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Biological Mechanism(s) Underpinning the Association between Antipsychotic Drugs and Weight Gain.

ABSTRACT: Weight gain and consequent metabolic alterations are common side-effects of many antipsychotic drugs. Interestingly, several studies have suggested that improvement in symptoms and adverse metabolic effects are correlated. We used next generation sequencing data from NT-2 (human neuronal) cells treated with aripiprazole, amisulpride, risperidone, quetiapine, clozapine, or vehicle control, and compared with the Pillinger P-score (ranked from 0 to 1, indicating greater increase in weight gain and related metabolic parameters) to identify the genes most associated with the drugs' propensity to cause weight gain. The top 500 genes ranked for their correlation with the drugs' propensity to cause weight gain were subjected to pathway analysis using DAVID (NIH). We further investigated transcription factors (TFs) that are more likely to regulate the genes involved in these processes using the prediction tool of key TFs from TRRUST. The results suggest an enrichment for genes involved in lipid biosynthesis and metabolism, which are of interest for mechanisms underpinning weight-gain. The list of genes involved in the lipid pathways that correlated with weight gain was enriched for genes transcriptionally regulated by SREBF1 and SREBF2. Furthermore, quetiapine significantly increased the expression of SREBF1 and SREBF2 in NT-2 cells. Our results suggest that the effects of these antipsychotic drugs on lipid metabolism may be mediated, at least in part, via regulation of SREBF1/SREBF2 expression, with evidence of a direct effect of quetiapine on the expression of SREBF1/2. The effects of antipsychotic drugs on lipid metabolism may influence white matter structure (therapeutic effect) and the risk of weight gain, lipid disturbances, and, consequently, metabolic syndrome (adverse effects). Understanding the different molecular effects of these drugs could inform a personalized medicine approach in treating patients with schizophrenia.

SUBMITTER: Panizzutti B

PROVIDER: S-EPMC8467356 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleWeight gain is a frequent side effect of treatment with SGAs (second-generation antipsychotics) and a leading cause for nonadherence. Several candidate genes have been identified that could influence the amount of AIWG (antipsychotic-induced weight gain). The polymorphism rs17782313 near the MC4R (human melanocortin 4 receptor gene) was strongly associated with obesity in a large scale GWAS (genome wide association study), yet previous studies investigating its impact on AIWG did not lead to a definite conclusion regarding its effect. In particular, they were all relatively short and had a naturalistic design.ObjectiveWe therefore examined the influence of the rs17782313 polymorphism on SGA-related weight gain.MethodsParticipants of a multicenter randomized, controlled, double-blind study comparing two treatment strategies in individuals with schizophrenia or schizoaffective disorder were genotyped using a rapid-cycle polymerase chain reaction. Up to 252 individuals completed the first 2 weeks (phase I), 212 the entire 8 weeks (hence 'completers'). Patients received either amisulpride or olanzapine or both consecutively. Thirty-seven had their first episode. Weight gain occurring in different genotypes was statistically compared and confounding factors were adjusted by stepwise multiple linear regression. A correction for multiple testing was included.ResultsWithin 212 'completers', carriers of the C allele had a higher absolute weight gain than those homozygous for the T allele (2.6 kg vs. 1.2 kg), though this observation was not significant (P = 0.063). In the amisulpride subpopulation, this association appeared stronger and reached significance (2.5 kg vs. 0.7 kg, P = 0.043), though failed to remain significant after correction for multiple testing. A stepwise multiple linear regression showed a significant association in both the whole study population (P < 0.001) and the amisulpride subpopulation (P < 0.001).ConclusionOur results indicate that the rs17782313 polymorphism might influence antipsychotic-induced weight gain and therefore confirm some of the earlier conclusions.

