Category: Bipolar Disorder

Over the past 30 years, numerous studies have linked Borna disease virus (BDV) with mental illnesses such as bipolar disorder, schizophrenia, anxiety disorder, and dementia. Genetic fragments and antibodies to this RNA virus, which causes behavior disorders in a range of mammals and birds, have been found to be prevalent in psychiatric patients, but study results have been inconsistent. Now, the first blinded, case-control study to examine this issue finds no association between the virus and psychiatric illness.

The study, conducted by researchers at the Center for Infection and Immunity at Columbia University's Mailman School of Public Health and collaborators at seven other institutions in the U.S., Germany and Australia, can be found online at Molecular Psychiatry.

The scientists evaluated 198 patients in California with schizophrenia, bipolar disorder, and major depressive disorder, carefully matched each one of them with a healthy control of the same sex, age, region, and socio-economic status, and tested blood of patients and controls for the presence of BDV genetic material and antibodies to BDV.

The investigators hypothesized that if the virus was, in fact, associated with a psychiatric disorder, genetic evidence of infection would be apparent in blood samples taken at the onset and/or at the peak of a psychiatric episode, and antibody evidence would be detectable several weeks afterward. Blood samples were therefore collected within six weeks of the onset of an acute episode or clinically significant worsening of symptoms and six weeks later to allow for changes in viral load or antibody levels. Not only did the researchers find no relationship between mental illness and bornavirus, they found no evidence of active or historical infection with BDV in any of the subjects.

"Our study provides compelling evidence that bornaviruses do not play a role in schizophrenia or mood disorders," says Mady Hornig, MD, director of translational research at the Center for Infection and Immunity.

In a commentary in the same issue of the journal, Michael B.A. Oldstone, MD, an expert in molecular virology and central nervous system infections at the Scripps Research Institute, observes that the design and experimental procedures carried out in the Hornig study provide a gold standard for investigating links between persistent viral infection and human disease.

CII director, W. Ian Lipkin, MD, senior author of the paper, notes that "it was concern over the potential role of BDV in mental illness and the inability to identify it using classical techniques that led us to develop molecular methods for pathogen discovery. Ultimately these new techniques enabled us to refute a role for BDV in human disease. But the fact remains that we gained strategies for the discovery of hundreds of other pathogens that have important implications for medicine, agriculture, and environmental health."

Scientists have gained insight into why lithium salts are effective at treating bipolar disorder in what could lead to more targeted therapies with fewer side-effects.

Bipolar disorder is characterised by alternating states of elevated mood, or mania, and depression. It affects between 1% and 3% of the general population.

The extreme 'mood swings' in bipolar disorder have been strongly associated with disruptions in circadian rhythms — the 24-hourly rhythms controlled by our body clocks that govern our day and night activity.

For the last 60 years, lithium salt (lithium chloride) has been the mainstay treatment for bipolar disorder but little research has been carried out to find out whether and how lithium impacts on the brain and peripheral body clockwork.

"Our study has shown a new and potent effect of lithium in increasing the amplitude, or strength, of the clock rhythms, revealing a novel link between the classic mood-stabiliser, bipolar disorder and body clocks," said lead researcher Dr Qing-Jun Meng, in the University's Faculty of Life Sciences.

"By tracking the dynamics of a key clock protein, we discovered that lithium increased the strength of the clockwork in cells up to three-fold by blocking the actions of an enzyme called glycogen synthase kinase or GSK3.

"Our findings are important for two reasons: firstly, they offer a novel explanation as to how lithium may be able to stabilise mood swings in bipolar patients; secondly, they open up opportunities to develop new drugs for bipolar disorder that mimic and even enhance the effect lithium has on GSK3 without the side-effects lithium salts can cause."

These side-effects include nausea, acne, thirstiness, muscle weakness, tremor, sedation and/or confusion. Promisingly, GSK3 inhibiting drugs are already in development, as they have been shown to be important in other diseases, including diabetes and Alzheimer's disease.

