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.

Improving the integrity and reproducibility of research that uses antibodies: a technical, data sharing, behavioral and policy challenge.

Antibodies are one of the most important reagents used in biomedical and fundamental research, used to identify, and quantify proteins, contribute to knowledge of disease mechanisms, and validate drug targets. Yet many antibodies used in research do not recognize their intended target, or recognize additional molecules, compromising the integrity of research findings and leading to waste of resources, lack of reproducibility, failure of research projects, and delays in drug development. Researchers frequently use antibodies without confirming that they perform as intended in their application of interest. Here we argue that the determinants of end-user antibody choice and use are critical, and under-addressed, behavioral drivers of this problem. This interacts with the batch-to-batch variability of these biological reagents, and the paucity of available characterization data for most antibodies, making it more difficult for researchers to choose high quality reagents and perform necessary validation experiments. The open-science company YCharOS works with major antibody manufacturers and knockout cell line producers to characterize antibodies, identifying high-performing renewable antibodies for many targets in neuroscience. This shows the progress that can be made by stakeholders working together. However, their work so far applies to only a tiny fraction of available antibodies. Where characterization data exists, end-users need help to find and use it appropriately. While progress has been made in the context of technical solutions and antibody characterization, we argue that initiatives to make best practice behaviors by researchers more feasible, easy, and rewarding are needed. Global cooperation and coordination between multiple partners and stakeholders will be crucial to address the technical, policy, behavioral, and open data sharing challenges. We offer potential solutions by describing our Only Good Antibodies initiative, a community of researchers and partner organizations working toward the necessary change. We conclude with an open invitation for stakeholders, including researchers, to join our cause.

Demographic and clinical features as predictors of clozapine response in patients with schizophrenia spectrum disorders: A systematic review and meta-analysis.

OBJECTIVES: Clozapine (CLZ) is prescribed to (relatively) treatment-resistant patients with schizophrenia spectrum disorders. Currently, it is unknown what factors predict response to CLZ. Therefore, we performed meta-analyses to identify predictors of CLZ response, hence aiming to facilitate timely and efficient prescribing of CLZ. METHODS: A systematic search was performed in 'Pubmed' and 'Embase' until 1 January 2019. Articles were eligible if they provided data on predictors of CLZ response measured demographic and clinical factors at baseline or biochemical factors at follow-up in schizophrenia spectrum disorder patients. RESULTS: A total of 34 articles, total number of participants = 9386; N unique = 2094, were eligible. Factors significantly associated with better CLZ response were: lower age, lower PANSS negative score and paranoid schizophrenia subtype. CONCLUSION: The results of our meta-analyses suggest that three baseline demographic and clinical features are associated with better clozapine response, i.e. relatively young age, few negative symptoms and paranoid schizophrenia subtype. These variables may be taken into account by clinicians who consider treating a specific patient with CLZ.

Vitamin D concentration and psychotic disorder: associations with disease status, clinical variables and urbanicity.

BACKGROUND: The association between schizophrenia and decreased vitamin D levels is well documented. Low maternal and postnatal vitamin D levels suggest a possible etiological mechanism. Alternatively, vitamin D deficiency in patients with schizophrenia is presumably (also) the result of disease-related factors or demographic risk factors such as urbanicity. METHODS: In a study population of 347 patients with psychotic disorder and 282 controls, group differences in vitamin D concentration were examined. Within the patient group, associations between vitamin D, symptom levels and clinical variables were analyzed. Group × urbanicity interactions in the model of vitamin D concentration were examined. Both current urbanicity and urbanicity at birth were assessed. RESULTS: Vitamin D concentrations were significantly lower in patients (B = -8.05; 95% confidence interval (CI) -13.68 to -2.42; p = 0.005). In patients, higher vitamin D concentration was associated with lower positive (B = -0.02; 95% CI -0.04 to 0.00; p = 0.049) and negative symptom levels (B = -0.03; 95% CI -0.05 to -0.01; p = 0.008). Group differences were moderated by urbanicity at birth (χ2 = 6.76 and p = 0.001), but not by current urbanicity (χ2 = 1.50 and p = 0.224). Urbanicity at birth was negatively associated with vitamin D concentration in patients (B = -5.11; 95% CI -9.41 to -0.81; p = 0.020), but not in controls (B = 0.72; 95% CI -4.02 to 5.46; p = 0.765). CONCLUSIONS: Lower vitamin D levels in patients with psychotic disorder may in part reflect the effect of psychosis risk mediated by early environmental adversity. The data also suggest that lower vitamin D and psychopathology may be related through direct or indirect mechanisms.

