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

ObjectiveAccumulating evidence suggests the opioid system may modulate ketamines rapid antidepressant effects. The objective of this study was to test whether opioid system modulation via naltrexone alters ketamines 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. MethodsIn a randomised, double-blind, crossover study, 26 adults (18-50 years) with MDD completed two sessions: oral naltrexone 50 mg or placebo, each followed by intravenous ketamine 0.5 mg/kg over 40 minutes during 3D pseudo-continuous arterial spin labelling (3D-pCASL) MRI to quantify rCBF. Subjective effects were assessed with the Clinician-Administered Dissociative States Scale and the Psychotomimetic States Inventory; clinical outcomes with the Montgomery-[A]sberg Depression Rating Scale and the Quick Inventory of Depressive Symptomatology Self-Report. Exploratory analyses spatially correlated CBF maps with receptor density profiles (MOR, KOR, NMDA, mGluR5, GABAA, GABAA5), correcting for spatial autocorrelation. ResultsKetamine increased CBF in subgenual, pregenual, and dorsal anterior cingulate cortices (p < 0.05, voxel-wise FWE-corrected), effects not attenuated by naltrexone. Under placebo pretreatment, baseline-adjusted infusion pregenual relative rCBF was associated with acute subjective effects (PSI-delusional: r = 0.56, p = 0.004; PSI-perceptual distortion: r = 0.64, p < 0.001), and baseline subgenual rCBF (adjusted for global CBF) was associated with day-one antidepressant response (MADRS r = 0.60, p = 0.002; QIDS-SR r = 0.67, p < 0.001). Naltrexone pretreatment disrupted these associations. Ketamine-induced CBF changes aligned with MOR and mGluR5 receptor profiles; naltrexones interaction aligned with MOR, mGluR5 and GABAA5 (pSA-corr < 0.05). ConclusionsThis study suggests that ketamines 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. RegistrationClinicalTrials.gov Identifier: NCT04977674