Different Genes, Same Risk Pathway in Schizophrenia

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Findings linking two biological mechanisms known to play a role in mental illness demonstrate how unrelated genes can work through effects on a common pathway. Many genes contribute to risk of schizophrenia; this work helps illuminate this complex pathway, a potential target for development of future medications.

Background

By identifying genes that underlie mental illness, scientists hope not only to be able to identify people at risk, but to understand how genes alter brain function to make a person vulnerable to illness.

Complementing the search for risk genes, investigators are also identifying how signaling processes in the brain are disrupted in mental illness. Prior research has established that in schizophrenia, there is a disruption in signaling involving the neurotransmitter glutamate. Drugs that block receptors for glutamate cause schizophrenia-like behavior. The chain of molecular events that enables glutamate signaling, however, is complex, and genes associated with schizophrenia risk could have an impact at many different steps in this pathway. A risk gene associated with schizophrenia, depression, and bipolar disorder has been the object of much research since it was discovered in 2000: The Disrupted-in-Schizophrenia-1 (DISC1) gene.

The Study

NIMH-supported scientists at the Johns Hopkins University School of Medicine, led by Mikhail V. Pletnikov, in collaboration with the laboratory of Solomon H. Snyder, explored whether DISC1 might have an impact on a molecule that plays a role in glutamate signaling—D-serine. There is evidence for a connection between D-serine and schizophrenia; in people with the disease, the level of D-serine is reduced and mutations in the gene for an enzyme that produces D-serine have been associated with schizophrenia. D-serine is found largely in cells called glia that surround and support neurons. Earlier work on DISC1 focused primarily on neurons, not glia. Findings in recent years, however, have suggested that these support cells, like the neurons themselves, are involved in the signaling that takes place in the brain.

The investigators found that normal DISC1 protein helps maintain normal levels of D-serine by binding to an enzyme that produces it, while mutant DISC1 protein does not. The result is lower levels of D-serine and reduced signaling involving glutamate and its receptor. To study the relationship between DISC1 and D-serine, the investigators developed a line of transgenic mice carrying a mutant form of the DISC1 gene that could be switched on or off in the type of glial cell that is the main source of D-serine. Adult mice in which the mutant DISC1 has been active throughout life show behavioral abnormalities typical of reduced glutamate signaling and suggestive of schizophrenia. Giving mutant mice D-serine reversed to some extent the behavioral abnormalities caused by the mutation. These results show that at least part of the impact of DISC1 on glutamate synaptic transmission is through its actions in glia on the D-serine pathway—the components of which are encoded by other genes.

Significance

Mental illnesses are genetically complex, with many different genes potentially contributing to risk, each individually having a small (and difficult to detect) impact. This work illustrates the variability of the genetic and biological underpinnings of mental illnesses. The vulnerability of any two people with a similar diagnosis may be the result of a different set of risk genes affecting a common pathway. Identifying the cascade of processes involved in pathways that shape disease risk—and in which numerous genes are involved at different steps—can clarify how individual genes raise or lower risk, and can provide a focus for development of future therapeutics.

The authors point out that, in the mice with mutant DISC1, D-serine levels were only altered at a very early stage of development. While subsequent levels were more normal, the early deficit was enough to alter later behavior. Mental illnesses are increasingly understood to be diseases of development, and this finding helps provides an example of how an early transient deficit might nonetheless have lasting effects.

Finally, the work offers new details on the interplay between neurons and glia in brain signaling, neurodevelopment, and mental illness. “Abnormalities in glia cells could be as important as abnormalities in neuronal cells themselves,” says Pletnikov. “Most gene work has been done with neurons. But we also need to understand a lot more about the role that genetic mutations in glia cells play because neuron-glia interaction appears crucial in ensuring the brain operates normally.”

–National Institute of Mental Health (NIMH)

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Taming Suspect Gene Reverses Schizophrenia-like Abnormalities in Mice

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Scientists have reversed behavioral and brain abnormalities in adult mice that resemble some features of schizophrenia by restoring normal expression to a suspect gene that is over-expressed in humans with the illness. Targeting expression of the gene Neuregulin1, which makes a protein important for brain development, may hold promise for treating at least some patients with the brain disorder, say researchers funded by the National Institutes of Health.

Like patients with schizophrenia, adult mice biogenetically-engineered to have higher Neuregulin 1 levels showed reduced activity of the brain messenger chemicals glutamate and GABA. The mice also showed behaviors related to aspects of the human illness. For example, they interacted less with other animals and faltered on thinking tasks.