No association between anti-thyroidperoxidase antibodies and bipolar disorder: a study in the Dutch Bipolar Cohort and a meta-analysis.

BACKGROUND: Thyroid autoimmunity has been associated with bipolar disorder (BD). However, results from previous studies on the seroprevalence of anti-thyroid peroxidase antibodies (TPO-abs) in BD are inconsistent. OBJECTIVES: The aim of the present study is to investigate whether the seroprevalence and titer levels of TPO-abs are related to BD. METHOD: TPO-abs were measured in plasma samples of 760 patients with bipolar disorder, 261 first-degree relatives and 363 controls by enzyme-linked immunosorbent assay (ELISA). To address methodological limitations of previous studies, we assessed clinical characteristics with several (self-reported) questionnaires to investigate whether TPO-abs positivity is related to particular clinical subgroups of BD patients. We performed an additional meta-analysis of seroprevalences of TPO-abs in BD patients including data from present and previous studies. RESULTS: Seroprevalence or titer levels of TPO-abs did not significantly differ between patients with BD, their first-degree relatives, and controls. In BD patients, the prevalence of TPO-abs was unrelated to specific clinical factors, including lithium use. Our meta-analysis of twelve studies showed an overall odds ratio of 1.3 (CI 95 %: 0.7-2.3; p = 0.30), reaffirming the absence of an association of BD with TPO-abs. CONCLUSIONS: In the largest study of TPO-abs in BD to date, our findings indicate that TPO-abs are not associated with (the risk for) bipolar disorder.

Phenotypic factors associated with amisulpride-induced weight gain in first-episode psychosis patients (from the OPTiMiSE cohort).

OBJECTIVE: Antipsychotic-induced weight gain (AiWG) is a debilitating adverse effect of most antipsychotics. First-episode psychosis patients are particularly vulnerable to the detrimental consequences of AiWG. Amisulpride has good efficacy and tolerability. We here aimed to identify the phenotypic factors associated with amisulpride-induced weight gain in first-episode psychosis patients. METHOD: Data were collected from the Optimization of Treatment and Management of Schizophrenia in Europe trial. Multivariable regression models with various phenotypic variables (N = 305) were performed with absolute AiWG and clinically relevant AiWG (≥7% AiWG) as outcomes. RESULTS: Four weeks of amisulpride treatment increased body weight from 69.7 to 72.4 kg (P < 0.001). In the regression model of absolute AiWG, unemployment (ß = 0.94, P = 0.016), younger age (ß = -0.07, P = 0.031) and absence of current comorbid major depression disorder (ß = -1.61, P = 0.034) were positively associated with absolute AiWG. In the regression model of clinically relevant AiWG, unemployment (OR = 2.83, P = 0.001), schizophreniform disorder (OR = 2.00, P = 0.025) and low baseline weight (OR = 0.97, P = 0.032) increased the likelihood of clinically relevant AiWG. CONCLUSIONS: Clinicians prescribing amisulpride should consider the relatively high susceptibility to AiWG in unemployed first-episode patients with psychosis, in particular young subjects with a diagnosis of schizophreniform disorder. We advise to carefully monitor these patients and, when needed, implement weight-reducing strategies.

Family interventions and prevention of suicide in first-episode schizophrenia.

