Clinical trial NCT01720316
Conditions: Schizo-affective Disorder Bipolar Disorder
Keywords: Glycine Glycine decarboxylase Psychosis Mutation
Sponsor: Mclean Hospital
Start date: 2012-12-10; Completion date: 2017-05-31
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess the efficacy of oral glycine as an augmentation strategy in two psychotic patients with a triplication (4 copies) of the gene glycine decarboxylase (GLDC). Subjects will first undergo a double-blind placebo-controlled clinical trial in which one 6-week arm will involve glycine (maximum daily dose of 0.8 g/kg, administered on a TID dosing schedule) and one 6-week arm will involve placebo. A 2-week period of no treatment will occur between treatment arms. A 6-week period of open-label glycine (maximum daily dose of 0.8 g/kg, administered on a TID dosing schedule) will follow the double-blind placebo-controlled clinical trial. Prior to the double-blind placebo-controlled clinical trial and at the end of the open-label glycine trial, the following procedures will be carried out: structural MRI (3T), Proton 1H MRS (4T), fMRI (3T), steady-state visual evoked potentials, and EEG. Positive, negative, and affective symptoms and neurocognitive function as well as plasma levels of large neutral and large and small neutral and excitatory amino acids and psychotropic drug levels will be assessed periodically. In addition, 1H MRS (4T) for 2 hours after a single oral dose of a glycine-containing drink will be assessed at baseline. Pharmaceutical grade glycine powder (Ajinomoto) or placebo will be dissolved in 20% solution and prepared by the McLean Hospital Pharmacy.

Because the results of the double-blind placebo-controlled and open-label glycine treatment arms showed substantial clinical benefit to the participants, the study has been extended to include six months of chronic open-label glycine in order to determine 1) whether the clinical benefits achieved within 6 weeks previously recur, 2) the clinical benefits are lasting, and 3) additional clinical benefits occur with longer exposure. The glycine for this extension will be provided by Letco Medical.

The investigators hypothesize that mutation carriers will have reduced endogenous brain glycine and GABA levels and increased brain glutamate and glutamine levels. Glycine administration will increase brain glycine in the two carriers, but to a lesser extent than in non-carrier family members and controls.

The investigators hypothesize reduced activation of magnocellular pathways and abnormal ERPs modulated by NMDA in mutation carriers compared with non-carrier family members and controls.

The investigators hypothesize that glycine, but not placebo, will improve positive, negative and affective symptoms as well as neurocognitive function.

The investigators also hypothesize that open-label glycine will improve clinical and cognitive functioning, will partially normalize decreased baseline glycine and GABA and increased glutamate and glutamine, and will partially normalize magnocellular pathway activation and abnormal evoked potentials.

Detailed description:
Multiple rare structural variants of relatively recent evolutionary origin are recognized as important risk factors for schizophrenia (SZ) and other neurodevelopmental disorders (e.g., autism spectrum disorders, mental retardation, epilepsy) with odds ratios as high as 7-30 (Sebat et al. 2009; Malhotra et al. 2011; Heinzen et al. 2010; Weiss et al. 2008; McCarthy et al. 2009). We have found a de novo structural rearrangement on chromosome 9p24.1 in two psychotic patients. One of the genes in this region is the gene encoding glycine decarboxylase (GLDC), which affects brain glycine metabolism. GLDC encodes the glycine decarboxylase or glycine cleavage system P-protein, which is involved in degradation of glycine in glia cells. Carriers of the GLDC triplication would be expected to have low levels of brain Gly, resulting in NMDA receptor-mediated hypofunction, which has been strongly implicated in the pathophysiology of schizophrenia (Olney \& Farber, 1995; Coyle, 2006; Javitt, 2007).

There is an extensive literature on the effects of NMDA enhancing agents on positive, negative, and depressive symptoms and on neurocognitive function (see Tsai \& Lin, 2010; Lin et al. 2011 for reviews). Although many studies have reported positive results in at least one symptom domain (Heresco-Levy et al. 1996, 1999, 2004; Tsai et al. 1998, 1999, 2004, 2006; Javitt et al. 2001; Goff et al. 1996; Lane et al. 2008), the results of other studies have been negative or ambiguous (Goff et al. 1999; Evins et al. 2000; Duncan et al. 2004; van Berckel et al. 1999). Factors likely to contribute to this variability include: mechanism of action of the agent, compliance, concurrent treatment with first- vs second generation antipsychotic drugs, baseline glycine blood levels, presence/absence of kynurenine pathway metabolic abnormalities (Wonodi et al. 2010; Erhardt et al. 2007) and individual differences in brain glycine uptake and metabolism (Kaufman et al. 2009; Buchanan et al. 2007). Genetic variants that impact the synthesis and breakdown of glycine, glutamate, or other modulators of NMDA receptor function are also likely to have significant effects. Although glycine augmentation has shown variable efficacy in patients unselected for having a mutation that would be expected to lower brain glycine levels, the GLDC triplication in the two carriers in this study would be expected to result in unusually low brain glycine levels, supporting its therapeutic potential as an augmentation strategy.

Thus, it is important to evaluate the therapeutic efficacy of glycine augmentation in individuals in whom there is a high prior probability of therapeutic benefit and to characterize the neurobiology of this mutation in terms of brain metabolites, brain function, and the pharmacokinetics of glycine metabolism using well-established methods (Kaufman et al. 2009; Prescot et al. 2006; Martinez et al. 2008; Butler et al. 2001; Jensen et al. 2009; Ongur et al. 2008).

Arms: arm 1: Glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Double-blind arm 2: placebo, TID dosing, 6 weeks Double-blind arm 3: glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks
Interventions: intervention 1: Glycine intervention 2: placebo
Intervention descriptions: intervention 1: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine intervention 2: None

Protocol documents:
ICF_000.pdf: 
 
Official Title: Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders 
 
NCT number:  NCT01720316 
 
Document Date: 11/11/2012 


McLean Hospital 
Research Consent Form 
 
 
 
General Template 
Version Date:  June 2009 
 
 
 
 
Version 7 – 11/11/2012                                    Page 2 of 17 
 
Subject Identification 
Protocol Title: Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders 
 
Principal Investigator: Deborah L. Levy, Ph.D. 
 
Site Principal Investigator: Deborah L. Levy, Ph.D. 
 
Description of Subject Population: 4 members of a family in which two members have a 
mutation in glycine metabolism and two members do not. 
 
About this consent form 
 
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form. 
 
If you have any questions about the research or about this form, please ask us.  Taking part in 
this research study is up to you.  If you decide to take part in this research study, you must sign 
this form to show that you want to take part.  We will give you a signed copy of this form to 
keep. 
 
Why is this research study being done? 
 
Dr. Levy and colleagues at McLean Hospital are investigating the effects of a specific genetic 
mutation on brain structure and metabolism.   
 
Three magnetic resonance imaging techniques 
 
1) Diagnostic Magnetic Resonance Imaging, 2) Diffusion Tensor Imaging at 3T (3T MRI & DTI) 
and 3) Magnetic Resonance Spectroscopy at 4T (4T MRS) are brain imaging techniques use 
magnetic fields and radio waves to give detailed anatomical and chemical pictures of the brain, 
but involve no radiation. These techniques allow us to measure the levels of chemicals in the 
brain that help brain cells communicate with each other. Some of these chemicals are 
glutamate, GABA, glycine, and glutamine. The purpose of this study is to examine the effects of 
a specific genetic mutation in glycine metabolism on brain levels of these chemicals. You have 
been asked to take part in this study because you have a specific mutation in glycine 
metabolism or are genetically related to someone who does. There may be up to 4 individuals 
enrolled in this study. The findings from these 4 individuals will be compared with large groups 
of adults diagnosed with bipolar disorder, schizophrenia, schizoaffective disorder, delusional 
disorder as well as from healthy adults. A condition of your participation in this study is that you 
also participate in other imaging studies and you will be asked to sign the consent forms for 
these studies as well. These other studies include Proton Magnetic Resonance Imaging and 
Spectroscopy Studies of Brain Chemistry in Bipolar Disorder, Schizophrenia, and Related 


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Disorders and Proton Magnetic Resonance Spectroscopy Studies of Glutathione and Gamma-
aminobutyric Acid in Bipolar Disorder, Schizophrenia and Related Disorders, both of which are 
directed by Dr. Dost Ongur. These procedures will be done at McLean Hospital. 
 
Magnetic Resonance Imaging and Spectroscopy 
Magnetic resonance imaging and spectroscopy will also be used to measure brain glycine levels 
before and for 2 hours after a single oral dose of glycine. You will be asked to drink a mixture 
that contains up to about 30 grams of glycine and lemon juice. Glycine is an amino acid that 
exists naturally in the body. The typical diet contains about 2 grams of glycine/day.  High-protein 
foods, such as fish, meat, beans, and dairy products, contain glycine.  This procedure will 
measure how the brains of different people absorb and breakdown glycine. You have been 
asked to take part in this study because you have a specific mutation in glycine metabolism or 
are genetically related to someone who does. There may be up to 4 individuals enrolled in this 
study. The findings from these 4 individuals will be compared with large groups of healthy adult 
men. A condition of your participation in this study is that you also participate in another imaging 
study and you will be asked to sign the consent form for this study as well. The other study is 
Acute Glycine Pharmacodynamic Study, directed by Dr. Marc J. Kaufman. This procedure will 
be done at McLean Hospital. 
 
Neuropsychological Tests 
An additional procedure involves some neuropsychological tests that test things memory, 
attention, and planning. There may be up to 4 individuals enrolled in this study. The findings 
from these 4 individuals will be compared with large groups of adults diagnosed with bipolar 
disorder, schizophrenia, schizoaffective disorder, delusional disorder as well as from healthy 
adults.  
 
Dr. Levy and colleagues at McLean Hospital are also investigating whether daily treatment with 
glycine will improve the beneficial effects of standard psychiatric drug treatment. There may be 
up to 2 individuals enrolled in this study. The findings from these 2 individuals will be compared 
while on glycine and on placebo (no active substance). 
 
These studies are funded by the National Institute of Mental Health and the Brain and Behavior 
Research Foundation.  
 
How long will I take part in this research study? 
The imaging procedures at McLean will take place on several days. On one day, you will have a 
health screen involving a physical exam, urine toxicology screen, a pregnancy test (if 
necessary), an EKG, a movement examination, and routine medical blood tests (5 cc of blood, 
less than 1 teaspoon) and urinalysis. These procedures, along with the consenting procedures, 
will take about 3 hours. 
 
On another day there will be a structural MRI (at 3.0 T), which takes 15 minutes, and a 
spectroscopy a MRI at 4.0 T, which takes one hour.  The neuropsychological evaluation will 
take about 2 hours. 
 


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Subject Identification 
These procedures will be carried out on consecutive days on two occasions, before the glycine-
placebo and open-label glycine trial, and at the end of the open-label glycine trial. 
 
On a different day, there will be the glycine administration and spectroscopy scans using a 4T 
scanner. The pre-glycine (or baseline) scan takes one hour. After the glycine drink, the scan will 
last 2 hours. This procedure will be carried out before the glycine-placebo and open-label 
glycine trial only. 
 
The glycine-placebo clinical treatment period will take 16 weeks. There will 6 weeks on glycine 
or placebo followed by 2 weeks of no treatment. There be another period of 6 weeks on glycine 
or placebo. If you received placebo during the first 6-week period, you will receive glycine during 
the second, and vice versa. After the second 6-week period, there be 2 weeks of no treatment. 
 
The open label glycine treatment period will last for 6 weeks. You will be receiving glycine 
during this time. In the 5th week you will be flown to Boston to repeat the original scans (except 
for the glycine loading one) and other procedures, which will take about one week. Depending 
on scheduling issues, the three arms of the glycine clinical trial may occur in sequence or there 
may be a break in between them.  
 
Length of the Study: 
 
Part I: 
Baseline measures will take up to  9 days including travel time 
Part II: 
Glycine-Placebo and Open-label Glycine Clinical Trials will take up to 16 weeks. 
Part III: 
Glycine Extension Study will take up to 8 weeks 
Total Participation may take up to 25 weeks and 2 days including travel time. 
 
What will happen in this research study? 
Brain Imaging Scans at McLean Hospital 
The MRI and MRS studies conducted at the McLean Hospital Brain Imaging Center will use 
scanners that have field strengths of 1.5T, 3T and 4T. This refers to the amount of magnetism 
used to collect the brain image. The magnetic resonance (MR) scanner looks like a large 
cylinder with a tube running down the center. You will be asked to lie down on your back on a 
foam-padded table and place your head into a special holder. The table will slide you inside the 
“hole” of the scanner. Soft foam rubber sponges may be placed on both sides of your head for 
comfort and to help keep your head from moving. Because the scanner contains a strong 
magnet, you will be asked to remove all metal objects from your person including, but not limited 
to: watches, rings, necklaces, bracelets, earrings, other body piercings, belts, loose change, 
wallet (with credit cards), cell phones, items of clothing containing magnetic materials (for 
example, underwire bras, certain types of zippers), and shoes. These items will be secured in a 
safe place until your scan is completed. You will be able to remain in your street clothes. 
 


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Subject Identification 
During the scanning procedure you will hear different sounds. Some of these sounds are loud 
and are part of the normal operation of the scanner. These noises vary with the type of scan 
being performed and include: sounds like a hammer hitting a piece of wood, repetitive buzzing 
noises, and long series of loud beeps. Some scans are silent. These sounds, or combinations of 
them, may be repeated several times. In both scanners, you will be given earplugs to help 
muffle the sounds of the scanners and you can also wear headphones. These headphones may 
further muffle the sounds, and they will allow you to more directly hear and speak to research 
staff and/or the technician. The longest session may be up to 50 minutes for the MRI scan and 
no more than 90 minutes for the MRS scan. You will be given breaks between scanning 
sessions. You can talk during the preparation time and during breaks, but you should not talk 
during the actual scanning process. During scans, you should try to remain as still as possible. 
The entire time that you will be in the scanner will be about 50 minutes or 90 minutes. When 
your session is over the technician will move you out of the scanner and assist you from the 
table. You may feel cramped inside the scanner, but in the 3T MR scanner a mirror has been 
placed so you can look out through the scanner "hole" into the scanning room. The technologist 
will be able to see and hear you at all times and you may end the procedure at any time. You 
will be given a squeeze-ball to hold while in both scanners. If you squeeze this ball, it will trigger 
an emergency alarm that will notify research staff and/or the technician that you need to be 
removed from the scanner. 
 
Glycine Imaging Study 
For the glycine imaging study, you will drink a single dose of glycine, which will be mixed with 
lemon juice. Before you consume the glycine drink, magnetic resonance spectroscopy will be 
used to measure levels of chemicals in your brain. This scan will take about 1 hour. . After you 
drink the drink, the scan will be repeated over the next two hours to measure changes in the 
levels of brain chemicals compared with baseline.   
 
Beginning at midnight before the scan, you will begin fasting overnight. You will not eat or drink  
any foods or drinks that contain caffeine or smoke tobacco cigarettes on the day of the glycine 
study. When you come to McLean Hospital you will be asked to: 1) provide a urine sample, 
which will be analyzed for the presence of drugs of abuse, and 2) have your breath tested for 
alcohol and carbon monoxide. If you are a woman, your urine will be tested for pregnancy. You 
will not be able to participate if your pregnancy test is positive.  
 
