Transcranial Stimulation Has Potential as Add-On Therapy For Bipolar Depression

MedicalResearch.com Interview with:

Yokoi and Sumiyoshi. 2015 tDCS administration at National Center of Neurology and Psychiatry Hospital. A subject (front) sits on a sofa relaxed, and a researcher (behind) controls the tDCS device (a). In this picture, anodal (b) and cathodal (c) electrodes with 35-cm2 size are put on F3 and right supraorbital region, respectively. We use a head strap (d) for convenience and reproducibility, and also use a rubber band (e) for reducing resistance

tDCS administration at National Center of Neurology and Psychiatry Hospital. A subject (front) sits on a sofa relaxed, and a researcher (behind) controls the tDCS device (a). In this picture, anodal (b) and cathodal (c) electrodes with 35-cm2 size are put on F3 and right supraorbital region, respectively. We use a head strap (d) for convenience and reproducibility, and also use a rubber band (e) for reducing resistance
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Andre Russowsky Brunoni, MD, PhD
Coordinator, Service of Interdisciplinary Neuromodulation, Laboratory of Neurosciences  Department and Institute of Psychiatry
Coordinator, Interdisciplinary Center for Applied Neuromodulation, University Hospital
University of São Paulo
São Paulo, Brasil 

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

Response: In this study, our aim was to evaluate the safety and efficacy of transcranial direct current stimulation (tDCS) as an add-on treatment for patients with bipolar depression. There are a only few treatment alternatives for bipolar depression, which often have important side effects. Thus, we wanted to evaluate the efficacy of this non-pharmacological treatment.

We found that active vs. sham tDCS effected greater response and remission for patients with bipolar depression. The frequency of adverse effects was similar, including treatment-emergent affective switches. However, higher rates of skin redness were observed in the active group.

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Positive Topline Results from Phase 3 Study of Cariprazine for the Treatment of Bipolar I Depression

MedicalResearch.com Interview with:
allergan
Gary Sachs, MD
Associate Clinical Professor of Psychiatry
Harvard Medical School 

MedicalResearch.com: What is the background for this data milestone?

Response: Bipolar disorder affects about 5.7 million adults in the United States.  It is a common, often disabling condition in which abnormal mood states impair a person’s ability to carry out everyday tasks. Bipolar disorder touches nearly every family and community in America, because periods of illness, a patient’s symptoms often impact their family, their friends, and their community.

There are a limited number of products approved to treat bipolar depression and even fewer products that have been studied and approved to treat the full spectrum of bipolar disorder, from mania through depression. Having another product proven to treat the full range of bipolar disorder would be a welcome addition to the treatment options currently available to the psychiatry community and patients.

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LATUDA Phase 3 Study Demonstrates Improvement in Pediatric and Adolescent Bipolar Depression

MedicalResearch.com Interview with:

Antony Loebel, M.D. Executive Vice President and Chief Medical Officer Sunovion, Head of Global Clinical Development Sumitomo Dainippon Pharma Group

Dr. Loebel

Antony Loebel, M.D.
Executive Vice President and Chief Medical Officer
Sunovion, Head of Global Clinical Development
Sumitomo Dainippon Pharma Group

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

In the six-week, randomized, double-blind, placebo-controlled study, 347 children and adolescents (10 to 17 years of age) with bipolar depression received once-daily LATUDA flexibly dosed (20-80 mg/day) or placebo.The Phase 3 clinical study met its primary endpoint, showing statistically significant and clinically meaningful improvement in symptoms compared to placebo. LATUDA was generally well tolerated, with minimal effects on weight and metabolic parameters.

The primary efficacy endpoint was change from baseline to week 6 on the Children Depression Rating Scale, Revised (CDRS-R) total score. LATUDA was associated with statistically significant and clinically meaningful improvement in bipolar depression symptoms compared to placebo, based on CDRS-R total score (-21.0 vs. -15.3; effect size = 0.45; p<0.0001) and CGI-BP-S score for depression (-1.49 vs. -1.05; effect size = 0.44; p<0.001).

