A Neuroimaging Study assessing Gender Differences in Neurobiological Mechanisms underlying the Placebo Response of Major Depressive Disorder

Aava Jahan, BS

Massachusetts General Hospital

Scientific Abstract

Background: The placebo response rate in clinical trials is a major obstacle in developing therapeutic interventions for major depressive disorder (MDD). Given that MDD is twice as prevalent in females relative to males, we aimed to investigate the possible role of gender differences in modulating mesolimbic dopaminergic mechanisms implicated in the MDD placebo response using neuroimaging techniques.

Methods: We recruited adults with MDD and designed a double-blind, placebo-controlled, randomized clinical trial (RCT). Employing the sequential parallel comparison design, the 8-week RCT was divided into 2 phases (4 weeks/ phase). During Phase 1, participants were randomized to the active drug (bupropion 300mg) or placebo condition, with an imbalanced placebo: drug ratio (7:1).

During Phase 2, placebo non-responders were re-randomized. The nucleus accumbens (NAcc), caudate and putamen were defined as a priori regions of interest (ROIs). Imaging sessions were conducted at baseline and after Phase 1 (follow-up). In the scanner, subjects performed a novel Monetary Incentive Delay (MID) task. The 11C-raclopride radiotracer was used to assess the availability of dopamine (DA) D2-receptors.

Results: PET neuroimaging results (F = 26; M = 20) revealed that at baseline, binding potential (BPND) in males was significantly lower than that of females in all striatal ROIs (p < 0.05). Between baseline and follow-up sessions, there was a significant increase in BPND in the caudate and putamen of male subjects (p < 0.01), but not females. At follow-up only, the NAcc exhibited sex differences in BPND (M < F, p < 0.05). Across both sessions, tracer displacement (interpreted as indexing DA release) was detected in the caudate and putamen of males (p < 0.05), but not females. The magnitude of estimated DA release was significantly greater in males than female subjects in the caudate in both baseline and follow-up sessions (p < 0.05).

Conclusions: These results raise the possibility that gender differences in mesolimbic DA contribute to the well-known gender difference in risk for MDD.

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research Areas


Aava B Jahan, BS, Yoann Petibon, PhD, Daniel G Dillon, PhD, Ashley K Meyer, BA, Marc Normandin, PhD, Emily Belleau, PhD, Nathaniel M Alpert, PhD, Georges El Fakhri, PhD, Jacob M Hooker, PhD, David Crowley, ALM, Cristina Cusin, MD, Diego A Pizzagalli, PhD, Maurizio Fava, MD

Principal Investigator

Cristina Cusin, MD