If your breath and urine screens are negative, you will undergo a baseline scan that will take 
about 1 hour. After that, a catheter (IV) will be inserted into your arm and blood will be drawn to 
determine baseline blood serum glycine levels. Then you will drink the glycine drink (250 ml, 
about 8 ounces) over a 10-minute period. After you drink the glycine drink, you will be 
positioned in the 4.0 Tesla scanner for 2 hours to undergo repeat scans. After each scan, a 
small blood sample will be drawn using the catheter in your arm. The amount of blood taken 
from you during each sample is 5 ml. There will be up to 10 blood samples, for a total of 50 ml, 
or about 2 tablespoons. These blood samples will be sent to the Nathan Kline Institute in 
Orangeburg, NY, where they will be analyzed for glycine levels. By signing this consent form, 
you give permission for Dr. Raymond Sukow and the Nathan Kline Institute permission to 


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provide Dr. Levy and her colleagues with the results of any blood samples that were analyzed at 
NKI. 
 
The glycine drink is prepared using lemon juice and dissolved glycine powder. If you know that 
you are allergic to either of them you must let us know in advance. You will be asked to notify 
your personal physician that you will be participating in a study in which you will drink a mixture 
of glycine powder and lemon juice to make sure that you can safely participate. Your physician 
will be asked to provide a written statement indicating that he/she believes that there is no 
medical reason why you should not be able to drink lemon juice or glycine. 
 
Neuropsychological Tests  
The neuropsychological tests assess aspects of cognitive function like memory, attention, and 
planning. 
 
Glycine-Placebo and Open-label Glycine Clinical Trials 
After the first set of scans and procedures, you will receive either placebo or glycine for 6 weeks 
each, with two weeks of no extra treatment between the two treatment periods. Neither you nor 
the investigators will know which substance you are taking. You will continue to take your usual 
medications as prescribed. Your medications will not be changed as part of your participation in 
this study. By signing this consent form, you give Dr. Levy permission to be notified by your 
psychiatrist or internist if any of your medications changes, what changes occurred and the date 
on which the changes occurred. 
 
Glycine comes in the form of a powder. The placebo will look and taste like glycine. It will 
consist of Isomaltulose (Palatinose®), a fully digestible, low glycemic, and tooth-friendly sugar 
that is lactose- and gluten-free.   
 
The McLean Hospital Pharmacy will know whether you are receiving glycine or placebo. The 
McLean Pharmacy will prepare the appropriate dose of glycine powder or placebo in a re-
closable plastic bottle. Each bottle will be marked with a fill line, indicating how much cold water 
should be added to the glycine or placebo dose. Each dose will include both the bottle of glycine 
or placebo and individual packets of lemon crystals and Splenda. Each dose will be labeled by 
the pharmacy with the date, dose (breakfast, lunch, dinner) and instructions (for example, fill the 
bottle with cold water to the fill line, shake, pour into a glass, add lemon crystals and Splenda. 
May be mixed with ice in a blender. Drink over a 15-20 minute period after a meal). Each dose 
will be in a self-contained package with instructions. Two weeks worth of doses will be FedEx’ed 
to you at a time by the McLean Pharmacy. The amount of glycine or placebo in each drink will 
gradually be increased until you are receiving 0.8 grams/kg/d of body weight. You will take a 
dose of glycine or placebo three times/day, after each meal. You will be given a log and asked 
to fill in the date and time of day that you took each dose of glycine or placebo. 
 
While you are at McLean for the scans, you will meet with the pharmacist and Dr. Levy and we 
will review exactly what to do to make the glycine drink, including a demonstration. 
 
Phone Calls with Dr. Levy and Dr. Bodkin or Dr. Ongur 


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Subject Identification 
At least once every week, you will receive a phone call from Dr. Levy to discuss how you are 
feeling. At the end of the first week of glycine or placebo, and at the end of weeks 3, 5, 9, 11, 
and 13 (more often if necessary), you will also be called by a study physician (Dr. Bodkin or Dr. 
Ongur) to assess how you are reacting to the glycine or placebo.  Your psychiatrist will also be 
monitoring your clinical state and side effects throughout the study. Your internist will be 
informed when the glycine-placebo and open-label glycine periods begin. 
 
You will also receive a phone call from Dr. Levy each week during the two weeks following 
glycine or placebo to discuss how you are feeling. You may be called by a study physician (Dr. 
Bodkin or Dr. Ongur) to follow up on your conversation with Dr. Levy if it seems medically 
necessary. 
 
Clinical Assessments  
In addition, every two weeks there will be a one-hour clinical assessment using a secure skype-
like connection (weeks 2, 4, 6, 8, 10, 12, 14, 16). In order to protect your confidentiality, you will 
not be using your usual skype credentials. Partners Collaborative Media, which is affiliated with 
McLean Hospital, will create generic credentials for you and will ensure that your computers and 
web cameras are secure. You will be provided with any additional hardware and software that 
are needed at no cost to you. The movement examination will also be repeated using a secure 
skype-like connection at the end of weeks 6 and 14. The neuropsychological tests will also be 
re-administered at the end of weeks 6 and 14 in the city in which you live.  You will be 
periodically weighed and your weight recorded. 
 
Blood Work 
Before the first treatment period, at the end of each treatment period, two weeks after the end of 
each treatment period, there will be blood work at a local medical center. This blood work is to 
measure the levels of various chemicals (such as glycine) in your blood as well as the level of 
psychiatric medications in your blood. The amount of blood drawn on each occasion will be 113 
or 114 cc (less than 4 ounces). These blood samples will be sent to the Nathan Kline Institute in 
Orangeburg, NY, where they will be analyzed for various amino acid levels and psychotropic 
medication levels. By signing this consent form, I give permission for Dr. Raymond Suckow and 
the Nathan Kline Institute to provide Dr. Levy and her colleagues with the results of the analyses 
of any blood samples that were performed at NKI. I also give permission for the Clinical 
Laboratories at McLean Hospital and the medical center of the city in which I live to provide Dr. 
Levy and her colleagues with the results of any blood tests that were performed at their 
facilities.  Throughout the study, you will continue to take all of your other medications as usual. 
 
Open-Label Glycine 
At the end of these 16 weeks, there will be two weeks of no treatment. This will be followed by 6 
weeks when you are on glycine (this 6-week period may or may not occur immediately after you 
finish the 16 weeks on glycine-placebo combination).  The McLean Pharmacy will prepare 
plastic containers containing glycine powder. Each container will be marked with a fill line, 
indicating how much water should be added to the glycine dose. Each dose will include both the 
container and individual packets of lemon crystals. Each dose will be labeled by the pharmacy 
with the date, dose (breakfast, lunch, dinner) and instructions (for example, fill the bottle with 


McLean Hospital 
Research Consent Form 
 
 
 
General Template 
Version Date:  June 2009 
 
 
 
 
Version 7 – 11/11/2012                                    Page 8 of 17 
 
Subject Identification 
cold water to the fill line, shake, pour into a glass, add lemon crystals and Splenda. May be 
mixed with ice in a blender. Drink over a 15-20 minute period after breakfast). Each dose will be 
in a self-contained package with instructions. Two weeks’ doses will be FedEx’ed to you at a 
time by the McLean Pharmacy. The amount of glycine in each drink will gradually be increased 
until you are receiving 0.8 grams/kg/d of body weight. You will take a dose of glycine three 
times/day after meals. 
 
Phone Calls with Dr. Levy and Dr. Bodkin or Dr. Ongur 
At least once every week, you will receive a phone call from Dr. Levy to discuss how you are 
feeling. At the end of the first week of glycine, and at the end of weeks 3 and 5, you will also be 
called by a study physician to assess how you are reacting to the glycine.  
 
You will also receive a phone call from Dr. Levy each week during the two weeks following 
glycine to discuss how you are feeling. You may be called by a study physician (Dr. Bodkin or 
Dr. Ongur) to follow up on your conversation with Dr. Levy if it seems medically necessary. 
 
Clinical Assessments 
In addition, every two weeks there will be a one-hour clinical assessment using secure skype-
like video conferencing. You will be periodically weighed and your weight recorded. 
 
Repeat Scans, Electroencephalogram, Neuropsychological Tests, Clinical Assessment, and 
Blood Work 
At the end of week 5, you will be flown to Boston to repeat the original set of brain imaging 
scans (but not the one involving glycine), the movement examination, clinical assessment, and 
the neuropsychological test assessment. The same blood work described above will be 
repeated. The amount of blood drawn will be 113 or 114 cc (less than 4 ounces). These blood 
samples will be sent to the Nathan Kline Institute in Orangeburg, NY, where they will be 
analyzed for various amino acid levels and psychotropic medication levels. 
 
Participation in each part of this study is completely voluntary. You may refuse to participate or 
withdraw at any time without jeopardy to the medical care you will receive at this institution. 
Should you choose to withdraw, you will notify Dr. Levy or the research staff. If you withdraw in 
the middle of the glycine study after blood has been withdrawn, Dr. Levy or her colleagues may 
request that you remain in the facility until it is safe for you to travel. This restriction is for your 
safety. Dr. Levy and her colleagues, or the FDA can remove you from the study at any time if it 
is determined that this is in your best interest or the best interest of the study.  
 
Discontinuation of the Study 
Although it is unlikely that you will experience side effects warranting permanent discontinuation 
of the study, it may be slowed down (slower dose increases, temporary discontinuation) if you 
develop side effects such as GI upset, nausea, or vomiting. If you develop side effects that 
make you too uncomfortable or that make it medically necessary to discontinue the study, the 
study will be stopped. 
 
What are the risks and possible discomforts from being in this research study? 


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There may be unknown risks in taking part in the study. 
 
Confidentiality 
One potential risk is a breach of your confidentiality. This could lead your employer, insurance 
company, or others to find out that you participated in a research study.  
 
Steps we take to prevent this are as follows: 
 
Appropriate precautions will be taken to preserve confidentiality and your privacy. Your private 
health information is maintained in a secure manner and your identity is never associated with 
research records, which are assigned an alpha-numeric code that is kept in a password-
protected file. However, there is some risk that identifying personal information could be shared 
or intercepted. Risks also include compromising identifying personal information on computers 
and compromising study documents with identifying information. These risks will be minimized 
by storing your data and personal information on a password protected computer or in a locked 
filing cabinet in a locked office that will be accessible only to study staff. 
 
MRI/MRS 
MRI/MRS technology does not use ionizing radiation. Instead, it uses strong magnetic fields and 
radio waves to collect the images and data. 
 
There are no known hazards or risks associated with MR techniques. Significant risks may exist 
for people with: 
Cardiac pacemakers 
Metal clips on blood vessels (also called stents) 
Artificial heart valves 
Artificial arms, hands, legs, etc. 
Brain stimulator devices 
Implanted drug pumps 
Ear implants 
Eye implants or known metal fragments in eyes 
Exposure to shrapnel or metal filings (wounded in military combat, sheetmetal workers, welders, 
and others) 
Other metallic surgical hardware in vital areas 
Certain tattoos with metallic ink (please tell us if you have a tattoo) 
Certain transdermal (skin) patches such as NicoDerm (nicotine for tobacco dependence), 
Transderm Scop (scopolamine for motion sickness), or Ortho Evra (birth control) 
Metal containing IUDs 
 
If you are unsure whether you have any of these items in your body, you should know that most 
would have been implanted as part of a surgical procedure. So, trying to remember any past 
operations may help you remember. You will be asked whether you have any implanted devices 
or history of exposure to shrapnel or metal filings, and if so, you will not be able to participate in 
this study. 


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Significant risks also can arise if certain materials (many types of metal objects) are brought into 
the scanning area, as they can be pulled into the magnet at great speed. Such items can cause 
serious injury if they hit you. Therefore, these types of items are not permitted in the scanning 
area. You will not be allowed to bring anything with you into the scanning room. The MR exams 
are painless, and except for pulsating sounds, you will not be aware that scanning is taking 
place. 
 
3T scanners are approved by the FDA for routine clinical studies in children or adults. Although 
there are no known risks from these scans, there could be adverse effects that are delayed or 
very mild, such that they have not yet been recognized. Most people experience no ill effects 
from these scans, but some people do report claustrophobia (fear of being in enclosed small 
spaces), dizziness, mild nausea, headaches, a metallic taste in their mouth, double vision, or 
sensation of flashing lights. These symptoms, if present, disappear shortly after leaving the 
scanner. 
 
Unlike a standard clinical MRI scanner (1.5 or 3 Tesla), one scan of the present study will be 
conducted in a high field (4T) MRI Scanner. This scanner is not used for routine clinical studies 
in children or adults, but the FDA has determined (July 14, 2003) that scanners with a magnetic 
field strength of less than 8 Tesla (double this scanner) or less do not represent a significant risk 
to adults, children, or infants aged more than 1 month. There could be adverse side effects that 
are delayed or very mild, such that they have not been recognized. Most people experience no 
ill effects from 4T scans, but some people do report claustrophobia (fear of being in enclosed 
small places), dizziness, and the other symptoms described in the previous paragraphs. These 
symptoms, if present, disappear shortly after leaving the scanner. No serious effects have been 
reported to date at any site operating at 4T strength. 
 
In rare cases, a very slight, uncomfortable tingling of the back due is induced in some people 
undergoing certain types of scans. If you experience this sensation, you are asked to report this 
immediately so the scan can be stopped. Although these precautions will avoid all known risks 
associated with MRI, this procedure may involve risks to you that are currently unforeseeable. 
The sounds that you hear inside the scanner are the normal operating sounds the scanner 
makes while it takes pictures of your brain. While they may be annoying, their intensity is not 
harmful to your hearing. However, you will be given a pair of earplugs to wear to muffle the 
sounds. You also may be asked to wear a set of headphones, which further reduces the noise 
level and permits the technician to speak to you. 
 
Women of childbearing age: 
While there are also no known risks for fetuses, the safety of MRI for pregnant women, women 
of childbearing potential, and nursing mothers has not been established. If you are a woman of 
childbearing potential, you must be using an IUD, oral contraceptive, or barrier methods or must 
be abstinent prior to each MRI scan. In addition, you must have a negative pregnancy test prior 
to each MRI scan. Nursing mothers may not participate in any brain imaging procedures. 
 
 


McLean Hospital 
Research Consent Form 
 
 
 
General Template 
Version Date:  June 2009 
 
 
 
 
Version 7 – 11/11/2012                                    Page 11 of 17 
 
Subject Identification 
Glycine 
Glycine is a dietary supplement. Side effects that have been associated with glycine include 
fatigue, stomachache, and vomiting (>10% of subjects in a prior study). Very rarely, (<1% of 
subjects), individuals who have a genetic abnormality that prevents them from metabolizing 
glycine normally may develop dangerously high blood glycine levels. To our knowledge, you do 
not have such an abnormality. Glycine is generally well tolerated without any negative effects. In 
research studies in which people consumed doses of glycine similar to (and even higher) than 
those used in this study, and for longer time periods, blood glycine levels rose, but no side 
effects occurred. In prior research studies we have conducted, 2/14 (14.3%) people who 
consumed more than 30 grams of glycine at one time developed nausea and vomiting. For that 
reason, the maximum glycine dose used in the glycine imaging study is 30 grams. The glycine 
mixture contains 300 calories per serving for a total of 900 calories per day. You may gain 
weight. 
 
