Pretreatment Rostral Anterior Cingulate Cortex Theta Activity in Relation to Symptom Improvement in Depression: A Randomized Clinical Trial

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.

Conflict of interest statement

Conflict of Interest Disclosures: For activities unrelated to the current research, the authors report the following financial disclosures. In the past 3 years, Dr Pizzagalli received funding from the National Institute of Mental Health (NIMH) and the Dana Foundation and consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, Pfizer, and Posit Science. In the past 3 years, Dr Dillon received funding from the NIMH and consulting fees from Pfizer. Dr Fava reports lifetime disclosures of research support from Abbott Laboratories, Acadia Pharmaceuticals, Alkermes Inc, American Cyanamid, Aspect Medical Systems, AstraZeneca, Avanir Pharmaceuticals, AXSOME Therapeutics, Biohaven, BioResearch, BrainCells Inc, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Cerecor, Clintara LLC, Covance, Covidien, Eli Lilly and Company, EnVivo Pharmaceuticals Inc, Euthymics Bioscience Inc, Forest Pharmaceuticals Inc, FORUM Pharmaceuticals, Ganeden Biotech Inc, GlaxoSmithKline, Harvard Clinical Research Institute, Hoffman-LaRoche, Icon Clinical Research, i3 Innovus/Ingenix, Janssen R&D LLC, Jed Foundation, Johnson & Johnson Pharmaceutical Research & Development, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Lundbeck Inc, Marinus Pharmaceuticals, MedAvante, Methylation Sciences Inc, National Alliance for Research on Schizophrenia and Depression (NARSAD), National Center for Complementary and Alternative Medicine, National Coordinating Center for Integrated Medicine, National Institute of Drug Abuse, NIMH, Neuralstem Inc, NeuroRx, Novartis AG, Organon Pharmaceuticals, Otsuka Pharmaceutical Development Inc, PamLab LLC, Pfizer Inc, Pharmacia-Upjohn, Pharmaceutical Research Associates Inc, Pharmavite LLC, PharmoRx Therapeutics, Photothera, Reckitt Benckiser, Roche Pharmaceuticals, RCT Logic LLC (formerly Clinical Trials Solutions LLC), Sanofi-Aventis US LLC, Shire, Solvay Pharmaceuticals Inc, Stanley Medical Research Institute, Synthelabo, Taisho Pharmaceuticals, Takeda Pharmaceuticals, Tal Medical, VistaGen, and Wyeth-Ayerst Laboratories; served on an advisory board or as a consultant for Abbott Laboratories, Acadia, Affectis Pharmaceuticals AG, Alkermes Inc, Amarin Pharma Inc, Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Avanir Pharmaceuticals, AXSOME Therapeutics, Bayer AG, Best Practice Project Management Inc, Biogen, BioMarin Pharmaceuticals Inc, Biovail Corporation, BrainCells Inc, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon Inc, Cerecor, CNS Response Inc, Compellis Pharmaceuticals, Cypress Pharmaceutical Inc, DiagnoSearch Life Sciences (P) Ltd, Dinippon Sumitomo Pharma Co Inc, Dov Pharmaceuticals Inc, Edgemont Pharmaceuticals Inc, Eisai Inc, Eli Lilly and Company, EnVivo Pharmaceuticals Inc, ePharmaSolutions, EPIX Pharmaceuticals Inc, Euthymics Bioscience Inc, Fabre-Kramer Pharmaceuticals Inc, Forest Pharmaceuticals Inc, Forum Pharmaceuticals, GenOmind LLC, GlaxoSmithKline, Grunenthal GmbH, Indivior, i3 Innovus/Ingenis, Intracellular, Janssen Pharmaceutica, Jazz Pharmaceuticals Inc, Johnson & Johnson Pharmaceutical Research & Development LLC, Knoll Pharmaceuticals Corp, Labopharm Inc, Lorex Pharmaceuticals, Lundbeck Inc, Marinus Pharmaceuticals, MedAvante Inc, Merck & Co Inc, MSI Methylation Sciences Inc, Naurex Inc, Navitor Pharmaceuticals Inc, Nestle Health Sciences, Neuralstem Inc, Neuronetics Inc, NextWave Pharmaceuticals, Novartis AG, Nutrition 21, Orexigen Therapeutics Inc, Organon Pharmaceuticals, Osmotica, Otsuka Pharmaceuticals, Pamlab LLC, Pfizer Inc, PharmaStar, Pharmavite LLC, PharmoRx Therapeutics, Precision Human Biolaboratory, Prexa Pharmaceuticals Inc, Pharmaceutical Product Development, Purdue Pharma, Puretech Ventures, PsychoGenics, Psylin