Cortical Connectivity Moderators of Antidepressant vs Placebo Treatment Response in Major Depressive Disorder: Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Despite the widespread awareness of functional magnetic resonance imaging findings suggesting a role for cortical connectivity networks in treatment selection for major depressive disorder, its clinical utility remains limited. Recent methodological advances have revealed functional magnetic resonance imaging-like connectivity networks using electroencephalography (EEG), a tool more easily implemented in clinical practice.

Objective: To determine whether EEG connectivity could reveal neural moderators of antidepressant treatment.

Design, setting, and participants: In this nonprespecified secondary analysis, data were analyzed from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinic Care study, a placebo-controlled, double-blinded randomized clinical trial. Recruitment began July 29, 2011, and was completed December 15, 2015. A random sample of 221 outpatients with depression aged 18 to 65 years who were not taking medication for depression was recruited and assessed at 4 clinical sites. Analysis was performed on an intent-to-treat basis. Statistical analysis was performed from November 16, 2018, to May 23, 2019.

Interventions: Patients received either the selective serotonin reuptake inhibitor sertraline hydrochloride or placebo for 8 weeks.

Main outcomes and measures: Electroencephalographic orthogonalized power envelope connectivity analyses were applied to resting-state EEG data. Intent-to-treat prediction linear mixed models were used to determine which pretreatment connectivity patterns were associated with response to sertraline vs placebo. The primary clinical outcome was the total score on the 17-item Hamilton Rating Scale for Depression, administered at each study visit.

Results: Of the participants recruited, 9 withdrew after first dose owing to reported adverse effects, and 221 participants (150 women; mean [SD] age, 37.8 [12.7] years) underwent EEG recordings and had high-quality pretreatment EEG data. After correction for multiple comparisons, connectome-wide analyses revealed moderation by connections within and between widespread cortical regions-most prominently parietal-for both the antidepressant and placebo groups. Greater alpha-band and lower gamma-band connectivity predicted better placebo outcomes and worse antidepressant outcomes. Lower connectivity levels in these moderating connections were associated with higher levels of anhedonia. Connectivity features that moderate treatment response differentially by treatment group were distinct from connectivity features that change from baseline to 1 week into treatment. The group mean (SD) score on the 17-item Hamilton Rating Scale for Depression was 18.35 (4.58) at baseline and 26.14 (30.37) across all time points.

Conclusions and relevance: These findings establish the utility of EEG-based network functional connectivity analyses for differentiating between responses to an antidepressant vs placebo. A role emerged for parietal cortical regions in predicting placebo outcome. From a treatment perspective, capitalizing on the therapeutic components leading to placebo response differentially from antidepressant response should provide an alternative direction toward establishing a placebo signature in clinical trials, thereby enhancing the signal detection in randomized clinical trials.

Trial registration: ClinicalTrials.gov identifier: NCT01407094.

Figure 1.. Cortical Regions of Interest (ROIs), Alpha Power Envelope Connectivity (PEC), and Gamma PEC

A, A total of 31 ROIs (right and left ROIs are numbered the same; 14 bilateral ROIs [28 total] and 3 midline ROIs) were defined in Montreal Neurological Institute space, derived from independent components analysis parcellation of resting-state functional magnetic resonance imaging connectivity from 38 participants. B, Resting eyes-closed PEC between left mid-temporal gyrus and right angular gyrus moderation of outcome with sertraline (SER) vs placebo (PLA) treatment within the alpha band. C, Resting eyes-closed PEC between left anterior mid-frontal gyrus and right mid-temporal gyrus moderation of outcome with SER vs PLA treatment within the gamma band. Left panel: z scores for significantly moderating ROIs are represented in the ROI × ROI matrix plots. Middle panel: summed cortical connectivity (z scores) at each significantly moderating ROI. Right panel: visualization of moderation results reveals that significant prediction of treatment only in the PLA group was probably the cause of the moderation results. Shown are model-predicted 17-item Hamilton Rating Scale for Depression (HAMD17) values for the PLA and SER groups using an arbitrary median split on PEC for visualization purposes only. Low = below-median connectivity and high = above-median connectivity. The 2 ROIs comprising the pairwise connectivity feature visualized are outlined in red on the cortical images. AMFG indicates anterior mid-frontal gyrus; ANG, angular gyrus; DACC, dorsal anterior cingulate cortex; FEF, frontal eye fields; IFJ, inferior frontal junction; INS, insular cortex; IPL, inferior parietal lobe; IPS, inferior parietal sulcus; L, left; MPFC, medial prefrontal cortex; MTG, mid-temporal gyrus; ORB, orbitofrontal cortex; PCC, posterior cingulate cortex; PMFG, posterior mid-frontal gyrus; R, right; SEF, superior eye fields; SMC, sensorimotor cortex; SUP, supramarginal gyrus; and VI, bilateral primary visual cortex.