Dr Meng added: "Lithium salt has a wide spectrum of targets within cells, in addition to GSK3; drugs which only block the actions of GSK3 would therefore have the major advantage of reduced 'off-target' effects of lithium.

"Our study has identified the robust rhythm-enhancing effect of GSK3 inhibition, which has potential to be developed as a new pharmacological approach to regulate body clocks. The implications of our study are that there may also be beneficial effects leading to new treatments for bipolar disorder, and this now needs to be tested."

The research, funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (BBSRC), is published in the journal Public Library of Science (PLoS) One.

Adolescents diagnosed with schizophrenia and other psychoses appear to show greater decreases in gray matter volume and increases in cerebrospinal fluid in the frontal lobe compared to healthy adolescents without a diagnosis of psychosis, according to a report in the January issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

"Progressive loss of brain gray matter (GM) has been reported in childhood-onset schizophrenia; however, it is uncertain whether these changes are shared by pediatric patients with different psychoses," the authors write as background information in the study.

Celso Arango, M.D., Ph.D., of the Hospital General Universitario Gregorio Marañón, Madrid, Spain, and colleagues, examined the progression of brain changes in first-episode early-onset psychosis and the relationship to diagnosis and prognosis at two-year follow-up among patients at six child and adolescent psychiatric units in Spain. The authors performed magnetic resonance imaging (MRI) of the brain for 61 patients (25 diagnosed with schizophrenia, 16 with bipolar disorder and 20 with other psychoses) and 70 healthy control participants. MRI scans were conducted at study baseline and after two years of follow-up.

Compared with control patients, those diagnosed with schizophrenia showed greater gray matter volume loss in the frontal lobe during the two-year follow-up. Patients with schizophrenia also showed cerebrospinal fluid increase in the left frontal lobe. Additionally, changes for total brain gray matter and left parietal gray matter were significantly different in patients with schizophrenia compared with patients in the control group.

Among patients with schizophrenia, progressive brain volume changes in certain areas were related to markers of poorer prognosis, such as more weeks of hospitalization during follow-up and less improvement in negative symptoms. Greater left frontal gray matter volume loss was related to more weeks of hospitalization whereas severity of negative symptoms correlated with cerebrospinal fluid increase in patients with schizophrenia.

The authors did not find any significant changes in patients with bipolar disorder compared to control patients, and longitudinal brain changes in the control group were consistent with the expected pattern described for healthy adolescents.

"In conclusion, we found progression of gray matter volume loss after a two-year follow-up in patients who ended up with a diagnosis of schizophrenia but not bipolar disease compared with healthy controls," the authors write. "Some of these pathophysiologic processes seem to be markers of poorer prognosis. To develop therapeutic strategies to counteract these pathologic progressive brain changes, future studies should focus on their neurobiological underpinnings."

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Journal Reference:

1. C. Arango, M. Rapado-Castro, S. Reig, J. Castro-Fornieles, A. Gonzalez-Pinto, S. Otero, I. Baeza, C. Moreno, M. Graell, J. Janssen, M. Parellada, D. Moreno, N. Bargallo, M. Desco. Progressive Brain Changes in Children and Adolescents With First-Episode Psychosis. Archives of General Psychiatry, 2012; 69 (1): 16 DOI: 10.1001/archgenpsychiatry.2011.150

A new study provides support for a bi-directional pathway between non-medical prescription opioid use and opioid-use disorder due to non-medical use and several mood anxiety disorders.

Individuals suffering from mood and anxiety disorders such as bipolar, panic disorder and major depressive disorder may be more likely to abuse opioids, according to a new study led by researchers from the Johns Hopkins Bloomberg School of Public Health. They found that mood and anxiety disorders are highly associated with non-medical prescription opioid use. The results are featured in a recent issue of the Journal of Psychological Medicine.