You may receive a bruise at the site of the catheter and your arm may be sore for a few hours 
after the catheter sticks. There is also the risk of infection at the site of blood withdrawal, but 
standard aseptic techniques will be used making this an unlikely event (<1% of subjects). 
 
Neuropsychological Test Procedures 
No adverse effects of the neuropsychological procedures are expected, but the testing may be 
tiring. 
 
Glycine-Placebo Treatment 
During the glycine-placebo treatment period and the open label-glycine treatment period: When 
you are taking glycine, you may experience nausea and vomiting, but this is unlikely. In 
research studies in which people consumed the same dose of glycine (0.8 g/kg/d) side effects 
were not common. If you experience any side effects, you must report them to Dr. Levy 
immediately (617-855-2854 or page through the McLean Hospital operator at 617-855-2000) so 
the dose can be lowered or the treatment period ended. If you are unable to reach Dr. Levy, you 
may also contact Dr. Alexander Bodkin at 617-855-3186 M-F 9-5 (can also be paged through 
617-855-2000), Dr. Dost Ongur at 617-855-3922 M-F 9-5 (can also be paged through 617-855-
2000), or Dr. Marc Kaufman at 617- 855-3469 M-F 9-5. Should you experience vomiting, you 
should go to your nearest emergency room and tell the medical staff that you are taking glycine 
as part of a research study. 
 
Blood Tests  
During the glycine-placebo and open-label glycine phases of the study, you will receive multiple 
blood tests. You are asked not to donate blood for at least one month after completion of the 
study. 
 
You will be told of any significant new findings that develop during the course of this study that 
may relate to your willingness to continue to participate. 
 
You may end any of these procedures at any time without penalty to current or future treatment. 
 


McLean Hospital 
Research Consent Form 
 
 
 
General Template 
Version Date:  June 2009 
 
 
 
 
Version 7 – 11/11/2012                                    Page 12 of 17 
 
Subject Identification 
What are the possible benefits from being in this research study? 
There are no direct benefits to participating in this research. The information obtained in this 
study may to explain the effects of a mutation in glycine metabolism on brain structure, function, 
and metabolism. One potential benefit of participating in this research is that structural scans 
obtained for this research will be analyzed by a radiologist and significant findings will be 
reported to you.  An additional potential benefit is that glycine may reduce your psychotic 
symptoms and improve your cognitive abilities. 
 
What other treatments or procedures are available for my condition? 
You may choose not to participate in any of these procedures and continue to receive standard 
psychiatric care. The treatment provided in this study, Glycine, is a nutritional supplement that 
may be available to you without taking part in this study. 
 
 
 
Can I still get medical care within McLean if I don’t take part in this research study, or if I 
stop taking part?  
Yes.  Your decision won’t change the medical care you get within McLean now or in the future.  
There will be no penalty, and you won’t lose any benefits you receive now or have a right to 
receive. 
 
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  We will tell you if we learn new 
information that could make you change your mind about taking part in this research study. 
 
What should I do if I want to stop taking part in the study? 
 
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed. 
 
It is possible that we will have to ask you to drop out before you finish the study.  If this 
happens, we will tell you why.  We will also help arrange other care for you, if needed. 
 
Will I be paid to take part in this research study? 
Yes. You will be paid $2,000 for completing these procedures, $1,000 for completing the 
baseline procedures and $1,000 for completing the glycine treatment studies and the follow-up 
procedures. If you do not complete the study, you will be compensated for the procedures that 
you did complete. All of your travel, lodging, food and local transportation expenses will also be 
paid.  
 
As an identifier for internal auditing purposes, your social security number is needed because 
you are receiving payment for participation in this study.  McLean Hospital is required to inform 
the IRS of any payments to you as a subject in research studies in a given calendar year 
totaling $600 or more.  If that occurs, you will receive a 1099 form at the end of the year.  No 
information identifying why you received payment is communicated to either the Hospitals 
accounting department or the government.  This information is kept strictly confidential. 
 


McLean Hospital 
Research Consent Form 
 
 
 
General Template 
Version Date:  June 2009 
 
 
 
 
Version 7 – 11/11/2012                                    Page 13 of 17 
 
Subject Identification 
What will I have to pay for if I take part in this research study? 
Study funds will pay for the cost of all of the research procedures, including your travel, lodging, 
food, and local transportation expenses while you are participating. 
 
What happens if I am injured as a result of taking part in this research study? 
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer. 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form. 
 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the next section of this consent form. 
 
For the blood draws at Bozeman Medical Center, McLean Hospital will not be involved in 
mitigation of any injuries that may occur. 
 
If I have questions or concerns about this research study, whom can I call? 
You can call us with your questions, concerns or complaints.  Our telephone numbers are listed 
below.  Ask questions as often as you want.  
 
Deborah L. Levy, Ph.D., is the person in charge of this research study.  You can call her at 617-
855-2854. Dr. Levy is available M-F 9-5 and can be paged 24/7 through the McLean Hospital 
operator by calling 617-855-2000.  You can also call Dr. Alexander Bodkin at 617-855-3186 M-F 
9-5, Dr. Dost Ongur at 617-855-3922 M-F 9-5 or Dr. Marc Kaufman at 617- 855-3469 M-F 9-5. 
Any of these people can also be reached through the McLean Hospital operator (617-855-2000) 
24/7. If you have questions about the scheduling of appointments or study visits, call Dr. Levy at 
617-855-2854. 
 
If you want to speak with someone not directly involved in this research study, please contact 
the McLean Human IRB office.  You can call them at 617-855-2932. 
 
You can talk to them about: 
 
Problems and questions that you may have 
 
Information that you may want 
 
Input or suggestions that you may have 
 
Your rights as a research subject 
 
Your concerns about the research 
 
A complaint about the research 
 


McLean Hospital 
Research Consent Form 
 
 
 
General Template 
Version Date:  June 2009 
 
 
 
 
Version 7 – 11/11/2012                                    Page 14 of 17 
 
Subject Identification 
Also, if you feel pressured to take part in this research study, or to continue with it, they want to 
know and can help. 
 
If I take part in this research study, how will you protect my privacy? 
Federal law requires McLean Hospital, its health care providers and researchers to protect the 
privacy of health information that identifies you.  This information is called Protected Health 
Information.  In the rest of this section, we refer to this simply as “health information.” 
 
If you decide to take part in this research study, your health information may be used within 
McLean and may be shared with others outside of McLean, as explained below. 
 
In addition, to protect the study participants and prevent any potential risk to the participants’ 
privacy, Dr. Levy will apply for a Certificate of Confidentiality from the Department of Health and 
Human Services.  To reduce the possibility that information learned from DNA/RNA studies will 
affect the subject’s access to health insurance or employability, no research study data will be 
included in the subject’s medical records.  Further, with the Certificate of Confidentiality from 
DHHS, the PI cannot be forced (e.g., by court subpoena) to disclose information that may 
identify a study participant in any federal, state, or local criminal, administrative, legislative, or 
other proceeding. 
 
We have marked with a 
 how we plan to use and share your health information.  If a 
box is not checked 
, it means that type of use or sharing is not planned for in this 
research study.  
 
We will also give you the McLean Hospital Notice for Use and Sharing of Protected Health 
Information.  The Notice gives more details about how we use and share your health 
information. 
 
 
Health Information About You That Might be Used or Shared During This Research 
 
Information from your hospital or office health records within McLean or elsewhere 
that may be reasonably related to the conduct and oversight of the research study.  
This may include information about hospital admissions or visits during this study, 
so that we know about any possible problems or side effects.  If health information 
is needed from your doctors or hospitals outside McLean, you will be asked to give 
permission for these records to be sent to researchers within McLean. 
 
New health information from tests, procedures, visits, interviews, or forms filled out 
as part of this research study 
 
 
Why Health Information About You Might be Used or Shared with Others 
The reasons we might use or share your health information are: 
 
To do the research described above 


McLean Hospital 
Research Consent Form 
 
 
 
General Template 
Version Date:  June 2009 
 
 
 
 
Version 7 – 11/11/2012                                    Page 15 of 17 
 
Subject Identification 
 
To make sure we do the research according to certain standards - standards set 
by ethics and law, and by quality groups 
 
For public health, and safety - for example, if we learn information that could mean 
harm to you or others, we may need to report this to a public health or public 
safety authority, or to specific individuals as required by law 
 
For treatment, payment, or health care operations 
 
 
People and Groups That May Use or Share Your Health Information 
1. People or groups within McLean 
 Researchers and the staff involved in this research study 
 The McLean review board that oversees the research 
 Staff within McLean who need the information to do their jobs (such as billing, or 
for overseeing quality of care or research) 
2. People or groups outside McLean 
 People or groups that we hire to do certain work for us, such as data storage 
companies, our insurers, or our lawyers 
 Federal and state agencies (such as the U.S. Department of Health and Human 
Services, the Food and Drug Administration, the National Institutes of Health, 
and/or the Office for Human Research Protections) and other U.S. or foreign 
government bodies, if required by law or involved in overseeing the research 
 Organizations that make sure hospital standards are met 
 The sponsor(s) of the research study, and people or groups it hires to help 
perform this research study  
 Other researchers and medical centers that are part of this research study 
 A group that oversees the data (study information) and safety of this research 
study 
 Other:  
Some people or groups who get your health information might not have to follow the 
same privacy rules that we follow.  We share your health information only when we 
must, and we ask anyone who receives it from us to protect your privacy.  However, 
once your information is shared outside McLean, we cannot promise that it will remain 
private. 
 
 
Time Period During Which Your Health Information Might be Used or Shared With 
Others 
 
Because research is an ongoing process, we cannot give you an exact date when we 
will either destroy or stop using or sharing your health information. 


McLean Hospital 
Research Consent Form 
 
 
 
General Template 
Version Date:  June 2009 
 
 
 
 
Version 7 – 11/11/2012                                    Page 16 of 17 
 
Subject Identification 
 
 
Your Privacy Rights 
 
You have the right not to sign this form permitting us to use and share your health 
information for research.  If you don’t sign this form, you can’t take part in this research 
study.  This is because we need to use the health information of everyone who takes 
part in this research study. 
 
You have the right to withdraw your permission for us to use or share your health 
information for this research study.  If you want to withdraw your permission, you must 
notify the person in charge of this research study in writing. 
If you withdraw your permission, we will not be able to take back information that has 
already been used or shared with others.  This includes information used or shared to 
carry out the research study or to be sure the research is safe and of high quality. 
If you withdraw your permission, you cannot continue to take part in this research study. 
 
You have the right to see and get a copy of your health information that is used or 
shared for treatment or for payment.  To ask for this information, please contact the 
person in charge of this research study.  
 
In this research study, you may only get such health information after the research is 
finished. 
 
If Research Results Are Published or Used to Teach Others 
The results of this research study may be published in a medical book or journal, or used to 
teach others.  However, your name or other identifying information will not be used for these 
purposes without your specific permission. 
 
Informed Consent and Authorization 
Statement of Study Doctor or Person Obtaining Consent 
 
 
I have explained the research to the study subject. 
 
I have answered all questions about this research study to the best of my ability. 
 
 
 
 
 
 
Study Doctor or Person Obtaining Consent 
Date/Time 
 
 
Statement of Person Giving Informed Consent and Authorization 
 
 
I have read this consent form. 


McLean Hospital 
Research Consent Form 
 
 
 
General Template 
Version Date:  June 2009 
 
 
 
 
Version 7 – 11/11/2012                                    Page 17 of 17 
 
Subject Identification 
 
This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the 
study. 
 
I have had the opportunity to ask questions. 
 
I understand the information given to me. 
 
 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my health information to 
be used and shared as described above. 
 
 
 
 
 
 
Subject 
Date/Time 
 
 
Consent Form Version Date:  11/11/2012 
 
 

Prot_002.pdf: 
 
Official Title: Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders 
 
NCT number:  NCT01720316 
 
Document Date: 10/2/2012 
 


BWH/MGH Human Subjects Research Application Form 
 
 
Filename: Protocol Summary 
Version 4:  Revised November 2001 
VERSION 3_10_02_2012 
Page 1 
 
 
Answer all questions accurately and completely in order to provide the McLean Hospital IRB with 
the relevant information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Deborah L. Levy, Ph.D. 
 
PROTOCOL TITLE 
Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders 
 
FUNDING 
NIMH 
 
VERSION DATE 
11/2009 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
We propose to (1) characterize the molecular, neurocognitive, and brain structural, functional 
and neurochemical properties of this mutation by carrying out targeted neurobiological follow-up 
of mutation carriers and non-carriers in this family and (2) to target the GLDC mutation by trying 
to normalize brain Gly levels using Gly augmentation.   
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
Multiple rare structural variants of relatively recent evolutionary origin are recognized as 
important risk factors for schizophrenia (SZ) and other neurodevelopmental disorders [e.g., 
autism spectrum disorders, mental retardation, epilepsy with odds ratios as high as 7-30 (Sebat 
et al. 2009; Malhotra et al. 2011; Heinzen et al. 2010; Weiss et al. 2008; McCarthy et al. 2009). 
We have found a de novo structural rearrangement on chromosome 9p24.1.  In addition to other 
genes, the duplicated region contains the gene encoding glycine decarboxylase (GLDC), which 
affects brain glycine (Gly) metabolism. Here we focus on the potential contributions of this gene 
to abnormal glycine homeostasis and N-methyl-D-aspartate receptor (NMDAR) dysfunction in 
SZ. This mutation is an obvious ‘smoking gun.’  GLDC encodes the glycine decarboxylase or 
glycine cleavage system P-protein, which is involved in degradation of glycine (Gly) in glia cells.  
Carriers of the GLDC triplication would be expected to have low levels of brain Gly, resulting in 
NMDA receptor-mediated hypofunction, which has been strongly implicated in the 
pathophysiology of SZ (Olney & Farmer, 1995; Coyle, 2006; Javitt, 2007). Individuals with 
mutations that lower brain Gly or alter other aspects of glutamatergic transmission are obvious 
candidates for Gly augmentation or complementary NMDAR modulatory strategies, which have 
been used with varying degrees of success Goff et al. 1999; Javitt et al. 2001; Lane et al. 2005; 
Heresco-Levy et al. 2004; Buchanan et al. 2007). Genetic risk factors, including variants that 
impact the synthesis and breakdown of Gly, are likely to contribute to this variability.  


McLean Hospital IRB Application Form 
 
 
Filename: Protocol Summary 
Version Date:  June 2009 
VERSION 4_10_02_2012 
 
 
 
3 
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be 
enrolled by researchers study-wide and by McLean researchers.  Provide a brief 
summary of the eligibility criteria (for example, age range, gender, medical condition).  
Include any local site restrictions, for example, “Enrollment at McLean will be limited to 
adults although the sponsor’s protocol is open to both children and adults.”
The total projected sample size is 4, consisting of two carriers of a 9p24.1 mutation and two 
non-carriers from the same family. The two carriers have diagnoses of bipolar disorder with 
psychotic features and schizo-affective disorder and will be recruited as outpatients.  The two 
non-carriers do not have diagnoses of a psychotic disorder. The age range is 21-59 and 
includes two males and two females.  
 
