2013 NARSAD Independent Investigator Grantees

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Read the 2013 NARSAD Independent Investigator Grantees Announcement

NARSAD Grants fund:

Scientific Council Member and Chair, Independent Investigator Grant Selection Committee, Robert M. Post, M.D., George Washington University, said: “The range of project proposals this year was exceptional in its variety of new approaches to understand and treat mental illness. Tackling the illnesses of the brain remains science’s most daunting challenge and requires these cutting-edge approaches that the Brain & Behavior Research Foundation has been supporting for 25 years with its NARSAD Grants. Each year we build upon the growing body of knowledge about the brain and its functioning and come closer to finding cures.”

DIAGNOSTIC TOOLS / EARLY INTERVENTION

Bipolar Disorder

Mark A. Ellenbogen, Ph.D., of Concordia University and a Canada Research Chair, will test a program aimed at heading off mental illness in children of parents with bipolar disorder. These children show high levels of the stress hormone cortisol and are more biologically sensitive to stress. The study will apply a program called Reducing Unwanted Stress in the Home (RUSH), developed in the Ellenbogen lab, which includes stress management techniques for the children and family-based interventions.

Michael F. Grunebaum, M.D., of Columbia University, hopes to lower the high rate of suicide risk in people with bipolar disorder. Studies have demonstrated rapid improvement in suicidal ideation in patients after infusion of the anesthetic ketamine. To learn how ketamine works to curtail suicide, Dr. Grunebaum proposes a pilot study to compare ketamine’s effects versus midazolam, a similarly sedative medication not known to reduce suicidal thoughts.

Vivian Kafantaris, M.D., of the Feinstein Institute for Medical Research, is seeking an early biomarker of response to lithium in adolescents with bipolar disorder to sort out those who will and will not benefit from lithium treatment. Increased volume in specific brain regions following lithium use suggests that one of lithium’s effects is to increase the volume of cell connections. Dr. Kafantaris is investigating volume increases in the hippocampus, the most neuroplastic brain area.

Depression

Heather C. Abercrombie, Ph.D., of the University of Wisconsin, will examine the role of the stress hormone cortisol in women with depression. Early life experience can alter gene expression into adulthood, through so-called epigenetic changes caused by non-genetic, environmental factors such as stress. Dr. Abercrombie wants to determine whether childhood adversity is predictive of epigenetic changes related to altered cortisol functioning in depressed women, a potentially reversible process.

James E. Swain, M.D., Ph.D., of the University of Michigan, will conduct a trial to identify hormonal biomarkers of risk for and resilience to postpartum depression and anxiety. His lab has identified regional brain responses in depression, during parenting behaviors and in responses to the stress hormone cortisol. The lab will now focus on responses in trial participants at one month postpartum, and their mood and behavior at three and six months postpartum.

Post-Traumatic Stress Disorder (PTSD)

Ananda B. Amstadter, Ph.D., of Virginia Commonwealth University, will test a form of psychotherapy called Risk Reduction Family Therapy to treat adolescents who have been exposed to sexual abuse and suffer from subsequent post-traumatic stress disorder and drug abuse. The study aims to examine the biological mechanisms of response to the treatment, results of which may then inform other treatment approaches to trauma-induced illness.

Schizophrenia

Deepak C. D’Souza, M.D., of Yale University, is interested in the consequences of chronic cannabis exposure and schizophrenia. Evidence suggesting a link between marijuana use and psychosis has relied mostly on self-reporting. Participants in this study will be members of a group whose early, unrestricted use of cannabis is central to their beliefs. Preliminary data show that these subjects underperform non-cannabis using controls on cognitive tests and have higher measures of schizophrenia symptoms.

Stephen J. Glatt, Ph.D., of the State University of New York, will study a risk gene for schizophrenia, DRD2, which encodes receptors for the brain chemical dopamine. How variant forms of DRD2 impart susceptibility to schizophrenia remains unclear. Dr. Glatt is focused on answering that question to gain further insight of the underlying pathology of schizophrenia and to identify better targets for new medications and earlier interventions.  

Christine I. Hooker, Ph.D., of Harvard University, hopes to improve the future of young people at risk for psychosis as it affects their cognitive skills. Research has shown that intensive cognitive and social skills training improve functioning in people with schizophrenia. In the proposed project, a group of youths at high risk will participate in a randomized trial of a computerized intervention targeting functions compromised in schizophrenia such as attention, memory and problem solving.

