The longstanding association between the major histocompatibility complex (MHC) locus and schizophrenia (SZ) risk has recently been accounted for, partially, by structural variation at the complement component 4 (C4) gene. This structural variation generates varying levels of C4 RNA expression, and genetic information from the MHC region can now be used to predict C4 RNA expression in the brain. Increased predicted C4A RNA expression is associated with the risk of SZ, and C4 is reported to influence synaptic pruning in animal models.

Based on our previous studies associating MHC SZ risk variants with poorer memory performance, we tested whether increased predicted C4A RNA expression was associated with reduced memory function in a large (n = 1238) dataset of psychosis cases and healthy participants, and with altered task-dependent cortical activation in a subset of these samples.

We observed that increased predicted C4A RNA expression predicted poorer performance on measures of memory recall (p = 0.016, corrected). Furthermore, in healthy participants, we found that increased predicted C4A RNA expression was associated with a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing (p < 0.05, corrected).

These data suggest that the effects of C4 on cognition were observable at both a cortical and behavioural level, and may represent one mechanism by which illness risk is mediated. As such, deficits in learning and memory may represent a therapeutic target for new molecular developments aimed at altering C4’s developmental role.

Cognitive behavioral therapy (CBT) can be delivered efficaciously through various modalities, including telephone (T-CBT) and face-to-face (FtF-CBT). The purpose of this study was to explore predictors of outcome in T-CBT and FtF-CBT for depression.

A total of 325 depressed participants were randomized to receive eighteen 45-min sessions of T-CBT or FtF-CBT. Depression severity was measured using the Hamilton Depression Rating Scale (HAMD) and the Patient Health Questionnaire-9 (PHQ-9). Classification and regression tree (CART) analyses were conducted with baseline participant demographics and psychological characteristics predicting depression outcomes, HAMD and PHQ-9, at end of treatment (week 18).

The demographic and psychological characteristics accurately identified 85.3% and 85.0% of treatment responders and 85.7% and 85.0% of treatment non-responders on the HAMD and PHQ-9, respectively. The Coping self-efficacy (CSE) scale predicted outcome on both the HAMD and PHQ-9; those with moderate to high CSE were likely to respond with no other variable influencing that prediction. Among those with low CSE, depression severity influenced response. Social support, physical functioning, and employment emerged as predictors only for the HAMD, and sex predicted response on the PHQ-9. Treatment delivery method (i.e. telephone or face-to-face) did not impact the prediction of outcome.

Findings suggest that the predictors of improved depression are similar across treatment modalities. Most importantly, a moderate to high level of CSE significantly increases the chance of responding in both T-CBT and FtF-CBT. Among patients with low CSE, those with lower depressive symptom severity are more likely to do well in treatment.

The selection hypothesis posits that the increased rates of psychosis observed among migrants are due to selective migration of people who are predisposed to develop the disorder. To test this hypothesis, we examined whether risk factors for psychosis are more prevalent among future emigrants.

A cohort of 49 321 Swedish military conscripts was assessed at age 18 years on cannabis use, IQ, psychiatric diagnosis, social adjustment, history of trauma and urbanicity of place of upbringing. Through data linkage we examined whether these exposures predicted emigration out of Sweden. We also calculated the emigrants' hypothetical relative risk compared with non-emigrants for developing a non-affective psychotic disorder.

Low IQ [odds ratio (OR) 0.5, 95% confidence interval (95% CI) 0.3–0.9] and ‘poor social adjustment’ (OR 0.4, 95% CI 0.2–0.8) were significantly less prevalent among prospective emigrants, whereas a history of urban upbringing (OR 2.3, 95% CI 1.4–3.7) was significantly more common. Apart from a non-significant increase in cannabis use among emigrants (OR 1.6, 95% CI 0.8–3.1), there were no major group differences in any other risk factors. Compared to non-emigrants, hypothetical relative risks for developing non-affective psychotic disorder were 0.7 (95% CI 0.4–1.2) and 0.8 (95% CI 0.7–1.0), respectively, for emigrants narrowly and broadly defined.

This study adds to an increasing body of evidence opposing the selection hypothesis.

Prior research has indicated that affiliation with delinquent peers activates genetic influences on delinquency during adolescence. However, because other studies have indicated that the socializing effects of delinquent peers vary dramatically across childhood and adolescence, it is unclear whether delinquent peer affiliation (DPA) also moderates genetic influences on delinquency during childhood.

The current study sought to evaluate whether and how DPA moderated the etiology of delinquency in a sample of 726 child twins from the Michigan State University Twin Registry (MSUTR).

