A systematic review of metabolic side effects related to the use of antipsychotic drugs in dementia

ABSTRACTBackground:In clinical practice, Second Generation Antipsychotics (SGAs) are often used as first-line treatment for the Behavioral and Psychological Symptoms of Dementia (BPSD) in older adults due to their fewer neurological adverse events and similar effectiveness compared with First Generation Antipsychotics (FGAs). SGAs, however, are associated with more severe metabolic side effects (weight gain, hyperglycemia, diabetes risk, and hyperlipidemia) than FGAs are. In general, older patients, especially those affected by dementia, are at increased risk for malnutrition, and tend to have lower basal metabolism and reduced liver and kidney function. However, little is known about the metabolic side effects of antipsychotic drugs in this population.Methods:A comprehensive review of the literature published between January 1996 and December 2012 investigating the metabolic side effects related to FGAs and SGAs use in old patients affected by dementia.Results:Antipsychotic drugs currently used to treat BPSD in subjects with mild to moderate dementia are associated with weight gain. Currently, there are insufficient data to support a causal relationship between the use of FGAs and SGAs and changes in glucose homeostasis or lipid metabolism in older persons affected by severe dementia (MMSE <14).Conclusion:A possible association between antipsychotic drugs use and weight gain might exist, in particular in subjects with mild to moderate dementia whereas no significant effects are demonstrated regarding glucose homeostasis and lipid metabolism. The antipsychotic drugs potential for causing metabolic abnormalities in older patients requires further specifically designed studies. Clinicians must be aware of this possibility even if the shorter periods of treatment administered in late-life might not be as harmful as it is in younger individuals.

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P.3.d.001 Development of novel antipsychotic drugs based on olanzapine that display reduced weight gain and metabolic side effects

European Neuropsychopharmacology ◽

10.1016/s0924-977x(11)70823-9 ◽

2011 ◽

Vol 21 ◽

pp. S506-S507

Author(s):

S. Jafari ◽

F. Fernandez ◽

X.F. Huang

Keyword(s):

Weight Gain ◽

Side Effects ◽

Antipsychotic Drugs ◽

Metabolic Side Effects ◽

Novel Antipsychotic

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Weight gain and metabolic side effects with antipsychotic drugs in children

Middle East Current Psychiatry ◽

10.1097/01.xme.0000418805.27224.cc ◽

2012 ◽

Vol 19 (4) ◽

pp. 237-244

Author(s):

Ghada A.M. Hassan

Keyword(s):

Weight Gain ◽

Side Effects ◽

Antipsychotic Drugs ◽

Metabolic Side Effects

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T200. METABOLIC SIDE EFFECTS OF ANTIPSYCHOTIC DRUGS – PROTOCOL OF A SYSTEMATIC REVIEW AND NETWORK- METAANALYSIS

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa029.760 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S308-S308

Author(s):

Johannes Schneider-Thoma ◽

Irene Bighelli ◽

Spyridon Siafis ◽

Stefan Leucht

Keyword(s):

Systematic Review ◽

Weight Gain ◽

Side Effects ◽

Antipsychotic Drugs ◽

Controlled Trial ◽

Sensitivity Analyses ◽

Continuous Change ◽

Randomized Controlled ◽

Metabolic Side Effects ◽

Number Of Patients

Abstract Background Antipsychotic drugs are the mainstay of the pharmacological treatment of schizophrenia, used in the acute episode of the disorder and for prevention of relapses. Unfortunately, antipsychotics cause side effects. Weight gain is one of the most prominent side effects. In line with weight gain, also alterations of lipid- and glucose homeostasis can occur and increase the risk for cardiovascular disorders. So far, the differences between the multiple antipsychotics in propensity to cause these alterations have not been examined based on data from randomized controlled trial. Therefore, we are conducting a systematic review and network-metaanalysis on metabolic side effects of antipsychotic drugs. Methods Systematic review and network-metaanalysis. Population Patients with schizophrenia. Interventions Antipsychotic drugs and placebo. Comparator In network-metaanalysis all interventions are compared with each other. For presentation of Results:, placebo will be used as reference. Outcomes The primary outcomes will be continuous change of body weight. Additional outcomes will be continuous change of blood glucose, triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol as well as dichotomous values of these outcomes (i.e. number of patients with a clinically relevant increase over pathological thresholds). Study design Randomized controlled trials. Statistical analysis Network-metaanalysis. Planned network-metaregression-, subgroup- and sensitivity-analyses will address the role of the potential effect modifiers baseline weight, study duration, age, gender, ethnicity, previous antipsychotic exposure, antipsychotic dose, sponsorship, and use of enriched-design. Results Funding for this project has been received from the German Ministry of Education and Research. At the time of abstract submission, the project has just started and is currently in the stage of protocol development. Discussion At the time of the conference the protocol of the study will be developed further and the literature search will have started. Thus, on the poster, details of the analytic approach can be presented and challenges discussed. Moreover, results of the search process can be presented.