Project description:Second-generation antipsychotics (SGAs) are increasingly used in the treatment of many psychotic and nonpsychotic disorders. Unfortunately, SGAs are often associated with substantial weight gain, with no means to predict which patients are at greatest risk.To identify single-nucleotide polymorphisms associated with antipsychotic drug–induced weight gain.Pharmacogenetic association study.The discovery cohort was from a US general psychiatric hospital. Three additional cohorts were from psychiatric hospitals in the United States and Germany and from a European antipsychotic drug trial.The discovery cohort consisted of 139 pediatric patients undergoing first exposure to SGAs. The 3 additional cohorts consisted of 73, 40, and 92 subjects.Patients in the discovery cohort were treated with SGAs for 12 weeks. Additional cohorts were treated for 6 and 12 weeks.We conducted a genomewide association study assessing weight gain associated with 12 weeks of SGA treatment in patients undergoing first exposure to antipsychotic drugs. We next genotyped 3 independent cohorts of subjects assessed for antipsychotic drug-induced weight gain.Our genome-wide association study yielded 20 single-nucleotide polymorphisms at a single locus exceeding a statistical threshold of P<10(-5). This locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by large-scale genome-wide association studies of obesity in the general population. Effects were recessive, with minor allele homozygotes gaining extreme amounts of weight during the 12-week trial. These results were replicated in 3 additional cohorts, with rs489693 demonstrating consistent recessive effects; meta-analysis revealed a genome-wide significant effect (P=5.59 X 10 (-12). Moreover, we observed consistent effects on related metabolic indices, including triglyceride, leptin, and insulin levels.These data implicate MC4R in extreme SGA-induced weight gain and related metabolic disturbances. A priori identification of high-risk subjects could lead to alternative treatment strategies in this population.

Project description:BackgroundNearly half of all women exceed the 2009 Institute of Medicine guidelines for gestational weight gain. Excess gestational weight gain is associated with adverse pregnancy outcomes.ObjectiveOur objective was to determine whether having a personal gestational weight gain goal consistent with the Institute of Medicine's recommendations for appropriate gestational weight gain and whether having a discussion with one's obstetrical provider regarding that goal were associated with appropriate gestational weight gain.Study designThis is a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be study, a prospective cohort study of nulliparous women. We asked women at their first study visit (between 6 and 13 weeks' gestation) whether they had a gestational weight gain goal and what that goal was. Furthermore, we asked whether their provider discussed a gestational weight gain goal and what that goal was. We classified personal and provider-recommended gestational weight gain goals as consistent or inconsistent with the Institute of Medicine guidelines, taking into account a woman's initial body mass index category (underweight, normal weight, overweight, and obese). We included women with live singleton term deliveries (between 37 and 43 weeks' gestation) in this analysis. We classified the primary outcome, which was gestational weight gain (defined as the difference between first visit weight and final weight before delivery), as inadequate, appropriate, or excessive, based on the Institute of Medicine guidelines and initial body mass index category. We used Student t, Wilcoxon rank-sum, and chi-square tests for bivariable analyses, and multinomial logistic regression was performed to control for confounding variables.ResultsOf 6727 eligible women, 3799 (56.5% of all eligible women) stated they had a gestational weight gain goal. Of the 3799 women with a stated goal, 2589 (38.5% of all women) had a goal consistent with the Institute of Medicine's recommendations. In addition, of the 6727 eligible women, 2188 (32.5%) reported that they discussed gestational weight gain with their provider, and 1548 of these (23.0% of all women) recalled that their provider gave a gestational weight gain goal in accordance with the Institute of Medicine guidelines. Although having any gestational weight gain goal was not associated with appropriate gestational weight gain, having a gestational weight gain goal that was consistent with the Institute of Medicine's recommendations was associated with a reduced risk of excessive (adjusted relative risk ratio, 0.77; 95% confidence interval, 0.64-0.92) and inadequate weight gain (adjusted relative risk ratio, 0.66; 95% confidence interval, 0.53-0.82). Conversely, discussing gestational weight gain goals with a provider was not associated with either inadequate or excessive gestational weight gain even if the provider's recommendations for gestational weight gain were consistent with the guidelines.ConclusionNulliparas who delivered singleton pregnancies at term who had a personal gestational weight gain goal consistent with the Institute of Medicine's recommendations were less likely to have excessive or inadequate gestational weight gain. Further study is required to evaluate the most effective way to communicate this information to patients.

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Biological Mechanism(s) Underpinning the Association between Antipsychotic Drugs and Weight Gain.

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