The results robustly supported etiological moderation of childhood delinquency by DPA. However, this effect was observed for shared environmental, rather than genetic, influences. Shared environmental influences on delinquency were found to be several-fold larger in those with higher levels of DPA as compared to those with lower levels. This pattern of results persisted even when controlling for the overlap between delinquency and DPA.

Our findings bolster prior work in suggesting that, during childhood, the association between DPA and delinquency is largely (although not solely) attributable to the effects of socialization as compared to selection. They also suggest that the process of etiological moderation is not specific to genetic influences. Latent environmental influences are also amenable to moderation by measured environmental factors.

Etiological research of depression and anxiety disorders has been hampered by diagnostic heterogeneity. In order to address this, researchers have tried to identify more homogeneous patient subgroups. This work has predominantly focused on explaining interpersonal heterogeneity based on clinical features (i.e. symptom profiles). However, to explain interpersonal variations in underlying pathophysiological mechanisms, it might be more effective to take biological heterogeneity as the point of departure when trying to identify subgroups. Therefore, this study aimed to identify data-driven subgroups of patients based on biomarker profiles.

Data of patients with a current depressive and/or anxiety disorder came from the Netherlands Study of Depression and Anxiety, a large, multi-site naturalistic cohort study (n = 1460). Thirty-six biomarkers (e.g. leptin, brain-derived neurotrophic factor, tryptophan) were measured, as well as sociodemographic and clinical characteristics. Latent class analysis of the discretized (lower 10%, middle, upper 10%) biomarkers were used to identify different patient clusters.

The analyses resulted in three classes, which were primarily characterized by different levels of metabolic health: ‘lean’ (21.6%), ‘average’ (62.2%) and ‘overweight’ (16.2%). Inspection of the classes’ clinical features showed the highest levels of psychopathology, severity and medication use in the overweight class.

The identified classes were strongly tied to general (metabolic) health, and did not reflect any natural cutoffs along the lines of the traditional diagnostic classifications. Our analyses suggested that especially poor metabolic health could be seen as a distal marker for depression and anxiety, suggesting a relationship between the ‘overweight’ subtype and internalizing psychopathology.

Numerous studies of resting-state functional imaging and voxel-based morphometry (VBM) have revealed differences in specific brain regions of patients with bipolar disorder (BD), but the results have been inconsistent.

A whole-brain voxel-wise meta-analysis was conducted on resting-state functional imaging and VBM studies that compared differences between patients with BD and healthy controls using Seed-based d Mapping with Permutation of Subject Images software.

A systematic literature search identified 51 functional imaging studies (1842 BD and 2190 controls) and 83 VBM studies (2790 BD and 3690 controls). Overall, patients with BD displayed increased resting-state functional activity in the left middle frontal gyrus, right inferior frontal gyrus (IFG) extending to the right insula, right superior frontal gyrus and bilateral striatum, as well as decreased resting-state functional activity in the left middle temporal gyrus extending to the left superior temporal gyrus and post-central gyrus, left cerebellum, and bilateral precuneus. The meta-analysis of VBM showed that patients with BD displayed decreased VBM in the right IFG extending to the right insula, temporal pole and superior temporal gyrus, left superior temporal gyrus extending to the left insula, temporal pole, and IFG, anterior cingulate cortex, left superior frontal gyrus (medial prefrontal cortex), left thalamus, and right fusiform gyrus.

The multimodal meta-analyses suggested that BD showed similar patterns of aberrant brain activity and structure in the insula extending to the temporal cortex, fronto-striatal-thalamic, and default-mode network regions, which provide useful insights for understanding the underlying pathophysiology of BD.

The course of illness in obsessive–compulsive disorder (OCD) varies significantly between patients. Little is known about factors predicting a chronic course of illness. The aim of this study is to identify factors involved in inducing and in maintaining chronicity in OCD.

The present study is embedded within the Netherlands Obsessive Compulsive Disorder Association (NOCDA) study, an ongoing multicenter naturalistic cohort study designed to identify predictors of long-term course and outcome in OCD. For this study, 270 subjects with a current diagnosis of OCD were included. Chronicity status at 2-year follow-up was regressed on a selection of baseline predictors related to OCD, to comorbidity and to stress and support.

Psychotrauma [odds ratio (OR) 1.98, confidence interval (CI) 1.22–3.22, p = 0.006], recent negative life events (OR 1.42, CI 1.01–2.01, p = 0.043), and presence of a partner (OR 0.28, CI 0.09–0.85, p = 0.025) influenced the risk of becoming chronic. Longer illness duration (OR 1.46, CI 1.08–1.96, p = 0.013) and higher illness severity (OR 1.09, CI 1.03–1.16, p = 0.003) increased the risk of remaining chronic.

