Vulnerable periods for cognitive development in individuals at high genomic risk of schizophrenia [Conference Abstract]

22q11.2 Deletion Syndrome (22q11.2DS) is caused by the deletion of approximately 60 genes on chromosome 22 and represents one of the strongest known genetic risk factors for schizophrenia. Approximately 1 in 4 adults with 22q11.2DS are diagnosed with schizophrenia spectrum disorders, presenting with psychotic symptomatology analogous to that exhibited in idiopathic schizophrenia. Cognitive deficits are a core feature of schizophrenia. 22q11.2DS presents a valuable model for understanding vulnerable periods of cognitive development which may be associated with psychosis development. Most previous studies report greater deficits in older individuals with 22q11.2DS than younger individuals but these studies have often focused solely on IQ, neglecting other neurocognitive domains associated with schizophrenia. Additionally, many studies of 22q11.2DS have not included adults, missing a crucial group at increased risk for schizophrenia. The first aim was therefore to examine whether there are increasing deficits in cognitive functioning on a wide range of domains in 22q11.2DS across developmental stages (children, adolescents and adults) compared to typically developing (TD) controls. The second aim was to take into account the presence of a psychotic disorder, and whether this explained variance in functioning. Methods We conducted the largest study to date of neurocognitive functioning beyond IQ in 22q11.2DS. This work was the result of international collaboration across 3 sites. The same battery of tasks measuring processing speed, attention and spatial working memory were completed by 219 participants with 22q11.2DS and 107 TD controls. Wechsler IQ tests were completed, yielding Full Scale (FSIQ), Verbal (VIQ) and Performance IQ scores (PIQ). An age-standardised difference score was produced for each participant taking into account TD control performance. The average performance of children (6–10 years), adolescents (10–18 years) and adults (18–56 years) was compared using an ANOVA approach. No children or adolescents reached diagnostic criteria for a psychotic disorder, but 13% of adults with 22q11.2DS were either diagnosed with a DSM-IV psychotic disorder. The cognitive performance of adults with or without a psychotic disorder was compared with independent t-tests with correction for unequal variance. Results Children and adults with 22q11.2DS displayed a greater deficit in working memory than adolescents (p=0.017 and p<0.001 respectively). Adults displayed greater deficits in FSIQ and PIQ than adolescents (p=0.018 and p=0.001 respectively). Adults diagnosed with a psychotic disorder displayed a greater deficit in VIQ than those without a psychotic disorder (p=0.040). Discussion Magnitude of cognitive deficit in individuals with 22q11.2DS varied by cognitive domain and developmental stage. There were specific deficits in working memory, PIQ and FSIQ in adults with 22q11.2DS compared to children and adolescents. The lack of differences between children and adolescents contradicts previous research which proposes that older children exhibit greater cognitive deficits, and suggests that there may be a longer developmental window to intervene and maintain cognitive functioning in a group at high genomic risk of schizophrenia. Adults with 22q11.2DS and psychotic disorder had a greater deficit in VIQ, which supports previous research. This international sample provides unique insights into cognitive functioning in 22q11.2DS across developmental stages

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

Functional Gene-Expression Analysis Shows Involvement of Schizophrenia-Relevant Pathways in Patients with 22q11 Deletion Syndrome

22q11 Deletion Syndrome (22q11DS) is associated with dysmorphology and a high prevalence of schizophrenia-like symptoms. Several genes located on chromosome 22q11 have been linked to schizophrenia. The deletion is thought to disrupt the expression of multiple genes involved in maturation and development of neurons and neuronal circuits, and neurotransmission. We investigated whole-genome gene expression of Peripheral Blood Mononuclear Cells (PBMC's) of 8 22q11DS patients and 8 age- and gender-matched controls, to (1) investigate the expression levels of 22q11 genes and (2) to investigate whether 22q11 genes participate in functional genetic networks relevant to schizophrenia. Functional relationships between genes differentially expressed in patients (as identified by Locally Adaptive Statistical procedure (LAP) or satisfying p<0.05 and fold-change >1.5) were investigated with the Ingenuity Pathways Analysis (IPA). 14 samples (7 patients, 7 controls) passed quality controls. LAP identified 29 deregulated genes. Pathway analysis showed 262 transcripts differentially expressed between patients and controls. Functional pathways most disturbed were cell death, cell morphology, cellular assembly and organization, and cell-to-cell signaling. In addition, 10 canonical pathways were identified, among which the signal pathways for Natural Killer-cells, neurotrophin/Trk, neuregulin, axonal guidance, and Huntington's disease. Our findings support the use of 22q11DS as a research model for schizophrenia. We identified decreased expression of several genes (among which COMT, Ufd1L, PCQAP, and GNB1L) previously linked to schizophrenia as well as involvement of signaling pathways relevant to schizophrenia, of which Neurotrophin/Trk and neuregulin signaling seems to be especially notable

