The incremental predictive validity of rostral anterior cingulate cortex activity in relation to symptom improvement in depression: a randomized clinical trial
Diego A. Pizzagalli1,*, Christian A. Webb1,*, Daniel G. Dillon1, Craig E. Tenke2, Jürgen Kayser2, Franziska Goer1, Maurizio Fava3, Patrick McGrath2, Myrna Weissman2, Ramin Parsey4, Phil Adams2, Joseph Trombello5, Crystal Cooper5, Patricia Deldin6, Maria A. Oquendo7, Melvin G. McInnis6, Thomas Carmody5, Gerard Bruder2, Madhukar H. Trivedi5
1Harvard Medical School ? McLean Hospital, Boston, MA; 2New York State Psychiatric Institute & Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY; 3Harvard Medical School ? Massachusetts General Hospital, Boston, MA; 4Stony Brook University, Stony Brook, NY; 5University of Texas, Southwestern Medical Center, Dallas, TX; 6University of Michigan, Ann Arbor, MI; 7University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
*These authors contributed equally
Received 11 September 2017; revised 26 January 2018; accepted 29 January 2018; published online 11 April 2018.
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.
Objective: Increased pretreatment rostral anterior cingulate (rACC) 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. We hypothesized that increased pre-treatment rACC theta activity would predict symptom improvement regardless of randomization arm.
Design: Randomized clinical trial enrolling MDD outpatients between August 2011 and December 2015 (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression; EMBARC). Resting electroencephalographic (EEG) data were recorded at baseline and one week after trial onset, and rACC theta activity was extracted using source localization.
Setting: Multi-center study at four university hospitals.
Participants: Non-psychotic outpatients with chronic or recurrent MDD (18-65 years) consecutively recruited from four university hospitals. 634 patients were screened, 296 were randomized, 266 had EEG recordings, and 248 had usable EEG data.
Intervention: Randomized clinical trial involving an 8-week course of sertraline or placebo. Main Outcome: Hamilton Rating Scale for Depression score (assessed at baseline, weeks 1, 2, 3, 4, 6 and 8).
Results: The 248 participants (160 women, 88 men) with usable EEG data had a mean age of 36.75 (SD = 13.15) and were mostly female (64.52%). Higher rACC theta activity at both baseline (b = -1.05, 95% CI, -1.77 to -0.34, p = .004) 78 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.
Conclusions and Relevance: Increased pre-treatment rACC theta activity represents a non-specific, ?prognostic? marker of treatment outcome. This is the first study to demonstrate that rACC theta activity has incremental predictive validity. The rACC marker?in combination with clinical and demographic variables?accounted for an estimated 39.6% of the variance in symptom change (with 8.6% of the variance uniquely attributable to the rACC marker).
Trial Registration: NCT01407094; http://clinicaltrials.gov/show/NCT01407094
Key Words: Biosignatures; antidepressant response; EMBARC; sertraline; rostral ACC; personalized treatment; LORETA; EEG; theta activity