Protein Functions of DISC1 Gene Linked to Schizophrenia Identified

MedicalResearch.com Interview with:
Marcelo Pablo Coba PhD
Assistant Professor of Psychiatry
Zilkha Neurogenetic Institute
Keck School of Medicine of USC

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Psychiatric diseases such as schizophrenia (SCZ) are complex brain disorders where a multitude or risk factors have been implicated in contributing to the disease, with a low number of genes that have been strongly implicated in a very low number of cases.

One of these genes is Disrupted in schizophrenia 1 (DISC1), which was first described in 2000 as a balanced translocation that segregates with schizophrenia and related psychiatric disorders in a large Scottish family. Because DISC1 does not have an identified protein function such as enzymatic, channel, transporter, etc… the field moved to try to understand what proteins are associated (physically connected) to DISC1 and to try to explain DISC1 function through the function of its protein interactors. This means that if DISC1 binds proteins X, Y and Z, then mutations in the DISC1 gene should affect the functions of   these proteins. Therefore, there has been much effort in trying to identify DISC1 protein interactors. However this task has not been straightforward.

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Functional Brain ‘Fingerprint’ Identified in Schizophrenia

MedicalResearch.com Interview with:

Tobias Kaufmann UiO Institute of Clinical Medicine

Dr. Kaufmann

Tobias Kaufmann PhD
Norwegian Centre for Mental Disorders Research (NORMENT), KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine
University of Oslo, Oslo, Norway

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Over the past years, a lot of work has pointed toward impaired brain networks in schizophrenia. With this work we assessed brain network stability across different loads of a cognitive task using functional magnetic resonance imaging of the brain.

Based on our earlier work on adolescents with pre-clinical signs of mental illness who showed decreased stability of networks across different tasks and conditions, we hypothesized that brain networks in adults with schizophrenia show similar properties of decreased stability. Our results confirmed this hypothesis. Stability was reduced in several large-scale brain networks across the sampled age range from early adulthood to the sixties. Further, network stability was associated with polygenic risk for schizophrenia as well as cognitive task performance.

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Psychosis: Early Integrated Bests Usual Care

MedicalResearch.com Interview with:

Christoph U. Correll, MD Professor of Psychiatry and Molecular Medicine The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Hempstead, NY Investigator, Center for Psychiatric Neuroscience Feinstein Institute for Medical Research Medical Director, Recognition and Prevention (RAP) Program The Zucker Hillside Hospital, Department of Psychiatry

Dr. Correll

Christoph U. Correll, MD
Professor of Psychiatry and Molecular Medicine
The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
Hempstead, NY
Investigator, Center for Psychiatric Neuroscience
Feinstein Institute for Medical Research
Medical Director, Recognition and Prevention (RAP) Program
The Zucker Hillside Hospital, Department of Psychiatry

 

MedicalResearch.com: What is the background for this study?

Response: Schizophrenia and other psychotic disorders are still all to often chronic and recurring mental health conditions that not uncommonly take a course during which individuals have varying degrees of significantly impaired personal, social and educational/vocational functioning.

Prior individual studies examining early specialty intervention services, which integrate multiple different and complementary treatment components, had shown that this treatment approach can yield superior outcomes for people with early-phase schizophrenia and other psychotic disorders compared to usual care given to all people with psychotic disorders. However, we were lacking a broad overview of the type and results of treatment programs that had been conducted across different countries, continents and mental health service delivery systems. Moreover, we did not yet have a synthesis across all important outcomes that had been examined across these individual studies. This first comprehensive meta-analysis on this topic provides previously missing information on the different early intervention programs and their components as well as on all relevant outcomes for people who did or did not receiving early integrated care, also recently called ‘coordinated specialty care.’

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Schizophrenia: Medications Reduce Psychotic Symptoms But Don’t Improve Real-Life Funtioning

MedicalResearch.com Interview with:

Silvana Galderisi MD President of the European Psychiatric Association Professor of Psychiatry University of Campania "Luigi Vanvitelli" Italy

Dr. Galderisi

Silvana Galderisi MD
President of the European Psychiatric Association
Professor of Psychiatry
University of Campania “Luigi Vanvitelli”
Italy

MedicalResearch.com: What is the background for this study?

