REVIEW OF: Shao T et al, Transl Psychiatry 2023;13:315; Cai J et al, BMC Med 2025;23:349

STUDY TYPE: Two open-label RCTs from the same research group

Cognitive impairment is one of the most disabling features of schizophrenia, and we still don’t have medications that reliably improve thinking or memory. Two related trials from China suggest that metformin, best known for limiting antipsychotic-related weight gain, may also offer modest cognitive benefits.

Both studies enrolled 58 clinically stable patients within 5 years of diagnosis who stayed on their antipsychotics and were randomized to add metformin (1500 mg/day) or continue usual care for 24 weeks. The 2023 study focused on cognitive performance and prefrontal brain networks, while the 2025 follow-up examined metabolic markers and hippocampal connectivity.

In the 2023 trial, adding metformin led to small-to-moderate improvements in working memory and verbal learning—changes that were apparent on testing and not seen in the control group. Brain imaging showed stronger coordination between prefrontal regions involved in attention and executive function.

The 2025 study linked these cognitive gains to shifts in the brain’s energy metabolism. The authors hypothesize that metformin may enhance cognition by helping brain cells produce energy more efficiently in hippocampal–frontal circuits involved in memory and executive function. Metformin was well tolerated, with decreased appetite as the only common side effect.

CARLAT TAKE
Metformin may offer more than metabolic protection in schizophrenia; it might also give cognition a small boost. These results come from small, unblinded studies, but the alignment of cognitive testing, metabolic changes, and brain imaging is intriguing. If your patient is already on metformin for weight or metabolic risk, consider any cognitive improvement a possible bonus. For patients with cognitive complaints and metabolic vulnerability, metformin is a reasonable off-label option to discuss while we wait for larger, placebo-controlled trials.