Diego Pizzagalli - US grants

DESCRIPTION (provided by applicant): Major depressive disorder (MOD) is common, recurrent, and disabling. Despite a wide range of antidepressant treatments available, MOD remains difficult to treat. Therefore, a better understanding of treatment mechanisms and identification of reliable predictors of treatment response would constitute major progress in the battle against MOD. Recently, there has been considerable interest in studying the efficacy of alternative medications in the treatment of MOD. In this regard, S-adenosyl-L-methionine (SAMe) has been widely investigated as a natural treatment of depression. Although preclinical studies have shown that SAMe influences neurotransmitter metabolism (including dopamine, a neurotransmitter implicated in reward brain mechanisms), membrane fluidity, and receptor activity, the precise mechanisms of its antidepressant actions are unknown in humans. As an initial step toward a mechanistic understanding of these processes, the investigators propose to compare the effects of SAMe to a standard, first-line treatment for depression (the selective serotonin reuptake inhibitor, escitalopram) on neural activity underlying reward processing in MOD. By using functional magnetic resonance imaging (fMRI) in conjunction with a reward task (a monetarily-reinforced button-press task) as well as a laboratory-based behavioral measure of hedonic capacity, this study will investigate: (1) the effects of SAMe and escitalopram on neural substrates underlying processing of reward- and punishment-related cues; (2) pre-treatment behavioral and neural predictors of treatment response to SAMe and escitalopram; and (3) putative differences in the effects of SAMe and escitalopram - due to their distinct pharmacological profiles - on neural and behavioral markers of hedonic capacity. To this end, 45 individuals with MOD (and 15 healthy control subjects) will be investigated (before and after a 12-week, double-blind, placebo-controlled administration of SAMe vs. escitalopram. Based on preclinical evidence suggesting that SAMe potentiates transmission in the mesolimbic dopaminergic reward system, we hypothesize that, compared to placebo, SAMe (and escitalopram) treatment will: (1) normalize (i.e., increase) brain activation in regions subserving reward processing (ventral striatum, orbitofrontal cortex, anterior cingulate cortex); (2) normalize (i.e., decrease) brain activation in regions subserving punishment processing (e.g., amygdala, insula, hippocampus, right dorsolateral prefrontal cortex); and (3) increase hedonic capacity, as assessed by a signal-detection task. Because anhedonia (lack of reactivity to pleasurable stimuli) has been considered a trait marker related to vulnerability to depression and a predictor of relapse, the use of a novel experimental approach capitalizing on state-of-the-art neuroimaging techniques and laboratory-based measures of hedonic capacity promises to shed important light on: (1) mechanisms underlying the antidepressant efficacy of a natural treatment for depression; and (2) objective predictors of treatment response. A better understanding of the mechanisms of actions of SAMe should, in turn, provide a foundation for future clinical trials.

[unreadable] DESCRIPTION (provided by applicant): Depressive disorders are a major public health problem. Epidemiological studies have highlighted links between stress, particularly early adverse life events, and increased vulnerability to depression. Although preclinical studies indicate that early stressors exert long-lasting neurobiological effects on the offspring, including altered stress responsiveness and blunted hedonic responsiveness, in humans, the precise mechanisms linking stress and depression are largely unknown. Further, progress in understanding the neurobiology of depression is hindered by the lack of objective measures of core depressive symptoms, such as anhedonia. The goals of the proposed work are: (a) to develop an objective measure of anhedonia, defined as decreased responsiveness to reward-related cues in a signal-detection task, in both humans and rats; and (b) to test the hypothesis that stress exerts its depressogenic effects by reducing hedonic capacity. To this end, the effects of early adverse events, specifically maltreatment and deviant care in infancy (human component) and early maternal separation (animal component) on reward responsiveness will be evaluated. Further, in humans, the effects of an acute stressor on reward responsiveness and brain mechanisms underlying stress-induced hedonic impairments will be investigated through 128-channel event-related potential (ERP) recordings. A particularly unique and innovative aspect of this application will be the use of a novel laboratory-based measure of hedonic capacity in 40 young adults, studied longitudinally from infancy, whose early caregiving histories, in particular maltreatment and deviant care, have been extensively characterized. In humans, we hypothesize that: (a) both deviant care in infancy and severity of childhood maltreatment will be linked to decreased reward responsiveness; (b) depressed individuals who have experienced early life adversity will show the most impaired reward responsiveness; and (c) an acute stressor will lead to reduced hedonic capacity and blunted ERP amplitudes to reward-related cues, due to blunted activation in cortical regions subserving reward processing. In rats, we hypothesize that: (a) animals exposed to a signal detection task in which one stimulus is disproportionally rewarded, will develop a response bias (i.e., a systematic preference) towards the more frequently rewarded stimulus; and (b) early maternal separation will lead to blunted hedonic capacity. In summary, the proposed work will utilize objective and parallel measures of hedonic capacity in humans and rats; will assess the effects of acute (laboratory) and chronic (naturalistic) stressors on the same measures; and will begin the exploration of brain regions that may be involved in stress-induced anhedonia. By creating a partnership between scientists with expertise in human neuroscience (Dr. Pizzagalli), animal neuroscience (Dr. Markou), and clinical psychology (Dr. Lyons-Ruth), this work will provide the building blocks for future interdisciplinary and translational work that may lead to a better understanding of the neurobiology and etiology of depression, and improved treatments for this debilitating disease. PUBLIC HEALTH RELEVANCE: Epidemiological studies emphasize the role of stress in the development and maintenance of depression, but in humans the precise mechanisms linking stress and depression are largely unexplored. The current project proposes a novel integration of human and animal studies to test the hypothesis that stress increases the risk for depression by reducing the individual's the ability to modulate behavior as a function of rewarding cues. [unreadable] [unreadable] [unreadable]