Metabolic side effects of antipsychotic drugs in individuals with schizophrenia during medium- to long-term treatment: protocol for a systematic review and network meta-analysis of randomized controlled trials

Schneider‐Thoma, Johannes; Burschinski, Angelika; Wang, Dongfang; Bighelli, Irene; Siafis, Spyridon; Wang, Hui; Hansen, Wulf–Peter; Davis, John M.; Salanti, Georgia; Leucht, Stefan

doi:10.1186/s13643-021-01760-z

Cited by 7 publications

(6 citation statements)

References 54 publications

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“…We report following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) extension statement for network meta‐analyses. The study protocol was registered with PROSPERO (registration number: CRD42020175414) and published 17 .…”

Section: Methodsmentioning

confidence: 99%

Metabolic side effects in persons with schizophrenia during mid‐ to long‐term treatment with antipsychotics: a network meta‐analysis of randomized controlled trials

et al. 2023

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Metabolic side effects of antipsychotic drugs can have serious health consequences and may increase mortality. Although persons with schizophrenia often take these drugs for a long time, their mid‐ to long‐term metabolic effects have been studied little so far. This study aimed to evaluate the mid‐ to long‐term metabolic side effects of 31 antipsychotics in persons with schizophrenia by applying a random‐effects Bayesian network meta‐analysis. We searched the Cochrane Schizophrenia Group's Study‐Based Register of Trials (up to April 27, 2020) and PubMed (up to June 14, 2021). We included published and unpublished, open and blinded randomized controlled trials with a study duration >13 weeks which compared any antipsychotic in any form of administration with another antipsychotic or with placebo in participants diagnosed with schizophrenia. The primary outcome was weight gain measured in kilograms. Secondary outcomes included “number of participants with weight gain”, fasting glucose, total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, and triglycerides. We identified 137 eligible trials (with 35,007 participants) on 31 antipsychotics, with a median follow‐up of 45 weeks. Chlorpromazine produced the most weight gain (mean difference to placebo: 5.13 kg, 95% credible interval, CrI: 1.98 to 8.30), followed by clozapine (4.21 kg, 95% CrI: 3.03 to 5.42), olanzapine (3.82 kg, 95% CrI: 3.15 to 4.50), and zotepine (3.87 kg, 95% CrI: 2.14 to 5.58). The findings did not substantially change in sensitivity and network meta‐regression analyses, although enriched design, drug company sponsorship, and the use of observed case instead of intention‐to‐treat data modified the mean difference in weight gain to some extent. Antipsychotics with more weight gain were often also among the drugs with worse outcome in fasting glucose and lipid parameters. The confidence in the evidence ranged from low to moderate. In conclusion, antipsychotic drugs differ in their propensity to induce metabolic side effects in mid‐ to long‐term treatment. Given that schizophrenia is often a chronic disorder, these findings should be given more consideration than short‐term data in drug choice.

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Section: Methodsmentioning

confidence: 99%

Metabolic side effects in persons with schizophrenia during mid‐ to long‐term treatment with antipsychotics: a network meta‐analysis of randomized controlled trials

et al. 2023

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“…To date, no comprehensive comparative studies have addressed whether and how antipsychotic-induced metabolic side effects differ between medium- and long-term therapy. Most recently, Schneider-Thoma et al [ 28 ] reported a protocol for conducting a meta-analysis of randomized controlled trials of antipsychotic drug-associated metabolic side effects (primarily weight gain and disturbances of glucose and lipid metabolism) in schizophrenia patients during medium- to long-term treatment. Their systematic review is presumably ongoing; no results have been reported to date.…”

Section: Side Effects Of Antipsychotic Drugsmentioning

confidence: 99%

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

Zhuo

Hou

et al. 2022

Transl Psychiatry

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Antipsychotic 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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“…In the first place, despite 70 percent or more receptor occupancy, standard antipsychotics are not helpful for all Oxidative Medicine and Cellular Longevity people with schizophrenia [3]. Second, traditional antipsychotics are only successful in treating about 70% of positive symptoms [4] and have been reported ineffective in treating negative and cognitive symptoms [95].…”

Section: Impacts Of Antipsychotic Medicationsmentioning

confidence: 99%

Insights into the Promising Prospect of G Protein and GPCR-Mediated Signaling in Neuropathophysiology and Its Therapeutic Regulation

Rahman

Islam

Mim

et al. 2022

Oxidative Medicine and Cellular Longevity

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G protein-coupled receptors (GPCRs) are intricately involved in the conversion of extracellular feedback to intracellular responses. These specialized receptors possess a crucial role in neurological and psychiatric disorders. Most nonsensory GPCRs are active in almost 90% of complex brain functions. At the time of receptor phosphorylation, a GPCR pathway is essentially activated through a G protein signaling mechanism via a G protein-coupled receptor kinase (GRK). Dopamine, an important neurotransmitter, is primarily involved in the pathophysiology of several CNS disorders; for instance, bipolar disorder, schizophrenia, Parkinson’s disease, and ADHD. Since dopamine, acetylcholine, and glutamate are potent neuropharmacological targets, dopamine itself has potential therapeutic effects in several CNS disorders. GPCRs essentially regulate brain functions by modulating downstream signaling pathways. GPR6, GPR52, and GPR8 are termed orphan GPCRs because they colocalize with dopamine D1 and D2 receptors in neurons of the basal ganglia, either alone or with both receptors. Among the orphan GPCRs, the GPR52 is recognized for being an effective psychiatric receptor. Various antipsychotics like aripiprazole and quetiapine mainly target GPCRs to exert their actions. One of the most important parts of signal transduction is the regulation of G protein signaling (RGS). These substances inhibit the activation of the G protein that initiates GPCR signaling. Developing a combination of RGS inhibitors with GPCR agonists may prove to have promising therapeutic potential. Indeed, several recent studies have suggested that GPCRs represent potentially valuable therapeutic targets for various psychiatric disorders. Molecular biology and genetically modified animal model studies recommend that these enriched GPCRs may also act as potential therapeutic psychoreceptors. Neurotransmitter and neuropeptide GPCR malfunction in the frontal cortex and limbic-related regions, including the hippocampus, hypothalamus, and brainstem, is likely responsible for the complex clinical picture that includes cognitive, perceptual, emotional, and motor symptoms. G protein and GPCR-mediated signaling play a critical role in developing new treatment options for mental health issues, and this study is aimed at offering a thorough picture of that involvement. For patients who are resistant to current therapies, the development of new drugs that target GPCR signaling cascades remains an interesting possibility. These discoveries might serve as a fresh foundation for the creation of creative methods for pharmacologically useful modulation of GPCR function.

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Metabolic side effects of antipsychotic drugs in individuals with schizophrenia during medium- to long-term treatment: protocol for a systematic review and network meta-analysis of randomized controlled trials

Cited by 7 publications

References 54 publications

Metabolic side effects in persons with schizophrenia during mid‐ to long‐term treatment with antipsychotics: a network meta‐analysis of randomized controlled trials

Metabolic side effects in persons with schizophrenia during mid‐ to long‐term treatment with antipsychotics: a network meta‐analysis of randomized controlled trials

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

Insights into the Promising Prospect of G Protein and GPCR-Mediated Signaling in Neuropathophysiology and Its Therapeutic Regulation

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