Prescription opioids such as oxycontin are a common and effective treatment for chronic and acute pain. Non-medical use of prescription opioids has increased dramatically and, according to the Substance Abuse and Mental Health Services Administration, prescription opioids are the second most frequently used illegal drug in the U.S. after marijuana. Prescription opioids are highly addictive and prolonged use can produce neurological changes and physiological dependence. For the study, researchers examined the association between individuals with mood and anxiety disorders with non-medical prescription opioid use and opioid disorder.

"Lifetime non-medical prescription opioid use was associated with the incidence of any mood disorder, major depressive disorder, bipolar disorder and all anxiety disorders. Non-medical opioid-use disorder due to non-medical prescription opioid use was associated with any mood disorder, any anxiety disorder, as well as with several incident mood disorders and anxiety disorders," said Silvia Martins, MD, PhD, lead author of the study and an associate scientist with the Bloomberg School's Department of Mental Health. "However, there is also evidence that the association works the other way too. Increased risk of incident opioid disorder due to non-medical use occurred among study participants with baseline mood disorders, major depressive disorder, dysthymia and panic disorder, reinforcing our finding that participants with mood disorders might use opioids non-medically to alleviate their mood symptoms. Early identification and treatment of mood and anxiety disorders might reduce the risk for self-medication with prescription opioids and the risk of future development of an opioid-use disorder."

Using data from the National Epidemiologic Study on Alcohol and Related Conditions (NESARC), a longitudinal face-to-face survey of individuals aged 18 years and older between 2001 to 2002 and 2004 to 2005, researchers assessed participants for a history of psychiatric disorders. Non-medical use of prescription opioids was defined to participants as using a prescription opioid without a prescription or in greater amounts more often or longer than prescribed or for a reason other than a doctor's instruction to use them. Logistic regression was used to determine whether lifetime non-medical prescription opioid use and opioid disorders due to this use predicted incident mood and anxiety disorders and the reverse. Researchers believe these findings provide support for a bi-directional pathway between non-medical prescription opioid use and opioid-use disorder due to non-medical use and several mood and anxiety disorders.

"With the current increased use of non-medical prescription drugs, especially among adolescents, the association with future psychopathology is of great concern. Using opioids, or even withdrawal from opioids, might precipitate anxiety disorders, suggesting that there is a subgroup of people who are vulnerable to future development of anxiety disorders," said Carla Storr, ScD, author of the study and an adjunct professor with the Bloomberg School's Department of Mental Health. Individuals using prescription opioids need to be closely monitored not only for the possibility of engaging in non-medical use, but also for the development of co-morbid psychiatric disorders.

"Additional studies are needed to examine the relationship between non-medical prescription opioid use and prescription opioid-use disorder with mood and anxiety disorders since they could co-occur due to shared genetic or environmental risk factors," Martins adds.

The research was supported by grants from the National Institute on Drug Abuse and by the New York State Psychiatric Institute.

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Journal Reference:

1. S. S. Martins, M.C. Fenton, K.M Keyes, C. Blanco, H. Zhu and C. L. Storr. Mood and anxiety disorders and their association with non-medical prescription opioid use and prescription opioid-use disorder: longitudinal evidence from the National Epidemiologic Study on Alcohol and Related Conditions. Journal of Psychological Medicine, 2011

Experiencing a psychiatric episode within the first 30 days post-partum appears to be associated with an increased risk of developing bipolar affective disorder, according to a report published Online First by Archives of General Psychiatry, one of the JAMA/Archives journals.

"Childbirth has an important influence on the onset and course of bipolar affective disorder, and studies have shown that episodes of post-partum psychosis are often best considered as presentations of bipolar affective disorder occurring at a time of dramatic psychological and physiological change," the authors write as background information in the article. "It is also clear, however, that a high number of women with the new onset of a psychiatric disorder in the immediate post-partum period do not receive a diagnosis of bipolar disorder."

