Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT-D Trial
Open accessAbstract
Although the cost of poor treatment outcomes of depression is staggering, we do not yet have clinically useful methods for selecting the most effective antidepressant for each depressed person. Emotional brain activation is altered in major depressive disorder (MDD) and implicated in treatment response. Identifying which aspects of emotional brain activation are predictive of general and specific responses to antidepressants may help clinicians and patients when making treatment decisions. We examined whether amygdala activation probed by emotion stimuli is a general or differential predictor of response to three commonly prescribed antidepressants, using functional magnetic resonance imaging (fMRI). A test-retest design was used to assess patients with MDD in an academic setting as part of the International Study to Predict Optimized Treatment in Depression. A total of 80 MDD outpatients were scanned prior to treatment and 8 weeks after randomization to the selective serotonin reuptake inhibitors escitalopram and sertraline and the serotonin-norepinephrine reuptake inhibitor, venlafaxine-extended release (XR). A total of 34 matched controls were scanned at the same timepoints. We quantified the blood oxygen level-dependent signal of the amygdala during subliminal and supraliminal viewing of facial expressions of emotion. Response to treatment was defined by ⩾50% symptom improvement on the 17-item Hamilton Depression Rating Scale. Pre-treatment amygdala hypo-reactivity to subliminal happy and threat was a general predictor of treatment response, regardless of medication type (Cohen's d effect size 0.63 to 0.77; classification accuracy, 75%). Responders showed hypo-reactivity compared to controls at baseline, and an increase toward 'normalization' post-treatment. Pre-treatment amygdala reactivity to subliminal sadness was a differential moderator of non-response to venlafaxine-XR (Cohen's d effect size 1.5; classification accuracy, 81%). Non-responders to venlafaxine-XR showed pre-treatment hyper-reactivity, which progressed to hypo-reactivity rather than normalization post-treatment, and hypo-reactivity post-treatment was abnormal compared to controls. Impaired amygdala activation has not previously been highlighted in the general vs differential prediction of antidepressant outcomes. Amygdala hypo-reactivity to emotions signaling reward and threat predicts the general capacity to respond to antidepressants. Amygdala hyper-reactivity to sad emotion is involved in a specific non-response to a serotonin-norepinephrine reuptake inhibitor. The findings suggest amygdala probes may help inform the personal selection of antidepressant treatments.
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Normalization of emotional processing at behavioural and neural levels takes place during antidepressant treatment and correlates with clinical improvement.
“normalization of emotional processing at behavioural and neural levels was shown to take place during AD treatment and to correlate with clinical improvement”
From Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment (2021) · cites this paper as Williams et al. 2015
In a study comparing the SSRIs escitalopram and sertraline and the dual 5-HT and NA reuptake inhibitor venlafaxine-XR, amygdala hyporeactivity to happy and fearful faces at baseline predicted clinical responses across treatments, but amygdala hyperreactivity to sad faces specifically predicted a nonresponse to venlafaxine-XR.
“In a study comparing the SSRIs escitalopram and sertraline and the dual 5-HT and NA reuptake inhibitor venlafaxine-XR, amygdala hyporeactivity to happy and fearful faces at baseline predicted clinical responses across treatments, but amygdala hyperreactivity to sad faces specifically predicted a nonresponse to venlafaxine-XR.82”
From The effects of drugs on human models of emotional processing: an account of antidepressant drug treatment (2015) · cites this paper as [82]
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- Authors
- Williams, L. M., Korgaonkar, M. S., Song, Y. C., Paton, R., Eagles, S., Goldstein-Piekarski, A., Grieve, S. M., Harris, A. W. F., Usherwood, T., & Etkin, A.
- Affiliations
- The University of Sydney (AU)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Williams, Leanne M
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2015-03-31
- Volume
- 40
- Issue
- 10
- Pages
- 2398-2408
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4538354
- OpenAlex
- W2026088841
- Cited by
- 195
- References
- 52
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 22 · 2023: 10 · 2022: 10 · 2021: 42 · 2020: 16 · 2019: 17 · 2018: 21 · 2017: 18 · 2016: 14 · 2015: 3
- FWCI
- 13.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- amygdala reactivity, major depressive disorder, antidepressant response, treatment response prediction, emotional face processing, venlafaxine extended release, sertraline, escitalopram, serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors
- MeSH terms
- Venlafaxine Hydrochloride, Adult, Amygdala, Antidepressive Agents, Major Depressive Disorder, Emotions, Facial Expression, Female, Humans, Image Processing, Computer-Assisted, Male, Middle Aged, Oxygen, Photic Stimulation, Predictive Value of Tests, Psychiatric Status Rating Scales, Citalopram, Case-Control Studies, Treatment Outcome, Young Adult
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