L-Arginine metabolism before and after 10 weeks of antipsychotic treatment in first-episode psychotic patients Beyazit Garip a , Hakan Kayir b, ⁎, Ozcan Uzun c a Gulhane Training and Research Hospital, Department of Psychiatry, Ankara, Turkey b Noro Saglik Brain Trainings Research Application Center, Istanbul, Turkey c Health Sciences University, Gulhane Medical School, Department of Psychiatry, Ankara, Turkey abstract article info Article history: Received 19 August 2018 Received in revised form 2 December 2018 Accepted 9 December 2018 Available online xxxx Agmatine is an endogenous NMDA (N-methyl-D-aspartate) antagonist which is synthesized from L-Arginine and described as a novel neurotransmitter. Agmatine is considered to play an important role for the development of schizophrenia. The aim of the present study is to explore the role of agmatine and L-arginine metabolism in medication-naive first-episode psychosis (FEP). We conducted a case control study in medication-naive patients with FEP (n = 40). The healthy volunteers with no family history of schizophrenia (n = 35) matched for age, gender and education level were selected as a control group. The patients were recruited to the study and followed up for 10 weeks. The plasma L-arginine, L-citrulline, L-ornithine and agmatine levels were measured using modified liquid chromatography/mass spectrometry. The plasma levels of L-arginine, L-citrulline and agmatine (p b 0.0001), but not L-ornithine and agmatinase (p N 0.05), were significantly increased during base- line analysis. After 10 weeks of treatment, plasma L-arginine and L-citrulline levels were still significantly in- creased (p b 0.05) while L-ornithine and agmatinase levels remained unchanged (p N 0.05). Conversely, plasma agmatine levels were significantly decreased after the treatment (p b 0.0001). Positive and negative predictive values of agmatine used for evaluating the diagnostic accuracy were 95.1% and 97.1%, respectively (p b 000.1). This is the first study of arginine metabolism and agmatine in medication-naive first-episode patients and pro- vides evidence of increased levels of an endogenous NMDA antagonist which decreases following antipsychotic treatment. © 2018 Elsevier B.V. All rights reserved. Keywords: Agmatine L-Citrulline L-Ornithine Agmatinase (AGMAT) First episode psychosis 1. Introduction Schizophrenia is one of the most debilitating psychiatric disorders characterized by positive, negative and cognitive symptoms; it affects approximately 1% of the population worldwide (Perälä et al. 2007). De- spite the tremendous human, social, and economic costs of the disease, there are no known biomarkers and the pathophysiological under- standing of the disease is still incomplete. Currently, two hypotheses of physiopathology dominate the schizophrenia field. The dopamine hy- pothesis is mainly based on the serendipitous finding that all the anti- psychotics have antagonistic activity on dopamine D2 receptors (D2R) to some extent and this activity is correlated with the treatment of pos- itive symptoms of schizophrenia (Howes and Kapur 2009; Seeman 1987; Snyder 1976). However, D2R antagonists act as antipsychotics for many types of psychosis, which may be observed in a multitude of disease states and are not sufficiently useful for the negative and cognitive symptoms of schizophrenia (Goff et al. 2011; Remington et al. 2016). Dopamine agonists, on the other hand, may cause a tempo- rary state of nonspecific psychosis clinically—mainly consisting of posi- tive symptoms—but are not known to produce dominant negative or cognitive symptoms (Krystal et al. 2005). The NMDA (N-methyl-D-aspartate) hypothesis of schizophrenia is based on the fact that antagonists of NMDA receptors (NMDARs), such as phencyclidine (PCP) and ketamine, produce a temporary psychotic state in otherwise healthy individuals which resembles the clinical pic- ture of schizophrenia and includes positive, negative, and cognitive symptoms (Javitt and Zukin 1991; Krystal et al. 1994; Lodge and Mercier 2015; Moghaddam and Javitt 2012; Moghaddam and Krystal 2012). Therefore, NMDAR hypofunction was proposed as a component of schizophrenia pathophysiology. However, glutamate—the endoge- nous agonist for NMDAR—has not been shown to decrease in schizo- phrenia (Moghaddam and Javitt 2012). A straightforward explanation could be the presence of an endogenous NMDAR antagonist, especially one which increases or releases at times of distress. This may trigger a first psychotic episode and possibly the subsequent exacerbations of schizophrenia. Agmatine is one such neurotransmitter that is insuffi- ciently studied in schizophrenia. Schizophrenia Research xxx (xxxx) xxx ⁎ Corresponding author at: Noro Saglık Beyin Egitimleri Arastirmalari Uygulamalari Merkezi, Bagdat Caddesi, Heper Apt. No: 2/6, Kadikoy, Istanbul, Turkey. E-mail address: hkayir@gmail.com (H. Kayir). SCHRES-08135; No of Pages 9 https://doi.org/10.1016/j.schres.2018.12.015 0920-9964/© 2018 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Please cite this article as: B. Garip, H. Kayir and O. Uzun, l-Arginine metabolism before and after 10weeks of antipsychotic treatment in first- episode psychoti..., Schizophrenia Research, https://doi.org/10.1016/j.schres.2018.12.015