Suicide is one of the leading causes of premature death among individuals with schizophrenia and psychotic spectrum disorders (1). Suicide and suicide attempts occur at a significantly greater rate in schizophrenia than in the general population. Common estimates are that 10% of people with schizophrenia will eventually have a completed suicide, and that attempts are made at two to five times that rate. This article is protected by copyright. All rights reserved.

Increased responses of the reward circuitry to positive task feedback following acute stress in healthy controls but not in siblings of schizophrenia patients.

Acute stress is known to affect the way we process rewards. For example, during, or directly after stress, activity within key brain areas of the reward circuitry is reduced when a reward is presented. Generally, the effects of stress on the brain are time-dependent, changing neural and cognitive processing in the aftermath of stress to aid recovery. Such a dynamic response to stress is important for resilience on the longer term. However, relatively little is known about reward processing during the recovery phase of stress and whether this is changed in individuals at increased risk for stress-related psychopathology. Healthy male individuals (N = 40) and unaffected siblings of schizophrenia patients (N = 40) were randomized to either an acute stress task (Trier Social Stress Test) or a no-stress task. Neural responses during reward anticipation and reward feedback (monetary gain or no gain) were examined 50 min later using an fMRI monetary incentive delay task. The ventral striatum and orbitofrontal cortex (OFC) were used as predefined hypothesis-driven regions of interest. Neural responses following stress differed between controls and siblings during reward feedback (group × stress interaction OFC p = 0.003, ventral striatum p = 0.031), showing increased ventral striatum and OFC responses following stress in healthy controls only. Exploratory analyses revealed that this effect was most pronounced during hit trials (compared to when a reward was omitted), and independent of monetary value. Stress did not affect subsequent reward processing in siblings of schizophrenia patients. We found no significant differences between controls and siblings in ventral striatum and OFC responses during reward anticipation following stress. This study shows that ventral striatum and OFC responses to positive task feedback are increased in the aftermath of stress in healthy male controls, regardless of monetary value. This indicates a dynamic shift from previously reported reduced responses in the striatum and OFC to reward feedback directly after stress to increased responses to both reward and non-reward feedback during the recovery phase of stress. These increased neural responses following stress were absent in siblings of schizophrenia patients. Together, these findings indicate that stress recovery is affected in this at-risk group, particularly in responses to positive feedback following stress.

Neurocognition and adaptive functioning in a genetic high risk model of schizophrenia.

BACKGROUND: Identifying factors that influence the functional outcome is an important goal in schizophrenia research. The 22q11.2 deletion syndrome (22q11DS) is a unique genetic model with high risk (20-25%) for schizophrenia. This study aimed to identify potentially targetable domains of neurocognitive functioning associated with functional outcome in adults with 22q11DS. METHODS: We used comprehensive neurocognitive test data available for 99 adults with 22q11DS (n = 43 with schizophrenia) and principal component analysis to derive four domains of neurocognition (Verbal Memory, Visual and Logical Memory, Motor Performance, and Executive Performance). We then investigated the association of these neurocognitive domains with adaptive functioning using Vineland Adaptive Behavior Scales data and a linear regression model that accounted for the effects of schizophrenia status and overall intellectual level. RESULTS: The regression model explained 46.8% of the variance in functional outcome (p < 0.0001). Executive Performance was significantly associated with functional outcome (p = 0.048). Age and schizophrenia were also significant factors. The effects of Executive Performance on functioning did not significantly differ between those with and without psychotic illness. CONCLUSION: The findings provide the impetus for further studies to examine the potential of directed (early) interventions targeting Executive Performance to improve long-term adaptive functional outcome in individuals with, or at high risk for, schizophrenia. Moreover, the neurocognitive test profiles may benefit caregivers and clinicians by providing insight into the relative strengths and weaknesses of individuals with 22q11DS, with and without psychotic illness.

Reward-related brain structures are smaller in patients with schizophrenia and comorbid metabolic syndrome.

