Safety and Effectiveness of D-serine in Schizophrenia

• Sponsor: Nathan Kline Institute for Psychiatric Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT00322023
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 55
• Locations: 3
• Arms: 3
• Duration (Months): 34.1
• Patients Per Site: 18.3
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This study will determine whether increasing D-serine within the body will improve negative symptoms and cognitive impairments in people with schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: D-serine; Drug: D-serine; Drug: D-serine; Drug: D-serine	Phase 2

Detailed Description

Schizophrenia is a life-long brain disorder affecting approximately 1 percent of Americans each year. Schizophrenia can be extremely disabling, causing people to hear voices, experience paranoia or hallucinations, believe that others are controlling their thoughts, and even fail at maintaining a job or caring for themselves. Current medications help to relieve most of these symptoms, but not all. Some people with schizophrenia still suffer from negative symptoms, such as difficulty with talking, expressing emotions, and motivation; they may also suffer from cognitive impairments, such as decreased concentration and memory loss. D-serine, an amino acid found within the body, activates brain cell receptors that appear to play a role in learning and memory. This study will determine whether adding a D-serine solution to a stable antipsychotic medication regimen will decrease negative symptoms in people with schizophrenia.

Participants in this open-label study will remain on their regular medication regimen for at least 2 weeks. During this time and before starting treatment, participants will be interviewed about their emotional problems, marital status, education, family background, employment history, and any drug or alcohol problems. Participants will also undergo a physical exam, an electrocardiogram (EKG), vital sign measurements, psychological tests, cognitive tasks, and an electroencephalogram (EEG). Participants will then begin 4 weeks of treatment with D-serine. In addition to participants' regular medication regimen, they will drink a D-serine powder mixed with water twice daily. Every 2 weeks, participants will undergo a physical exam and an interview about any changes in symptoms or emotional problems that they may be experiencing. Blood and urine samples will be taken throughout the study. After 4 weeks, participants will undergo an EKG, EEG, and the same psychological tests and cognitive tasks completed prior to treatment. A follow-up visit will occur 2 weeks post-treatment to monitor any changes in negative symptoms.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: PK/PD Study of Escalating Dose D-serine as Adjunctive Treatment in Schizophrenia
• Study Start Date: Mar 1, 2006
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: D-serine 30 mg/kg D-serine 30 mg/kg	Drug: D-serine; D-serine at following dose levels: 30 mg/kg, 60 mg/kg, and 120 mg/kg. PK/PD studies done at day 1. Medication will be administered as powder dissolved in liquid given in two divided doses daily for 4 weeks.; Drug: D-serine
Experimental: D-serine 60 mg/kg D-serine 60 mg/kg	Drug: D-serine; D-serine at following dose levels: 30 mg/kg, 60 mg/kg, and 120 mg/kg. PK/PD studies done at day 1. Medication will be administered as powder dissolved in liquid given in two divided doses daily for 4 weeks.; Drug: D-serine
Experimental: D-serine 120 mg/kg D-serine 120 mg/kg	Drug: D-serine; D-serine at following dose levels: 30 mg/kg, 60 mg/kg, and 120 mg/kg. PK/PD studies done at day 1. Medication will be administered as powder dissolved in liquid given in two divided doses daily for 4 weeks.; Drug: D-serine

Outcome Measures

Primary Outcome Measures

1. Renal Safety Measures [Measured at Week 4]

   number of renal adverse events (serum and urinalysis)

Secondary Outcome Measures

1. Positive and Negative Symptoms Scale (PANSS) [Measured at Week 4]

   Absolute Change in PANSS over four weeks (change between baseline and final measurements). The PANSS is a 30-item rating scale widely used in assessment of medication effects in schizophrenia. The PANSS ranges from 30-210, with lower scores showing less symptoms. Larger change is better.

2. Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery [Measured at Week 4]

   Change over 4 weeks. The MATRICS is a scale measuring cognition, and reported as T-score, with 50 as the population average and every 10 points representing a change of 1 standard deviation from the population average. Higher scores represent an improvement

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Structured Clinical Interview for DSM-III-R diagnosis of schizophrenia or schizoaffective disorder

• PANSS 3 factor negative symptom inclusion score greater than 20 prior to study entry

• PANSS total score between 60 and 110

• Simpson-Angus Scale total score of 12 or less

• Calgary Depression Inventory total score of 10 and suicide score less than 2

• No change in Clinical Global Impressions (CGI) Scale score prior to study entry

• Chlorpromazine (CPZ) equivalent of 1500 or less

• Willing to use an effective form of birth control throughout the study if sexually active

Exclusion Criteria:

• High extrapyramidal symptom (EPS) levels

• Began, discontinued, or adjusted psychotropic medication within 2 weeks of study entry

• Taking investigational medication within 2 weeks of study entry

• Contraindication to study medication

• Serious or unstable medical illness

• Pregnant or breastfeeding

• Alcohol or drug abuse within 6 months of study entry

• Diagnosed with neurodegenerative disease or a seizure disorder

• History of a kidney impairment

• Currently taking clozapine

• Currently taking more than two antipsychotic medications

• Currently taking stimulants or cholinesterase inhibitors

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University School of Medicine	New Haven	Connecticut	United States	06512
2	The Zucker Hillside Hospital	Glen Oaks	New York	United States	11004
3	The Nathan S. Kline Institute for Psychiatric Research	Orangeburg	New York	United States	10962

