Advances in the Neurobiology of Mental Illness

Agenda

* Presentation times are subject to change.

Abstracts

Medical Consequences of Depression and Neuroimmune Interactions
K. Ranga Rama Krishnan, MBBS, Rush Medical College, Chicago

When we get a cold, a viral or bacterial infection, we often feel tired lethargic, a bit more sleepy, depressed, and irritable. This constellation of features called sickness behavior is very similar to the features of clinical depression. This behavior is related to the release of proinflammatory cytokines such as Interleukin 6, Tumor Necrosis Factor (TNF), etc. In animal experiments when TNF is centrally administered, it can induce sickness behavior. In humans, significant depression occurs when cytokines and interferons are administered. Major depression is more prevalent amongst patients with conditions that are related to chronic inflammation including psoriasis. The brain circuitry and mechanisms by which proinflammatory cytokines are linked to this behavior have not been fully elucidated. One putative mechanism is the marked reduction of tryptophan that happens when patients are given immunotherapy. This reduction is due to activation indoleamine 2,3 dioxygenase in the liver which can be mediated by TNF and interferons. This activation increases kynurenine which is metabolized in the brain one pathway can lead to production of quinolinic acid that work through the N-methyl-D-aspartate receptors. In a large study of patients with psoriasis using a TNF antagonist, the antagonist was shown to reduce depression and fatigue, supporting the notion that testing proinflammatory antagonists as a potential means of ameliorating depression may be worthwhile.

Prediction and Prevention of Psychosis: The Schizophrenia Prodrome
Tyrone D. Cannon, PhD, Yale University

Subtle changes in belief, thought, and perception appear to precede onset of delusions, formal thought disorder, and hallucinations in the majority of patients with schizophrenia and related disorders. In a young person who is distressed and treatment seeking, onset or worsening of these sub-psychotic features within the past 12 months portends a heightened risk for onset of schizophrenia or a related disorder. This talk will present findings on risk prediction algorithms and potential mechanisms of onset in youth at clinical high risk for psychosis. An independently validated individualized risk calculator is available that incorporates risk factors from clinical, demographic, neurocognitive, and psychosocial assessments to predict likelihood of conversion to psychosis among individuals who meet criteria for a prodromal risk syndrome. At risk individuals who convert to psychosis show a steeper rate of gray matter reduction, most prominent in prefrontal cortex, compared with those who do not. Higher levels of proinflammatory cytokines at baseline predict the accelerated reduction in prefrontal gray matter. These same markers are associated with microglial-mediated synaptic pruning and dendritic retraction in animal models. Processes that modulate microglial activation, such as dysregulated immune function and deficient synaptic plasticity, may represent convergent mechanisms that influence brain dysconnectivity and risk for onset of schizophrenia. This work encourages the development and testing of interventions that target the contributing molecular signaling pathways and that could potentially prevent onset of full symptoms and long-term functional disability in those at elevated risk.

Rapid Relief from Severe Depression and Suicidal Ideation within Hours: From Synapses to Symptoms to New Treatments
Carlos A. Zarate, Jr., MD, National Institute of Mental Health, U.S. National Institutes of Health

Currently approved antidepressant medications for major depressive disorder (MDD) and bipolar disorder act primarily on the monoaminergic system. Unfortunately, these pharmacological agents are efficacious in approximately two-thirds of patients. Glutamate is the major excitatory neurotransmitter in the central nervous system, and the glutamatergic system has been implicated in the pathophysiology of mood disorders. In this lecture, I will review the putative involvement of the glutamate receptor subtypes-N-methyl-D-aspartate (NMDA) and its allosteric sites—α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA), kainate, and metabotropic glutamate receptors (mGluRs)—in the development of novel treatments for MDD as well as preclinical and clinical trials of drugs targeting these receptors. Here, I highlight some of the most interesting results, including: 1) the glycine partial agonist GLYX-13 appears to be effective both as monotherapy and adjunctive treatment in the treatment of MDD. An oral analogue, NRX-1074, is currently under investigation; 2) glycine antagonists, 3) mGluR modulators targeting mGluR2 and mGluR5 have demonstrated convincing preclinical results, 4) Esketamine has rapid antidepressant and antisuicidal properties, and 6) The ketamine metabolite Hydroxyketamine, an AMPA potentiator, appears to be important to the antidepressant mechanisms of ketamine and a promising drug for further development. These targets may be of substantial interest in defining future directions in drug development, as well as in developing the next generation of therapeutic agents for the treatment of mood disorders. Overall, further study of these and similar drugs may lead to a better understanding of relevant and clinically useful drug targets in the treatment of these devastating illnesses.