Oliver D. Howes, M.D., Ph.D., of King’s College London, wants to determine whether changes in behavior of the brain chemical dopamine occur with the onset of psychosis. Dopamine dysfunction is linked to schizophrenia, but only a third of those thought at risk develop psychosis. Confirming a dynamic process of dopamine deregulation would advance understanding of the neurobiology of psychotic disorders and could lead to interventions targeted on dopamine synthesis regulation to prevent onset of psychosis.


NEW TECHNOLOGIES

Bipolar Disorder

Manon H. J. Hillegers, M.D., Ph.D., of Utrecht University, is looking for biomarkers for bipolar disorder in adolescence, which is peak time for bipolar onset. The project will apply magnetic resonance imaging studies to compare the brains of un-medicated adolescents at high genetic risk with healthy controls to observe how vulnerability for bipolar disorder affects brain function.

Beny Lafer, M.D., Ph.D., of the University of Sao Paulo, proposes to conduct a trial of creatine monohydrate, a medication that boosts energy metabolism, as a treatment strategy for bipolar depression, based on the hypothesis that creatine improves depressive symptoms through changes in the brain levels of metabolites of energy production. Via a technology called phosphorus magnetic resonance spectroscopy, the trial will examine relevant brain events before and after creatine treatment.

Depression

Christopher G. Beevers, Ph.D., of the University of Texas at Austin, wants to determine the role of genetic variation in how individuals respond to treatment for depression. Single nucleotide polymorphisms, or SNPs (pronounced “snips”), are variations in the DNA sequence of a gene. Dr. Beevers will apply a newly developed technique, genome-wide complex trait analysis, to assess 500,000 SNPs associated with rare and common genetic variations as predictors of treatment response.

Schizophrenia

Dost Öngür, M.D., Ph.D., of Harvard University, is investigating reduced brain energy production in people with schizophrenia. Mitochondria are the energy-producing factories within cells. Dr. Öngür and colleagues have developed a specialized MRI tool that can follow changes in levels of energy molecules within the living brain. To rule out the influence of medication or chronic psychosis, the research will examine brain mitochondrial processes in un-medicated patients undergoing their first psychotic episode.
 

NEXT GENERATION THERAPIES

Depression

Charles L. Raison, M.D., of the University of Arizona, will conduct a trial of whole body hyperthermia—raising the body temperature—to treat depression. A preliminary trial showed rapid, lasting improvement after a single session. Animal research suggests hyperthermia affects a neural pathway from the skin to specific brain cells. The research will try to confirm whole body hyperthermia as a safe, fast-acting new antidepressant and evaluate the relevance of peripheral neural pathways.

Jonathan P. Roiser, Ph.D., of the University of London, will examine the neural mechanisms affected by transcranial direct current stimulation (tDCS), a brain stimulation treatment for depression, and its ability to boost the effectiveness of cognitive behavioral psychotherapy. Treatment with tDCS stimulates the left dorsolateral prefrontal cortex region of the brain, which is involved in higher cognitive functions.

Gabrielle Rudenko, Ph.D., of the University of Michigan, will test a protein call ΔFosB as a target for treatment of intractable depression. In normal responses to stress, ΔFosB accumulates in specific brain regions and spurs resilience mechanisms—the ability to cope with stress. ΔFosB levels appear dramatically reduced in postmortem brain tissue of depressed patients. By clarifying mechanisms and function of ΔFosB, Dr. Rudenko hopes to exploit and enhance the protein’s antidepressant action.

John A. Wemmie, M.D., Ph.D., of the University of Iowa, will explore the contribution of a particular ion channel, ASIC1a, to mood and behavior, and its potential as an antidepressant target. Ion channels are proteins on cell membranes that control ion flow into and out of the cell. The lab’s prior animal research showed that disturbed ASIC1a contributes to depression and anxiety behaviors and that inhibiting the ASIC1a gene in the brain reduced these behaviors.

Schizophrenia

Christopher R. Bowie, Ph.D., of Queen’s University, Ontario, will test a new online application of cognitive remediation for people with schizophrenia. Cognitive remediation is psychotherapy that improves schizophrenia-associated deficits in cognitive functions such as attention, memory and planning, but many patients lack access to it. Online delivery, if effective, may provide patients the ability to achieve even better, more consistent skill development than is achievable with weekly face-to-face psychotherapy.

