Prediction of antipsychotics efficacy based on a polygenic risk score: a real-world cohort study.

Background: Response to antipsychotics is subject to a wide interindividual variability, due to genetic and non-genetic factors. Several single nucleotide polymorphisms (SNPs) have been associated with response to antipsychotics in genome-wide association studies (GWAS). Polygenic risk scores (PRS) are a powerful tool to aggregate into a single measure the small effects of multiple risk alleles. Materials and methods: We studied the association between a PRS composed of SNPs associated with response to antipsychotics in GWAS studies (PRSresponse) in a real-world sample of patients (N = 460) with different diagnoses (schizophrenia spectrum, bipolar, depressive, neurocognitive, substance use disorders and miscellaneous). Two other PRSs composed of SNPs previously associated with risk of schizophrenia (PRSschizophrenia1 and PRSschizophrenia2) were also tested for their association with response to treatment. Results: PRSresponse was significantly associated with response to antipsychotics considering the whole cohort (OR = 1.14, CI = 1.03-1.26, p = 0.010), the subgroup of patients with schizophrenia, schizoaffective disorder or bipolar disorder (OR = 1.18, CI = 1.02-1.37, p = 0.022, N = 235), with schizophrenia or schizoaffective disorder (OR = 1.24, CI = 1.04-1.47, p = 0.01, N = 176) and with schizophrenia (OR = 1.27, CI = 1.04-1.55, p = 0.01, N = 149). Sensitivity and specificity were sub-optimal (schizophrenia 62%, 61%; schizophrenia spectrum 56%, 55%; schizophrenia spectrum plus bipolar disorder 60%, 56%; all patients 63%, 58%, respectively). PRSschizophrenia1 and PRSschizophrenia2 were not significantly associated with response to treatment. Conclusion: PRSresponse defined from GWAS studies is significantly associated with response to antipsychotics in a real-world cohort; however, the results of the sensitivity-specificity analysis preclude its use as a predictive tool in clinical practice.

DNA methylation may partly explain psychotropic drug-induced metabolic side effects: results from a prospective 1-month observational study.

BACKGROUND: Metabolic side effects of psychotropic medications are a major drawback to patients' successful treatment. Using an epigenome-wide approach, we aimed to investigate DNA methylation changes occurring secondary to psychotropic treatment and evaluate associations between 1-month metabolic changes and both baseline and 1-month changes in DNA methylation levels. Seventy-nine patients starting a weight gain inducing psychotropic treatment were selected from the PsyMetab study cohort. Epigenome-wide DNA methylation was measured at baseline and after 1 month of treatment, using the Illumina Methylation EPIC BeadChip. RESULTS: A global methylation increase was noted after the first month of treatment, which was more pronounced (p < 2.2 × 10-16) in patients whose weight remained stable (< 2.5% weight increase). Epigenome-wide significant methylation changes (p < 9 × 10-8) were observed at 52 loci in the whole cohort. When restricting the analysis to patients who underwent important early weight gain (≥ 5% weight increase), one locus (cg12209987) showed a significant increase in methylation levels (p = 3.8 × 10-8), which was also associated with increased weight gain in the whole cohort (p = 0.004). Epigenome-wide association analyses failed to identify a significant link between metabolic changes and methylation data. Nevertheless, among the strongest associations, a potential causal effect of the baseline methylation level of cg11622362 on glycemia was revealed by a two-sample Mendelian randomization analysis (n = 3841 for instrument-exposure association; n = 314,916 for instrument-outcome association). CONCLUSION: These findings provide new insights into the mechanisms of psychotropic drug-induced weight gain, revealing important epigenetic alterations upon treatment, some of which may play a mediatory role.

[Antipsychotic prescribing in adults : what to watch out for ?] / Prescription d'antipsychotiques chez les adultes : à quoi faut-il être attentif ?

