Trial of D-Cycloserine in Schizophrenia

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00000371
• Collaborator: (none)
• Enrollment: 60
• Arms: 2
• Duration (Months): 68

Study Details

Study Description

Brief Summary

To characterize further the effects of D-cycloserine augmentation of antipsychotic treatment on negative symptoms, performance on neurocognitive tasks, and on markers for glutamatergic, dopaminergic and serotonergic function in serum and cerebrospinal fluid. To determine if negative symptoms and cognitive function improve over time, if these improvements meaningfully impact quality of life factors, if they correlate with markers of neuronal function, and if subpopulations can be identified according to response.

Dysfunction of glutamatergic neuronal systems has recently been implicated in the pathophysiology of schizophrenia based on the finding that non-competitive inhibitors of the NMDA receptor can reproduce in normals the positive symptoms, negative symptoms, and cognitive deficits of schizophrenia. Furthermore, glutamatergic dysfunction may alter forebrain dopaminergic neuronal activity, a system central to the antipsychotic action of typical neuroleptics. It is believed that enhancing NMDA receptor function by systemic treatment with D-cycloserine, a partial agonist at the glycine modulatory site of the NMDA receptor, will reduce symptoms in schizophrenia.

Sixty schizophrenic outpatients with prominent, primary negative symptoms are treated with antipsychotic medication and are randomly assigned to D-cycloserine or placebo for a 6-month, fixed-dose trial. The primary outcome measure is the total score on the Scale for Assessment of Negative Symptoms (SANS). A neuropsychological battery, which emphasizes tests sensitive to prefrontal cortical function, is administered. Blood is obtained at several time points and CSF is obtained at Week 8 for assay of concentrations of D-cycloserine, glutamate, HVA, and 5HIAA.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: D-cycloserine; Drug: Placebo	Phase 3

Detailed Description

To characterize further the effects of D-cycloserine augmentation of antipsychotic treatment on negative symptoms, performance on neurocognitive tasks, and on markers for glutamatergic, dopaminergic, and serotonergic function in serum and cerebrospinal fluid. To determine if negative symptoms and cognitive function improve over time, if these improvements meaningfully impact quality of life factors, if they correlate with markers of neuronal function, and if subpopulations can be identified according to response.

Dysfunction of glutamatergic neuronal systems has recently been implicated in the pathophysiology of schizophrenia based on the finding that non-competitive inhibitors of the NMDA receptor can reproduce in normals the positive symptoms, negative symptoms and cognitive deficits of schizophrenia. Furthermore, glutamatergic dysfunction may alter forebrain dopaminergic neuronal activity, a system central to the antipsychotic action of typical neuroleptics. It is believed that enhancing NMDA receptor function by systemic treatment with D-cycloserine, a partial agonist at the glycine modulatory site of the NMDA receptor, will reduce symptoms in schizophrenia.

Sixty schizophrenic outpatients with prominent, primary negative symptoms are treated with antipsychotic medication and are randomly assigned to D-cycloserine or placebo for a 6-month, fixed-dose trial. The primary outcome measure is the total score on the Scale for Assessment of Negative Symptoms (SANS). A neuropsychological battery, which emphasizes tests sensitive to prefrontal cortical function, is administered. Blood is obtained at several time points and CSF is obtained at Week 8 for assay of concentrations of D-cycloserine, glutamate, HVA, and 5HIAA.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Six Month, Placebo-Controlled Trial of D-Cycloserine Co-Administered With Conventional Antipsychotics in Schizophrenia Patients
• Study Start Date: Aug 1, 1996
• Actual Primary Completion Date: Apr 1, 2002
• Actual Study Completion Date: Apr 1, 2002

Arms and Interventions

Arm	Intervention/Treatment
Experimental: D-Cycloserine Subjects were given 50 mg/day of D-Cycloserine for 24 weeks	Drug: D-cycloserine; 50 mg/daily by mouth; Other Names: Cycloserine
Placebo Comparator: Placebo Participants were given 50 mg/day of Placebo for 24 weeks.	Drug: Placebo; 50 mg/day of placebo by mouth

Outcome Measures

Primary Outcome Measures

1. Scale for the Assessment of Negative Symptoms (SANS) [Baseline, Week 4, Week 8]

   The slope of SANS total score from baseline to week 8 in the treatment and placebo groups on the scale for the assessment of negative symptoms (SANS) total score. Total SANS scores range from 0-100. The SANS is comprised of 5 subscores: Affective Flattening or Blunting (score range 0-35), Alogia (score range 0-20), Avolition-Apathy (score range 0-15), Anhedonia-Asociality (score range 0-20), and Attention (0-10). For each scale, the higher the score the more prominent the negative symptoms were. The slopes were obtained by plotting the group SANS total score mean for treatment vs. placebo on Baseline, Week 4, and Week 8 and performing a random slopes model.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of Schizophrenia as per DSM IV criteria

