Treatment discontinuation impact on long-term (10-years) weight gain and lipid metabolism in first-episode psychosis: results from the PAFIP-10 cohort

Background: patients with a first episode of psychosis (FEP) are at higher risk of gaining weight and presenting metabolic disturbances, partly related to antipsychotic exposure. Previous studies suggest that treatment discontinuation might have a positive impact on weight in schizophrenia. The aim of this study was to evaluate the effect of treatment discontinuation on weight and metabolic changes in a FEP cohort. Methods: a total of 209 FEP patients and 57 healthy controls were evaluated at study entry and prospectively at 10-year follow-up. Anthropometric measures and, clinical, metabolic, and sociodemographic data were collected. Results: patients discontinuing antipsychotic treatment presented a significantly lower increase in weight and better metabolic parameter results than those still on antipsychotic treatment at 10-year follow-up. Conclusions: treatment discontinuation had a positive effect on the weight and metabolic changes observed in FEP patients; however, this effect was not sufficient to reaching a complete reversal to normal levels

Effects of polygenic risk for suicide attempt and risky behavior on brain structure in young people with familial risk of bipolar disorder

AbstractAimsBipolar Disorder (BD) is associated with a 20-30 fold increased suicide risk compared to the general population. First-degree relatives of BD patients show inflated rates of psychopathology including suicidal behaviors. As reliable biomarkers of suicide attempts (SA) are lacking, we examined associations between suicide-related polygenic risk scores (PRS) – a quantitative index of genomic risk – and variability in brain structures implicated in SA.MethodsParticipants (n=206; aged 12-30 years) were unrelated individuals of European ancestry and comprised three groups: 41 BD cases, 96 BD relatives (‘high-risk’), and 69 controls. Genotyping employed PsychArray, followed by imputation. Three PRS were computed using genome-wide association data for SA in BD (SA-in-BD), SA in Major Depressive Disorder (SA-in-MDD) [Mullins et al., 2019], and risky behavior [Karlsson Linnér et al., 2019]. Structural MRI processing employed FreeSurfer v5.3.0. General linear models were constructed using 32 regions-of-interest identified from suicide neuroimaging literature, with false-discovery-rate correction.ResultsSA-in-MDD and SA-in-BD PRS negatively predicted parahippocampal thickness, with the latter association modified by group membership. SA-in-BD and Risky Behavior PRS inversely predicted rostral and caudal anterior cingulate structure, respectively, with the latter effect driven by the ‘high-risk’ group. SA-in-MDD and SA-in-BD PRS positively predicted cuneus structure, irrespective of group.ConclusionsThis study demonstrated associations between PRS for suicide-related phenotypes and structural variability in brain regions implicated in SA. Future exploration of extended PRS, in conjunction with a range of biological, phenotypic, environmental and experiential data in high-risk populations, may inform predictive models for suicidal behaviors.</jats:sec

Confirmatory test of two factors and four subtypes of bipolar disorder based on lifetime psychiatric co-morbidity

Background The first aim was to use confirmatory factor analysis (CFA) to test a hypothesis that two factors (internalizing and externalizing) account for lifetime co-morbid DSM-IV diagnoses among adults with bipolar I (BPI) disorder. The second aim was to use confirmatory latent class analysis (CLCA) to test the hypothesis that four clinical subtypes are detectible: pure BPI; BPI plus internalizing disorders only; BPI plus externalizing disorders only; and BPI plus internalizing and externalizing disorders. Method A cohort of 699 multiplex BPI families was studied, ascertained and assessed (1998-2003) by the National Institute of Mental Health Genetics Initiative Bipolar Consortium: 1156 with BPI disorder (504 adult probands; 594 first-degree relatives; and 58 more distant relatives) and 563 first-degree relatives without BPI. Best-estimate consensus DSM-IV diagnoses were based on structured interviews, family history and medical records. MPLUS software was used for CFA and CLCA. Results The two-factor CFA model fit the data very well, and could not be improved by adding or removing paths. The four-class CLCA model fit better than exploratory LCA models or post-hoc-modified CLCA models. The two factors and four classes were associated with distinctive clinical course and severity variables, adjusted for proband gender. Co-morbidity, especially more than one internalizing and/or externalizing disorder, was associated with a more severe and complicated course of illness. The four classes demonstrated significant familial aggregation, adjusted for gender and age of relatives. Conclusions The BPI two-factor and four-cluster hypotheses demonstrated substantial confirmatory support. These models may be useful for subtyping BPI disorders, predicting course of illness and refining the phenotype in genetic studies

