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.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AT002974-02
Application #
7268096
Study Section
Special Emphasis Panel (ZAT1-DB (21))
Program Officer
Glowa, John R
Project Start
2006-07-01
Project End
2008-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$201,725
Indirect Cost
Name
Harvard University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Admon, R; Nickerson, L D; Dillon, D G et al. (2015) Dissociable cortico-striatal connectivity abnormalities in major depression in response to monetary gains and penalties. Psychol Med 45:121-31
Treadway, Michael T; Waskom, Michael L; Dillon, Daniel G et al. (2015) Illness progression, recent stress, and morphometry of hippocampal subfields and medial prefrontal cortex in major depression. Biol Psychiatry 77:285-294
Pizzagalli, Diego A (2014) Depression, stress, and anhedonia: toward a synthesis and integrated model. Annu Rev Clin Psychol 10:393-423
Huys, Quentin Jm; Pizzagalli, Diego A; Bogdan, Ryan et al. (2013) Mapping anhedonia onto reinforcement learning: a behavioural meta-analysis. Biol Mood Anxiety Disord 3:12
Vanderhasselt, Marie-Anne; De Raedt, Rudi; Dillon, Daniel G et al. (2012) Decreased cognitive control in response to negative information in patients with remitted depression: an event-related potential study. J Psychiatry Neurosci 37:250-8
Santesso, Diane L; Bogdan, Ryan; Birk, Jeffrey L et al. (2012) Neural responses to negative feedback are related to negative emotionality in healthy adults. Soc Cogn Affect Neurosci 7:794-803
Dillon, Daniel G; Deveney, Christen M; Pizzagalli, Diego A (2011) From Basic Processes to Real-World Problems: How Research on Emotion and Emotion Regulation Can Inform Understanding of Psychopathology, and Vice Versa. Emot Rev 3:74-82
Pizzagalli, Diego A (2011) Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology 36:183-206
Pizzagalli, Diego A (2010) The ""anhedonia paradox"" in schizophrenia: insights from affective neuroscience. Biol Psychiatry 67:899-901
Pizzagalli, Diego A; Holmes, Avram J; Dillon, Daniel G et al. (2009) Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. Am J Psychiatry 166:702-10

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