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Cited by 775Treatment of Major DepressionNeural and Behavioral Psychology StudiesAnxiety, Depression, Psychometrics, Treatment, Cognitive Processes

Attenuation of the Neural Response to Sad Faces in Major Depressionby Antidepressant Treatment: A Prospective, Event-Related Functional Magnetic Resonance ImagingStudy

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Fu, Cynthia H. Y., Williams, Steven C. R., Cleare, Anthony J., Brammer, Michael J., Walsh, Nicholas D., Kim, Jieun, Andrew, Chris M., Pich, Emilio Merlo +5 more·2004·Archives of General Psychiatry
DOI 10.1001/archpsyc.61.9.877
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Abstract

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.

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  • Studies on MDD have found that SSRI intervention often normalises abnormal neural processing, which in turn improves cognitive functioning and at a later time point, mood.

    “Studies on MDD have found that SSRI intervention often normalises abnormal neural processing [49–52], which in turn improves cognitive functioning and at a later time point, mood [52].”

    From Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study (2023) · cites this paper as [49]

    The treatment and group-by-time sections (page unavailable) report that patients with depression received the SSRI fluoxetine and that their abnormal responses to sad faces diminished over eight weeks. But the behavioral-data section reports no significant treatment-related improvement in task performance, and the paper does not establish that neural changes improved cognition before mood improved; neural responses and mood were assessed at the same follow-up point. (LLM, conf=0.89)

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  • 8 weeks of sertraline treatment normalized amygdalar hyper-activation to sad faces in MDD.

    “These findings were complemented by data showing that 8 weeks of sertraline treatment normalized amygdalar hyper-activation to sad faces in MDD [194], replicating prior findings [195,196].”

    From Prefrontal cortex and depression (2022) · cites this paper as [196]

    The treatment and Effects of Antidepressant Treatment sections (page not provided) support reduced amygdala activation to sad faces after eight weeks in patients with depression. But this paper treated its patients with fluoxetine, not sertraline; it describes an earlier sertraline study as using fearful faces. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Antidepressant treatment normalizes hyperactive amygdala responses following 7 days or longer treatment with an SSRI.

    “Antidepressant treatment modifies this, and hyperactive responses in the amygdala are normalised following 7 days'46 or longer44,45 treatment with an SSRI.”

    From The effects of drugs on human models of emotional processing: an account of antidepressant drug treatment (2015) · cites this paper as [44]

  • Antidepressant medications reduce amygdala activation to threatening stimuli and increase visual association cortex response to positive stimuli.

    “Direct experimental evidence indicates that antidepressant medications reduce amygdala activation to threatening stimuli and increase visual association cortex response to positive stimuli (16–21)”

    From Lateral prefrontal cortex mediates the cognitive modification of attentional bias (2010) · cites this paper as [21]

  • Antidepressant drugs may alter attentional habit via an effect on early stimulus appraisal rather than on higher order control processes.

    “suggesting that these drugs may alter attentional habit via an effect on early stimulus appraisal rather than on higher order control processes.”

    From Lateral prefrontal cortex mediates the cognitive modification of attentional bias (2010) · cites this paper as [21]

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Research works printed but not linked: 5

  1. Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. A functional anatomy of unipolar depression. J Neurosci. 1992;12:3628-3641.
  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994.
  3. Bullmore ET, Brammer MJ, Rabe-Hesketh S, Curtis VA, Morris RG, Williams SCR, Sharma T, McGuire PK. Methods for diagnosis and treatment of stimulus- correlated motion in generic brain activation studies using fMRI. Hum Brain Mapp. 1999;7:38-48.
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Authors
Fu, C. H. Y., Williams, S. C. R., Cleare, A. J., Brammer, M. J., Walsh, N. D., Kim, J., Andrew, C. M., Pich, E. M., Williams, P. M., Reed, L. J., Mitterschiffthaler, M. T., Suckling, J., & Bullmore, E. T.
Affiliations
King's College London (GB)
ORCID
Venue
Archives of General Psychiatry
Publisher
American Medical Association (AMA)
Published
2004-09-01
Volume
61
Issue
9
Pages
877
ISSN
0003-990X (ISSN-L)
DOI
10.1001/archpsyc.61.9.877
OpenAlex
W2110290939
Cited by
775
References
98
Citations by year
2026: 8 · 2025: 14 · 2024: 14 · 2023: 13 · 2022: 22 · 2021: 44 · 2020: 16 · 2019: 33 · 2018: 25 · 2017: 31 · 2016: 25 · 2015: 39 · 2014: 36 · 2013: 59 · 2012: 56
FWCI
19.89
Type
journal article
Language
en
Open access
Locations
  • Archives of General Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • UEA Digital Repository (University of East Anglia) (submittedVersion)
Funders
  • GlaxoSmithKline
  • Wellcome Trust
  • King's College London
  • National Institute of Mental Health
  • National Institute of Biomedical Imaging and Bioengineering
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Keywords
major depressive disorder, facial expression recognition, antidepressant response, fluoxetine, amygdala, ventral striatum, prefrontal cortex, anterior cingulate cortex, treatment response biomarkers, limbic system
MeSH terms
Affect, Brain, Brain Mapping, Depressive Disorder, Evoked Potentials, Facial Expression, Fluoxetine, Humans, Limbic System, Magnetic Resonance Imaging, Prospective Studies, Regression Analysis, Visual Perception, Treatment Outcome, Selective Serotonin Reuptake Inhibitors, Neocortex

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