Pretreatment Reward Sensitivity and Frontostriatal Resting-State Functional Connectivity Are Associated With Response to Bupropion After Sertraline Nonresponse

Abstract

Background: Standard guidelines recommend selective serotonin reuptake inhibitors as first-line antidepressants for adults with major depressive disorder, but success is limited and patients who fail to benefit are often switched to non-selective serotonin reuptake inhibitor agents. This study investigated whether brain- and behavior-based markers of reward processing might be associated with response to bupropion after sertraline nonresponse.

Methods: In a two-stage, double-blinded clinical trial, 296 participants were randomized to receive 8 weeks of sertraline or placebo in stage 1. Individuals who responded continued on another 8-week course of the same intervention in stage 2, while sertraline and placebo nonresponders crossed over to bupropion and sertraline, respectively. Data from 241 participants were analyzed. The stage 2 sample comprised 87 patients with major depressive disorder who switched medication and 38 healthy control subjects. A total of 116 participants with major depressive disorder treated with sertraline in stage 1 served as an independent replication sample. The probabilistic reward task and resting-state functional magnetic resonance imaging were administered at baseline.

Results: Greater pretreatment reward sensitivity and higher resting-state functional connectivity between bilateral nucleus accumbens and rostral anterior cingulate cortex were associated with positive response to bupropion but not sertraline. Null findings for sertraline were replicated in the stage 1 sample.

Conclusions: Pretreatment reward sensitivity and frontostriatal connectivity may identify patients likely to benefit from bupropion following selective serotonin reuptake inhibitor failures. Results call for a prospective replication based on these biomarkers to advance clinical care.

Keywords: Antidepressant response; Biomarkers; Bupropion; Frontostriatal connectivity; Reward sensitivity; Sertraline.

Figure 1.. Comparison of (A) response bias, (B) reward sensitivity and (C) learning rate for the probabilistic reward task at baseline.

Bupropion responders in Phase 2 have significantly greater baseline (pretreatment) response bias and reward sensitivity, but not learning rate, compared to non-responders (*p<0.05, **p<0.01). On the other hand, there was no difference on these metrics between responders and non-responders to sertraline. Note that the reward sensitivity and learning rate parameters have been transformed to prevent issues with non-Gaussianity.

Figure 2.. Baseline resting-state functional connectivity (RSFC) of bilateral nucleus accumbens (NACC) is associated with differential response to bupropion (BUP) compared with sertraline (SER).

(A) Shown is the seed region of interest (ROI) in bilateral nucleus accumbens, anatomically defined using the AAL atlas. (B) The interaction between antidepressant type and response to treatment was associated with RSFC (Fisher’s z-transformed Pearson’s correlations across the full duration of the resting scan) between bilateral nucleus accumbens and a region of rostral anterior cingulate cortex (rACC). (C) Patients randomized to bupropion for Stage 2 who responded to treatment showed higher NACC-rACC RSFC before the onset of Stage 1 than patients who failed to respond to bupropion, and this pattern also emerged in separate voxelwise analysis within the bupropion group (Fig. 3). Patients randomized to sertraline who responded to treatment showed lower NACC-rACC RSFC than sertraline non-responders, but this effect failed to emerge in separate voxelwise analyses within the sertraline group (Fig. 3). Note: Voxelwise analyses thresholded at peak p<0.001, two-sided, FDR corrected p<0.05.

Figure 3.. Voxelwise resting-state functional connectivity (RSFC) of bilateral nucleus accumbens (NACC) of responders versus non-responders, within treatment groups.

(A) Shown is the seed region of interest (ROI) in bilateral nucleus accumbens, anatomically defined using the AAL atlas. (B) Patients randomized to bupropion who responded to treatment showed higher NACC-rACC RSFC than patients who failed to respond to bupropion. (C) Among patients randomized to sertraline (SER), there was no difference in NACC RSFC between those who responded, or failed to respond, to treatment. Note: Voxelwise static analyses thresholded at peak p<0.005, two-sided, FDR corrected p<0.05.