What brain scans show about ketamine and reward circuits in depression: a systematic review

The question

Does ketamine change how the brain’s reward circuits work in people with depression, and could that explain its rapid effects on low mood and loss of pleasure?

What they did

Researchers searched several medical databases for human brain-imaging studies of adults with major depression who received ketamine or esketamine. Eligible studies used functional MRI (which tracks brain activity and connections) or PET (which tracks brain chemistry and metabolism), either at rest or during tasks involving reward or emotion. Thirteen studies met the criteria, covering 623 people in total: 482 with major or treatment-resistant depression and 141 comparison participants without depression. Most were randomized, double-blind and placebo-controlled. No eligible esketamine imaging studies were found.

What they found

Ketamine given intravenously, typically at 0.5 mg/kg over 40 minutes, was associated with short-term changes in brain networks linking the frontal lobes, the striatum (a reward-related region) and limbic areas. Resting-state MRI studies often showed altered connectivity between the ventral striatum and prefrontal/anterior cingulate regions, with wider network reorganization roughly 2 to 48 hours after dosing and some effects shifting by about 10 days. Task-based scans showed changed striatal responses when people anticipated or received rewards, plus changes in medial prefrontal and cingulate activity during emotion tasks. PET studies suggested increased prefrontal-cingulate metabolism and region-specific changes in serotonin 5-HT1B receptor measures, with baseline ventral striatal 5-HT1B linked to symptom profiles and symptom change. The authors noted that few studies directly measured anhedonia, the loss of pleasure itself.

The fine print

This is a narrative synthesis, not a pooled statistical analysis, and the included studies were small and used different imaging methods, tasks and timepoints. The outcomes are brain measures, which are indirect stand-ins for how a person actually feels; few studies measured loss of pleasure directly. Follow-up was mostly hours to about 10 days, so nothing can be said about lasting effects, and no esketamine imaging studies were available. This summary is based on the abstract only.

What it means

Brain scans suggest ketamine rapidly shifts activity in reward-related circuits in people with depression, but the evidence is early and does not yet show that these changes explain improvements in mood or loss of pleasure.

Evidence grade: Low. A narrative systematic review of 13 small, varied brain-imaging studies with no pooled statistics, and the outcomes are brain measures rather than how people actually felt.

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