Trine Munk-Olsen, Ph.D., of the National Centre for Register-Based Research, Arhus University, Arhus, Denmark, and colleagues collected data on 120,378 women born in Denmark from 1950 to 1991 who were alive in 2006 and had a history of a first-time psychiatric contact with any type of psychiatric disorder (admission or outpatient contact) with any type of psychiatric disorder excluding bipolar affective disorder. Each woman was followed up with individually from the day of discharge, with data collected on inpatient or outpatient psychiatric contacts during the follow-up period.

A total of 2,870 of these women had their initial psychiatric contact within the first year after delivery of their first child. During follow-up, 3,062 of the 120,378 women received diagnoses of bipolar affective disorder, of which 132 had their initial psychiatric contact 0 to 12 months post-partum. After adjusting for first diagnosis and family history of psychiatric illness, conversion rates to bipolar disorder were significantly predicted by the timing of initial psychiatric contact. The authors found a significantly higher conversion rate to bipolar affective disorder in women having their initial contact within the first post-partum month. Additionally, the authors found evidence that the severity of the initial post-partum psychiatric episode may be important, as inpatient admissions were associated with a higher conversion rate than were outpatient contacts.

Fifteen years after initial contact, 13.87 percent of women with onset in the immediate post-partum period (0 to 30 days) had converted to bipolar disorder, 4.69 percent of women with later onset (31 to 365 days post-partum) and 4.04 percent of women with onset at other points had converted to bipolar disorder. Additionally, an extended analysis showed that 18.98 percent of women with onset in the immediate post-partum period had converted to bipolar disorder within 22 years after initial psychiatric contact. Conversely, 6.51 percent of women with later post-partum onset and 5.43 percent of women with onset at other points had converted to bipolar disorder after 22 years.

"The present study confirms the well-established link between childbirth and bipolar affective disorder and specifically adds to this field of research by demonstrating that initial psychiatric contact within the first 30 days post-partum significantly predicted conversion to bipolar affective disorder during the follow-up period," the authors conclude. "Results indicate that the presentation of mental illness in the early post-partum period is a marker of possible underlying bipolarity."

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Journal Reference:

1. Trine Munk-Olsen; Thomas Munk Laursen; Samantha Meltzer-Brody; Preben Bo Mortensen; Ian Jones. Psychiatric Disorders With Postpartum Onset: Possible Early Manifestations of Bipolar Affective Disorders. Archives of General Psychiatry, 2011; DOI: 10.1001/archgenpsychiatry.2011.157

Functional psychosis can be diagnosed from the first indications of the patient, thanks to affective symptomatology. Depressive moods, hyperactivity and lack of concentration are affective symptoms that can present themselves during the first psychotic episodes, and the presence or absence of any of them may contribute to differentiating, at an early stage, between the different variations of the mental disease. Thus concludes researcher Ms Marta Arrasate, who also pointed to the symptoms belonging to the activation dimension (verborrhea, lack of concentration, hyperactivity, etc.) as the best indicators.

Her thesis, defended at the UPV/EHU, was entitled Valor predictivo de la sintomatología afectiva en primeros episodios psicóticos (Predictive value of affective symptomatology during the first psychotic episodes).

This is the first European PhD undertaken at the Álava/Araba Unit of the Faculty of Medicine of the UPV/EHU, and was codirected by Ana González-Pinto, 2010 National Award winner of the Spanish Society for Biological Psychiatry. According to Ms González-Pinto, the relevance of the research lies in that "affective symptoms can help not only in telling future prognosis but also in contributing to diagnosis — something difficult in psychiatry because diagnostic tests equivalent to a radiograph, an analysis or a scanner do not exist. This is why, if a test were found, however simple, or rudimentary, it would be of great use."

Evaluation in three stages

Ms Arrasate undertook the study based on a sample of 112 hospitalised patients with a first psychotic episode, and analysed the predictive value of the affective symptoms that present themselves in three concrete moments: initial hospital admission, the third year and the fifth year. In order to evaluate the results, the different affective symptoms were grouped according to dimensions (these classifications being based on a previous study of patients with bipolar disorders), and associated with variables such as the number of relapses, hospital or health centre admissions, suicide attempts, etc.

