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



Primary analysis was on MMN after double-blind crossover (60mg/kg/d, n=16, 6weeks) treatment with d-serine/placebo. Secondary measures included clinical symptoms, neurocognition, and the effects of open-label (30-120mg/kg/d, n=21) d-serine and bitopertin/placebo (10mg, n=29), a glycine transport inhibitor.



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.



These findings represent the first randomized double-blind placebo-controlled study with 60mg/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.



Clinicaltrials.gov: NCT00322023/NCT00817336 (d-serine); NCT01116830 (bitopertin).
Schizophrenia Research Center, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States; Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, United States. Electronic address: jk3380@cumc.columbia.edu.
Joshua T
JT
Kantrowitz
Schizophrenia Research Center, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States; Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, United States; Graduate Center, City University of New York, 365 5th Ave, New York, NY, United States.
Michael L
ML
Epstein
Schizophrenia Research Center, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States; Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, United States.
Migyung
M
Lee
Schizophrenia Research Center, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States.
Nayla
N
Lehrfeld
Schizophrenia Research Center, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States; Department of Psychiatry, New York University School of Medicine, 1 Park Ave, New York, NY, United States.
Karen A
KA
Nolan
Schizophrenia Research Center, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States.
Constance
C
Shope
Schizophrenia Research Center, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States; Department of Child and Adolescent Psychiatry, New York University School of Medicine, 1 Park Ave, New York, NY, United States.
Eva
E
Petkova
Schizophrenia Research Center, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States.
Gail
G
Silipo
Schizophrenia Research Center, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States; Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, United States.
Daniel C
DC
Javitt
D000161:Acoustic Stimulation; D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000209:etiology; D003265:Contingent Negative Variation / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005072:Evoked Potentials, Auditory / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology; D012694:Serine / Q000627:therapeutic use*; D013450:Sulfones / Q000627:therapeutic use; D013997:Time Factors; D055815:Young Adult
C550631:(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone; D014150:Antipsychotic Agents; D010879:Piperazines; D013450:Sulfones; D012694:Serine