NPJ Schizophrenia最新文献

Schizophrenia is a neurodevelopmental disorder likely caused by environmental and genetic risk factors but functional interactions between the risk factors are unclear. We tested the hypothesis that dysbindin-1 (Dtnbp1) gene mutation combined with postnatal exposure to viral mimetic polyI:C results in schizophrenia-related behavioural changes in adulthood, and mediates polyI:C-induced inflammation in the subventricular zone (SVZ). Adult Sandy (Sdy, Dtnbp1 mutant) mice given early postnatal polyI:C injections displayed reduced prepulse inhibition of startle, reduced locomotion and deficits in novel object recognition. PolyI:C induced a canonical immune response in the SVZ; it increased mRNA expression of its toll-like receptor 3 (Tlr3) and downstream transcription factors RelA and Sp1. PolyI:C also increased SVZ Dtnbp1 mRNA expression, suggesting dysbindin-1 regulates immune responses. Dysbindin-1 loss in Sdy mice blocked the polyI:C-induced increases in mRNA expression of Tlr3, RelA and Sp1 in the SVZ. Dtnbp1 overexpression in SVZ-derived Sdy neurospheres rescued Tlr3, RelA and Sp1 mRNA expression supporting a functional interaction between dysbindin-1 and polyI:C-induced inflammation. Immunohistochemistry showed higher Iba1+ immune cell density in the SVZ of Sdy mice than in WT postnatally. PolyI:C did not alter SVZ Iba1+ cell density but increased CD45+/Iba1- cell numbers in the SVZ of Sdy mice. Finally, polyI:C injections in Sdy, but not WT mice reduced postnatal and adult SVZ proliferation. Together, we show novel functional interactions between the schizophrenia-relevant dysbindin-1 gene and the immune response to polyI:C. This work sheds light on the molecular basis for amplified abnormalities due to combined genetic predisposition and exposure to environmental schizophrenia risk factors.

People with schizophrenia are at considerably higher risk of cardiometabolic morbidity than the general population. Second-generation antipsychotic drugs contribute to that risk partly through their weight gain effects, exacerbating an already high burden of disease. While standard 'as-randomized' analyses of clinical trials provide valuable information, they ignore adherence patterns across treatment arms, confounding estimates of realized treatment exposure on outcome. We assess the effect of specific second-generation antipsychotics on weight gain, defined as at least a 7% increase in weight from randomization, using a Bayesian hierarchical model network meta-analysis with individual patient level data. Our data consisted of 14 randomized clinical trials contributing 5923 subjects (mean age = 39 [SD = 12]) assessing various combinations of olanzapine (n = 533), paliperidone (n = 3482), risperidone (n = 540), and placebo (n = 1368). The median time from randomization to dropout or trial completion was 6 weeks (range: 0-60 weeks). The unadjusted probability of weight gain in the placebo group was 4.8% across trials. For each 10 g chlorpromazine equivalent dose increase in olanzapine, the odds of weight gain increased by 5 (95% credible interval: 1.4, 5.3); the effect of risperidone (odds ratio = 1.6 [0.25, 9.1]) was estimated with considerable uncertainty but no different from paliperidone (odds ratio = 1.3 [1.2, 1.5]).

Clinical trial data are the gold standard for evaluating pharmaceutical safety and efficacy. There is an ethical and scientific imperative for transparency and data sharing to confirm published results and generate new knowledge. The Open Translational Science in Schizophrenia (OPTICS) Project was an open-science initiative aggregating Janssen clinical trial and NIH/NIMH data from real-world studies and trials in schizophrenia. The project aims were to show the value of using shared data to examine: therapeutic safety and efficacy; disease etiologies and course; and methods development. The success of project investigators was due to collaboration from project applications through analyses, with support from the Harvard Catalyst. Project work was independent of Janssen; all intellectual property was dedicated to the public. Efforts such as this are necessary to gain deeper insights into the biology of disease, foster collaboration, and to achieve the goal of developing better treatments, reducing the overall public health burden of devastating brain diseases.