The results show that the activation dimension (involving symptoms of hyperactivity, lack of concentration and verborrhea, amongst others) can be an especially useful tool for early distinguishing between the various types of psychotic symptoms. This is what has been deduced from the data obtained from a study of one of the principal diseases in this field: bipolar disorder. According to Ms Arrasate's research, the activation and manic dimensions are those which best characterise bipolar disorder. Nevertheless, the manic dimension is absent in the first episodes; moreover, that which is present during these first episodes is the depressive dimension, thus possibly giving rise to confusion and inability in making an early and correct diagnosis. Thus, the results point to the activation dimension as the reliable path to follow: it is a useful predictive factor in the early diagnosis of bipolar disorder with psychotic symptoms.

These results open a new line of research as they prove that affective symptoms are able to discriminate between different psychoses, and contribute to an early diagnosis during its course. In fact, the evaluating panel for Ms Arrasate's thesis have made a point of informing those experts responsible for reviewing diagnostic criteria of mental diseases worldwide of these findings.

— Low levels of a brain protein that regulates gene expression may play a role in the origin of bipolar disorder, a complex and sometimes disabling psychiatric disease. As reported in the latest issue of Bipolar Disorders, the journal of The International Society for Bipolar Disorders, levels of SP4 (specificity protein 4) were lower in two specific regions of the brain in postmortem samples from patients with bipolar disorder. The study suggests that normalization of SP4 levels could be a relevant pharmacological strategy for the treatment of mood disorders.

"We found that levels of SP4 protein in the brain's prefrontal cortex and the cerebellum were lower in postmortem samples from patients with bipolar disorder, compared with samples from control subjects who did not have the disease," said co-senior author Grace Gill, PhD, an associate professor in the department of anatomy and cellular biology at Tufts University School of Medicine and a member of the neuroscience; genetics; and cell, molecular and developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

Gill's laboratory team at Tufts collaborated with researchers from Spain and used postmortem samples from Spain's University of the Basque Country brain collection program to examine SP4 protein levels in samples from 10 bipolar subjects and 10 control subjects matched for gender, age, and time since death.

The team focused on the prefrontal cortex and the cerebellum because brain imaging studies suggest that bipolar disorder is associated with changes in the structure of these brain regions. Little is known about the cellular and molecular changes that occur in bipolar disorder, especially in the cerebellum.

"Our findings suggest that reduced activity of the SP4 protein may be common in bipolar disorder," stated co-senior author Belén Ramos, PhD, a former postdoctoral fellow in Gill's lab and now a researcher at the Parc Sanitari Sant Joan de Déu (PSSJD) and the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) in Barcelona, Spain.

Ramos explained that SP4 belongs to a category of proteins known as transcription factors, which regulate gene expression. "While this study examined the SP4 protein levels, mutations in the gene encoding the SP4 protein have been associated with psychiatric diseases including bipolar disorder, a poorly understood disease characterized by episodes of abnormally elevated energy levels with or without depressive episodes, as well as schizophrenia, and major depressive disorder. Thus, our study adds to the growing body of evidence that alterations in gene regulation contribute to the development of psychiatric disorders," said Ramos.

Further analysis showed that SP4 levels are regulated by neuronal activity, indicating that this transcription factor is important for normal neuronal signaling. "Looking at normal rat neurons in culture, we found that SP4 is rapidly degraded by enzymes in the absence of neuronal signaling, which we refer to as the non-depolarized state," said first author Raquel Pinacho, BS, MS, a graduate student in Ramos' lab in PSSJD.

In previous work, the researchers had identified an essential role for SP4 in regulating the structure of nerve cells during development. Taken together, the findings suggest that reduced levels of this protein may contribute to altered patterns of nerve cells in the brain.

