Risk Assessment of Acute Myocardial Infarction and Stroke Associated with Long-Acting Muscarinic Antagonists, Alone or in Combination, versus Long-Acting beta2-Agonists.

Background: The long-acting muscarinic antagonist (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). A post-authorization safety study was initiated to assess potential cardiovascular risks associated with LAMAs versus long-acting beta2-agonists. Purpose: To estimate incidence rates and adjusted incidence rate ratios (IRRs) for acute myocardial infarction (AMI), stroke, and major adverse cardiac events (MACE) in new users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA compared with initiators of LABA. Patients and Methods: This population-based cohort study included patients with COPD aged ≥40 years initiating COPD medications in the UK Clinical Practice Research Datalink (CPRD) Aurum database from 2012 to 2019. Poisson regression models were used to estimate the IRR for AMI, stroke, and MACE in users of COPD medications versus LABA, adjusting for clinically relevant covariables. Results: The study included 11,121 new users of aclidinium, 4804 of aclidinium/formoterol, 56,198 of tiotropium, 23,856 of other LAMA, 17,450 of LAMA/LABA, 70,289 of LABA/ICS, and 13,716 of LABA. During periods of continuous medication use after initiation (current use), crude incidence rates per 1000 person-years for AMI ranged from 8.7 (aclidinium/formoterol) to 12.4 (LAMA/LABA), for stroke ranged from 4.8 (aclidinium/formoterol) to 7.2 (LAMA/LABA), and for MACE ranged from 13.5 (aclidinium/formoterol) to 19.3 (LAMA/LABA). Using LABA as reference, adjusted IRRs [95% confidence intervals] were close to 1 for all study drugs for AMI (lowest for aclidinium/formoterol, 0.95 [0.60-1.52], and highest for LAMA/LABA, 1.23 [0.91-1.67]), stroke (lowest for aclidinium/formoterol, 0.64 [0.39-1.06], and highest for tiotropium, 1.02 [0.81-1.27] for tiotropium) and for MACE (lowest for aclidinium, 0.93 [0.75-1.16], and highest for LAMA/LABA, 1.24 [0.97-1.59]). Conclusion: Risks of AMI, stroke, and MACE in current users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, LAMA/LABA, or LABA/ICS were similar to the risks among current users of LABA.

Characteristics of New Users of Aclidinium Bromide, Aclidinium/Formoterol, and Other COPD Medications in the United Kingdom, Denmark, and Germany.

BACKGROUND AND OBJECTIVES: Aclidinium bromide was approved in the European Union for the treatment of chronic obstructive pulmonary disease (COPD) in adult patients in 2012 and in a fixed-dose combination with formoterol in 2014. We characterised new users of aclidinium, aclidinium/formoterol and other COPD medications and evaluated off-label prescribing of these medications in three European populations. METHODS: We described demographic characteristics, comorbidities, comedications, COPD severity and off-label prescribing of new users of aclidinium, aclidinium/formoterol and other COPD medications in patients with COPD aged ≥ 40 years in the Clinical Practice Research Datalink (CPRD, UK), Danish National Health Databases, and German Pharmacoepidemiological Research Database (GePaRD) between 2015 and 2017. RESULTS: We included 17,668 new users of aclidinium (CPRD, 4871; Denmark, 2836; GePaRD, 9961) and 14,808 new users of aclidinium/formoterol (CPRD, 2153; Denmark, 2586; GePaRD, 10,069). Study patients were of similar age, except in GePaRD, where users of long-acting beta2-agonists (LABA)/inhaled corticosteroids were younger. Patients had multiple comorbidities and used multiple comedications-most frequently hypertension (50-79%) and short-acting beta2-agonists (26-84%). Aclidinium users in CPRD and long-acting anticholinergics/LABA users in Denmark and GePaRD had the highest frequency of severe/very severe COPD. Off-label prescribing of aclidinium (5.0% [CPRD]-8.9% [Denmark]) and aclidinium/formoterol (2.6% [GePaRD]-3.2% [CPRD]) was low, and the main reason was asthma without a COPD diagnosis. CONCLUSIONS: Aclidinium and aclidinium/formoterol were mostly prescribed according to label, with preference given to older patients with more severe COPD and to patients with a high prevalence of comorbidities and comedication use.

