Metformin-improved cognitive impairment in patients with schizophrenia is correlated with activation of tricarboxylic acid cycle and restored functional connectivity of hippocampus.

Background: Cognitive impairment is a prominent feature that adversely affects the long-term prognosis of schizophrenia; yet effective clinical strategies for treatment remain limited. Disruptions in the tricarboxylic acid (TCA) cycle and functional brain abnormalities in the hippocampus may underlie cognitive deficits, although the intrinsic connections between these factors have yet to be fully elucidated. Notably, metformin, a biguanide anti-hyperglycemic agent, has been shown to improve several cognitive domains in patients with schizophrenia and may have the potential to regulate the TCA cycle. Previously, we found the cognitive improvement effect of adding metformin. In this study, we will further explore the relationship between cognitive improvement and TCA cycle metabolites and brain function.

Methods: This study included 58 patients with schizophrenia who were in similar clinical conditions and assigned to 24-week 1500 mg metformin add-on treatment or the control group. We used the liquid chromatography tandem mass spectrometry (LC-MS/MS) method to detect the levels of key TCA cycle metabolites in the blood of schizophrenia patients, conducted MRI scans, and assessed clinical condition using the Positive and Negative Syndrome Scale (PANSS) and cognitive performance using the Chinese version of MATRICS Consensus Cognitive Battery (MCCB).

Results: Twenty-four weeks of metformin treatment downregulated levels of upstream lactic acid (- 80.81 (- 96.85, - 64.77) μg/mL at week 24) and pyruvic acid (- 17.51 (- 20.52, - 14.49) μg/mL at week 24), while upregulating levels of other seven downstream metabolites in TCA cycle (all p values < 0.001). Functional connectivity between left caudal hippocampus and right medio ventral occipital cortex (week 12, between-group difference =  - 0.334), and right caudal hippocampus and right middle frontal gyrus (week 24, between-group difference = 0.284) were significantly different between groups (p < 0.001). Moreover, metformin-improved cognition (working memory and verbal learning) and hippocampal functional connectivity (right caudal hippocampus and right middle frontal gyrus) were associated with changes in TCA cycle metabolites.

Limitation: Limited sample size and follow-up time, and lack of in-depth mechanism exploration.

Conclusions: Our results suggested that repurposing of metformin may have the potential to improve cognition by regulating energy metabolism pathways.

Clinical Trials Registration: NCT03271866.