P.K. McGuire

Tryptophan depletion reduces right inferior prefrontal activation during response inhibition in fast, event-related fMRI

Rationale and objectiveIn animal and human studies, the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) has been implicated in mediating impulsiveness and aggression. To test the hypothesis that 5-HT modulates neuro-cognitive brain activation during inhibitory control, we examined the effect of acute tryptophan depletion (ATD), a dietary challenge, which has been shown to decrease 5-HT synthesis in the brain, on functional brain activation during a go/no-go task.MethodsNine healthy, right-handed volunteers performed a rapid, event-related go/no-go task in two functional magnetic resonance imaging (fMRI) scanning sessions, 5 h after either a tryptophan-free or a balanced amino acid drink in a double-blind, sham depletion-controlled, counterbalanced, crossover design. The task required subjects to selectively execute or inhibit a motor response. Tryptophan depletion significantly lowered total plasma tryptophan concentration by 80%, but did not significantly alter inhibitory performance or mood ratings.ResultsATD significantly reduced right orbito-inferior prefrontal activation during the no-go condition, and increased activation in superior and medial temporal cortices.ConclusionsThese findings provide neuro-functional evidence of a serotonergic modulation of right inferior prefrontal during inhibitory motor control. The increased engagement of temporal brain regions may reflect compensatory mechanisms.

Are cavum septum pellucidum abnormalities more common in schizophrenia spectrum disorders? A systematic review and meta-analysis

Magnetic resonance imaging (MRI) studies have reported a variety of brain abnormalities in association with schizophrenia. These include a higher incidence of cavum septum pellucidum (CSP), which is consistent with a neurodevelopmental model for this disorder. In this meta-analytic review, we describe and discuss the main CSP MRI findings in schizophrenia spectrum disorders (SSDs) to date. We adopted as keywords cavum and schizophrenia or psychosis, and the inclusion criteria were articles in English, with samples of SSD patients compared to healthy subjects, which used MRI to assess CSP, without time limit. From 18 potential reports, fifteen were eligible to be part of the current review. These studies included 1054 patients with SSD and 866 healthy volunteers. Six out of 15 studies pointed to a higher prevalence of CSP of any size in SSD patients, while five out of 15 showed that subjects with SSD had a greater occurrence of a large CSP than healthy individuals. However, the meta-analysis demonstrated that only the incidence of a large CSP was significantly higher in SSD relative to healthy comparisons (odds ratio=1.59; 95%CI 1.07-2.38; p=0.02). Overall our results suggest that only a large CSP is associated with SSD while a small CSP may be considered a normal neuroanatomical variation. Our review revealed a large degree of variability in the methods employed across the MRI studies published to date, as well as evidence of publication bias. Studies in large, community-based samples with greater standardization of methods should clarify the true significance of CSP in SSD.

The interplay of cannabinoid and NMDA glutamate receptor systems in humans: preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects.

BACKGROUND Interactions between glutamatergic and endocannabinoid systems may contribute to schizophrenia, dissociative states, and other psychiatric conditions. Cannabidiol (CBD), a cannabinoid-1/2 (CB1/2) receptor weak partial agonist or antagonist, may play a role in the treatment of schizophrenia. OBJECTIVE This study tested the hypothesis that CBD would attenuate the behavioral effects of the NMDA receptor antagonist, ketamine, in healthy human subjects. METHODS Ten male healthy volunteers were evaluated twice in a randomized order. In both sessions they received ketamine (bolus of 0.26 mg/kg/1 min followed by IV infusion of 0.25mg/kg over 30 min) preceded by either CBD (600 mg) or placebo. Psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS) and the CADSS (Clinician Administered Dissociative States Scale) at regular intervals from 30 min before to 90 min after ketamine administration. RESULTS CBD significantly augmented the activating effects of ketamine, as measured by the activation subscales of the BPRS. However, CBD also showed a non-significant trend to reduce ketamine-induced depersonalization, as measured by the CADSS. CONCLUSION These data describe a complex pattern of psychopharmacologic interactions between CBD and ketamine at the doses of each agent studied in this experiment.