Socio-economic position as a moderator of cardiometabolic outcomes in patients receiving psychotropic treatment associated with weight gain: results from a prospective 12-month inception cohort study and a large population-based cohort.

Weight gain and metabolic complications are major adverse effects of many psychotropic drugs. We aimed to understand how socio-economic status (SES), defined as the Swiss socio-economic position (SSEP), is associated with cardiometabolic parameters after initiation of psychotropic medications known to induce weight gain. Cardiometabolic parameters were collected in two Swiss cohorts following the prescription of psychotropic medications. The SSEP integrated neighborhood-based income, education, occupation, and housing condition. The results were then validated in an independent replication sample (UKBiobank), using educational attainment (EA) as a proxy for SES. Adult patients with a low SSEP had a higher risk of developing metabolic syndrome over one year versus patients with a high SSEP (Hazard ratio (95% CI) = 3.1 (1.5-6.5), n = 366). During the first 6 months of follow-up, a significant negative association between SSEP and body mass index (BMI), weight change, and waist circumference change was observed (25 ≤ age < 65, n = 526), which was particularly important in adults receiving medications with the highest risk of weight gain, with a BMI difference of 0.86 kg/m2 between patients with low versus high SSEP (95% CI: 0.03-1.70, n = 99). Eventually, a causal effect of EA on BMI was revealed using Mendelian randomization in the UKBiobank, which was notably strong in high-risk medication users (beta: -0.47 SD EA per 1 SD BMI; 95% CI: -0.46 to -0.27, n = 11,314). An additional aspect of personalized medicine was highlighted, suggesting the patients' SES represents a significant risk factor. Particular attention should be paid to patients with low SES when initiating high cardiometabolic risk psychotropic medications.

Use of intravenous iron and risk of anaphylaxis: A multinational observational post-authorisation safety study in Europe.

PURPOSE: This post-authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non-dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. METHODS: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. RESULTS: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13-16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2-0.9) to 0.5 (95% CI, 0.3-1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8-1.7 per 10 000 treatments). CONCLUSION: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non-dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature.

A Cohort Study to Evaluate the Risk of Hospitalisation for Congestive Heart Failure Associated with the Use of Aclidinium and Other Chronic Obstructive Pulmonary Disease Medications in the UK Clinical Practice Research Datalink.

BACKGROUND: The long-acting anticholinergic (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD). A Post-Authorisation Safety Study (PASS) was initiated to assess potential cardiovascular safety concerns for aclidinium. OBJECTIVE: To estimate the adjusted incidence rate ratio (IRR) for hospitalisation for heart failure in patients with COPD who were new users of aclidinium, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA were compared with initiators of LABA. METHODS: This population-based cohort study included patients with COPD aged ≥40 years initiating COPD medications in the Clinical Practice Research Datalink (CPRD) GOLD in the United Kingdom from 2012 to 2017. Medications were identified via general practice prescriptions. The first-ever hospitalisations for heart failure were identified in the Hospital Episode Statistics, and general practitioner records from the CPRD. Poisson regression models were used to estimate the IRR for hospitalisation for heart failure in users of COPD medications versus LABA, adjusting for clinically relevant covariates. RESULTS: The study included 4350 new users of aclidinium, 23,405 of tiotropium, 6977 of other LAMAs, 3122 of LAMA/LABA, 26,093 of LABA/ICS, and 5678 of LABA. Mean age was 69-70 years across medication groups. Aclidinium users had the highest proportion of severe COPD, and LABA users had the lowest (35% vs 19%, respectively). Crude incidence rates per 1000 person-years for the first-ever hospitalisation for heart failure ranged from 6.9 in LABA to 9.5 in aclidinium. Using LABA as reference, adjusted IRRs (95% confidence interval) for first-ever hospitalisation for heart failure were 0.90 (0.53-1.53) for aclidinium, 1.02 (0.69-1.51) for tiotropium, 0.86 (0.50-1.47) for other LAMAs, 1.09 (0.41-2.92) for LAMA/LABA, and 1.01 (0.69, 1.48) for LABA/ICS. CONCLUSION: The study did not find increased risks of hospitalisations for heart failure in new users of aclidinium, tiotropium, other LAMAs, LAMA/LABA, and LABA/ICS compared with LABA.