“The deficits reversed when we normalized Neuregulin 1 expression in animals that had been symptomatic, suggesting that damage which occurred during development is recoverable in adulthood,” explained Lin Mei, M.D., Ph.D., of the Medical College of Georgia at Georgia Regents University, a grantee of NIH’s National Institute of Mental Health (NIMH).

Mei, Dong-Min Yin, Ph.D., Yong-Jun Chen, Ph.D., and colleagues report on their findings May 22, 2013, in the journal Neuron.

“While mouse models can’t really do full justice to a complex brain disorder that impairs our most uniquely human characteristics, this study demonstrates the potential of dissecting the workings of intermediate components of disorders in animals to discover underlying mechanisms and new treatment targets,” said NIMH Director Thomas R. Insel, M.D. “Hopeful news about how an illness process that originates early in development might be reversible in adulthood illustrates the promise of such translational research.”

Schizophrenia is thought to stem from early damage to the developing fetal brain, traceable to a complex mix of genetic and environmental causes. Although genes identified to date account for only a small fraction of cases, evidence has implicated variation in the Neuregulin 1 gene. For example, postmortem studies have found that it is overexpressed in the brain’s thinking hub, or prefrontal cortex, of some people who had schizophrenia. It codes for a chemical messenger that plays a pivotal role in communication between brain cells, as well as in brain development.

Prior to the new study, it was unclear whether damage caused by abnormal prenatal Neuregulin 1 expression might be reversible in adulthood. Nor was it known whether any resulting behavioral and brain deficits must be sustained by continued errant Neuregulin 1 expression in adulthood.

To find out, the researchers engineered laboratory mice to mimic some components of the human illness by over-expressing the Neuregulin 1 gene in the forebrain, comparable to the prefrontal cortex in humans. Increasing Neuregulin 1 expression in adult animals was sufficient to produce behavioral features, such as hyperactivity, social and cognitive impairments, and to hobble neural communications via the messenger chemicals glutamate and GABA.

Unexpectedly, the abnormalities disappeared when the researchers experimentally switched off Neuregulin 1 overexpression in the adult animals. Treatment with clozapine, an antipsychotic medication, also reversed the behavioral abnormalities. The researchers traced the glutamate impairment to an errant enzyme called LIMK1, triggered by the overexpressed Neuregulin 1 – a previously unknown potential pathological mechanism in schizophrenia.

The study results suggest that even if their illness stems from disruptions early in brain development, adult patients whose schizophrenia is rooted in faulty Neuregulin 1 activity might experience a reduction in some of the symptoms following treatments that target overexpression of the protein, say the researchers.

–National Institute of Mental Health (NIMH)

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Meet the Scientist Webinar–July 9th

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Meet the Scientist logoPlease join us by phone or on the web on the second Tuesday of each month for our Meet the Scientist Webinar Series hosted by Brain & Behavior Research Foundation President and CEO, Jeffrey Borenstein, M.D. Hear leading mental health researchers present the latest in new technologies, diagnostic tools, early intervention strategies and next generation therapies for mental illness.

“Resilience: The Science of Mastering Life’s Greatest Challenges” with Dennis S. Charney, M.D.

Date: Tuesday, July 9, 2013, 2-3 pm Eastern Standard Time

Location: Online

This month, hear from Dennis S. Charney, M.D.; Anne and Joel Ehrenkranz, Dean, Icahn School of Medicine at Mount Sinai as he presents ”Resilience: The Science of Mastering Life’s Greatest Challenges”

Information and Registration

Meet the Scientist June-July Webinar Flyer

Diagnosis of the Future? Brain Scan Shows Promise in Diagnosing Bipolar

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Using magnetic resonance imaging (MRI) may be an effective way to diagnose mental illnesses, such as bipolar disorder, according to new research.

In a new study, researchers from the Icahn School of Medicine at Mount Sinai were able to correctly distinguish bipolar patients from healthy individuals based on their brain scans alone most, but not all, of the time.

“Bipolar disorder affects patients’ ability to regulate their emotions successfully, which puts them at great disadvantage in their lives,” said Sophia Frangou, professor of psychiatry at Mount Sinai Hospital in New York.

“The situation is made worse by unacceptably long delays, sometimes of up to 10 years, in making the correct diagnosis. Bipolar disorder may be easily misdiagnosed for other disorders, such as depression or schizophrenia.”

