No abstract

BackgroundThe recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders.ObjectiveTo define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion.MethodsWe collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls.ResultsWhen compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations.ConclusionsThe 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Schizophrenia is a complex multifactorial brain disorder with a genetic component. Convergent evidence has implicated oxidative stress and glutathione (GSH) deficits in the pathogenesis of this disease. The aim of the present study was to test whether schizophrenia is associated with a deficit of GSH synthesis. Cultured skin fibroblasts from schizophrenia patients and control subjects were challenged with oxidative stress, and parameters of the ratelimiting enzyme for the GSH synthesis, the glutamate cysteine ligase (GCL), were measured. Stressed cells of patients had a 26% (P ‫؍‬ 0.002) decreased GCL activity as compared with controls. This reduction correlated with a 29% (P < 0.001) decreased protein expression of the catalytic GCL subunit (GCLC). Genetic analysis of a trinucleotide repeat (TNR) polymorphism in the GCLC gene showed a significant association with schizophrenia in two independent case-control studies. The most common TNR genotype 7/7 was more frequent in controls [odds ratio (OR) ‫؍‬ 0.6, P ‫؍‬ 0.003], whereas the rarest TNR genotype 8/8 was three times more frequent in patients (OR ‫؍‬ 3.0, P ‫؍‬ 0.007). Moreover, subjects with disease-associated genotypes had lower GCLC protein expression (P ‫؍‬ 0.017), GCL activity (P ‫؍‬ 0.037), and GSH contents (P ‫؍‬ 0.004) than subjects with genotypes that were more frequent in controls. Taken together, the study provides genetic and functional evidence that an impaired capacity to synthesize GSH under conditions of oxidative stress is a vulnerability factor for schizophrenia.genetic association ͉ glutamate cysteine ligase ͉ oxidative stress ͉ GAG trinucleotide repeat polymorphism ͉ skin fibroblasts

Patients presenting with FEP have high rates of SUD. Effective management of psychosis within a specialized service is associated with reductions in SUD over the course of treatment, although persistent substance use is associated with non-compliance, treatment drop-out and poor remission rates. As such, young people with FEP and comorbid substance use should be offered integrated treatment that addresses both disorders.

Bipolar disorder is common, and both difficult to detect and diagnose. Treatment is contingent on clinical needs, which differ according to phase and stage of the illness. A staging model could allow examination of the longitudinal course of the illness and the temporal impact of interventions and events. It could allow for a structured examination of the illness, which could set the stage for algorithms that are tailored to the individuals needs. A staging model could further provide as structure for assessment, gauging treatment and outcomes. The model incorporates prodromal stages and emphasizes early detection and algorithm appropriate intervention where possible. At the other end of the spectrum, the model attempts to operationalize treatment resistance. The utility of the model will need to be validated by empirical research.

In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex-and age-matched healthy controls (p ¼ 0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p ¼ 0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

Cannabis use is highly prevalent among people with schizophrenia, and coupled with impaired cognition, is thought to heighten the risk of illness onset. However, while heavy cannabis use has been associated with cognitive deficits in long-term users, studies among patients with schizophrenia have been contradictory. This article consists of 2 studies. In Study I, a meta-analysis of 10 studies comprising 572 patients with established schizophrenia (with and without comorbid cannabis use) was conducted. Patients with a history of cannabis use were found to have superior neuropsychological functioning. This finding was largely driven by studies that included patients with a lifetime history of cannabis use rather than current or recent use. In Study II, we examined the neuropsychological performance of 85 patients with first-episode psychosis (FEP) and 43 healthy nonusing controls. Relative to controls, FEP patients with a history of cannabis use (FEP 1 CANN; n 5 59) displayed only selective neuropsychological impairments while those without a history (FEP 2 CANN; n 5 26) displayed generalized deficits. When directly compared, FEP 1 CANN patients performed better on tests of visual memory, working memory, and executive functioning. Patients with early onset cannabis use had less neuropsychological impairment than patients with later onset use. Together, these findings suggest that patients with schizophrenia or FEP with a history of cannabis use have superior neuropsychological functioning compared with nonusing patients. This association between better cognitive performance and cannabis use in schizophrenia may be driven by a subgroup of ''neurocognitively less impaired'' patients, who only developed psychosis after a relatively early initiation into cannabis use.

No abstract