Response: The goal of schizophrenia treatment has gradually shifted from reduction of symptoms and prevention of relapse to improvement of real-life functioning. In fact, these outcomes not always coincide and, in spite of progress in treatments reducing symptoms and preventing relapses, people with schizophrenia live 15-20 years less than the general population, are often unemployed, and show severe disabilities.

Enhanced understanding of factors associated with real-life functioning is instrumental to design effective integrated and personalized treatment plans for persons with schizophrenia.

To this aim, the Italian Network for Research on Psychoses, including 26 twenty-six Italian university psychiatric clinics and/or mental health departments, has focused on the identification of variables influencing real-life functioning, in particular on the interrelationships among illness-related variables, personal resources, context-related variables and real-life functioning. The number of variables and subjects included in the study was larger than in any other study on this topic, and for the first time the network analysis was used to model the interplay among cognitive, psychopathological and psychosocial variables in a large sample of community dwelling subjects with schizophrenia. The network analysis is a data-driven approach; it does not rely on an a priori model of relationships among variables, provides quantitative measures of variable centrality within the network, thus indicating which variables play a key role in the network, and which ones are instead more peripheral. In addition, by inspecting the network, it is possible to understand the extent to which variables belonging to the same construct are connected, and how different constructs are mutually interacting and reinforcing each other.  Continue reading

Greater Risk of Breast Cancer in Women With Schizophrenia

MedicalResearch.com Interview with:
Chuanjun Zhuo, MD, PhD

Department of Psychiatric Laboratory
Department of Psychiatric Neuroimaging Faculty
Tianjin Mental Health Center
Tianjin, China 

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: According to previous epidemiological studies, women with schizophrenia may be associated with significantly increased risk of breast cancer. However, the results of these studies were not always consistent. In view of the fact that medical care for patients with schizophrenia is becoming multidisciplinary, we aimed to evaluate the risk of breast cancer in women with schizophrenia via a meta-analysis of relevant cohort studies. We included twelve cohorts and adopted the recently proposed prediction interval to evaluate the heterogeneity among the included studies.

We found that schizophrenia was associated with about 30% increased risk of breast cancer incidence in women. However, significant heterogeneity existed of the included studies, which indicates that more extensive researches into the potential mechanisms underlying the associations between schizophrenia and breast cancer risk are needed.

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Add-On Preservative May Improve Outcomes in Refractory Schizophrenia

MedicalResearch.com Interview with:

Hsien-Yuan Lane

Dr. Hsien-Yuan Lane

Hsien-Yuan Lane, MD,PhD
Distinguished Professor, Director, Graduate Institute of Biomedical Sciences
China Medical University, Taichung, Taiwan
Director, Brain Diseases Research Center (BDRC), Addiction Research Center, and Department of Psychiatry,
China Medical University and Hospital, Taichung, Taiwan
PI, Taiwan Clinical Trial Consortium for Mental Disorders 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Schizophrenia is a chronic and severe mental illness affecting more than 21 million people worldwide. Clozapine has been regarded as the last-line antipsychotic agent for patients with refractory schizophrenia. However, an estimated 40–70% of patients with refractory schizophrenia fail to improve even with clozapine , referred to as “clozapine-resistant”. To date, there is no convincing evidence for augmentation on clozapine.

Activation of N-methyl-D-aspartate (NMDA) receptors, including inhibition of D-amino acid oxidase (DAAO) that may metabolize D-amino acids, has been reported to be beneficial for patients receiving antipsychotics other than clozapine.

Sodium benzoate is a DAAO inhibitor. A recent randomized, double-blind, placebo-controlled clinical trial found that add-on sodium benzoate improved the clinical symptoms in patients with clozapine-resistant schizophrenia, possibly through DAAO inhibition and antioxidation as well.

