Alterations in gray matter (GM) are commonly observed in schizophrenia. Accumulating studies suggest that the brain changes associated with schizophrenia are distributed rather than focal, involving interconnected networks of areas as opposed to single regions. In the current study we aimed to explore GM volume (GMV) changes in a relatively large sample of treatment-naive first-episode schizophrenia (FES) patients using optimized voxel-based morphometry (VBM) and covariation analysis.

High-resolution T1-weighted images were obtained using 3.0-T magnetic resonance imaging (MRI) from 86 first-episode drug-naive patients with schizophrenia and 86 age- and gender-matched healthy volunteers. Symptom severity was evaluated using the Positive and Negative Syndrome Scale (PANSS). GMV was assessed using optimized VBM and in 16 regions of interest (ROIs), selected on the basis of a previous meta-analysis. The relationships between GMVs in the ROIs were examined using an analysis of covariance (ANCOVA).

The VBM analysis revealed that first-episode patients showed reduced GMV in the hippocampus bilaterally. The ROI analysis identified reductions in GMV in the left inferior frontal gyrus, bilateral hippocampus and right thalamus. The ANCOVA revealed different patterns of regional GMV correlations in patients and controls, including of inter- and intra-insula, inter-amygdala and insula–postcentral gyrus connections.

Schizophrenia involves regional reductions in GMV and changes in GMV covariance in the insula, amygdala and postcentral gyrus. These findings were evident at the onset of the disorder, before treatment, and therefore cannot be attributable to the effects of chronic illness progression or medication.

Genetic influences contribute significantly to co-morbidity between conduct disorder and substance use disorders. Estimating the extent of overlap can assist in the development of phenotypes for genomic analyses.

Multivariate quantitative genetic analyses were conducted using data from 9577 individuals, including 3982 complete twin pairs and 1613 individuals whose co-twin was not interviewed (aged 24–37 years) from two Australian twin samples. Analyses examined the genetic correlation between alcohol dependence, nicotine dependence and cannabis abuse/dependence and the extent to which the correlations were attributable to genetic influences shared with conduct disorder.

Additive genetic (a2 = 0.48–0.65) and non-shared environmental factors explained variance in substance use disorders. Familial effects on conduct disorder were due to additive genetic (a2 = 0.39) and shared environmental (c2 = 0.15) factors. All substance use disorders were influenced by shared genetic factors (rg = 0.38–0.56), with all genetic overlap between substances attributable to genetic influences shared with conduct disorder. Genes influencing individual substance use disorders were also significant, explaining 40–73% of the genetic variance per substance.

Among substance users in this sample, the well-documented clinical co-morbidity between conduct disorder and substance use disorders is primarily attributable to shared genetic liability. Interventions targeted at generally reducing deviant behaviors may address the risk posed by this shared genetic liability. However, there is also evidence for genetic and environmental influences specific to each substance. The identification of these substance-specific risk factors (as well as potential protective factors) is critical to the future development of targeted treatment protocols.

Offspring of patients with schizophrenia exhibit poorer school performance compared with offspring of non-schizophrenic parents. We aimed to elucidate the mechanisms behind this association.

We linked longitudinal national population registers in Sweden and compared school performance among offspring of schizophrenic parents with offspring of non-schizophrenic parents (1 439 215 individuals with final grades from compulsory school 1988–2006). To investigate the mechanisms, we studied offspring of schizophrenic patients and controls within the same extended families. We investigated genetic effects by stratifying analyses of parent–child associations according to genetic relatedness (half-cousins, full cousins and half-siblings). Environmental effects were investigated by comparing school performance of offspring of schizophrenic fathers and of schizophrenic mothers, respectively, and by stratifying the analyses according to environmental relatedness while controlling genetic relatedness (paternal and maternal half-cousins, paternal and maternal half-siblings).

Offspring of parents with schizophrenia had poorer overall school performance than unrelated offspring of non-schizophrenic parents (−0.31 s.d.). Variability in genetic relatedness greatly moderated the strength of the within-family association (β=−0.23 within exposure-discordant half-cousins, β=−0.13 within exposure-discordant full cousins, β=0.04 within exposure-discordant half-siblings), while no evidence was found that the environment affected offspring school performance.