Sponsors and Collaborators

• Nathan Kline Institute for Psychiatric Research
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Daniel C. Javitt, MD, PhD, Nathan Kline Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daniel C. Javitt, MD, PhD, PI, National Institute of Mental Health (NIMH)
• ClinicalTrials.gov Identifier: NCT00322023
• Other Study ID Numbers: U01MH074356; U01MH074356; DATR A5-EPTD
• First Posted: May 4, 2006
• Last Update Posted: Oct 5, 2020
• Last Verified: Sep 1, 2020

• Keywords provided by Daniel C. Javitt, MD, PhD, PI, National Institute of Mental Health (NIMH): Negative symptoms; NMDA; Glutamate; Glycine
• Additional relevant MeSH terms: Schizophrenia

Study Results

Participant Flow

Recruitment Details	Nathan Kline Institute, Yale University, Zucker Hillside

Arm/Group Title	D-serine 30 mg/kg	D-serine 60 mg/kg	D Serine 120 mg/kg
Arm/Group Description	Open label, adjunctive to antipsychotics for 4 weeks	Open label, adjunctive to antipsychotics for 4 weeks	Open label, adjunctive to antipsychotics for 4 weeks
Period Title: Overall Study
STARTED	12	21	22
COMPLETED	12	19	16
NOT COMPLETED	0	2	6

Baseline Characteristics

Arm/Group Title	D-serine 30 mg/kg	D-serine 60 mg/kg	D Serine 120 mg/kg	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	12	21	22	55
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	12 100%	21 100%	22 100%	55 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.7 (11.4)	43.9 (9.4)	43.2 (9.6)	43 (10)
Sex: Female, Male (Count of Participants)
Female	3 25%	4 19%	4 18.2%	11 20%
Male	9 75%	17 81%	18 81.8%	44 80%

Outcome Measures

1. Primary Outcome

Title	Renal Safety Measures
Description	number of renal adverse events (serum and urinalysis)
Time Frame	Measured at Week 4

Outcome Measure Data

Analysis Population Description

study completers

Arm/Group Title	D-serine 30 mg/kg	D-serine 60 mg/kg	D Serine 120 mg/kg
Arm/Group Description	4 weeks of adjunctive treatment	4 weeks of adjunctive treatment	4 weeks of adjunctive treatment
Measure Participants	12	19	16
Number [adverse events]	0	0	1

2. Secondary Outcome

Title	Positive and Negative Symptoms Scale (PANSS)
Description	Absolute Change in PANSS over four weeks (change between baseline and final measurements). The PANSS is a 30-item rating scale widely used in assessment of medication effects in schizophrenia. The PANSS ranges from 30-210, with lower scores showing less symptoms. Larger change is better.
Time Frame	Measured at Week 4

Outcome Measure Data

Analysis Population Description

Study completers

Arm/Group Title	D-serine 30 mg/kg	D-serine 60 mg/kg	D Serine 120 mg/kg
Arm/Group Description	4 weeks of adjunctive treatment	4 weeks of adjunctive treatment	4 weeks of adjunctive treatment
Measure Participants	12	19	16
Mean (Standard Deviation) [units on a scale]	5.1 (5.3)	4.4 (8.9)	6.3 (5.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	D-serine 30 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments	These are paired t test baseline vs final for the 30 mg/kg dose

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	D-serine 60 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments	These are paired t test baseline vs final for the 60 mg/kg dose

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	D Serine 120 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments	These are paired t test baseline vs final for the 120 mg/kg dose
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery
Description	Change over 4 weeks. The MATRICS is a scale measuring cognition, and reported as T-score, with 50 as the population average and every 10 points representing a change of 1 standard deviation from the population average. Higher scores represent an improvement
Time Frame	Measured at Week 4

Outcome Measure Data

Analysis Population Description

study completers

Arm/Group Title	D-serine 30 mg/kg	D-serine 60 mg/kg	D Serine 120 mg/kg
Arm/Group Description	4 weeks of adjunctive treatment	4 weeks of adjunctive treatment	4 weeks of adjunctive treatment
Measure Participants	12	19	16
Mean (Standard Deviation) [units on a scale]	0.8 (3.0)	3.9 (3.5)	2.8 (2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	D-serine 30 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments	These are paired t test baseline vs final for 30mg/kg
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	D-serine 60 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	These are paired t test baseline vs final for 60mg/kg
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	D Serine 120 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments	These are paired t test baseline vs final for 120mg/kg
	Method	t-test, 2 sided
	Comments

Adverse Events

Arm/Group Title	D-serine 30 mg/kg		D-serine 60 mg/kg		D Serine 120 mg/kg
Arm/Group Description	4 weeks of adjunctive treatment		4 weeks of adjunctive treatment		4 weeks of adjunctive treatment
All Cause Mortality
	D-serine 30 mg/kg		D-serine 60 mg/kg		D Serine 120 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	D-serine 30 mg/kg		D-serine 60 mg/kg		D Serine 120 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/19 (0%)		1/16 (6.3%)
Renal and urinary disorders
Proteinuria	0/12 (0%)	0	0/19 (0%)	0	1/16 (6.3%)	1
Other (Not Including Serious) Adverse Events
	D-serine 30 mg/kg		D-serine 60 mg/kg		D Serine 120 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/19 (0%)		2/16 (12.5%)
Hepatobiliary disorders
asymptomatic transaminitis	0/12 (0%)	0	0/19 (0%)	0	2/16 (12.5%)	2

Limitations/Caveats

Open Label

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.