S11. PLASMA LEPTIN AND ANTHRANILIC ACID IN SCHIZOPHRENIA PATIENTS: NEW BIOMARKERS OF PREDISPOSITION TO METABOLIC ABNORMALITIES

BACKGROUND: Leptin was implicated in pathophysiology of schizophrenia (Sz) and in increased risk of Sz patients for overweight and hyperlipidemia, especially in patients treated with anti-psychotic medications known to elevate plasma leptin levels. Our finding of increased plasma levels of anthranilic (ANA) and kynurenic (KYNA) acids in leptin-receptors deficient Zucker fatty rats [Oxenkrug et al., 2016], and causative association between KYNA and major psychopathology of Sz [Erhard et al., 2007; Schwarcz et al., 2001] warranted our further evaluation of plasma levels of leptin and tryptophan – kynurenine pathway metabolites in Sz patients. METHODS: Tryptophan (Trp), kynurenine (Kyn), ANA, KYNA, 3-hydroxykynurenine (3HK), and xanthurenic acid (XA) were evaluated by HPLC–mass spectrometry [Oxenkrug et al., 2015] in fasting plasma samples of fifty-two [19 drug-naïve first-episode and 33 previously-treated, but not medicated for, at least, 6 weeks] acutely ill Sz patients (DSM-IV) and fifty-two healthy subjects matched for age, gender, body mass index (BMI), and waist circumference [Steiner et al., 2017]. Plasma leptin levels, and other metabolic markers were previously assessed in study participants [Steiner et al., 2017]. The study was approved by the University of Magdeburg Review Board and Tufts Medical Center IRB, and written informed consent was obtained RESULTS: The main (and, to the best of our knowledge, original) finding of our study is the strong correlation of leptin plasma levels with ANA (but not with other studied kynurenines) in Sz patients (r=0.44, p<0.006, Spearman’s rank correlations, two-tailed). There was a high tendency to such a correlation in control subjects (r=0.26, p=0.06). In patients (but not in controls) plasma levels of leptin and ANA correlated with waist circumference (r=0.27, p<0.004 and r=0.37, p<0.01, resp.) and BMI (r=0.30, p<0.03 and r=0.34, p<0.01, resp.). Plasma leptin and ANA levels did not differ between Sz patients and control subjects (Mann-Whitney U test). DISCUSSION: The strong positive correlation between plasma leptin and ANA (but not other kynurenines) might be explained by the shift of Kyn down-stream metabolism from formation of 3HK toward production of ANA and KYNA by adipocytes, the major source of leptin production. Notably, literature data pointed out to elevation of leptin and decrease of ANA levels after treatment with antipsychotic medications suggesting a switch from positive to negative correlation between leptin and ANA after treatment. A different regulation of ANA compared to other kynurenines in relation to leptin has previously been described in obesity: weight loss was accompanied by drop of circulating leptin levels while ANA was the only Kyn metabolite increased after weight loss [Theofylaktopoulou et al., 2013]. Our data further support the special role of ANA in leptin involvement in energy regulation in Sz patients. Evaluation of plasma leptin/ANA correlation may be useful in identification of Sz patients at increased risk for the development of metabolic abnormalities. REFERENCES: Erhardt S, Schwieler L, Nilsson L. 2007. Physiol Behav 92:203. Oxenkrug G. 2015. Mol Neurobiol. 52:805. Oxenkrug G, Cornicelli J, van der Hart M, et al. 2016. Integr Mol Med, 3: 761. Schwarcz, R., Rassoulpour, A., Wu, H.Q., et al. 2001. Biol. Psychiatry 50: 521. Steiner J, Berger M, Guest PC, et al. 2017. JAMA Psychiatry, 74:968. Theofylaktopoulou D, Midttun O, Ulvik A, et al. Clin Exp Immunol. 2013;173:121.