Genetic factors account for poorer school performance in children of parents with schizophrenia. This supports that cognitive deficits found in individuals with schizophrenia and their relatives might be genetically inherited. Early detection of prodromal signs and impaired functioning of offspring of patients with schizophrenia could lead to earlier and better tailored interventions.

In search of empirical classifications of depression and anxiety, most subtyping studies focus solely on symptoms and do so within a single disorder. This study aimed to identify and validate cross-diagnostic subtypes by simultaneously considering symptoms of depression and anxiety, and disability measures.

A large cohort of adults (Lifelines, n = 73 403) had a full assessment of 16 symptoms of mood and anxiety disorders, and measurement of physical, social and occupational disability. The best-fitting subtyping model was identified by comparing different hybrid mixture models with and without disability covariates on fit criteria in an independent test sample. The best model's classes were compared across a range of external variables.

The best-fitting Mixed Measurement Item Response Theory model with disability covariates identified five classes. Accounting for disability improved differentiation between people reporting isolated non-specific symptoms [‘Somatic’ (13.0%), and ‘Worried’ (14.0%)] and psychopathological symptoms [‘Subclinical’ (8.8%), and ‘Clinical’ (3.3%)]. Classes showed distinct associations with clinically relevant external variables [e.g. somatization: odds ratio (OR) 8.1–12.3, and chronic stress: OR 3.7–4.4]. The Subclinical class reported symptomatology at subthreshold levels while experiencing disability. No pure depression or anxiety, but only mixed classes were found.

An empirical classification model, incorporating both symptoms and disability identified clearly distinct cross-diagnostic subtypes, indicating that diagnostic nets should be cast wider than current phenomenology-based categorical systems.

There has been increasing interest in the validity and familial transmission of subthreshold psychiatric conditions and the relationship between subthreshold conditions and full syndrome (FS) disorders. However, most of these studies examined a single subthreshold condition and thus fail to take into account the high co-morbidity among subthreshold conditions and between subthreshold conditions and FS disorders.

A family study of subthreshold psychiatric conditions was conducted with 739 community-drawn young adults and their 1744 relatives. We examined (1) whether relatives of probands with subthreshold major depression, bipolar disorder, anxiety disorders, alcohol use, substance use, and/or conduct disorder exhibited an increased rate of the corresponding (homotypic) FS disorder; (2) whether subthreshold disorders were associated with increased familial rates of other (heterotypic) FS disorders; (3) whether subthreshold and FS conditions are associated with similar familial liabilities; and (4) whether these homotypic and heterotypic associations persisted after controlling for co-morbidity.

Significant homotypic associations were observed for subthreshold anxiety, alcohol, conduct, and a trend was observed for major depression. Only the homotypic association for alcohol and conduct remained after controlling for co-morbid subthreshold and FS conditions. Many heterotypic associations were observed and most remained after controlling for co-morbidity.

It is important to broaden the study of subthreshold psychopathology to multiple disorders. In particular cases, controlling for co-morbidity with other subthreshold and FS conditions altered the patterns of familial aggregation. Etiological processes that are common to particular disorders and subthreshold conditions are discussed.

Though meta-analyses of neuropsychological and social cognitive deficits in behavioral variant frontotemporal dementia (bvFTD) have been conducted, no study has comprehensively characterized and compared the neuropsychological, social cognitive, and olfactory profiles in the behavioral and language variants of FTD.

Our search yielded 470 publications meeting inclusion criteria representing 11 782 FTD patients and 19 451 controls. For each domain, we calculated Hedges’ g effect sizes, which represent the mean difference between the patient and control group divided by the pooled standard deviation. The heterogeneity of these effects was assessed with Cochran's Q-statistic using a random-effects model. Meta-regressions were employed to analyze the influence of demographic and disease characteristics.

Though semantic variant primary progressive aphasia patients showed the greatest impairment across all task types, the three groups showed similar cognitive effect sizes once contributions from the language subdomain were excluded from analysis. Contrary to expectation, the magnitude of deficits in executive functioning, social cognition and olfaction were comparable between the three subgroups. Among indices, a metric of executive errors distinguished the behavioral variant of FTD from the language phenotypes.

These data indicate that social cognitive and traditional executive functioning measures may not capture differences between FTD syndromes. These results have important implications for the interpretation of neuropsychological assessments, particularly when applied to the differential diagnosis of FTD. It is hoped that these findings will guide clinical and research assessments and spur new studies focused on improving the measurement of FTD syndromes.