"Moreover," added Ramos, "we demonstrated that the destruction of SP4 by enzymes was inhibited by lithium, a drug widely used as a mood stabilizer for patients with bipolar disorder. When lithium was added to cells in the non-depolarized — inactive — state, levels of SP4 were stabilized and increased. This finding suggests that the therapeutic effects of lithium may be related, at least in part, to changes in gene expression leading to changes in cellular structure and function."

In addition to measuring levels of SP4, Gill and colleagues assessed levels of SP1, a related transcription factor protein that has been reported to be altered in schizophrenia. Like SP4, SP1 was reduced in the cerebellum of subjects with bipolar disorder. According to the authors, this finding suggests that both factors may be relevant transcriptional regulators, low levels of which may contribute to the pathogenesis of bipolar disorder and other psychiatric diseases. However, unlike SP4, levels of SP1 did not appear to be regulated by neuronal activity, highlighting the complexity of the mechanisms involved in functional specificity in the SP transcription factor family.

Additional authors on the study are Nuria Villalmanzo, a research assistant in Ramos's lab in PSSJD, Jasmin Lalonde, PhD, a postdoctoral fellow in Gill's lab at TUSM; Josep Maria Haro, MD, PhD, of PSSJD and CIBERSAM; and J. Javier Meana, MD, PhD, professor in the department of pharmacology at the University of the Basque Country in Bizkaia, Spain, and CIBERSAM.

The study was funded by the National Institute of Child Health and Human Development, part of the National Institutes of Health, a Marie Curie International Reintegration Grant (European Union) and the Plan National de Investigación (Spain). This study was also supported by fellowships to authors from the Spanish Ministry of Science and Education /Fulbright, CIBERSAM, and from the Canadian Institutes of Health Research.

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Journal Reference:

1. Raquel Pinacho, Nuria Villalmanzo, Jasmin Lalonde, Josep Maria Haro, J Javier Meana, Grace Gill, Belén Ramos. The transcription factor SP4 is reduced in postmortem cerebellum of bipolar disorder subjects: control by depolarization and lithium. Bipolar Disorders, 2011; 13 (5-6): 474 DOI: 10.1111/j.1399-5618.2011.00941.x

Knowledge about the biological origin of diseases like schizophrenia, bipolar disorder and other psychiatric conditions is critical to improving diagnosis and treatment.

In an effort to push the field forward, three UCLA researchers, along with scientists from more than 20 countries, have been taking part in one of the largest collaborative efforts in psychiatry — a genome-wide study involving more than 50,000 study participants aimed at identifying which genetic variants make people susceptible to psychiatric disease.

This collaborative, the Psychiatric Genome-Wide Association Study Consortium (PGC), now reports in the current online edition of the journal Nature Genetics that it has discovered that common genetic variants contribute to a person's risk of schizophrenia and bipolar disorder.

The PGC's studies provide new molecular evidence that 11 regions on the genome are strongly associated with these diseases, including six regions not previously observed. The researchers also found that several of these DNA variations contribute to both diseases.

The findings, the researchers say, represent a significant advance in understanding the causes of these chronic, severe and debilitating disorders.

The UCLA researchers who contributed to the schizophrenia study are Roel A. Ophoff, a professor of psychiatry and human genetics and one of the founding principal investigators of the schizophrenia portion of the study; Dr. Nelson Freimer, a professor of psychiatry and director of the Center for Neurobehavioral Genetics at the Semel Institute for Neuroscience and Human Behavior at UCLA; and Rita Cantor, a professor of psychiatry and human genetics.

Schizophrenia and bipolar disorder are common and often devastating brain disorders. Some of the most prominent symptoms of schizophrenia are persistent delusions, hallucinations and cognitive problems. Bipolar disorder is characterized by severe, episodic mood swings. Both affect about 1 percent of the world's population and usually strike in late adolescence or early adulthood.

Despite the availability of treatments, these illnesses are usually chronic, and patients' response to treatment is often incomplete, leading to prolonged disability and personal suffering. Family history, which reflects genetic inheritance, is a strong risk factor for both schizophrenia and bipolar disorder, and it has generally been assumed that dozens of genes, along with environmental factors, contribute to disease risk.

