title: Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT-D Trial.
abstract: 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.
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA [2] Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC) Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA [3] The Brain Dynamics Center, Sydney Medical School, University of Sydney and Westmead Millennium Institute, Sydney, NSW, Australia.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Williams
authors.affiliation: 1] The Brain Dynamics Center, Sydney Medical School, University of Sydney and Westmead Millennium Institute, Sydney, NSW, Australia [2] Discipline of Psychiatry, Sydney Medical School, University of Sydney, Westmead Hospital, Sydney, NSW, Australia.
authors.forename: Mayuresh S
authors.initials: MS
authors.lastname: Korgaonkar
authors.affiliation: The Brain Dynamics Center, Sydney Medical School, University of Sydney and Westmead Millennium Institute, Sydney, NSW, Australia.
authors.forename: Yun C
authors.initials: YC
authors.lastname: Song
authors.affiliation: The Brain Dynamics Center, Sydney Medical School, University of Sydney and Westmead Millennium Institute, Sydney, NSW, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Paton
authors.affiliation: The Brain Dynamics Center, Sydney Medical School, University of Sydney and Westmead Millennium Institute, Sydney, NSW, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Eagles
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA [2] Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC) Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Goldstein-Piekarski
authors.affiliation: 1] The Brain Dynamics Center, Sydney Medical School, University of Sydney and Westmead Millennium Institute, Sydney, NSW, Australia [2] Discipline of Psychiatry, Sydney Medical School, University of Sydney, Westmead Hospital, Sydney, NSW, Australia [3] Sydney Translational Imaging Laboratory, Sydney Medical School, Sydney, NSW, Australia.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Grieve
authors.affiliation: 1] The Brain Dynamics Center, Sydney Medical School, University of Sydney and Westmead Millennium Institute, Sydney, NSW, Australia [2] Discipline of Psychiatry, Sydney Medical School, University of Sydney, Westmead Hospital, Sydney, NSW, Australia.
authors.forename: Anthony W F
authors.initials: AW
authors.lastname: Harris
authors.affiliation: Department of General Practice, Sydney Medical School Westmead, University of Sydney, Sydney, NSW, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Usherwood
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA [2] Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC) Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Etkin
mesh_terms: D000328:Adult; D000679:Amygdala / Q000098:blood supply / Q000187:drug effects*; D000928:Antidepressive Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D015283:Citalopram / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000473:pathology*; D004644:Emotions; D005149:Facial Expression; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D010775:Photic Stimulation; D011237:Predictive Value of Tests; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome; D000069470:Venlafaxine Hydrochloride / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram; D000069470:Venlafaxine Hydrochloride; D010100:Oxygen
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