Original Investigation


, Volume 179, Issue 1, pp 144-150

First online:

A six-month, placebo-controlled trial of d-cycloserine co-administered with conventional antipsychotics in schizophrenia patients

  • Donald C. GoffAffiliated withSchizophrenia Program, Massachusetts General HospitalFreedom Trail ClinicHarvard Medical School Email author 
  • , Lawrence HerzAffiliated withBedford Veteran’s Affairs Medical Center, Boston University Medical School
  • , Thomas PoseverAffiliated withLemuel Shattuck Hospital, Tufts Medical School
  • , Vivian ShihAffiliated withHarvard Medical SchoolPediatric Neurology Service, Massachusetts General Hospital
  • , Guochuan TsaiAffiliated withMcLean Hospital
  • , David C. HendersonAffiliated withSchizophrenia Program, Massachusetts General HospitalHarvard Medical School
  • , Oliver FreudenreichAffiliated withSchizophrenia Program, Massachusetts General HospitalHarvard Medical School
  • , A. Eden EvinsAffiliated withSchizophrenia Program, Massachusetts General HospitalHarvard Medical School
  • , Iftah YovelAffiliated withSchizophrenia Program, Massachusetts General HospitalHarvard Medical School
    • , Hui ZhangAffiliated withBiostatistics, Massachusetts General Hospital
    • , David SchoenfeldAffiliated withHarvard Medical SchoolBiostatistics, Massachusetts General Hospital

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d-Cycloserine, a partial agonist at the glycine site of the N-methyl-d-aspartate receptor, has demonstrated inconsistent efficacy for negative and cognitive symptoms of schizophrenia. The strongest evidence for efficacy has come from studies using d-cycloserine at a dose of 50 mg/day added to conventional antipsychotics in trials of 8 weeks duration or less.


To assess the efficacy for negative symptoms and cognitive impairment of d-cycloserine augmentation of conventional antipsychotics in a 6-month trial.


Fifty-five schizophrenia patients with prominent negative symptoms, treated with conventional antipsychotics, were randomly assigned to treatment with d-cycloserine 50 mg/day or placebo for 6 months in a double-blind, parallel group design.


Twenty-six subjects completed the 6-month trial; drop-out rates did not differ between treatment groups. d-Cycloserine treatment did not differ from placebo treatment on any primary outcome measure at 8 or 24 weeks, including response of negative symptoms and performance on a cognitive battery. Serum d-cycloserine concentrations did not correlate with response of negative symptoms.


d-Cycloserine did not exhibit therapeutic effects in this trial, possibly reflecting the high drop-out rate, a narrow range of therapeutic serum concentrations, a modest magnitude of therapeutic effect for the selected outcome measures, or loss of efficacy over time. Because d-cycloserine is a partial agonist with relatively low affinity for the glycine site, the magnitude of potential therapeutic effect may be smaller than that achieved by the higher-affinity full agonists, glycine and d-serine.