In the schizophrenia study, a total of seven locations on the genome were implicated in the disease, five of which had not been identified before. When similar data from the bipolar disorder study, which ran concurrently, were combined with results from the schizophrenia study, three gene locations were identified that proved to be involved in both disorders, suggesting a "genetic overlap" between schizophrenia and bipolar disorder.

"Genetic factors play an important role in the susceptibility to develop schizophrenia," Ophoff said, "but identifying these genetic factors has been very difficult. We know that schizophrenia is not caused by a single gene that explains everything but an interplay of many genetic and non-genetic factors."

At the same time, he said, the disease itself is not uniform but manifests itself in different ways; currently, there is no objective biological marker or "sign" that can be used for diagnosis.

"This so-called heterogeneity at the genetic and clinical level is the biggest challenge for genetic studies of neuropsychiatric disorders," Ophoff said. "One way to deal with these difficulties is to increase the size of the study so there is sufficient 'power' to detect genetic effects, even amidst this clinical and genetic diversity."

The fact that even this large study resulted in a limited number of schizophrenia and bipolar genes demonstrates once again, he said, the complex nature of the disease.

Formed in 2007, the PGC is the largest consortium ever in psychiatry. Over 250 researchers from more than 20 countries have come together in an unparalleled spirit of cooperation to advance knowledge of the genetic causes of mental illness. Crucial to the success of the project was the willingness of many groups to share genetic data from tens of thousands of patients collected over many years.

The research was funded by numerous European, American and Australian funding bodies. Funds for coordination of the consortium were provided by the National Institute of Mental Health in the U.S.

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Journal References:

1. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nature Genetics, 2011; DOI: 10.1038/ng.940
2. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nature Genetics, 2011; DOI: 10.1038/ng.943

— In the first study to systematically investigate genome-wide epigenetic differences in a large number of psychosis discordant twin-pairs, research at the Institute of Psychiatry (IoP) at King's College London provides further evidence that epigenetic processes play an important role in neuropsychiatric disease.

Published in Human Molecular Genetics, the findings may offer potential new avenues for treatment.

Previous quantitative genetic analyses of schizophrenia and bipolar disorder reveal strong inherited components to both. However, although heritability for schizophrenia and bipolar disorder is estimated at 70%, disease concordance between twin-pairs is far from 100%, indicating that non-genetic factors play an important role in the onset of the diseases.

Dr. Jonathan Mill, lead author of the study at the IoP says, 'We studied a group of 22 identical twin-pairs, so 44 individuals in all, one of the largest twin studies performed for any complex disease to date. In each twin-pair, one had either schizophrenia or bipolar disorder. Because we know that twins are genetically identical, we can rule out any genetic cause of illness in the affected twin — the aim of our study was to investigate epigenetic variations associated with these disorders.'

Epigenetic mechanisms are linked to heritable, but reversible, changes in gene expression without a change in the underlying DNA sequence. This happens principally through alterations in DNA methylation and chromatin structure. Epigenetic changes in the brain have previously been associated with a range of biological and cognitive processes, including neurogenesis, drug addiction and neurodegeneration. It has also been suggested that epigenetic changes in the brain may be involved in a spectrum of psychiatric disorders including psychosis.

The researchers looked at differences in DNA methylation across the genome using DNA taken from both the affected and unaffected twins in each monozygotic twin-pair. The findings were then compared to DNA samples taken from post-mortem brain material from psychosis patients and controls.

Whilst the researchers found no alterations in overall DNA methylation content between affected and unaffected twins, there were considerable disease-associated differences between twins at specific sites across the genome. The findings confirmed previously known sites implicated in psychiatric disorders as well as revealing previously unknown ones.

