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 (fixed/flexible dose), parallel group, double blind controlled study
assessing the efficacy of olanzapine (OLA) (up to 40 mg/day) vs. DSR (up to 4000 mg/day) 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.