OBJECTIVE: Metabolic syndrome (MS) is highly prevalent in schizophrenia and often a consequence of unhealthy behaviour. Reward-related brain areas might be associated with MS, since they play a major role in regulating health behaviour. This study examined the relationship between MS and brain volumes related to the reward system in schizophrenia. METHOD: We included patients with schizophrenia, with MS (MS+; n = 23), patients with schizophrenia, without MS (MS-; n = 48), and healthy controls (n = 54). Global brain volumes and volumes of (sub)cortical areas, part of the reward circuit, were compared between patients and controls. In case of a significant brain volume difference between patients and controls, the impact of MS in schizophrenia was examined. RESULTS: Patients had smaller total brain (TB; P = 0.001), GM (P = 0.010), larger ventricles (P = 0.026), and smaller reward circuit volume (P < 0.001) than controls. MS+ had smaller TB (P = 0.017), GM (P = 0.008), larger ventricles (P = 0.015), and smaller reward circuit volume (P = 0.002) than MS-. MS+ had smaller orbitofrontal cortex (OFC; P = 0.002) and insula volumes (P = 0.005) and smaller OFC (P = 0.008) and insula cortical surface area (P = 0.025) compared to MS-. CONCLUSION: In schizophrenia, structural brain volume reductions in areas of the reward circuitry appear to be related to comorbid MS.

Clozapine as a first- or second-line treatment in schizophrenia: a systematic review and meta-analysis.

OBJECTIVE: No consensus exists on whether clozapine should be prescribed in early stages of psychosis. This systematic review and meta-analysis therefore focus on the use of clozapine as first-line or second-line treatment in non-treatment-resistant patients. METHODS: Articles were eligible if they investigated clozapine compared to another antipsychotic as a first- or second-line treatment in non-treatment-resistant schizophrenia spectrum disorders (SCZ) patients and provided data on treatment response. We performed random-effects meta-analyses. RESULTS: Fifteen articles were eligible for the systematic review (N = 314 subjects on clozapine and N = 800 on other antipsychotics). Our meta-analysis comparing clozapine to a miscellaneous group of antipsychotics revealed a significant benefit of clozapine (Hedges' g = 0.220, P = 0.026, 95% CI = 0.026-0.414), with no evidence of heterogeneity. In addition, a sensitivity analysis revealed a significant benefit of clozapine over risperidone (Hedges' g = 0.274, P = 0.030, 95% CI = 0.027-0.521). CONCLUSION: The few eligible trials on this topic suggest that clozapine may be more effective than other antipsychotics when used as first- or second-line treatment. Only large clinical trials may comprehensively probe disease stage-dependent superiority of clozapine and investigate overall tolerability.

Genetic vulnerability to DUSP22 promoter hypermethylation is involved in the relation between in utero famine exposure and schizophrenia.

Epigenetic changes may account for the doubled risk to develop schizophrenia in individuals exposed to famine in utero. We therefore investigated DNA methylation in a unique sample of patients and healthy individuals conceived during the great famine in China. Subsequently, we examined two case-control samples without famine exposure in whole blood and brain tissue. To shed light on the causality of the relation between famine exposure and DNA methylation, we exposed human fibroblasts to nutritional deprivation. In the famine-exposed schizophrenia patients, we found significant hypermethylation of the dual specificity phosphatase 22 (DUSP22) gene promoter (Chr6:291687-293285) (N = 153, p = 0.01). In this sample, DUSP22 methylation was also significantly higher in patients independent of famine exposure (p = 0.025), suggesting that hypermethylation of DUSP22 is also more generally involved in schizophrenia risk. Similarly, DUSP22 methylation was also higher in two separate case-control samples not exposed to famine using DNA from whole blood (N = 64, p = 0.03) and postmortem brains (N = 214, p = 0.007). DUSP22 methylation showed strong genetic regulation across chromosomes by a region on chromosome 16 which was consistent with new 3D genome interaction data. The presence of a direct link between famine and DUSP22 transcription was supported by data from cultured human fibroblasts that showed increased methylation (p = 0.048) and expression (p = 0.019) in response to nutritional deprivation (N = 10). These results highlight an epigenetic locus that is genetically regulated across chromosomes and that is involved in the response to early-life exposure to famine and that is relevant for a major psychiatric disorder.

