Regional Blood Flow Signatures of Opioidergic Modulation of Ketamine in Major Depressive Disorder: A Randomized Crossover Study.
Luke A Jelen, Owen O'daly, Fernando O Zelaya, James M Stone, Allan H Young, Mitul A Mehta
The American journal of psychiatry June 1, 2026 Peer reviewed DOI: 10.1176/appi.ajp.20250903 via PubMed
Summary
Ketamine significantly increased regional cerebral blood flow (rCBF) in specific brain areas associated with major depressive disorder (MDD), and this effect was not reduced by the opioid blocker naltrexone. While ketamine's impact on rCBF correlated with subjective effects and antidepressant response under placebo, these correlations were disrupted when naltrexone was administered. The study highlights the complex interactions between glutamatergic, opioidergic, and GABAergic systems in modulating ketamine's effects.
Study at a glance
| Design | randomized controlled trial |
|---|---|
| Sample size | 26 |
| Population | adults aged 18-50 years with major depressive disorder |
| Key finding | Ketamine significantly increased CBF in subgenual, pregenual, and dorsal anterior cingulate cortices, and these effects were not attenuated by naltrexone. |
Abstract
Accumulating evidence suggests that the opioid system may modulate ketamine's rapid antidepressant effects. The objective of this study was to test whether opioid system modulation via naltrexone alters ketamine's acute effects on regional cerebral blood flow (rCBF) in major depressive disorder (MDD), and whether these changes relate to symptom measures and map onto receptor density profiles. In a randomized, double-blind, crossover study, 26 adults (18-50 years of age) with MDD completed two treatment sessions: oral naltrexone 50 mg or placebo, each followed by intravenous ketamine (0.5 mg/kg over 40 minutes) during 3-D pseudo-continuous arterial spin labeling MRI to quantify rCBF. Subjective effects were assessed with the Clinician-Administered Dissociative States Scale and the Psychotomimetic States Inventory (PSI), and clinical outcomes with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR). Exploratory analyses spatially correlated CBF maps with receptor density profiles (MOR, KOR, NMDA, mGluR5, GABAA, GABAAα5), correcting for spatial autocorrelation. Ketamine significantly increased CBF in subgenual, pregenual, and dorsal anterior cingulate cortices, and the effects were not attenuated by naltrexone. Under placebo pretreatment, baseline-adjusted infusion pregenual relative rCBF was significantly associated with acute subjective effects (PSI delusional score: r=0.56; PSI perceptual distortion score: r=0.64), and baseline subgenual rCBF (adjusted for global CBF) was significantly associated with day 1 antidepressant response (MADRS, r=0.60; QIDS-SR, r=0.67). Naltrexone pretreatment disrupted these associations. Ketamine-induced CBF changes aligned with MOR and mGluR5 receptor profiles; naltrexone's interaction aligned with MOR, mGluR5, and GABAAα5. The results suggest that ketamine's effects on CBF in MDD are influenced by complex interactions between glutamatergic, opioidergic, and GABAergic systems. These findings provide mechanistic insights with potential implications for optimizing ketamine-based treatments.