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GLP1 receptor agonism protects against acute olanzapine-induced hyperglycemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00309.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. E1101-E1111 ◽

Cited By ~ 1

Author(s):

Kyle D. Medak ◽

Hesham Shamshoum ◽

Willem T. Peppler ◽

David C. Wright

Keyword(s):

Lipid Metabolism ◽

Side Effects ◽

Antipsychotic Drug ◽

Antipsychotic Drugs ◽

Glucose And Lipid Metabolism ◽

Metabolic Dysregulation ◽

Metabolic Side Effects ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Effective Adjunct

Antipsychotic drugs cause rapid perturbations in glucose and lipid metabolism. In the present study we have demonstrated that cotreatment with glucagon-like peptide 1 (GLP1) receptor agonists, such as liraglutide, protects against metabolic dysregulation caused by the antipsychotic drug olanzapine. These findings suggest that pharmacological targeting of the GLP1 receptor could be an effective adjunct approach to mitigate the harmful acute metabolic side effects of antipsychotic drugs.

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Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy

Translational Psychiatry ◽

10.1038/s41398-021-01778-w ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Chuanjun Zhuo ◽

Yong Xu ◽

Weihong Hou ◽

Jiayue Chen ◽

Qianchen Li ◽

...

Keyword(s):

Lipid Metabolism ◽

Weight Gain ◽

Side Effects ◽

Antipsychotic Drugs ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Target Of Rapamycin ◽

Glucose And Lipid Metabolism ◽

Pathway Activation ◽

Extrapyramidal Motor

AbstractAntipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.

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Metabolomic profiles associated with a mouse model of antipsychotic-induced food intake and weight gain

Scientific Reports ◽

10.1038/s41598-020-75624-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Rizaldy C. Zapata ◽

Sara Brin Rosenthal ◽

Kathleen Fisch ◽

Khoi Dao ◽

Mohit Jain ◽

...

Keyword(s):

Weight Gain ◽

Side Effects ◽

Food Intake ◽

Palmitoleic Acid ◽

Antipsychotic Drugs ◽

Plasma Metabolites ◽

Plasma Citrulline ◽

Metabolic Side Effects ◽

Psychiatric Conditions ◽

Underlying Mechanisms

Abstract Antipsychotic drugs (AP) are used to treat a multitude of psychiatric conditions including schizophrenia and bipolar disorder. However, APs also have metabolic side effects including increased food intake and body weight, but the underlying mechanisms remain unknown. We previously reported that minocycline (MINO) co-treatment abrogates olanzapine (OLZ)-induced hyperphagia and weight gain in mice. Using this model, we investigated the changes in the pharmacometabolome in the plasma and hypothalamus associated with OLZ-induced hyperphagia and weight gain. Female C57BL/6 mice were divided into groups and fed either i) control, CON (45% fat diet) ii) CON + MINO, iii) OLZ (45% fat diet with OLZ), iv) OLZ + MINO. We identified one hypothalamic metabolite indoxylsulfuric acid and 389 plasma metabolites (including 19 known metabolites) that were specifically associated with AP-induced hyperphagia and weight gain in mice. We found that plasma citrulline, tricosenoic acid, docosadienoic acid and palmitoleic acid were increased while serine, asparagine and arachidonic acid and its derivatives were decreased in response to OLZ. These changes were specifically blocked by co-treatment with MINO. These pharmacometabolomic profiles associated with AP-induced hyperphagia and weight gain provide candidate biomarkers and mechanistic insights related to the metabolic side effects of these widely used drugs.

