Associations between psychosis endophenotypes across brain functional, structural, and cognitive domains.

BACKGROUND: A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. METHODS: This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes. RESULTS: The P300 amplitude and latency were not associated (regression coef. -0.06, 95% CI -0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10-0.28, p 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships. CONCLUSIONS: The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.

Neuropsychological and neuroimaging underpinnings of schizoaffective disorder: a systematic review.

OBJECTIVES: The neurobiological basis and nosological status of schizoaffective disorder remains elusive and controversial. This study provides a systematic review of neurocognitive and neuroimaging findings in the disorder. METHODS: A comprehensive literature search was conducted via PubMed, ScienceDirect, Scopus and Web of Knowledge (from 1949 to 31st March 2015) using the keyword 'schizoaffective disorder' and any of the following terms: 'neuropsychology', 'cognition', 'structural neuroimaging', 'functional neuroimaging', 'multimodal', 'DTI' and 'VBM'. Only studies that explicitly examined a well defined sample, or subsample, of patients with schizoaffective disorder were included. RESULTS: Twenty-two of 43 neuropsychological and 19 of 51 neuroimaging articles fulfilled inclusion criteria. We found a general trend towards schizophrenia and schizoaffective disorder being related to worse cognitive performance than bipolar disorder. Grey matter volume loss in schizoaffective disorder is also more comparable to schizophrenia than to bipolar disorder which seems consistent across further neuroimaging techniques. CONCLUSIONS: Neurocognitive and neuroimaging abnormalities in schizoaffective disorder resemble more schizophrenia than bipolar disorder. This is suggestive for schizoaffective disorder being a subtype of schizophrenia or being part of the continuum spectrum model of psychosis, with schizoaffective disorder being more skewed towards schizophrenia than bipolar disorder.

P300 waveform and dopamine transporter availability: a controlled EEG and SPECT study in medication-naive patients with schizophrenia and a meta-analysis.

BACKGROUND: Reduced P300 event-related potential (ERP) amplitude and latency prolongation have been reported in patients with schizophrenia compared to healthy controls. However, the influence of antipsychotics (and dopamine) on ERP measures are poorly understood and medication confounding remains a possibility. METHOD: We explored ERP differences between 36 drug-naive patients with schizophrenia and 138 healthy controls and examined whether P300 performance was related to dopamine transporter (DAT) availability, both without the confounding effects of medication. We also conducted a random effects meta-analysis of the available literature, synthesizing the results of three comparable published articles and our local study. RESULTS: No overall significant difference was found in mean P300 ERP between patients and controls in latency or in amplitude. There was a significant gender effect, with females showing greater P300 amplitude than males. A difference between patients and controls in P300 latency was evident with ageing, with latency increasing faster in patients. No effect of DAT availability on P300 latency or amplitude was detected. The meta-analysis computed the latency pooled standardized effect size (PSES; Cohen's d) of -0.13 and the amplitude PSES (Cohen's d) of 0.48, with patients showing a significant reduction in amplitude. CONCLUSIONS: Our findings suggest the P300 ERP is not altered in the early stages of schizophrenia before medication is introduced, and the DAT availability does not influence the P300 ERP amplitude or latency. P300 ERP amplitude reduction could be an indicator of the progression of illness and chronicity.

White matter microstructural abnormalities in families multiply affected with bipolar I disorder: a diffusion tensor tractography study.

BACKGROUND: White matter (WM) abnormalities are proposed as potential endophenotypic markers of bipolar disorder (BD). In a diffusion tensor imaging (DTI) voxel-based analysis (VBA) study of families multiply affected with BD, we previously reported that widespread abnormalities of fractional anisotropy (FA) are associated with both BD and genetic liability for illness. In the present study, we further investigated the endophenotypic potential of WM abnormalities by applying DTI tractography to specifically investigate tracts implicated in the pathophysiology of BD. METHOD: Diffusion magnetic resonance imaging (MRI) data were acquired from 19 patients with BD type I from multiply affected families, 21 of their unaffected first-degree relatives and 18 healthy volunteers. DTI tractography was used to identify the cingulum, uncinate fasciculus (UF), arcuate portion of the superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), corpus callosum, and the anterior limb of the internal capsule (ALIC). Regression analyses were conducted to investigate the effect of participant group and genetic liability on FA and radial diffusivity (RD) in each tract. RESULTS: We detected a significant effect of group on both FA and RD in the cingulum, SLF, callosal splenium and ILF driven by reduced FA and increased RD in patients compared to controls and relatives. Increasing genetic liability was associated with decreased FA and increased RD in the UF, and decreased FA in the SLF, among patients. CONCLUSIONS: WM microstructural abnormalities in limbic, temporal and callosal pathways represent microstructural abnormalities associated with BD whereas alterations in the SLF and UF may represent potential markers of endophenotypic risk.

MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Copy number variations of chromosome 16p13.1 region associated with schizophrenia.

Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.

Expanding the range of ZNF804A variants conferring risk of psychosis.

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).

Do COMT, BDNF and NRG1 polymorphisms influence P50 sensory gating in psychosis?

BACKGROUND: Auditory P50 sensory gating deficits correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The well-supported role of catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin 1 (NRG1) genes in neurodevelopment and cognition make a strong theoretical case for their influence on the P50 endophenotype. METHOD: The possible role of NRG1, COMT Val158Met and BDNF Val66Met gene polymorphisms on the P50 endophenotype was examined in a large sample consisting of psychotic patients, their unaffected relatives and unrelated healthy controls using linear regression analyses. RESULTS: Although P50 deficits were present in patients and their unaffected relatives, there was no evidence for an association between NRG1, COMT Val158Met or BDNF Val66Met genotypes and the P50 endophenotype. CONCLUSIONS: The evidence from our large study suggests that any such association between P50 indices and NRG1, COMT Val158Met or BDNF Val66Met genotypes, if present, must be very subtle.

Exaggerated neural response to emotional faces in patients with bipolar disorder and their first-degree relatives.

Neuroimaging studies have demonstrated abnormalities in patients with bipolar disorder, including overactivity in anterior limbic structures in response to fearful or happy facial expressions. We investigated whether such anomalies might constitute heritable deviations underlying bipolar disorder, by virtue of being detectable in unaffected relatives carrying genetic liability for illness. Twenty patients with bipolar I disorder, twenty of their unaffected 1st degree relatives and twenty healthy volunteers participated in functional magnetic resonance imaging experiments of facial emotion processing. In one of these experiments, the participants watched faces expressing fear of varying intensities (moderate and high), intermixed with the non-emotional faces, and in another experiment - faces expressing moderate or high degrees of happiness intermixed with non-emotional faces. Repeated measures 2x3x3 ANOVA with emotion (fear and happy), intensity (neutral, moderate, and high) as within-subjects variables and group (patients, relatives, and controls) as between-subjects variable produced two clusters of differential activation, located in medial prefrontal cortex and left putamen. Activity in medial prefrontal cortex was greater in patients and in relatives compared with healthy volunteers in response to both fearful and happy faces. Activity in left putamen in response to moderate fear was greater in patients and in relatives compared with controls. Patients (but not relatives) showed also a greater activation in response to high intensity happy faces, compared with controls. Region of Interest analysis of amygdala activation showed increased activity in left amygdala in both patients and relatives groups in response to intensively happy faces. Exaggerated medial prefrontal cortical and subcortical (putamen and amygdala) responses to emotional signals may represent heritable neurobiological abnormalities underlying bipolar disorder.

Genetic modelling of childhood social development and personality in twins and siblings with schizophrenia.

BACKGROUND: Abnormalities in early social development and personality are present in patients with schizophrenia and their unaffected relatives. This study aimed to establish the degree to which these childhood and adolescent developmental abnormalities are genetically determined. METHOD: We used a combined twin and family study design (n=531) to assess childhood and adolescent social adjustment and schizotypal personality traits in 98 twin pairs (n=196) varying in their zygosity and concordance for schizophrenia and 156 sibling clusters (n=335) varying in their concordance for schizophrenia. RESULTS: Schizophrenia was significantly associated with childhood and adolescent deficits in social adjustment and personality, with additive genetic effects being the main source of these phenotypic correlations. CONCLUSIONS: Abnormalities of social adjustment and personality are present in children and adolescents who later develop schizophrenia, reflecting the influence of common genetic risk.

Neural correlates of visuospatial working memory in the 'at-risk mental state'.

