High dose D-serine in the treatment of schizophrenia.
BACKGROUND
D-serine is an allosteric modulator of the brain N-methyl-d-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia. Double-blind studies have been performed at 30 mg/kg/day (approximately 2 g/day) with encouraging results, but no formal dose escalation studies have been performed. We describe the first evaluation of the efficacy and safety of d-serine at doses >30 mg/kg/day; a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day).


METHODS
42 antipsychotic-stabilized patients with schizophrenia or schizoaffective disorder participated. PANSS was obtained bi-weekly and neuropsychological (MATRICS) was obtained pre- and post medication phase. The pharmacokinetics/pharmacodynamics (PK/PD), and safety of doses> or =30 mg/kg was also evaluated.


RESULTS
Significant improvement in symptoms and neuropsychological measures was noted across doses. On the PANSS, improvement was observed for positive (p=0.006;d=0.46), negative (p<0.001;d=0.68), general (p=0.001;d=0.53), and total (p<0.0001;d=0.74) symptoms. On MATRICS, while only non-significant improvement was noted at 30 mg/kg, highly significant, large effect size improvement was noted on the composite score (p<0.01;d=1.0) for doses> or =60 mg/kg, leading to a significant dose-by-time interaction (p<0.01). In PK analyses, significant dose-dependent increases in plasma D-serine levels were seen during the study, predictive of significantly increased brain levels. Furthermore, increases in plasma levels correlated with improved symptomatic and neuropsychological function.


CONCLUSIONS
These findings support double-blind investigation of D-serine at doses> or =60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction.
Kantrowitz
Joshua T
JT
Schizophrenia Research Center, Nathan Kline Institute for Psychiatric Research/New York University Langone School of Medicine, Orangeburg, NY, United States.
Malhotra
Anil K
AK
Cornblatt
Barbara
B
Silipo
Gail
G
Balla
Andrea
A
Suckow
Raymond F
RF
D'Souza
Cyril
C
Saksa
John
J
Woods
Scott W
SW
Javitt
Daniel C
DC
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D003072:Cognition Disorders / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D012044:Regression Analysis; D012559:Schizophrenia / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D012694:Serine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
D014150:Antipsychotic Agents; D012694:Serine