The Promise of Biological Markers for Treatment Response in First-Episode Psychosis: A Systematic Review

Successful treatment of first-episode psychosis is one of the major factors that impacts long-term prognosis. Currently, there are no satisfactory biological markers (biomarkers) to predict which patients with a first-episode psychosis will respond to which treatment. In addition, a non-negligible rate of patients does not respond to any treatment or may develop side effects that affect adherence to the treatments as well as negatively impact physical health. Thus, there clearly is a pressing need for defining biomarkers that may be helpful to predict response to treatment and sensitivity to side effects in first-episode psychosis. The present systematic review provides (1) trials that assessed biological markers associated with antipsychotic response or side effects in first-episode psychosis and (2) potential biomarkers associated with biological disturbances that may guide the choice of conventional treatments or the prescription of innovative treatments. Trials including first-episode psychoses are few in number. Most of the available data focused on pharmacogenetics markers with so far only preliminary results. To date, these studies yielded-beside markers for metabolism of antipsychotics-no or only a few biomarkers for response or side effects, none of which have been implemented in daily clinical practice. Other biomarkers exploring immunoinflammatory, oxidative, and hormonal disturbances emerged as biomarkers of first-episode psychoses in the last decades, and some of them have been associated with treatment response. In addition to pharmacogenetics, further efforts should focus on the association of emergent biomarkers with conventional treatments or with innovative therapies efficacy, where some preliminary data suggest promising results.

A Shared Genetic Propensity Underlies Experiences of Bullying Victimization in Late Childhood and Self-Rated Paranoid Thinking in Adolescence

Background: Bullying is a risk factor for developing psychotic experiences (PEs). Whether bullying is associated with particular PEs, and the extent to which genes and environments influence the association, are unknown. This study investigated which specific PEs in adolescence are associated with earlier bullying victimization and the genetic and environmental contributions underlying their association. Method: Participants were 4826 twin pairs from a longitudinal community-based twin study in England and Wales who reported on their bullying victimization at the age of 12 years. Measures of specific PEs (self-rated Paranoia, Hallucinations, Cognitive disorganization, Grandiosity, Anhedonia, and parent-rated Negative Symptoms) were recorded at age of 16 years. Results: Childhood bullying victimization was most strongly associated with Paranoia in adolescence (r = .26; P < .01), with weaker associations with Hallucinations, Cognitive Disorganization, parent-rated Negative Symptoms (r = .12–.20; P < .01), Grandiosity (r = .04; P < .05), and Anhedonia (r = .00, n.s.). Bivariate twin model-fitting demonstrated that bullying victimization and Paranoia were both heritable (35% and 52%, respectively) with unique environmental influences (39% and 48%, respectively), and bullying victimization showed common environmental influences (26%). The association between bullying victimization and Paranoia operated almost entirely via genetic influences (bivariate heritability = 93%), with considerable genetic overlap (genetic correlation = .55). Conclusion: In contrast to the assumed role of bullying victimization as an environmental trigger, these data suggest that bullying victimization in late childhood is particularly linked to self-rated Paranoia in adolescence via a shared genetic propensity. Clinically, individuals with a history of bullying victimization are predicted to be particularly susceptible to paranoid symptoms.

Adolescents and young adults who are not in employment, education, or training

Their problems are more than economic

Adhesio interthalamica alterations in schizophrenia spectrum disorders: A systematic review and meta-analysis.