Antipsychotics are known to produce frequent and/or potentially serious adverse effects, including neurological, cardiovascular, metabolic and endocrine effects. The side-effects of antipsychotics vary according to their affinity for different central and peripheral receptors, and individual vulnerabilities. Some of these side-effects are dose-dependent, while others are little or not ; thus, management strategies need to be adapted. Good management of adverse events is important to encourage patients' medication adherence and to reduce the cardiovascular morbidity and mortality of side effects. Good collaboration between psychiatrists and general practitioners or specialists is essential.

Les antipsychotiques sont connus pour engendrer des effets indésirables fréquents et/ou potentiellement graves, notamment neurologiques, cardiovasculaires, métaboliques et endocriniens. Les effets secondaires des antipsychotiques varient selon leur profil d'affinités pour les différents récepteurs cérébraux et périphériques et selon les vulnérabilités individuelles. Certains d'entre eux sont dose-dépendants, d'autres peu ou pas ; les stratégies de prise en charge sont donc à adapter. Une bonne gestion des effets indésirables est importante pour favoriser l'adhésion médicamenteuse des patients et atténuer leur impact en termes de morbimortalité. Une bonne collaboration entre médecins psychiatres et généralistes ou spécialistes est nécessaire.

Is Clozapine-induced Weight Gain Dose-dependent? Results From a Prospective Cohort Study.

BACKGROUND: Antipsychotic-induced metabolic adverse effects are risk factors for cardiometabolic comorbidities. Whether dose lowering could mitigate such effects remains unclear. The present study aims to investigate the associations between clozapine doses and modifications of weight, blood pressure, blood glucose, and lipid levels. STUDY DESIGN: Linear mixed-effects models of weight changes over 1 year and of variations of other metabolic parameters over 4 months were applied to a prospective cohort of 115 patients. Age- and sex-stratified analyses of weight changes were also performed. STUDY RESULTS: Each 100 mg dose increment of clozapine was associated on average with a +0.48% weight increase (P = .004) over 1 year of treatment. Weight increase was greater for treatment duration ≤3 vs >3 months (+0.84% and +0.47% per month, respectively, P < .001), with a significant association with the dose for durations >3 months (+0.54%, P = .004) and a trend for durations ≤3 months (+0.33%, P = .075). Dose increments of 100 mg were also associated with weight increases of +0.71% among adults (P = .001), +1.91% among the elderly (P < .001) and +1.32% among men (P < .001) with no associations among women (P = .62). Among young adults, weight change was positively associated with doses ≤300 mg/day (+2.19% per 100 mg, P = .001), whereas no association was found with doses >300 mg/day (P = .60). No significant effect of clozapine dose on other metabolic parameters was found. CONCLUSIONS: This study reports a modest effect of clozapine dose increases on weight gain over 1 year with differences among age categories and sexes and no dose effect on other metabolic parameters over 4 months.

Clozapine once- versus multiple-daily dosing: a two-center cross-sectional study, systematic review and meta-analysis.

Evidence regarding effectiveness and safety of clozapine once- vs. multiple-daily dosing is limited. We compared demographic and clinical parameters between patients with once- vs. multiple-daily dosing in the Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (AGATE dataset), and the Department of Psychiatry, Lausanne University Hospital, Switzerland, using non-parametric tests. Effectiveness and safety outcomes were available in the AGATE dataset. We performed a systematic review in PubMed/Embase until February 2022, meta-analyzing studies comparing clozapine once- vs. multiple-daily-dosing. We estimated a pooled odds ratio for adverse drug-induced reactions (ADRs) and meta-analyzed differences regarding clinical symptom severity, age, percentage males, smokers, clozapine dose, and co-medications between patients receiving once- vs. multiple-daily dosing. Study quality was assessed using the Newcastle-Ottawa-Scale. Of 1494 and 174 patients included in AGATE and Lausanne datasets, clozapine was prescribed multiple-daily in 74.8% and 67.8%, respectively. In the AGATE cohort, no differences were reported for the clinical symptoms severity or ADR rate (p > 0.05). Meta-analyzing eight cohorts with a total of 2810 clozapine-treated individuals, we found more severe clinical symptoms (p = 0.036), increased ADR risk (p = 0.01), higher clozapine doses (p < 0.001), more frequent co-medication with other antipsychotics (p < 0.001), benzodiazepines (p < 0.001), anticholinergics (p = 0.039), and laxatives (p < 0.001) in patients on multiple- vs. once-daily dosing. Of six studies, five were rated as good, and one as poor quality. Patients responding less well to clozapine may be prescribed higher doses multiple-daily, also treated with polypharmacy, potentially underlying worse safety outcomes. Patient preferences and adherence should be considered during regimen selection.