Design of the study: 1) baseline procedures at McLean: physical exam (Dr. Ongur), EKG, 
movement disorders (extrapyramidal side effects, tardive dyskinesia - AIMS/SAS – Dr. Bodkin) 
(Guy, 1976; Simpson & Angus, 1970), structural MRI, Proton 1H MRS for GABA, glutamate, 
glutamine and GABA levels, pre-and post-glycine loading Proton 1H MRS scans and 5 cc blood 
samples at (pre, 20, 40, 60, 90, 120, 150, 180, 210, and 240 minutes post-Gly loading), clinical 
ratings (PANSS, Clinical Global Impression scale, Brief Psychiatric Rating Scale, Young Mania 
Rating Scale, HAM-D), neurocognitive testing (MATRICS Consensus Cognitive Battery-MCBB), 
and urinalysis and plasma levels [SMA-20, large neutral & excitatory amino acid, kynurenic acid 
(KYNA), psychotropic drug plasma levels. Total blood independent of the samples obtained for 
the glycine loading scan: 90 cc for non-carriers; 113 and 114 cc for the carriers 
 
Dr. Ongur will be responsible for medical oversight of the imaging components of the study. Dr. 
Bodkin will be responsible for medical oversight of the glycine augmentation component of the 
study. 
 
Subjects will also be asked to inform their personal physicians about their participation and their 
exposure to glycine to ensure that all appropriate oversight for safety has been carried out. 
Each physician will be asked to provide a written statement indicating that he/she believes that 
there is no medical contraindication to the subject’s exposure to lemon juice or glycine. 
 
2) baseline procedures at Nathan Kline Institute (NKI): functional MRI, ERPs/EEGs  
 
All four subjects will receive the procedures described in 1) and 2) above, including the glycine 
loading imaging study. At the completion of steps 1 and 2), the participation of the two non-
carriers will be complete. Only the mutation carriers will participate in the procedures described 
below. 
 
3) Double-blind cross-over placebo-controlled oral Glycine (Gly) (titrated to a maximum of 0.8 
g/kg/d on a TID dosing schedule) (based on the subjects’ weights at date of initial screening) 
or Placebo (a mixture of Isomaltulose (Palatinose®), true lemon crystals, sucrolose) in the two 
mutation carriers: An FDA application for an IND will be obtained before initiation of this part of 
the study and the open-label glycine arm (see below) and approval documents will be submitted 
to the IRB. The placebo will look and taste like glycine. Only FDA approved products will be 
used. The same flavorings used for the glycine powder will be used for the placebo. The 
McLean Pharmacy will prepare and ship the glycine and placebo mixtures. Subjects will add the 
flavoring and a specified amount of cold water to the glycine or placebo immediately before 
drinking the dose to prevent changing the stability of the glycine.  If the subjects’ weights are 
substantially different by the time this part of the study is scheduled to take place, their revised 


McLean Hospital IRB Application Form 
 
 
Filename: Protocol Summary 
Version Date:  June 2009 
VERSION 4_10_02_2012 
 
 
 
4 
weights will be used in the calculation of the doses. The start of this arm will be set in 
collaboration with the pharmacist to make sure that there is adequate time to titrate the 
appropriate amounts of glycine. 
 
 
a) 6 weeks on Gly or placebo with clinical ratings at end of weeks 2, 4, and 6 using skype-like 
video conferencing; SMA-20, large neutral & excitatory amino acid, KYNA, and psychotropic 
drug plasma levels, movement disorders (113 and 114 cc) (AIMS/SAS - extrapyramidal side 
effects, tardive dyskinesia – using skype-like video conferencing) and MCCB, at the end of 
week 6 (MCCB will be administered by Dr. Levy in the subject’s city of residence and the blood 
samples for these assays will be obtained in the clinical lab of the local medical center, which 
will prepare and ship the samples to the Analytical Psychopharmacology Laboratory at NKI or 
perform other assays in house). The subjects are well known to the PI, who will be in touch with 
them by phone on a weekly basis or more often as needed. Both subjects’ psychiatrists will also 
be monitoring their clinical states and side effects throughout the study. In addition, at the end of 
the first week of glycine or placebo, and at the end of weeks 3, 5, 9, 11, and 13 (more often if 
necessary), the subjects will also be called by a study physician (Dr. Bodkin) to assess how they 
are reacting to the glycine or placebo. The subjects will be given emergency contact numbers 
for Drs. Levy, Bodkin, Ongur, and Kaufman. The subjects will also be told to go the nearest 
emergency room if they experience any acute side effects (e.g., vomiting). The patients’ usual 
psychotropic drug regimen will not be altered as part of the study, but an attempt will be made to 
keep those medications unchanged if possible. 
 
The McLean Pharmacy will order pharmaceutical grade glycine powder (10kg/box) from 
Ajinomoto North America, Inc. The glycine will be stored in closed containers in a dry area, 
avoiding humidity, sunlight and high temperature.  
 
The McLean Pharmacy will prepare the appropriate dose of glycine powder or placebo in a re-
closable plastic bottle. Each bottle will be marked with a fill line, indicating how much cold water 
should be added for the glycine or placebo dose to be dissolved as a 20% solution. Each dose 
will include both the container and individual packets of lemon crystals. Each dose will be 
labeled by the pharmacy with the date, dose (breakfast, lunch, dinner) and instructions (e.g., Fill 
with cold water to the fill line, shake, pour into a glass, add lemon crystals. Drink over a 15-20 
minute period after breakfast, lunch or dinner as relevant for that dose). Each dose will be in a 
self-contained package with instructions. Doses will be shipped in two- week supplies.  
 
It is anticipated that all of the glycine will be used. If additional glycine is needed and there is 
any unused glycine, it will be disposed of according to the instructions on the Material Safety 
Data Sheet, (item 13): “Dispose of the material as you would with a non-hazardous material in 
accordance with all applicable national, state and local regulations.” 
 
b) 2 weeks of no treatment, followed by clinical ratings at the end of week 8 using secure skype-
like video conferencing; SMA-20, large neutral & excitatory amino acid, KYNA, and psychotropic 
drug plasma levels (113 and 114 cc) 
 
c) 6 weeks on Gly or placebo with clinical ratings at end of weeks 10, 12, 14 using secure 
skype-like video conferencing; SMA-20, large neutral & excitatory amino acid, KYNA, and 
psychotropic drug plasma levels (113 and 114 cc), movement disorders (AIMS/SAS - 
extrapyramidal side effects, tardive dyskinesia – using skype-like video conferencing) and 
MCCB, at the end of week 6 (MCCB will be administered by Dr. Levy in the subject’s city of 
residence and the blood samples for these assays will be obtained in the clinical lab of the local 
medical center, which will prepare and ship the samples to the Analytical Psychopharmacology 
Laboratory at NKI or perform other assays in house). The PI will be in touch with the subjects by 


McLean Hospital IRB Application Form 
 
 
Filename: Protocol Summary 
Version Date:  June 2009 
VERSION 4_10_02_2012 
 
 
 
5 
phone on a weekly basis or more often as needed. Both subjects’ psychiatrists will also be 
monitoring their clinical states and side effects throughout the study. In addition, at the end of 
the first week of glycine or placebo (week 9), and at the end of weeks 11 and 13, the subjects 
will also be called by a study physician to assess how they are reacting to the glycine or 
placebo. This schedule of side effect monitoring can be more frequent, as needed. The subjects 
will be given emergency contact numbers for Drs. Levy, Bodkin, Ongur, and Kaufman. The 
subjects will also be told to go the nearest emergency room if they experience any acute side 
effects (e.g., vomiting). 
 
d) 2 weeks of no treatment, followed by clinical ratings at the end of week 16 using secure 
skype-like video conferencing and SMA-20, large neutral & excitatory amino acid, KYNA, and 
psychotropic drug plasma levels (113 and 114 cc).  
 
4) Open-label glycine: 6 weeks on a maximum dose of 0.8 g/kg/d (based on the subjects’ 
weights at date of initial screening) (titrated according to the attached titration schedule, TID 
dosing schedule) in a Gly powder-water mixture (dissolved as a 20% solution) prepared by the 
McLean pharmacy and sent by Fed Ex in 2-week supplies, which will be mixed with lemon 
crystals. Clinical ratings will be performed at the end weeks 2 and 4 using secure skype-like 
video conferencing. At the end of week 6, clinical ratings and MCCB will be performed at 
McLean, where the baseline procedures (structural MRI, MRS, but no glycine loading), will be 
repeated. Urinalysis, SMA-20, large neutral & excitatory amino acid, KYNA, and psychotropic 
drug plasma levels (113 and 114 cc) will be obtained at this time. An FDA IND will be obtained. 
The PI will be in touch with the subjects by phone on a weekly basis or more often as needed. 
Both subjects’ psychiatrists will also be monitoring their clinical states and side effects 
throughout the study. In addition, at the end of the first week of glycine or placebo, and at the 
end of weeks 3 and 5, the subjects will also be called by a study physician (Dr. Bodkin) to 
assess how they are reacting to the glycine or placebo. The subjects will also be given 
emergency contact numbers for Drs. Levy, Bodkin, Ongur, and Kaufman. The subjects will also 
be told to go the nearest emergency room if they experience any acute side effects (e.g., 
vomiting). If the subjects’ weights are substantially different by the time this part of the study is 
scheduled to take place, their revised weights will be used in the calculation of the doses. The 
start of this arm will be set in collaboration with the pharmacist to make sure that there is 
adequate time to titrate the appropriate amounts of glycine. 
 
During the 5th week of open-glycine treatment, the procedures described in sections 1) and 2) 
above will be repeated, with the exception of the physical examination, EKG, and glycine-
loading scan. SMA-20, large neutral & excitatory amino acid, KYNA, and psychotropic drug 
plasma levels (113 and 114 cc) will also be repeated 2 weeks after the end of the 6-week 
treatment period (week 8). 
 
The consent forms contain a provision for subjects to give permission for Dr. Javitt and the 
Nathan Kline Institute to provide Dr. Levy and her colleagues with the results of any tests that 
were performed at NKI, for Dr. Raymond Suckow and the Nathan Kline Institute to provide Dr. 
Levy and her colleagues with the results of the analyses of the blood samples analyzed at NKI, 
and for the Clinical Laboratories at McLean Hospital and at the medical center in the subjects’ 
home city to provide Dr. Levy and her colleagues with the results of any blood tests. 
 
Blood samples drawn at McLean or in the subject’s city of residence will be sent to the 
Analytical Psychopharmacology Laboratory at NKI for analysis (SMA-20, large neutral & 
excitatory amino acid, KYNA, and psychotropic drug plasma levels). The urinalyses and blood 
samples for lithium levels will be done either by the clinical lab of the local medical center or by 
the clinical lab at McLean. All samples will be coded with the subject’s 4-digit ID number, the 
date and the time of day. 


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Partners Collaborative Media (PCM) will provide oversight (for a fee) to ensure that the clinical 
assessments taking place every two weeks using skype-like video conferencing are secure (see 
additional details below; statement from PCM has been uploaded). 
 
Briefly describe study procedures.  Include any local site restrictions, for example, 
“Subjects enrolled at McLean will not participate in the pharmacokinetic portion of the 
study.”  Describe study endpoints.
Study procedures at McLean: 3T structural MRI scan; 4T Proton 1H MRS; serial 4T Proton 1H 
MRS scans pre-glycine loading and at +20, 40, 60, 90, 120, 150, 180, 210, and 240 minutes 
post-Gly loading, plasma samples for glycine at the same time points, MCCB, clinical ratings, 
urinalysis, physical exam, EKG. 
  
Study procedures at NKI: functional MRI, ERPs/EEGs  
 
For studies involving treatment or diagnosis, provide information about standard of care 
at McLean (e.g., BWH, MGH) and indicate how the study procedures differ from 
standard care.  Provide information on available alternative treatments, procedures, or 
methods of diagnosis.
Glycine augmentation has been used to try to enhance the antipsychotic and neurocognitive 
efficacy of standard antipsychotic drug treatment. It is not considered part of standard care. 
Glycine augmentation has shown variable efficacy in patients unselected for having a mutation 
that would be expected to lower brain Gly levels. In contrast, the GLDC triplication in the two 
carriers would be expected to result in unusually low brain Gly levels. Both carriers of the GLDC 
mutation are currently being treated with clozapine, which is known to increase glycine. 
However, in order to neutralize the excess dosage effect of the GLDC triplication, these patients 
should need more glycine augmentation than clozapine alone is likely to provide. In the absence 
of GLDC inhibitors that can directly target this mutation, the real issue is whether any 
augmentation strategy can keep up with the excess degradation of glycine. The most logical 
approach to a targeted treatment intervention would be to enhance NMDAR function using 
glycine site agonists. The primary advantage of oral glycine powder is that the dosing has been 
well worked out for optimizing potential treatment response, and it can be taken indefinitely. In a 
recent meta-analysis, it also had the best symptom improvement profile among NMDA 
enhancing agents (Tsai & Lin, 2010). D-serine performed pretty comparably to Gly, but it is 
unlikely to receive IRB approval for more than 12 weeks, because there are no long-term 
toxicity data. D-cycloserine can be used indefinitely, but as a partial agonist it is less efficacious 
than glycine or D-serine (Heresco-Levy & Javitt, 2004b; Tsai & Lin, 2010). Sarcosine, a weak 
GlyT1 inhibitor, is not currently available from manufacturers for efficacy studies.   
 
Describe how risks to subjects are minimized, for example, by using procedures which 
are consistent with sound research design and which do not unnecessarily expose 
subjects to risk or by using procedures already being performed on the subject for 
diagnostic or treatment purposes.
Glycine Augmentation Trials: Oral glycine has been widely used to augment standard 
psychotropic drug treatment and is well tolerated. By using a maximum daily dose of 0.8 
gm/kg/d TID (based on the subjects’ weights at date of initial screening) administered after 
meals, the dose will be well within the range of a glycine dose that is tolerated without undue 
adverse effects. If necessary, the dose can be lowered to minimize GI side effects. The subjects 
will be monitored closely by the research team and by their own psychiatrists. Blood 


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chemistries, including liver/kidney function tests, will be monitored at baseline and at the end of 
each treatment arm.   
 
The glycine-loading dose in the imaging study will be 0.4g/kg of body weight on the day of the 
scan (not to exceed 30 g). Dr. Kaufman has had considerable experience with this dose, which 
is substantially lower than peak doses of glycine used in his and others’ previous studies 
(0.8g/kg/day of body weight), was well tolerated and is designed to minimize the likelihood of 
side effects (e.g., nausea and vomiting). 
 
The imaging procedures have been used extensively at McLean and NKI without complications 
and subjects will be carefully screened. 
 
