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.

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.

Factors associated with repetitive violent behavior of psychiatric inpatients.

A small number of psychiatric inpatients displays a large proportion of Violent Behaviors (VB). These can have a major impact on both victims and patients themselves. This study explored personal, situational and institutional risk factors and their combined effects, which could lead to repetitive VB (three or more assaults). Data from 4518 patients, aged 18 to 65, admitted to an acute psychiatric care facility, were included in the analysis. VB, defined as physical aggressions against another person, were assessed by the Staff Observation Aggression Scale-Revised. 414 VB were reported during the study period, involving 199 patients. 0.75 % of all patients were repetitively violent and committed 43% of all VB. Factors that were linked to repetitive VB were living in sheltered housing before hospitalization, suffering from schizophrenia with substance abuse comorbidity, cumulating hospitalization days and some situational factors, like the fact of being in nursing offices and pharmacies. When all personal, situational and institutional factors were considered together, the combined effects of length of stay and living in sheltered housing increased the risk of repetitive VB. We have identified a small group of vulnerable patients for whom new modalities of inter-institutional networking should be developed to prevent repetitive VB.

Retrospectively assessed trajectories of PTSD symptoms and their subsequent comorbidities.

BACKGROUND: Dynamic trajectories of psychopathology, such as post-traumatic stress disorder (PTSD) provide a key to understanding human adjustment processes after trauma exposure. Recent studies have suggested more heterogeneous mental health outcomes than the initially identified four adjustment trajectories. To explore this heterogeneity, we investigated the after-trauma adjustment patterns of psychopathology based on retrospective lifetime data. This was first carried out on the PTSD symptoms (PTSS, including no symptoms, few symptoms, partial and full PTSD), and secondly together with their post-trauma comorbidities. METHODS: Data of trauma and the post-trauma mental disorders were collected for a large and randomly selected community sample, resulting in a N = 960 trauma-exposed subsample. Pattern recognition as carried out by latent class analysis (LCA) was implemented on this subsample. LCA was first exploited to identify the potential trajectory patterns of PTSS and next to explore the patterns of mental adjustments when additional post-trauma comorbid disorders, such as anxiety, mood and substance use disorders, were assessed. RESULTS: Four PTSS trajectory patterns were found, namely resilient, chronic, recovered, and delayed onset, consistent with findings from longitudinal PTSD studies. When post-trauma comorbidities were evaluated, other than the trajectory pattern of delayed onset which retained a low comorbidity profile, the other three split respectively and paired up with either low, moderate or high comorbidity profile. CONCLUSIONS: Mental health outcomes after trauma exposure were considerably more complex than the four previously established adjustment trajectories. Here, we uncovered additional and more heterogeneous adjustment patterns comprised of PTSS trajectories and post-trauma comorbidity profiles.

Temperament and self-esteem in high-risk offspring of bipolar parents: Vulnerability and scar effects.

BACKGROUND: The nature of the temporal relationship between psychological factors and mood episodes is unclear. The objectives of this study were to determine if temperament and self-esteem predict the onset of mood episodes, and if prior mood episodes influence the stability of these factors over time in high-risk offspring of bipolar parents. METHODS: Offspring of a parent with bipolar disorder participating in the Flourish Prospective Offspring Study were clinically assessed repeatedly using semi-structured KSADS-PL/SADS-L format interviews, and completed repeated measures of self-esteem, and temperament. Shared frailty survival models and mixed effects regression models were used to determine if psychological factors predicted incident mood episodes, and whether these factors change over time after the incident mood episode, respectively. RESULTS: Emotionality, shyness and self-esteem were not associated with the hazard of incident major depression; however, increased activity reduced the hazard of this outcome (hazard ratio [HR]: 0.51; 95% CI: 0.27, 0.98). Emotionality and shyness scores increased, while sociability, activity and self-esteem scores decreased after the incident major depressive episode (emotionality: mean change [MC]: 0.35, p = 0.0289; shyness: MC: 0.40, p = 0.0196; sociability: MC: -0.49, p = 0.0001, activity: MC: -0.32, p = 0.0001; self-esteem: MC: -0.79, p = 0.001). LIMITATIONS: Psychological measures were based on self-report and some models had low numbers limiting the numbers of covariates included as potential confounders. DISCUSSION: Among the assessed temperamental dimensions, activity showed a protective effect for major depressive episode onset suggesting this temperamental characteristic could serve as a protective target in high risk youth. Conversely, all assessed psychological factors shifted towards increased vulnerability after the first depressive episode.