Evolutions of Metabolic Parameters Following Switches of Psychotropic Drugs: A Longitudinal Cohort Study.

BACKGROUND: Several psychotropic drugs can induce weight gain and metabolic alterations. The authors compared metabolic evolutions of patients switching versus continuing psychotropic treatments with different risk profiles. METHODS: Patients either switched from a high- to a medium- (N = 36) or low-risk drug (N = 27), from a medium- to a low-risk drug (N = 71), or to a same-risk drug (N = 61). Controls were kept using either a high- (N = 35), medium- (N = 155), or low-risk drug (N = 47). The evolution over 2 years of weight and metabolic parameters was analyzed using linear mixed-effect models, also examining the influence of polygenic risk scores for body mass index (BMI) or BMI and psychiatric disorders. STUDY RESULTS: High-, medium-, or low-risk controls gained on average 1.32%, 0.42%, and 0.36% more weight per month than patients switching from or within these risk categories (P < .001, P < .001, and P = .003, respectively). High-to-high or high-to-medium switches resulted in a greater weight increase than switching to lower-risk categories (+0.77% and + 0.39% respectively, P < .001). No difference was found between switching medium-to-medium and medium-to-low (P ≈ 1). Switching high-to-low resulted in 10% weight loss after 2 years, with the greatest loss occurring the first 6 months after the switch. Compared with high-risk controls, lower total cholesterol (-0.27 mmol/l, P = .043) in the high-to-low group, and lower glucose (-0.44 mmol/l, P = .032) and systolic blood pressure (-5.50 mmHg, P = .034) in the low-to-low group were found. Polygenic scores were not associated with weight changes in controls or after switching. CONCLUSION: Psychotropic switches to a lower- or same-risk drug can attenuate weight gain, with only switching high to low resulting in weight loss.

Body Composition Assessment by Dual-Energy X-Ray Absorptiometry: A Useful Tool for the Diagnosis of Lipedema.

INTRODUCTION: Lipedema is a poorly known condition. Diagnosis is based almost exclusively on clinical criteria, which may be subjective and not always reliable. This study aimed to investigate regional body composition (BC) by dual-energy X-ray absorptiometry (DXA) in patients with lipedema and healthy controls and to determine cut-off values of fat mass (FM) indices to provide an additional tool for the diagnosis and staging of this condition. METHODS: This study is a single-center case-control study performed at Lausanne University Hospital, Switzerland. Women with clinically diagnosed lipedema underwent regional BC assessment by DXA. The control group without clinical lipedema was matched for age and body mass index (BMI) at a ratio of 1:2 and underwent similar examination. Regional FM (legs, arms, legs and arms, trunk, android and gynoid FM) was measured in (kg) and divided by FM index (FMI) (kg/m2) and total FM (kg). The trunk/legs and android/gynoid ratios were calculated. For all indices of FM distribution showing a significant difference between cases and controls, we defined the receiver operating characteristic (ROC) curves, calculating the area under the curve (AUC), sensitivity, specificity, and Youden's index. Types and stages of lipedema were compared in terms of FM indices. Correlation analyses between all FM distribution indices and lipedema stages were performed. RESULTS: We included 222 women (74 with lipedema and 148 controls). Overall, the mean age was 41 years (standard deviation [SD] 11), and mean BMI was 30.9 kg/m2 (SD 7.6). A statistically significant difference was observed for all DXA-derived indices of FM distribution between groups, except for arm FM indices. The ROC curve analysis of leg FM/total FM, as a potential indicator of lipedema, resulted in an AUC of 0.90 (95% confidence interval 0.86-0.94). According to Youden's index, optimal cut-off value identifying lipedema was 0.384. Sensitivity and specificity were 0.95 and 0.73, respectively. We found no significant differences between lipedema types and stages in terms of FM indices, nor significant correlations between the latter and lipedema stages. DISCUSSION/CONCLUSION: BC assessment by DXA, and particularly calculation of the leg FM/total FM index, is a simple tool that may help clinicians rule out lipedema in doubtful cases.

