 A first generation of clinical studies, performed during the last decade, demonstrates that adjuvant treatment with compounds that enhance NMDAR-mediated neurotransmission due to their agonistic activity at the NMDAR-associated glycine GLY site e.g. GLY, D-serine DSR leads to significant symptom reductions in chronic schizophrenia patients.Furthermore, preliminary findings suggest that treatment with NMDAR-GLY site modulators may also be beneficial as antipsychotic monotherapy In the proposed project, during a three year period, 60 schizophrenia patients that fulfill treatment resistance criteria will be randomly entered in a 10 week, two phase fixedflexible dose, parallel group, double blind controlled study assessing the efficacy of olanzapine OLA up to 40 mgday vs. DSR up to 4000 mgday as antipsychotic monotherapy.Clinical, neurocognitive, electrophysiological, and amino acids i.e. GLY, DSR levels assessments will be performed during the study. The specific aims of the proposed project are: 1 to assess the efficacy and safety of DSR as a new medication for treatment refractory schizophrenia, and 2 to assess DSR effects in terms of relevant amino acids serum levels, neurocognitive performance, and relevant brain electrophysiological parameters. The overall importance of the proposed project consists of its potential to lay the foundations for an innovative type of intervention for treatment resistant schizophrenia patients. 