This K23 award application requests support for a career development and research plan to study the neurobiology and treatment of generalized anxiety disorder [GAD]. Although GAD is common, chronic, and disabling, it is vastly under studied, and its nosological status has been uncertain. During the past 3 years the applicant has conducted research with patients with GAD, and anxiously-reared nonhuman primates, using MRS as a non-invasive technique for neurochemical imaging. In both the preclinical and clinical samples, this preliminary research suggested anatomically-specific abnormalities in N-acetyl aspartate [NAA], a putative marker of neuronal density or viability, with disturbances in patients greatest in the right DLPFC. There were also abnormalities in glutamate/glutamine/GABA [GIx] resonance in regions implicated in anxiety regulation. Accordingly, the research plan aims to: (1) Use a new high field 3T MR system to test the hypothesis that patients with GAD have increased NAA in the right DLPFC, and, more broadly, to characterize baseline MRS characteristics in medication-free GAD patients compared to healthy adults; (2) Test the hypothesis of regionally-specific differences between patients with GAD and healthy controls in GABA and ultimately glutamate/glutamine levels, utilizing novel proton MRS editing methods that allow reliable and valid assessment of these transmitters that previously have been difficult to separate; (3) Determine whether treatment of GAD patients with cognitive behavioral therapy [CBT] or paroxetine normalizes baseline MRS group differences following an acute treatment phase or after continuation therapy; and (4) Test the hypothesis that, in the long-term (6 mo after acute treatment), NAA levels do not match control values even among patients with sustained remission, suggesting a trait-level abnormality. The applicant and primary mentor have identified several domains requiring formal instruction and rigorous training: (1) advanced proton MRS/MRI methods; (2) biostatistics and clinical research methodology; (3) neurobiology and neuropsychology of anxiety; (4) therapeutics of anxiety disorders. A distinguished group has been identified with expertise in the substantive and methodological issues at the core of the training and research goals. In concert with the mentor, this group of preceptors, and a formal didactic program, the applicant plans to acquire the skills needed to appreciate advances in the neuroscience of mood and anxiety and apply them in increasingly sophisticated studies of the pathophysiology and treatment of GAD. A specific long-term goal is for the candidate to develop sufficient expertise in MRS to sustain valid and creative application to problems of GAD and related conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23MH069656-02
Application #
6945217
Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Wynne, Debra K
Project Start
2004-09-01
Project End
2009-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$159,316
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Coplan, Jeremy D; Webler, Ryan; Gopinath, Srinath et al. (2018) Neurobiology of the dorsolateral prefrontal cortex in GAD: Aberrant neurometabolic correlation to hippocampus and relationship to anxiety sensitivity and IQ. J Affect Disord 229:1-13
Abdallah, Chadi G; Jackowski, Andrea; Salas, Ramiro et al. (2017) The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder. Neuropsychopharmacology 42:1739-1746
Raparia, Eva; Coplan, Jeremy D; Abdallah, Chadi G et al. (2016) Impact of childhood emotional abuse on neocortical neurometabolites and complex emotional processing in patients with generalized anxiety disorder. J Affect Disord 190:414-423
Abdallah, Chadi G; Jackowski, Andrea; Sato, João R et al. (2015) Prefrontal cortical GABA abnormalities are associated with reduced hippocampal volume in major depressive disorder. Eur Neuropsychopharmacol 25:1082-90
Lapidus, Kyle A B; Gabbay, Vilma; Mao, Xiangling et al. (2014) In vivo (1)H MRS study of potential associations between glutathione, oxidative stress and anhedonia in major depressive disorder. Neurosci Lett 569:74-9
Murrough, James W; Wan, Le-Ben; Iacoviello, Brian et al. (2013) Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response. Psychopharmacology (Berl) :
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Abdallah, Chadi G; Coplan, Jeremy D; Jackowski, Andrea et al. (2012) Riluzole effect on occipital cortex: a structural and spectroscopy pilot study. Neurosci Lett 530:103-7
Murrough, James W; Perez, Andrew M; Mathew, Sanjay J et al. (2011) A case of sustained remission following an acute course of ketamine in treatment-resistant depression. J Clin Psychiatry 72:414-5
Krystal, John H; Mathew, Sanjay J; D'Souza, D Cyril et al. (2010) Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs 24:669-93

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