A Study of the Effects of Sarcosine on Symptoms and Brain Glycine Levels in People With Schizophrenia

Study Overview
=================
Brief Summary
-----------------
The NMDA receptor has been identified as having a role in substance use disorders as well as in schizophrenia. One example of the former is nicotine's effect on dopaminergic activity not only by increasing the release of dopamine in the Midbrain reward centers, but also through less direct mechanisms affecting alpha-7 nicotinic receptors, NMDA receptors, and Glycine, a co-agonist for the NMDA receptors. In terms of schizophrenia, it has been hypothesized that NMDA receptor hypofunction plays a role in the mechanism for negative symptoms and cognitive dysfunction in these patients. The NMDA hypofunction may be reversed with increased synaptic glycine availability. Sarcosine, or n-methyl-glycine, is a GlyT-1 and System A transport inhibitor actions which could be expected to increase the availability of glycine, in the synaptic space. Sarcosine is a dietary supplement which could be found in several food items such as egg yolks and turkey. Our collaborative team has developed a novel, non-invasive magnetic resonance spectroscopy (MRS) technique for measuring brain glycine changes that allows us to study glycine homeostasis. The purpose of this study is to explore the effect of sarcosine (n-methyl-glycine) on brain glycine concentrations. It is our hypothesis that oral sarcosine, at a dose of 2 grams per day, will be well tolerated and associated with increased brain glycine concentrations. It is our secondary exploratory hypothesis that increases in brain glycine will be associated with behavioral signs of increased NMDA and dopamine activity. This modulation could have future therapeutic potential for disorders of hedonic and cognitive function.

Detailed Description
-----------------
Research subjects will undergo a screening visit at the Massachusetts General Hospital Center for Addiction Medicine. If they meet inclusion criteria, they will be invited for the baseline visit when they will have their first MRS and will begin taking the study drug/placebo. The randomization will be done in blocks of four. The study drug/placebo is prescribed to take 2 capsules of 500 mg each, two times per day, with or without food. They will continue weekly visits for six weeks and will receive new supplies of the study drug/placebo on weeks 2 and 4. On week 6, they will have the second MRS. On weeks 8 and 16, subjects will undergo follow up visits. On several of these visits, study staff will assess for the presence of adverse events (with the UKU instrument), cigarettes use (with carbon monoxide monitoring), and abnormal involuntary movements (with the abnormal involuntary movement scale, the barnes akathisia scale, and the sympson angus scale).

Official Title
-----------------
The Effects of Glycine Transport Inhibition on Brain Glycine Concentration

Conditions
-----------------
Schizophrenia

Intervention / Treatment
-----------------
* Dietary Supplement: Sarcosine


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: Women and men aged 18-65 with DSM-IV diagnosis of schizophrenia or schizoaffective disorder by diagnostic interview and chart review. Clinically stable on a stable dose of antipsychotic medication for at least one month, no current active suicidal ideation. Competent to provide informed consent. Women of childbearing age must have a negative pregnancy test at screening and agree to use an approved form of contraception throughout the study. Screening labs within normal limits for age and gender except for liver function tests as specified below. EXCLUSION CRITERIA: Diagnosis of bipolar disorder, dementia, neurodegenerative disease, or other organic mental disorder. History of seizure disorder or CNS tumor. Liver function tests elevated over twice normal. Bulimia, or major depressive disorder within the last 6 months. Life-threatening arrhythmia, cerebro-vascular, or cardiovascular event within 6 months. Current serious unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease such that hospitalization for treatment of that illness is likely within the next 2 months. Lifetime history of multiple head injuries with neurological sequelae or a single severe head injury with lasting neurological sequelae. Use of investigational medication within 30 days of enrollment. Use of clozapine. Substance use disorder other than nicotine or caffeine in the last 6 months (by self report and salivary drug and alcohol screen). Posing a current risk of homicide or suicide.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>You will receive two grams of placebo per day. You will take two 500 mg placebo capsules twice per day, once in the morning and once in the evening, every day for six weeks. You can take the pills with or without food. You should continue to take all your other medications throughout the study. | Dietary Supplement: Sarcosine<br>* You will receive two grams of sarcosine or placebo per day. Each capsule will contain 500 mg of sarcosine or placebo. You will take two capsules twice per day, once in the morning and once in the evening, every day for six weeks. You can take the pills with or without food. You should continue to take all your other medications throughout the study.<br>* Other names: glycine transport inhibitor;|
| Experimental: Sarcosine<br>You will receive two grams of sarcosine per day. You will take two 500 mg capsules twice per day, once in the morning and once in the evening, every day for six weeks. You can take the pills with or without food. You should continue to take all your other medications throughout the study. | Dietary Supplement: Sarcosine<br>* You will receive two grams of sarcosine or placebo per day. Each capsule will contain 500 mg of sarcosine or placebo. You will take two capsules twice per day, once in the morning and once in the evening, every day for six weeks. You can take the pills with or without food. You should continue to take all your other medications throughout the study.<br>* Other names: glycine transport inhibitor;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increases in brain glycine concentration as measured by magnetic resonance spectroscopy |  | baseline and endpoint | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sarcosine, Glycine, Magnetic Resonance Spectroscopy, Schizophrenia