Association Between Common Variants Near the Melanocortin 4 Receptor Gene and Severe Antipsychotic Drug–Induced Weight Gain

Malhotra, Anil K.; Correll, Christoph U.; Chowdhury, Nabilah I.; Müller, Daniel J.; Gregersen, Peter K.; Lee, Annette T.; Tiwari, Arun K.; Kane, John M.; Fleischhacker, W. Wolfgang; Kahn, René S.; Ophoff, Roel A.; Lieberman, Jeffrey A.; Meltzer, Herbert Y.; Lencz, Todd; Kennedy, James L.

doi:10.1001/archgenpsychiatry.2012.191

Cited by 164 publications

(119 citation statements)

References 31 publications

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“…145 A GWAS in a cohort of drug-naive adolescents showed significant association of an SNP near this gene with weight gain induced by several APs, which was replicated independently by our group. 146 In a different study, our group has also shown a significant association of another SNP in the promoter region of MC4R with AIWG. 147 A recent GWAS found significant associations of AIWG with SNPs in the Meis homeobox 2 (MEIS2), protein kinase, cyclic adenosine monophosphate-dependent, regulatory, type II, beta (PRKAR2B), G protein-coupled receptor 98 (GPR98), formin homology 2 domain containing 3 (FHOD3), ring finger protein 144A (RNF144A), astrotactin 2 (ASTN2), sex determining region Y-box 5 (SOX5), and activating transcription factor 7 interacting protein 2 (ATF7IP2) genes 148 but these findings have not yet been replicated in other studies.…”

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confidence: 77%

Pharmacogenetics of Antipsychotics

2014

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Objective: During the past decades, increasing efforts have been invested in studies to unravel the influence of genetic factors on antipsychotic (AP) dosage, treatment response, and occurrence of adverse effects. These studies aimed to improve clinical care by predicting outcome of treatment with APs and thus allowing for individualized treatment strategies. We highlight most important findings obtained through both candidate gene and genome-wide association studies, including pharmacokinetic and pharmacodynamic factors. Methods:We reviewed studies on pharmacogenetics of AP response and adverse effects published on PubMed until early 2012. Owing to the high number of published studies, we focused our review on findings that have been replicated in independent studies or are supported by meta-analyses.Results: Most robust findings were reported for associations between polymorphisms of the cytochrome P450 system, the dopamine and the serotonin transmitter systems, and dosage, treatment response, and adverse effects, such as AP-induced weight gain or tardive dyskinesia. These associations were either detected for specific medications or for classes of APs. Conclusion:First promising and robust results show that pharmacogenetics bear promise for a widespread use in future clinical practice. This will likely be achieved by developing algorithms that will include many genetic variants. However, further investigation is warranted to replicate and validate previous findings, as well as to identify new genetic variants involved in AP response and for replication of existing findings. W W W La pharmacogénétique des antipsychotiquesObjectif : Au cours des dernières décennies, des efforts croissants ont été déployés dans des études visant à percer l'influence des facteurs génétiques sur le dosage des antipsychotiques (AP), la réponse au traitement, et la survenue d'effets indésirables. Ces études voulaient améliorer les soins cliniques en prédisant le résultat du traitement par AP, et en donnant lieu ainsi à des stratégies de traitement individualisées. Nous présentons les résultats les plus importants obtenus par des études tant de gènes candidats que d'association pangénomique, notamment les facteurs pharmacocinétiques et pharmacodynamiques. Méthodes :Nous avons passé en revue les études sur la pharmacogénétique de la réponse aux AP et des effets indésirables publiées dans PubMed jusqu'au début de 2012. Vu le nombre élevé d'études publiées, notre revue a mis l'accent sur les résultats qui ont été reproduits dans des études indépendantes ou qui sont soutenus par des méta-analyses.

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confidence: 77%

Pharmacogenetics of Antipsychotics

2014

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“…However, a recent genetic study reported that neither the POMC single nucleotide polymorphisms (SNPs) (rs6713532, rs1047521, rs3754860) nor the CART SNP (rs10515115, rs3763153, rs3857384, rs11575893, rs16871471) gene variants was associated with weight gain in chronic schizophrenia patients treated with SGAs [162]. On the other hand, a genetic polymorphism study suggested that MC 4 R is relevant to SGA-induced weight gain and related metabolic disorders [163].…”

Section: The Role Of Pomc and Cart In Sga-induced Weight Gainmentioning

confidence: 99%

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Lian

Huang

Pai

et al. 2016

Pharmacological Research

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Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPKα (NPY: neuropeptide Y; AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapineinduced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPARα: Peroxisome proliferator-activated receptor-α) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders.

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“…A GWAS has recently identified marker rs489693, approx. 200 kb downstream of the MC4R gene to be associated with AIWG (125). Given that this finding was replicated across various samples in different populations using different APs, a major role for rs489693 is likely in AIWG (125Á127).…”

Section: Pharmacodynamicsmentioning

confidence: 70%

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

Changasi

Shams

Pouget

et al. 2014

Translational Developmental Psychiatry

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Background and purpose: Antipsychotics (APs) are the primary method of treatment for schizophrenia and other psychotic disorders. Unfortunately, lengthy trial-and-error approaches are typically required to find the optimal medication and dosage due to a large interindividual variability with outcome to AP treatment. The literature has shown abundant evidence for a genetic component in individuals' responses to APs. Pharmacogenetic studies analyze specific genetic markers and their association with symptom improvement and occurrence of side effects with APs. This research aims to optimize AP drug treatment by usage of predictive testing and to personalize medicine. Recent findings: This review will highlight the most consistent findings in pharmacogenetics of APs and will update the reader on the clinical implications. This will include how genetic variants modulate AP drug levels, side effects, and therapeutic symptom improvement (i.e. response) to AP treatment. Summary: Several promising findings were obtained implicating gene variants of the dopamine receptor genes in addition to gene variants of serotonin receptors for response and common side effects. Notably, effect sizes appear to be particularly high in the genetics of side effects compared to response. One example is antipsychotic-induced weight gain where the leptin, HTR2C and in particular the melanocortin-4-receptor (MC4R) genes have been implicated in weight gain in children and adolescents. Consistent findings were also obtained for genes implicated in tardive dyskinesia and agranulocytosis. However, the most clinically relevant findings pertain to genes involved in drug metabolism such as the CYP2D6 and CYP2C19 genes which have been included in the first genetic test kits such as the Amplichip †

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Association Between Common Variants Near the Melanocortin 4 Receptor Gene and Severe Antipsychotic Drug–Induced Weight Gain

Cited by 164 publications

References 31 publications

Pharmacogenetics of Antipsychotics

Pharmacogenetics of Antipsychotics

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

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