Charles Nemeroff

Emory University School of Medicine, USA

Abstract

[O28] The role of corticotropin-releasing factor circuits in the pathophysiology of depression:Implications for the CRF receptor antagonists as novel antidepressants

Corticotropin-releasing factor (CRF), a 41 amino acid-containing neuropeptide, is the preeminent mediator of the mammalian stress response.  There is considerable evidence for hyperactivity of CRF-containing circuits in depression in both hypothalamic and extrahypothalamic brain regions including the amygdala and the bed nucleus of the stria terminalis.  Chronically elevated activity of extrahypothalamic CRF systems and its associated increased synaptic availability of CRF are thought to be responsible for the decreased density of CRF1 receptors and decreased mRNA expression of cortical CRF1 receptors in depressed suicide victims.  Elevated cerebrospinal fluid (CSF) concentrations of CRF, observed in many MDD patients, are also thought to reflect the same hyperactivity in these extrahypothalamic and hypothalamic CRF-producing regions.  In particular, CRF mRNA expression in the central nucleus of the amygdala (CeA) has been posited to be upregulated in MDD patients.  As one main output of the amygdala, CRF projections from the CeA travel to cortical and brainstem regions including the noradrenergic cells in the locus coeruleus (LC). Overactivity in this CeA-LC projection could explain the observations of elevated CRF concentrations in the LC observed in MDD patients.

The endocrine response to stress is regulated by the hypothalamic-pituitary-adrenal (HPA) axis, and ultimately CRF.  HPA axis activation is initiated by CRF release from the paraventricular nucleus of the hypothalamus (PVN), resulting in adrenocorticotropic hormone (ACTH) release from the anterior pituitary.  ACTH acts on the adrenal cortex to provoke glucocorticoid release.   Cortisol, the main glucocorticoid in primates, mobilizes energy stores to respond to a threat.   In many depressed patients, the HPA axis is hyperactive, as evidenced by elevated plasma ACTH and cortisol concentrations and by ACTH and cortisol responses in standardized endocrine challenge tests, including the dexamethasone suppression test (DST) and CRF stimulation test.  In the DST, the synthetic glucocorticoid dexamethasone decreases plasma ACTH and cortisol concentrations via negative feedback at the level of the pituitary gland.  It is well established, however, that many MDD patients are dexamethasone nonsuppressors, suggesting that the HPA axis is hyperactive and/or that the negative feedback mechanism is disrupted in these patients.  Interestingly, among MDD patients, those who were DST non-suppressors exhibited higher CSF CRF concentrations than DST suppressors.

A combination of the DST and the CRF stimulation test, the dex/CRF test, developed by Holsboer and colleagues is generally considered to be the most sensitive measure of HPA axis activity.  In this test, many MDD patients exhibit elevated plasma ACTH and cortisol concentrations relative to healthy control subjects, suggesting that both glucocorticoid insensitivity and CRF overexpression contribute to HPA  axis hyperactivity in depression.

Individual differences in genes involved in the CRF system and genes whose products are involved in HPA axis activation and feedback have been hypothesized to contribute to disturbed CRF signaling and HPA axis activity in MDD.  A SNP in the CRF1 receptor gene has been associated with high anxiety in MDD patients and has also been correlated with response to fluoxetine treatment.  Most recently, our group has demonstrated that SNPs of the CRF1 receptor gene predict vulnerability to depression in adult victims of child abuse.  A burgeoning database from preclinical and clinical research approaches have revealed that CRF1 receptor antagonists possess antidepressant and anxiolytic properties and likely represent a novel class of antidepressants.  Both positive and negative clinical trials with CRF1 receptor antagonists have been reported in depressed patients.  The current state of clinical studies with these putative novel antidepressants will be described.

Biography

Dr. Nemeroff was born in New York City in 1949 and educated in the New York City Public School System.  After graduating from the City College of New York in 1970, he enrolled in graduate school at Northeastern University and received a Master's degree in Biology in 1973.  He received his MD and PhD (Neurobiology) from the University of North Carolina at Chapel Hill. His residency training in psychiatry was conducted at both the University of North Carolina and at Duke University, after which he joined the faculty of Duke University.  At Duke he was Professor of Psychiatry and Pharmacology and Chief of the Division of Biological Psychiatry before relocating in 1991 to Emory University School of Medicine in Atlanta, Georgia, where he is the Reunette W. Harris Professor of the Department of Psychiatry and Behavioral Sciences.  His research has concentrated on the biological basis of the major neuropsychiatric disorders, including affective disorders, schizophrenia, and anxiety disorders.  His clinical research is focused on the use of genetic, neuroendocrine, neuroimaging and neurochemical methods to comprehensively understand the pathophysiology of depression.  In recent years he has uncovered the neurobiological mechanisms that mediate the increased risk for depression in victims of child abuse.  He has also contributed to other seminal findings such as the burgeoning area of research concerning the relationship of depression to cardiovascular disease, as well as to identifying predictors of specific antidepressant treatment responses.

Dr. Nemeroff has received numerous honors during his career, including the A.E. Bennett Award from the Society of Biological Psychiatry (1979), the Judith Silver Memorial Young Scientist Award from the National Alliance for the Mentally Ill (1989), both the Kempf Award in Psychobiology (1989) and the Samuel Hibbs Award (1990) from the American Psychiatric Association (APAP, and the Gold Medal Award and the Research Prize (1996) from the Society of Biological Psychiatry.  In 1993 he was awarded the Edward J. Sachar Award from Columbia University and the Edward A. Strecker Award from The Institute of Pennsylvania Hospital.  In 1997, he was the recipient of the Gerald Klerman Award from the National Depressive and Manic-Depressive Disorders Association and the Selo Prize from the National Alliance for Research in Schizophrenia and Depression.  In 1998 he was the recipient of the Research Award in Mood Disorders from the American College of Psychiatrists and in 1999 he received the Bowis Award from the same organization.  He was awarded the Menninger Prize in 2000 from the American College of Physicians, the Research Award from the American Foundation for Suicide Prevention in 2001, and the Burlingame Prize from the Institute of Living in 2002.  In 2006 he received the American Psychiatric Association Research Mentoring Award and Vestermark Award, and in 2008 The Judson Marmor Award for Research. Dr. Nemeroff served as the Editor-in-Chief of Neuropsychopharmacology (2001-2006).  With Alan F. Schatzberg, MD, he is co-Editor of the Textbook of Psychopharmacology, in its Fourth Edition, published by the American Psychiatric Association Press. He has served on the Mental Health Advisory Council of the National Institutes of Mental Health and the Biomedical Research Council for NASA. He is past President of the American College of Neuropsychopharmacology and the American College of Psychiatrists. He is currently a member of the Board of Directors of the American Foundation for Suicide Prevention. He is chair of the APA Committee on Research Training. In 2002 he was elected as a member of the Institute of Medicine of the National Academy of Sciences.