LATUDA also demonstrated statistically significant improvement on secondary efficacy endpoints.

The most common treatment-emergent adverse events reported for LATUDA compared to placebo were nausea (16% vs. 5.8%), somnolence (9.1% vs. 4.7%), weight gain (6.9% vs. 1.7%), vomiting (6.3% vs. 3.5%), dizziness (5.7% vs. 4.7%) and insomnia (5.1% vs. 2.3%). LATUDA was associated with no increases in fasting glucose or lipids, and minimal increase in mean weight vs. placebo (+0.74 kg vs. +0.44 kg).

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Children born to parents with bipolar disorder or schizophrenia more likely to suffer mental health issues by age 7

MedicalResearch.com Interview with:
Merete Nordentoft DrMSc
Professor, chief Psychiatrist
University of Copenhagen
Mental Health Centre Copenhagen

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

Response: We knew that children born to parents with mental illness had an increased risk for developing a mental disorder them selves, either the same disorder as their parent or another menal disorder. We also knew that some of these children would have pootrt motor function and other difficulties in functioning. However previous studies were smaller, they were not based on a representative sample, and children were at different age. That is the background for The Danish High Risk and Resilience Study-VIA 7, in which a large group of 522 children and their families were thoroughly assessed. The children were seven year old, and 202 had a parent who had schizophrenia, 120 had a parent with bipolar disorder and 200 had parent with neither of these disorders.

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Alterations in Reward Function Precede Psychotic Disorders

MedicalResearch.com Interview with:

Thomas M. Lancaster, PhD Neuroscience and Mental Health Research Institute Cardiff University Brain Imaging Research Centre Cardiff University, Cardiff, United Kingdom

Dr. Thomas Lancaster

Thomas M. Lancaster, PhD
Neuroscience and Mental Health Research Institute
Cardiff University Brain Imaging Research Centre
Cardiff University, Cardiff, United Kingdom  

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

Response: Psychotic disorders such as schizophrenia and bipolar disorders are heritable. Part of this genetic risk may be conferred by the combined effects of common risk alleles identified via genome wide association studies. Individuals with psychosis are also more likely to experience alterations in the ventral striatum (VS); a key node in the brain’s reward processing network. We hypothesized that common genetic risk for psychosis may confer risk via alterations in the VS. Using functional magnetic resonance imaging (fMRI) data from an adolescent sample (the IMAGEN cohort), we showed that increased psychosis risk was associated with increased BOLD (blood oxygen level dependency) in the VS, during reward processing.

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Candida Yeast Infections Linked to Schizophrenia and Bipolar Disorder

MedicalResearch.com Interview with:

Emily G. Severance, Ph.D Stanley Division of Developmental Neurovirology Department of Pediatrics Johns Hopkins University School of Medicine Baltimore, MD

Dr. Emily Severance

Emily G. Severance, Ph.D
Stanley Division of Developmental Neurovirology
Department of Pediatrics
Johns Hopkins University School of Medicine
Baltimore, MD 

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

Dr. Severance: This research stems in part from anecdotal dialogues that we had with people with psychiatric disorders and their families, and repeatedly the issue of yeast infections came up. We found that Candida overgrowth was more prevalent in people with mental illness compared to those without psychiatric disorders and the patterns that we observed occurred in a surprisingly sex-specific manner.  The levels of IgG antibodies directed against the Candida albicans were elevated in males with schizophrenia and bipolar disorder compared to controls. In females, there were no differences in antibody levels between these groups, but in women with mental illness who had high amounts of these antibodies, we found significant memory deficits compared to those without evidence of past infection.

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Does Lithium Really Cause Kidney Toxicity?

MedicalResearch.com Interview with:
Dr. Stefan Clos MSc
Applied Health Statistics
Psychiatrist
Murray Royal Hospital
Scotland UK

Medical Research: What is the background for this study?