Figure 2.. Resting Eyes-Open Power Envelope Connectivity (PEC) Moderation of Outcome With Sertraline (SER) vs Placebo (PLA) Treatment Within the Alpha, Beta, and Gamma Bands

A, Alpha PEC between left and right primary visual cortex. B, Beta PEC between medial prefrontal cortex and left inferior parietal sulcus. C, Gamma PEC between left inferior parietal lobe and right primary visual cortex. Left panel: z scores for significantly moderating regions of interest (ROIs) are represented in the ROI × ROI matrix plots. Middle panel: summed cortical connectivity (z scores) at each significantly moderating ROI; ROIs with greater summed z scores are those with greater total moderating connectivity. Right panel: visualization of moderation results reveals that significant prediction of treatment only in the PLA group was probably the cause of the moderation results. Shown are model-predicted 17-item Hamilton Rating Scale for Depression (HAMD17) values for the PLA and SER groups using an arbitrary median split on PEC for visualization purposes only. Low = below-median connectivity, high = above-median connectivity. Two ROIs comprising the pairwise connectivity feature visualized are outlined in red on the cortical images. AMFG indicates anterior mid-frontal gyrus; ANG, angular gyrus; DACC, dorsal anterior cingulate cortex; FEF, frontal eye fields; IFJ, inferior frontal junction; INS, insular cortex; IPL, inferior parietal lobe; IPS, inferior parietal sulcus; L, left; MPFC, medial prefrontal cortex; MTG, mid-temporal gyrus; ORB, orbitofrontal cortex; PCC, posterior cingulate cortex; PMFG, posterior mid-frontal gyrus; R, right; SEF, superior eye fields; SMC, sensorimotor cortex; SUP, supramarginal gyrus; and VI, bilateral primary visual cortex.

Figure 3.. Alpha Power Envelope Connectivity (PEC) Node Strength Moderation of Outcome With Sertraline (SER) vs Placebo (PLA) Treatment

Left panel: z scores for significantly moderating features are represented in the above matrix plots. Right angular gyrus (RANG), right inferior parietal lobe (RIPL), and right supramarginal gyrus (RSUP) node strength significantly moderated treatment outcome within the alpha carrier frequency. Middle panel: summed cortical connectivity (z scores) at each significantly moderating region of interest. Right panel: visualization of RANG (outlined in red on cortical image) moderation results reveals that significant prediction of treatment only in the PLA group was probably the cause of the moderation results. Shown are model-predicted 17-item Hamilton Rating Scale for Depression (HAMD17) values for the PLA and SER groups using an arbitrary median split on PEC for visualization purposes only. Low = below-median connectivity, high = above-median connectivity. AMFG indicates anterior mid-frontal gyrus; DACC, dorsal anterior cingulate cortex; FEF, frontal eye fields; IFJ, inferior frontal junction; INS, insular cortex; IPS, inferior parietal sulcus; L, left; MPFC, medial prefrontal cortex; MTG, mid-temporal gyrus; ORB, orbitofrontal cortex; PCC, posterior cingulate cortex; PMFG, posterior mid-frontal gyrus; R, right; SEF, superior eye fields; SMC, sensorimotor cortex; and VI, bilateral primary visual cortex.

Figure 4.. Association Between Electroencephalography Connectivity Moderators and Anhedonia

A, Alpha power envelope connectivity (PEC) between the left middle temporal gyrus and right angular gyrus. B, Gamma PEC between left angular gyrus and left inferior parietal sulcus (see eTable 7 in the Supplement for statistics). C, Greater anhedonia (as measured by the Snaith-Hamilton Pleasure Scale [SHAPS]) is associated with lower alpha PEC node strength in the right angular gyrus (see eTable 8 in the Supplement for statistics). Two regions of interest (ROIs) comprising the pairwise connectivity feature, or single ROI comprising the node strength feature, are visualized are outlined in red on the cortical images. Diagonal lines indicate same ROI-to-ROI connections.