BACKGROUND: Impaired spatial working memory (SWM) is a robust feature of schizophrenia and has been linked to the risk of developing psychosis in people with an at-risk mental state (ARMS). We used functional magnetic resonance imaging (fMRI) to examine the neural substrate of SWM in the ARMS and in patients who had just developed schizophrenia. METHOD: fMRI was used to study 17 patients with an ARMS, 10 patients with a first episode of psychosis and 15 age-matched healthy comparison subjects. The blood oxygen level-dependent (BOLD) response was measured while subjects performed an object-location paired-associate memory task, with experimental manipulation of mnemonic load. RESULTS: In all groups, increasing mnemonic load was associated with activation in the medial frontal and medial posterior parietal cortex. Significant between-group differences in activation were evident in a cluster spanning the medial frontal cortex and right precuneus, with the ARMS groups showing less activation than controls but greater activation than first-episode psychosis (FEP) patients. These group differences were more evident at the most demanding levels of the task than at the easy level. In all groups, task performance improved with repetition of the conditions. However, there was a significant group difference in the response of the right precuneus across repeated trials, with an attenuation of activation in controls but increased activation in FEP and little change in the ARMS. CONCLUSIONS: Abnormal neural activity in the medial frontal cortex and posterior parietal cortex during an SWM task may be a neural correlate of increased vulnerability to psychosis.

Neural correlates of movement generation in the 'at-risk mental state'.

OBJECTIVE: People with 'prodromal' symptoms have a very high risk of developing psychosis. We examined the neurocognitive basis of this vulnerability by using functional MRI to study subjects with an at-risk mental state (ARMS) while they performed a random movement generation task. METHOD: Cross-sectional comparison of individuals with an ARMS (n = 17), patients with first episode schizophreniform psychosis (n = 10) and healthy volunteers (n = 15). Subjects were studied using functional MRI while they performed a random movement generation paradigm. RESULTS: During random movement generation, the ARMS group showed less activation in the left inferior parietal cortex than controls, but greater activation than in the first episode group. CONCLUSION: The ARMS is associated with abnormalities of regional brain function that are qualitatively similar to those in patients who have recently presented with psychosis but less severe.

Are auditory P300 and duration MMN heritable and putative endophenotypes of psychotic bipolar disorder? A Maudsley Bipolar Twin and Family Study.

BACKGROUND: Impaired P300 auditory response has been reported in patients with psychotic bipolar disorder (BPD) and unaffected relatives of psychotic bipolar patients. Deficits in mismatch negativity (MMN), however, have not been observed in bipolar patients. To our knowledge, no family study of MMN in BPD has been reported. The current study combined the Maudsley twin and bipolar family samples using genetic model fitting analyses to: (1) assess the relationship between BPD and MMN, (2) substantiate the association between psychotic BPD and P300 variables, (3) verify the genetic overlap of BPD with P300 amplitude previously reported in the twin sample, and (4) examine the shared genetic influences between BPD and bilateral temporal scalp locations of P300 components. METHOD: A total of 301 subjects were included in this study, including 94 twin pairs, 31 bipolar families, and 39 unrelated healthy controls. Statistical analyses were based on structural equation modelling. RESULTS: Both P300 and MMN are heritable, with heritability estimates of 0.58 for MMN, 0.68-0.80 for P300 amplitude, and 0.21-0.56 for P300 latency. The bipolar patients and their relatives showed normal MMN. No significant association, either genetic or environmental, was found with BPD. BPD was significantly associated with reduced P300 amplitude and prolonged latency on midline and bilateral temporal-posterior scalp areas. Shared genetic factors were the main source of these associations. CONCLUSIONS: The results confirm that MMN is not an endophenotype for psychotic BPD whereas P300 amplitude and latency components are valid endophenotypes for psychotic BPD.

Economic impact of early intervention in people at high risk of psychosis.

BACKGROUND: Despite the increasing development of early intervention services for psychosis, little is known about their cost-effectiveness. We assessed the cost-effectiveness of Outreach and Support in South London (OASIS), a service for people with an at-risk mental state (ARMS) for psychosis. METHOD: The costs of OASIS compared to care as usual (CAU) were entered in a decision model and examined for 12- and 24-month periods, using the duration of untreated psychosis (DUP) and rate of transition to psychosis as key parameters. The costs were calculated on the basis of services used following referral and the impact on employment. Sensitivity analysis was used to test the robustness of all the assumptions made in the model. RESULTS: Over the initial 12 months from presentation, the costs of the OASIS intervention were pound1872 higher than CAU. However, after 24 months they were pound961 less than CAU. CONCLUSIONS: This model suggests that services that permit early detection of people at high risk of psychosis may be cost saving.

