Transcriptional Signatures of Mitochondrial Metabolism Predict Esketamine-Induced rACC Structural Changes in Adolescent Major Depression.

Objective: To investigate neurobiological mechanisms through which esketamine produces rapid antidepressant effects in adolescents with major depressive disorder (MDD), focusing on structural changes in the rostral anterior cingulate cortex (rACC) and associated molecular pathways.

Method: A total of 49 adolescents (13-18 years of age) with DSM-5 MDD were randomized to receive intravenous esketamine (0.25 mg/kg) or midazolam (0.02 mg/kg) over 5 days (3 infusions total) and were compared with 25 age-matched healthy controls. Structural magnetic resonance imaging scans were obtained at baseline and 24 hours post treatment to assess bilateral rACC surface area, volume, and thickness using FreeSurfer. Clinical symptoms were evaluated using the Hamilton Depression Rating Scale and Columbia-Suicide Severity Rating Scale. Transcriptomic-neuroimaging coupling analyses were performed using partial least squares regression on Allen Human Brain Atlas data, followed by gene set enrichment and protein-protein interaction analyses.

Results: At baseline, adolescents with MDD showed increased right rACC surface area compared with healthy controls (Cohen d = 0.47, 95% CI = 0.08, 1.02, p = .020). Following esketamine treatment, right rACC surface area decreased to levels comparable to those of healthy controls (Cohen d = 0.17, 95% CI = -0.41, 0.75, p = .523), showing a significant group by time interaction (F1,47 = 8.06, partial η2 = 0.15, p = .006). In the esketamine group, greater reductions in right rACC surface area were associated with larger decreases in Hamilton Depression Rating Scale scores (r = -0.44, 95% CI = -0.77, -0.09, p = .040). Partial least-squares regression analysis identified a brain-gene coupling component (r = 0.44, p = .008; p_spin = .018) enriched for pathways related to mitochondrial energy metabolism (oxidative phosphorylation: normalized enrichment score = 5.66, false discovery rate <0.001; tricarboxylic acid cycle: normalized enrichment score = 5.33, false discovery rate <0.001). Protein-protein interaction network analysis highlighted electron transport chain complexes I and V as central modules.

Conclusion: Esketamine rapidly reduced elevated right rACC surface area in adolescents with MDD, and this structural change correlated with clinical improvement. Moreover, enhanced mitochondrial function-particularly oxidative phosphorylation and electron transport chain activity-may contribute to these structural and clinical effects, providing insight into the mechanisms underlying esketamine's antidepressant action. Clinical trial registration information: A Study to evaluate the efficacy and safety of Esketamine combined with oral antidepressants in the treatment of major depressive disorder with suicidal ideation; https://www.chictr.org.cn/showproj.html?proj=66172 DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. Diverse cell lines and/or genomic datasets were not available. We actively worked to promote sex and gender balance in our author group.