Establishing Evidence for Clinical Utility of a Neuroimaging Biomarker in Major Depressive Disorder: Prospective Testing and Implementation Challenges

Abstract

Background: Although a number of neuroimaging biomarkers for response have been proposed, none have been tested prospectively for direct effects on treatment outcomes. To the best of our knowledge, this is the first prospective test of the clinical utility of the use of an imaging biomarker to select treatment for patients with major depressive disorder.

Methods: Eligible participants (n = 60) had a primary diagnosis of major depressive disorder and were assigned to either escitalopram or cognitive behavioral therapy based on fluorodeoxyglucose positron emission tomography activity in the right anterior insula. The overall study remission rate after 12 weeks of treatment, based on the end point Hamilton Depression Rating Scale score, was then examined for futility and benefit of the strategy.

Results: Remission rates demonstrated lack of futility at the end of stage 1 (37%, 10/27), and the study proceeded to stage 2. After adjustment for the change in stage 2 sample size, the complete remission rate did not demonstrate evidence of benefit (37.7%, 95% confidence interval, 26.3%-51.4%, p = .38). However, total remission rates (complete and partial remission) did reach significance in post hoc analysis (49.1%, 95% confidence interval, 37.6%-60.7%, p = .020).

Conclusions: The study shows some evidence for a role of the right anterior insula in the clinical choice of major depressive disorder monotherapy. The effect size, however, is insufficient for the use of insula activity as a sole predictive biomarker of remission. The study also demonstrates the logistical difficulties in establishing clinical utility of biomarkers.

Trial registration: ClinicalTrials.gov NCT02137369.

Keywords: Antidepressant; Clinical trial; Cognitive behavioral therapy (CBT); Major depressive disorder (MDD); Neuroimaging; Positron emission tomography (PET); Selective serotonin reuptake inhibitor (SSRI); Treatment response.

Conflict of interest statement

Disclosures: Dr. Mayberg has received consulting and licensing fees from Abbott Labs. Dr. Dunlop has received research support from Acadia, Compass Pathways, Aptinyx, NIMH, Sage, and Takeda, and has served as a consultant to Greenwich Biosciences, Myriad Neuroscience, Otsuka, Sage, and Sophren Therapeutics. Dr. Rakofsky has received research support from Compass Pathways, Otsuka, and the American Board of Psychiatry and Neurology, and has received honoraria from SMI Clinical Advisor. Dr. Craighead receives book royalties from John Wiley & Sons; he has received research support from NIH, the Fuqua family foundations, the Mary and John Brock Foundation, and he is a consultant to the George West Mental Health Foundation and AIM for Mental Health Foundation. All other authors report no biomedical financial interests or potential conflicts of interest.

Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1:

Treatment selection biomarker location and measurement

Figure 2:

Remission rates achieved with use of treatment selection biomarker (TSB)

Figure 3:

Distribution of right anterior insula values in derivation (n=80) and testing (n=60) samples