Improvement in mismatch negativity generation during d -serine treatment in schizophrenia: Correlation with symptoms

Abstract Background Deficits in N -methyl- d -aspartate-type (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia. The efficacy of NMDAR agonists in the treatment of persistent symptoms of schizophrenia has been variable, potentially reflecting limitations in functional target engagement. We recently demonstrated significant improvement in auditory mismatch negativity (MMN) with once-weekly treatment with d -serine, a naturally occurring NMDAR glycine-site agonist. This study investigates effects of continuous (daily) NMDAR agonists in schizophrenia/schizoaffective disorder. Methods Primary analysis was on MMN after double-blind crossover (60 mg/kg/d, n = 16, 6 weeks) treatment with d -serine/placebo. Secondary measures included clinical symptoms, neurocognition, and the effects of open-label (30–120 mg/kg/d, n = 21) d -serine and bitopertin/placebo (10 mg, n = 29), a glycine transport inhibitor. Results Double-blind d -serine treatment led to significant improvement in MMN frequency ( p = 0.001, d = 2.3) generation and clinical symptoms ( p = 0.023, d = 0.80). MMN frequency correlated significantly with change in symptoms (r = − 0.63, p = 0.002) following co-variation for treatment type. d -Serine treatment led to a significant, large effect size increase vs. placebo in evoked α-power in response to standards ( p = 0.036, d = 0.81), appearing to normalize evoked α power relative to previous findings with controls. While similar results were seen with open-label d -serine, no significant effects of bitopertin were observed for symptoms or MMN. Conclusions These findings represent the first randomized double-blind placebo-controlled study with 60 mg/kg d -serine in schizophrenia, and are consistent with meta-analyses showing significant effects of d -serine in schizophrenia. Results overall support suggest that MMN may have negative, as well as positive, predictive value in predicting efficacy of novel compounds. Clinical trials registration Clinicaltrials.gov : NCT00322023 /NCT00817336 ( d -serine); NCT01116830 (bitopertin).