The PI has talked with all of the people involved in the study (Drs. Kaufman, Ongur, Bodkin, 
Javitt, Visschers, Vukovic; Mr. Rosen) to ascertain that they are all in agreement that the 
proposed plan for medical and/or psychiatric monitoring for the patients while they are taking a 
novel compound is adequate.  
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective 
criteria for removing a subject from the study, for example, objective criteria for 
worsening disease/lack of improvement and/or unacceptable adverse events.  The 
inclusion of objective drop criteria is especially important in studies designed with 
placebo control groups.
See below. 
 
FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include 
those related to drugs/devices/procedures being studied and/or administered/performed 
solely for research purposes.  In addition, include psychosocial risks, and risks related 
to privacy and confidentiality.  When applicable, describe risks to a developing fetus or 
nursing infant.
The procedures described above pose no serious physical risk to subjects and no 
psychological, social, or legal risks are anticipated.  
 
Although there are no known general risks associated with MRI scans, there are risks to 
individual subjects who have contraindications to MRI scanning, including those with metal 
implants in their body (pacemaker, aneurysm clips, metal screws and plates for orthopedic 
purposes, hearing implants, certain kinds of tattoos, sheetmetal workers with lodged metal 
fragments in the eyes).  Subjects are screened carefully and excluded if there are even 
suspected contraindications to scanning.  All subjects are asked to remove jewelry, belts and 
other metal-containing objects.  Surgical records will be retrieved prior to scan for subjects who 
have had metal placed in their body intra-operatively to ensure the hardware is MRI safe, even 
if the subject has been told the hardware is MRI-safe or if they have had MRI scans since the 
operation.  As an additional precaution, subjects are screened with a handheld metal-detection 
wand prior to the scan to ensure that no unidentified metal objects remain on the subject.  The 
noise generated by the pulsing of the gradients can lead to temporary decrease in hearing. 
The use of disposable earplugs is an easy and reliable means of preventing hearing loss. The 
risks associated with Specific Absorption Rate (SAR) are related to the fact that given a large 
enough SAR, heating of the tissue may occur. These experiments will comply with all FDA 
guidelines with regard to RF power deposition. There is also the potential risk of injury from a 
projectile (i.e., ferromagnetic objects being attracted into the magnet); and of asphyxiation due 


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to large amounts of cryogenic gases generated during a quench (i.e., the event which occurs 
when a magnet makes the sudden transition from superconducting to resistively conducting). 
Routine safety procedures are in place at both scanning centers to screen subjects prior to 
scanning, maintain security of the restricted access areas, and ensure that system security 
features are in good working order. Both imaging centers associated with this study (McLean, 
NKI) are very experienced with MRI scanning and have impeccable safety records. The effects 
of MRI on the fetus are not well characterized. Therefore, females of childbearing age must be 
sexually inactive or be using a contraceptive measure for three months prior to being scanned.  
A urine test will be used to establish that the one female of childbearing age is not pregnant. 
 
The scans involve use of a standard clinical MRI scanner (3T) as well as a high field (4T) MRI 
scanner. The 4T scanner is not used for routine clinical studies in children or adults, but the 
FDA has determined (July 14, 2003) that scanners with magnetic field strengths of less than 8 
Tesla do not represent a significant risk to adults, children, or infants older than 1 month. 164 
Most people experience no ill effects from 3T or 4 T scans, but some do report claustrophobia, 
dizziness, mild nausea, headaches, a metallic taste in their mouth, back tingling, double vision, 
or sensation of flashing lights.  These symptoms, if present, disappear shortly after leaving the 
scanner.  During the scan, the examiner can see and hear the subjects and will ask them to 
report any problems so the scan can be stopped if necessary.  A magnetic resonance scan may 
be uncomfortable due to claustrophobia, lying still for an hour, or loud sounds. Subjects who 
express serious concern about these will not be included. The scan will be stopped if the subject 
expresses discomfort. Total time in the scanner for the structural scan and 2 MRS scans at 
McLean is 150 minutes, with breaks occurring between scans (structural: 15 minutes; 
MEGAPRESS: 60 minutes; J-PRESS: 75 minutes).  Total time for the structural and fMRI scan 
at NKI is I hour. The glycine-loading scan requires multiple scans over the 4 hour period in the 
scanner. Subjects will be allowed to leave the scanner between scans and can be re-positioned 
for the next scan, as described in the application. All four subjects have successfully completed 
imaging procedures. 
 
The glycine-loading dose in the imaging study will be 0.4g/kg (not to exceed 30 g). Dr. Kaufman 
has had considerable experience with this dose, which is substantially lower than peak doses of 
glycine used in his and others’ previous studies (0.8g/kg/day of body weight), was well tolerated 
and is designed to minimize the likelihood of side effects (e.g., nausea and vomiting). The 
maximum dose of 30g is substantially lower than the dose used in Dr. Kaufman’s previous study 
(Kaufman et al. 2009). 
 
Glycine Augmentation Clinical Trial: Pharmaceutical grade glycine (Ajinomoto) will be used. 
Glycine powder-water mixtures (dissolved in 20% solution) will be prepared by the McLean 
Hospital pharmacy. The dose of glycine will be slowly titrated until a maximum dose of 0.8 
g/kg/d (based on the subjects’ weights at date of initial screening )(administered TID after 
meals) is reached. This dose is well within the range of doses that were well tolerated in 
previous patient studies (Goff et al. 1999; Heresco-Levy et al. 1996, 1999, 2004). The most 
common side effect is mild gastrointestinal distress, which is reversible upon discontinuation, 
should that be necessary. At a mean dose similar to that proposed here, 82% and 95% of 
patients, respectively, completed the clinical trial (Heresco-Levy et al. 1999, 2004). No adverse 
effects on kidney, liver, hematology or blood chemistry values were observed over a 6-week 
period. If necessary, the dose can be lowered to minimize GI side effects. The subjects will be 
monitored closely by the research team and by their own psychiatrists. Blood chemistries, 
including liver/kidney function tests, will be monitored at baseline and at the end of each 
treatment arm.  If the subjects’ weights are substantially different by the time this part of the 
study is scheduled to take place, their revised weights will be used in the calculation of the 
doses. The start of this arm will be set in collaboration with the pharmacist to make sure that 
there is adequate time to titrate the appropriate amounts of glycine. 


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Periodic blood samples and the IV involve the slight discomfort of a needle stick and the small 
risk of a bruise. Every attempt is made to have the subject feel comfortable and at ease with the 
environment and the staff. Subjects are debriefed at the end of the day by the study coordinator 
at which time they can ask questions and express their reactions to the study. Subjects who 
wish to discontinue the study may withdraw at any time. 
 
Other than the paste used to adhere ERPs/EEGs electrodes to the scalp, no discomforts or 
risks should be incurred from these procedures, which are quite routine.  
 
Risks to privacy and confidentiality are minimal. All subjects are assigned a random4-digit ID 
number, which is used to code all material.  
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
The general goal of this study is to clarify the neurobiology of a mutation in glycine mutation and 
to determine whether carriers of this mutation may preferentially benefit from glycine 
augmentation of their medication regimen. Although subjects receive no immediate benefit from 
the brain imaging and ERP/EEG procedures beyond contributing to important research and 
reasonable monetary compensation for the time commitment, the potential scientific yield could 
have a major impact on identifying causal mechanisms in psychotic disorders. If the glycine 
augmentation is beneficial, these two subjects may experience a significant reduction in 
psychotic symptoms and improvement in neurocognition, which may also help other subjects 
with mutations impacting the glycine metabolic pathway.  
 
EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
The only scientific and ethical justification for including subjects in this study is if their 
participation can help to clarify the neurobiology of a mutation in glycine metabolism and if they 
might benefit from glycine augmentation. All other subjects are excluded. Therefore, the only 
eligible participants are two carriers of a specific genetic mutation who also have a diagnosis of 
a psychotic disorder or clinically unaffected members of the same family.  
 
When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.
N/A 
 


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For guidance, refer to the following McLean policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
           
RECRUITMENT PROCEDURES 
Explain in detail the specific methodology that will be used to recruit subjects.  
Specifically address how, when, where and by whom subjects will be identified and 
approached about participation.  Include any specific recruitment methods used to 
enhance recruitment of women and minorities.
The subjects have already been identified and recruited by the PI and have agreed to 
participate. They were selected on the basis of either having a mutation involving an 
abnormality in glycine metabolism that may be implicated in psychotic disorders, or being a 
family member who does not have this mutation. Prior to beginning the study, subjects will be 
called by the PI and all of the procedures and time frames will be re-reviewed. The subjects will 
be flown to Boston for the McLean procedures and will travel by train (with Dr. Levy) to NY for 
the NKI procedures. The procedures will be scheduled well in advance to minimize 
inconvenience to the subjects and to optimize successful data collection at McLean and NKI.  
 
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available
Each of four subjects will be paid $1,000 for completing the baseline procedures (structural and 
spectroscopy scans, glycine loading spectroscopy, and the MATRICS Consensus Cognitive 
Battery (MCCB) at McLean, followed by fMRI and ERP/EEG procedures at NKI.  These 
procedures will involve 1.5 weeks away from work, school and other responsibilities. Two 
subjects will be paid an additional $1000 after a 16-week double-blind placebo controlled trial of 
oral glycine, followed by 6 weeks of open-label glycine, at the end of which structural and 
spectroscopy scans and the MATRICS battery will be repeated at McLean and fMRI and 
ERP/EEG procedures will be repeated at NKI, again necessitating 1.5 weeks away from work, 
school and other responsibilities. All expenses incurred as part of participating (e.g., travel, 
hotel, local transportation, and meal costs) will be paid for by the grant supporting this study. 
 
For guidance, refer to the following McLean IRB policies 
http://irb.mclean.harvard.edu/investigators/policy/: 
          Recruitment of Research Subject
         Guidelines for Advertisements for Recruiting Subjects
         Remuneration for Research Subjects
          
 
 
CONSENT PROCEDURES 
Explain in detail how, when, where, and by whom consent is obtained, and the timing of 
consent (i.e., how long subjects will be given to consider participation).  For most 
studies involving more than minimal risk and all studies involving investigational 
drugs/devices, a licensed physician investigator must obtain informed consent.  When 


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subjects are to be enrolled from among the investigators’ own patients, describe how 
the potential for coercion will be avoided.
Written informed consent will be obtained for each procedure as well as for all procedures in 
aggregate. Drs. Kaufman, Ongur, and Javitt already have IRB approval to perform the imaging 
and ERP/EEG procedures included in this study. Because the procedures included in this 
protocol constitute a self-contained study of this mutation, separate written informed consent will 
be obtained for all of the procedures involved. Drs. Levy, Kaufman, Ongur, and Javitt will obtain 
written informed consent after reviewing the purposes of the study, detailing the procedures and 
explaining the informed consent documents. The subject is given an opportunity to ask 
questions after which written informed consent is obtained. Competence to give informed 
consent will be determined by the PI and co-investigators based on the subject’s understanding 
of the purpose of the study and procedures, what they involve, how long they take, and risk and 
benefits. The subject receives a copy of the Informed Consent for his/her own files. 
 
NOTE: When subjects are unable to give consent due to age (minors) or impaired 
decision-making capacity, complete the forms for Research Involving Children as 
Subjects of Research and/or Research Involving Individuals with Impaired Decision-
making Capacity, available on the McLean IRB website: 
 
For guidance, refer to the following McLean policy: 
          Informed Consent of Research Subjects
          
N/A 
 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.        
 
NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
Data safety monitoring is carried out to ensure and maintain the scientific integrity of research 
projects involving human participants and to protect the safety of the participants. Safety 
monitoring is any process during a study that involves the review of accumulated outcome data 
for groups of participants to determine if any of the study procedures should be altered or 
stopped. The plan includes details of how the data collections are monitored and how adverse 
events are detected and reported. The safety data include all imaging procedures, ERPs/EEGs, 
then neurocognitive function battery, as well as the double-blind placebo-controlled and open-
label glycine augmentation trials. Efficacy data includes all glycine-related procedures.  
 
Drs. Levy, Bodkin, Kaufman, and Öngür will be responsible for monitoring the safety of this 
study, executing the DSMP, and complying with the reporting requirements to the McLean 
Hospital Institutional Review Board (IRB).  The investigators are very familiar with these 


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responsibilities and Dr. Kaufman serves as Vice-Chair of the McLean Hospital IRB. All adverse 
events will be promptly reported to the McLean IRB, NIMH, and the FDA as appropriate. 
 
The research will be altered or stopped if subjects have adverse reactions to any of the 
procedures (e.g., claustrophobia in the scanners) or significant side effects to glycine. The dose 
of glycine in the glycine loading imaging study (0.4g/kg) will not exceed 30 grams, a dose that is 
unlikely to cause significant side effects in our experience. The dose of glycine used in the 
augmentation trials (a maximum 0.8 g/kg based on the subjects’ weights at date of initial 
screening administered on a TID dosing schedule after meals) is well tolerated and is a 
standard dose used in clinical trials with minimal, if any, side effects. Dr. Javitt, a consultant on 
this project, has a great deal of experience in using glycine to augment the therapeutic effects of 
antipsychotic medication. At least once every week, the subjects will receive a phone call from 
Dr. Levy to discuss how they are feeling. At the end of the first week of glycine or placebo, and 
every two weeks afterward, the subjects will also be called by a study physician (Dr. Bodkin) to 
assess how they are reacting to the glycine or placebo. Both subjects’ psychiatrists will also be 
monitoring their clinical states and side effects throughout the study.  Subjects will be told that if 
they experience any side effects, they must report them to Dr. Levy or any of the other co-
investigators immediately (phone and page numbers through the McLean Hospital operator will 
be provided) so the dose can be lowered or the treatment period ended. The subjects will also 
be told to go the nearest emergency room if they experience any acute side effects (e.g., 
vomiting). If the subjects’ weights are substantially different by the time this part of the study is 
scheduled to take place, their revised weights will be used in the calculation of the doses. The 
start of this arm will be set in collaboration with the pharmacist to make sure that there is 
adequate time to titrate the appropriate amounts of glycine. 
 
Partners Collaborative Media (PCM) will provide oversight (for a fee) to ensure that the clinical 
assessments taking place every two weeks using skype-like video conferencing are secure. 
Specific web cameras recommended by PCM will be used by McLean staff and by the subjects. 
All calls will be initiated from McLean using a Partners computer. This computer will have the 
Cisco program, “movi” [mobile video], installed. PCM will create generic credentials for the 
subjects such that they will not be using their own actual skype credentials. Thus, if the skype 
material is stolen, it cannot be linked to the subjects themselves.  A McLean clinician will call the 
subjects by clicking on customized phone numbers and allow the McLean caller to lock the 
virtual meeting room. 
 
Prior to this, PCM will run tests on the subjects’ computers to determine if they have enough 
bandwidth, are hooked into a land line or use a provider (i.e., Comcast) and if their computers 
have a web camera built in. The systems at the subjects’ homes will be customized to be secure 
and compatible with the system in place at McLean. 
 
A technical statement about how the secure connection will be implemented will be uploaded in 
e-irb as soon as it is received. 
 
