Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study

Cynthia H Y Fu, Steven C R Williams, Anthony J Cleare, Michael J Brammer, Nicholas D Walsh, Jieun Kim, Chris M Andrew, Emilio Merlo Pich, Pauline M Williams, Laurence J Reed, Martina T Mitterschiffthaler, John Suckling, Edward T Bullmore

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679 Citations (Scopus)


BACKGROUND: Depression is associated with interpersonal difficulties related to abnormalities in affective facial processing.

OBJECTIVES: To map brain systems activated by sad facial affect processing in patients with depression and to identify brain functional correlates of antidepressant treatment and symptomatic response.

DESIGN: Two groups underwent scanning twice using functional magnetic resonance imaging (fMRI) during an 8-week period. The event-related fMRI paradigm entailed incidental affect recognition of facial stimuli morphed to express discriminable intensities of sadness.

SETTING: Participants were recruited by advertisement from the local population; depressed subjects were treated as outpatients.

PATIENTS AND OTHER PARTICIPANTS: We matched 19 medication-free, acutely symptomatic patients satisfying DSM-IV criteria for unipolar major depressive disorder by age, sex, and IQ with 19 healthy volunteers. Intervention After the baseline assessment, patients received fluoxetine hydrochloride, 20 mg/d, for 8 weeks.

MAIN OUTCOME MEASURES: Average activation (capacity) and differential response to variable affective intensity (dynamic range) were estimated in each fMRI time series. We used analysis of variance to identify brain regions that demonstrated a main effect of group (depressed vs healthy subjects) and a group x time interaction (attributable to antidepressant treatment). Change in brain activation associated with reduction of depressive symptoms in the patient group was identified by means of regression analysis. Permutation tests were used for inference.

RESULTS: Over time, depressed subjects showed reduced capacity for activation in the left amygdala, ventral striatum, and frontoparietal cortex and a negatively correlated increase of dynamic range in the prefrontal cortex. Symptomatic improvement was associated with reduction of dynamic range in the pregenual cingulate cortex, ventral striatum, and cerebellum.

CONCLUSIONS: Antidepressant treatment reduces left limbic, subcortical, and neocortical capacity for activation in depressed subjects and increases the dynamic range of the left prefrontal cortex. Changes in anterior cingulate function associated with symptomatic improvement indicate that fMRI may be a useful surrogate marker of antidepressant treatment response.

Original languageEnglish
Pages (from-to)877-89
Number of pages13
JournalArchives of General Psychiatry
Issue number9
Publication statusPublished - Sep 2004


  • Affect
  • Brain
  • Brain Mapping
  • Depressive Disorder
  • Evoked Potentials
  • Facial Expression
  • Fluoxetine
  • Humans
  • Limbic System
  • Magnetic Resonance Imaging
  • Neocortex
  • Prospective Studies
  • Regression Analysis
  • Serotonin Uptake Inhibitors
  • Treatment Outcome
  • Visual Perception

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