Therapeutic Drug Monitoring of Olanzapine: Effects of Clinical Factors on Plasma Concentrations in Psychiatric Patients.

BACKGROUND: Therapeutic drug monitoring (TDM) is strongly recommended for olanzapine due to its high pharmacokinetic variability. This study aimed to investigate the impact of various clinical factors on olanzapine plasma concentrations in patients with psychiatric disorders. METHODS: The study used TDM data from the PsyMetab cohort, including 547 daily dose-normalized, steady-state, olanzapine plasma concentrations (C:D ratios) from 248 patients. Both intrinsic factors (eg, sex, age, body weight) and extrinsic factors (eg, smoking status, comedications, hospitalization) were examined. Univariate and multivariable, linear, mixed-effects models were employed, with a stepwise selection procedure based on Akaike information criterion to identify the relevant covariates. RESULTS: In the multivariable model (based on 440 observations with a complete data set), several significant findings emerged. Olanzapine C:D ratios were significantly lower in smokers (ß = -0.65, P < 0.001), valproate users (ß = -0.53, P = 0.002), and inpatients (ß = -0.20, P = 0.025). Furthermore, the C:D ratios decreased significantly as the time since the last dose increased (ß = -0.040, P < 0.001). The male sex had a significant main effect on olanzapine C:D ratios (ß = -2.80, P < 0.001), with significant interactions with age (ß = 0.025, P < 0.001) and body weight (ß = 0.017, P = 0.011). The selected covariates explained 30.3% of the variation in C:D ratios, with smoking status accounting for 7.7% and sex contributing 6.9%. The overall variation explained by both the fixed and random parts of the model was 67.4%. The model facilitated the prediction of olanzapine C:D ratios based on sex, age, and body weight. CONCLUSIONS: The clinical factors examined in this study, including sex, age, body weight, smoking status, and valproate comedication, remarkably influence olanzapine C:D ratios. Considering these factors, in addition to TDM and the clinical situation, could be important for dose adjustment.

Risk factors for mood disorders among offspring of parents with bipolar disorder: Findings from a discordant-sibling study.

The purpose of this naturalistic, prospective study was to identify risk factors for mood disorders in offspring of parents with bipolar disorder (BPD) using the discordant-sibling design by comparing premorbid psychopathology or symptoms, temperament, personality traits and coping style as well as the perception of family-related characteristics among affected and unaffected siblings within the same family. This approach controls for confounding by unmeasured genetic and environmental factors shared within families. Our sample comprised 24 families of a parent with BPD with at least one child that developed BPD or major depressive disorder (n = 31), and at least one child who did not. Offspring were followed for a mean duration of 16.2 (s.d: 4.6) years. Information was collected from the offspring themselves. Generalized linear mixed models only revealed differences in three dimensions of the Dimension of Temperament Survey-Revised (DOTS-R) version: Offspring with mood disorders scored higher on "Approach-withdrawal", "Rhythmicity for daily habits", and "Task orientation" than their unaffected siblings. The higher scores, and not lower scores as expected, on these temperament dimensions observed in offspring that subsequently developed mood disorders may reflect increased vulnerability, but they could also mirror premorbid mood swings or strategies to cope with them.

Plant sterols and cholesterol metabolism are associated with five-year cognitive decline in the elderly population.

Dysregulations in cholesterol metabolism are associated with neurodegenerative and vascular pathologies, and dementia. Diet-derived plant sterols (phytosterols) have cholesterol-lowering, anti-inflammatory, and antioxidant properties and may interfere with neurodegeneration and cognitive decline. Here we performed multivariate analysis in 720 individuals enrolled in a population-based prospective study to determine whether circulating cholesterol precursors and metabolites, triglycerides, and phytosterols, are associated with cognitive impairment and decline in the older population. We report specific dysregulations of endogenous cholesterol synthesis and metabolism, and diet-derived phytosterols, and their changes over time associated with cognitive impairment, and decline in the general population. These findings suggest circulating sterols levels could be considered in risk evaluation and are relevant for the development of strategies to prevent cognitive decline in older people.

Psychotic features, particularly mood incongruence, as a hallmark of severity of bipolar I disorder.

