Balanced translocation linked to psychiatric disorder, glutamate and cortical structure/function

Rare genetic variants of large effect can help elucidate the pathophysiology of brain disorders. Here we expand the clinical and genetic analyses of a family with a (1;11)(q42;q14.3) translocation multiply affected by major psychiatric illness and test the effect of the translocation on the structure and function of prefrontal, and temporal brain regions. The translocation showed significant linkage (LOD score 6.1) with a clinical phenotype that included schizophrenia, schizoaffective disorder, bipolar disorder, and recurrent major depressive disorder. Translocation carriers showed reduced cortical thickness in the left temporal lobe, which correlated with general psychopathology and positive psychotic symptom severity. They showed reduced gyrification in prefrontal cortex, which correlated with general psychopathology severity. Translocation carriers also showed significantly increased activation in the caudate nucleus on increasing verbal working memory load, as well as statistically significant reductions in the right dorsolateral prefrontal cortex glutamate concentrations. These findings confirm that the t(1;11) translocation is associated with a significantly increased risk of major psychiatric disorder and suggest a general vulnerability to psychopathology through altered cortical structure and function, and decreased glutamate levels

The impact of childhood trauma on developing bipolar disorder: Current understanding and ensuring continued progress

Childhood trauma (CT) has been repeatedly linked to earlier onset and greater severity of bipolar disorder (BD) in adulthood. However, such knowledge is mostly based on retrospective and cross-sectional studies in adults with BD. The first objective of this selective review is to characterize the short-term effects of CT in the development of BD by focusing on studies in young people. The second objective is to describe the longer-term consequences of CT by considering studies with adult participants. This review first outlines the most prominent hypotheses linking CT exposure and the onset of BD. Then, it sum-marizes the psychological and biological risk factors implicated in the development of BD, followed by a discussion of original studies that investigated the role of CT in young people with early-onset BD, youths at increased risk of developing BD, or young people with BD with a focus on subclinical and clinical outcome measures. The review considers additional biological and psychological factors associated with a negative impact of CT on the long-term course of BD in later adulthood. Finally, we discuss how the integration of information of CT can improve ongoing early identification of BD and mitigate severe clinical expression in later adulthood

Neurotoxic Vulnerability Underlying Schizophrenia Spectrum Disorders

Neurotoxic vulnerability that putatively contributes to the etiopathogenesis of schizophrenia spectrum disorders encompasses perinatal adversity, genetic linkage, epigenetic disadvantage and neurodegenerative propensities that affect both symptom domains, positive, negative and cognitive, and biomarkers of the disorder. Molecular and cellular apoptosis/excitotoxicity that culminates in regional brain loss, reductions in reelin expression, trophic disruption, perinatal adversity, glycogen synthase kinase-3 dysregulation and various instances of oxidative stress all influence the final end-point disorder. The existence of prodromal psychotic phases, structural-functional aspects of regional neuroimaging, dopamine signal overexpression and psychosis propensity provide substance for neurodegenerative influences. The pathophysiology of schizophrenia spectrum disorder encompasses the destruction of normal functioning of the neurotrophins, in particular brain-derived neurotrophic factor (BDNF), dyskinesia of necessary movements, and metabolic-metabolomic and proteomic markers. Neurotoxic accidents combined with genetic susceptibility appears to play a role in interfering normal neurodevelopment or in the tissue-destructive neurodegeneration or both, thereby elevating the eventual risk for disorder tendencies and eventual expression