In addition, to protect the study participants and prevent any potential risk to the participants’ 
privacy, Dr. Levy will apply for a Certificate of Confidentiality from the Department of Health and 
Human Services.  To reduce the possibility that information learned from DNA/RNA studies will 
affect the subject’s access to health insurance or employability, no research study data will be 
included in the subject’s medical records.  Further, with the Certificate of Confidentiality from 
DHHS, the PI cannot be forced (e.g., by court subpoena) to disclose information that may 
identify a study participant in any federal, state, or local criminal, administrative, legislative, or 
other proceeding. 
 


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Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the McLean IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the McLean IRB.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.   
 
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the McLean Hospital IRB guidelines for Adverse Event Reporting
 
See above 
 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be followed by the principal investigator/study staff to monitor and 
assure the validity and integrity of the data and adherence to the IRB-approved 
protocol.  Specify who will be responsible for monitoring, and the planned frequency of 
monitoring.  For example, specify who will review the accuracy and completeness of 
case report form entries, source documents, and informed consent.   
 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for ensuring that the study is conducted at his/her 
investigative site in accordance with the IRB-approved protocol, and applicable 
regulations and requirements of the IRB.
The PI will monitor the validity and integrity of the data and ensure that all appropriate forms 
(e.g., consent forms) have been thoroughly completed and that all blood samples are collected 
and shipped in accordance with the approved protocol. Monitoring will be done on an ongoing 
basis in close collaboration with the co-investigators.  
 
For guidance, refer to the following McLean policies: 
          Data and Safety Monitoring Plans and Quality Assurance
          
          Adverse Event Reporting Guidelines
           
 
PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.   
 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of 
sensitive data, such as sexual, criminal or illegal behaviors.


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Each subject will be assigned a 4-digit randomly generated ID number. All scans and blood 
samples will be labeled with this ID number. Signed consent forms and demographics forms 
with identifying information will be kept in locked file cabinets stored in a secure location with 
access limited to Drs. Levy, Kaufman, Ongur, Bodkin, or Javitt. Computer databases are 
password protected.   
 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE MCLEAN 
Specimens or data collected by McLean investigators will be sent to research collaborators 
outside McLean, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.
Blood samples will be sent to Dr. Raymond Suckow, Analytical Psychopharmacology 
Laboratory at the Nathan Kline Institute, for amino acid and psychotropic drug levels. Samples 
will be labeled with a 4-digit randomly generated ID number for each subject, a date and a time 
of day. The identity of the subjects will not be known to Dr. Sukow. 
 
Specifically address whether specimens/data will be stored at collaborating sites outside 
McLean for future use not described in the protocol.  Include whether subjects can withdraw 
their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
Dr. Javitt has agreed to make the results of the ERP/EEG and fMRI studies performed at NKI 
available to McLean investigators, but the original data will remain at NKI and will not be used 
for any purpose other than this protocol. Subjects can withdraw their fMRI and EEG/ERP data 
from NKI by written request. The fMRI and EEG/ERP protocols and consent forms at NKI are 
IRB approved. Attached with this application are copies of the approved consent forms and the 
protocol approval. 
 
Dr. Suckow will make the results of the analytical chemistry results available to McLean 
investigators. Specimens will be used up as they are assayed, so there will be no specimens 
stored at NKI. 
 
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
MCLEAN 
When specimens or data collected by research collaborators outside McLean will be 
sent to McLean investigators, indicate from where the specimens/data will be obtained 
and whether the specimens/data will contain identifiers that could be used by McLean 
investigators to link the specimens/data to individual subjects.  When appropriate, 
submit documentation of IRB approval and a copy of the IRB-approved consent form 
from the institution where the specimens/data were collected.
 
N/A 
 
References 
Bainbridge MN, Wiszniewski W, Murdock DR, Friedman J, Gonzaga-Jauregui C, Newsham I, 
Reid JG, Fink JK, Morgan MB, Gingras M-C, Muzny DM, Hoang LD, Yousaf S, Lupski JR, 
Gibbs RA. Whole-genome sequencing for optimized patient management. Sci Translational 
Med 2011;3:87re3. 
 


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Buchanan RW, Javitt DC, Marder SR, Schooler NR, Gold JM, McMahon RP, Heresco-Levy U, 
Carpenter WT. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): The 
efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J 
Psychiatry 2007;164:1593-1602. 
 
Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony K, Abbs S, Garralda ME, 
Bourke J, Wells DJ, Dickson G, Wood MJA, Wilton SD, Straub V, Kole R, Shrewsbury SB, 
Sewry C, Morgan JE, Bushby K, Muntoni F. Exon skipping and dystrophin restoration in patients 
with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer 
treatment: An open-label, phase 2, dose-escalation study. Lancet 2011;378:595-605. 
 
Coyle JT. Glutamate and schizophrenia: Beyond the dopamine hypothesis. Cell Mol Neurobiol 
2006;26:365-384. 
 
Goff DC, Henderson DC, Evins AE, Amico E. A placebo-controlled crossover trial of D-
cycloserine added to clozapine in patients with schizophrenia. Biol Psychiatry 1999;45:512-524. 
 
Guy W. Abnormal involuntary movement scale (AIMS). In: Guy W, ed. ECDEU assessment 
Manual for Psychopharmacology: Revised. Rockville, MD: US Department of Health, Education 
and Welfare; 1976:118-119. 
 
Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C, Need AC, Walley NM, Nicoletti P, 
Ge D, Catarino CB, Duncan JS, Kasperaviciutey D, Tate SK, Caboclo LO, Sander JW, Clayton 
L, Linney KN, Shianna KV, Gumbs CE, Smith J, Cronin KD, Maia JM, Doherty CP, Pandolfo M, 
Duncan JS, Sander JW, Delanty N, Leppert D, Middleton LT, Gibson RA, Johnson MR, 
Matthews PM, Hosford D, Kalviainen R, Eriksson K, Kantanen A-M, Dorn T, Hansen J, Kramer 
G, Steinhoff BJ, Wieser H-G, Steinhoff BJ, Kramer G, Hansen J, Dorn T, Zumsteg D, Ortega M, 
Wood NW, Huxley-Jones J, Mikati M, Gallentine WB, Husain AM, Buckley PG, Stallings RL, 
Podgoreanu MV, Delanty N, Sisodiya SM, Goldstein DB. Rare deletions at 16p13.11 predispose 
to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet 2010;86:707-718. 
 
Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M. Efficacy of high-dose 
glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 
1999;56:29-36. 
 
Heresco-Levy U, Ermilov M, Lichtenberg P, Bar G, Javitt DC. High-dose glycine added to 
olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry 2004;55:165-171. 
 
Heresco-Levy U, Javitt DC. Comparative effects of glycine and D-cycloserine on persistent 
negative symptoms in schizophrenia: A retrospective analysis. Schizophr Res 2004b;66:89-96. 
 
Javitt DC. Glutamate and schizophrenia: Phencyclidine, N-methyl-D-aspartate receptors, and 
dopamine-glutamate interactions. Int Rev Neurobiol 2007;78:69-108. 
 
Javitt DC, Silipo G, Cienfuegos A, Shelley AM, Bark N, Park M, Lindenmayer JP, Suckow R, 
Zukin SR. Adjunctive high-dose glycine in the treatment of schizophrenia. Int J 
Neuropsychopharmacol 2001;4:385-391. 
 
Kaufman MJ, Prescot AP, Ongur D, Evins AE, Barros TL, Medeiros CL, Covell J, Wang L, Fava 
M, Renshaw PF. Oral glycine administration increases brain glycine/creatine ratios in men: a 
proton magnetic resonance spectroscopy study. Psychiatry Res 2009;173:143-149. 
 


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Filename: Protocol Summary 
Version Date:  June 2009 
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Lane HY, Chang YC, Liu YC, Chiu CC, Tsai GE. Sarcosine or D-serine add-on treatment for 
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Gary S, Gershon ES, Gill M, Karayiorgou M, Kelsoe JR, Krastoshevsky O, Krause V, Leibenluft 
E, Levy DL, Makarov V, Bhandari A, Malhotra AK, McMahon FJ, Nothen MM, Potash JB, 
Rietschel M, Schulze TG, Sebat J. High frequencies of de novo CNVs in bipolar disorder and 
schizophrenia. Neuron 2011;72:951-963. 
 
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Gallagher L, Mendell NR, Wellcome Trust Case Control Consortium, Craddock N, Owen MJ, 
O'Donovan MC, Shaikh TH, Susser E, DeLisi LE, Sullivan PF, Deutsch CK, Rapoport J, Levy 
DL, King M-C, Sebat J. Microduplications of 16p11.2 are associated with schizophrenia. Nat 
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1995;52:998-1007. 
 
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McLean Hospital IRB Application Form 
 
 
Filename: Protocol Summary 
Version Date:  June 2009 
VERSION 4_10_02_2012 
 
 
 
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McLean Hospital IRB Application Form 
 
 
Filename: Protocol Summary 
Version Date:  June 2009 
VERSION 4_10_02_2012 
 
 
 
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SAP_001.pdf: 
 
Official Title: Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders 
 
NCT number:  NCT01720316 
 
Document Date: 10/17/2012 


Version 6_10_17_2012 
DETAILED PROTOCOL 
 
Principal Investigator: Deborah L. Levy, Ph.D. 
 
Protocol Title: Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders 
 
I. Background and Significance 
 
a. Historical background 
Multiple rare structural variants of relatively recent evolutionary origin are recognized as 
important risk factors for schizophrenia (SZ) and other neurodevelopmental disorders [e.g., 
autism spectrum disorders, mental retardation, epilepsy with odds ratios as high as 7-30 (Sebat 
et al. 2009; Malhotra et al. 2011; Heinzen et al. 2010; Weiss et al. 2008; McCarthy et al. 2009). 
We have found a de novo structural rearrangement on chromosome 9p24.1.  In addition to other 
genes, the duplicated region contains the gene encoding glycine decarboxylase (GLDC), which 
affects brain glycine (Gly) metabolism. A specific focus of this project is on potential 
contributions of this gene to abnormal glycine homeostasis and N-methyl-D-aspartate receptor 
(NMDAR) dysfunction in SZ. This mutation is an obvious ‘smoking gun.’  GLDC encodes the 
glycine decarboxylase or glycine cleavage system P-protein, which is involved in degradation of 
glycine (Gly) in glia cells.  Carriers of the GLDC triplication would be expected to have low levels 
of brain Gly, resulting in NMDA receptor-mediated hypofunction, which has been strongly 
implicated in the pathophysiology of SZ (Olney & Farber, 1995; Coyle, 2006; Javitt, 2007). 
Individuals with mutations that lower brain Gly or alter other aspects of glutamatergic 
transmission are obvious candidates for Gly augmentation or complementary NMDAR 
modulatory strategies, which have been used with varying degrees of success (Goff et al. 1999; 
Javitt et al. 2001; Lane et al. 2005; Heresco-Levy et al. 2004; Buchanan et al. 2007). Genetic 
risk factors, including variants that impact the synthesis and breakdown of Gly, are likely to 
contribute to this variability.  
 
b. Previous pre-clinical or clinical studies leading to and supporting the proposed 
research 
There is an extensive literature on the effects of NMDA enhancing agents on positive, negative, 
and depressive symptoms and on neurocognitive function (see Tsai & Lin, 2010; Lin et al. 2011 
for reviews).  Although many studies have reported positive results in at least one symptom 
domain (Heresco-Levy et al. 1996, 1999, 2004; Tsai et al. 1998, 1999, 2004a, 2006; Javitt et al. 
2001; Goff et al. 1996; Lane et al. 2008), 
the results of other studies have been negative or ambiguous (Goff et al. 1999; Evins et al. 
2000; Duncan et al. 2004; van Berckel et al. 1999). Individual agents also differ in their impact 
on various domains of psychopathology and cognition. Factors likely to contribute to this 
variability are: mechanism of action of the agent, compliance, concurrent treatment with first- vs 
second generation antipsychotic drugs, baseline Gly blood levels, presence/absence of 
kynurenine pathway metabolic abnormalities [e.g., increased kynurenic acid) (KYNA)] (Wonodi 
et al. 2010; Erhardt et al. 2007) and individual differences in brain Gly uptake and metabolism 
(Kaufman et al. 2009; Buchanan et al. 2007). Genetic variants that impact the synthesis and 
breakdown of Gly, Glu, or other modulators of NMDAR function are also likely to have 
significant effects.  Although Gly augmentation has shown variable efficacy in patients 
unselected for having a mutation that would be expected to lower brain Gly levels, the GLDC 
triplication in the two carriers would be expected to result in unusually low brain Gly levels, 
supporting its therapeutic potential as an augmentation strategy. 
 


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In previous work Kaufman and colleagues have shown that 14 days of oral Gly increases brain 
Gly levels (P) compared with baseline (B) levels (Kaufman et al. 2009). Oral high dose Gly also 
increases total brain and plasma Gly levels in mice, and the increments in brain and plasma Gly 
covary for several hours (Toth & Lajtha, 1986).  These findings support the utility of examining 
how glycine uptake and degradation following a glycine loading dose using proton 1H MRS. 
 
It is possible to obtain J-resolved proton MRS provides high quality information on glutamine, 
glycine, and glutamate (Ongur et al. 2008; Jensen et al. 2009; Prescott et al. 2006). GABA can 
be quantified separately from MEGAPRESS difference spectra (Jensen et al. 2009), permitting 
the measurement of levels of other metabolites that may be impacted by the GLDC triplication. 
 
c. Rationale behind the proposed research and potential benefits to patients and/or 
society 
 
The successful discovery of genetic variants underlying adverse and optimized treatment 
responses underscores the high potential for genetic discoveries to impact personalized 
medicine (Chung et al. 2004; McCormack et al. 2011; Chen et al. 2011; Ge et al. 2009; Tanaka 
et al. 2009; Suppiah et al. 2009; O’Brien, 2009; Klein et al. 2009; Takeuchi et al. 2009; Cooper 
et al. 2008; Bollag et al 2010; Daly et al. 2009; Mallal et al. 2008; Sorlie et al. 2001; Loi et al. 
2010; Bennett et al. 2012; Nathwani et al. 2011). Of particular importance, the identification of 
mutations in specific genes can lead to “medically actionable” treatment interventions tailored to 
the underlying disease biology, with positive therapeutic effects (Bainbridge et al. 2011; Worthey 
et al. 2011). Such individually tailored treatments may not only improve clinical response and 
outcome in appropriately selected patients, but also may reduce the heterogeneity in symptom 
reduction in clinical trials. 
 
II. Specific Aims 
 
a. Objectives/hypotheses 
 
Ideally, the identification of mutations in specific genes would result in personalized, “medically 
actionable” treatment interventions (Bainbridge et al. 2011; Worthey et al. 2011; Cirak et al. 
2011). We have found such a potentially informative mutation and it has high potential to impact 
clinical response. This project will investigate effects of a de novo structural rearrangement on 
chromosome 9p24.1 that segregates with psychosis in an extended family.  In addition to other 
genes, the duplicated region contains the gene encoding glycine decarboxylase (GLDC), which 
affects brain glycine metabolism. A specific focus, therefore, is on potential contributions of this 
gene to abnormal glycine homeostasis and N-methyl-D-aspartate receptor (NMDAR) 
dysfunction in SZ.   
 
