2026 ECNP Congress

PS02-2248

Insulin resistance as a predictor of cognitive decline following a first episode of psychosis: a 1- and 2-Year follow-up study

Pablo Andrés Camazón — A. Sánchez, R. Panadero, V. Cavone, A. Andreu, J. Galvañ, M. Ayora, R. Rodríguez, F. Legnani, J.L. Ayuso, A. Muñoz, M.F. Bravo, K. McDowell, J.C. Leza, M. Díaz-Marsá, Á. Ibáñez, E. Baca, C. Arango, C. Díaz-Caneja · Department of Child and Adolescent Psychiatry- Institute of Psychiatry and Mental Health- Hospital General Universitario Gregorio Marañón- IiSGM- CIBERSAM- School of Medicine- Universidad Complutense- Madrid- Spain-, Institute of Psychiatry and Mental Health, Madrid, Spain

2026 ECNP Congress

Cognitive dysfunction is strongly associated with functional outcomes in people with psychosis and is already evident at illness onset (1). Insulin resistance is associated with cognitive dysfunction (2) and occurs frequently in individuals with chronic psychotic disorders (3). This association contributes to the cognitive decline observed in some patients over the course of the illness, particularly in middle and older age. It is unclear at what stage of life insulin resistance begins to contribute to cognitive decline (4), with the possibility that it may emerge as early as in the first episode of psychosis. Understanding this relationship could inform interventions aimed at improving insulin resistance from the earliest phases of the disorder, with the potential to enhance cognition across the lifespan.

Objetives: To examine whether insulin resistance is associated with poorer cognition during the two years following a first episode of psychosis.

Methods

We recruited 365 participants with a first episode of psychosis (7–40 years), along with 185 controls. The study included baseline, 1-year, and 2-year assessments, with 952 observations, as not all participants completed every visit. Cognition was assessed using the MATRICS battery, while a subset was evaluated with other batteries. Fasting glucose and insulin were collected to calculate the HOMA index of insulin resistance. We used linear mixed-effects models, with each cognitive domain as the dependent variable and time×group× baseline HOMA and time×group×ΔHOMA as predictors along with covariates.

Results

Overall, cognitive performance remained stable and showed some improvement over time, less pronounced in participants with a first episode of psychosis, likely reflecting a practice effect. Among participants with a first episode of psychosis, higher baseline HOMA was associated with poorer cognition during follow-up. This was statistically significant for working memory at 1-year (β = -0.30; t = -3.21; pFDR = 0.01) and 2-years (β = -0.30; t = -3.19; pFDR = 0.01), and for reasoning at 1-year (β = -0.46; t = -3.67; pFDR = 0.03); and an increase in insulin resistance was associated with poorer reasoning (β = -0.30; t = -3.20; pFDR < 0.01) at 1-year. In participants with schizophrenia, higher baseline HOMA was associated with poorer reasoning (β = -0.42; t = -2.65; pFDR = 0.046), poorer general cognition (β = -2.44; t = -3.08; pFDR = 0.03), and poorer neurocognition (β = -0.21; t = -2.60; pFDR = 0.049) at 1-year, and an increase in HOMA with poorer attention (β = -0.09; t = -3.50; pFDR < 0.01) also at 1-year.

Conclusions

Insuline resistance may contribute to cognitive dysfunction immediately after the onset of psychosis. Interventions aimed at improving insulin resistance in the early phases of the disorder could potentially enhance long-term cognitive and functional outcomes. Future studies should examine longer follow-up periods and the role of antipsychotic treatment.

References

  1. Fett, A. K. J., Viechtbauer, W., Penn, D. L., van Os, J., & Krabbendam, L. (2011). The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: a meta-analysis. Neuroscience & Biobehavioral Reviews, 35(3), 573-588. 2, Ennis, G. E., Koscik, R. L., Ma, Y., Jonaitis, E. M., Van Hulle, C. A., Betthauser, T. J., … & Bendlin, B. B. (2021). Insulin resistance is related to cognitive decline but not change in CSF biomarkers of Alzheimer’s disease in non‐demented adults. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, 13(1), e12220. 3. Tomasik, J., Harrison, S. J., Rustogi, N., Olmert, T., Barton-Owen, G., Han, S. Y. S., … & Bahn, S. (2024). Metabolomic biomarker signatures for bipolar and unipolar depression. JAMA psychiatry, 81(1), 101-106. 4. Salvi, V., Tripodi, B., Cerveri, G., Migliarese, G., Bertoni, L., Nibbio, G., … & Mencacci, C. (2024). Insulin-resistance as a modifiable pathway to cognitive dysfunction in schizophrenia: A systematic review. Schizophrenia Research, 274, 78-89.