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Original Investigation
April 11, 2018

Pretreatment Rostral Anterior Cingulate Cortex Theta Activity in Relation to Symptom Improvement in DepressionA Randomized Clinical Trial

Author Affiliations
  • 1Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts
  • 2Department of Psychiatry, New York State Psychiatric Institute & Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York
  • 3Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston
  • 4Department of Psychiatry, Stony Brook University, Stony Brook, New York
  • 5Department of Psychiatry, University of Texas, Southwestern Medical Center, Dallas
  • 6Department of Psychiatry, University of Michigan, Ann Arbor
  • 7Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia
JAMA Psychiatry. Published online April 11, 2018. doi:10.1001/jamapsychiatry.2018.0252
Key Points

Question  Does increased pretreatment rostral anterior cingulate cortex theta activity have incremental predictive validity with respect to treatment outcome in major depression?

Findings  In a randomized clinical trial including 296 patients with major depressive disorder, higher rostral anterior cingulate cortex theta activity at both baseline and week 1 predicted greater improvement in depressive symptoms, even when controlling for clinical and demographic variables previously linked to treatment response.

Meaning  Increased pretreatment rostral anterior cingulate cortex theta activity represents a nonspecific prognostic marker of treatment outcome that has now been replicated in several studies and thus warrants consideration for implementation in clinical care.

Abstract

Importance  Major depressive disorder (MDD) remains challenging to treat. Although several clinical and demographic variables have been found to predict poor antidepressant response, these markers have not been robustly replicated to warrant implementation in clinical care. Increased pretreatment rostral anterior cingulate cortex (rACC) theta activity has been linked to better antidepressant outcomes. However, no prior study has evaluated whether this marker has incremental predictive validity over clinical and demographic measures.

Objective  To determine whether increased pretreatment rACC theta activity would predict symptom improvement regardless of randomization arm.

Design, Setting, and Participants  A multicenter randomized clinical trial enrolled outpatients without psychosis and with chronic or recurrent MDD between July 29, 2011, and December 15, 2015 (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care [EMBARC]). Patients were consecutively recruited from 4 university hospitals: 634 patients were screened, 296 were randomized to receive sertraline hydrochloride or placebo, 266 had electroencephalographic (EEG) recordings, and 248 had usable EEG data. Resting EEG data were recorded at baseline and 1 week after trial onset, and rACC theta activity was extracted using source localization. Intent-to-treat analysis was conducted. Data analysis was performed from October 7, 2016, to January 19, 2018.

Interventions  An 8-week course of sertraline or placebo.

Main Outcomes and Measures  The 17-item Hamilton Rating Scale for Depression score (assessed at baseline and weeks 1, 2, 3, 4, 6, and 8).

Results  The 248 participants (160 [64.5%] women, 88 [35.5%] men) with usable EEG data had a mean (SD) age of 36.75 (13.15) years. Higher rACC theta activity at both baseline (b =−1.05; 95% CI, −1.77 to −0.34; P = .004) and week 1 (b =−0.83; 95% CI, −1.60 to −0.06; P < .04) predicted greater depressive symptom improvement, even when controlling for clinical and demographic variables previously linked with treatment outcome. These effects were not moderated by treatment arm. The rACC theta marker, in combination with clinical and demographic variables, accounted for an estimated 39.6% of the variance in symptom change (with 8.5% of the variance uniquely attributable to the rACC theta marker).

Conclusions and Relevance  Increased pretreatment rACC theta activity represents a nonspecific prognostic marker of treatment outcome. This is the first study to date to demonstrate that rACC theta activity has incremental predictive validity.

Trial Registration  clinicaltrials.gov Identifier: NCT01407094

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