D-serine, an allosteric modulator at the glycine co-agonist binding site, has also been investigated as an augmenting strategy primarily for improving the deficit symptoms of schizophrenia. D-serine may be more effective than glycine as it has a greater affinity for the glycine/serine binding site and also has an increased ability to cross the blood-brain barrier (162–164). Serum concentrations of D-serine have also been found to be reduced in schizophrenia (165). D-serine selectively binds to synaptic NMDA receptors and may strengthen circuit connectivity and have more of a neuroprotective effect as compared to glycine, which binds to both synaptic and extrasynaptic NMDA receptors (138, 166). The therapeutic effects of D-serine to improve refractory negative symptoms in schizophrenia have been demonstrated when added to antipsychotic therapy in patients with acute (156), chronic (167), and treatment-resistant illness (168). D-serine is well-tolerated and has been reported to be safe and effective used at dosages up to 120 mg/kg per day (169). D-cycloserine, a drug that was initially used to treat tuberculosis and an anolog of D-serine, is also active at the glycine site and has been reported to benefit the negative symptom domain of schizophrenia (170–172). Unfortunately, in patients with TRS, glycine, D-serine, and D-cycloserine have all been reported to be less effective at improving the negative and cognitive symptom domains in those patients receiving clozapine therapy (138, 152, 154, 172, 173).