Structural brain abnormalities have consistently been found in schizophrenia, with increased familial risk for the disease associated with these abnormalities. Some brain volume changes are progressive over the course of the illness.

To investigate whether these progressive brain volume changes are mediated by genetic or disease-related factors.

We carried out a 5-year follow-up study in monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia (DISC) and healthy comparison (HC) twin pairs using brain magnetic resonance imaging. A total of 92 participants completed the study (DISC: 9 MZ and 10 DZ; HC: 14 MZ and 13 DZ). Percentage volume changes of the whole brain and cerebral gray and white matter were estimated. Structural equation modeling was applied to estimate contributions of additive genetic and common and unique environmental factors.

Significant decreases over time in whole brain volume was found in patients with schizophrenia and their unaffected co-twins compared with control twins. Bivariate structural equation modeling using cross-trait/cross-twin correlations revealed significant additive genetic influences on the correlations between schizophrenia liability and progressive whole brain (66%; 95% confidence interval [CI], 51%-100%), frontal lobe (76%; 95% CI, 54%-100%), and temporal lobe (79%; CI, 56%-100%) volume change.

The progressive brain volume loss found in patients with schizophrenia and their unaffected co-twins is at least partly attributable to genetic factors related to the illness.

Progressive gray matter volume reductions have been found in schizophrenia and greater changes seem to be related to poorer outcome1,2. As patients with schizophrenia who use cannabis have a worse prognosis 3, the progressive gray matter change in these patients might be even greater.

Fifty-one patients with recent-onset schizophrenia (cannabis users n=19; non-users n=32) and thirty-one matched healthy comparison subjects were included in this five year longitudinal MRI study. All subjects were assessed at inclusion and after five years. Total brain, gray and white matter, cerebellar, lateral and third ventricle volumes were measured. Percentages of volume change over time were calculated. Univariate analysis of covariance and pairwise comparisons were performed.

Cannabis using patients, non-using patients and healthy comparison subjects differed significantly in total brain, gray matter, lateral and third ventricles and cerebellum volumes. No change in white matter was observed between the groups.

Cannabis using patients with schizophrenia showed a more rapid decrease in total brain and cerebellar volume and increase in lateral and third ventricle volumes as compared to healthy subject and non-using patients. Gray matter volume decrease occurred in all patients with schizophrenia as compared to healthy subjects, but was significantly greater in patients using cannabis.

In schizophrenia progressive gray matter volume decrease occurs during the first five years of illness. Cannabis use causes an additional decrease of gray matter in patients with schizophrenia and could be explained by either a worse illness outcome or the effects of cannabis.

Modafinil was tested for efficacy in facilitating abstinence in cocaine-dependent patients, compared to placebo.

This is a double-blind placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. 210 treatment-seekers with DSM-IV diagnosis of cocaine dependence consented and enrolled. 72 participants were randomized to placebo, 69 to modafinil 200mg, and 69 to modafinil 400mg, taken once daily on awakening. Participants attended the clinic three times per week for assessments and urine drug screens, and had one hour of individual psychotherapy once per week. The primary outcome was the increase in weekly percentage of non-use days. Secondary outcomes included: decrease in the weekly median log of urine benzoylecgonine, subgroup analyses of balancing factors and co-morbid conditions, self-report of alcohol use, addiction severity, craving, and risk behaviors for HIV.

125 participants completed 12 weeks of treatment (60%). The GEE regression analysis showed that for the total sample, the difference between modafinil groups and placebo in the weekly percentage of cocaine non-use days over the 12-week treatment period was not statistically significant (p=0.95). A post-hoc analysis showed a significant effect for modafinil, only in the subgroup of cocaine patients without alcohol dependence. Modafinil 200mg also showed significant effects of an increase in the total number of consecutive non-use days for cocaine (p=0.02), and a reduction in craving (p=0.04).

These data suggest that modafinil, in combination with individual behavioral therapy, was effective for increasing cocaine non-use days in participants without co-morbid alcohol dependence, and in reducing craving.

Peer relationships play a critical role in the development of adolescents, not only for the acquisition of social skills but also for the sense of personal identity and competence. Thus the quality of peer relationships influences actual and future mental health of the adolescent.

SEYLE (Saving and Empowering Young Lives in Europe) is a randomized controlled trial, funded by the EU, evaluating interventions for mental health promotion and suicide prevention. The study comprised 12,395 high-school students from 11 European countries.

We investigated the differences on psychological problems between students with poor and good peer relationships.

