Supplemental Material for: Circulating glutamate and incident metabolic syndrome during antidepressant treatment in major depressive disorder

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Introduction. Metabolic Syndrome (MetS) is increasingly prevalent worldwide, raising the risk of diabetes and cardiovascular diseases. Glutamate, a key excitatory neurotransmitter involved in depression and antidepressant response, is also implicated in metabolic dysregulation ; whereas glutamine/glutamate ratio, reflecting the balance between neurotransmission and metabolism, may provide additional insight into this relationship. This study prospectively examines the associations of blood glutamate levels and the glutamine/glutamate ratio with MetS in depressed patients treated with antidepressants for six months. Methods. In the METADAP cohort, 164 non-overweight patients with major depressive disorder were evaluated for blood glutamate and glutamine levels at baseline, three months (M3), and six months (M6) after initiating antidepressant treatment. Logistic and linear regression models were used to explore associations between glutamate levels, the glutamine/glutamate ratio, MetS incidence, its individual components, and insulin resistance. The cut-off threshold was internally validated using 1,000 bootstrap resamples with optimism correction. Results. Glutamate levels decreased significantly over time. Higher odds of MetS were observed with elevated glutamate at M3 [OR = 1.032, 95% CI 1.01–1.06, p = 0.001] and with smaller reduction from baseline [OR = 1.03, 95% CI 1.028–1.034, p < 0.001]. Glutamate levels above 38 µmol/L at M3 tripled the risk of developing MetS [OR = 3.24, 95% CI 1.83–5.72, p < 0.001]. r. Similar trends were observed for the glutamine/glutamate ratio, supporting its value as a complementary metabolic marker, with the strongest predictive signal for both glutamate and the glutamine/glutamate ratio observed at M3 rather than M0. Conclusion. Monitoring circulating glutamate levels and the glutamine/glutamate ratio at month 3 may help identify patients at higher metabolic risk during antidepressant treatment and support increased clinical vigilance with respect to metabolic outcomes.

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