BACKGROUND: The occurrence of psychotic features within mood episodes in patients with bipolar I disorder (BD I) has been associated in some studies with a more severe clinical and socio-professional profile. In contrast, other studies establishing the associations of psychotic features in BD I, and in particular of mood-congruent (MC) and mood-incongruent (MI) features, with clinical characteristics have yielded contradictory results. However, many pre-existing studies have been affected by serious methodological limitations. Using a sample of thoroughly assessed patients with BD I our aims were to: (1) establish the proportion of those with MI and MC features, and (2) compare BD I patients with and without psychotic features as well as those with MI to those with MC features on a wide array of socio-demographic and clinical characteristics including course, psychiatric comorbidity and treatment. METHODS: A sample of 162 treated patients with BD I (60.5% female, mean age = 41.4 (s.d: 10.2) years) was recruited within a large family study of mood disorders. Clinical, course and treatment characteristics relied on information elicited through direct diagnostic interviews, family history reports and medical records. RESULTS: (1) A total of 96 patients (59.3%) had experienced psychotic features over their lifetime. Among them, 44.8% revealed MI features at least once in their lives. (2) Patients with psychotic features were much less likely to be professionally active, revealed alcohol abuse more frequently and used health care, particularly inpatient treatment, more frequently than those without psychotic features. Within patients with psychotic symptoms, those with MI features showed more clinical severity in terms of a higher likelihood of reporting hallucinations, suicidal attempts and comorbid cannabis dependence. CONCLUSION: Our data provide additional support for both the distinction between BD-I with and without psychotic features as well as the distinction between MI and MC psychotic features. The more severe course of patients with psychotic features, and particularly those with MI psychotic features, highlights the need for thorough psychopathological evaluations to assess the presence of these symptoms to install appropriate treatment.

Daily Dose Effects of Risperidone on Weight and Other Metabolic Parameters: A Prospective Cohort Study.

Background: Atypical antipsychotics can induce metabolic side effects, but whether they are dose-dependent remains unclear.Objective: To assess the effect of risperidone and/or paliperidone dosing on weight gain and blood lipids, glucose, and blood pressure alterations.Methods: Data for 438 patients taking risperidone and/or its metabolite (paliperidone) for up to 1 year were obtained between 2007 and 2018 from a longitudinal study monitoring metabolic parameters.Results: For each milligram increase in dose, we observed a weight increase of 0.16% at 1 month of treatment (P = .002) and increases of 0.29%, 0.21%, and 0.25% at 3, 6, and 12 months of treatment, respectively (P < .001 for each). Moreover, dose increases of 1 mg raised the risk of a ≥ 5% weight gain after 1 month (OR = 1.18; P = .012), a strong predictor of important weight gain in the long term. When we split the cohort into age categories, the dose had an effect on weight change after 3 months of treatment (up to 1.63%, P = .008) among adolescents (age ≤ 17 years), at 3 (0.13%, P = .013) and 12 (0.13%, P = .036) months among adults (age > 17 and < 65 years), and at each timepoint (up to 1.58%, P < .001) among older patients (age ≥ 65 years). In the whole cohort, for each additional milligram we observed a 0.05 mmol/L increase in total cholesterol (P = .018) and a 0.04 mmol/L increase in LDL cholesterol (P = .011) after 1 year.Conclusions: Although of small amplitude, these results show an effect of daily risperidone dose on weight gain and blood cholesterol levels. Particular attention should be given to the decision of increasing the drug dose, and minimum effective dosages should be preferred.

Environmental factors in offspring of parents with mood disorders and their role in parent-child transmission: findings from a 14-year prospective high-risk study.