Cannabis, a Significant Risk Factor for Violent Behavior in the Early Phase Psychosis. Two Patterns of Interaction of Factors Increase the Risk of Violent Behavior: Cannabis Use Disorder and Impulsivity; Cannabis Use Disorder, Lack of Insight and Treatment Adherence.

Background: Previous literature suggests that prevalence of cannabis use in the early phase of psychosis is high, and that early psychosis patients are at high-risk for violent behavior. However, the link between cannabis use and violent behavior in early psychosis patients is unclear. We carried out a study on a sample of early psychosis patients, in order to explore the impact of cannabis use on the risk of violent behavior (VB), while taking into account (1) potential confounding factors and, (2) interactions with other dynamic risk factors of VB. Method: In a sample of 265 early psychosis patients, treated at the Treatment and Early Intervention in Psychosis Program (TIPP) in Lausanne, we used logistic regression models to explore the link between various dynamic risk factors of VB [positive symptoms, substance use disorder (drugs including cannabis, alcohol and others drugs), insight, impulsivity, affective instability, and treatment adherence], and VB occurring during treatment. In order to understand hierarchical effects attributable to the combinations of risk factors on VB we conducted a Classification and Regression Tree (CART). Results: Our results show that cannabis use disorder is a risk factor for VB. The associations among risk factors suggest the presence of two patient profiles with an increased rate of VB: the first is composed of patients with cannabis use disorder and impulsivity, and the second of patients combining cannabis use disorder, absence of insight and non-adherence to treatment. The results also show the moderating role of insight and adherence to treatment on the rate of VB in patients with cannabis use disorder. Conclusion: This study suggests that cannabis use disorder is a significant risk factor for VB amongst early psychosis patients, particularly when combined with either impulsivity, lack of insight and non-adherence to treatment. These results suggest that preventive strategies could be developed on the basis of such patient profiles.

Decreasing body mass index is associated with cerebrospinal fluid markers of Alzheimer's pathology in MCI and mild dementia.

BACKGROUND: Several studies have identified an association between body mass index (BMI) and the incidence and severity of Alzheimer's disease (AD) but this relationship is not fully understood. OBJECTIVE: The primary objective of this study was to assess the possible association between BMI and cerebrospinal fluid (CSF) biomarkers of AD pathology in subjects with normal cognition and cognitive impairment. The secondary objective was to test whether BMI may contribute to improve the accuracy of a clinical model to predict AD pathology in memory clinic patients with cognitive impairment. METHOD: One hundred and seven elderly subjects with cognitive impairment (91 memory clinic patients with mild cognitive impairment [MCI] and 16 with dementia of AD type) and 55 cognitively healthy volunteers were included in this study. All subjects received a comprehensive clinical and neuropsychological evaluation and a lumbar puncture for CSF biomarker analysis. Multiple linear regressions and receiver operating characteristic (ROC) analyses were carried out to assess the association between BMI and the CSF biomarkers of AD pathology. RESULTS: BMI was positively correlated with the CSF levels of Aß42 and negatively with tau and P-tau181 in participants with cognitive impairment. The associations were independent of age, sex, educational level, type and severity of cognitive impairment, cerebrovascular risk factors and the presence of the APOEε4 allele. Furthermore, BMI significantly improved the sensitivity and specificity of a multi-factorial model to predict the presence of an AD CSF biomarker profile. CONCLUSION: Lower BMI is associated with cerebral AD pathology rather than with cognitive impairment in elderly subjects with MCI and mild dementia. Along with other clinical factors, decreasing BMI may help the clinician to identify patients with cognitive impairment due to AD.