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Allergan’s VRAYLAR (carprazine) Receives FDA Approval For Maintenance Treatment of Schizophrenia

MedicalResearch.com Interview with:

Dr. David Nicholson PhD EVP and Chief R&D Officer Allergan

Dr. Nicholson

Dr. David Nicholson PhD
EVP and Chief R&D Officer
Allergan

Discusses Allergan’s announcement that:
New Data Shows Long-Term VRAYLAR Therapy Delayed Time to Relapse Compared to Placebo Over the Course of up to 72 Weeks and has received FDA approval for the Maintenance Treatment of Schizophrenia

MedicalResearch.com: What is the background for this FDA approval?

Response: As many clinicians know, schizophrenia is among one of the most challenging mental health disorders to manage – due to the complexity of patient symptoms, varying response to treatment and high rates of relapse. Schizophrenia requires long-term medication management, and without maintenance treatment, 60 – 70% of schizophrenia patients relapse within one year.

The approval of Vraylar (carprazine) for the maintenance treatment of schizophrenia was based upon the results of a clinical trial, which found long-term cariprazine therapy delayed time to relapse compared to placebo over the course of up to 72 weeks.

MedicalResearch.com: What does this extended indication mean for people living with schizophrenia? 

Response: Schizophrenia affects about 2.4 million American adults, and there remains serious unmet needs in the treatment of schizophrenia. The differences in how patients with schizophrenia respond to treatment underscore the importance of having more treatment options available. With its proven efficacy and well-characterized safety profile, cariprazine provides another treatment option for patients and clinicians. This study demonstrates cariprazine efficacy in the long-term (i.e., maintenance) treatment of schizophrenia.

MedicalResearch.com: What should readers take away from this announcement?

Response: As a chronic disease and disabling disorder, schizophrenia requires long-term medication management. Cariprazine is a safe and effective treatment for schizophrenia in both the short and long-term management of the illness. 

MedicalResearch.com: Is there anything else you would like to add about this FDA approval and what it means for the mental health community?

Response: On behalf of Allergan as Chief Research & Development Officer at the company, we are pleased that the FDA has recognized the benefits of cariprazine for maintenance treatment of adults with schizophrenia. This approval demonstrates our continued investment in cariprazine, as well as our commitment to developing treatments that address unmet needs facing people living with mental illness. Additionally, VRAYLAR is also approved in the U.S. in adults for the acute treatment of schizophrenia and acute treatment of manic or mixed episodes of bipolar I disorder.

David Nicholson is the Chief R&D Officer, and has served in this role since March 2015. Dr. Nicholson joined the company (then Actavis) as Senior Vice President, Global Brands R&D in August 2014. He has been in research and development in the pharmaceutical industry since 1978.

Previously, he served as Chief Technology Officer and EVP, R&D for Bayer CropScience from March 2012 to August 2014; Senior Vice President of Licensing and Knowledge Management at Merck from 2009 to December 2011; and Senior Vice President, responsible for Global Project Management and Drug Safety at Schering-Plough from 2007 to 2009. From 1988 to 2007, Dr. Nicholson held various leadership positions at Organon, where he most recently served as Executive Vice President, R&D and was a member of the company’s Executive Management Committee.

Dr. Nicholson earned his B.Sc. from the University of Manchester and his Ph.D. from the University of Wales.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Allergan Receives FDA Approval For Use of VRAYLAR™ (cariprazine) in the Maintenance Treatment of Schizophrenia

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

 

 

 

 

 

Brain Imaging Patterns Moving Closer To Identifying Schizophrenia on Functional MRI

MedicalResearch.com Interview with:

Irina Rish PhD IBM T.J. Watson Research Center Yorktown Heights, NY 10598

Dr. Rish

Irina Rish PhD
IBM T.J. Watson Research Center
Yorktown Heights, NY 10598 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Schizophrenia is a chronic and severe psychiatric disorder that affects roughly about 1% of population. Although it is not as common as other mental disorders, such as depression, anxiety, and attention deficit disorder (ADD), and so on, schizophrenia  is perhaps one of  the most debilitating psychiatric disorders,  preventing people from normal  functioning in daily life. It is characterized primarily by a range of psychotic symptoms, including hallucinations (false auditory, visual or tactile perceptions detached from reality), as well as delusions, disorganized thoughts, speech and behavior, and multiple other symptoms including difficulty showing (and recognizing) emotions, poor executive functioning, inattentiveness, problems with working memory,  and so one. Overall, schizophrenia has a devastating impact not only on patients and their families, but on the economy, as it was estimated to cost the US about 2% off  gross national product in treatment costs, missed work, etc.
Thus, taking steps towards better understanding of the disease can potentially lead to more accurate early diagnosis and better treatments.

