Prediction of early weight gain during psychotropic treatment using a combinatorial model with clinical and genetic markers.

Psychotropic drugs can induce significant (>5%) weight gain (WG) already after 1 month of treatment, which is a good predictor for major WG at 3 and 12 months. The large interindividual variability of drug-induced WG can be explained in part by genetic and clinical factors. The aim of this study was to determine whether extensive analysis of genes, in addition to clinical factors, can improve prediction of patients at risk for more than 5% WG at 1 month of treatment. Data were obtained from a 1-year naturalistic longitudinal study, with weight monitoring during weight-inducing psychotropic treatment. A total of 248 Caucasian psychiatric patients, with at least baseline and 1-month weight measures, and with compliance ascertained were included. Results were tested for replication in a second cohort including 32 patients. Age and baseline BMI were associated significantly with strong WG. The area under the curve (AUC) of the final model including genetic (18 genes) and clinical variables was significantly greater than that of the model including clinical variables only (AUCfinal: 0.92, AUCclinical: 0.75, P<0.0001). Predicted accuracy increased by 17% with genetic markers (Accuracyfinal: 87%), indicating that six patients must be genotyped to avoid one misclassified patient. The validity of the final model was confirmed in a replication cohort. Patients predicted before treatment as having more than 5% WG after 1 month of treatment had 4.4% more WG over 1 year than patients predicted to have up to 5% WG (P≤0.0001). These results may help to implement genetic testing before starting psychotropic drug treatment to identify patients at risk of important WG

Association of genetic risk scores with body mass index in Swiss psychiatric cohorts.

OBJECTIVE: Weight gain is associated with psychiatric disorders and/or with psychotropic drug treatments. We analyzed in three psychiatric cohorts under psychotropic treatment the association of weighted genetic risk scores (w-GRSs) with BMI by integrating BMI-related polymorphisms from the candidate-gene approach and Genome-Wide Association Studies (GWAS). MATERIALS AND METHODS: w-GRS of 32 polymorphisms associated previously with BMI in general population GWAS and 20 polymorphisms associated with antipsychotics-induced weight gain were investigated in three independent psychiatric samples. RESULTS: w-GRS of 32 polymorphisms were significantly associated with BMI in the psychiatric sample 1 (n=425) and were replicated in another sample (n=177). Those at the percentile 95 (p95) of the score had 2.26 and 2.99 kg/m higher predicted BMI compared with individuals at the percentile 5 (p5) in sample 1 and in sample 3 (P=0.009 and 0.04, respectively). When combining all samples together (n=750), a significant difference of 1.89 kg/m predicted BMI was found between p95 and p5 individuals at 12 months of treatment. Stronger associations were found among men (difference: 2.91 kg/m of predicted BMI between p95 and p5, P=0.0002), whereas no association was found among women. w-GRS of 20 polymorphisms was not associated with BMI. The w-GRS of 52 polymorphisms and the clinical variables (age, sex, treatment) explained 1.99 and 3.15%, respectively, of BMI variability. CONCLUSION: The present study replicated in psychiatric cohorts previously identified BMI risk variants obtained in GWAS analyses from population-based samples. Sex-specific analysis should be considered in further analysis

Impact of HSD11B1 polymorphisms on BMI and components of the metabolic syndrome in patients receiving psychotropic treatments.

BACKGROUND: Metabolic syndrome (MetS) associated with psychiatric disorders and psychotropic treatments represents a major health issue. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme that catalyzes tissue regeneration of active cortisol from cortisone. Elevated enzymatic activity of 11β-HSD1 may lead to the development of MetS. METHODS: We investigated the association between seven HSD11B1 gene (encoding 11β-HSD1) polymorphisms and BMI and MetS components in a psychiatric sample treated with potential weight gain-inducing psychotropic drugs (n=478). The polymorphisms that survived Bonferroni correction were analyzed in two independent psychiatric samples (nR1=168, nR2=188) and in several large population-based samples (n1=5338; n2=123 865; n3>100 000). RESULTS: HSD11B1 rs846910-A, rs375319-A, and rs4844488-G allele carriers were found to be associated with lower BMI, waist circumference, and diastolic blood pressure compared with the reference genotype (Pcorrected<0.05). These associations were exclusively detected in women (n=257) with more than 3.1 kg/m, 7.5 cm, and 4.2 mmHg lower BMI, waist circumference, and diastolic blood pressure, respectively, in rs846910-A, rs375319-A, and rs4844488-G allele carriers compared with noncarriers (Pcorrected<0.05). Conversely, carriers of the rs846906-T allele had significantly higher waist circumference and triglycerides and lower high-density lipoprotein-cholesterol exclusively in men (Pcorrected=0.028). The rs846906-T allele was also associated with a higher risk of MetS at 3 months of follow-up (odds ratio: 3.31, 95% confidence interval: 1.53-7.17, Pcorrected=0.014). No association was observed between HSD11B1 polymorphisms and BMI and MetS components in the population-based samples. CONCLUSIONS: Our results indicate that HSD11B1 polymorphisms may contribute toward the development of MetS in psychiatric patients treated with potential weight gain-inducing psychotropic drugs, but do not play a significant role in the general population

Association of CRTC1 polymorphisms with obesity markers in subjects from the general population with lifetime depression.