Childhood adversities have been associated with chronic inflammation and risk for cardiovascular disease. With some exceptions, existing knowledge of this relationship is based on retrospective self-reports, potentially subject to recall bias or memory problems. We seek to determine whether childhood maltreatment is associated with higher C-reactive protein (CRP) later in life and whether individuals with official and retrospective self-reports of maltreatment and men and women show similar increases in risk.

Data are from in-person interviews in 2009–2010 with 443 offspring (mean age = 23.4) of parents in a longitudinal study of the consequences of childhood maltreatment. Official reports of maltreatment were abstracted from 2011–2013 Child Protective Services records. Eleven measures were used to assess self-reported maltreatment retrospectively. Seventeen percent of offspring had official reports, whereas self-reported prevalence rates ranged from 5.4% to 64.8%. CRP was assessed through blood spot samples. Regression models were used to estimate the effect of maltreatment on inflammation, adjusting for age, sex, race, parent occupational status, current depression, smoking, and heavy drinking.

Individuals with official reports of child maltreatment and, specifically, physical abuse, had significantly higher levels of CRP than non-maltreated individuals. Maltreated females showed elevated CRP, independent of control variables, whereas no significant association was observed in males. Retrospective self-report measures of child maltreatment did not predict elevated CRP.

Individuals with documented histories of childhood maltreatment are at increased risk for chronic inflammation and may benefit from targeted interventions. The results strengthen inferences about the effects of childhood maltreatment on inflammation in females.

Depression is a significant problem and it is vital to understand its underlying causes and related policy implications. Neighborhood characteristics are implicated in depression but the nature of this association is unclear. Unobserved or unmeasured factors may confound the relationship. This study addresses confounding in a twin study investigating neighborhood-level effects on depression controlling for genetics, common environment, and gene×environment (G × E) interactions.

Data on neighborhood deprivation and depression were gathered from 3155 monozygotic twin pairs and 1275 dizygotic pairs (65.7% female) between 2006 and 2013. The variance for both depression and neighborhood deprivation was decomposed into three components: additive genetic variance (A); shared environmental variance (C); and non-shared environmental variance (E). Depression was then regressed on neighborhood deprivation to test the direct association and whether that association was confounded. We also tested for a G × E interaction in which the heritability of depression was modified by the level of neighborhood deprivation.

Depression and neighborhood deprivation showed evidence of significant A (21.8% and 15.9%, respectively) and C (13.9% and 32.7%, respectively) variance. Depression increased with increasing neighborhood deprivation across all twins (p = 0.009), but this regression was not significant after controlling for A and C variance common to both phenotypes (p = 0.615). The G × E model showed genetic influences on depression increasing with increasing neighborhood deprivation (p < 0.001).

Neighborhood deprivation is an important contributor to depression via increasing the genetic risk. Modifiable pathways that link neighborhoods to depression have been proposed and should serve as targets for intervention and research.

Catatonia, a severe neuropsychiatric syndrome, has few studies of sufficient scale to clarify its epidemiology or pathophysiology. We aimed to characterise demographic associations, peripheral inflammatory markers and outcome of catatonia.

Electronic healthcare records were searched for validated clinical diagnoses of catatonia. In a case–control study, demographics and inflammatory markers were compared in psychiatric inpatients with and without catatonia. In a cohort study, the two groups were compared in terms of their duration of admission and mortality.

We identified 1456 patients with catatonia (of whom 25.1% had two or more episodes) and 24 956 psychiatric inpatients without catatonia. Incidence was 10.6 episodes of catatonia per 100 000 person-years. Patients with and without catatonia were similar in sex, younger and more likely to be of Black ethnicity. Serum iron was reduced in patients with catatonia [11.6 v. 14.2 μmol/L, odds ratio (OR) 0.65 (95% confidence interval (CI) 0.45–0.95), p = 0.03] and creatine kinase was raised [2545 v. 459 IU/L, OR 1.53 (95% CI 1.29–1.81), p < 0.001], but there was no difference in C-reactive protein or white cell count. N-Methyl-d-aspartate receptor antibodies were significantly associated with catatonia, but there were small numbers of positive results. Duration of hospitalisation was greater in the catatonia group (median: 43 v. 25 days), but there was no difference in mortality after adjustment.