BACKGROUND: The factors involved in the transmission of mood disorders are only partially elucidated. Aside from genes, the family environment might play a crucial role in parent-child transmission. Our goals were to (1) assess the associations of parental bipolar disorder (BPD) and Major Depressive Disorder (MDD) with individual or shared family environmental factors, including traumatic events in offspring, parental separation, family cohesion and parental attitudes; and 2) test whether these factors were mediators of the association between exposure to parental mood disorders and the onset of these disorders in offspring. METHODS: The sample stems from an ongoing family high-risk study of mood disorders conducted in the French-speaking part of Switzerland. Given the strong impact of the age of onset of parental disorders on their transmission to children, parental disorders were dichotomized according to the onset (cut-off 21 years). Probands with early-onset (n = 30) and later-onset BPD (n = 51), early-onset (n = 21) and later-onset MDD (n = 47) and controls (n = 65), along with their spouses (n = 193) and offspring (n = 388; < 18 years on study inclusion), were assessed over a mean follow-up duration of 14 years (s.d: 4.6). The environmental measures were based on reports by offspring collected before the onset of their first mood episode. RESULTS: Offspring of probands with later-onset BPD and offspring of probands with both early-onset and later-onset MDD reported traumatic events more frequently than comparison offspring, whereas exposure to parental separation was more frequent in all groups of high-risk offspring. Moreover, several familial environment scores including parenting attitudes differed between offspring of probands with BPD and comparison offspring. However, none of these factors were mediators of the parent-child transmission of BPD. Among the environmental factors, traumatic events were shown to be modest mediators of the transmission of early-onset MDD. CONCLUSIONS: Our data do not support the implication of the assessed environmental factors in the parent-child transmission of BPD. In contrast to BPD, traumatic events partially mediate the parent-child transmission of early-onset MDD, which has important implications for intervention and prevention. Early therapeutic efforts in offspring exposed to these events are likely to reduce their deleterious impact on the risk of subsequent MDD.

Short-term and long-term effects of major depressive disorder subtypes on obesity markers and impact of sex on these associations.

BACKGROUND: Only a few studies with conflicting results have examined the effects of sex on the prospective association between depression and subsequent obesity. OBJECTIVE: (1) To simultaneously assess the associations of the subtypes (atypical, melancholic, unspecified) of major depressive disorder (MDD) measured at baseline and subtypes of major depressive episodes (MDE) that emerged during a 5.5-year follow-up with changes in obesity markers (body mass index, waist circumference, fat mass) during this follow-up, and (2) to test the effect of sex on these associations. METHODS: Data from CoLaus|PsyCoLaus, a population-based cohort study including 2702 participants (50.1% women, mean age 49.6 years). Criteria for mental disorders were elicited using semi-structured interviews. RESULTS: History of atypical MDD at baseline was associated with a steeper increase in BMI and waist circumference, whereas atypical MDE during follow-up was associated with a steeper increase in the three studied obesity markers. Melancholic MDD at baseline was associated with a steeper increase in BMI. Several significant interactions with sex were found indicating higher increase in fat mass in men than in women following melancholic MDD reported at baseline, higher decrease in BMI and fat mass in women than in men related to melancholic MDE emerging during follow-up and higher increase in waist circumference in men than in women following unspecified MDD reported at baseline. LIMITATIONS: Urban sample which may not be representative for the whole population. CONCLUSIONS: Our results further advocate for the specific need of a thorough monitoring of obesity markers in patients with atypical MDD and suggest less favorable obesity marker changes mainly related to melancholic MDE in men.

Study protocol for the ETMED-L project: longitudinal study of mental health and interpersonal competence of medical students in a Swiss university using a comprehensive framework of empathy.

INTRODUCTION: Physician interpersonal competence is crucial for patient care. How interpersonal competence develops during undergraduate medical education is thus a key issue. Literature on the topic consists predominantly of studies on empathy showing a trend of decline over the course of medical school. However, most existing studies have focused on narrow measures of empathy. The first aim of this project is to study medical students' interpersonal competence with a comprehensive framework of empathy that includes self-reported cognitive and affective empathy, performance-based assessments of emotion recognition accuracy, and a behavioural dimension of empathy. The second aim of the present project is to investigate the evolution of mental health during medical school and its putative link to the studied components of interpersonal competence. Indeed, studies documented a high prevalence of mental health issues among medical students that could potentially impact their interpersonal competence. Finally, this project will enable to test the impact of mental health and interpersonal competence on clinical skills as evaluated by experts and simulated patients. METHODS AND ANALYSIS: This project consists of an observational longitudinal study with an open cohort design. Each year during the four consecutive years of the project, every medical student (curriculum years 1-6) of the University of Lausanne in Switzerland will be asked to complete an online questionnaire including several interpersonal competence and mental health measures. Clinical skills assessments from examinations and training courses with simulated patients will also be included. Linear mixed models will be used to explore the longitudinal evolutions of the studied components of interpersonal competence and mental health as well as their reciprocal relationship and their link to clinical skills. ETHICS AND DISSEMINATION: The project has received ethical approval from the competent authorities. Findings will be disseminated through internal, regional, national and international conferences, news and peer-reviewed journals.