Response to initial antipsychotic treatment in first episode psychosis is related to anterior cingulate glutamate levels: a multicentre 1H-MRS study (OPTiMiSE).

Conventional antipsychotic medication is ineffective in around a third of patients with schizophrenia, and the nature of the therapeutic response is unpredictable. We investigated whether response to antipsychotics is related to brain glutamate levels prior to treatment. Proton magnetic resonance spectroscopy was used to measure glutamate levels (Glu/Cr) in the anterior cingulate cortex (ACC) and in the thalamus in antipsychotic-naive or minimally medicated patients with first episode psychosis (FEP, n = 71) and healthy volunteers (n = 60), at three sites. Following scanning, patients were treated with amisulpride for 4 weeks (n = 65), then 1H-MRS was repeated (n = 46). Remission status was defined in terms of Positive and Negative Syndrome Scale for Schizophrenia (PANSS) scores. Higher levels of Glu/Cr in the ACC were associated with more severe symptoms at presentation and a lower likelihood of being in remission at 4 weeks (P < 0.05). There were longitudinal reductions in Glu/Cr in both the ACC and thalamus over the treatment period (P < 0.05), but these changes were not associated with the therapeutic response. There were no differences in baseline Glu/Cr between patients and controls. These results extend previous evidence linking higher levels of ACC glutamate with a poor antipsychotic response by showing that the association is evident before the initiation of treatment.

At-risk individuals display altered brain activity following stress.

Stress is a major risk factor for almost all psychiatric disorders, however, the underlying neurobiological mechanisms remain largely elusive. In healthy individuals, a successful stress response involves an adequate neuronal adaptation to a changing environment. This adaptive response may be dysfunctional in vulnerable individuals, potentially contributing to the development of psychopathology. In the current study, we investigated brain responses to emotional stimuli following stress in healthy controls and at-risk individuals. An fMRI study was conducted in healthy male controls (N = 39) and unaffected healthy male siblings of schizophrenia patients (N = 39) who are at increased risk for the development of a broad range of psychiatric disorders. Brain responses to pictures from the International Affective Picture System (IAPS) were measured 33 min after exposure to stress induced by the validated trier social stress test (TSST) or a control condition. Stress-induced levels of cortisol, alpha-amylase, and subjective stress were comparable in both groups. Yet, stress differentially affected brain responses of schizophrenia siblings versus controls. Specifically, control subjects, but not schizophrenia siblings, showed reduced brain activity in key nodes of the default mode network (PCC/precuneus and mPFC) and salience network (anterior insula) as well as the STG, MTG, MCC, vlPFC, precentral gyrus, and cerebellar vermis in response to all pictures following stress. These results indicate that even in the absence of a psychiatric disorder, at-risk individuals display abnormal functional activation following stress, which in turn may increase their vulnerability and risk for adverse outcomes.

Epidemiology of primary systemic vasculitis in children: a population-based study from southern Sweden.