Magnetic resonance imaging (MRI) studies have reported a variety of brain abnormalities in association with schizophrenia. These include a higher prevalence of an absent adhesio interthalamica (AI; also known massa intermedia), a gray matter junction that is present between the two thalami in approximately 80% of healthy subjects. In this meta-analytic review, we describe and discuss the main AI MRI findings in schizophrenia spectrum disorders (SSDs) to date. The MEDLINE and ISI Web of Knowledge databases were searched up to December 2010, for studies that used MRI to assess AI in patients with SSD and controls. From fourteen potential reports, eleven were eligible to be part of the current review. These studies included 822 patients with SSD and 718 healthy volunteers. There was a large degree of variability in the MRI methods they employed. Patients with SSD had a higher prevalence of absent AI than healthy volunteers (odds ratio = 1.98; 95% confidence interval 1.33-2.94; p = 0.0008). This association was evident in both male and female SSD subjects, and there was no evidence that the prevalence was related to age or duration of illness. The significance of the absence of an AI for SSD may be clarified by studies in large, longitudinal community-based samples using standardized methods.

Total agenesis of the corpus callosum in a patient with childhood-onset schizophrenia

The hypothesis that schizophrenia involves aberrant inter-hemispheric communication has a long pedigree, however its precise role remains unclear. We therefore report the case of a total agenesis of the corpus callosum in a 21-year-old man with childhood-onset schizophrenia. The presence of schizophrenia with very early onset on absence of corpus callosum offers an opportunity to examine neurodevelopmental model and theories regarding to interhemispheric communication in the pathogenesis of psychosis.

Association between stressful life events and psychotic experiences in adolescence: evidence for gene-environment correlations.

Background Stressful life events (SLEs) are associated with psychotic experiences. SLEs might act as an environmental risk factor, but may also share a genetic propensity with psychotic experiences. Aims To estimate the extent to which genetic and environmental factors influence the relationship between SLEs and psychotic experiences. Method Self- and parent reports from a community-based twin sample (4830 16-year-old pairs) were analysed using structural equation model fitting. Results SLEs correlated with positive psychotic experiences (r = 0.12–0.14, all P<0.001). Modest heritability was shown for psychotic experiences (25–57%) and dependent SLEs (32%). Genetic influences explained the majority of the modest covariation between dependent SLEs and paranoia and cognitive disorganisation (bivariate heritabilities 74–86%). The relationship between SLEs and hallucinations and grandiosity was explained by both genetic and common environmental effects. Conclusions Further to dependent SLEs being an environmental risk factor, individuals may have an underlying genetic propensity increasing their risk of dependent SLEs and positive psychotic experiences.

Child Maltreatment and Clinical Outcome in Individuals at Ultra-High Risk for Psychosis in the EU-GEI High Risk Study

Background Child maltreatment has been associated with a wide range of mental disorders in adulthood. Whether child maltreatment is specifically associated with psychosis risk in individuals at ultra-high risk (UHR) for psychosis, or leads to a general vulnerability for overall psychopathology in the UHR stage remains unclear. The present study examines the association between child maltreatment and transition to psychosis and other mental disorders. Methods The sample consisted of 259 UHR individuals from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Participants were followed-up for 2 years to assess clinical outcome. Clinical outcome was assessed at 6 months, 12 months, and 24 months after baseline. Child maltreatment before the age of 17 years was assessed at baseline. Results Our findings show that a history of emotional abuse was associated with an increased risk for transition to psychosis (OR = 3.78, 95% CI = 1.17 to 12.39, P = .027). Apart from psychosis, a history of physical abuse was associated with depressive disorder (OR = 4.92, 95% CI = 2.12 to 11.39, P = .001), post-traumatic stress disorder (OR = 2.06, 95% CI = 1.10 to 3.86, P = .023), panic disorder (OR = 2.00, 95% CI = 1.00 to 3.99, P = .048) and social phobia (OR = 2.47, 95% CI = 1.18 to 5.16, P = .016) at follow-up. Conclusion Our findings suggest that in the UHR stage child maltreatment is a pluripotent risk factor for developing psychosis, depressive disorder, post-traumatic stress disorder (PTSD), panic disorder, and social phobia in adulthood.