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bioRxiv · 10.64898/2026.01.14.699270

2-AG as a potential biomarker for predicting response to short-term fluoxetine treatment in a mouse model of depression

Rodriguez-Lopez, A.·Ibrahim, E. C.·Gorgievski, V.·Martin, M.·Robledo, P.·Maldonado, R.·Tzavara, E.·Alvarez-Perez, B.
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Abstract

Major depressive disorder (MDD) is a complex psychiatric condition with significant individual and social impact and marked variability in treatment response. Identifying biomarkers that predict antidepressant efficacy remains a major challenge, and metabolomic approaches offer a powerful tool to uncover biochemical changes associated with depression and treatment outcome. The prefrontal cortex and the hippocampus are key brain regions involved in the pathophysiology of MDD and antidepressant response. Fluoxetine, one of the most commonly prescribed antidepressants, influences not only serotonergic signaling but also the endocannabinoid system. Accordingly, evaluating endocannabinoid levels in these brain regions might provide critical insight into their contribution to mood disorders and the effect of fluoxetine. To identify biomarkers associated with early antidepressant response, male mice were exposed for 5 weeks to the unpredictable chronic mild stress (UCMS) protocol, with fluoxetine treatment administered during the final week. Liquid chromatography-tandem mass spectrometry analyses of hippocampal and prefrontal cortex samples revealed that the depression-like phenotype induced by UCMS was associated with increased hippocampal anandamide (AEA) levels. Behavioral improvement following short-term fluoxetine treatment was accompanied by enhanced hippocampal 2-arachidonoylglycerol (2-AG), which was associated with reduced GABA and glutamate levels in the prefrontal cortex. These findings suggest that increased 2-AG levels may serve as a predictor of early response to fluoxetine.

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Rodriguez-Lopez, A., Ibrahim, E. C., Gorgievski, V., Martin, M., Robledo, P., Maldonado, R., Tzavara, E., Alvarez-Perez, B.. 2026-01-14. 2-AG as a potential biomarker for predicting response to short-term fluoxetine treatment in a mouse model of depression. https://doi.org/10.64898/2026.01.14.699270

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