[Gabapentinoids : misuses and addictions]. / Gabapentinoïdes : mésusages et addictions.

Cases of addictions and misuses on gabapentinoids are increasingly reported. But the underlying pharmacological mechanism is not completely understood. Here is an uptodate of the current knowledges on this dependence and its management.

Des cas de mésusages et d'addictions aux gabapentinoïdes sont de plus en plus fréquemment rapportés, sans que le mécanisme pharmacologique sous-jacent ne soit complètement compris. Nous faisons un état des lieux des connaissances sur cette dépendance et sa prise en charge.

[Recommendations for management of misuses and addictions to benzodiazepines]. / Recommandations de prise en charge des mésusages et addictions aux benzodiazepines.

The management of patients who have become dependent on benzodiazepines and analogues is a problem frequently encountered in both somatic and psychiatric medicine. No pharmacological treatment is currently recognized as effective in the management of these addictions, apart from a gradual reduction of doses. We propose practical strategies for the implementation of gradual dose reduction and choice of molecules while promoting individual adaptation to the withdrawal symptoms presented by the patient.

La prise en charge de patients ayant développé une dépendance aux benzodiazépines et analogues est une problématique rencontrée fréquemment tant en médecine somatique que psychiatrique. Aucun traitement pharmacologique n'est actuellement reconnu comme efficace dans la prise en charge de ces dépendances, en dehors d'une réduction progressive des doses. Nous proposons des stratégies pratiques de mise en œuvre de réduction progressive des doses et de choix de molécules tout en favorisant une adaptation individuelle aux symptômes de sevrage présentés par le patient.

[Treatment of insomnia, with what to start ?] / Traitement de l'insomnie, par quoi commencer ?

Confronted with a complaint of insomnia, several points must be considered before prescribing a specific treatment. In particular, it is necessary to optimize the management of somatic and psychiatric comorbidities that can affect sleep and to review the intake of sleep-disrupting substances and drugs. The current guidelines for insomnia rank treatment options based on the quality of the evidence. They all agree to recommend cognitive behavioural therapy for insomnia as first-line treatment. Pharmacological treatment should only be considered if this therapy fails. We then propose to start with the drugs presenting the best safety profile before prescribing, if necessary, those having better effectiveness evidence but carrying a greater risk of side effects.

Face à une plainte d'insomnie, plusieurs points sont à prendre en compte avant d'envisager un traitement spécifique, notamment l'optimisation de la prise en charge des comorbidités somatiques et psychiatriques pouvant péjorer le sommeil et la revue de la prise de substances et médicaments le perturbant. Les recommandations sur l'insomnie classent les options thérapeutiques selon la qualité des études à disposition. Elles s'accordent toutes à recommander la thérapie cognitivo-comportementale spécifique pour l'insomnie en première intention. Un traitement pharmacologique ne devrait être envisagé qu'en cas d'échec de cette thérapie. Nous proposons alors de débuter avec les molécules présentant le meilleur profil de sécurité avant de passer, si nécessaire, à celles ayant mieux démontré leur efficacité mais comportant un plus grand risque d'effets secondaires.

[Rapid tranquilisation in adults†: algorithm proposed for psychopharmacological treatment]. / Agitation aiguë chez l'adulte†: proposition d'un algorithme de traitement psychopharmacologique.

Acute treatment of agitation in psychiatry is one of the urgent situations for which management recommendations are needed. Various existing international recommendations have been evaluated and adapted to our clinical practice and to the drugs available in Switzerland in order to propose a uniform management strategy in our hospital. This strategy includes a treatment choice algorithm with different options depending on the clinical situation and the possible route of administration. Dose recommendations for the oral and intramuscular routes, certain pharmacokinetic parameters, as well as risks of interactions and important warnings are also included in this clinical recommendation.