Macrophage Migration Inhibitory Factor is Associated with Biomarkers of Alzheimer's Disease Pathology and Predicts Cognitive Decline in Mild Cognitive Impairment and Mild Dementia.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory protein playing a regulatory role in the immune response. First evidence from in vitro and animal studies suggests that MIF may be involved in the development of Alzheimer's disease (AD) pathology. OBJECTIVE: To address in older subjects (i) the relationships between AD pathology and MIF plasma and cerebrospinal fluid (CSF) levels; and (ii) to investigate whether increased MIF-related systemic and CNS inflammation is associated with clinical disease progression. METHODS: CSF and plasma concentrations of MIF as well as biomarkers of amyloid, neuronal injury, and tau hyperphosphorylation (CSF Aß1-42, tau, and ptau, respectively) were assessed in 97 subjects with MCI or mild dementia (cognitive impairment, CI) and 52 healthy volunteers with normal cognition. Clinical and neuropsychological evaluations were performed at inclusion and at follow up visits. RESULTS: CSF MIF levels were higher in participants with CI with an AD CSF biomarker profile, but not in CI with a non-AD profile, compared to the healthy controls. Higher MIF CSF levels were associated with higher CSF tau and ptau and lower CSF Aß1-42 after adjusting for potential confounders. In CI, MIF CSF independently predicted cognitive decline at a follow-up visit after controlling for potential confounders including CSF Aß1-42 and tau levels. CONCLUSION: Our study provides evidence that MIF-related inflammation is related to amyloid pathology, tau hyperphosphorylation, and neuronal injury at the early clinical stages of AD. Higher MIF CSF levels are associated with accelerated cognitive decline in MCI and mild dementia.

Association of nicotine metabolism and sex with relapse following varenicline and nicotine replacement therapy.

Nicotine is metabolized into cotinine and then into trans-3'-hydroxycotinine, mainly by cytochrome P450 2A6. Recent studies reported better effectiveness of varenicline in women and in nicotine normal metabolizers phenotypically determined by nicotine-metabolite ratio. Our objective was to study the influence of nicotine-metabolite ratio, CYP2A6 genotype and sex on the response to nicotine replacement therapy and varenicline. Data were extracted from a longitudinal study which included smokers participating in a smoking cessation program. Response to treatment was defined by the absence of relapse when a set threshold of reduction in cigarettes per day relative to the week before the study was no more reached. The analysis considered total and partial reduction defined by a diminution of 100% and of 90% in cigarettes per day, respectively. The hazard ratio of relapsing was estimated in multivariate Cox regression models including the sex and the nicotine metabolism determined by the phenotype or by CYP2A6 genotyping (rs1801272 and rs28399433). In the normal metabolizers determined by phenotyping and in women, the hazard ratio for relapsing was significantly lower with varenicline for a partial decrease (HR = 0.33, 95% CI [0.12, 0.89] and HR = 0.20, 95% CI [0.04, 0.91], respectively) and nonsignificantly lower for a total cessation (HR = 0.45, 95% CI [0.20, 1.0] and HR = 0.38, 95% CI [0.14, 1.0]). When compared with the normal metabolizers determined by phenotyping, the hazard ratio for a partial decrease was similar in the normal metabolizers determined by genotyping (HR = 0.42, 95% CI [0.18, 0.94]) while it was significantly lower with varenicline for a total cessation (HR = 0.50, 95% CI [0.26, 0.98]). Women and normal nicotine metabolizers may benefit more from varenicline over nicotine replacement therapy. (PsycINFO Database Record

The association between self-reported and clinically determined hypomanic symptoms and the onset of major mood disorders.

BACKGROUND: Hypomanic symptoms may be a useful predictor of mood disorder among young people at high risk for bipolar disorder. AIMS: To determine whether hypomanic symptoms differentiate offspring of parents with bipolar disorder (high risk) and offspring of well parents (control) and predict the development of mood episodes. METHOD: High-risk and control offspring were prospectively assessed using semi-structured clinical interviews annually and completed the Hypomania Checklist-32 Revised (HCL-32). Clinically significant sub-threshold hypomanic symptoms (CSHS) were coded. RESULTS: HCL-32 total and active or elated scores were higher in control compared with high-risk offspring, whereas 14% of high-risk and 0% of control offspring had CSHS. High-risk offspring with CSHS had a fivefold increased risk of developing recurrent major depression (P=0.0002). The median onset of CSHS in high-risk offspring was 16.4 (6-31) years and was before the onset of major mood episodes. CONCLUSIONS: CSHS are precursors to major mood episodes in high-risk offspring and could identify individuals at ultra-high risk for developing bipolar disorder. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.