In a startling new study, researchers have discovered that metformin – a drug known for its ability to treat type 2 diabetes – might also help fight back against cognitive impairment in people living with schizophrenia. The findings, published in BMC Medicine, suggest that the drug’s influence on brain metabolism could carve new pathways to treating symptoms that have long resisted standard interventions.
Cognitive impairment remains one of schizophrenia’s most devastating traits. Attacking one’s attention span, ability to learn, and simple recall, these symptoms of schizophrenia’s devastation can seriously threaten one’s quality of life. And contemporary treatments offer little to no relief.
But researchers have started turning their attention to the role of metabolic dysfunction in the brain, particularly the tricarboxylic acid (TCA) cycle.
Testing the Metformin Hypothesis
Previous research hinted that metformin might help treat cognitive symptoms in patients with schizophrenia. This new 24-week clinical trial, led by a multidisciplinary team in China, took it a step further by tying cognitive improvement to changes in blood metabolites and brain connectivity.
Researchers enrolled 58 patients, each of whom had received a schizophrenia diagnosis and been prescribed stable doses of antipsychotics. Roughly two-thirds of the participants received an add-on dose of metformin (1,500 mg daily), while the rest continued with just the antipsychotic treatment.
Through the length of the study, researchers evaluated changes in cognition, TCA cycle metabolites in the blood, and brain activity – all captured by MRI scans.
A Metabolic Shift
The results surprised the researchers. Patients who took metformin showed elevated levels of seven critical downstream metabolites in the TCA cycle—including citric acid, α-ketoglutaric acid, and succinic acid. The authors noted these improvements alongside drops in upstream metabolites, such as lactic acid and pyruvic acid. This collective shift suggests accelerated energy metabolism, a change missing in the control group.
In fact, the non-metformin group showed the opposite trend, with metabolite levels pointing to suppressed mitochondrial activity.
The authors added that scientists have long suspected that mitochondrial dysfunction played a part in schizophrenia-related cognitive deficits. The authors speculate that by restoring energy metabolism, metformin might help the brain perform more efficiently.
Connectivity and Cognitive Gains
But the story that emerged from the study didn’t just focus on metabolism. Using functional MRI scans, the researchers also clocked changes in the brain’s wiring – especially the hippocampus.
In the metformin group, connectivity between the right caudal hippocampus and the right middle frontal gyrus jumped dramatically. Research has established that this pathway supports working memory, and its strengthening paralleled improvements in two cognitive domains: working memory and verbal learning.
Notably, the degree of cognitive improvement correlated with changes in specific TCA metabolites.
For example, stronger working memory scores showed a connection to higher levels of α-ketoglutaric and succinic acid. These relationships didn’t crop up in the control group, bolstering the case that metformin’s metabolic influence plays a powerful, direct role in powering cognitive gains.
A Repurposing Opportunity
Metformin’s ability to cross the blood-brain barrier – along with its proven safety profile – make it a compelling candidate for off-label use. While traditionally prescribed to manage blood sugar, scientists are now looking at it as a way to treat neurodegenerative conditions. And this study adds some strong evidence for its potential to make a difference in psychiatric care.
That being said, the authors of this study acknowledge that this was a preliminary, post hoc analysis, with a modest sample size. Still, the findings mark a significant step forward in understanding the biological underpinnings of cognitive dysfunction in schizophrenia—and how they might be modulated by accessible, affordable treatments.
Moving Forward
Schizophrenia’s cognitive symptoms have remained stubbornly resistant to treatment, frustrating both clinicians and patients. But this study offers some hope. A safe, proven drug, repurposed through the lens of energy metabolism, might help restore some of what the illness threatens to take.
For now, metformin’s role in psychiatry remains a work in progress.
“Further replication clinical studies with larger sample sizes and basic [research] on animal models are needed to validate the effectiveness of interventions and explore mechanisms in depth,” the authors concluded.
As a result, the drug could soon secure a place in the psychiatrist’s toolkit, with the potential to offer metabolic stability as well as cognitive renewal.
Further Reading
Antipsychotic Adherence Halves Crash Risk for Drivers with Schizophrenia
Children of Parents with Schizophrenia Face More Mental Health Issues
Global Experts Unveil New Schizophrenia Treatment Guidelines