Ariel Graff, M.D., Ph.D., of the Centre for Addiction and Mental Health (CAMH), will conduct a pilot trial to see whether levels of the brain chemical glutamate are increased in schizophrenia patients who do not respond to antipsychotic medications. If increased glutamate can be linked to lack of treatment response, it should facilitate development of new treatments aimed at normalizing glutamate levels.

Gregory A. Light, Ph.D., of the University of California, San Diego, is working to improve cognitive ability in people with schizophrenia. The cognitive impairments that affect schizophrenia patients are not helped by current medications, but are helped by cognitive training. One promising approach, Targeted Cognitive Training, sharpens auditory information processing. The study will ascertain utility of this intervention and provide possible biomarkers to predict which individuals are most likely to respond to it.

Alessandro Usiello, Ph.D., of Ceinge Biotecnologie Avanzate, will explore the possible role of an amino acid, D-aspartate, in schizophrenia and its potential as a schizophrenia treatment. Amino acids are small compounds that can perform as chemical messengers in the brain. Postmortem brain studies suggest altered metabolism of D-aspartate in schizophrenia and animal research has shown that D-aspartate can induce effects similar to those of the antipsychotic haloperidol.

Xiang Yang Zhang, M.D., Ph.D., of the Baylor College of Medicine, will conduct a trial to see if the apparent cognitive benefits of smoking for people with schizophrenia can be pharmacologically mimicked. Nicotine appears to improve cognitive function through nicotinic receptors in the brain, but the effect is short-lived and has toxic consequences. The antiemetic drug tropisetron also interacts with a nicotinic receptor and Dr. Zhang’s preliminary studies indicate that tropisetron also improves cognitive deficits.

Multiple Disorders

Elizabeth W. Twamley, Ph.D., of the University of California, San Diego, hopes to develop and test a mobile application of a quick, low-tech intervention that improves cognitive impairment, which is a common feature of schizophrenia, bipolar disorder and major depression. If the method, called Compensatory Cognitive Training, can be adapted for smartphones and tablets, it would greatly increase access to therapy while decreasing cost.

Analia Bortolozzi Ph.D., of the Institut d’Investigacions Biomediques August Pii Sunyer, is seeking new therapeutic targets for mood and cognitive disorders. Potassium channels are structures on cell membranes that regulate the flow of substances in and out of cells. This study will test the hypothesis that selective suppression of the activity of two potassium channels in the brain’s hippocampal region induces resilience to stress, evoking antidepressant-like effects and improved cognitive function.
 

BASIC RESEARCH

Bipolar Disorder

Anabel Martinez-Aran, Ph.D., of Institut D'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), will conduct a clinical trial to examine the role of the growth factor BDNF (brain-derived neurotrophic factor) in cognitive impairment and long-term functioning in bipolar disorder to determine the efficacy of cognitive remediation. The study will compare BDNF levels in 100 patients in a euthymic (nondepressive, nonmanic) state after half received a neurocognitive intervention and half received a pharmacological treatment-as-usual.

Depression

Robert C. Thompson, Ph.D., of the University of Michigan, will investigate how stress affects gene expression in different brain cell types to contribute to depression. Using animal models, the research will begin by determining the impact of stress on cells called astrocytes, based on findings that reduced astrocyte cell density is seen in several brain regions in postmortem studies of depression. The resultant findings may be applicable to other cell types as well.

Qin Wang, M.D., Ph.D., of the University of Alabama at Birmingham, will explore the link between a molecule called α2AAR and depression. The α2AAR is a key receptor involved in regulating brain neurotransmitter systems thought to be disrupted in depressive disorders. The research will use transgenic mice to observe cellular and molecular alterations in the brain associated with α2AAR overexpression in depressive behaviors, and the possibilities for corrective therapy targeting α2AAR.

Post-Traumatic Stress Disorder (PTSD)

Julia A. Chester, Ph.D., of Purdue University, is exploring the role of stress in genetic risk for co-occurring (co-morbid) post-traumatic stress disorder and alcohol abuse toward the goal of developing new treatments. Utilizing mice bred for high or low alcohol preference she has found that high-alcohol preference mice show greater anxiety-related behavior than low-alcohol preference mice, suggesting that common genetic mechanisms influence the two behaviors.