In the largest clinical study of catatonia, we found catatonia occurred in approximately 1 per 10 000 person-years. Evidence for a proinflammatory state was mixed. Catatonia was associated with prolonged inpatient admission but not with increased mortality.

Brain-derived neurotrophic factor (BDNF) is an important regulator of synaptogenesis and synaptic plasticity underlying learning. However, a relationship between circulating BDNF levels and brain activity during learning has not been demonstrated in humans. Reduced brain BDNF levels are found in schizophrenia and functional neuroimaging studies of probabilistic association learning in schizophrenia have demonstrated reduced activity in a neural network that includes the prefrontal and parietal cortices and the caudate nucleus. We predicted that brain activity would correlate positively with peripheral BDNF levels during probabilistic association learning in healthy adults and that this relationship would be altered in schizophrenia.

Twenty-five healthy adults and 17 people with schizophrenia or schizo-affective disorder performed a probabilistic association learning test during functional magnetic resonance imaging (fMRI). Plasma BDNF levels were measured by enzyme-linked immunosorbent assay (ELISA).

We found a positive correlation between circulating plasma BDNF levels and brain activity in the parietal cortex in healthy adults. There was no relationship between plasma BDNF levels and task-related activity in the prefrontal, parietal or caudate regions in schizophrenia. A direct comparison of these relationships between groups revealed a significant diagnostic difference.

This is the first study to show a relationship between peripheral BDNF levels and cortical activity during learning, suggesting that plasma BDNF levels may reflect learning-related brain activity in healthy humans. The lack of relationship between plasma BDNF and task-related brain activity in patients suggests that circulating blood BDNF may not be indicative of learning-dependent brain activity in schizophrenia.

Previous work has shown that amygdala responsiveness to fearful expressions is inversely related to level of callous-unemotional (CU) traits (i.e. reduced guilt and empathy) in youth with conduct problems. However, some research has suggested that the relationship between pathophysiology and CU traits may be different in those youth with significant prior trauma exposure.

In experiment 1, 72 youth with varying levels of disruptive behavior and trauma exposure performed a gender discrimination task while viewing morphed fear expressions (0, 50, 100, 150 fear) and Blood Oxygenation Level Dependent responses were recorded. In experiment 2, 66 of these youth performed the Social Goals Task, which measures self-reports of the importance of specific social goals to the participant in provoking social situations.

In experiment 1, a significant CU traits-by-trauma exposure interaction was observed within right amygdala; fear intensity-modulated amygdala responses negatively predicted CU traits for those youth with low levels of trauma but positively predicted CU traits for those with high levels of trauma. In experiment 2, a bootstrapped model revealed that the indirect effect of fear intensity amygdala response on social goal importance through CU traits is moderated by prior trauma exposure.

This study, while exploratory, indicates that the pathophysiology associated with CU traits differs in youth as a function of prior trauma exposure. These data suggest that prior trauma exposure should be considered when evaluating potential interventions for youth with high CU traits.

Paliperidone palmitate is one of the most widely prescribed long-acting injectable (LAI) antipsychotics in the UK. However, it is relatively expensive and there are few data comparing its effectiveness to that of other LAI antipsychotics. We sought to address this issue by analyzing a large anonymized electronic health record (EHR) dataset from patients treated with LAI antipsychotics.

EHR data were obtained from 1281 patients in the South London and Maudsley NHS Foundation Trust (SLaM) who started treatment with a LAI antipsychotic between 1 April 2011 and 31 January 2015. The number of days spent as a psychiatric inpatient and the number of admissions to a psychiatric hospital were analyzed in each of the 3 years before and after LAI prescription.

Patients treated with paliperidone palmitate (n = 430; 33.6%) had a greater number of inpatient days and a greater number of admissions in the year prior to treatment than those treated with other LAI antipsychotics. Nevertheless, in the 3 years after initiation there were no significant differences between paliperidone and the other LAI antipsychotics in the number of days as an inpatient (B coefficient 5.4 days, 95% confidence interval (CI) −57.3 to 68.2, p = 0.86) or number of hospital admissions (Incidence rate ratio 1.07, 95% CI 0.62 to 1.83, p = 0.82).