Innovative Tools Utilized as Biomarkers and Clinical Indicators in Autism Spectrum Disorder
Geraldine Dawson, PhD, Duke Center for Autism and Brain Development, Duke University School of Medicine

Capitalizing on advances in genetics and neuroscience, recent research has identified novel therapeutics that have the potential to modify core symptoms of Autism Spectrum Disorder (ASD), such as deficits in social communication. Success in demonstrating the efficacy of these treatments will be enhanced if clinical trials use strategies to reduce the heterogeneity of ASD, measure target engagement, and objectively quantify symptom improvement. Dr. Dawson will discuss the potential utility of several biomarkers that can be used for stratification and assessing early efficacy in ASD clinical trials, with a focus on electroencephalographic, eye-gaze tracking, and magnetic resonance iamging measures. Two ongoing efforts to validate ASD biomarkers will be described. One is a multi-site study funded by the National Institutes of Health entitled the Autism Biomarker Consortium for Clinical Trials, and the second is a recently-completed study with the Janssen Autism Knowledge Engine (JAKE™). Autism Biomarker Consortium for Clinical Trials is a longitudinal study of 200 children with ASD and 75 typically-developing children, age 4–11 years, who are being followed over 6 months with a comprehensive phenotypic, genomic, and repeated measures electroencephalogram and eye-gaze tracking biomarker assessment battery. The JAKE™ study was designed to validate a comprehensive and scalable system that utilizes biosensors and novel behavioral assessments and is feasible for use in large multi-site ASD clinical trials. It is hoped that these novel approaches to clinical trial design will facilitate the development of new and more effective treatments for ASD.

Using Neuroscience to Inform Clinical Thinking: Applications in Pediatric Anxiety
Daniel S. Pine, MD, National Institute of Mental Health, US National Institutes of Health, Bethesda, Maryland, United States

This presentation will review research in three areas. First, the presentation briefly will review key principles in translational research applications to pediatric anxiety disorders. This will delineate the way in which neuroscience concepts can be applied to clinical problems at a relatively broad level, with specific relevance to pediatric anxiety. Second, the presentation will describe the ways in which brain-behavior relationship differ in healthy children and adolescents, relative to children and adolescents with anxiety disorders. This will focus on specific aspects of attention and memory. Third, the presentation will describe the way in which this understanding of brain-behavior relationships informs understandings of developmental trajectories and novel approaches to treatment. As such, across these three levels, the presentation will describe research on pediatric anxiety disorders, as it relates to underlying brain circuitry and clinically-relevant extensions of research in animal models.

The Emerging Neurobiology of Anorexia Nervosa
B. Timothy Walsh, MD, New York State Psychiatric Institute and College of Physicians & Surgeons, Columbia University

Anorexia nervosa is an enigmatic disorder. Many individuals who develop it make a complete recovery, physically, psychologically, and behaviorally. Yet others become chronically ill, and may even die. The salient behavioral problem is a simple one: insufficient food intake. Affected individuals are not psychotic, and some have good insight into their illness, but, even so, find it very difficult to change their eating behavior. These facts, universally acknowledged, challenge our current understanding of anorexia nervosa.
 
This talk will briefly review recent studies probing the neurobiology of anorexia nervosa, and describe a newly formulated hypothesis that attempts to explain the persistence of the disorder using recent insights from cognitive neuroscience.

Harnessing Mobile and Sensor Technology to Help Patients with Diseases of the Brain and Central Nervous System
Vaibhav Narayan, MBA, PhD, Janssen Research & Development, LLC

This talk will focus on how advances in mobile computing and sensor technology may be harnessed to develop solutions that help us move from a "diagnose and treat" to a "predict and preempt" paradigm in treating diseases of the brain and central nervous system. Today, ubiquitous mobile technologies and small unobtrusive sensors make it possible to capture streaming data that report aspects of patients' physiology, behavior, and symptoms, both quantitatively and in real time. The growing content available from these devices, and the fact that these data can be passively collected and analyzed in real-time present a tremendous opportunity for early detection and monitoring of brain and CNS diseases. Measures of changes in daily activity levels, sleep, energy consumption, and social interaction patterns could have ramifications in predicting and preempting relapse in neuropsychiatric diseases such depression, bipolar disorder and schizophrenia. Neurodegenerative diseases such as Alzheimer's impact cognitive domains related to episodic memory, spatial orientation, and processing speed, all of which can be measured passively and unobtrusively.

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