Identification of peripheral biomarkers through metabolomic analysis in patients with bipolar disorder treated with mood stabilizers: an exploratory study

Piras, Cristina;Pisanu, Claudia;Spada, Martina;Meloni, Anna;Congiu, Donatella;Palmas, Vanessa;Severino, Giovanni;Ardau, Raffaella;Chillotti, Caterina;Contu, Martina;Paribello, Pasquale;Pinna, Marco;Suprani, Federico;Del Zompo, Maria;Carpiniello, Bernardo;Manzin, Aldo;Manchia, Mirko;Atzori, Luigi;Squassina, Alessio

2025-01-01

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Abstract

Importance: Bipolar disorder (BD) is mainly treated with mood stabilizers, among which lithium represents the gold standard. Despite its high clinical efficacy, the molecular players involved in lithium response and nonresponse remain partly unclear. Therefore, the identification of peripheral biomarkers would significantly improve the management of pharmacological interventions in BD. Objective and Design: In this study, we sought to investigate the blood metabolome in patients with BD to identify biosignatures of treatment with different mood stabilizers as well as possible biomarkers of response to lithium. Setting and Participants: The blood metabolome was measured in a sample of 89 patients with BD either under prophylactic lithium treatment (n=47), and characterized as responders or nonresponders, or with other mood stabilizers (MS, n=42). For each patient the plasma metabolome was measured with hydrogen nuclear magnetic resonance (1H-NMR) and gas chromatography–mass spectrometry (GC-MS). Data were investigated with multivariate analyses accounting for covariates. Results: Patients exposed to lithium or to other MS showed different, specific metabolic signatures, with different levels of metabolites belonging to pathways involved in glucose, pyruvate, and glutamate metabolism, which were previously suggested to be implicated in BD and to be regulated by lithium. On the other hand, we were not able to identify significant differences in the metabolomic profile between responders and nonresponders to lithium. Conclusions and Relevance: The findings from this exploratory study suggest that patients treated with lithium show distinctive metabolomic biosignatures, specifically pointing to energy metabolism and mitochondria functioning, thus potentially suggesting possible biosignatures of mood-stabilizing treatments.