Person:

Keshavan, Matcheri

Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans. It is typified by highly variable symptoms, which might be explained by epigenetic regulation of genes in the interval. Using computational algorithms, our laboratory previously predicted that DiGeorge critical region 6 (DGCR6), which lies within the deletion interval, is imprinted in humans. Expression and epigenetic regulation of this gene have not, however, been examined in 22q11DS subjects. The purpose of this study was to determine if the expression levels of DGCR6 and its duplicate copy DGCR6L in 22q11DS subjects are associated with the parent-of-origin of the deletion and childhood psychopathologies. Our investigation showed no evidence of parent-of-origin-related differences in expression of both DGCR6 and DGCR6L. However, we found that the variability in DGCR6 expression was significantly greater in 22q11DS children than in age and gender-matched control individuals. Children with 22q11DS who had anxiety disorders had significantly lower DGCR6 expression, especially in subjects with the deletion on the maternal chromosome, despite the lack of imprinting. Our findings indicate that epigenetic mechanisms other than imprinting contribute to the dysregulation of these genes and the associated childhood psychopathologies observed in individuals with 22q11DS. Further studies are now needed to test the usefulness of DGCR6 and DGCR6L expression and alterations in the epigenome at these loci in predicting childhood anxiety and associated adult-onset pathologies in 22q11DS subjects.

Schizophrenia is a highly disabling disorder whose causes remain to be better understood, and treatments have to be improved. However, several recent advances have been made in diagnosis, etiopathology, and treatment. Whereas reliability of diagnosis has improved with operational criteria, including Diagnostic and Statistical Manual of Mental Disorders, (DSM) Fifth Edition, validity of the disease boundaries remains unclear because of substantive overlaps with other psychotic disorders. Recent emphasis on dimensional approaches and translational bio-behavioral research domain criteria may eventually help move toward a neuroscience-based definition of schizophrenia. The etiology of schizophrenia is now thought to be multifactorial, with multiple small-effect and fewer large-effect susceptibility genes interacting with several environmental factors. These factors may lead to developmentally mediated alterations in neuroplasticity, manifesting in a cascade of neurotransmitter and circuit dysfunctions and impaired connectivity with an onset around early adolescence. Such etiopathological understanding has motivated a renewed search for novel pharmacological as well as psychotherapeutic targets. Addressing the core features of the illness, such as cognitive deficits and negative symptoms, and developing hypothesis-driven early interventions and preventive strategies are high-priority goals for the field. Schizophrenia is a severe, chronic mental disorder and is among the most disabling disorders in all of medicine. It is estimated by the National Institute of Mental Health (NIMH) that 2.4 million people over the age of 18 in the US suffer from schizophrenia. This illness typically begins in adolescence and derails the formative goals of school, family, and work, leading to considerable suffering and disability and reduced life expectancy by about 20 years. Treatment outcomes are variable, and some people are successfully treated and reintegrated (i.e. go back to work). Despite the effort of many experts in the field, however, schizophrenia remains a chronic relapsing and remitting disorder associated with significant impairments in social and vocational functioning and a shortened lifespan. Comprehensive treatment entails a multi-modal approach, including psychopharmacology, psychosocial interventions, and assistance with housing and financial sustenance. Research to date suggests a network of genetic, neural, behavioral, and environmental factors to be responsible for its development and course. This article aims to summarize and explain recent advancements in research on schizophrenia, to suggest how these recent discoveries may lead to a better understanding and possible further development of effective therapies, and to highlight the paradigm shifts that have taken place in our understanding of the diagnosis, etiopathology, and treatment.

Introduction: Chronic medicated patients with schizophrenia have marked reductions in sleep spindle activity and a correlated deficit in sleep-dependent memory consolidation. Using archival data, we investigated whether antipsychotic-naïve early course patients with schizophrenia and young non-psychotic first-degree relatives of patients with schizophrenia also show reduced sleep spindle activity and whether spindle activity correlates with cognitive function and symptoms. Method: Sleep spindles during Stage 2 sleep were compared in antipsychotic-naïve adults newly diagnosed with psychosis, young non-psychotic first-degree relatives of schizophrenia patients and two samples of healthy controls matched to the patients and relatives. The relations of spindle parameters with cognitive measures and symptom ratings were examined. Results: Early course schizophrenia patients showed significantly reduced spindle activity relative to healthy controls and to early course patients with other psychotic disorders. Relatives of schizophrenia patients also showed reduced spindle activity compared with controls. Reduced spindle activity correlated with measures of executive function in early course patients, positive symptoms in schizophrenia and IQ estimates across groups. Conclusions: Like chronic medicated schizophrenia patients, antipsychotic-naïve early course schizophrenia patients and young non-psychotic relatives of individuals with schizophrenia have reduced sleep spindle activity. These findings indicate that the spindle deficit is not an antipsychotic side-effect or a general feature of psychosis. Instead, the spindle deficit may predate the onset of schizophrenia, persist throughout its course and be an endophenotype that contributes to cognitive dysfunction.