Genetic and clinic predictors of new onset diabetes mellitus after transplantation.

New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (ORmain: 1.60 [1.36-1.90], p = 3.72*10-8 and ORreplication: 2.14 [1.39-3.41], p = 0.0008, respectively). Two w-GRS were significantly associated with NODAT in the main sample (ORw-GRS 2:1.09 [1.04-1.15], p = 0.001 and ORw-GRS 3:1.14 [1.01-1.29], p = 0.03) and a similar ORw-GRS 2 was found in the replication sample, although it did not reach significance probably due to a power issue. Despite the low OR of w-GRS on NODAT compared to clinical covariates, when integrating w-GRS 2 and w-GRS 3 in the clinical model, the Area under the Receiver Operating Characteristics curve (AUROC), specificity, sensitivity and accuracy were 0.69, 0.71, 0.58 and 0.68, respectively, with significant Likelihood Ratio test discrimination index (p-value 0.0004), performing better in NODAT discrimination than the clinical model alone. Twenty-five patients needed to be genotyped in order to detect one misclassified case that would have developed NODAT 1 year after transplantation if using only clinical covariates. To our knowledge, this is the first study extensively examining genetic risk scores contributing to NODAT development.

New-onset obesity after liver transplantation-outcomes and risk factors: the Swiss Transplant Cohort Study.

Weight gain after liver transplantation (LTx) facilitates development of new-onset obesity; however, its risk factors and outcomes are poorly understood. We identified the impact of new-onset obesity on cardiovascular events (CVEs) and patient survival, and risk factors for new-onset obesity. Multiple Cox regression models examined risk factors for CVEs, patient survival, and new-onset obesity in 253 adults (mean age 52.2 ± 11.6 years, male gender 63.6%, mean follow up 5.7 ± 2.1 years). Cumulative incidence of post-LTx CVE was 28.1%; that of new-onset obesity was 21.3%. Regardless of CVE at LTx, post-LTx CVEs were predicted by new-onset obesity [Hazard Ratio (HR), 2.95; P = 0.002] and higher age at LTx (HR, 1.05; P < 0.001). In patients without known pre-LTx CVEs (n = 214), risk factors for post-LTx CVEs were new-onset obesity (HR, 2.59; P = 0.014) and higher age (HR, 1.04; P = 0.001). Survival was not associated with new-onset obesity (P = 0.696). Alcoholic liver disease predicted new-onset obesity (HR, 3.37; P = 0.025), female gender was protective (HR, 0.39; P = 0.034). In 114 patients with available genetic data, alcoholic liver disease (HR, 12.82; P = 0.014) and hepatocellular carcinoma (HR, 10.02; P = 0.048) predicted new-onset obesity, and genetics remained borderline significant (HR, 1.07; P = 0.071). Early introduction of post-LTx weight management programs may suggest a potential pathway to reduce CVE risk.

Early changes of blood lipid levels during psychotropic drug treatment as predictors of long-term lipid changes and of new onset dyslipidemia.

