Functional connectivity between the amygdala and subgenual cingulate gyrus predicts the antidepressant effects of ketamine in patients with treatment-resistant depression

Abstract

Aim: Approximately one-third of patients with major depressive disorder develop treatment-resistant depression. One-third of patients with treatment-resistant depression demonstrate resistance to ketamine, which is a novel antidepressant effective for this disorder. The objective of this study was to examine the utility of resting-state functional magnetic resonance imaging for the prediction of treatment response to ketamine in treatment-resistant depression.

Methods: An exploratory seed-based resting-state functional magnetic resonance imaging analysis was performed to examine baseline resting-state functional connectivity differences between ketamine responders and nonresponders before treatment with multiple intravenous ketamine infusions.

Results: Fifteen patients with treatment-resistant depression received multiple intravenous subanesthetic (0.5 mg/kg/40 minutes) ketamine infusions, and nine were identified as responders. The exploratory resting-state functional magnetic resonance imaging analysis identified a cluster of significant baseline resting-state functional connectivity differences associating ketamine response between the amygdala and subgenual anterior cingulate gyrus in the right hemisphere. Using anatomical region of interest analysis of the resting-state functional connectivity, ketamine response was predicted with 88.9% sensitivity and 100% specificity. The resting-state functional connectivity of significant group differences between responders and nonresponders retained throughout the treatment were considered a trait-like feature of heterogeneity in treatment-resistant depression.

Conclusion: This study suggests the possible clinical utility of resting-state functional magnetic resonance imaging for predicting the antidepressant effects of ketamine in treatment-resistant depression patients and implicated resting-state functional connectivity alterations to determine the trait-like pathophysiology underlying treatment response heterogeneity in treatment-resistant depression.

Keywords: functional connectivity; ketamine; resting-state functional MRI; treatment response prediction; treatment-resistant depression.

FIGURE 1

Schematic overview of the study design. Intravenous racemic ketamine infusion was scheduled four times in 2 weeks, following the wash out period, under the double‐blind random assignment of pretreatment with lithium carbonate (600‐800 mg/day) or placebo. Resting‐state fMRI scans were performed before treatment (baseline; 16 hours before the first ketamine administration) and after the last infusion (follow‐up; 6‐24 hours after the last infusion) of ketamine.fMRI, functional magnetic resonance imaging

FIGURE 2

Significant cluster showing the significant RSFC differences between ketamine responders and nonresponders at baseline. A, Thresholded t map depicting the regions of significant RSFC difference between ketamine responders and nonresponders at baseline. Circles indicate the location of significant clusters (Right amygdala seed. Peak at x = 4, y = 38, z = −4; in MNI coordinates. The color bar indicates the t‐value). B, Overlap of the thresholded region and subdivision of the ACC. The dotted area indicates sc/sgACC defined by Beckmann et al ²⁷ ). (B‐1) Sagittal, (B‐2) Coronal, (B‐3) Axial. The RSFCs‐t is defined as the RSFC between the dotted area and the right amygdala. ACC, anterior cingulate cortex; MNI, Montreal Neurological Institute; RSFC, resting‐state functional connectivity; scACC, subcallosal anterior cingulate cortex; sgACC, subgenual anterior cingulate cortex

FIGURE 3

RSFC between the amygdala and the sc/sgACC in the right hemisphere (RSFCs‐t) at baseline predicts treatment response to ketamine. A, Time course change in depression severity as measured using the MADRS score (mean ± SD) throughout the study. Trajectories of depression severity are plotted for responder and nonresponder subgroups, defined using the final MADRS score. Each measurement corresponds to before and 40 minutes after each scheduled infusion of racemic ketamine (0.5 mg/kg/40 minutes). B, Distribution of baseline RSFCs‐t and %change in the MADRS score after the treatment. Correlation is significant with Spearman's rank‐order correlation (ρ = −0.56, P =.02). C, The box plot represents the RSFCs‐t indicating a significant difference between responders and nonresponders at baseline. Responders are shown in white dots and nonresponders are shown in black dots (P =.004, Mann‐Whitney U‐test. Box = 25th and 75th percentiles; bars = minutes and max values.). D, Nonparametric ROC curve analysis for RSFCs‐t (AUC = 0.92). AUC, area under the curve; MADRS, Montgomery‐Asberg Depression Rating Scale; ROC, receiver operating characteristics; RSFC, resting‐state functional connectivity; scACC, subcallosal anterior cingulate cortex; SD, standard deviation; sgACC, subgenual anterior cingulate cortex

FIGURE 4

Change in RSFCs‐t postketamine treatment. The box plot represents the group differences in RSFCs‐t between the responders and nonresponders at baseline and at the follow‐up scan. The RSFCs‐t retained significant baseline difference between the responders and nonresponders at the follow‐up scan (P =.04, Mann‐Whitney U‐test). RSFCs‐t, resting‐state functional connectivity between the seed and the target