COGNITIVE deficits are a debilitating and persistent symptom of schizophrenia, significantly impacting patients’ functional outcomes and quality of life. Despite being well recognised, effective clinical interventions targeting cognitive impairments in schizophrenia remain limited. Disruptions in the brain’s energy metabolism, particularly involving the tricarboxylic acid (TCA) cycle, and altered functional connectivity in the hippocampus have been proposed as underlying mechanisms. Metformin, a commonly prescribed anti-diabetic drug, has previously shown potential cognitive benefits in schizophrenia. A recent study provided new evidence that metformin may improve cognitive function in schizophrenia by modulating both TCA cycle metabolites and hippocampal connectivity.
In a 24-week controlled trial, 58 patients with schizophrenia, all in comparable clinical states, were randomly assigned to receive either 1500 mg of adjunctive metformin daily or no additional treatment. Researchers used liquid chromatography tandem mass spectrometry (LC-MS/MS) to measure blood levels of key TCA cycle metabolites, while brain function was assessed through MRI scans. Cognitive outcomes were evaluated using the Chinese version of the MATRICS Consensus Cognitive Battery (MCCB), and psychiatric symptoms with the Positive and Negative Syndrome Scale (PANSS).
The results showed that metformin significantly reduced upstream metabolites lactic acid (mean change: –80.81 μg/mL) and pyruvic acid (–17.51 μg/mL), while increasing levels of seven downstream TCA cycle metabolites (all p<0.001). Notable changes in brain connectivity included reduced functional coupling between the left caudal hippocampus and right medioventral occipital cortex at week 12 (difference: –0.334), and increased connectivity between the right caudal hippocampus and right middle frontal gyrus at week 24 (difference: 0.284). Improvements in working memory and verbal learning were significantly associated with both altered TCA metabolite profiles and hippocampal connectivity changes.
These findings suggest that metformin may exert cognitive benefits in schizophrenia by rebalancing brain energy metabolism and modulating hippocampal network dynamics. Although limited by the relatively small sample size and short duration of follow-up, the study highlights a promising repurposing strategy with direct implications for clinical practice. Future research should aim to validate these results in larger, more diverse populations and explore underlying mechanisms in greater detail.
