Pharmacological fMRI to Identify New Anxiolytics: A Human Bioassay
Principal Investigator: M B Stein
Abstract: [unreadable] DESCRIPTION (provided by applicant): The long-term objective of this application is to validate and optimize a human, in vivo bioassay for dentifying pharmaceutical compounds that are highly likely to have anti-anxiety properties. No new classes of anxiolytic medications have entered the marketplace in the past two decades, and the current drug development pathway suffers from many costly, time-consuming failures of compounds that enter Phase studies. The FDA has pointed to this "pipeline problem" as a significant challenge to drug development in the 21st century. Among their recommendations is the need to invent new drug development tools to enhance the movement along the "critical path" from Phase I to Phase III. This proposal outlines a series of studies aimed at determining whether functional magnetic resonance imaging (fMRI) in conjunction with the administration of pharmacological agents can be used as a human, in vivo bioassay at the juncture between Phase I and Phase II drug development for anxiety disorders. This predictive tool would be used to guide selection of lead compound(s) and optimal dosing, and would increase the prior probability of success in Phase II. In this application, we propose to examine the sensitivity, specificity, and reliability of a two emotion-processing tasks during blood oxygen dependent (BOLD) and arterial spin labeling (ASL) fMRI to probe the activation in amygdala, insula, and medial prefrontal cortex with standard anxiolytic and other psychopharmacological agents. A goal of this line of research is to be able to relate the degree of attenuation of the BOLD-fMRI signal in the target areas to the anxiolytic potential of a novel drug. The studies proposed here over 3 years are intended to establish the utility of these techniques for this purpose. Studies in healthy volunteers will optimize the procedures and paradigms and document their sensitivity and reliability (Aim #1). Dose-response studies in anxious subjects will examine sensitivity and specificity of the procedures to known anxiolytic agents in the contexts of acute dose-response (alprazolam and pregabalin) and subchronic (4 weeks of escitalopram) administration (Aim #2). Anxiety disorders are the most prevalent form of mental disorder in the United States, and are disabling to individuals and costly to society. Current pharmacotherapies fail to provide complete relief to 50% of patients. Enhancing the development of new treatments for anxiety is a public health priority. The projects proposed in this application have the potential to achieve this important aim. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-07-20 - 2010-06-30
more information: NIH RePORT
- Lorazepam dose-dependently decreases risk-taking related activation in limbic areasEstibaliz Arce
Department of Psychiatry, Laboratory of Biological Dynamics and Theoretical Medicine, University of California San Diego, 8950 Villa La Jolla Dr, Suite C213, La Jolla, CA 92037 0985, USA
Psychopharmacology (Berl) 189:105-16. 2006..Several studies have examined the role of different neurotransmitter systems in modulating risk-taking behavior...
- Role of functional magnetic resonance imaging in drug discoveryMartin P Paulus
Department of Psychiatry, University of California, San Diego UCSD, 8950 Villa La Jolla Drive, Suite C 213, La Jolla, CA 92037, USA
Neuropsychol Rev 17:179-88. 2007....
- Escitalopram effects on insula and amygdala BOLD activation during emotional processingEstibaliz Arce
Department of Psychiatry, Laboratory of Biology Dynamics and Theoretical Medicine, University of California San Diego, La Jolla, CA 92037, USA
Psychopharmacology (Berl) 196:661-72. 2008..The amygdala and insular cortex are integral to the processing of emotionally salient stimuli. We have shown in healthy volunteers that an anxiolytic agent, lorazepam, dose-dependently attenuates activation of limbic structures...
- Subchronic SSRI administration reduces insula response during affective anticipation in healthy volunteersAlan N Simmons
University of California, San Diego, CA 92161 0151B, USA
Int J Neuropsychopharmacol 12:1009-20. 2009....
- Escitalopram attenuates posterior cingulate activity during self-evaluation in healthy volunteersScott C Matthews
Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA
Psychiatry Res 182:81-7. 2010..These results show that SSRIs change medial cortical activity and may alter self-evaluation...
- Pregabalin influences insula and amygdala activation during anticipation of emotional imagesRobin L Aupperle
Department of Psychiatry, University of California San Diego UCSD, La Jolla, CA 92037 0985, USA
Neuropsychopharmacology 36:1466-77. 2011..These results provide further support for the viability of using pharmaco-fMRI to determine the anxiolytic potential of pharmacologic agents...
- The effect of pregabalin on sensorimotor gating in 'low' gating humans and miceDean T Acheson
Mental Illness Research, Education and Clinical Center MIRECC, Veterans Affairs VISN22, USA
Neuropharmacology 63:480-5. 2012..These data support further exploration of pregabalin as a potential treatment for disorders characterized by sensorimotor gating deficits and glutamatergic hypersignaling, such as schizophrenia...