TNF and major depressive disorder: Although clinical studies have correlated higher KYN/Trp ratios, a proxy for IDO1 activation, with depressive symptom burden in patients with mood disorders, the evidence remains controversial when leptin signaling is considered: some human data show elevated leptin in MDD, which is consistent with inflammation-linked hyperleptinemia and increased IL-6/TNF-α signaling that can activate IDO1, whereas other reports (including bipolar disorder (BD) cohorts) describe lower leptin or state-dependent variation.