To date, no study has evaluated the joint role of symptoms and adverse events as mediators of the effect of second-generation antipsychotics on patients' social functioning. We used recently developed methods for mediation analysis with multiple mediators to clarify the interplay of adverse events and symptoms in explaining the effects of paliperidone (R code for implementing the mediation analysis for multiple mediators is provided). We used data from 490 participants in a 6-week randomized dose-response trial that assigned three fixed dosages of ER OROS paliperidone (3, 9, and 15 mg/day). The primary outcome was an individual's score on the social performance scale assessed after 6 weeks. The sum of Positive and Negative Syndrome Scale (PANSS), weight gain, and extrapyramidal symptoms measured via the Simpson-Angus Scale after 5 weeks were investigated as potential mediators and effect modifiers of treatment effects. Results from mediation analyses showed that the improvements in social functioning are partly explained by reduction in PANSS symptoms. Suggestive evidence that adverse events could play a role as mediators was found. In particular, weight gain displayed a non-linear relationship with social functioning, whereby beneficial effects observed at small levels of weight gain were reduced in the presence of excessive weight gain. In conclusion, we found that the short-term effects of paliperidone on social functioning were dependent on the successful reduction in PANSS symptoms and possibly the occurrence of excessive weight gain, thus suggesting future directions for treatment and interventions.

This study reports a medium-term follow-up of a randomised, double-blind, placebo-controlled trial of omega-3 polyunsaturated fatty acids (PUFA) in ultra-high risk for psychosis (UHR) patients. Primary outcomes of interest were transition to psychosis and symptomatic and functional outcome. A secondary aim was to investigate clinical predictors of medium-term outcome. Three hundred four UHR participants were recruited across 10 specialised early psychosis services in Australia, Asia, and Europe. The intervention consisted of 1.4 g/daily of omega-3 PUFA or placebo, plus up to 20 sessions of cognitive-behavioural case management (CBCM), over the 6-month study period, with participants receiving further CBCM sessions on basis of need between months 6-12. Mean time to follow-up was 3.4 (median = 3.3; SD = 0.9) years. There was a modest increase in transitions between 12-month and medium-term follow-up (11-13%) and substantial improvement in symptoms and functioning between baseline and follow-up, with no differences between the treatment groups. Most improvement had been achieved by end of the intervention. 55% of the sample received mental health treatment between end of intervention and follow-up. Omega-3 PUFA did not provide additional benefits to good quality psychosocial intervention over the medium term. Although most improvement had been achieved by end of intervention the substantial rates of post-intervention mental health service use indicate longer-term clinical need in UHR patients. The post-intervention phase treatment or the longer-term effect of CBCM, or a combination of the two, may have contributed to maintaining the gains achieved during the intervention phase and prevented significant deterioration after this time.

Effective early detection of impending relapse may offer opportunities for early interventions to prevent full relapse in schizophrenia patients. Previously reported early warning signs were not consistently validated by prospective studies. It remains unclear which symptoms are most predictive of relapse. To prioritize the symptoms to be captured by periodic self-report in technology-enabled remote assessment solutions for monitoring symptoms and detecting relapse early, we analyzed data from three relapse-prevention studies to identify individual items of the Positive and Negative Syndrome Scale (PANSS) that changed the most prior to relapse and to understand exactly when these symptoms manifested. Relapse was defined by a composite endpoint: hospitalization, suicidal/homicidal ideation, violent behavior, a 25% increase in the PANSS total score, or a significant increase in at least one of several pre-specified PANSS items. Longitudinal mixed effect models were applied to model the trajectories of individual PANSS items before relapse. Among 267 relapsed patients, the PANSS items that increased the most at relapse from randomization did not differ much by different relapse reasons or medications. A subset of seven PANSS items, including delusions, suspiciousness, hallucinations, anxiety, excitement, tension, and conceptual disorganization, had on average > 1-point of increase at relapse. The trajectories of these items suggested these items started to increase 7-10 days before relapse and reached on average 1-point of increase 0.3 ~ 1.2 days before relapse. Our results indicated that a subset of PANSS items could be leveraged to develop remote assessment solutions for monitoring symptoms and detecting relapse early in schizophrenia patients.