Neurosciences Inc, RCT Logic LLC (formerly Clinical Trials Solutions LLC), Relmada Therapeutics Inc, Rexahn Pharmaceuticals Inc, Ridge Diagnostics Inc, Roche, Sanofi-Aventis US LLC, Sepracor Inc, Servier Laboratories, Schering-Plough Corporation, Shenox Pharmaceuticals, Solvay Pharmaceuticals Inc, Somaxon Pharmaceuticals Inc, Somerset Pharmaceuticals Inc, Sunovion Pharmaceuticals, Supernus Pharmaceuticals Inc, Synthelabo, Taisho Pharmaceuticals, Takeda Pharmaceutical Company Limited, Tal Medical Inc, Tetragenex, Teva Pharmaceuticals, TransForm Pharmaceuticals Inc, Transcept Pharmaceuticals Inc, Usona Institute Inc, Vanda Pharmaceuticals Inc, Versant Venture Management LLC, and VistaGen; has received compensation for speaking or publishing from Adamed Co, Advanced Meeting Partners, American Psychiatric Association, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Cephalon Inc, CME Institute/Physicians Postgraduate Press Inc, Eli Lilly and Company, Forest Pharmaceuticals Inc, GlaxoSmithKline, Imedex LLC, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, Novartis AG, Organon Pharmaceuticals, Pfizer Inc, PharmaStar, United BioSource Corp, and Wyeth-Ayerst Laboratories; has equity holdings in Compellis and PsyBrain Inc and hold patents for Sequential Parallel Comparison Design, licensed by MGH to Pharmaceutical Product Development LLC (US_7840419, US_7647235, US_7983936, US_8145504, and US_8145505). In the past 3 years, Dr Weissman received funding from the NIMH, NARSAD, the Sackler Foundation, and the Templeton Foundation and royalties from the Oxford University Press, Perseus Press, the American Psychiatric Association Press, and MultiHealth Systems. In the past 3 years, Dr Oquendo received funding from the NIMH and royalties for the commercial use of the Columbia-Suicide Severity Rating Scale. Her family owns stock in Bristol-Myers Squibb. In the past 3 years, Dr McInnis received funding from the NIMH and consulting fees from Janssen and Otsuka Pharmaceuticals. In the past 3 years, Dr Trivedi has served in either a consulting or advisory role for Alkermes Inc, Akili Interactive, Allergan Pharmaceuticals, Arcadia Pharmaceuticals, Avanir Pharmaceuticals, Brintellix Global, Bristol-Myers Squibb, Caudex, Cerecor, Forest Pharmaceuticals, Global Medical Education Inc, Health Research Associates, Insys, Johnson & Johnson Pharmaceutical Research & Development, Lilly Research Laboratories, Lundbeck Research USA, Medscape, Merck & Co Inc, Mitsubishi Pharma, MSI Methylation Sciences–Pamlab Inc, Navitor, Otsuka America Pharmaceutical Inc, One Carbon Therapeutics, Otsuka America Pharmaceutical Inc, Pfizer Inc, and Takeda Global Research; received royalties from Janssen Research and Development LLC; signed author agreements with Janssen Asia Pacific and Oxford University Press; received honoraria from the American Psychiatric Association; and been awarded grants from the Agency for Healthcare Research and Quality, Cancer Prevention and Research Institute of Texas, NIMH, National Institute of Drug Abuse, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, Johnson & Johnson, and Patient-Centered Outcomes Research Institute. No other disclosures are reported.

Figures

Figure 1.. CONSORT Flow Diagram

Primary hierarchical linear model analyses were intent-to-treat (ie, include dropouts). Thus, the flow diagram summarizes information relevant to intent-to-treat analyses. Information regarding dropout rates between groups and reasons for dropout is available in eTable 2 in Supplement 1. EEG indicates electroencephalographic.

Figure 2.. Estimated Week 8 Hamilton Rating Scale for Depression (HRSD) Scores for the Sertraline and Placebo Groups

Three values of baseline (A) and week 1 (B) rACC theta activity shown: 1 SD below the mean, the mean, and 1 SD above the mean. Error bars represent ±1 SE. rACC indicates rostral anterior cingulate cortex; SSRI, selective-serotonin reuptake inhibitor.