Title Page : 1 Elevated serum adenosine deaminase levels in neuroleptic - naïve patients with recent - 2 onset schizophrenia 3

30 Schizophrenia is characterized by pathophysiological alterations of multiple neurotransmitter 31 systems such as dopaminergic, glutamatergic, GABA-ergic and serotonergic pathways. 32 Adenosine, a homeostatic neuromodulator that mediates signaling through multiple 33 neurotransmitter pathways, is an emerging candidate neurobiological substrate of 34 schizophrenia. The present study examined peripheral blood levels of adenosine deaminase, 35 an adenosine metabolizing enzyme, in 16 neuroleptic-naive patients with recent-onset 36 schizophrenia (mean age = 25.59 years (range: 16-35)) and 18 age-matched healthy 37 comparison subjects (mean age = 25.17 years (range: 18-28)). Serum adenosine deaminase 38 levels were assayed at two time points; before (7 p.m.) and after (7 a.m.) sleep. The 39 adenosine deaminase levels were compared between groups and were correlated to positive 40 and negative symptom severity measures. Adenosine deaminase levels were found to be 41 higher at both evening (p=0.013) and morning (p<0.001) time points in our sample of 42 patients with recent-onset schizophrenia who were never exposed to neuroleptic medications. 43 Correlational analysis revealed evidence for a possible link between evening rise in adenosine 44 deaminase and severity of auditory hallucinations (p=0.003) as well as morning rise in 45 adenosine deaminase and severity of avolition-apathy in patients with schizophrenia 46 (p=0.013). The results of the study provide strong support to the adenosine hypothesis of 47 schizophrenia and highlight the potential utility of serum adenosine deaminase as a peripheral 48 biomarker of schizophrenia.