Frangou said that is why bipolar disorder ranks among the top 10 disorders worldwide in terms of significant disability.

by Janice Wood, PsychCentral

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Treatment of Mental Illness Saves Your Taxpayer Dollars

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Emerging research suggests outpatient treatment of mental illness significantly reduces arrest rates for people with mental health problems — and saves taxpayers money to boot.

Researchers looked at the extent to which treating mental illness can keep people with mental health problems out of trouble with the law.

“This study shows that providing mental health care is not only in the best interest of people with mental illness, but in the best interests of society,” said Sarah Desmarais, Ph.D., an assistant professor of psychology at North Carolina State University and coauthor of the paper.

It is well-established that people with mental health problems — such as schizophrenia or bipolar disorder — make up a disproportionate percentage of defendants, inmates and others who come into contact with the criminal justice system.

….“It costs about $10 less per day to provide treatment and prevent crime. That’s a good investment,” Desmarais said.

by Rick Nauert PhD, PsychCentral

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Metabolic Syndrome and Metabolic Abnormalities in Schizophrenia and Related Disorders

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Individuals with schizophrenia have high levels of medical comorbidity and cardiovascular risk factors. The presence of 3 or more specific factors is indicative of metabolic syndrome, which is a significant influence upon future morbidity and mortality. We aimed to clarify the prevalence and predictors of metabolic syndrome (MetS) in adults with schizophrenia and related disorders, accounting for subgroup differences. A PRISMA systematic search, appraisal, and meta-analysis were conducted of 126 analyses in 77 publications (n = 25 692). The overall rate of MetS was 32.5% (95% CI = 30.1%–35.0%), and there were only minor differences according to the different definitions of MetS, treatment setting (inpatient vs outpatient), by country of origin and no appreciable difference between males and females. Older age had a modest influence on the rate of MetS (adjusted R 2 = .20; P < .0001), but the strongest influence was of illness duration (adjusted R 2 = .35; P < .0001). At a study level, waist size was most useful in predicting high rate of MetS with a sensitivity of 79.4% and a specificity of 78.8%. Sensitivity and specificity of high blood pressure, high triglycerides, high glucose and low high-density lipoprotein, and age (>38 y) are shown in supplementary appendix 2 online. Regarding prescribed antipsychotic medication, highest rates were seen in those prescribed clozapine (51.9%) and lowest rates of MetS in those who were unmedicated (20.2%). Present findings strongly support the notion that patients with schizophrenia should be considered a high-risk group. Patients with schizophrenia should receive regular monitoring and adequate treatment of cardio-metabolic risk factors.

To the authors’ knowledge, the present large-scale meta-analysis is the first to demonstrate that almost 1 in 3 of unselected patients with schizophrenia suffer from MetS. We found 126 valid analyses in 77 publications within the period 2003 to July 2011 (see figure 1). This indicates that the cardio-metabolic risk in patients with schizophrenia is clearly becoming recognized as a key consideration in the long-term health of these patients. Examining individual cardio-metabolic risk abnormalities, 1 in 2 patients with schizophrenia are overweight, 1 in 5 appear to have significant hyperglycaemia, and at least 2 in 5 have lipid abnormalities when systematically tested .

Although with limitations, our findings demonstrate that patients with schizophrenia are a high-risk group for MetS. They should therefore be routinely screened for MetS risk factors at key stages.[54,55] This can be achieved by establishing a risk profile based on consideration of medical factors (eg, obesity, dyslipidaemia, hypertension, hyperglycaemia, and established diabetes) but also behavioral factors (eg, poor diet, smoking, and physical inactivity). This risk profile can then be used as a basis for ongoing monitoring, treatment selection, and management.

Our meta-analysis clearly demonstrates that MetS risk factors are highly prevalent in patients with schizophrenia. Psychiatrists need to be aware of the potential metabolic side effects of antipsychotic medication and to include them in the risk/benefit assessment when choosing a specific antipsychotic. The treating psychiatrists should also be responsible for the implementation of the necessary screening assessments and referral for treatment. Multidisciplinary assessment of medical and behavioral conditions is needed. Psychiatric treatment facilities should offer and promote healthy lifestyle intervention early in the course of disease aiming to prevent serious metabolic adverse effects. Future research should focus on evaluating interventions that target MetS and examine if cardio-metabolic outcomes are moderated by clinical characteristics and genetic factors.

