Reduced Context Effects on Retrieval in First-Episode Schizophrenia

Background: A recent modeling study by the authors predicted that contextual information is poorly integrated into episodic representations in schizophrenia, and that this is a main cause of the retrieval deficits seen in schizophrenia. Methodology/Principal Findings: We have tested this prediction in patients with first-episode schizophrenia and matched controls. The benefit from contextual cues in retrieval was strongly reduced in patients. On the other hand, retrieval based on item cues was spared. Conclusions/Significance: These results suggest that reduced integration of context information into episodic representations is a core deficit in schizophrenia and one of the main causes of episodic memory impairment

Association between the DTNBP1 gene and intelligence: a case-control study in young patients with schizophrenia and related disorders and unaffected siblings

BACKGROUND: The dystrobrevin-binding protein 1 (DTNBP1) gene is a susceptibility gene for schizophrenia. There is growing evidence that DTNPB1 contributes to intelligence and cognition. In this study, we investigated association between single nucleotide polymorphisms (SNPs) in the DTNBP1 gene and intellectual functioning in patients with a first episode of schizophrenia or related psychotic disorder (first-episode psychosis, FEP), their healthy siblings, and unrelated controls. METHODS: From all subjects IQ measurements were obtained (verbal IQ [VIQ], performance IQ [PIQ], and full scale IQ [FSIQ]). Seven SNPs in the DTNBP1 gene were genotyped using single base primer extension and analyzed by matrix-assisted laser deionization mass spectrometry (MALDI-TOF). RESULTS: Mean VIQ, PIQ, and FSIQ scores differed significantly (p < 0.001) between patients, siblings, and controls. Using a family-based and a case-control design, several single SNPs were significantly associated with IQ scores in patients, siblings, and controls. CONCLUSION: Although preliminary, our results provide evidence for association between the DTNBP1 gene and intelligence in patients with FEP and their unaffected siblings. Genetic variation in the DTNBP1 gene may increase schizophrenia susceptibility by affecting intellectual functioning

Prescription of antipsychotic medication to patients at ultra high risk of developing psychosis

Little is known about medication prescription in a naturalistic setting to patients at ultra high risk (UHR) of developing psychosis. Antipsychotic medication prescription to UHR patients is not recommended in clinical practice guidelines based on the current evidence. The aim of this study is to investigate medication prescription to UHR patients in the Netherlands. The frequency of antipsychotic medication prescription to UHR patients (n=72) was compared with the frequency of antipsychotic medication prescription to patients who were diagnosed with a Diagnostic and Statistical Manual of Mental Disorders, fourth edition psychotic disorder at first diagnostic evaluation (n=90). Within the UHR group, frequency of antipsychotic medication prescription at baseline was compared between UHR patients who did make the transition to psychosis (n=18) and UHR patients who did not (n=54). No significant differences were found in antipsychotic medication prescription to UHR patients and to patients who turned out to have a florid psychosis: 51% in the psychotic group and 58% in the UHR group used no medication. Thirty-four percent in the psychotic group and 21% in the UHR group used antipsychotic medication. There was also no difference in medication prescription between UHR patients who did and did not make the transition to psychosis. More research should be aimed at developing and implementing clinical practice guidelines for the treatment of UHR patients

Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets

Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ~80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10−5; odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ

A Genetic Deconstruction of Neurocognitive Traits in Schizophrenia and Bipolar Disorder

Background: Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders. Methods: Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium. Results: The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope. Conclusions: Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders

AMPT-induced monoamine depletion in humans: evaluation of two alternative [123I]IBZM SPECT procedures

Purpose Acute monoamine depletion paradigms using alpha-methyl-para-tyrosine (AMPT) combined with single photon emission computed tomography (SPECT) have been used successfully to evaluate disturbances in central dopaminergic neurotransmission. However, severe side effects due to relatively high doses (4,500 to 8,000 mg) of AMPT have been reasons for study withdrawal. Thus, we assessed the effectiveness and tolerability of two alternative procedures, using lower doses of AMPT. Methods Six healthy subjects underwent three measurements of striatal dopamine D2 receptor (D2R)-binding potential (BPND) with SPECT and the selective radiolabeled D2R antagonist [123I]IBZM. All subjects were scanned in the absence of pharmacological intervention (baseline) and after two different depletion procedures. In the first depletion session, over 6 h, subjects were administered 1,500 mg of AMPT before scanning. In the second depletion session, over 25 h, subjects were administered 40 mg AMPT/kg body weight. We also administered the Subjective Well-being Under Neuroleptic Treatment Scale, a self-report instrument designed to measure the subjective experience of patients on neuroleptic medication. Results We found no change of mean D2R BPND after the first and short AMPT challenge compared to the baseline. However, we found a significant increase in striatal D2R BPND binding after the AMPT challenge adjusted for bodyweight compared to both other regimen. Although subjective well-being worsened after the prolonged AMPT challenge, no severe side effects were reported. Conclusions Our results imply a low-dosage, suitable alternative to the common AMPT procedure. The probability of side effects and study withdrawal can be reduced by this procedure

