Although bipolar disorder and major depressive disorder share similar depressive and cognitive symptoms, their biological underpinnings are different. New research appearing in Biological psychiatry: cognitive neuroscience and neuroimagingThe paper, published by Elsevier, identifies for the first time clinically relevant pathways linking metabolic dysfunction, brain structure and cognition in mood disorders, with stronger and more specific effects observed in bipolar disorder. This highlights the potential of targeting metabolic pathways to improve cognitive symptoms in bipolar disorder.
Major depressive disorder and bipolar disorder cause mental illness and severely impair mood regulation and biological rhythms. Even if your mood is stable, continued challenges with memory and concentration can make daily life difficult. Increasing evidence suggests a strong association between mood disorders and metabolic dysfunction. Conditions such as obesity, diabetes, and insulin resistance are associated with increased risk of depression, and vice versa.
Because mood disorders are so diverse, diagnosis and effective treatment are often delayed, highlighting the need for more targeted approaches. In a cohort of 78 patients with major depressive disorder and 81 patients 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 important role of insulin in neurotransmission, learning, and memory. ”
Dr. Elena Mazza, Principal Investigator, Department of Neuroscience, Psychiatry and Clinical Psychobiology, IRCCS Ospedale San Raffaele, Milan, Italy
Researchers combined metabolic biomarkers, structural brain imaging, and cognitive assessments to examine how metabolic dysfunction relates to brain structure and cognition. They applied a multivariate statistical approach to examine these relationships and assess whether the relationships differed between diagnoses.
Patients with bipolar disorder have been found to exhibit a more severe metabolic profile characterized by insulin resistance and leptin dysregulation, likely reflecting a more severe disease course, and a greater disease burden, particularly a higher number of mood and manic episodes, may be associated with worsening metabolic dysfunction and lifelong disease burden.
Researchers have found that metabolic changes, such as insulin resistance, are associated with cognitive impairment through effects on gray matter volume in key brain regions involved in cognitive function, and are associated with poorer performance in memory, attention, and executive functions. Of note, these associations were only observed in bipolar disorder, suggesting that insulin and leptin resistance may play an important role in linking metabolic dysfunction and cognitive impairment by promoting inflammatory and neurotoxic processes that affect brain structures, particularly areas that support cognition.
Editor-in-chief Biological psychiatry: cognitive neuroscience and neuroimaging “Interestingly, the impact of metabolic dysfunction on clinical and neurological outcomes was primarily observed in bipolar disorder,” said Cameron S. Carter, M.D., Ph.D., of the University of California, Irvine School of Medicine. “This may be consistent with a neuroprogressive model of bipolar disorder that can lead to significant metabolic and neurobiological changes. This highlights the importance of early and effective intervention to prevent both clinical deterioration and associated biological consequences.”
The findings point to a previously unknown, clinically relevant pathway linking metabolic dysfunction and cognitive impairment in bipolar disorder through effects on brain structure.
“Interventions aimed at increasing insulin sensitivity beyond traditional antidepressant treatment (such as insulin sensitizers and intranasal insulin) have already shown promising cognitive effects,” notes first author Laura Raffaelli, PhD candidate in psychiatry and clinical psychobiology, Department of Neuroscience, IRCCS Ospedale San Raffaele University, Vita Salute San Raffaele University, Milan, Italy. “More recently, GLP-1 receptor agonists, currently used in metabolic diseases, have received attention for their potential to have positive effects on both mood and cognition, making them a promising avenue for future therapeutic development.”
Dr. Mazza said: “Our findings highlight that metabolic health is not just a peripheral issue, but is an important factor influencing brain structure and cognitive function in mood disorders. Our findings also shed light on why cognitive symptoms persist even when mood symptoms improve. “By uncovering these mechanisms, our study opens the door to more personalized treatment strategies that integrate metabolic and psychiatric care.”
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Reference magazines:
Raffaelli, L. Others. (2026). Insulin resistance and leptin dysregulation affect in vivo brain structure and cognitive function in mood disorders: a multimodal partial least squares path modeling study. Biological psychiatry: cognitive neuroscience and neuroimaging. 10.1016/j.bpsc.2026.02.003. https://www.sciencedirect.com/science/article/pii/S2451902226000479?via%3Dihub