BACKGROUND: Cardiovascular diseases and dyslipidemia represent a major health issue in psychiatry. Many psychotropic drugs can induce a rapid and substantial increase of blood lipid levels. OBJECTIVE: This study aimed to determine the potential predictive power of an early change of blood lipid levels during psychotropic treatment on long-term change and on dyslipidemia development. METHODS: Data were obtained from a prospective study including 181 psychiatric patients with metabolic parameters monitored during the first year of treatment and with adherence ascertained. Blood lipid levels (ie, total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], non-high-density lipoprotein cholesterol [non-HDL-C], and fasting triglycerides [TGs]) were measured at baseline and after 1, 3, and/or 12 months of treatment. RESULTS: Receiver-operating characteristic analyses indicated that early (ie, after 1 month of psychotropic treatment) increases (≥5%) for TC, LDL-C, TG, and non-HDL-C and decrease (≥5%) for HDL-C were the best predictors for clinically relevant modifications of blood lipid levels after 3 months of treatment (≥30% TC, ≥40% LDL-C, ≥45% TG, ≥55% non-HDL-C increase, and ≥20% HDL-C decrease; sensitivity 70%-100%, specificity 53%-72%). Predictive powers of these models were confirmed by fitting longitudinal multivariate models in the same cohort (P ≤ .03) as well as in a replication cohort (n = 79; P ≤ .003). Survival models showed significantly higher incidences of new onset dyslipidemia (TC, LDL-C, and non-HDL-C hypercholesterolemia, HDL-C hypocholesterolemia, and hypertriglyceridemia) for patients with early changes of blood lipid levels compared to others (P ≤ .01). CONCLUSION: Early modifications of blood lipid levels following prescription of psychotropic drugs inducing dyslipidemia should therefore raise questions on clinical strategies to control long-term dyslipidemia.

Influence of polygenic risk scores on lipid levels and dyslipidemia in a psychiatric population receiving weight gain-inducing psychotropic drugs.

OBJECTIVES: Dyslipidemia represents a major health issue in psychiatry. We determined whether weighted polygenic risk scores (wPRSs) combining multiple single-nucleotide polymorphisms (SNPs) associated with lipid levels in the general population are associated with lipid levels [high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides] and/or dyslipidemia in patients receiving weight gain-inducing psychotropic drugs. We also determined whether genetics improve the predictive power of dyslipidemia. PATIENTS AND METHODS: The influence of wPRS on lipid levels was firstly assessed in a discovery psychiatric sample (n=332) and was then tested for replication in an independent psychiatric sample (n=140). The contribution of genetic markers to predict dyslipidemia was evaluated in the combined psychiatric sample. RESULTS: wPRSs were significantly associated with the four lipid traits in the discovery (P≤0.02) and in the replication sample (P≤0.03). Patients whose wPRS was higher than the median wPRS had significantly higher LDL, TC, and triglyceride levels (0.20, 0.32 and 0.26 mmol/l, respectively; P≤0.004) and significantly lower HDL levels (0.13 mmol/l; P<0.0001) compared with others. Adding wPRS to clinical data significantly improved dyslipidemia prediction of HDL (P=0.03) and a trend for improvement was observed for the prediction of TC dyslipidemia (P=0.08). CONCLUSION: Population-based wPRSs have thus significant effects on lipid levels in the psychiatric population. As genetics improved the predictive power of dyslipidemia development, only 24 patients need to be genotyped to prevent the development of one case of HDL hypocholesterolemia. If confirmed by further prospective investigations, the present results could be used for individualizing psychotropic treatment.

Association between 28 single nucleotide polymorphisms and type 2 diabetes mellitus in the Kazakh population: a case-control study.

BACKGROUND: We evaluated the associations between single nucleotide polymorphisms and different clinical parameters related to type 2 diabetes mellitus (T2DM), obesity risk, and metabolic syndrome (MS) in a Kazakh cohort. METHODS: A total of 1336 subjects, including 408 T2DM patients and 928 control subjects, were recruited from an outpatient clinic and genotyped for 32 polymorphisms previously associated with T2DM and obesity-related phenotypes in other ethnic groups. For association studies, the chi-squared test or Fisher's exact test for binomial variables were used. Logistic regression was conducted to explore associations between the studied SNPs and the risk of developing T2DM, obesity, and MS, after adjustments for age and sex. RESULTS: After excluding four SNPs due to Hardy-Weinberg disequilibrium, significant associations in age-matched cohorts were found betweenT2DM and the following SNPs: rs9939609 (FTO), rs13266634 (SLC30A8), rs7961581 (TSPAN8/LGR5), and rs1799883 (FABP2). In addition, examination of general unmatched T2DM and control cohorts revealed significant associations between T2DM and SNPsrs1799883 (FABP2) and rs9939609 (FTO). Furthermore, polymorphisms in the FTO gene were associated with increased obesity risk, whereas polymorphisms in the FTO and FABP2 genes were also associated with the risk of developing MS in general unmatched cohorts. CONCLUSION: We confirmed associations between polymorphisms within the SLC30A8, TSPAN8/LGR5, FABP2, and FTO genes and susceptibility to T2DM in a Kazakh cohort, and revealed significant associations with anthropometric and metabolic traits. In particular, FTO and FABP2 gene polymorphisms were significantly associated with susceptibility to MS and obesity in this cohort.

