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 Stone, Allan H. Young, Mitul A. Mehta
The American journal of psychiatry June 1, 2026 DOI: 10.1176/appi.ajp.20250903 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, double-blind, crossover study Peer reviewed |
|---|---|
| Sample size | 26 |
| Population | Adults (18-50 years) with major depressive disorder |
| Interventions | oral naltrexone 50 mg placebo intravenous ketamine (0.5 mg/kg over 40 minutes) |
| Dose | 50 mg naltrexone, 0.5 mg/kg ketamine |
| Topics | Depression Esketamine Ketamine |
| Keywords | Depressive disorders Ketamine/esketamine Neuroimaging Psychopharmacology |
| Citations | 2 |
| Key points | Ketamine increased cerebral blood flow in anterior cingulate regions independently of opioid receptor blockade, but naltrexone disrupted the associations between these blood flow changes and clinical outcomes. |
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.
Comparable studies
Other randomized controlled trials on ketamine for depression, most cited first.