Psychiatric disorders have been hypothesized to share common etiological pathways with obesity, suggesting related neurobiological bases. We aimed to examine whether CRTC1 polymorphisms were associated with major depressive disorder (MDD) and to test the association of these polymorphisms with obesity markers in several large case-control samples with MDD. The association between CRTC1 polymorphisms and MDD was investigated in three case-control samples with MDD (PsyCoLaus n1=3,362, Radiant n2=3,148 and NESDA/NTR n3=4,663). The effect of CRTC1 polymorphisms on obesity markers was then explored. CRTC1 polymorphisms were not associated with MDD in the three samples. CRTC1 rs6510997C>T was significantly associated with fat mass in the PsyCoLaus study. In fact, a protective effect of this polymorphism was found in MDD cases (n=1,434, β=-1.32%, 95% CI -2.07 to -0.57, p<0.001), but not in controls. In the Radiant study, CRTC1 polymorphisms were associated with BMI, exclusively in individuals with MDD (n=2,138, β=-0.75kg/m(2), 95% CI -1.30 to -0.21, p=0.007), while no association with BMI was found in the NESDA/NTR study. Estimated fat mass using bioimpedance that capture more accurately adiposity was only present in the PsyCoLaus sample. CRTC1 polymorphisms seem to play a role with obesity markers in individuals with MDD rather than non-depressive individuals. Therefore, the weak association previously reported in the population-based samples was driven by cases diagnosed with lifetime MDD. However, CRTC1 seems not to be implicated directly in the development of psychiatric diseases

Association of PCK1 with Body Mass Index and Other Metabolic Features in Patients With Psychotropic Treatments.

Weight gain is a major health problem among psychiatric populations. It implicates several receptors and hormones involved in energy balance and metabolism. Phosphoenolpyruvate carboxykinase 1 is a rate-controlling enzyme involved in gluconeogenesis, glyceroneogenesis and cataplerosis and has been related to obesity and diabetes phenotypes in animals and humans. The aim of this study was to investigate the association of phosphoenolpyruvate carboxykinase 1 polymorphisms with metabolic traits in psychiatric patients treated with psychotropic drugs inducing weight gain and in general population samples. One polymorphism (rs11552145G > A) significantly associated with body mass index in the psychiatric discovery sample (n = 478) was replicated in 2 other psychiatric samples (n1 = 168, n2 = 188), with AA-genotype carriers having lower body mass index as compared to G-allele carriers. Stronger associations were found among women younger than 45 years carrying AA-genotype as compared to G-allele carriers (-2.25 kg/m, n = 151, P = 0.009) and in the discovery sample (-2.20 kg/m, n = 423, P = 0.0004). In the discovery sample for which metabolic parameters were available, AA-genotype showed lower waist circumference (-6.86 cm, P = 0.008) and triglycerides levels (-5.58 mg/100 mL, P < 0.002) when compared to G-allele carriers. Finally, waist-to-hip ratio was associated with rs6070157 (proxy of rs11552145, r = 0.99) in a population-based sample (N = 123,865, P = 0.022). Our results suggest an association of rs11552145G > A polymorphism with metabolic-related traits, especially in psychiatric populations and in women younger than 45 years

Influence of MCHR2 and MCHR2-AS1 Genetic Polymorphisms on Body Mass Index in Psychiatric Patients and In Population-Based Subjects with Present or Past Atypical Depression.

Obesity development during psychotropic treatments represents a major health issue in psychiatry. Melanin-concentrating hormone receptor 2 (MCHR2) is a central receptor involved in energy homeostasis. MCHR2 shares its promoter region with MCHR2-AS1, a long antisense non-coding RNA. The aim of this study was to determine whether tagging single nucleotide polymorphisms (tSNPs) of MCHR2 and MCHR2-AS1 are associated with the body mass index (BMI) in the psychiatric and in the general population. The influence of MCHR2 and MCHR2-AS1 tSNPs on BMI was firstly investigated in a discovery psychiatric sample (n1 = 474). Positive results were tested for replication in two other psychiatric samples (n2 = 164, n3 = 178) and in two population-based samples (CoLaus, n4 = 5409; GIANT, n5 = 113809). In the discovery sample, TT carriers of rs7754794C>T had 1.08 kg/m2 (p = 0.04) lower BMI as compared to C-allele carriers. This observation was replicated in an independent psychiatric sample (-2.18 kg/m2; p = 0.009). The association of rs7754794C>T and BMI seemed stronger in subjects younger than 45 years (median of age). In the population-based sample, a moderate association was observed (-0.17 kg/m2; p = 0.02) among younger individuals (<45y). Interestingly, this association was totally driven by patients meeting lifetime criteria for atypical depression, i.e. major depressive episodes characterized by symptoms such as an increased appetite. Indeed, patients with atypical depression carrying rs7754794-TT had 1.17 kg/m2 (p = 0.04) lower BMI values as compared to C-allele carriers, the effect being stronger in younger individuals (-2.50 kg/m2; p = 0.03; interaction between rs7754794 and age: p-value = 0.08). This study provides new insights on the possible influence of MCHR2 and/or MCHR2-AS1 on obesity in psychiatric patients and on the pathophysiology of atypical depression

Influence of CRTC1 Polymorphisms on Body Mass Index and Fat Mass in Psychiatric Patients and the General Adult Population.

