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Original Research

Successful Pharmacologic Treatment of Major Depressive Disorder Attenuates Amygdala Activation to Negative Facial Expressions: A Functional Magnetic Resonance Imaging Study

Henricus G. Ruhé, MD, PhD; Jan Booij, MD, PhD; Dick J. Veltman, MD, PhD; Martin C. Michel, MD, PhD; and Aart H. Schene, MD, PhD

Published: August 9, 2011

Article Abstract

Objective: Studies of the effects of pharmacotherapy for major depressive disorder (MDD) on limbic-subcortical-prefrontal brain networks show variable results. We quantified functional changes in the amygdala and the related limbic-subcortical-prefrontal structures after paroxetine treatment with functional magnetic resonance imaging relative to clinical responder status.

Method: We scanned 22 patients with unipolar, DSM-IV-defined MDD (men and women aged 25-55 years; 17-item Hamilton Depression Rating Scale [HDRS17] score > 18) at study entry and after 6 (T0) and 12 (T1) weeks of paroxetine treatment. Our paradigm contrasted negative (fearful, angry), happy, and neutral faces relative to scrambled faces. Twenty-one age-matched (± 2.5 y) and sex-matched controls were scanned once. Patients received open-label paroxetine 20 mg/d for 6 weeks (T0). Nonresponders at T0 were randomly assigned to receive double-blind true dose escalation (paroxetine 30-50 mg/d) or placebo dose escalation for another 6 weeks (T1). The study was conducted from July 2005 to February 2007.

Results: At study entry, MDD patients showed increased ventral/limbic and decreased dorsal prefrontal activations to negative faces. At T0 and T1, respectively, 5/20 and 13/20 patients responded to paroxetine. After 12 weeks (at T1), overall amygdala activations remained unchanged relative to study entry. However, amygdala activations were significantly lower in treatment responders versus nonresponders (P = .001). Amygdala activations correlated with HDRS17 scores (P < .04). Left amygdala activation correlated inversely with pregenual anterior cingulate cortex activation (P = .001). Dorsal cingulate gyrus and dorsolateral prefrontal activations increased after 6 and 12 weeks of treatment, regardless of clinical response.

Conclusions: Successful paroxetine treatment decreases amygdala activation, presumably by improved frontolimbic control, in line with selective serotonin reuptake inhibitor-induced increased functional connectivity between the pregenual anterior cingulated cortex, prefrontal cortex, and amygdala. Changes in amygdala activation when processing negative faces might serve as an indicator for improved frontolimbic control, which is required for clinical response.

Trial Registration: ISRCTN identifier: ISRCTN44111488

J Clin Psychiatry

Submitted: September 16, 2010; accepted January 4, 2011.

Online ahead of print: August 9, 2011 (doi:10.4088/JCP.10m06584).

Corresponding author: Henricus G. Ruhé, MD, PhD, PA1-148, Program for Mood Disorders, Department of Psychiatry, Academic Medical Center, PO-Box 22660, 1100 DD Amsterdam, The Netherlands (

Volume: 72

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