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Psychotropic drug-induced genetic-epigenetic modulation of CRTC1 gene is associated with early weight gain in a prospective study of psychiatric patients

Clinical Epigenetics ◽

10.1186/s13148-019-0792-0 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Aurélie Delacrétaz ◽

Anaïs Glatard ◽

Céline Dubath ◽

Mehdi Gholam-Rezaee ◽

Jose Vicente Sanchez-Mut ◽

...

Keyword(s):

Weight Gain ◽

Side Effects ◽

Prospective Study ◽

Psychotropic Drugs ◽

Energy Homeostasis ◽

Psychiatric Patients ◽

Metabolic Disturbances ◽

Drug Induced ◽

Metabolic Side Effects ◽

Early Weight Gain

Abstract Background Metabolic side effects induced by psychotropic drugs represent a major health issue in psychiatry. CREB-regulated transcription coactivator 1 (CRTC1) gene plays a major role in the regulation of energy homeostasis and epigenetic mechanisms may explain its association with obesity features previously described in psychiatric patients. This prospective study included 78 patients receiving psychotropic drugs that induce metabolic disturbances, with weight and other metabolic parameters monitored regularly. Methylation levels in 76 CRTC1 probes were assessed before and after 1 month of psychotropic treatment in blood samples. Results Significant methylation changes were observed in three CRTC1 CpG sites (i.e., cg07015183, cg12034943, and cg 17006757) in patients with early and important weight gain (i.e., equal or higher than 5% after 1 month; FDR p value = 0.02). Multivariable models showed that methylation decrease in cg12034943 was more important in patients with early weight gain (≥ 5%) than in those who did not gain weight (p = 0.01). Further analyses combining genetic and methylation data showed that cg12034943 was significantly associated with early weight gain in patients carrying the G allele of rs4808844A>G (p = 0.03), a SNP associated with this methylation site (p = 0.03). Conclusions These findings give new insights on psychotropic-induced weight gain and underline the need of future larger prospective epigenetic studies to better understand the complex pathways involved in psychotropic-induced metabolic side effects.

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Use of antipsychotic drugs was associated with increased risk for hyperglycemia in older patients with diabetes

Annals of Internal Medicine ◽

10.7326/0003-4819-151-10-200911170-02012 ◽

2009 ◽

Vol 151 (10) ◽

pp. JC5

Author(s):

Bradley Ng

Keyword(s):

Older Patients ◽

Antipsychotic Drugs ◽

Increased Risk ◽

Patients With Diabetes

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Fatty Acid Desaturase Gene Polymorphisms and Metabolic Measures in Schizophrenia and Bipolar Patients Taking Antipsychotics

Cardiovascular Psychiatry and Neurology ◽

10.1155/2013/596945 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 11

Author(s):

Kyle J. Burghardt ◽

Kristen N. Gardner ◽

Joshua W. Johnson ◽

Vicki L. Ellingrod

Keyword(s):

Insulin Resistance ◽

Bipolar Disorder ◽

Fatty Acid ◽

Side Effects ◽

High Risk ◽

Atypical Antipsychotics ◽

Fatty Acid Desaturase ◽

Metabolic Side Effects ◽

Increased Risk ◽

Bipolar Patients

Atypical antipsychotics have become a common therapeutic option in both schizophrenia and bipolar disorder. However, these medications come with a high risk of metabolic side effects, particularly dyslipidemia and insulin resistance. Therefore, identification of patients who are at increased risk for metabolic side effects is of great importance. The genetics of fatty acid metabolism is one area of research that may help identify such patients. Therefore, in this present study, we aimed to determine the effect of one commonly studied genetic polymorphism from both fatty acid desaturase 1 (FADS1) and FADS2 gene on a surrogate measure of insulin resistance and lipid levels in a metabolically high-risk population of patients largely exposed to atypical antipsychotics. This study used a cross-sectional design, fasting blood draws, and genetic analysis to investigate associations between polymorphisms, haplotypes, and metabolic measures. A total of 320 subjects with schizophrenia (n=226) or bipolar disorder (n=94) were included in this study. The mean age of the population was 42.5 years and 45% were male. A significant association between FADS1 and FADS2 haplotypes was found with insulin resistance while controlling for confounders. Further investigation is required to replicate this finding.

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