Paliperidone palmitate was more likely to be prescribed in patients with more frequent and lengthy hospital admissions prior to initiation. However, the absence of differences in outcomes after initiation indicates that paliperidone palmitate was not more effective than other cheaper LAI antipsychotics.

Cross-sectional and longitudinal studies have shown a positive association between attention deficit hyperactivity disorder (ADHD) and problematic alcohol use in adults. To what extent this association is explained by genetic and environmental factors is largely unknown.

Data on ADHD and alcohol consumption were collected by self-report in 6024 adult Dutch twins. ADHD symptoms were assessed by three subscales of the Conners' Adult ADHD Rating Scales – Self-Report: Screening Version (CAARS–S:SV): inattentiveness, hyperactivity and the ADHD index (ADHD-I). Problem drinking was defined as at least two self-reported alcohol-related problems on the CAGE questionnaire. Structural equation modelling was applied to the bivariate twin data to estimate genetic and environmental influences.

Heritability of ADHD symptoms ranged between 32% and 40% and heritability of problem drinking was 50%. The positive correlation between ADHD symptoms and problem drinking was confirmed in this general population sample, with phenotypic correlations between 0.20 and 0.28 and genetic correlations between 0.39 and 0.50. Phenotypic correlations are primarily (61–100%) explained by genetic influences with non-shared environmental influences explaining the remaining covariance. No significant quantitative or qualitative gender differences in covariance structure were found.

This study convincingly shows that ADHD symptoms and problem drinking are moderately but significantly correlated in adults and that genetic correlations are primarily underlying this association. This suggests that early interventions are required to prevent adolescents with ADHD from developing problematic levels of alcohol use. Furthermore, clinicians who treat alcohol-dependent patients should be aware that the patient may have a co-morbid condition of ADHD; integrated interventions are required.

Bipolar disorder type I (BD-I) is associated with emotion dysregulation. However, experimentally controlled studies of emotion regulation (ER), particularly those examining the brain correlates of the putative deficits, are scarce and their results inconsistent.

Nineteen euthymic BD-I patients and 17 healthy controls (HC) underwent functional magnetic resonance imaging while performing a visual ER 2 × 2 factorial task, with instruction (Look or Decrease) and valence (Negative or Neutral) as within-subject factors. Emotional ratings were collected after each picture presentation to assess regulation success.

BD-I patients were successful at downregulating their emotions, although to a lesser degree than HC. Both groups engaged brain regions previously implicated in ER; however, unlike HC, patients engaged some of those regions, particularly the ventrolateral prefrontal cortex (VLPFC) in the Negative Look and Neutral Decrease conditions. Moreover, patients failed to show the reduced amygdala activation in the Negative Decrease condition observed in HC.

Our findings suggest that BD-I patients are able to downregulate their emotions when instructed to do so. However, they also appear to engage their ER network, particularly the VLPFC, even when not required to do so. These findings may help explain their often-reported difficulty in regulating emotions in everyday life despite their attempts to do so.

Although psychiatric diagnostic systems have conceptualized mania as a discrete phenomenon, appropriate latent structure investigations testing this conceptualization are lacking. In contrast to these diagnostic systems, several influential theories of mania have suggested a continuous conceptualization. The present study examined whether mania has a continuous or discrete latent structure using a comprehensive approach including taxometric, information-theoretic latent distribution modeling (ITLDM) and predictive validity methodologies in the Epidemiologic Catchment Area (ECA) study.

Eight dichotomous manic symptom items were submitted to a variety of latent structural analyses, including factor analyses, taxometric procedures and ITLDM, in 10105 ECA community participants. In addition, a variety of continuous and discrete models of mania were compared in terms of their relative abilities to predict outcomes (i.e. health service utilization, internalizing and externalizing disorders, and suicidal behavior).

Taxometric and ITLDM analyses consistently supported a continuous conceptualization of mania. In ITLDM analyses, a continuous model of mania demonstrated 6.52:1 odds over the best-fitting latent class model (LCM) of mania. Factor analyses suggested that the continuous structure of mania was best represented by a single latent factor. Predictive validity analyses demonstrated a consistent superior ability of continuous models of mania relative to discrete models.

The present study provided three independent lines of support for a continuous conceptualization of mania. The implications of a continuous model of mania are discussed.