Transcriptional Signatures of Mitochondrial Metabolism Predict Esketamine-Induced rACC Structural Changes in Adolescent Major Depression.
Yanling Zhou, Weicheng Li, Xiaofeng Lan et al.
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In 30 seconds
This randomized controlled trial examined whether esketamine-related changes in the rostral anterior cingulate cortex (rACC) were associated with clinical improvement and molecular pathways in adolescents aged 13–18 years with major depressive disorder. Forty-nine adolescents received intravenous esketamine or midazolam, with 25 healthy controls providing a comparison group. Esketamine was associated with a significant group-by-time reduction in elevated right rACC surface area (F 1,47 = 8.06, partial η 2 = 0.15, p = .006); greater reductions correlated with larger decreases in depression scores (r = -0.44, p = .040). Transcriptomic analyses implicated mitochondrial energy metabolism.
Key findings
- At baseline, right rACC surface area was greater in adolescents with MDD than in healthy controls (Cohen d = 0.47, 95% CI = 0.08, 1.02, p = .020).
- After esketamine, right rACC surface area was comparable to healthy-control levels, with a significant group-by-time interaction (F 1,47 = 8.06, partial η 2 = 0.15, p = .006).
- In the esketamine group, greater right rACC surface-area reductions correlated with larger Hamilton Depression Rating Scale score decreases (r = -0.44, 95% CI = -0.77, -0.09, p = .040).
- Brain-gene coupling analyses implicated oxidative phosphorylation and the tricarboxylic acid cycle (normalized enrichment scores = 5.66 and 5.33, respectively; false discovery rate <0.001).
Why it matters
The findings connect a measurable brain-structure change with symptom improvement after esketamine in adolescents, while pointing to mitochondrial energy pathways as possible biological correlates. This may help frame future research into how rapid antidepressant effects relate to brain structure and molecular processes. The transcriptomic results are mechanistic clues, not evidence that mitochondrial changes caused the clinical or imaging effects.
What to keep in mind
The imaging assessment was limited to baseline and 24 hours after treatment. The molecular pathway analyses used transcriptomic data from the Allen Human Brain Atlas, rather than direct measurement of mitochondrial function in participants.