Background: Early intervention services for psychotic disorders optimally interlock strategies to deliver: (i) Early Detection (ED) to shorten the time between onset of psychotic symptoms and effective treatment (i.e. Duration of Untreated Psychosis, DUP); and (ii) comprehensive intervention during the subsequent 2 to 5 years. In the latter category, are teams (‘First-episode Services’ or FES) that integrate several empirically supported treatments and adapt their delivery to younger patients and caregivers. There is an urgent need to hasten access to established FES in the U.S. Despite improved outcomes for those in treatment, these FES routinely engage patients a year or more after psychosis onset. The Scandinavian TIPS study was able to effectively reduce DUP in a defined geographic catchment. The guiding questions for this study are: can a U.S. adaptation of the TIPS approach to ED substantially reduce DUP and improve outcomes beyond existing FES? Methods/Design The primary aim is to determine whether ED can reduce DUP in the US, as compared to usual detection. ED will be implemented by one FES (STEP) based in southern Connecticut, and usual detection efforts will continue at a comparable FES (PREPR) serving the greater Boston metropolitan area. The secondary aim is to determine whether DUP reduction can improve presentation, engagement and early outcomes in FES care. A quasi-experimental design will compare the impact of ED on DUP at STEP compared to PREPR over 3 successive campaign years. The campaign will deploy 3 components that seek to transform pathways to care in 8 towns surrounding STEP. Social marketing approaches will inform a public education campaign to enable rapid and effective help-seeking behavior. Professional outreach and detailing to a wide variety of care providers, including those in the healthcare, educational and judicial sectors, will facilitate rapid redirection of appropriate patients to STEP. Finally, performance improvement measures within STEP will hasten engagement upon referral. Discussion STEP-ED will test an ED campaign adapted to heterogeneous U.S. pathways to care while also improving our understanding of these pathways and their impact on early outcomes. Trial registration ClinicalTrials.gov: NCT02069925. Registered 20 February 2014.

Cognitive deficits in schizophrenia are pervasive, severe, and largely independent of the positive and negative symptoms of the illness. These deficits are increasingly considered to be core features of schizophrenia with evidence that the extent of cognitive impairment is the most salient predictor of daily functioning. Unfortunately, current schizophrenia treatment has been limited in addressing the cognitive deficits of the illness. Alterations in neuroplasticity are hypothesized to underpin these cognitive deficits, though preserved neuroplasticity may offer an avenue towards cognitive remediation. Key neuroplastic principles to consider in designing remediation interventions include ensuring sufficient intensity and duration of remediation programs, "bottom-up" training that proceeds from simple to complex cognitive processes, and individual tailoring of remediation regimens. We discuss several cognitive remediation programs, including cognitive enhancement therapy, which embrace these principles to target neurocognitive and social cognitive improvements and which havebeen demonstrated to be effective in schizophrenia. Future directions in cognitive remediation research include potential synergy with pharmacologic treatment, non-invasive stimulation techniques, and psychosocial interventions, identification of patient characteristics that predict outcome with cognitive remediation, and increasing the access to these interventions in front-line settings.

There is a critical need for mapping early metabolic changes in schizophrenia to capture failures in regulation of biochemical pathways and networks. This information could provide valuable insights about disease mechanisms, trajectory of disease progression, and diagnostic biomarkers. We used a lipidomics platform to measure individual lipid species in 20 drug-naïve patients with a first episode of schizophrenia (FE group), 20 patients with chronic schizophrenia that had not adhered to prescribed medications (RE group), and 29 race-matched control subjects without schizophrenia. Lipid metabolic profiles were evaluated and compared between study groups and within groups before and after treatment with atypical antipsychotics, risperidone and aripiprazole. Finally, we mapped lipid profiles to n3 and n6 fatty acid synthesis pathways to elucidate which enzymes might be affected by disease and treatment. Compared to controls, the FE group showed significant down-regulation of several n3 polyunsaturated fatty acids (PUFAs), including 20:5n3, 22:5n3, and 22:6n3 within the phosphatidylcholine and phosphatidylethanolamine lipid classes. Differences between FE and controls were only observed in the n3 class PUFAs; no differences where noted in n6 class PUFAs. The RE group was not significantly different from controls, although some compositional differences within PUFAs were noted. Drug treatment was able to correct the aberrant PUFA levels noted in FE patients, but changes in re patients were not corrective. Treatment caused increases in both n3 and n6 class lipids. These results supported the hypothesis that phospholipid n3 fatty acid deficits are present early in the course of schizophrenia and tend not to persist throughout its course. These changes in lipid metabolism could indicate a metabolic vulnerability in patients with schizophrenia that occurs early in development of the disease.