Metabolomic alteration induced by psychotropic drugs: Short-term metabolite profile as a predictor of weight gain evolution.

Psychotropic drugs can induce strong metabolic adverse effects, potentially increasing morbidity and/or mortality of patients. Metabolomic profiling, by studying the levels of numerous metabolic intermediates and products in the blood, allows a more detailed examination of metabolism dysfunctions. We aimed to identify blood metabolomic markers associated with weight gain in psychiatric patients. Sixty-two patients starting a treatment known to induce weight gain were recruited. Two hundred and six selected metabolites implicated in various pathways were analyzed in plasma, at baseline and after 1 month of treatment. Additionally, 15 metabolites of the kynurenine pathway were quantified. This latter analysis was repeated in a confirmatory cohort of 24 patients. Among the 206 metabolites, a plasma metabolomic fingerprint after 1 month of treatment embedded 19 compounds from different chemical classes (amino acids, acylcarnitines, carboxylic acids, catecholamines, nucleosides, pyridine, and tetrapyrrole) potentially involved in metabolic disruption and inflammation processes. The predictive potential of such early metabolite changes on 3 months of weight evolution was then explored using a linear mixed-effects model. Of these 19 metabolites, short-term modifications of kynurenine, hexanoylcarnitine, and biliverdin, as well as kynurenine/tryptophan ratio at 1 month, were associated with 3 months weight evolution. Alterations of the kynurenine pathway were confirmed by quantification, in both exploratory and confirmatory cohorts. Our metabolomic study suggests a specific metabolic dysregulation after 1 month of treatment with psychotropic drugs known to induce weight gain. The identified metabolomic signature could contribute in the future to the prediction of weight gain in patients treated with psychotropic drugs.

Effect of Quetiapine, from Low to High Dose, on Weight and Metabolic Traits: Results from a Prospective Cohort Study.

INTRODUCTION: The atypical antipsychotic quetiapine is known to induce weight gain and other metabolic complications. The underlying mechanisms are multifactorial and poorly understood with almost no information on the effect of dosage. Concerns were thus raised with the rise in low-dose quetiapine off-label prescription (i. e.,<150 mg/day). METHODS: In this study, we evaluated the influence of quetiapine dose for 474 patients included in PsyMetab and PsyClin studies on weight and metabolic parameter evolution. Weight, blood pressure, lipid, and glucose profiles were evaluated during a follow-up period of 3 months after treatment initiation. RESULTS: Significant dose-dependent metabolic alterations were observed. The daily dose was found to influence weight gain and increase the risk of undergoing clinically relevant weight gain (≥7% from baseline). It was also associated with a change in plasma levels of cholesterol (total cholesterol, LDL cholesterol, and HDL cholesterol) as well as with increased odds of developing hypertriglyceridemia, as well as total and LDL hypercholesterolemia. No impact of a dose increase on blood pressure and plasma glucose level was observed. DISCUSSION: The dose-dependent effect highlighted for weight gain and lipid alterations emphasizes the importance of prescribing the minimal effective dose. However, as the effect size of a dose increase on metabolic worsening is low, the potential harm of low-dose quetiapine should not be dismissed. Prescriptions must be carefully evaluated and regularly questioned in light of side effect onset.

Predicting involuntary hospitalization in psychiatry: A machine learning investigation.

BACKGROUND: Coercion in psychiatry is a controversial issue. Identifying its predictors and their interaction using traditional statistical methods is difficult, given the large number of variables involved. The purpose of this study was to use machine-learning (ML) models to identify socio-demographic, clinical and procedural characteristics that predict the use of compulsory admission on a large sample of psychiatric patients. METHODS: We retrospectively analyzed the routinely collected data of all psychiatric admissions that occurred between 2013 and 2017 in the canton of Vaud, Switzerland (N = 25,584). The main predictors of involuntary hospitalization were identified using two ML algorithms: Classification and Regression Tree (CART) and Random Forests (RFs). Their predictive power was compared with that obtained through traditional logistic regression. Sensitivity analyses were also performed and missing data were imputed through multiple imputation using chain equations. RESULTS: The three models achieved similar predictive balanced accuracy, ranging between 68 and 72%. CART showed the lowest predictive power (68%) but the most parsimonious model, allowing to estimate the probability of being involuntarily admitted with only three checks: aggressive behaviors, who referred the patient to hospital and primary diagnosis. The results of CART and RFs on the imputed data were almost identical to those obtained on the original data, confirming the robustness of our models. CONCLUSIONS: Identifying predictors of coercion is essential to efficiently target the development of professional training, preventive strategies and alternative interventions. ML methodologies could offer new effective tools to achieve this goal, providing accurate but simple models that could be used in clinical practice.