IMPORTANCE There is a high prevalence of obesity in psychiatric patients, possibly leading to metabolic complications and reducing life expectancy. The CREB-regulated transcription coactivator 1 (CRTC1) gene is involved in energy balance and obesity in animal models, but its role in human obesity is unknown. OBJECTIVE To determine whether polymorphisms within the CRTC1 gene are associated with adiposity markers in psychiatric patients and the general population. DESIGN, SETTING, AND PARTICIPANTS Retrospective and prospective data analysis and population-based samples at Lausanne and Geneva university hospitals in Switzerland and a private clinic in Lausanne, Switzerland. The effect of 3 CRTC1 polymorphisms on body mass index (BMI) and/or fat mass was investigated in a discovery cohort of psychiatric outpatients taking weight gain-inducing psychotropic drugs (sample 1, n = 152). The CRTC1 variant that was significantly associated with BMI and survived Bonferroni corrections for multiple comparison was then replicated in 2 independent psychiatric samples (sample 2, n = 174 and sample 3, n = 118) and 2 white population-based samples (sample 4, n = 5338 and sample 5, n = 123 865). INTERVENTION Noninterventional studies. MAIN OUTCOME AND MEASURE Difference in BMI and/or fat mass between CRTC1 genotype groups. RESULTS Among the CRTC1 variants tested in the first psychiatric sample, only rs3746266A>G was associated with BMI (Padjusted = .003). In the 3 psychiatric samples, carriers of the rs3746266 G allele had a lower BMI than noncarriers (AA genotype) (sample 1, P = .001; sample 2, P = .05; and sample 3, P = .0003). In the combined analysis, excluding patients taking other weight gain-inducing drugs, G allele carriers (n = 98) had a 1.81-kg/m2 lower BMI than noncarriers (n = 226; P < .0001). The strongest association was observed in women younger than 45 years, with a 3.87-kg/m2 lower BMI in G allele carriers (n = 25) compared with noncarriers (n = 48; P < .0001), explaining 9% of BMI variance. In the population-based samples, the T allele of rs6510997C>T (a proxy of the rs3746266 G allele; r2 = 0.7) was associated with lower BMI (sample 5, n = 123 865; P = .01) and fat mass (sample 4, n = 5338; P = .03). The strongest association with fat mass was observed in premenopausal women (n = 1192; P = .02). CONCLUSIONS AND RELEVANCE These findings suggest that CRTC1 contributes to the genetics of human obesity in psychiatric patients and the general population. Identification of high-risk subjects could contribute to a better individualization of the pharmacological treatment in psychiatry

Association of variants in SH2B1 and RABEP1 with worsening of low-density lipoprotein and glucose parameters in patients treated with psychotropic drugs.

Genetic factors associated with Body Mass Index (BMI) have been widely studied over the last decade. We examined whether genetic variants previously associated with BMI in the general population are associated with cardiometabolic parameter worsening in the psychiatric population receiving psychotropic drugs, a high-risk group for metabolic disturbances. Classification And Regression Trees (CARTs) were used as a tool capable of describing hierarchical associations, to pinpoint genetic variants best predicting worsening of cardiometabolic parameters (i.e total, HDL and LDL-cholesterol, triglycerides, body mass index, waist circumference, fasting glucose, and blood pressure) following prescription of psychotropic drugs inducing weight gain in a discovery sample of 357 Caucasian patients. Significant findings were tested for replication in a second Caucasian psychiatric sample (n=140). SH2B1 rs3888190C>A was significantly associated with LDL levels in the discovery and in the replication sample, with A-allele carriers having 0.2mmol/l (p=0.005) and 0.36mmol/l (p=0.007) higher LDL levels compared to others, respectively. G-allele carriers of RABEP1 rs1000940A>G had lower fasting glucose levels compared to others in both samples (-0.16mmol/l; p<0.001 and -0.77mmol/l; p=0.03 respectively). The present study is the first to observe such associations in human subjects, which may in part be explained by a high risk towards dyslipidemia and diabetes in psychiatric patients receiving psychotropic treatments compared to population-based individuals. These results may therefore give new insight into the etiology of LDL-cholesterol and glucose regulation in psychiatric patients under psychotropic drug therapy

The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation

Purpose: In children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients. Methods: Data were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition. Results: Forty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5-17.7 and 0.05-14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07-0.35) vs. 0.09 (0.02-0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04-0.32) vs. 0.09 (0.01-0.18) mg/kg/12h, p