The effect of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on hippocampal and lateral ventricular volume in psychosis.

BACKGROUND: Morphometric endophenotypes which have been proposed for psychotic disorders include lateral ventricular enlargement and hippocampal volume reductions. Genetic epidemiological studies support an overlap between schizophrenia and bipolar disorder, and COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes have been implicated in the aetiology of both these disorders. This study examined associations between these candidate genes and morphometric endophenotypes for psychosis. METHOD: A total of 383 subjects (128 patients with psychosis, 194 of their unaffected relatives and 61 healthy controls) from the Maudsley Family Psychosis Study underwent structural magnetic resonance imaging and genotyping. The effect of candidate genes on brain morphometry was examined using linear regression models adjusting for clinical group, age, sex and correlations between members of the same family. RESULTS: The results showed no evidence of association between variation in COMT genotype and lateral ventricular, and left or right hippocampal volumes. Neither was there any effect of the BDNF, 5-HTTLPR, NRG1 and DTNBP1 genotypes on these regional brain volumes. CONCLUSIONS: Abnormal hippocampal and lateral ventricular volumes are among the most replicated endophenotypes for psychosis; however, the influences of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on these key brain regions must be very subtle if at all present.

The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder1.

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737.

Is there an association between the COMT gene and P300 endophenotypes?

P300 wave anomalies correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The COMT gene is thought to influence cognitive performance and to be a susceptibility gene for schizophrenia. Unlike two previous studies, we found no significant influence of the COMT gene on P300 amplitude or latency in 189 individuals examined. The well-supported role of the COMT gene both in dopamine catabolism as well as in prefrontal cognition makes a strong theoretical case for the influence of COMT Val158Met polymorphism on P300 endophenotypes. However, the available neurophysiologic evidence suggests that any such association, if present, must be very subtle.

Obstetric complications in patients with schizophrenia and their unaffected siblings.

OBJECTIVE: We sought to explore whether obstetric complications (OCs) are more likely to occur in the presence of familial/genetic susceptibility for schizophrenia or whether they themselves represent an independent environmental risk factor for schizophrenia. METHODS: The presence of OCs was assessed through maternal interview on 216 subjects, comprising 36 patients with schizophrenia from multiply affected families, 38 of their unaffected siblings, 31 schizophrenic patients with no family history of psychosis, 51 of their unaffected siblings and 60 normal comparison subjects. We examined the familiality of OCs and whether OCs were commoner in the patient and sibling groups than in the control group. RESULTS: OCs tended to cluster within families, especially in multiply affected families. Patients with schizophrenia, especially those from multiply affected families, had a significantly higher rate of OCs compared to normal comparison subjects, but there was no evidence for an elevated rate of OCs in unaffected siblings. CONCLUSION: Our data provides little evidence for a link between OCs and genetic susceptibility to schizophrenia. If high rates of OCs are related to schizophrenia genes, this relationship is weak and will only be detected by very large sample sizes.

Failure to deactivate medial prefrontal cortex in people at high risk for psychosis.

Impaired working memory is a core feature of schizophrenia and is linked with altered engagement the lateral prefrontal cortex. Although altered PFC activation has been reported in people with increased risk of psychosis, at present it is not clear if this neurofunctional alteration differs between familial and clinical risk states and/or increases in line with the level of psychosis risk. We addressed this issue by using functional MRI and a working memory paradigm to study familial and clinical high-risk groups. We recruited 17 subjects at ultra-high-risk (UHR) for psychosis, 10 non-affected siblings of patients with schizophrenia (familial high risk [FHR]) and 15 healthy controls. Subjects were scanned while performing the N-back working memory task. There was a relationship between the level of task-related deactivation in the medial PFC and precuneus and the level of psychosis risk, with deactivation weakest in the UHR group, greatest in healthy controls, and at an intermediate level in the FHR group. In the high-risk groups, activation in the precuneus was associated with the level of negative symptoms. These data suggest that increased vulnerability to psychosis is associated with a failure to deactivate in the medial PFC and precuneus during a working memory task, and appears to be most evident in subjects at clinical, as opposed to familial high risk.