The association between smoking behaviour, social cognition and social functioning in patients with a non-affective psychotic disorder:A prospective follow-up study

INTRODUCTION: In patients with psychotic disorders, both tobacco smoking and deficits in social cognition and social functioning are highly prevalent. However, little is known about their relationship in psychosis. The authors sought to evaluate the multi-cross-sectional and longitudinal associations between tobacco smoking, social cognition and social functioning in a large prospective study. METHODS: This study was performed within the Genetic Risk and Outcome of Psychosis (GROUP) Study, a cohort study conducted in patients with non-affective psychosis (N = 1074), their unaffected siblings (N = 1047) and healthy controls (N = 549). At baseline, three years and six years of follow-up, data on tobacco smoking (using the Composite International Diagnostic Review), social cognition (emotion processing and theory of mind) and social functioning were collected. To assess associations between tobacco smoking and social cognition or social functioning, multivariate linear mixed-effects models and multiple linear regression models were used. Bonferroni correction for multiple testing was applied. RESULTS: A significant positive association was found between smoking and emotion processing (as part of social cognition) in the patient group (estimate = 1.96, SE = 0.6, p = 0.003). However, smoking was significantly negatively associated with participating in pro-social activities compared with smoking (estimate = 2.55, SE = 0.9, p = 0.004). Change in smoking behaviour was not associated with social cognition or social functioning in the longitudinal analyses. CONCLUSION: Findings indicate that smoking patients with a non-affective psychotic disorder slightly outperformed their non-smoking peers on a task on social cognition, but participated less in pro-social activities. Commencement or cessation of smoking was not related to social cognition or functioning

The Community Assessment of Psychic Experiences:Optimal cut-off scores for detecting individuals with a psychotic disorder

OBJECTIVES: The need for a brief screening tool for psychosis is widely recognized. The Community Assessment of Psychic Experiences (CAPE) is a popular self‐report measure of psychosis, but a cut‐off score that can detect those most likely to fulfill diagnostic criteria for psychotic disorder is not established. METHODS: A case–control sample from the Genetic Risk and Outcome of Psychosis Project study (N = 1375, healthy individuals, n = 507, and individuals with a psychotic disorder, n = 868), was used to examine cut‐off scores of the CAPE with receiver operating curve analyses. We examined 27 possible cut‐off scores computed from a combination of scores from the frequency and distress scales of the various factors of the CAPE. RESULTS: The weighted severity positive symptom dimension was most optimal in detecting individuals with a psychotic disorder (>1.75 cut‐off; area under the curve = 0.88; sensitivity, 75%; specificity, 88%), which correctly identified 80% of the sample as cases or controls with a diagnostic odds ratio of 22.69. CONCLUSIONS: The CAPE can be used as a first screening tool to detect individuals who are likely to fulfill criteria for a psychotic disorder. The >1.75 cut‐off of the weighted severity positive symptom dimension provides a better prediction than all alternatives tested so far

Blended care in the treatment of subthreshold symptoms of depression and psychosis in emerging adults:A randomised controlled trial of Acceptance and Commitment Therapy in Daily-Life (ACT-DL)

In this study, the feasibility and efficacy of Acceptance and Commitment Therapy in Daily Life (ACT-DL), ACT augmented with a daily life application, was investigated in 55 emerging adults (age 16 to 25) with subthreshold depressive and/or psychotic complaints. Participants were randomized to ACT-DL (n = 27) or to active control (n = 28), with assessments completed at pre- and post-measurement and 6- and 12-months follow-up. It took up to five (ACT-DL) and 11 (control) months to start group-based interventions. Participants attended on average 4.32 out of 5 ACT-DL sessions. On the app, they filled in on average 69 (48%) of signal-contingent beep-questionnaires, agreed to 15 (41%) of offered beep-exercises, initiated 19 on-demand exercises, and rated ACT-DL metaphors moderately useful. Relative to active control, interviewer-rated depression scores decreased significantly in ACT-DL participants (p =.027). Decreases in self-reported depression, psychotic-related distress, anxiety, and general psychopathology did not differ between conditions. ACT-DL participants reported increased mean NA (p =.011), relative to active controls. Mean PA did not change in either group, nor did psychological flexibility. ACT-DL is a feasible intervention, although adaptations in future research may improve delivery of and compliance with the intervention. There were mixed findings for its efficacy in reducing subthreshold psychopathology in emerging adults. Dutch Trial Register no.: NTR3808