OBJECTIVES: To estimate the annual incidence rate of paediatric primary systemic vasculitis (PSV) in a defined geographical area in southern Sweden. METHODS: Potential cases of PSV [IgA vasculitis (IgAV, Henoch-Schönlein purpura), Kawasaki disease (KD), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), polyarteritis nodosa (PAN), and Takayasu's arteritis (TAK)] were identified in a comprehensive regional healthcare register. The study area is Skåne, the southernmost county of Sweden (population 1.29 million; 21.4% aged <18 years). Case records for children (0-17 years) assigned a diagnosis code between M300 and M319 and/or D690 were reviewed to ascertain diagnosis. Only patients diagnosed between 2004 and 2014 were included. RESULTS: In total, 556 patients with PSV were identified. The annual incidence rate per million children (95% confidence interval) was estimated to be 200 (183-217) for all PSV, 175.5 for IgAV (160-191), 20.1 for KD (14.9-25.4), 1.4 (0-2.8) for each of GPA and MPA, 0.7 (0-1.7) for PAN, and 0.4 (0-1.1) for each of EGPA and TAK. Among children aged <10 years, 99.5% of cases were either IgAV or KD, both exhibiting a seasonal pattern paralleling infections. There were no deaths, but three cases of end-stage renal disease were noted, all in MPA. CONCLUSIONS: Vasculitis is relatively common during childhood. Mild cases associated with the infection season are most common in the youngest age groups, while during adolescence a substantial proportion has more severe forms of vasculitis.

Tumour necrosis factor-α/etanercept complexes in serum predict long-term efficacy of etanercept treatment in seronegative rheumatoid arthritis.

OBJECTIVE: To study whether serum levels of tumour necrosis factor-α (TNF-α), free or bound to etanercept, in biological-naïve adults with rheumatoid arthritis (RA) could predict the long-term efficacy of etanercept, measured as drug survival. METHOD: We identified 145 biological-naïve patients with RA starting treatment with etanercept at the Department of Rheumatology, Skåne University Hospital (1999-2008), of whom 16 had seronegative and 129 seropositive RA. TNF-α in serum was quantified using enzyme-linked immunosorbent assay in samples from the onset of treatment and at 6 week follow-up. Drug survival time was used to evaluate the long-term efficacy of etanercept. RESULTS: Levels of TNF-α were significantly increased at follow-up compared to at the start. At the 6 week follow-up, circulating TNF-α mainly comprised TNF-α in complex with etanercept. Longer drug survival time correlated with increased TNF-α at 6 week follow-up in the patients with seronegative RA, but not in the seropositive patients. CONCLUSION: We demonstrated that levels of circulating TNF-α increased in almost all individuals after initiation of treatment with etanercept and that this increase mainly comprised TNF-α in complex with etanercept. More importantly, this increase may predict drug survival in adults with seronegative, but not seropositive, RA and suggests that measuring TNF-α/etanercept complexes in serum may be relevant in patients with seronegative RA.

Impaired self-agency inferences in schizophrenia: The role of cognitive capacity and causal reasoning style.

BACKGROUND: The sense of self-agency, i.e., experiencing oneself as the cause of one's own actions, is impaired in patients with schizophrenia. Normally, inferences of self-agency are enhanced when actual outcomes match with pre-activated outcome information, where this pre-activation can result from explicitly set goals (i.e., goal-based route) or implicitly primed outcome information (i.e., prime-based route). Previous research suggests that patients show specific impairments in the prime-based route, implicating that they do not rely on matches between implicitly available outcome information and actual action-outcomes when inferring self-agency. The question remains: Why? Here, we examine whether neurocognitive functioning and self-serving bias (SSB) may explain abnormalities in patients' agency inferences. METHODS: Thirty-six patients and 36 healthy controls performed a commonly used agency inference task to measure goal- and prime-based self-agency inferences. Neurocognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS) and the SSB was assessed with the Internal Personal and Situational Attributions Questionnaire. RESULTS: Results showed a substantial smaller effect of primed outcome information on agency experiences in patients compared with healthy controls. Whereas patients and controls differed on BACS and marginally on SSB scores, these differences were not related to patients' impairments in prime-based agency inferences. CONCLUSIONS: Patients showed impairments in prime-based agency inferences, thereby replicating previous studies. This finding could not be explained by cognitive dysfunction or SSB. Results are discussed in the context of the recent surge to understand and examine deficits in agency experiences in schizophrenia.

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.

BACKGROUND: Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. METHODS: This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores). RESULTS: Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (ß std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged. CONCLUSIONS: Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

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.