We propose to (1) characterize the molecular, neurocognitive, and brain structural, functional 
and neurochemical properties of this mutation by carrying out targeted neurobiological follow-up 
of mutation carriers and non-carriers in this family and (2) to target the GLDC mutation by trying 
to normalize brain Gly levels using Gly augmentation.   
 
Specific Aim 1: To characterize the pathophysiology of disrupted Gly homeostasis using 
structural magnetic resonance imaging (3.0 Tesla) and proton magnetic resonance 
spectroscopy (MRS; 4.0 Tesla). The MRS studies will characterize endogenous brain Gly levels 
as well as brain and plasma pharmacodynamics after a single oral Gly dose (30 g). MRS will 
also be used to measure GABA, glutamate (Glu) and glutamine (Gln) metabolite levels. 
Hypothesis: Mutation carriers will have reduced endogenous brain Gly and GABA levels and 


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increased brain Glu and Gln levels. Gly administration will increase brain Gly in carriers, but to a 
lesser extent than in non-carrier family members and controls.   
 
Specific Aim 2: To probe the effect of dysregulated NMDA-mediated neurotransmission on 
visual processing. Functional MRI using behavioral paradigms that preferentially bias activity in 
magnocellular pathways, and visual evoked responses (ERPs) [e.g., mismatch negativity 
(MMN), P300] that are modulated, at least in part, by decreased NMDAR function, will be used. 
Hypothesis: reduced activation of magnocellular pathways and abnormal ERPs modulated by 
NMDA in carriers.   
 
Specific Aim 3: To carry out a double-blind placebo-controlled trial of Gly augmentation in the 
two mutation carriers. Hypothesis: Gly, but not placebo, will improve positive and negative 
symptoms as well as neurocognitive function. Specific aims 1-2 will be carried out prior to the 
Gly augmentation trial. 
 
Specific Aim 4: To determine the effects of open-label chronic Gly treatment (6 weeks) on 1) 
clinical and cognitive functioning, 2) brain metabolite levels of Gly, GABA, Glu and Gln 
measured with proton MRS and 3) NMDAR function as reflected in visual steady state ERPs 
and magnocellular activation. Hypotheses: improved clinical and cognitive functioning; partial 
normalization of decreased baseline Gly and GABA and increased Glu and partially normalized 
magnocellular pathway activation and abnormal ERPs. 
 
III. Subject Selection 
The four subjects have already been identified and recruited by the PI and have agreed to 
participate. They were selected on the basis of either having a mutation involving an 
abnormality in glycine metabolism (N=2) that may be implicated in psychotic disorders, or being 
a family member who does not have this same mutation (N=2). Prior to beginning the study, all 
subjects will be called by the PI and all of the procedures and time frames will be re-reviewed. 
The subjects will be flown to Boston for the McLean procedures and will travel by train (with Dr. 
Levy) to NY for the NKI procedures. The procedures will be scheduled well in advance to 
minimize inconvenience to the subjects and to optimize successful data collection at McLean 
and NKI.  
 
IV. Subject Enrollment 
The total projected sample size is 4, consisting of two carriers of a 9p24.1 mutation and two 
individuals from the same family who are not carriers of this same mutation. The two carriers 
have diagnoses of bipolar disorder with psychotic features and schizo-affective disorder and will 
be recruited as outpatients.  The two non-carriers do not have diagnoses of a psychotic 
disorder. The age range is 21-59 and includes two males and two females.  Note that there are 
two consent forms, one for the two subjects who will be receiving a double-blind glycine-placebo 
cross-over trial and open-label glycine and one for the two subjects who will not. 
 
V. Study Procedures 
Design of the study: Overview 
1) Baseline procedures at McLean: All four subjects will receive these baseline procedures. 
 
Physical exam/EKG (by Dr. Ongur). 
Movement disorders exam (extrapyramidal side effects, tardive dyskinesia - AIMS/SAS) (Guy, 
1976; Simpson 
 & Angus, 1970) (by Dr. Bodkin). 
Structural MRI (3T - 15 minutes), proton 1H MRS (4T) for GABA levels (MEGAPRESS - 1 hour); 


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Proton 1H MRS (4T-J-Resolved) for glycine, glutamate, and glutamine levels, pre-glycine 
loading (1 hour) and post-glycine loading [serial scans after a glycine dose of 0.4g/kg 
(not to exceed 30 g – no IND necessary) and 5 cc blood samples at (pre, 20, 40, 60, 90, 
120, 150, 180, 210, and 240 minutes post-Gly coinciding with serial MRS scans). All 
scan procedures have been approved by the McLean IRB as part of the following 
protocols: “Acute Glycine Pharmacodynamic Study” (Kaufman MJ, PI); “Proton Magnetic 
Resonance Imaging and Spectroscopy Studies of Brain Chemistry in Bipolar Disorder, 
Schizophrenia, and Related Disorders (Ongur, D, PI);” “Proton Magnetic Spectroscopy 
Studies of Glutathione and Gamma-butyric Acid in Bipolar Disorder, Schizophrenia and 
Related Disorders” ((Ongur, D, PI). Approved consent forms have been uploaded. Dr. 
Ongur will be responsible for medical oversight of the imaging components of the study.   
Clinical ratings:  PANSS (Kay et al. 1987); Clinical Global Impression Scale (Guy, 1976); Brief  
Psychiatric Rating Scale (Overall & Gorham, 1962); Young Mania Rating Scale (Young  
et al. 1978); Hamilton Depression Scale (Hamilton, 1960) (by Michael Coleman, M.A.). 
Neurocognitive testing (MATRICS Consensus Cognitive Battery-MCBB (Kern et al. 2011) (by 
Dr. Levy). 
Urinalysis and plasma levels: SMA-20, large neutral & excitatory amino acid, kynurenic acid 
(KYNA),  
psychotropic drug plasma levels.  
 
Blood sample quantities for all subjects (two mutation carriers and two non-mutation carriers) 
are as follows:  
 
5 cc blood samples at (pre, 20, 40, 60, 90, 120, 150, 180, 210, and 240 minutes post-Gly 
loading - IV), for a  
subtotal of 50cc;  
5 cc – SMA-20;  
6 cc - large neutral amino acid plasma levels;  
6 cc - small neutral/excitatory amino acid plasma levels;  
6 cc – homocysteine plasma level;  
6 cc - d-serine plasma level;  
4 cc –GABA plasma level;  
7 cc – KYNA plasma level, KYN plasma level, and quinolinic acid plasma levels – fasting – pre-
breakfast - all  
subjects.  
Thus, for all 4 subjects, 90 cc will be drawn for the baseline procedures.  
 
Additional blood samples for the two mutation carriers: 
Additional blood sample quantities for one of the mutation carriers are as follows: Note that if the 
subject’s medications change prior to the baseline scans, plasma levels for specific dugs may 
change. If this results in a change in the amount of blood required, the IRB will be informed. 
6 cc - cymbalta steady state plasma level;  
6 cc- clozaril steady state plasma level;  
5 cc - lithium steady state plasma level;  
6 cc - gabapentin steady state plasma level, all prior to AM dose.  
Thus, for this subject a total of 113 (including the 90 cc mentioned above) cc will be drawn at 
this time point.  
 
Additional blood sample quantities for the second mutation carrier are as follows: Note that if the 
subject’s medications change prior to the baseline scans, plasma levels for specific dugs may 
change. If this results in a change in the amount of blood required, the IRB will be informed. 


Version 6_10_17_2012 
 
6 cc- clozaril steady state plasma level;  
6 cc – remeron steady state plasma level;  
6 cc – abilify steady state plasma level;  
6 cc – celexa steady state plasma level, all prior to AM dose.  
Thus, for this one subject a total of 114 cc will be drawn (including the 90 cc mentioned above) 
at this time 
point.  
 
This amount of blood is well within safe guidelines for any healthy individual weighing at least 35 
pounds according to the McLean IRB and OHRP guidelines (< 550 ml in an 8 week period). 
 
The personal physicians of the subjects will be informed about their planned participation in a 
study that involves exposure to glycine and lemon juice. Each physician will be asked to provide 
a written statement indicating that he/she believes that there is no medical contraindication to 
the subject’s exposure to lemon juice/crystals or glycine. The internist for both mutation carriers 
and one non-carrier has provided a written statement saying that she sees no problem with their 
exposure to glycine and lemon juice. We are still waiting to receive a statement from the 
physician for the second non-carrier, who recently relocated and does not yet have a physician. 
However, this person will receive only the single glycine loading dose in relation to the 
spectroscopy scan; he will not receive glycine chronically since he is not part of the double-blind 
placebo-controlled or open-label glycine treatment trial. 
 
2) Baseline procedures at Nathan Kline Institute (NKI): functional MRI, ERPs/EEGs, all of which 
have been approved by the NKI IRB (approved consent forms have been uploaded). 
 
At the completion of steps 1 and 2, the participation of the two non-carriers will be complete.  
 
Additional Procedures for Mutation Carriers Only: 
 
3) Double-blind placebo-controlled oral glycine (Gly) (gradual titration to a maximum daily dose 
of 0.8 g/kg based on the subjects’ weights at date of initial screening distributed using a TID 
dosing schedule;) or Placebo: An FDA application for an IND will be obtained before initiation of 
this part of the study. A Certificate of Analysis, Material Data Safety Sheet, Sample Label, and 
Product Description from the manufacturer of the glycine powder, Ajinomoto, have been 
uploaded with the application. The titration schedule has also been uploaded. The placebo, 
Isomaltulose (Palatinose®), will be obtained from Beneo, Inc, which has a branch in New 
Jersey. A Certificate of Analysis, Material Data Safety Sheet, Sample Label, and Product 
Description have been uploaded. If the subjects’ weights are substantially different by the time 
this part of the study is scheduled to take place, their revised weights will be used in the 
calculation of the doses. The start of this arm will be set in collaboration with the pharmacist to 
make sure that there is adequate time to titrate the appropriate amounts of glycine. 
 
Dr. Bodkin will be responsible for medical oversight of the glycine augmentation component of 
the study. Dr. Ongur will serve as back-up medical coverage. 
 
The patients’ usual psychotropic drug regimen will not be altered as part of the study, but an 
attempt will be made to keep those medications unchanged throughout the study if possible. 
Any changes will be left up to the patients’ psychiatrists.  
 


Version 6_10_17_2012 
An FDA IND will be obtained for this part of the study and for the open-label glycine arm and the 
IRB will sent all documentation from the FDA.  
 
a) 6 Weeks on Gly or Placebo 
 
The McLean Pharmacy will order pharmaceutical grade glycine powder (10kg/box) from 
Ajinomoto North America, Inc. The glycine will be stored in closed containers in a dry area, 
avoiding humidity, sunlight and high temperature.  
 
The McLean Pharmacy will prepare the appropriate dose of glycine powder or placebo in a re-
closable plastic bottle. The placebo is Isomaltulose (Palatinose®), which looks and tastes 
like glycine; it is a fully digestible, tooth-friendly, low glycemic sugar. Each dose will be in a self-
contained package that includes an opaque plastic bottle containing glycine or placebo and 
individual packets of lemon crystals. Each bottle will be marked with a fill line, indicating how 
much cold water should be added for the glycine or placebo dose to be dissolved as a 20% 
solution. Each dose will be labeled by the pharmacy with the date, dose (breakfast, lunch, 
dinner) and instructions (e.g., “Fill the bottle with cold water to the fill line, shake, pour into a 
glass, add lemon crystals. Drink over a 15-20 minute period after a meal.”). The McLean 
Pharmacy will prepare both the active and placebo mixtures. Doses will be shipped in two-week 
supplies. While the subjects are at McLean for the baseline scans, the pharmacist and Dr. Levy 
will meet with the subjects and show them what the packaging of each dose looks like and what 
they have to do to combine the ingredients.  
 
It is anticipated that all of the glycine that is ordered will be used. If additional glycine is needed 
and there is any unused glycine powder, it will be disposed of according to the instructions on 
the Material Safety Data Sheet, (item 13): ‘Dispose of the material as you would with a non-
hazardous material in accordance with all applicable national, state and local regulations.’” 
 
Dosage Titration (see attached Titration Schedule): Glycine will be started at a dose of 3g/d and 
increased by 3-6 g/d until a maximum daily dose of 0.8 g/kg (based on the subjects’ weights at 
date of initial screening) is achieved. Dosing will be TID. This titration schedule is based on that 
of Heresco-Levy et al. 2004. For someone who weighs 99 kg (217.8 pounds), the estimated 
weight of one subject, the estimated maximum daily dose would be 79.2 g/d. For someone who 
weighs 85 kg (187 pounds), the estimated weight of the other subject, the estimated maximum 
daily dose would be 68 g/d. The maximum dosage ranges used in two previous studies, based 
on the same maximum dosage of 0.8g/kg/d of body weight, were 40-90 g/d (Heresco-Levy et al. 
1999) and 40-80 g/d (Heresco-Levy et al. 2004). The estimated maximum doses we are 
proposing to use are within these ranges. If the subjects’ weights are substantially different by 
the time this part of the study is scheduled to take place, their revised weights will be used in the 
calculation of the doses. The start of this arm will be set in collaboration with the pharmacist to 
make sure that there is adequate time to titrate the appropriate amounts of glycine. 
 
Subjects will keep a daily log to mark the time each dose was taken (sample log attached)  
 
At the end of weeks 2, 4, and 6: 
Clinical ratings using “skype-like” video conferencing (see below and uploaded document for 
details on measures that will be taken to ensure confidential and secure connections under the 
auspices of Partners Collaborative Media);  
 
At the end of week 6: 


Version 6_10_17_2012 
SMA-20, large neutral & excitatory amino acids, KYNA, and psychotropic drug plasma levels 
(drawn in the Clinical Laboratory of a local medical center and shipped to the Analytical 
Psychopharmacology Laboratory at NKI for processing (other assays may be performed in 
house). The same quantities described above will be drawn on the two participating subjects, for 
a total of 113 cc for one subject and a total of 114 cc for the other. 
 
An assessment of movement disorders (extrapyramidal side effects, tardive dyskinesia - 
AIMS/SAS- using “skype-like” video conferencing); 
 
MCCB, at the end of week 6 (administered in the subject’s city of residence). 
 
Clinical Oversight: 
The subjects are well known to the PI, who will be in touch with them by phone on a weekly 
basis or more often as needed, including weekly during the two weeks post-drug or placebo. 
Both subjects’ psychiatrists will also be monitoring their clinical states and side effects. Dr. Levy 
will inform Dr. Bodkin or Dr. Ongur immediately if any side effects are reported that warrant 
medical follow-up.  The subjects’ internist will be informed when the glycine-placebo and open-
label glycine periods begin (see sample letter to physician). 
 
