Cerebral Blood Perfusion Predicts Response to Sertraline versus Placebo for Major Depressive Disorder in the EMBARC Trial

Crystal M Cooper, Cherise R Chin Fatt, Manish Jha, Gregory A Fonzo, Bruce D Grannemann, Thomas Carmody, Aasia Ali, Sina Aslan, Jorge R C Almeida, Thilo Deckersbach, Maurizio Fava, Benji T Kurian, Patrick J McGrath, Melvin McInnis, Ramin V Parsey, Myrna Weissman, Mary L Phillips, Hanzhang Lu, Amit Etkin, Madhukar H Trivedi, Crystal M Cooper, Cherise R Chin Fatt, Manish Jha, Gregory A Fonzo, Bruce D Grannemann, Thomas Carmody, Aasia Ali, Sina Aslan, Jorge R C Almeida, Thilo Deckersbach, Maurizio Fava, Benji T Kurian, Patrick J McGrath, Melvin McInnis, Ramin V Parsey, Myrna Weissman, Mary L Phillips, Hanzhang Lu, Amit Etkin, Madhukar H Trivedi

Abstract

Background: Major Depressive Disorder (MDD) has been associated with brain-related changes. However, biomarkers have yet to be defined that could "accurately" identify antidepressant-responsive patterns and reduce the trial-and-error process in treatment selection. Cerebral blood perfusion, as measured by Arterial Spin Labelling (ASL), has been used to understand resting-state brain function, detect abnormalities in MDD, and could serve as a marker for treatment selection. As part of a larger trial to identify predictors of treatment outcome, the current investigation aimed to identify perfusion predictors of treatment response in MDD.

Methods: For this secondary analysis, participants include 231 individuals with MDD from the EMBARC study, a randomised, placebo-controlled trial investigating clinical, behavioural, and biological predictors of antidepressant response. Participants received sertraline (n = 114) or placebo (n = 117) and response was monitored for 8 weeks. Pre-treatment neuroimaging was completed, including ASL. A whole-brain, voxel-wise linear mixed-effects model was conducted to identify brain regions in which perfusion levels differentially predict (moderate) treatment response. Clinical effectiveness of perfusion moderators was investigated by composite moderator analysis and remission rates. Composite moderator analysis combined the effect of individual perfusion moderators and identified which contribute to sertraline or placebo as the "preferred" treatment. Remission rates were calculated for participants "accurately" treated based on the composite moderator (lucky) versus "inaccurately" treated (unlucky).

Findings: Perfusion levels in multiple brain regions differentially predicted improvement with sertraline over placebo. Of these regions, perfusion in the putamen and anterior insula, inferior temporal gyrus, fusiform, parahippocampus, inferior parietal lobule, and orbital frontal gyrus contributed to sertraline response. Remission rates increased from 37% for all those who received sertraline to 53% for those who were lucky to have received it and sertraline was their perfusion-preferred treatment.

Interpretation: This large study showed that perfusion patterns in brain regions involved with reward, salience, affective, and default mode processing moderate treatment response favouring sertraline over placebo. Accurately matching patients with defined perfusion patterns could significantly increase remission rates.

Funding: National Institute of Mental Health, the Hersh Foundation, and the Center for Depression Research and Clinical Care, Peter O'Donnell Brain Institute at UT Southwestern Medical Center.Trial Registration.Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMARC) Registration Number: NCT01407094 (https://ichgcp.net/clinical-trials-registry/NCT01407094).

Figures

Fig. 1
Fig. 1
EMBARC CONSORT Flow Diagram. For this analysis patients were included (1) regardless of their HAMD17 score, (2) had relative cerebral blood flow scans pass quality control, and (3) had at least one follow up visit.
Fig. 2
Fig. 2
Brain regions in which relative, normalised, cerebral blood flow (nCBF; perfusion) was a moderator of treatment response (scaled by FDR corrected p-values).
Fig. 3
Fig. 3
The relationship between the combined moderator and the slope outcome is shown. Smaller values of the slope indicate a more favourable result, i.e., lower depression severity scores. The “preferred” treatment group is the line with the lowest position. Below the point where the two lines intersect (0.003), sertraline should be preferred as it has the smaller outcome values and above this point placebo should be preferred (left panel). Remission rates are presented for the lucky (those who were randomised to their statistically-preferred treatment) and unlucky (those who were randomised to their statistically-not-preferred treatment) as identified by the composite moderator (right panel).

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Source: PubMed

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