In this work, the objective was to identify “statistical biomarkers’ of schizophrenia from brain imaging data (specifically, functional MRI), i.e. brain activity patterns that would be capable of accurately discriminating between schizophrenic patients and controls, and reproducible (stable) across multiple datasets. The focus on both predictive accuracy (generalization to previously unseen subjects) as well as on stability (reproducibility) across multiple datsets differentiates our work from majority of similar studies in neuroimaging field that tend to focus only on statistically significant differences between such patterns on a fixed dataset, and may not reliably generalize to new data.

Our prior work on neuroimaging-based analysis of schizoprenia http://journals.plos.org/plosone/article/related?id=10.1371/journal.pone.0050625, as well as other research in the field, suggest that disrupted functional connectivity can be a much more informative source of discriminative patterns than local changes in brain activations, since schizophrenia is well known to be a “network disease”, rather than a localized one.

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Schizophrenia: Impaired White Matter Linked To Deficits in Cognitive Processing Speed

MedicalResearch.com Interview with:

Peter Kochunov PhD Professor Maryland Psychiatric Research Center

Dr. Kochunov

Peter Kochunov PhD
Professor
Maryland Psychiatric Research Center 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Schizophrenia is a debilitating disorder that strikes young people at the point of entering adulthood. In the past, we and others demonstrated that patients with schizophrenia are characterized by deficits in the white matter of the brain. White matter is the part of the brain that serves the backbone of cerebral networks transmitting information and interconnecting brain regions.

In this report, we link the impaired white matter of the brain in schizophrenia patients with the disorder-related deficits in the processing speed. We also showed that mental processing speed is a fundamental cognitive construct that partially supports other functions like working memory in patients, where processing speed acting as the intermediate between white matter deficits and reduced working memory. This interesting relationship between processing speed, working memory, and white matter is most obvious in white matter regions most vulnerable to schizophrenia. That was the main finding of the study.

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Genetic Risk of Schizophrenia May Contribute to Cognitive Dysfunction

MedicalResearch.com Interview with:

Olav B. Smeland MD PhD Postdoctoral researcher SFF NORMENT, KG Jepsen Centre for Psychosis Research, Division of Mental  Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine University of Oslo Oslo, Norway

Dr. Smeland

Olav B. Smeland MD PhD
Postdoctoral researcher
SFF NORMENT, KG Jepsen Centre for Psychosis Research, Division of Mental
Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine
University of Oslo Oslo, Norway

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Schizophrenia is a severe mental disorder associated with widespread cognitive impairments. The cognitive deficits are associated with disabilities in social, economic and occupational functioning and lower quality of life among individuals with schizophrenia. Despite this, current treatment strategies largely fail to ameliorate these cognitive impairments.

To develop more efficient treatment strategies in schizophrenia, a better understanding of the disease mechanisms underlying cognitive deficits is needed. For a long time we have known that schizophrenia is heritable, and in recent years many schizophrenia risk genes have been identified. Moreover, several studies have indicated that genetic risk of schizophrenia may contribute to cognitive dysfunction.

In this study, we aimed to identify schizophrenia risk genes that also influence cognitive function. In a large international collaboration of researchers, we combined genome-wide association studies on schizophrenia and the cognitive traits of verbal-numerical reasoning, reaction time and general cognitive function. In total, we analyzed genetic data from more than 250.000 participants. We were able to identify 21 genetic variants shared between schizophrenia and cognitive traits. For 18 of these genetic variants, schizophrenia risk was associated with poorer cognitive performance.

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