Dr. Clos: For more than 40 years there has been a debate about the long-term effect of lithium maintenance therapy on renal function. There is a lack of good quality data from randomized clinical trials and two previous meta-analyses from 2010 and 2012 suggest that little evidence exists for a clinically significant reduction in renal function in most patients who are on lithium therapy. However, the two publications point out the poor quality of available study data, emphasising the need for large scale epidemiological studies that control for confounders. Several population-based studies have since attempted to address this problem, but had insufficient ability to adjust for confounders or had limitations because of inappropriate cross-sectional study design or did not include an appropriate comparator group.  Continue reading

Emotion Regulation Differs Between Patients With Depressive and Bipolar Disorders

MedicalResearch.com Interview with:
Maaike M. M. Rive

Program for mood disorders
AMC/De Meren, Department of Psychiatry PA3.221
Amsterdam  The Netherlands

Medical Research: What is the background for this study? What are the main findings?

Response: For clinicians, it can be difficult to distinguish whether a depressed patient suffers from major depressive disorder (characterized by depressive episodes only) or bipolar disorder (characterized by both depressive and (hypo)manic episodes). Differentiation between the two disorders is important because e.g. the treatment approaches are different. Although we know that both types of mood disorders are characterized by emotion regulation disturbances, little is known about differences in emotion regulation between the two disorders.

Better insight in these differences would be helpful for differentiation between uni- and bipolar disorder. However, previous studies comparing these disorders often allowed medication use, and this may have influenced results. Furthermore, much is unknown about the effect of mood state on emotion regulation differences.

We therefore investigated emotion regulation by showing happy, sad and fearful pictures to patients and healthy controls. Participants were instructed to either passively view the pictures, or to distance themselves from their feelings, by thoughts like: ‘this is only a picture’, ‘this will never happen to me’, etc. Emotion regulation success was measured by the difference between subjective ratings of emotional intensity after passive viewing versus distancing. Brain activity was measured with fMRI.

The results of our study indicate that emotion regulation does indeed differ between medication-free major depressive or bipolar patients, and that specific differences depend on mood state. During remission, bipolar patients showed impaired emotion regulation across different types of emotions. In contrast, patients with major depressive disorder did not how such impairments during remission. During depression, patients differed regarding happy and sad emotion regulation: bipolar patients showed impaired sad, but unexpectedly normal happy emotion regulation, whereas in major depressive disorder, both sad and happy emotion regulation were compromised. These emotion regulation difficulties were associated with differences in brain activity in the dorsolateral prefrontal cortex (involved in effortful emotion regulation) and the rostral anterior cingulate cortex (connecting emotional and cognitive brain areas).

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Pathology Reveals Overlap Between Schizophrenia and Bipolar Disorder

Glenn T. Konopaske, MD McLean Hospital, Belmont, Massachusetts Department of Psychiatry, Harvard Medical School Boston, MassachusettsMedicalResearch.com Interview with:
Glenn T. Konopaske, MD
McLean Hospital, Belmont, Massachusetts
Department of Psychiatry, Harvard Medical School
Boston, Massachusetts


Medical Research: What are the main findings of the study?

Dr. Konopaske: Using postmortem human brain tissue this study did reconstructions of basilar dendrites localized to pyramidal cells in the deep layer III of the dorsolateral prefrontal cortex. Tissue from individuals with schizophrenia, bipolar disorder or controls was examined. Dendritic spine density (number of spines per μm dendrite) was significantly reduced in bipolar disorder and also reduced in schizophrenia at a trend level. The number of dendritic spines per dendrite and dendrite length were significantly reduced in subjects with schizophrenia and bipolar disorder.

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Bipolar Disorder: Protective Genetic Discovery May Lead To New Drug Treatment

Edward I. Ginns, MD, PhD, Director Program in Medical Genetics and Lysosomal Disorders Treatment and Research Program University of Massachusetts Medical School Reed Rose Gordon Building, Room 137 Shrewsbury, MA 01545MedicalResearch.com: Interview with:
Edward I. Ginns, MD, PhD, Director
Program in Medical Genetics and
Lysosomal Disorders Treatment and Research Program
University of Massachusetts Medical School
Reed Rose Gordon Building, Room 137
Shrewsbury, MA 01545

Medical Research: What are the main findings of the study?

