2026 ECNP Congress

PS03-3136

Dorsomedial prefrontal neurometabolites predict functional remediation outcomes in older adults with bipolar disorder

Enric Vilajosana — M. Ortuño, L. Montejo, L. Fortea, B. Solé, A. Ruiz, C. Torrent, J. Nova, A. Martínez-Aran, E. Vieta, E. Jiménez, J. Sánchez-Moreno, J. Radua · Institut d'Investigacions Biomèdiques August Pi i Sunyer IDIBAPS, Clinical and experimental neuroscience, Barcelona, Spain

2026 ECNP Congress

Introduction

Functional Remediation (FR) is a structured, group-based intervention that combines cognitive training with real-world strategy coaching to improve daily functioning. In older-age bipolar disorder (OABD), FR has been specifically adapted to address age-related cognitive and functional challenges [1]. However, treatment response shows substantial inter-individual variability, and its neurobiological predictors remain poorly understood. Identifying neurometabolic markers of treatment response may help stratify patients and optimize intervention strategies [2]. We investigated whether pre-treatment dorsomedial prefrontal (dmPF) metabolites measured with proton magnetic resonance spectroscopy (¹H-MRS) predicts functional improvement following FR in OABD.

Methods

Seventeen OABD patients in full or partial remission, diagnosed according to DSM-5 criteria by experienced psychiatrists, underwent 3T proton MRS prior to FR. The acquisition and analysis pipeline had been pre-registered [3] and was based on a previously published protocol in healthy controls [4]. Single-voxel spectra were acquired from the dorsomedial prefrontal region (dmPF; ~20×20×20 mm³). Prior to quantification, T1-weighted images were segmented using SPM12 to obtain tissue probability maps, which were used to estimate within-voxel water concentration. This allowed partial volume correction of absolute metabolite concentrations. Spectra were quantified using LCModel (version 6.3), fitting the full spectrum to a basis set including glutamate (Glu), glutamate + glutamine (Glx), myo-inositol (Ins), N-acetylaspartate + N-acetylaspartylglutamate (tNAA), and glycerophosphocholine + phosphocholine (tCho). Both absolute concentrations and ratios relative to total creatine + phosphocreatine (tCr) were estimated, using the unsuppressed water signal for eddy current correction and as an internal reference for quantification. Selected measures reflect glutamatergic metabolism, neuronal integrity, glial/osmoregulatory processes, membrane turnover, and cerebral energy buffering capacity. Quality control excluded spectra with FWHM ≥ 0.1 ppm or SNR < 10, and metabolite estimates with CRLB > 15%. Psychosocial functioning was assessed at baseline and post-treatment using the FAST. Twelve patients (mean age = 66 years, SD = 10; 42% female) had ¹H-MRS data that met quality criteria and completed follow-up. Linear regression models tested whether baseline metabolite levels predicted post-treatment FAST scores, adjusting for baseline FAST.

Results

Lower baseline tCr was associated with better post-treatment psychosocial functioning (β = 4.1, p = 0.041). At trend level (p < 0.1), higher baseline Glu/tCr and Ins/tCr ratios were associated with better post-treatment psychosocial functioning. Consistently, exploratory analyses combining standardized Glu/tCr and Ins/tCr ratios into a composite index showed a stronger association with post-treatment psychosocial functioning (β = −3.19, p = 0.019).

Discussion

The association between baseline tCr and post-treatment psychosocial functioning suggests that individual differences in cerebral energy buffering capacity may be relevant for treatment response. Consistently, the stronger association observed for the composite Glu–Ins index suggests that a shared neurometabolic axis involving excitatory and glial processes may underlie treatment response. At a trend level, the pattern of higher Glu/tCr being associated with better outcomes may indicate that a more metabolically responsive or functionally adaptive neurometabolic state favors psychosocial improvement following FR whereas the association of higher Ins/tCr with better functioning may suggest a potential contribution of glial or osmoregulatory processes. These findings are preliminary and require replication in larger samples.

References

  1. Montejo, L., Jiménez, E., Torrent, C., Del Mar Bonnín, C., Solé, B., Martinez-Aran, A., Vieta, E., & Sánchez Moreno, J. (2024). Functional Remediation for Older Adults with Bipolar Disorder (FROA-BD): Study protocol for a randomized controlled trial. Spanish Journal of Psychiatry and Mental Health, 17:179-250.
  2. Oliva, V., Fico, G., De Prisco, M., Gonda, X., Rosa, A. R., & Vieta, E. (2024). Bipolar disorders: an update on critical aspects. The Lancet regional health. Europe, 48, 101135.
  3. Montejo, L., Sole, B., Fortea, L., Jimenez, E., Martinez-Aran, A., Martinez-Heras, E., Sanchez-Moreno, J., Ortuño, M., Pariente, J., Solanes, A., Torrent, C., Vilajosana, E., De Prisco, M., Vieta, E,, & Radua, J. (2024). Study protocol - elucidating the neural correlates of functional remediation for older adults with bipolar disorder. Front Psychiatry, 14:1302255.
  4. Ortuño, M., Fortea, A., Valli, I., Muñoz-Moreno, E., Borràs, R., Martínez-Serrano, I., Masias Bruns, M., Camprodon-Boadas, P., Vilajosana, E., Fortea, L., Raduà, J., de la Serna, E., Baeza, I., Castro-Fornieles, J., & Sugranyes, G. (2025). The effect of age and sex on brain metabolites: from childhood to adulthood. Neuroimage, 317:121353.