Traumatic Stress Interacts With Bipolar Disorder Genetic Risk to Increase Risk for Suicide Attempts

Objective Bipolar disorder (BD) is one of the most heritable psychiatric conditions and is associated with high suicide risk. To explore the reasons for this link, this study examined the interaction between traumatic stress and BD polygenic risk score in relation to suicidal ideation, suicide attempt, and nonsuicidal self-injury (NSSI) in adolescent and young adult offspring and relatives of persons with BD (BD-relatives) compared with adolescent and young adult offspring of individuals without psychiatric disorders (controls). Method Data were collected from 4 sites in the United States and 1 site in Australia from 2006 through 2012. Generalized estimating equation models were used to compare rates of ideation, attempts, and NSSI between BD-relatives (n = 307) and controls (n = 166) and to determine the contribution of demographic factors, traumatic stress exposure, lifetime mood or substance (alcohol/drug) use disorders, and BD polygenic risk score. Results After adjusting for demographic characteristics and mood and substance use disorders, BD-relatives were at increased risk for suicidal ideation and attempts but not for NSSI. Independent of BD-relative versus control status, demographic factors, or mood and substance use disorders, exposure to trauma within the past year (including bullying, sexual abuse, and domestic violence) was associated with suicide attempts (p =.014), and BD polygenic risk score was marginally associated with attempts (p =.061). Importantly, the interaction between BD polygenic risk score and traumatic event exposures was significantly associated with attempts, independent of demographics, relative versus control status, and mood and substance use disorders (p =.041). Conclusion BD-relatives are at increased risk for suicide attempts and ideation, especially if they are exposed to trauma and have evidence of increased genetic vulnerability

Reduced fronto-temporal and limbic connectivity in the 22q11.2 deletion syndrome: vulnerability markers for developing schizophrenia?

The 22q11.2 deletion syndrome (22q11DS) is a widely recognized genetic model allowing the study of neuroanatomical biomarkers that underlie the risk for developing schizophrenia. Recent advances in magnetic resonance image analyses enable the examination of structural connectivity integrity, scarcely used in the 22q11DS field. This framework potentially provides evidence for the disconnectivity hypothesis of schizophrenia in this high-risk population. In the present study, we quantify the whole brain white matter connections in 22q11DS using deterministic tractography. Diffusion Tensor Imaging was acquired in 30 affected patients and 30 age- and gender-matched healthy participants. The Human Connectome technique was applied to register white matter streamlines with cortical anatomy. The number of fibers (streamlines) was used as a measure of connectivity for comparison between groups at the global, lobar and regional level. All statistics were corrected for age and gender. Results showed a 10% reduction of the total number of fibers in patients compared to controls. After correcting for this global reduction, preserved connectivity was found within the right frontal and right parietal lobes. The relative increase in the number of fibers was located mainly in the right hemisphere. Conversely, an excessive reduction of connectivity was observed within and between limbic structures. Finally, a disproportionate reduction was shown at the level of fibers connecting the left fronto-temporal regions. We could therefore speculate that the observed disruption to fronto-temporal connectivity in individuals at risk of schizophrenia implies that fronto-temporal disconnectivity, frequently implicated in the pathogenesis of schizophrenia, could precede the onset of symptoms and, as such, constitutes a biomarker of the vulnerability to develop psychosis. On the contrary, connectivity alterations in the limbic lobe play a role in a wide range of psychiatric disorders and therefore seem to be less specific in defining schizophrenia