Valproate is associated with early decrease of high-density lipoprotein cholesterol levels in the psychiatric population.

Few studies have evaluated the influence of valproate on the deterioration of the lipid profile in psychiatric patients. This observational study aimed to compare the evolution of metabolic parameters in a sample of adult patients starting valproate (n = 39) with a control group (n = 39) of patients starting aripiprazole, a drug associated with a low risk of metabolic deterioration. Data were obtained from a prospective study including psychiatric patients with metabolic parameters monitored during the first year of treatment. During the first month of treatment with valproate (median: 31 days [IQR: 25-36]), mean body mass index increased significantly (from 24.8 kg/m2 at baseline to 25.2 kg/m2 after one month; P = .03) and mean HDL-C levels decreased significantly (from 1.39 mmol/L to 1.27 mmol/L; P = .02). In comparison, these metabolic variables remained stable during the first month of treatment with aripiprazole. The proportion of patients with early (ie during the first month of treatment) HDL-C decrease of ≥ 5% was significantly higher under valproate (54%) than aripiprazole (15%) treatment (P < .001). These findings remind the importance of a prospective metabolic monitoring in patients who initiate valproate treatment. Further research should be conducted on larger samples and should focus on finding effective interventions to prevent such metabolic adverse effects.

Factors associated with subjective cognitive decline in dementia-free older adults-A population-based study.

BACKGROUND: Subjective cognitive decline (SCD) is common in older adults, affects quality of life (QoL), and may represent the earliest clinical manifestation of cognitive decline evolving to dementia. Still little is known about factors associated with SCD. OBJECTIVES: (1) Assess the associations between SCD and demographic, social, clinical, and personality characteristics as well as QoL, with and without adjustment for objective cognitive performance, and (2) investigate the relations between neuroticism, QoL, and SCD. METHODS: Cross-sectional analysis of a cohort of 1567 dementia-free community-dwellers from the urban area of Lausanne, Switzerland, aged 64 years and older (mean age 70.9 ± 4.7 years), from CoLaus/PsyCoLaus. SCD was assessed using a validated 10-item questionnaire. Personality traits, QoL, and perceived social support were evaluated using self-report measures. Information on depression and anxiety status and socioeconomic characteristics including professional activity were elicited using a semi-structured interview. Cognitive functioning was assessed through a comprehensive neuropsychological test battery. Statistical analysis was based on logistic regression. RESULTS: SCD was present in 18.5% of the sample and it was associated with lower performance in memory and verbal fluency tasks. After controlling for possible confounders, professional activity, neuroticism, and current depression were associated with SCD. Exploratory analysis revealed associations of SCD with QoL, neuroticism, and their interaction. CONCLUSION: Besides objective cognitive performance, SCD is related to several psychosocial factors in dementia-free community-dwelling older people. These findings are relevant for the development of healthcare interventions to reduce cognitive complaints, improve QoL, and prevent cognitive decline in general population.

Does Cognitive Functioning Predict Chronic Pain in Older Adult? Results From the CoLaus|PsyCoLaus Longitudinal Study.

Chronic pain (CP) and cognitive impairment are common in older adults. CP was found to be associated with cognitive impairment in many cross-sectional studies. However, their cross-sectional design precluded inference on temporality. Accordingly, we aimed to prospectively assess the association between cognitive functioning and the occurrence of CP in older community dwellers. Analyses were based on data of the first (FU1) and the second follow-up (FU2) of CoLaus|PsyCoLaus, a prospective cohort study conducted in the general population of Lausanne (Switzerland) including the participants aged 65 and over. Neuropsychological functioning including memory, language, attention and executive function was measured at FU1. CP was assessed at FU1 and FU2 by self-rating questionnaire. The association between cognitive scores and subsequent CP was determined using multiple logistic regressions. Among the 337 participants without CP at FU1, 107 (31.8%) developed CP at FU2. A significant association was observed between higher Stroop color-time and interference index at FU1 and a higher risk of CP at FU2 (OR = 1.02; P = .03 and OR = 1.49; P = .03, respectively). Our results suggest that patients with inhibitory deficit may be at higher risk of developing CP in the presence of painful events. A cognitive assessment could be recommended to identify frail patients in these situations. PERSPECTIVE: This study suggests that presence of inhibitory deficits is associated with a higher risk of developing subsequent CP in older adults. In the presence of painful events, a cognitive assessment should be recommended to identify frail patients and to manage them carefully.

