.

    “The risk of bias assessment is presented in Table S1 (19).”

  • The paper relies on this without support.

    Visual inspection of funnel plots is a sufficient method to detect publication bias.

    “Visual inspection of Funnel plots (Figures S1 and S2) did not reveal any signs of publication bias.”

  • The paper relies on this without support.

    Reversing antipsychotic-induced weight gain carries a risk of relapse.

    “balanced against the risk of relapse”

  • The paper relies on this without support.

    Antipsychotic-induced weight gain can lead to lifelong obesity.

    “if they run a risk of lifelong obesity”
8 of 8

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Discontinuation subgroup estimates differ between text and Table 2

    Major

    For the same 31-study primary-outcome subgroup, the text reports −1.60 kg (CI −2.25 to −0.95), whereas Table 2 reports −1.57 kg (CI −2.02 to −0.98).

  • Switching subgroup results differ between text and Table 3

    Major

    The secondary-outcome text reports −.57 kg with a CI of −1.46 to −0.83; that point estimate is outside its stated interval. Table 3 instead reports −1.57 kg with a CI of −1.94 to −1.20 for the same 18-study subgroup.

  • Schizophrenia subgroup estimate disagrees with Table 4

    Major

    The text reports −2.24 kg for the 22-study schizophrenia subgroup, but Table 4 reports −1.16 kg. Their confidence intervals also differ.

  • Bipolar subgroup confidence intervals disagree

    Major

    Table 4 gives an upper confidence limit of positive 0.96 kg, while the accompanying text gives a negative upper limit of −0.896 kg. The table's interval also includes zero despite its reported p < 0.001.

  • Suzuki study description conflicts with its reference

    Minor

    Table 1 classifies Suzuki et al. (60) as a switch to aripiprazole, while reference 60 describes dose-dependent effects of olanzapine.

  • Berwaerts study has conflicting antipsychotic identifications

    Minor

    Table 1 identifies the antipsychotic in Berwaerts et al. (36) as risperidone, but reference 36 describes a paliperidone maintenance study.

  • Stated reference range omits an included study

    Minor

    The results describe the 55 included studies as references 23-76, but Table 1 includes Stroup et al. (77).

  • Ishigooka study description conflicts with its reference

    Minor

    Table 1 describes Ishigooka et al. (66) as a schizophrenia study switching to brexpiprazole. Reference 66 instead describes a lurasidone study in bipolar I depression.

  • Discussion gives a third pooled primary estimate and interval

    Minor

    The discussion reports 1.54 kg with a 95% confidence interval of −2.08 to −1.2, differing from the −1.51 kg and −1.95 to −1.06 reported in the primary results.

  • Yatham study has conflicting antipsychotic identifications

    Minor

    Table 1 lists aripiprazole for Yatham et al. (62), whereas reference 62 describes risperidone or olanzapine adjunctive therapy.

  • Weisler study is labeled uncontrolled despite its cited design

    Minor

    Table 1 labels Weisler et al. (25) as having no control group, but both its intervention description and the cited title describe comparisons against placebo or lithium.

  • Abstract and main results give different pooled confidence intervals

    Minor

    The abstract gives a 95% confidence interval of −2.03 to −0.98 kg, while the main results give −1.95 to −1.06 kg for the pooled primary outcome.

  • Secondary-outcome heterogeneity is reported as both 97.8% and 92.8%

    Minor

    The heterogeneity section states that secondary-outcome I2 was 97.8%, while Table 3 gives 92.8% for the pooled secondary outcome.

13 of 13

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Higgins, 2011, Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [Updated March 2011]

Cited by

Sorted by citations

Related

Authors
Speyer, H., Westergaard, C., Albert, N., Karlsen, M., Stürup, A. E., Nordentoft, M., & Krogh, J.
Affiliations
  • Copenhagen University Hospital (DK)
  • Glostrup Hospital (DK)
  • University of Copenhagen (DK)
Corresponding author
Speyer, Helene
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2021-07-28
Volume
12
Pages
577919-577919
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2021.577919
PMC
PMC8355990
OpenAlex
W3184707054
Semantic Scholar
24553f56592795ddcae7efd17fb432bb6616001b
Cited by
44
References
99
Citations by year
2026: 7 · 2025: 15 · 2024: 14 · 2023: 4 · 2022: 4
FWCI
0.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
  • Social Sciences › Psychology › Clinical Psychology › Eating Disorders and Behaviors
Keywords
antipsychotic-induced weight gain, weight loss, dose reduction, antipsychotic discontinuation, adverse drug reactions, schizophrenia, bipolar disorder
MeSH terms
Humans, Obesity, Psychotic Disorders, Research Design, Antipsychotic Agents, Weight Gain, Weight Loss, Randomized Controlled Trials as Topic, Treatment Outcome, Polypharmacy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-02.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-02.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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