Kynurenic acid is reduced in females and oral contraceptive users: Implications for depression

• Published in: Brain, behavior, and immunity behavior, and immunity, 2018-01, Vol.67, p.59-64
• Main Authors: Meier, Timothy B., Drevets, Wayne C., Teague, T. Kent, Wurfel, Brent E., Mueller, Sven C., Bodurka, Jerzy, Dantzer, Robert, Savitz, Jonathan
• Format: Article
• Language: English
• Subjects: Adult; Bipolar disorder; Bipolar Disorder - blood; Bipolar Disorder - immunology; C-reactive protein; C-Reactive Protein - metabolism; Contraceptives, Oral, Hormonal - administration & dosage; Cross-Sectional Studies; Depression; Depressive Disorder, Major - blood; Depressive Disorder, Major - immunology; Estradiol; Female; Humans; Inflammation; Kynurenic acid; Kynurenic Acid - blood; Kynurenic Acid - metabolism; Kynurenine pathway; Male; Oral contraceptives; Progesterone; Sex Characteristics; Sex differences
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2017.08.024

•Women have reduced levels of protective vs. toxic kynurenine metabolites than men.•This diagnosis-independent effect is driven by a decrease in kynurenic acid (KynA).•Women using oral contraceptives (OC) have higher CRP levels than women not using OC.•Women using OC have lower KynA concentrations than women not using OC.•Women may be more vulnerable to depression due to a hormonal-immune interaction. The incidence of depression is approximately 2-fold greater in women than men but the biological mechanisms underlying this phenomenon remain unclear. One potential mechanism that has been understudied is immune function, which is modulated by sex hormones and differs considerably between males and females. The immune-regulating kynurenine pathway previously has been implicated in the pathogenesis of mood disorders. In particular, a decreased ratio of neuroprotective (kynurenic acid; KynA) to neurotoxic (3-hydroxykynurenine; 3HK and quinolinic acid; QA) kynurenine pathway metabolites has been reported in several mood disorder subtypes. Yet there is a paucity of research investigating sex differences in the kynurenine pathway in the context of depression. Similarly, oral contraceptive (OC) use has been shown to be a risk factor for depression but to our knowledge this epidemiological relationship has not been considered within the framework of immune dysfunction. Here, we compared the concentrations of c-reactive protein (CRP) and kynurenine pathway metabolites in a combined sample of subjects with major depressive disorder (MDD), bipolar disorder (BD), and healthy controls (HC) comprising 130 men and 350 women. CRP was measured in a CLIA-certified hospital laboratory. Kynurenine metabolites were quantified using high performance liquid chromatography with tandem mass spectrometry. Estradiol and progesterone were quantified with the Mesoscale Discovery (MSD) platform. After controlling for diagnosis, age, sex, BMI, analysis batch, and self-reported childhood trauma we found that women had significantly lower KynA/3HK and KynA/QA ratios than men, and that these results were driven by a decrease in KynA. There was no significant difference between males and females in the concentration of CRP. Further, women taking OC showed significantly higher levels of CRP and lower ratios of KynA/3HK and KynA/QA compared with women on no form of contraception. Moreover, among women using OC, progesterone concentrations were positively correlated with KynA, KynA/3HK, and KynA