• Have been treated for at least 6 months with any conventional neuroleptic

• Have prominent negative symptoms as defined by a total score of 40 or greater on the scale for the assessment of negative symptoms (SANS)

Exclusion Criteria:

• Active alcohol or drug abuse

• Unstable Medical Illness, seizure disorder, or other serious neurological disorder

• Pregnant or Nursing

• Unable to complete a cognitive battery

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Massachusetts General Hospital

Investigators

• Principal Investigator: Donald Goff, MD,

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Donald C. Goff, MD, Director of the Schizophrenia Clinical and Research Program, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00000371
• Other Study ID Numbers: R01MH054245-01A2
• First Posted: Nov 3, 1999
• Last Update Posted: Sep 10, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by Donald C. Goff, MD, Director of the Schizophrenia Clinical and Research Program, Massachusetts General Hospital: Adult; Cognition; Cycloserine; Dopamine; Female; Glutamic Acid; Human; Male; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Serotonin; Quality of Life; Cycloserine -- *therapeutic use; Dopamine -- blood; Dopamine -- cerebrospinal fluid; Glutamic Acid -- blood; Glutamic Acid -- cerebrospinal fluid; Serotonin -- blood; Serotonin -- cerebrospinal fluid
• Additional relevant MeSH terms: Schizophrenia; Cycloserine

Study Results

Participant Flow

Recruitment Details	Subjects were adult outpatients recruited from three urban community health centers and two Veteran's Affairs medical centers in the greater Boston area. All eligible participants at these sites were invited to participate by their clinicians.
Pre-assignment Detail	Sixty subjects met eligibility criteria and provided informed consent, but just 55 completed baseline assessments and were randomized to d-cycloserine or placebo.

Arm/Group Title	D-Cycloserine	Placebo
Arm/Group Description	Patients were given 50 mg of D-Cycloserine daily in addition to their treatment as usual with conventional neuroleptics.	Patients were given 50 mg of placebo daily in addition to their treatment as usual with conventional neuroleptics.
Period Title: Overall Study
STARTED	27	28
COMPLETED	14	12
NOT COMPLETED	13	16

Baseline Characteristics

Arm/Group Title	D-Cycloserine	Placebo	Total
Arm/Group Description	Patients were given 50 mg of D-Cycloserine daily in addition to their treatment as usual with conventional neuroleptics.	Patients were given 50 mg of placebo daily in addition to their treatment as usual with conventional neuroleptics.	Total of all reporting groups
Overall Participants	27	28	55
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	45.9 (7.4)	47.0 (8.6)	46.5 (8.0)
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	27 100%	28 100%	55 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	3 11.1%	8 28.6%	11 20%
Male	24 88.9%	20 71.4%	44 80%
Region of Enrollment (participants) [Number]
United States	27 100%	28 100%	55 100%

Outcome Measures

1. Primary Outcome

Title	Scale for the Assessment of Negative Symptoms (SANS)
Description	The slope of SANS total score from baseline to week 8 in the treatment and placebo groups on the scale for the assessment of negative symptoms (SANS) total score. Total SANS scores range from 0-100. The SANS is comprised of 5 subscores: Affective Flattening or Blunting (score range 0-35), Alogia (score range 0-20), Avolition-Apathy (score range 0-15), Anhedonia-Asociality (score range 0-20), and Attention (0-10). For each scale, the higher the score the more prominent the negative symptoms were. The slopes were obtained by plotting the group SANS total score mean for treatment vs. placebo on Baseline, Week 4, and Week 8 and performing a random slopes model.
Time Frame	Baseline, Week 4, Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine	Placebo
Arm/Group Description	Patients were given 50 mg of D-Cycloserine daily in addition to their treatment as usual with conventional neuroleptics.	Patients were given 50 mg of placebo daily in addition to their treatment as usual with conventional neuroleptics.
Measure Participants	28	27
Mean (Standard Error) [units on a scale/weeks]	-.46 (.29)	-.41 (.31)

Adverse Events

Adverse Event Reporting Description	The only information known for this study regarding occurrence of Adverse Events is that 2 and 6 participants dropped out of the D-Cycloserine and Placebo Arms/Groups, respectively (reported in the publication associated with this clinical trials profile). However, specific adverse event data are lost and cannot be retrieved
Arm/Group Title	D-Cycloserine		Placebo
Arm/Group Description	Patients were given 50 mg of D-Cycloserine daily in addition to their treatment as usual with conventional neuroleptics.		Patients were given 50 mg of placebo daily in addition to their treatment as usual with conventional neuroleptics.
All Cause Mortality
	D-Cycloserine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	D-Cycloserine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	D-Cycloserine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

A biased sample may have been produced by restricting the analysis to patients with prominent negative symptoms receiving conventional agents (less compliant with study medication). Additionally, Adverse Event data was lost for the study.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.