Proton Magnetic Resonance Spectroscopy in 22q11 Deletion Syndrome

OBJECTIVE: People with velo-cardio-facial syndrome or 22q11 deletion syndrome (22q11DS) have behavioral, cognitive and psychiatric problems. Approximately 30% of affected individuals develop schizophrenia-like psychosis. Glutamate dysfunction is thought to play a crucial role in schizophrenia. However, it is unknown if and how the glutamate system is altered in 22q11DS. People with 22q11DS are vulnerable for haploinsufficiency of PRODH, a gene that codes for an enzyme converting proline into glutamate. Therefore, it can be hypothesized that glutamatergic abnormalities may be present in 22q11DS. METHOD: We employed proton magnetic resonance spectroscopy ((1)H-MRS) to quantify glutamate and other neurometabolites in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of 22 adults with 22q11DS (22q11DS SCZ+) and without (22q11DS SCZ-) schizophrenia and 23 age-matched healthy controls. Also, plasma proline levels were determined in the 22q11DS group. RESULTS: We found significantly increased concentrations of glutamate and myo-inositol in the hippocampal region of 22q11DS SCZ+ compared to 22q11DS SCZ-. There were no significant differences in levels of plasma proline between 22q11DS SCZ+ and 22q11DS SCZ-. There was no relationship between plasma proline and cerebral glutamate in 22q11DS. CONCLUSION: This is the first in vivo(1)H-MRS study in 22q11DS. Our results suggest vulnerability of the hippocampus in the psychopathology of 22q11DS SCZ+. Altered hippocampal glutamate and myo-inositol metabolism may partially explain the psychotic symptoms and cognitive impairments seen in this group of patients

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

Obsessive-compulsive symptoms in first episode psychosis and in subjects at ultra high risk for developing psychosis; onset and relationship to psychotic symptoms

Objective: To determine the prevalence of obsessive-compulsive symptoms and obsessive compulsive disorder in patients with schizophrenia or related disorders or subjects at ultra high risk for development of psychosis. Secondly, to determine the time of occurrence of obsessive-compulsive symptoms related to the onset of first psychosis. Method: We collected data on all patients who were referred consecutively to our specialized clinic for first episode psychosis patients and ultra high risk subjects in Amsterdam between 1 July 2006 and 1 July 2008. Diagnosis of psychotic disorders was established using the Comprehensive Assessment of Symptoms and History schedule. Obsessions and compulsions were defined in accordance with DSM-III-R criteria and assessed by clinicians. We analyzed the onset of obsessive-compulsive symptoms and its relation to the onset of first episode psychosis. Results: When a strict definition of obsessive-compulsive symptoms is used, 9.3% (n = 18) of patients with schizophrenia or a related disorder exhibited obsessive-compulsive symptoms and 1.5% also met criteria for obsessive-compulsive disorder. The onset of obsessive -compulsive symptoms occurred before, concurrent with and after onset of first episode psychosis in the following proportion of patients: 7/18, 3/18, 8/18. We found a prevalence of 20.7% of obsessive-compulsive symptoms in ultra high risk subjects. Conclusion: Using a strict definition of obsessive-compulsive symptoms, we found relatively low prevalence rates of obsessive-compulsive symptoms and obsessive-compulsive disorder in patients with schizophrenia or related disorders; the rates are even lower than known rates of obsessive-compulsive symptoms and obsessive-compulsive disorder in the general population. Obsessive-compulsive symptoms rates in ultra high risk subjects are comparable to those in the general population. Further investigation of the predictive validity of obsessive-compulsive symptoms in ultra high risk subjects for developing psychosis is needed. Obsessive-compulsive symptoms either develop prior, during or after the onset of first episode psychosi