Regional blood flow signatures of opioidergic modulation of ketamine in major depressive disorder: a randomised crossover study
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This article is not in any list yet, why not save it to one of your lists.Abstract
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-Åsberg 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 pretreatment, 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 pretreatment 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
