Opioid systems influence ketamine’s antidepressant effect

Complex interactions between glutamatergic, opioidergic, and GABAergic systems modulate the antidepressant effects of ketamine on cerebral blood flow (CBF) in patients with major depressive disorder (MDD), suggests a recent study.

Ketamine use led to a significant increase in CBF in subgenual, pregenual, and dorsal anterior cingulate cortices. Naltrexone did not lessen these effects.

Under placebo pretreatment, a significant association was observed between baseline-adjusted infusion pregenual relative regional CBF and acute subjective effects (Psychotomimetic States Inventory [PSI] delusional score: r=0.56; PSI perceptual distortion score: r=0.64).

Similarly, baseline subgenual regional CBF (adjusted for global CBF) significantly correlated with day 1 antidepressant response (Montgomery-Åsberg Depression Rating Scale [MADRS], r=0.60; Quick Inventory of Depressive Symptomatology–Self-Report [QIDS-SR], r=0.67).

Notably, pretreatment with naltrexone disrupted these associations.

Ketamine-induced CBF changes aligned with MOR and mGluR5 receptor profiles, while naltrexone’s interaction aligned with MOR, mGluR5, and GABA_Aα5, according to the investigators.

“These findings provide mechanistic insights with potential implications for optimizing ketamine-based treatments,” they said.

Twenty-six adults aged 18‒50 years with MDD were included in this randomized, crossover study. They completed two treatment sessions: oral naltrexone 50 mg or placebo, each followed by intravenous ketamine (0.5 mg/kg over 40 min) during 3-D pseudo-continuous arterial spin labelling MRI to quantify regional BCF.

The investigators assessed subjective effects using the Clinician-Administered Dissociative States Scale and the PSI, and clinical outcomes via the MADRS and the QIDS-SR. Exploratory analyses spatially correlated CBF maps with receptor density profiles (ie, MOR, KOR, NMDA, mGluR5, GABA_A, GABA_Aα5), correcting for spatial autocorrelation.