The association between amygdalar volume changes and depressive symptom improvements after repeated ketamine infusion in treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with the following open-label study.

Background: Ketamine is effective for treatment-resistant depression (TRD), where its mechanism remains unclear. Though the amygdala plays an important role in emotional processing and mood state, no study has explored the relationship between amygdalar subfield volumes and ketamine's effect in patients with TRD. We hypothesized that amygdalar subfield volume changes would correlate with clinical response to ketamine in patients with TRD.

Methods: We used data from a double-blind, randomized, placebo-controlled trial (jRCTs031210124). Among 31 completers, 11 (35.5 %) participants in the ketamine group and 15 (48.4 %) participants in the placebo group underwent 0.8 mm-isotropic T1-and T2-weighted multimodal magnetic resonance imaging scans before and after the interventions. Depressive symptoms were assessed with the Montgomery Åsberg Depression Rating Scale (MADRS). We focused on the three amygdalar subfields: laterobasal (LB), centromedial, and superficial nuclei. Multivariable and post-hoc univariate regression analyses were conducted to explore the factors associated with the change in the MADRS total and subdomain scores.

Results: There was a significant interaction between the volume changes in the right LB and group for the MADRS dysphoria score changes (F (3, 22) = 3.63, p = 0.029, R = 0.24, treatment by volume change interaction: β = 0.61, p = 0.028). Post-hoc analyses found that changes in MADRS dysphoria scores related to volume changes in the right LB in the ketamine group (β = 0.65, p = 0.028), but not in the placebo group.

Conclusions: The reductions in right LB volumes correlate with better clinical responses to ketamine in patients with TRD, suggesting ketamine may exert its effect by attenuating amygdalar overactivity in this population.