Dr. Mill adds, 'Our findings suggest that it is not only genetic variations that are important. The epigenetic differences we see may tell us more about the causes or schizophrenia and bipolar disorder, as some alterations were specific to either disease. Importantly, epigenetic processes are potentially reversible meaning that our research could open up new avenues for the development of novel therapeutic drugs.'

The research was funded by the National Alliance for Research on Schizophrenia and Depression (NARSAD), the National Institute of Health (NIH), the Medical Research Council (MRC) and the Wellcome Trust. The work was supported by the European Community's Sixth Framework Programme through a Marie Curie Training Network called the European Twin Study Network on Schizophrenia (EUTwinsS). Postmortem brains were donated by The Stanley Medical Research Institute courtesy of Michael B. Knable, E. Fuller Torrey, Maree J. Webster, and Robert H. Yolken.

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Journal Reference:

1. E. L. Dempster, R. Pidsley, L. C. Schalkwyk, S. Owens, A. Georgiades, F. Kane, S. Kalidindi, M. Picchioni, E. Kravariti, T. Toulopoulou, R. M. Murray, J. Mill. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Human Molecular Genetics, 2011; DOI: 10.1093/hmg/ddr416

A team of over 250 researchers from more than 20 countries have discovered that common genetic variations contribute to a person's risk of schizophrenia and bipolar disorder.

The study of more than 50,000 adults ages 18 and older provides new molecular evidence that 11 DNA regions in the human genome have strong association with these diseases, including six regions not previously observed. The researchers also found that many of these DNA variants contribute to both diseases.

The findings, reported by the Psychiatric Genome-Wide Association Study Consortium and published online Sept. 18, 2011 in two papers in the journal Nature Genetics, represent significant advances in the understanding the causes of these chronic, severe, and debilitating disorders.

Also known as a whole genome association study, a genome-wide association study examines all or most of the genes of different individuals to see how much the genes vary from individual to individual.

"This is the largest study of its kind by far," said Patrick F. Sullivan, MD, Ray M. Hayworth & Family Distinguished Professor of Psychiatry and professor of genetics at the University of North Carolina at Chapel Hill. Sullivan, a PGC coordinator and principal investigator in the study, is also a member of the UNC Lineberger Comprehensive Cancer Center and the Carolina Center for Genome Sciences.

The study that focused on schizophrenia identified "strong evidence for seven different places in the human genome, five of which were new and two previously implicated, that contain DNA changes that are significantly associated with schizophrenia," Sullivan said.

And in a joint analysis of a schizophrenia and bipolar disorder sample, the Consortium found three different DNA regions, or loci, in which both disorders reached genome-wide statistical significance. "This tells us that these disorders, which many of us have considered to be separate things, actually share fundamental similarity," Sullivan said.

Schizophrenia and bipolar disorder are common and often devastating brain disorders. Some of the most prominent symptoms in schizophrenia are persistent delusions, hallucinations and cognitive problems. Bipolar disorder (or manic-depressive illness) is characterized by episodes of severe mood problems including mania and depression. Both affect about 1 percent of the world's population and usually strike in late adolescence or early adulthood. Despite the availability of treatments, these illnesses are usually chronic, and response to treatment is often incomplete leading to prolonged disability and personal suffering. Family history, which reflects genetic inheritance, is a strong risk factor for both schizophrenia and bipolar disorder, and it has generally been assumed that dozens of genes, along with environmental factors, contribute to disease risk.

"The consortium is the largest research consortium ever in psychiatry and is certainly the largest biological experiment we've ever done in the field," Sullivan said. "We are studying on the order of 90,000 individuals across multiple disorders, while trying to do something for the greater good, which is effectively to go as far and as deep as we can in understanding the genomics of mental illness."

The research was funded by numerous European, U.S., and Australian funding bodies. Funds for coordination of the consortium were provided by the National Institute of Mental Health in Bethesda, Md.

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Journal References:

1. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nature Genetics, 2011; DOI: 10.1038/ng.940
2. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nature Genetics, 2011; DOI: 10.1038/ng.943