1,195 adolescents (mean age 15.3 ± 0.6; 68% females) from the Molise region constituted the Italian sample. Adolescents were identified as with poor peer relationships if they never or just sometimes get along with people of their age, feel that peers like having them in the group and feel that peers were kind and helpful. Psychometric measures were used to assess mental health problems such as depression (Beck Depression Inventory II), anxiety (Zung Self-Assessment Anxiety Scale), well-being (WHO-5) and suicidal ideation (Paykel Suicide Scale).

Adolescents who reported poor peer relationships scored significantly higher (p < .005) on the scales assessing depression, anxiety and suicidal ideation and significantly lower (p < .001) on the WHO-5.

Particularly in adolescence peer relationships may influence psychological well-being and vice versa mental health influences the openness to the others. So promoting mental health and contemporary improve social skills could lead adolescents to a better life.

Most studies aiming to predict transition to psychosis for individuals at ultra-high risk (UHR) have focused on either neurocognitive or clinical variables and have made little effort to combine the two. We aimed to investigate the relative value of neurocognitive and clinical variables for predicting transition to psychosis as well as long-term functional outcome.

Sixty-seven adolescents at UHR and 72 controls completed an extensive clinical and neurocognitive assessment. Forty-three UHR individuals and 47 controls participated in long-term follow-up approximately six years later. UHR adolescents who had converted to psychosis (UHR-P) were compared to individuals who had not (UHR-NP) and controls on clinical and neurocognitive variables. Regression analyses were performed to determine which baseline measures best predicted transition to psychosis and long-term functional outcome for UHR individuals.

Low IQ was the single neurocognitive parameter that discriminated UHR-P individuals from UHR-NP individuals and controls. The severity of attenuated positive symptoms was the only significant predictor of a transition to psychosis and disorganized symptoms were highly predictive of functional outcome.

IQ was lowest for those individuals at ultra high risk for psychosis who later went on to have a psychotic episode. However, IQ was not a good predictor of either transition or functional outcome. Rather, clinical measures proved to be the most important vulnerability markers for long-term outcome.

Altered cancer mortality among psychiatric patients has been reported, but competing death causes were often ignored.

To investigate whether observed cancer mortality in patients with various psychiatric disorders might be biased by competing death causes.

To assess the importance of cancer as death cause and as cause of physical comorbidity among patients with a mental illness.

In this retrospective cohort study on data from the Psychiatric Case Register Middle Netherlands linked to the death register of Statistics Netherlands, the risk of cancer death among patients with schizophrenia (N = 4,590), bipolar disorder (N = 2,077) and depression (N = 15,130) and their matched controls (N = 87,405) was analyzed using a competing risk model.

Compared to controls from the general population, higher hazards of cancer death were found in patients (schizophrenia: HR = 1.61, 95%CI: 1.26−2.06; bipolar disorder: HR = 1.20, 95%CI: 0.81−1.79), depression: HR = 1.26, 95%CI: 1.10− 1.44). However, the HRs of death due to suicide and other death causes were more increased. Therefore, among those who died, the 12-years-cumulative risk of cancer death was significantly lower among the three patient groups.

Our analysis shows that, compared to the general population, patients with a mental illness are at higher risk of dying from cancer, given that they survive the much more increased risks of suicide and other death causes.

Multimorbidity may impose an overwhelming burden on patients with psychosis and is affected by gender and age. Our aim is to study the independent role of familial liability to psychosis as a risk factor for multimorbidity.

We performed the study within the framework of the Genetic Risk and Outcome of Psychosis (GROUP) project. Overall, we compared 1024 psychotic patients, 994 unaffected siblings and 566 controls on the prevalence of 125 lifetime diseases, and 19 self-reported somatic complaints. Multimorbidity was defined as the presence of two or more complaints/diseases in the same individual. Generalized linear mixed model (GLMM) were used to investigate the effects of gender, age (adolescent, young, older) and familial liability (patients, siblings, controls) and their interactions on multimorbidity.

Familial liability had a significant effect on multimorbidity of either complaints or diseases. Patients had a higher prevalence of multimorbidity of complaints compared to siblings (OR 2.20, 95% CI 1.79–2.69, P < 0.001) and to controls (3.05, 2.35–3.96, P < 0.001). In physical health multimorbidity, patients (OR 1.36, 95% CI 1.05–1.75, P = 0.018), but not siblings, had significantly higher prevalence than controls. Similar finding were observed for multimorbidity of lifetime diseases, including psychiatric diseases. Significant results were observed for complaints and disease multimorbidity across gender and age groups.

Multimorbidity is a common burden, significantly more prevalent in patients and their unaffected siblings. Familial liability to psychosis showed an independent effect on multimorbidity; gender and age are also important factors determining multimorbidity.

