A multicenter, add-on randomized controlled trial of low-dose d-serine for negative and cognitive symptoms of schizophrenia.
BACKGROUND
Observations that antagonists of the N-methyl-d-aspartate (NMDA) receptor of glutamatergic neurons can mimic symptoms of schizophrenia have raised the hope that NMDA agonists can improve symptoms. On the basis of encouraging results of trials in which NMDA agonists were added to antipsychotics, we conducted an adequately powered randomized controlled trial adding d-serine, an NMDA modulator, to antipsychotics.


METHODS
This study was a 195-patient, multicenter, double-blind, randomized, placebo-controlled, 16-week trial of d-serine 2 g/d as an add-on treatment to antipsychotics. Subjects had DSM-IV schizophrenia or schizoaffective disorder and were inpatients or outpatients stabilized on antipsychotics, with persistent negative symptoms. The primary outcome measures were changes in negative symptoms and cognition as measured by the Scale for the Assessment of Negative Symptoms (SANS) and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery, respectively. The study was performed between 2003 and 2007.


RESULTS
Mean total Positive and Negative Syndrome Scale scores at baseline were 75.5. Subjects receiving d-serine and placebo improved in scores on the SANS and MATRICS, but no significant differences were observed between groups: improvement on SANS was 11.4% for d-serine vs 14.8% for placebo, F1,147=1.18, P=.32; and improvement on MATRICS was 6.8% for d-serine vs 6.1% for placebo, F1,125=0.96, P=.39, respectively. d-Serine was well tolerated.


CONCLUSIONS
This study did not find a significant difference between drug and placebo. However, the results are limited by a relatively large placebo response and somewhat lower-achieved doses than in prior studies. Future studies will administer higher doses and will attempt to affect the NMDA receptor using other mechanisms, such as agonists of the presynaptic metabotropic glutamate 2/3 receptor or glycine reuptake inhibitors.


BACKGROUND
ClinicalTrials.gov identifier: NCT00138775.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Jerusalem. mweiser@netvision.net.il
Mark
M
Weiser
Uriel
U
Heresco-Levy
Michael
M
Davidson
Daniel C
DC
Javitt
Nomi
N
Werbeloff
Ari A
AA
Gershon
Yehuda
Y
Abramovich
Daniela
D
Amital
Adiel
A
Doron
Shai
S
Konas
Yehiel
Y
Levkovitz
David
D
Liba
Alexander
A
Teitelbaum
Mordechai
M
Mashiach
Yosef
Y
Zimmerman
D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods / Q000523:psychology*; D005260:Female; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D011618:Psychotic Disorders / Q000188:drug therapy; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D012694:Serine / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*
D014150:Antipsychotic Agents; D012694:Serine