Dr. Ginns: Our study identified that sonic hedgehog signaling, an important brain pathway, is involved in bipolar affective disorder.

This finding shows a mechanism and provides new targets for drug development. It suggests that sonic hedgehog signaling can be modulated to help manage bipolar symptoms in adults by using drugs already being studied in clinical trials for other medical conditions.

The new findings were uncovered by decades of translational research in the Old Order Amish families of Pennsylvania, where in a few special families in the Amish Study there is a high incidence of both bipolar disorder and a rare genetic dwarfism, Ellis van‐Creveld (EvC) syndrome. No person with EvC had bipolar disorder despite forty years of documented research across multiple generations, suggesting that the genetic cause of this rare dwarfism was protective of bipolar affective disorder.
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Children of Bipolar Parents Have Increased Novelty-Seeking and Impulsivity

MedicalResearch.com Interview with:
Manpreet K. Singh, MD MS
Assistant Professor of Psychiatry and Behavioral Sciences
Akiko Yamazaki and Jerry Yang Faculty Scholar in Pediatric Translational Medicine
Stanford University School of Medicine

Medical Research: What are the main findings of the study?

Dr. Singh: Our research team used a monetary incentive delay paradigm to measure fronto-limbic activity and connectivity associated with anticipation and receipt of reward and loss in healthy offspring of parents with bipolar I disorder. We found that compared to youth offspring without any family history of psychopathology, high-risk offspring had aberrant prefrontal and cingulate activations and connectivity during reward processing. Further, greater striatal, amygdalar, and insula activations while anticipating and receiving rewards and losses were associated with greater novelty-seeking and impulsivity traits in high-risk youth.
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Bipolar Disorder: Biological Pathways Becoming Clearer

John I. Nurnberger, Jr., M.D., Ph.D. Professor of Psychiatry Joyce and Iver Small Professor of PsychiatryMedicalResearch.com Interview with:
John I. Nurnberger, Jr., M.D., Ph.D.
Professor of Psychiatry
Joyce and Iver Small Professor of Psychiatry
Indiana University School of Medicine

 

MedicalResearch.com: What are the main findings of this study?

Dr. Nurnberger: The main findings of the study are the biological pathways identified to be associated with bipolar disorder, including those involved in hormonal regulation, calcium channels, second messenger systems, and glutamate signaling. Gene expression studies implicated neuronal development pathways as well.

These findings highlight the role of certain neurobiological processes that have been considered in prior hypotheses of bipolar disorder. They underline a role for calcium signaling, which has only been clearly implicated in the genetics of bipolar disorder in recent years. They also feature hormonal processes such as the hypothalamic-pituitary-adrenal axis, which has been known to be involved in stress responses, but has not been prominent in many recent theories of the pathogenesis of bipolar disorder.
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Maternal Influenza and Offspring Bipolar Disorder

MedicalResearch.com Interview with:
Alan S. Brown, M.D., M.P.H. Professor of Clinical Psychiatry and Clinical Epidemiology College of Physicians and Surgeons of Columbia University Director Unit in Birth Cohort Studies Division of Epidemiology New York State Psychiatric Institute New York, NY 10032Alan S. Brown, M.D., M.P.H.
Professor of Clinical Psychiatry and Clinical Epidemiology College of Physicians and Surgeons of Columbia University Director
Unit in Birth Cohort Studies Division of Epidemiology New York State Psychiatric Institute
New York, NY

MedicalResearch.com: What are the main findings of the study?

Dr. Brown: We found that a mother’s exposure to influenza during pregnancy, documented by antibodies in her serum, increased the risk of bipolar disorder with psychotic symptoms in her offspring.  We did not show a relationship between influenza and bipolar disorder not accompanied by psychosis.
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Study finds genetic ‘overlap’ between schizophrenia, bipolar disorder

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.

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.