Biomarker changes are associated with depression improvement after one month on a low glutamate diet in veterans with Gulf War Illness

Glutamatergic dysregulation and excitotoxicity are known contributors to the pathophysiology of depression. Previous work in our lab demonstrated a significant reduction in depression using the low glutamate diet for veterans with Gulf War Illness (GWI). Among deployed veterans of the Gulf War, the incidence of depression is twice as high as non-deployed veterans. The objective of this study was to examine biomarker changes associated with depression improvement, including serum levels of homocysteine and inflammatory cytokines IFN-gamma, IL-6, IL-1beta, and TNF-alpha, after one month on the low glutamate diet. Depression was measured using the Center for Epidemiologic Studies Depression Scale (CES-D), serum blood samples, and an excitotoxin food frequency questionnaire (FFQ) pre- and post-diet to measure dietary adherence. Change in serum levels of homocysteine and cytokines were examined relative to change in depression using multivariable linear regression and logistic regression, with adjustment for potential confounding factors. Serum folate and vitamin B12 were assessed as potential mediators of the association. R studio was used for all analyses.Fifty two percent of participants experienced significant improvement in depression scores (p<0.01). Those who improved had better dietary adherence as evidenced by a larger reduction in excitotoxic food intake compared to the unimproved group (median (IQR) of -70 (10) vs. -54.5 (18), p<0.01). Consistent with the literature, median homocysteine concentrations at baseline were higher in the depressed group than the non-depressed group (11.3 μmoL/L (5.7) vs. 9.0 μmoL/L (2.3), p=0.03). Post-diet, there was a significant association between the change in CES-D scores and change in homocysteine levels (ß = 2.31, p = 0.05). Serum folate and vitamin B12 were not mediators of the association between change in homocysteine and depression scores. Change in inflammatory cytokines were not associated with improvements in depression, except for a marginal relationship with IFN-gamma (p=0.08).Using logistic regression, homocysteine change, and the cytokines IL-6, IL-1beta, and TNF-alpha were not able to predict depression improvement; however, FFQ change was a significant predictor, OR (95% CI) = 0.95 (0.90, 0.99), (p=0.02). The change in IFN-gamma fell just short of predicting depression improvement (OR (95% CI) = 0.90 (0.80, 1.00), (p=0.06).Overall, this study suggests that homocysteine, and possibly IFN-gamma, may serve as biomarkers for depression on the low glutamate diet in veterans with GWI. Larger clinical trials are needed to confirm these findings.