Blocking opioid receptors did not change ketamine's effects on brain blood flow in depression

The question

Does blocking the body’s opioid system change how ketamine affects blood flow in the brain in people with major depression, and do those blood flow patterns relate to how people feel?

What they did

Twenty-six adults aged 18 to 50 with major depressive disorder each completed two sessions, in random order and with neither participants nor researchers knowing which was which. In one session they took 50 mg of naltrexone (a drug that blocks opioid receptors) by mouth, and in the other a placebo. Each was followed by an intravenous ketamine infusion of 0.5 mg/kg over 40 minutes, given inside an MRI scanner that measured regional cerebral blood flow. Researchers also tracked dissociation and psychosis-like experiences during the infusion, and depression scores afterwards.

What they found

Ketamine increased blood flow in several parts of the anterior cingulate cortex, a brain region involved in mood, and naltrexone did not reduce this effect. In the placebo sessions, blood flow in one of these regions during infusion was linked to the intensity of unusual acute experiences (correlation r=0.56 for delusional-type scores and r=0.64 for perceptual distortion). Also in the placebo sessions, baseline blood flow in the subgenual region was linked to day 1 improvement in depression scores (r=0.60 on the clinician-rated MADRS scale and r=0.67 on the self-reported QIDS-SR). These links were disrupted when people had taken naltrexone. Exploratory mapping suggested the blood flow changes overlapped with the distribution of opioid, glutamate and GABA-related receptors.

The fine print

Only 26 people took part, which is small for brain imaging and correlation analyses. The main outcomes were blood flow measures, not clinical recovery, and the depression findings were correlations measured just one day after infusion with no longer follow-up. The receptor mapping was exploratory. Participants were aged 18 to 50, so results may not apply more broadly, and this summary is based on the abstract alone.

What it means

Blocking opioid receptors did not stop ketamine from changing blood flow in mood-related brain regions, but it did appear to alter how those brain changes tracked with people’s experiences and short-term symptom scores, pointing to a more complex mechanism than any single receptor system.

Evidence grade: Moderate. A randomized, double-blind crossover trial, but with only 26 people, brain-imaging outcomes rather than clinical endpoints, and exploratory correlations.

This summary is based on the study’s published abstract.