Subtypes of narcissistic personality disorder based on psychotherapy process: A longitudinal nonparametric analysis.

The present study aims at empirically exploring subtypes of narcissistic personality disorder (NPD), based on patient descriptors of the psychotherapeutic process. Subtype identification and characterization of NPD is central, in particular, to increase diagnostic precision, linking categorical and dimensional conceptualizations of psychopathology, and to individualize treatments. A total of N = 161 patients diagnosed with NPD undergoing clarification-oriented psychotherapy were included in the present reanalysis of a naturalistic pre-post process-outcome study. At three crucial time-points of the therapy (Sessions 15, 20, and 25), the patient's in-session quality of content, process, and relationship are assessed using intensive video- and audio analyses. Levels of psychopathology were assessed using self-reported questionnaires. Data were analyzed using longitudinal nonparametric analysis. Based on in-session processes across three time-points, a two-subtype solution was retained (optimal vs. suboptimal process qualities). Optimal process quality of time was linked with the intensity of narcissistic symptoms; suboptimal process quality was linked with a variety of general symptom loads and problematic personality traits. The two empirical subtypes were predicted by the quality of real-life functioning with an accuracy of more than 92% and were partially associated with outcome. NPD may be empirically differentiated between patients engaging in optimal psychotherapy process versus those who engage in suboptimal psychotherapy process. This differentiation has reliable clinical predictors at the outset of treatment. The present study has implications in terms of personalizing psychotherapy for patients presenting NPD, or pathological narcissism. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Psychopathological precursors of the onset of mood disorders in offspring of parents with and without mood disorders: results of a 13-year prospective cohort high-risk study.

BACKGROUND: There is still limited evidence from prospective high-risk research on the evolution of specific disorders that may emerge early in the development of mood disorders. Moreover, few studies have examined the specificity of mood disorder subtypes among offspring of parents with both major subtypes of mood disorders and controls based on prospective tracking across the transition from childhood to adulthood. Our specific objectives were to (a) identify differences in patterns of psychopathological precursors among youth with (hypo)mania compared to MDD and (b) examine whether these patterns differ by subtypes of parental mood disorders. METHODS: Our data stem from a prospective cohort study of 449 directly interviewed offspring (51% female, mean age 10.1 years at study intake) of 88 patients with BPD, 71 with MDD, 30 with substance use disorders and 60 medical controls. The mean duration of follow-up was 13.2 years with evaluations conducted every three years. RESULTS: Within the whole cohort of offspring, MDE (Hazard Ratio = 4.44; 95%CI: 2.19-9.02), CD (HR = 3.31;1.55-7.07) and DUD (HR = 2.54; 1.15-5.59) predicted the onset of (hypo)manic episodes, whereas MDD in offspring was predicted by SAD (HR = 1.53; 1.09-2.15), generalized anxiety (HR = 2.56; 1.05-6.24), and panic disorder (HR = 3.13; 1.06-9.23). The early predictors of (hypo)mania in the whole cohort were also significantly associated with the onset of (hypo)mania among the offspring of parents with BPD. CONCLUSIONS: The onset of mood disorders is frequently preceded by identifiable depressive episodes and nonmood disorders. These precursors differed by mood subtype in offspring. High-risk offspring with these precursors should be closely monitored to prevent the further development of MDD or conversion to BPD.

Associations Between High Plasma Methylxanthine Levels, Sleep Disorders and Polygenic Risk Scores of Caffeine Consumption or Sleep Duration in a Swiss Psychiatric Cohort.