Alex J. Mitchell, Davy Vancampfort, Kim Sweers, Ruud van Winkel, Weiping Yu, Marc De Hert

Schizophr Bull. 2013;39(2):306-318.

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High C-Reactive Protein Linked to Late-Onset Schizophrenia

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A new study shows a link between elevated levels of C- reactive protein (CRP) and increased risk for late- and very-late-onset schizophrenia.

CRP has previously been linked to increased risk for cardiovascular disease, and more recently, in a study by these same researchers, with risk for depression. In this prospective study, elevated baseline levels of CRP were associated with a significantly increased risk for late-onset and very-late-onset schizophrenia in a general population in Denmark.

“These are novel findings,” the researchers, with lead author Marie Kim Wium-Andersen, MD, from the Department of Clinical Biochemistry at Herlev Hospital and the Copenhagen University Hospital in Denmark, conclude.

“We had up to 19 years of follow-up, and after adjusting for all the other factors that would also increase CRP — smoking, body mass index, alcohol, education, income, diabetes, and all risk factors — we still saw significantly increased risk of schizophrenia; for those who had even very small elevations of CRP, they still have a 6-times increased risk for schizophrenia,” Dr. Wium-Andersen told Medscape Medical News.

by Susan Jeffrey, Medscape

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Medicare Won’t Approve Vegas Nerve Stimulation (VNS) for Depression Treatment

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The federal Centers for Medicare and Medicaid Services (CMS) has rejected a request from the manufacturer of a vagus nerve stimulation (VNS) device to approve it for treatment of severe depression in Medicare beneficiaries. Cyberonics announced on Tuesday that its request that CMS approve the company’s VNS Therapy for treatment-resistant depression was not successful.

The company had originally applied for CMS approval in 2007, but the agency rejected the application at that time. Cyberonics had hoped that additional evidence over the last five years supporting VNS’s efficacy in depression treatment would lead CMS administrators to reverse their earlier decision, but that did not happen. Cyberonics is hopeful that VNS Therapy will eventually gain that approval, with CEO Dan Moore saying that “The company plans to work with other interested parties to continue to pursue access to this important therapeutic option….” The VNS system has already been approved by the Food and Drug Administration for use in patients with treatment-resistant depression and with epilepsy patients. CMS has approved reimbursement for its use in Medicare beneficiaries with refractory epilepsy.

–Psychiatry News Alert

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A New Psychiatry Subspecialty?

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Interventional psychiatry is an emerging subspecialty that uses brain stimulation techniques to modulate the dysfunctional circuitry underlying medically resistant psychiatric diseases. Physicians who deliver procedures in the spectrum between standard care and surgery are sometimes referred to as “interventionalists” in other areas of medicine (eg, cardiology, radiology, and neurology). Currently, the field of psychiatry does not recognize interventionalists or offer formal training and certification. Our group is proposing the concept of “interventional psychiatrist” in place of procedure-specific terms such as “somatic therapist” or “ECT (electroconvulsive therapy) practitioner,” which fail to encompass the scope of brain stimulation strategies. It is not meant to replace current psychiatric therapies (medication and psychotherapy) but rather to enhance the practice of psychiatry with an additional set of tools. This can be viewed much in the same way that interventional cardiologists do not replace general cardiologists.

by Bret S. Stetka, MD, Edward M. Kantor, MD, Nolan R. Williams, MD

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Association Between Parental Hospital-Treated Infection and the Risk of Schizophrenia in Adolescence and Early Adulthood

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It has been suggested that infection during perinatal life may lie at the etiological root of schizophrenia. It has thus been hypothesized that the origin of schizophrenia may lie either in direct fetal infection and/or in a generally increased familial susceptibility to infections, some of which may occur during pregnancy. We explored these 2 hypotheses by assessing maternal infection during pregnancy and maternal as well as paternal infection in general as predictors of schizophrenia in their offspring. We found a slightly increased risk to be associated with prenatal infection exposure. However, the effect of prenatal infection exposure was not statistically significantly different from the effect of infection exposure in general. Parental infection appeared to be associated with development of schizophrenia in adolescence and early adulthood. Our study does not exclude a specific effect of infection during fetal life; yet, it does suggest that schizophrenia is associated with an increased familial liability to develop severe infection.

by Philip R. Nielsen, Thomas M. Laursen, Preben B. Mortensen

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