Schizophrenia (SZ) is a biochemically complex disorder characterized by widespread defects in multiple metabolic pathways whose dynamic interactions, until recently, have been difficult to examine. Rather, evidence for these alterations has been collected piecemeal, limiting the potential to inform our understanding of the interactions amongst relevant biochemical pathways. We herein review perturbations in purine and neurotransmitter metabolism observed in early SZ using a metabolomic approach. Purine catabolism is an underappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. We have observed a homeostatic imbalance of purine catabolism in first-episode neuroleptic-naïve patients with SZ (FENNS). Precursor and product relationships within purine pathways are tightly correlated. Although some of these correlations persist across disease or medication status, others appear to be lost among FENNS suggesting that steady formation of the antioxidant uric acid (UA) via purine catabolism is altered early in the course of illness. As is the case for within-pathway correlations, there are also significant cross-pathway correlations between respective purine and tryptophan (TRP) pathway metabolites. By contrast, purine metabolites show significant cross-pathway correlation only with tyrosine, and not with its metabolites. Furthermore, several purine metabolites (UA, guanosine, or xanthine) are each significantly correlated with 5-hydroxyindoleacetic acid (5-HIAA) in healthy controls, but not in FENNS at baseline or 4-week after antipsychotic treatment. Taken together, the above findings suggest that purine catabolism strongly associates with the TRP pathways leading to serotonin (5-hydroxytryptamine, 5-HT) and kynurenine metabolites. The lack of a significant correlation between purine metabolites and 5-HIAA, suggests alterations in key 5-HT pathways that may both be modified by and contribute to oxidative stress via purine catabolism in FENNS.

Several lines of evidence implicate dysfunction in brain energy production as a key component of bipolar disorder. In particular, elevated brain lactate levels observed in this condition suggest a shift from aerobic to anaerobic metabolism, possibly as a result of mitochondrial abnormalities. Most prior imaging studies of brain metabolites were performed in either euthymic or depressed bipolar patients or compared different populations in different mood states. We sought to measure brain metabolite concentrations in the same patients in both manic and euthymic states. Given the dramatic changes in clinical state of bipolar disorder patients, we hypothesized that previously observed abnormalities in lactate concentrations in bipolar disorder might show state dependent changes. In this study 15 patients (mean age 36.1 years) diagnosed with bipolar I disorder underwent proton magnetic resonance spectroscopy of the anterior cingulate cortex and parieto-occipital cortex during hospitalization for acute mania (mean Young Mania Rating Scale (YMRS) 22.1). Seven of these subjects returned (mean interval 21.16 months) to have imaging repeated while euthymic (mean YMRS 2.0). A group of age- and gender-matched control participants (N=6) were scanned as well. We report that during mania, bipolar disorder subjects had lactate levels comparable to healthy control subjects but during euthymia these levels were significantly reduced. No significant change was observed for other metabolites. These results implicate mood dependent alterations in energy metabolism in the biology of bipolar disorder. Additionally, this finding has potential use as a biomarker for both evaluating novel treatments as well as diagnostic clarification between mood disorders.

Mobile and connected devices like smartphones and wearable sensors can facilitate the collection of novel naturalistic and longitudinal data relevant to psychiatry at both the personal and population level. The National Institute of Mental Health’s Research Domain Criteria framework offers a useful roadmap to organize, guide and lead new digital phenotyping data towards research discoveries and clinical advances.

Schizophrenia is characterized by significant and widespread impairments in the regulation of emotion. Evidence is only recently emerging regarding the neural basis of these emotion regulation impairments, and few studies have focused on the regulation of emotion during effortful cognitive processing. To examine the neural correlates of deficits in effortful emotion regulation, schizophrenia outpatients (N = 20) and age- and gender-matched healthy volunteers (N = 20) completed an emotional faces n-back task to assess the voluntary attentional control subprocess of emotion regulation during functional magnetic resonance imaging. Behavioral measures of emotional intelligence and emotion perception were administered to examine brain-behavior relationships with emotion processing outcomes. Results indicated that patients with schizophrenia demonstrated significantly greater activation in the bilateral striatum, ventromedial prefrontal, and right orbitofrontal cortices during the effortful regulation of positive emotional stimuli, and reduced activity in these same regions when regulating negative emotional information. The opposite pattern of results was observed in healthy individuals. Greater fronto-striatal response to positive emotional distractors was significantly associated with deficits in facial emotion recognition. These findings indicate that abnormalities in striatal and prefrontal cortical systems may be related to deficits in the effortful emotion regulatory process of attentional control in schizophrenia, and may significantly contribute to emotion processing deficits in the disorder.