Regional blood flow signatures of opioidergic modulation of ketamine in major depressive disorder: a randomised crossover study

Importance: Accumulating evidence suggests that the opioid system may modulate ketamine's rapid antidepressant effects. Ketamine acutely increases regional and global cerebral blood flow (CBF), yet opioid system influence on these changes remains unclear. Objective: To investigate how opioid system modulation via naltrexone affects ketamine-induced CBF changes in individuals with major depressive disorder (MDD) and to explore the relationship between CBF changes and receptor density profiles. Design: Randomised, double-blind, crossover study. Setting: Single-site clinical research setting. Participants: Twenty-six adults (18-50 years) diagnosed with MDD, all exhibiting inadequate response to at least two prior antidepressant treatments (medication and/or psychotherapy). Interventions: Participants received either oral naltrexone (50 mg) or placebo, followed by intravenous ketamine (0.5 mg/kg over 40 minutes) during 3D pseudo-Continuous Arterial Spin Labelling (3D-pCASL) MRI. Main Outcome(s) and Measure(s): Main outcomes were CBF changes, assessed using 3D-pCASL MRI, and their relationship with subjective effects (Clinician-Administered Dissociative States Scale [CADSS] and Psychotomimetic States Inventory [PSI]) and clinical outcomes (Montgomery-Asberg Depression Rating Scale [MADRS] and Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR]). Exploratory outcomes included correlations between CBF changes and receptor density profiles (MOR, KOR, NMDA, mGluR5, GABAA, and GABAAα5). Results: Ketamine significantly increased CBF in the subgenual, pregenual, and dorsal anterior cingulate cortices (p < 0.05, FWE-corrected), effects not attenuated by naltrexone. Under placebo pre-treatment, CBF changes after ketamine in the pregenual anterior cingulate were associated with immediate subjective effects (PSI-delusional: r = 0.56, p = 0.004; PSI-perceptual distortion: r = 0.64, p < 0.001), and baseline CBF in the subgenual anterior cingulate cortex predicted day-one antidepressant response (MADRS: r = 0.6, p = 0.002; QIDS-SR: r = 0.67, p < 0.001). Naltrexone pre-treatment disrupted these predictive relationships. Ketamine-induced CBF changes correlated with MOR, and mGluR5 receptor profiles, while naltrexone's interaction was linked to MOR and GABAAα5 (corrected for spatial autocorrelation, pSA-corr < 0.05). Conclusions and Relevance: This study demonstrates 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 optimising ketamine-based treatments. Registration: ClinicalTrials.gov Identifier: NCT04977674