Schizophrenia

Alessandro Bertolino, M.D., Ph.D., of the University of Bari, is studying epigenetic risk for schizophrenia. Epigenetics refers to environmentally induced events that alter gene activity. Having demonstrated that methylation of the gene COMT (Catechol-O-methyltransferase) affects the functioning of dopamine, a brain chemical involved in schizophrenia, the Bertolino lab plans to now evaluate DNA methylation interaction with genes controlling dopamine pathways.

Peng Jin, Ph.D., of Emory University, proposes to expand testing his hypothesis that malfunction of a genetic regulator of neurodevelopment called microRNA-137 (miR-137) contributes to the development of schizophrenia. Postmortem brain-tissue studies suggest that miR-137 is down-regulated in schizophrenia. To explore its activity in a living organism, Dr. Jin and colleagues have bred mice with a disabled miR-137 gene.

Carsten Korth, M.D. Ph.D., of the University of Düsseldorf, is examining the interaction of DISC1, a key risk gene for schizophrenia, and dopamine, a chemical neurotransmitter of messages between nerve cells. The Korth lab has identified a novel function of DISC1 in modulating the dopamine transporter, the molecule critical to reuptake of released dopamine following neural communication. The lab will now conduct animal studies to characterize DISC1 and dopamine transporter interaction.

Antonieta Lavin, Ph.D., of the Medical University of South Carolina, will explore the underlying mechanisms of the decreases in release of the brain chemical glutamate and the role of the protein dysbindin in relation to the cognitive deficits associated with schizophrenia. Brain tissues from schizophrenia patients show decreases in both glutamate and dysbindin, and decreases in glutamate release also appear in dysbindin-deficient mice that the Lavin lab will use as experimental models.

Todd Lencz, Ph.D., of The Feinstein Institute for Medical Research, aims to identify rare genetic variants associated with schizophrenia by utilizing DNA from an Ashkenazi Jewish population, in which there is much less genetic variation than in the general public. Preliminary testing of a small number of Ashkenazi subjects with schizophrenia identified a set of possible candidate genes that Dr. Lencz now intends to pursue in a larger number of participants.

Daniel J. Mueller, M.D., Ph.D., of the Centre for Addiction and Mental Health (CAMH), is exploring the genetics of the weight gain caused by antipsychotic medications. Commonly prescribed drugs for schizophrenia like clozapine and reserpine induce substantial weight gain in up to half of patients, posing risks for serious illness and for treatment noncompliance. Dr. Mueller and colleagues are working to identify the responsible gene variants and their role in antipsychotic-induced weight gain and possibly in obesity generally.

Brien P. Riley, Ph.D., of Virginia Commonwealth University, proposes to sequence all protein-coding DNA in the genomes of a group of Irish patients with schizophrenia in multiple affected families in order to identify rare, damaging genetic variations. Such families have a substantially higher risk of illness than the general population, and likely harbor gene variations with greater impact in the causation of a disease in which hundreds of variants have been implicated.

Multiple Disorders

Alon Chen, Ph.D., of the Weizmann Institute of Science, is studying the role of microRNAs, molecules that repress gene expression, in regulating the brain chemical serotonin in depression and anxiety. Levels of brain microRNAs are affected by behavioral and pharmacological manipulations. In-depth understanding of mechanisms regulating serotonin function may contribute to more effective, faster-acting antidepressant and anti-anxiety drugs with fewer negative side effects than now available.

Todd Denton Gould, M.D., of the University of Maryland, will study changes in a gene called CACNA1C that appear to confer susceptibility to mental illness, primarily bipolar disorder and depression. The goal is first to identify CACNA1C variants expressed in adult and fetal brains to assess whether the mechanism regulating gene expression is specific to developmental stages, and then to determine the mechanisms of gene expression that lead to illness susceptibility.  

Andrew L. Gundlach, Ph.D., of the University of Melbourne, will investigate the involvement in anxiety and depressive disorders of a molecule called RXFP3. Acute RXFP3 activation reduces levels of anxiety-like behavior in genetically-engineered “anxious” mice and increases their social interactions. The proposed study will elucidate the targets of RXFP3, which may uncover new targets for treatment.

Yasushi Nakagawa, M.D., Ph.D., of the University of Minnesota, will examine interactions in the brain between the thalamus and the prefrontal cortex. Defects in these interactions are implicated in many psychiatric disorders, including schizophrenia, bipolar disorder and autism. Projections from the thalamus to the cortex play a central role in conveying visual and auditory information. Projections from the mediodorsal area are important for learning and memory.

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