External influences increase the risk of becoming chronic, whereas the factors involved in maintaining chronicity are illness-related. As the latter are potentially difficult to modify, treatment should be devoted to prevent chronicity from occurring in the first place. Therapeutic strategies aimed at alleviating stress and at boosting social support might aid in achieving this goal.

Studies investigating the underlying mechanisms of hallucinations in patients with schizophrenia suggest that an imbalance in top-down expectations v. bottom-up processing underlies these errors in perception. This study evaluates this hypothesis by testing if individuals drawn from the general population who have had auditory hallucinations (AH) have more misperceptions in auditory language perception than those who have never hallucinated.

We used an online survey to determine the presence of hallucinations. Participants filled out the Questionnaire for Psychotic Experiences and participated in an auditory verbal recognition task to assess both correct perceptions (hits) and misperceptions (false alarms). A hearing test was performed to screen for hearing problems.

A total of 5115 individuals from the general Dutch population participated in this study. Participants who reported AH in the week preceding the test had a higher false alarm rate in their auditory perception compared with those without such (recent) experiences. The more recent the AH were experienced, the more mistakes participants made. While the presence of verbal AH (AVH) was predictive for false alarm rate in auditory language perception, the presence of non-verbal or visual hallucinations were not.

The presence of AVH predicted false alarm rate in auditory language perception, whereas the presence of non-verbal auditory or visual hallucinations was not, suggesting that enhanced top-down processing does not transfer across modalities. More false alarms were observed in participants who reported more recent AVHs. This is in line with models of enhanced influence of top-down expectations in persons who hallucinate.

Post-traumatic stress disorder (PTSD) is often associated with attention allocation and emotional regulation difficulties, but the brain dynamics underlying these deficits are unknown. The emotional Stroop task (EST) is an ideal means to monitor these difficulties, because participants are asked to attend to non-emotional aspects of the stimuli. In this study, we used magnetoencephalography (MEG) and the EST to monitor attention allocation and emotional regulation during the processing of emotionally charged stimuli in combat veterans with and without PTSD.

A total of 31 veterans with PTSD and 20 without PTSD performed the EST during MEG. Three categories of stimuli were used, including combat-related, generally threatening and neutral words. MEG data were imaged in the time-frequency domain and the network dynamics were probed for differences in processing threatening and non-threatening words.

Behaviorally, veterans with PTSD were significantly slower in responding to combat-related relative to neutral and generally threatening words. Veterans without PTSD exhibited no significant differences in responding to the three different word types. Neurophysiologically, we found a significant three-way interaction between group, word type and time period across multiple brain regions. Follow-up testing indicated stronger theta-frequency (4–8 Hz) responses in the right ventral prefrontal (0.4–0.8 s) and superior temporal cortices (0.6–0.8 s) of veterans without PTSD compared with those with PTSD during the processing of combat-related words.

Our data indicated that veterans with PTSD exhibited deficits in attention allocation and emotional regulation when processing trauma cues, while those without PTSD were able to regulate emotion by directing attention away from threat.

The significant proportion of schizophrenia patients refractory to treatment, primarily directed at the dopamine system, suggests that multiple mechanisms may underlie psychotic symptoms. Reinforcement learning tasks have been employed in schizophrenia to assess dopaminergic functioning and reward processing, but these have not directly compared groups of treatment-refractory and non-refractory patients.

In the current functional magnetic resonance imaging study, 21 patients with treatment-resistant schizophrenia (TRS), 21 patients with non-treatment-resistant schizophrenia (NTR), and 24 healthy controls (HC) performed a probabilistic reinforcement learning task, utilizing emotionally valenced face stimuli which elicit a social bias toward happy faces. Behavior was characterized with a reinforcement learning model. Trial-wise reward prediction error (RPE)-related neural activation and the differential impact of emotional bias on these reward signals were compared between groups.

Patients showed impaired reinforcement learning relative to controls, while all groups demonstrated an emotional bias favoring happy faces. The pattern of RPE signaling was similar in the HC and TRS groups, whereas NTR patients showed significant attenuation of RPE-related activation in striatal, thalamic, precentral, parietal, and cerebellar regions. TRS patients, but not NTR patients, showed a positive relationship between emotional bias and RPE signal during negative feedback in bilateral thalamus and caudate.