Le traitement aigu de l'agitation en psychiatrie fait partie des situations urgentes pour lesquelles des recommandations de prise en charge sont nécessaires. Diverses recommandations internationales existantes ont été évaluées et adaptées à notre pratique clinique ainsi qu'aux médicaments disponibles en Suisse afin de proposer une stratégie de prise en charge uniformisée au sein de notre hôpital. Cette stratégie inclut un algorithme de choix de traitement avec différentes options selon la situation clinique et la voie d'administration possible. Des recommandations de doses pour les voies orale et intramusculaire, certains paramètres pharmacocinétiques, ainsi que les risques d'interactions et des mises en garde importantes figurent également dans cette recommandation clinique.

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.

Concentrações plasmáticas de paroxetina em pacientes adultos e idosos com depressão / Paroxetine plasma concentrations in adult and elderly depressed patients

INTRODUÇÃO: O efeito do envelhecimento nas concentrações plasmáticas em estado de equilíbrio da paroxetina foi investigado em 136 pacientes com depressão, tratados com doses variando entre 10 e 120 mg/dia de paroxetina. MÉTODOS: Os pacientes foram separados em três grupos: com idade até 64 anos (idade média ± desvio padrão: 41,7±12,6 anos; n = 44), entre 65 e 79 anos (72,8±4,7 anos; n = 64), e com mais de 80 anos (82,8±3,3 anos; n = 28). As doses de paroxetina foram normalizadas para 20 mg/dia. Amostras de sangue foram coletadas em condições de estado de equilíbrio. Os níveis plasmáticos de paroxetina foram medidos por cromatografia gasosa - espectrometria de massa. As funções hepática e renal foram medidas por testes laboratoriais clínicos estandardizados. RESULTADOS: Uma grande variabilidade interindividual dos níveis plasmáticos de paroxetina (37 vezes) foi medida para uma mesma dose. A média dos níveis plasmáticos de paroxetina corrigida para uma dose diária de 20 mg foi 87 por cento maior no grupo com mais de 80 anos (56,4±64,1 ng/mL; p < 0,05) e 57 por cento maior no grupo com idades entre 65 e 79 anos (46,7±33,4 ng/mL; p < 0,001) quando comparada com a média dos pacientes com menos de 64 anos (29,9±11,9 ng/mL). A idade foi correlacionada significativamente com os níveis plasmáticos de paroxetina (r = 0,21, p < 0,05) CONCLUSÃO: A redução de doses da paroxetina em pacientes idosos parece justificada.

INTRODUCTION: The effect of aging on steady-state plasma concentrations of paroxetine was investigated in 136 depressive patients treated with paroxetine 10-120 mg/day. METHODS: The patients were divided into three groups: aged up to 64 years (mean age ± standard deviation: 41.7±12.6 years; n = 44), between 65 and 79 years (72.8±4.7 years; n = 64), and 80 years or older (82.8±3.3 years; n = 28). Paroxetine doses were normalized to 20 mg/day. Blood samples were collected under steady-state conditions. Paroxetine plasma levels were measured by gas chromatography/mass spectrometry. Hepatic and renal functions were measured by standardized clinical laboratory tests. RESULTS: A large interindividual variability of paroxetine plasma levels (37-fold) was measured for a given dose. The mean plasma levels of paroxetine corrected for a 20 mg daily dose were 87 percent higher in the very elderly (≥ 80 years) patients (56.4±64.1 ng/mL; p < 0.05) and 57 percent higher in the elderly (65-79 years) patients (46.7±33.4 ng/mL; p < 0.001) when compared to the adult patients (< 64 years) (29.9±11.9ng/mL). Age correlated significantly with paroxetine plasma levels (r = 0.21, p < 0.05). CONCLUSION: Recommended dose reduction of paroxetine in elderly patients seems therefore justified.