Metabolic disease tied to cognitive impairment in bipolar disorder

A recent study has identified pathways that may connect insulin resistance, leptin dysregulation, brain structure and cognitive symptoms in mood disorders, with the strongest effects found in bipolar disorder

A novel study has identified clinically relevant pathways that may connect metabolic dysfunction, brain structure and cognitive impairment in mood disorders, with stronger and more specific effects observed in bipolar disorder than in major depressive disorder.

The research examined how insulin resistance and related hormonal changes relate to brain structure and clinical outcomes in people with bipolar disorder and major depressive disorder. The findings have suggested that metabolic health may have a direct role in cognitive symptoms that often persist even after mood symptoms have improved.

Major depressive disorder and bipolar disorder are disabling psychiatric conditions that can substantially impair mood regulation, biological rhythms and daily functioning. Although the two conditions share depressive and cognitive symptoms, their biological mechanisms are not the same. Many patients continue to experience difficulties with memory, attention and focus even during periods of relative mood stability which in turn can optimally limit work, social participation and quality of life.

Evidence has increasingly linked mood disorders with metabolic dysfunction. Obesity, diabetes and insulin resistance have each been associated with a higher risk of depression while depression itself has also been linked to later metabolic disease. The novel study has extended this area of research by examining whether metabolic abnormalities may affect cognition through changes in brain structure.

“Mood disorders are highly heterogeneous which often delays diagnosis and effective treatment, highlighting the need for more targeted approaches,” explained lead investigator Dr. Elena Mazza, a researcher in psychiatry and clinical psychobiology, at the division of neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milan, Italy.

“In a cohort of 78 patients with major depressive disorder and 81 with bipolar disorder, we investigated how insulin resistance and related hormones are associated with brain structure and clinical outcomes, with a particular focus on cognitive function, given the critical role of insulin in neuronal communication, learning and memory.”

The researchers combined metabolic biomarkers, structural brain imaging and cognitive assessments to explore the relationships between metabolic dysfunction, grey matter volume and cognitive performance. They used a multivariate statistical approach to assess whether these relationships differed between people with major depressive disorder and those with bipolar disorder.

Patients with bipolar disorder had a more severe metabolic profile, characterised by insulin resistance and leptin dysregulation. Leptin is a hormone involved in appetite regulation, energy balance and metabolic signalling. The researchers suggested that this metabolic pattern may reflect a more severe illness course, as greater lifetime illness burden, including a higher number of mood and manic episodes, was associated with worse metabolic dysfunction.

The study found that metabolic alterations, including insulin resistance, were associated with cognitive deficits, potentially through their effects on grey matter volume in brain regions involved in cognitive function. These changes were linked to poorer performance in memory, attention and executive function. Notably, these associations were observed only in bipolar disorder which suggested that insulin and leptin resistance may have a specific role in the biological pathway that connects metabolic dysfunction with cognitive impairment in this condition.

The investigators said these mechanisms may involve inflammatory and neurotoxic processes that affect brain structure, particularly in regions that support cognition. The findings therefore point to a previously unrecognised and clinically meaningful pathway through which metabolic dysfunction may contribute to cognitive symptoms in bipolar disorder.

The results may have implications for future treatment strategies. Conventional antidepressant and mood-stabilising therapies do not always resolve cognitive symptoms, and the study suggested that metabolic pathways could provide an additional therapeutic target, particularly in bipolar disorder.

“Beyond traditional antidepressant treatments, interventions aimed at enhancing insulin sensitivity – such as insulin-sensitizing agents or intranasal insulin – have already shown promising cognitive benefits,” noted lead author Laura Raffaelli, a doctoral candidate in psychiatry and clinical psychobiology, at the Vita-Salute San Raffaele University, Milan, Italy.

“More recently, glucagon-like peptide-1 receptor agonists, currently used for metabolic conditions, have gained attention for their potential positive effects on both mood and cognition, representing a promising avenue for future therapeutic development.”

Glucagon-like peptide-1 receptor agonists are medicines used to treat metabolic conditions including type 2 diabetes and obesity. Their potential relevance to psychiatric care has attracted interest because of the close relationship between metabolism, inflammation, brain function and cognition.

“Our findings highlight that metabolic health is not just a peripheral concern, but a key factor influencing brain structure and cognitive functioning in mood disorders.

“The results of our study help explain why cognitive symptoms often persist even when mood symptoms improve, underscoring the complex interplay between brain and metabolic health.

“By clarifying these mechanisms, our study opens the door to more personalized treatment strategies that integrate metabolic and psychiatric care,” Mazza concluded.

For further reading please visit: 10.1016/j.bpsc.2026.02.003