TRS can be dissociated from NTR on the basis of a different neural mechanism underlying reinforcement learning. The data support the hypothesis that a favorable response to antipsychotic treatment is contingent on dopaminergic dysfunction, characterized by aberrant RPE signaling, whereas treatment resistance may be characterized by an abnormality of a non-dopaminergic mechanism – a glutamatergic mechanism would be a possible candidate.

Mood plays an important role in our life which is illustrated by the disruptive impact of aberrant mood states in depression. Although vagus nerve stimulation (VNS) has been shown to improve symptoms of depression, the exact mechanism is still elusive, and it is an open question whether non-invasive VNS could be used to swiftly and robustly improve mood.

Here, we investigated the effect of left- and right-sided transcutaneous auricular VNS (taVNS) v. a sham control condition on mood after the exertion of physical and cognitive effort in 82 healthy participants (randomized cross-over design) using linear mixed-effects and hierarchical Bayesian analyses of mood ratings.

We found that 90 min of either left-sided or right-sided taVNS improved positive mood [b = 5.11, 95% credible interval, CI (1.39–9.01), 9.6% improvement relative to the mood intercept, BF10 = 7.69, pLME = 0.017], yet only during the post-stimulation phase. Moreover, lower baseline scores of positive mood were associated with greater taVNS-induced improvements in motivation [r = −0.42, 95% CI (−0.58 to −0.21), BF10 = 249].

We conclude that taVNS boosts mood after a prolonged period of effort exertion with concurrent stimulation and that acute motivational effects of taVNS are partly dependent on initial mood states. Collectively, our results show that taVNS may help quickly improve affect after a mood challenge, potentially by modulating interoceptive signals contributing to the reappraisal of effortful behavior. This suggests that taVNS could be a useful add-on to current behavioral therapies.

Patients with bipolar disorder (BD) experience persistent impairments in both affective and non-affective cognitive function, which is associated with a worse course of illness and poor functional outcomes. Nevertheless, the temporal progression of cognitive dysfunction in BD remains unclear and the identification of objective endophenotypes can inform the aetiology of BD.

The present study is a cross-sectional investigation of cognitive baseline data from the longitudinal Bipolar Illness Onset-study. One hundred seventy-two remitted patients newly diagnosed with BD, 52 of their unaffected relatives (UR), and 110 healthy controls (HC) were compared on a large battery of behavioural cognitive tasks tapping into non-affective (i.e. neurocognitive) and affective (i.e. emotion processing and regulation) cognition.

Relative to HCs, patients with BD exhibited global neurocognitive deficits (ps < 0.001), as well as aberrant emotion processing and regulation (ps ⩽ 0.011); including decreased emotional reactivity to positive social scenarios, impaired ability to down-regulate positive emotion, as well as a specific deficit in the ability to recognise surprised facial expressions. Their URs also showed a trend towards difficulties identifying surprised faces (p = 0.075). No other differences in cognitive function were found for URs compared to HCs.

Neurocognitive deficits and impairments within emotion processing and regulation may be illness-related deficits of BD that present after illness-onset, whereas processing of emotional faces may represent an early risk marker of BD. However, longitudinal studies are needed to examine the association between cognitive impairments and illness progression in BD.

The cognitive process of worry, which keeps negative thoughts in mind and elaborates the content, contributes to the occurrence of many mental health disorders. Our principal aim was to develop a straightforward measure of general problematic worry suitable for research and clinical treatment. Our secondary aim was to develop a measure of problematic worry specifically concerning paranoid fears.

An item pool concerning worry in the past month was evaluated in 250 non-clinical individuals and 50 patients with psychosis in a worry treatment trial. Exploratory factor analysis and item response theory (IRT) informed the selection of scale items. IRT analyses were repeated with the scales administered to 273 non-clinical individuals, 79 patients with psychosis and 93 patients with social anxiety disorder. Other clinical measures were administered to assess concurrent validity. Test-retest reliability was assessed with 75 participants. Sensitivity to change was assessed with 43 patients with psychosis.

A 10-item general worry scale (Dunn Worry Questionnaire; DWQ) and a five-item paranoia worry scale (Paranoia Worries Questionnaire; PWQ) were developed. All items were highly discriminative (DWQ a = 1.98–5.03; PWQ a = 4.10–10.7), indicating small increases in latent worry lead to a high probability of item endorsement. The DWQ was highly informative across a wide range of the worry distribution, whilst the PWQ had greatest precision at clinical levels of paranoia worry. The scales demonstrated excellent internal reliability, test-retest reliability, concurrent validity and sensitivity to change.

The new measures of general problematic worry and worry about paranoid fears have excellent psychometric properties.