An adaptive neural stress response is essential to adequately cope with a changing environment. It was previously argued that sympathetic/noradrenergic activity during acute stress increases salience network (SN) connectivity and reduces executive control network (ECN) connectivity in healthy controls, with opposing effects in the late aftermath of stress. Altered temporal dynamics of these networks in response to stress are thought to play a role in the development of psychopathology in vulnerable individuals.

We exposed male healthy controls (n = 40, mean age = 33.9) and unaffected siblings of schizophrenia patients (n = 39, mean age = 33.2) to the stress or control condition of the trier social stress test and subsequently investigated resting state functional connectivity of the SN and ECN directly after and 1.5 h after stress.

Acute stress resulted in increased functional connectivity within the SN in healthy controls, but not in siblings (group × stress interaction pfwe < 0.05). In the late aftermath of stress, stress reduced functional connectivity within the SN in both groups. Moreover, we found increased functional connectivity between the ECN and the cerebellum in the aftermath of stress in both healthy controls and siblings of schizophrenia patients.

The results show profound differences between siblings of schizophrenia patients and controls during acute stress. Siblings lacked the upregulation of neural resources necessary to quickly and adequately cope with a stressor. This points to a reduced dynamic range in the sympathetic response, and may constitute a vulnerability factor for the development of psychopathology in this at-risk group.

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.

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 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.

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.

In a large and comprehensively assessed sample of patients with bipolar disorder type I (BDI), we investigated the prevalence of psychotic features and their relationship with life course, demographic, clinical, and cognitive characteristics. We hypothesized that groups of psychotic symptoms (Schneiderian, mood incongruent, thought disorder, delusions, and hallucinations) have distinct relations to risk factors.

In a cross-sectional study of 1342 BDI patients, comprehensive demographical and clinical characteristics were assessed using the Structured Clinical Interview for DSM-IV (SCID-I) interview. In addition, levels of childhood maltreatment and intelligence quotient (IQ) were assessed. The relationships between these characteristics and psychotic symptoms were analyzed using multiple general linear models.

A lifetime history of psychotic symptoms was present in 73.8% of BDI patients and included delusions in 68.9% of patients and hallucinations in 42.6%. Patients with psychotic symptoms showed a significant younger age of disease onset (β = −0.09, t = −3.38, p = 0.001) and a higher number of hospitalizations for manic episodes (F11 338 = 56.53, p < 0.001). Total IQ was comparable between groups. Patients with hallucinations had significant higher levels of childhood maltreatment (β = 0.09, t = 3.04, p = 0.002).

In this large cohort of BDI patients, the vast majority of patients had experienced psychotic symptoms. Psychotic symptoms in BDI were associated with an earlier disease onset and more frequent hospitalizations particularly for manic episodes. The study emphasizes the strength of the relation between childhood maltreatment and hallucinations but did not identify distinct subgroups based on psychotic features and instead reported of a large heterogeneity of psychotic symptoms in BD.

There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.

To investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls.

Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls.

Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest.

Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.

R.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.

A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related.

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.

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 < 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (all 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.

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.

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.

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).

Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (β 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.

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.

Poor educational achievement is associated with a range of psychiatric disorders. Several studies suggest that this underperformance is due to cognitive deficits that commence before disease onset and reflect a genetic risk for this disorder. However, the specificity and the familial contribution of this cognitive deficit are not clear. We analysed lifetime educational achievement of psychiatric patients diagnosed with schizophrenia, bipolar or depressive disorder and their unaffected siblings.

In a register-based case-control study, 1561 patients with schizophrenia, 813 patients with bipolar disorder, 8112 patients with depression, and their siblings were each matched with eight population controls. Patients, siblings and controls were compared on the highest educational stream they completed.

Lower educational achievement was present in schizophrenia patients from primary school onwards [completing primary school: odds ratio (OR) 0.69; completing secondary school: OR 0.69; completing academic education: OR 0.46], compared to patients with bipolar disorder or depression. Siblings of schizophrenia, bipolar or depressed patients showed no underachievement at primary or secondary school, but siblings of schizophrenia patients as well as siblings of depressed patients were less successful in their educational achievement after secondary school (completing academic education, schizophrenia siblings: OR 0.90; depressive disorder siblings: OR 0.91).

Educational underachievement from primary school onwards is specifically related to schizophrenia and not to bipolar disorder or depression. Moreover, it appears to be a harbinger of the illness, since it is not found in their siblings. These results add to evidence that early cognitive deficits are a distinct feature of the schizophrenia phenotype.