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.

Weighted Genetic Risk Scores and Prediction of Weight Gain in Solid Organ Transplant Populations.

BACKGROUND: Polygenic obesity in Solid Organ Transplant (SOT) populations is considered a risk factor for the development of metabolic abnormalities and graft survival. Few studies to date have studied the genetics of weight gain in SOT recipients. We aimed to determine whether weighted genetic risk scores (w-GRS) integrating genetic polymorphisms from GWAS studies (SNP group#1 and SNP group#2) and from Candidate Gene studies (SNP group#3) influence BMI in SOT populations and if they predict ≥10% weight gain (WG) one year after transplantation. To do so, two samples (nA = 995, nB = 156) were obtained from naturalistic studies and three w-GRS were constructed and tested for association with BMI over time. Prediction of 10% WG at one year after transplantation was assessed with models containing genetic and clinical factors. RESULTS: w-GRS were associated with BMI in sample A and B combined (BMI increased by 0.14 and 0.11 units per additional risk allele in SNP group#1 and #2, respectively, p-values<0.008). w-GRS of SNP group#3 showed an effect of 0.01 kg/m2 per additional risk allele when combining sample A and B (p-value 0.04). Models with genetic factors performed better than models without in predicting 10% WG at one year after transplantation. CONCLUSIONS: This is the first study in SOT evaluating extensively the association of w-GRS with BMI and the influence of clinical and genetic factors on 10% of WG one year after transplantation, showing the importance of integrating genetic factors in the final model. Genetics of obesity among SOT recipients remains an important issue and can contribute to treatment personalization and prediction of WG after transplantation.

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

BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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). CONCLUSION: These results may help to implement genetic testing before starting psychotropic drug treatment to identify patients at risk of important WG.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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, ß=-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, ß=-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. LIMITATIONS: Estimated fat mass using bioimpedance that capture more accurately adiposity was only present in the PsyCoLaus sample. CONCLUSIONS: 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 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(2) 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(2) 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(2) 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.

Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment.

BACKGROUND: Psychotropic drugs can induce substantial weight gain, particularly during the first 6 months of treatment. The authors aimed to determine the potential predictive power of an early weight gain after the introduction of weight gain-inducing psychotropic drugs on long-term weight gain. METHOD: Data were obtained from a 1-year longitudinal study ongoing since 2007 including 351 psychiatric (ICD-10) patients, with metabolic parameters monitored (baseline and/or 1, 3, 6, 9, 12 months) and with compliance ascertained. International Diabetes Federation and World Health Organization definitions were used to define metabolic syndrome and obesity, respectively. RESULTS: Prevalences of metabolic syndrome and obesity were 22% and 17%, respectively, at baseline and 32% and 24% after 1 year. Receiver operating characteristic analyses indicated that an early weight gain > 5% after a period of 1 month is the best predictor for important long-term weight gain (≥ 15% after 3 months: sensitivity, 67%; specificity, 88%; ≥ 20% after 12 months: sensitivity, 47%; specificity, 89%). This analysis identified most patients (97% for 3 months, 93% for 12 months) who had weight gain ≤ 5% after 1 month as continuing to have a moderate weight gain after 3 and 12 months. Its predictive power was confirmed by fitting a longitudinal multivariate model (difference between groups in 1 year of 6.4% weight increase as compared to baseline, P = .0001). CONCLUSION: Following prescription of weight gain-inducing psychotropic drugs, a 5% threshold for weight gain after 1 month should raise clinician concerns about weight-controlling strategies.

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.

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.

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. 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is an enzyme that catalyzes tissue regeneration of active cortisol from cortisone. Elevated enzymatic activity of 11ß-HSD1 may lead to the development of MetS. METHODS: We investigated the association between seven HSD11B1 gene (encoding 11ß-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.