A measure of planning and impulse control, the delay-discounting (DD) task estimates the extent to which an individual decreases the perceived value of a reward as the reward is delayed. We examined cross-disorder performance between healthy controls (n = 88), individuals with bipolar disorder (n = 23), major depressive disorder (n = 43), and primary psychotic disorders (schizophrenia and schizoaffective disorder; n = 51) on the DD task (using a $10 delayed larger reward), as well as the interaction of DD scores with other symptom domains (cognition, psychosis, and affect). We found that individuals with schizophrenia and schizoaffective disorder display significantly greater rates of discounting compared to healthy controls, while individuals with a primary mood disorder do not differ from healthy controls after adjustment for IQ. Further, impairment in working memory is associated with higher discounting rates among individuals with schizophrenia and schizoaffective disorder, but cognitive dysfunction alone does not account for the extent of impairment in DD. Taken together, these results suggest an impaired ability to plan for the future and make adaptive decisions that are specific to individuals with psychotic disorders, and likely related to adverse functional outcomes. More generally, this work demonstrates the presence of variation in impulsivity across major psychiatric illnesses, supporting the use of a trans-diagnostic perspective.

To understand the mechanism of cognitive control dysfunction in schizophrenia, it is critical to characterize brain function without the confounding effect of medication. It is also important to establish the extent to which antipsychotic medication restores brain function and whether those changes are related to psychosis improvement. Twenty-two patients with schizophrenia, initially unmedicated and after a 6-week course of risperidone, and 20 healthy controls (HC) studied twice, 6 weeks apart, performed an fMRI task. We examined group and longitudinal differences in anterior cingulate cortex (ACC), striatum, and midbrain functional activity during performance of a Stroop color task as well as activity patterns associated with improvement in psychosis symptoms. Unmedicated patients showed reduced functional activity in the ACC, striatum, and midbrain compared to HC. Post hoc contrasts from significant group-by-time interactions indicated that, in patients, drug administration was associated with both activity increases and decreases. In unmedicated patients, greater baseline functional activity in the striatum and midbrain predicted subsequent better treatment response. Greater changes in functional activity in ACC and ventral putamen over the course of 6 weeks positively correlated with better treatment response. Unmedicated patients show reduced activity in brain networks pivotal for cognitive control and medication is associated with functional changes in these regions. These results suggest a mechanism by which antipsychotic medication has a beneficial effect on cognition. Our results also support the notion that treatment response is determined by a combination of the baseline pattern of brain function and by the pharmacological modulation of these regions.

Monozygotic twins are assumed to have identical genomes. Based on this assumption, phenotypic discordance in monozygotic twins has been previously attributed to environmental factors. However, recent genomic studies have identified characteristic somatic mutations in monozygotic twins discordant for Darier disease, Van der Woude syndrome, and Dravet syndrome. Here, we explored somatic mutations in four pairs of monozygotic twins discordant for schizophrenia or delusional disorder. We analyzed whole exome sequence data obtained from blood samples and identified seven somatic mutations in one twin pair discordant for delusional disorder. All seven of these mutations were validated by independent amplicon sequencing, and five of them were further validated by pyrosequencing. One somatic mutation in the patient with delusional disorder showed a missense variant in ABCC9 with an allele fraction of 7.32%. Although an association between the somatic mutations and phenotypic discordance could not be established conclusively in this study, our results suggest that somatic mutations in monozygotic twins may contribute to the development of psychiatric disorders, and can serve as high-priority candidates for genetic studies.