Phase 3 Trial of Cariprazine (Vraylar) Shows Promise in Bipolar Depression

MedicalResearch.com Interview with:

Dr. C. David Nicholson, PhD Chief R&D Officer  Allergan

Dr. C. David Nicholson

Dr. C. David Nicholson, PhD
Chief R&D Officer
Allergan

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

Response: Bipolar I depression refers to the depressive episodes of bipolar I disorder, the overarching brain and behavioral disorder. People with bipolar I disorder can have manic and depressive episodes, as well as mixed episodes that feature both manic and depressive symptoms at the same time. Bipolar I depression typically lasts at least two weeks, and can be difficult to differentiate from major depression during diagnosis.

Once diagnosed, treating bipolar depression can be difficult given the few therapies available to manage these symptoms of bipolar I disorder. Additionally, patients with bipolar disorder may experience shifts from depression to mania or mania to depression as well as mixed states. More treatment options are needed so that physicians can find a therapy that will treat bipolar depression effectively, while also addressing the myriad of other symptoms that patients can experience.

Cariprazine is already approved for the treatment of mania and mixed episodes. With this new data, we have the potential to also treat bipolar depression, effectively addressing the full spectrum of symptoms associated with bipolar I disorder with just one medication.

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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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