Objective: We first sought to examine the relationship between plasma levels of methylxanthines (caffeine and its metabolites) and sleep disorders, and secondarily between polygenic risk scores (PRS) of caffeine consumption or sleep duration with methylxanthine plasma levels and/or sleep disorders in a psychiatric cohort. Methods: Plasma levels of methylxanthines were quantified by ultra-high performance liquid chromatography/tandem mass spectrometry. In inpatients, sleep disorder diagnosis was defined using ICD-10 "F51.0," sedative drug intake before bedtime, or hospital discharge letters, while a subgroup of sedative drugs was used for outpatients. The PRS of coffee consumption and sleep duration were constructed using publicly available GWAS results from the UKBiobank. Results: 1,747 observations (1,060 patients) were included (50.3% of observations with sleep disorders). Multivariate analyses adjusted for age, sex, body mass index, setting of care and psychiatric diagnoses showed that patients in the highest decile of plasma levels of methylxanthines had more than double the risk for sleep disorders compared to the lowest decile (OR = 2.13, p = 0.004). PRS of caffeine consumption was associated with plasma levels of caffeine, paraxanthine, theophylline and with their sum (ß = 0.1; 0.11; 0.09; and 0.1, pcorrected = 0.01; 0.02; 0.02; and 0.01, respectively) but not with sleep disorders. A trend was found between the PRS of sleep duration and paraxanthine levels (ß = 0.13, pcorrected = 0.09). Discussion: Very high caffeine consumption is associated with sleep disorders in psychiatric in- and outpatients. Future prospective studies should aim to determine the benefit of reducing caffeine consumption in high caffeine-consuming patients suffering from sleep disorders.

Early onset of cannabis use and violent behavior in psychosis.

BACKGROUND: Although evidence from psychosis patients demonstrates the adverse effects of cannabis use (CU) at a young age and that the rate of CU is high in subgroups of young violent patients with psychotic disorders, little is known about the possible effect of the age of onset of CU on later violent behaviors (VB). So, we aimed to explore the impact of age at onset of CU on the risk of displaying VB in a cohort of early psychosis patients. METHOD: Data were collected prospectively over a 36-month period in the context of an early psychosis cohort study. A total of 265 patients, aged 18-35 years, were included in the study. Logistic regression was performed to assess the link between age of onset of substance use and VB. RESULTS: Among the 265 patients, 72 had displayed VB and 193 had not. While violent patients began using cannabis on average at age 15.29 (0.45), nonviolent patients had started on average at age 16.97 (0.35) (p = 0.004). Early-onset CU (up to age 15) was a risk factor for VB (odds ratio = 4.47, confidence interval [CI]: 1.13-20.06) when the model was adjusted for age group, other types of substance use, being a user or a nonuser and various violence risk factors and covariates. History of violence and early CU (until 15) were the two main risk factors for VB. CONCLUSIONS: Our results suggest that early-onset CU may play a role in the emergence of VB in early psychosis.

Prevalence of ECG abnormalities and risk factors for QTc interval prolongation in hospitalized psychiatric patients.

BACKGROUND: Psychiatric patients are at risk of cardiovascular diseases, and many psychotropic drugs can prolong QTc interval. Requirements for electrocardiogram (ECG) monitoring have been set up in our psychiatric university hospital. The objective of this study was to determine the proportion of adult patients who had an ECG during their hospitalization, the prevalence of ECG abnormalities, the evolution of the QTc after admission, and the risk factors for QTc prolongation. METHODS: Retrospective analysis of ECGs and clinical data of all patients with a complete hospitalization in 2015. Assessment of the influence of covariates on QTc using linear mixed-effects models. RESULTS: At least one ECG (n = 600) was performed during 37.6% of the stays (n = 1198) and in 45.5% of the patients (n = 871). Among the patients with an ECG, 17.9% had significant ECG abnormalities, including 7.6% with a prolonged QTc. QTc measured at admission and during hospitalization did not change significantly (n = 46, 419.4 ± 29.7 ms, 417.2 ± 27.6 ms, p = 0.71). In the multivariate model (292 patients, 357 ECGs), the covariates significantly associated with the QTc were gender (+15.9 ms if female, p < 0.0001), age (+0.4 ms/year, p = 0.0001), triglyceride levels (+5.7 ms/mmol/l, p = 0.005), and drugs with known risk of torsades de pointes (+6.2 ms if ⩾1 drug, p = 0.028). CONCLUSIONS: The prevalence of hospitalized psychiatric patients with an abnormal ECG indicates that ECGs should be performed systematically in this population. Prescription of psychotropic drugs should be done cautiously, particularly in patients with QTc prolongation risk factors.