At the end of the first week of glycine or placebo, and at the end of weeks 3 and 5 (more often if 
necessary), the subjects will be called by a study physician (Dr. Bodkin) to assess how they are 
reacting to the glycine or placebo. The subjects will also be given emergency contact numbers 
for Drs. Levy, Bodkin, Ongur, and Kaufman. The subjects will also be told to go the nearest 
emergency room if they experience any acute side effects (e.g., vomiting).  
 
b) 2 Weeks of No Augmentation Treatment (weeks 7-8) 
During weeks 7 and 8, the PI will contact to the subjects each week. Dr. Levy will inform Dr. 
Bodkin or Dr. Ongur immediately if any side effects are reported that warrant medical follow-up.   
At the end of week 8:  
Clinical ratings “skype-like” video conferencing;  
SMA-20, large neutral & excitatory amino acids, KYNA, and psychotropic drug plasma levels 
(drawn in the Clinical Laboratory of a local medical center and shipped to the Analytical 
Psychopharmacology Laboratory at NKI for processing (other assays may be performed in 
house). The same quantities described above will be drawn on the two participating subjects, for 
a total of 113 cc for one subject and a total of 114 cc for the other. 
 
c) 6 Weeks on Gly or Placebo (weeks 9-14; may or may not be contiguous with first glycine-
placebo arm) 
 
Subjects will keep a daily log to mark the time each dose was taken (sample log attached)  
 
At the end of weeks 10, 12, and 14: 
Clinical ratings using “skype-like” video conferencing.  
 
At the end of week 14: 
SMA-20, large neutral & excitatory amino acids, KYNA, and psychotropic drug plasma levels 
(drawn in the Clinical Laboratory of a local medical center and shipped to the Analytical 
Psychopharmacology Laboratory at NKI for processing (other assays may be performed in 
house). The same quantities described above will be drawn on the two participating subjects, for 
a total of 113 cc for one subject and a total of 114 cc for the other. 
 


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An assessment of movement disorders (extrapyramidal side effects, tardive dyskinesia - 
AIMS/SAS- using “skype-like” video conferencing); 
 
MCCB, at the end of week 6 (administered in the subject’s city of residence). 
 
Clinical Oversight: 
The subjects are well known to the PI, who will be in touch with them by phone on a weekly 
basis or more often as needed. Both subjects’ psychiatrists will also be monitoring their clinical 
states and side effects. See also above. 
 
At the end of the first week of glycine or placebo (week 9), and at the end of weeks 11 and 13, 
the subjects will be called by a study physician (Dr. Bodkin) to assess how they are reacting to 
the glycine or placebo. The subjects will also be given emergency contact numbers for Drs. 
Levy, Bodkin, Ongur, and Kaufman. The subjects will also be told to go the nearest emergency 
room if they experience any acute side effects (e.g., vomiting).  
 
d) 2 weeks of No Augmentation Treatment (weeks 15-16) 
During weeks 15 and 16, the PI will contact to the subjects each week. Dr. Levy will inform Dr. 
Bodkin or Dr. Ongur immediately if any side effects are reported that warrant medical follow-up.   
 
At the end of week 16: 
 
Clinical ratings at the end of week 16 using a “skype-like” video conferencing tool;   
SMA-20, large neutral & excitatory amino acids, KYNA, and psychotropic drug plasma levels 
(drawn in the Clinical Laboratory of a local medical center and shipped to the Analytical 
Psychopharmacology Laboratory at NKI for processing (other assays may be performed in 
house). The same quantities described above will be drawn on the two participating subjects, for 
a total of 113 cc for one subject and a total of 114 cc for the other. 
 
4) Open-Label Glycine: 6 weeks on a maximum daily dose of 0.8 g/kg (based on the subjects’ 
weights at date of initial screening) distributed using a TID dosing schedule taken after meals. 
The same titration schedule used in the cross-over double-blind glycine-placebo trial (described 
above) will be used.  At least one month will pass between the end of the double-blind glycine-
placebo cross-over arms and the beginning of the open-label glycine trial. The time interval will 
depend on subject schedules and the need for them to travel to Boston and NY at the end of 
week 5 for re-scanning and other procedures in week 6. If the subjects’ weights are substantially 
different by the time this part of the study is scheduled to take place, their revised weights will 
be used in the calculation of the doses. The start of this arm will be set in collaboration with the 
pharmacist to make sure that there is adequate time to titrate the appropriate amounts of 
glycine. 
 
Subjects will keep a daily log to mark the time each dose was taken (sample log attached)  
 
The McLean Pharmacy will prepare and label each dose as described above, which will be 
FedEx’ed in 2-week supplies.  
 
Baseline: Prior to beginning the open-label glycine trial, 113 and 114 cc of blood will be drawn 
for baseline levels of the same amino acid and psychotropic blood levels as indicated above.  
 
At the end weeks 2, and 4:  
Clinical ratings will be performed using a “skype-like” video conferencing tool.  


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During week 6:  
The imaging and ERP/EEG procedures at McLean and NKI described in sections 1) and 2) 
above will be repeated, with the exception of the physical examination, EKG, and glycine-
loading scan. 
 
At the end of week 6: 
 
Clinical ratings, an assessment of movement disorders, and the MCCB will be performed at 
McLean, where the baseline procedures (structural MRI, MRS, but no glycine loading), will be 
repeated.  
 
Urinalysis, SMA-20, large neutral & excitatory amino acid, KYNA, and psychotropic drug plasma 
levels will be obtained at this time and at the end of week 8.  
 
Clinical Oversight: 
The PI will be in touch with the subjects by phone on a weekly basis or more often as needed. 
Both subjects’ psychiatrists will also be monitoring their clinical states and side effects 
throughout the study. The subjects’ internist will be informed when the glycine-placebo and 
open-label glycine periods begin (see sample letter to physician). In addition, at the end of the 
first week of glycine, and at the end of weeks 3 and 5, the subjects will also be called by a study 
physician to assess how they are reacting to the glycine. The subjects will also be given 
emergency contact numbers for Drs. Levy, Bodkin, Ongur, and Kaufman. The subjects will also 
be told to go the nearest emergency room if they experience any acute side effects (e.g., 
vomiting). The same quantities as described above will be drawn on the two participating 
subjects, for a total of 113 and 114 cc at the end of week 6. 
 
During weeks 7 and 8, the PI will contact to the subjects each week. Dr. Levy will inform Dr. 
Bodkin or Dr. Ongur immediately if any side effects are reported that warrant medical follow-up.   
 
The consent forms contain a provision for subjects to give permission for Dr. Javitt and the 
Nathan Kline Institute to provide Dr. Levy and her colleagues at McLean with the results of any 
tests that were performed at NKI, for Dr. Raymond Suckow and the Nathan Kline Institute to 
provide Dr. Levy and her colleagues at McLean with the results of any blood samples that were 
analyzed at NKI, and for the Clinical Laboratories at McLean Hospital and at the medical center 
in the subjects’ home city to provide Dr. Levy and her colleagues with the results of any blood 
tests.  
 
Blood samples drawn at McLean or in the subject’s city of residence will be sent to the 
Analytical Psychopharmacology Laboratory at NKI for analysis (SMA-20, large neutral & 
excitatory amino acid, KYNA, and psychotropic drug plasma levels). The urinalyses and blood 
samples for lithium levels will be done either by the clinical lab of the local medical center or by 
the clinical lab at McLean. All samples will be coded with the subject’s 4-digit ID number, the 
date and the time of day. Dr. Suckow will not know the identities of the subjects whose blood 
samples he receives. 
 
Total Amount of Blood Drawn: The total amount of blood drawn at baseline is 90cc for the two 
non-mutation carriers and 113 and 114 cc for the two mutation carriers. The participation of the 
non-carriers will be complete at this time. The baseline procedures will be carried out at least 
two months prior to the beginning of the glycine-placebo cross-over arms in the mutation 
carriers. The total amount of blood drawn from the two mutation carriers during that 16-week 


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period will be 113 or 114 cc at weeks 6, 8, 14, and 16, for a maximum total of 452 cc and 456 
cc. Note that the two arms will not necessarily be contiguous, depending on the subjects’ 
schedules. Even if the two arms are contiguous, the total amount of blood will not exceed 550 
cc in an 8-week period. For the open-label glycine study, 113 and 114 cc will be drawn at 
baseline and weeks 6 and 8, again not exceeding the 550 cc limit within two months. The two 
carriers will be advised not to donate blood for at least one month after completing the glycine-
placebo cross-over arms and the open-label glycine arm. 
 
Neuropsychological Assessment: Cognitive functioning will be assessed using the battery 
developed by the Measurement and Treatment Research to Improve Cognition in Schizophrenia 
(MATRICS) initiative (Kern et al. 2011). The MATRICS battery (MCCB) includes 10 tasks that 
measure processing speed (Brief Assessment of Cognition in Schizophrenia, Symbol Coding, 
Animal Fluency, Trails A), attention (Continuous Performance Test), working memory (WMS-III 
Spatial Span, Letter-Number Span), verbal learning (Hopkins Verbal Learning Test – Revised), 
visual learning (Brief Visuospatial Memory Test - Revised), problem solving 
(Neuropsychological Assessment Battery) and social cognition (Mayer-Salovey-Caruso 
Emotional Intelligence Test). Total administration time is 60-90 minutes. The MATRICS is well 
tolerated by patients and can be administered repeatedly. Use of this battery will permit 
comparisons between baseline, post-glycine, and post-placebo effects on neurocognition.  See 
attachment on the MATRICS battery. 
 
It is anticipated that all of the glycine will be used. If there is any unused glycine powder, it will 
be disposed of according to the instructions on the Material Safety Data Sheet, (item 13): 
“Dispose of the material as you would with a non-hazardous material in accordance with all 
applicable national, state and local regulations.” 
 
Partners Collaborative Media (PCM) will provide oversight (for a fee) to ensure that the clinical 
and movement disorders assessments taking place every two weeks using skype-like video 
conferencing are secure. Specific web cameras recommended by PCM will be used by McLean 
staff and by the subjects. All calls will be initiated from McLean using a Partners computer. This 
computer will have the Cisco program, “blue jeans,” installed. PCM will create generic 
credentials for the subjects such that they will not be using their own actual skype credentials. 
Thus, if the skype material is stolen, it cannot be linked to the subjects themselves.  A McLean 
clinician will call the subjects by clicking on customized phone numbers and allow the McLean 
caller to lock the virtual meeting room. 
 
Prior to this, PCM will run tests on the subjects’ computers to determine if they have enough 
bandwidth, are hooked into a land line or use a provider (i.e., Comcast) and if their computers 
have a web camera built in. The systems at the subjects’ homes will be customized to be secure 
and compatible with the system in place at McLean. 
 
A technical statement from PCM about how the secure connection will be implemented has 
been uploaded in e-irb. 
 
VI. Biostatistical Analysis 
All data acquisition and processing will be carried out blind to mutation status. The McLean 
investigators and Dr. Javitt have extensive imaging and ERP databases involving controls and 
patients with psychotic disorders. Thus, we are well positioned to compare fMRI activation, 
ERPs and MRS spectra between carriers and non-carriers even if formal statistical testing is not 
always possible. At a minimum, using data from groups scanned on the same scanners under 
the same conditions, we can establish where our subjects fall in the range of values compared 


Version 6_10_17_2012 
with other subject groups using z-scores or % difference scores (e.g., Glu, GABA, Gln 
metabolite levels; Gly and other metabolite concentrations; Gln:Glu ratios). Pharmacokinetic 
curves of brain and plasma Gly levels (pre-/post-bolus administration) will be generated and 
tested for correlation, which can be compared with controls who undergo the same protocol. In 
the carriers, it will be possible to assess the magnitude of change in clinical and neurocognitive 
function and to correlate change in amino acid levels with clinical and neurocognitive change 
scores during Gly vs placebo. This is not a population study; it is designed to provide 
mechanistic insights about the effects of this mutation in the brain. 
 
VII. Risk and Discomforts 
 
The imaging procedures have been used extensively at McLean and NKI without complications 
and subjects will be carefully screened. 
 
The procedures described above pose no serious physical risk to subjects and no 
psychological, social, or legal risks are anticipated.  
 
Although there are no known general risks associated with MRI scans, there are risks to 
individual subjects who have contraindications to MRI scanning, including those with metal 
implants in their body (pacemaker, aneurysm clips, metal screws and plates for orthopedic 
purposes, hearing implants, certain kinds of tattoos, sheetmetal workers with lodged metal 
fragments in the eyes).  Subjects are screened carefully and excluded if there are even 
suspected contraindications to scanning.  All subjects are asked to remove jewelry, belts and 
other metal-containing objects.  Surgical records will be retrieved prior to scan for subjects who 
have had metal placed in their body intra-operatively to ensure the hardware is MRI safe, even 
if the subject has been told the hardware is MRI-safe or if they have had MRI scans since the 
operation.  As an additional precaution, subjects are screened with a handheld metal-detection 
wand prior to the scan to ensure that no unidentified metal objects remain on the subject.  The 
noise generated by the pulsing of the gradients can lead to temporary decrease in hearing. 
The use of disposable earplugs is an easy and reliable means of preventing hearing loss. The 
risks associated with Specific Absorption Rate (SAR) are related to the fact that given a large 
enough SAR, heating of the tissue may occur. These experiments will comply with all FDA 
guidelines with regard to RF power deposition. There is also the potential risk of injury from a 
projectile (i.e., ferromagnetic objects being attracted into the magnet); and of asphyxiation due 
to large amounts of cryogenic gases generated during a quench (i.e., the event which occurs 
when a magnet makes the sudden transition from superconducting to resistively conducting). 
Routine safety procedures are in place at both scanning centers to screen subjects prior to 
scanning, maintain security of the restricted access areas, and ensure that system security 
features are in good working order. Both imaging centers associated with this study (McLean, 
NKI) are very experienced with MRI scanning and have impeccable safety records. The effects 
of MRI on the fetus are not well characterized. Therefore, females of childbearing age must be 
sexually inactive or be using a contraceptive measure for three months prior to being scanned.  
A urine test will be used to establish that the one female of childbearing age is not pregnant. 
 
The scans involve use of a standard clinical MRI scanner (3T) as well as a high field (4T) MRI 
scanner. The 4T scanner is not used for routine clinical studies in children or adults, but the 
FDA has determined (July 14, 2003) that scanners with magnetic field strengths of less than 8 
Tesla do not represent a significant risk to adults, children, or infants older than 1 month. 164 
Most people experience no ill effects from 3T or 4 T scans, but some do report claustrophobia, 
dizziness, mild nausea, headaches, a metallic taste in their mouth, back tingling, double vision, 
or sensation of flashing lights.  These symptoms, if present, disappear shortly after leaving the 


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scanner.  During the scan, the examiner can see and hear the subjects and will ask them to 
report any problems so the scan can be stopped if necessary.  A magnetic resonance scan may 
be uncomfortable due to claustrophobia, lying still for an hour, or loud sounds. Subjects who 
express serious concern about these will not be included. The scan will be stopped if the subject 
expresses discomfort. Total time in the scanner for the structural scan and 2 MRS scans at 
McLean is 150 minutes, with breaks occurring between scans (structural: 15 minutes; 
MEGAPRESS: 60 minutes; J-PRESS: 75 minutes).  Total time for the structural and fMRI scan 
at NKI is I hour. The glycine-loading scan requires multiple scans over the 4 hour period in the 
scanner. Subjects will be allowed to leave the scanner between scans and can be re-positioned 
for the next scan, as described in the application. All four subjects have successfully completed 
imaging procedures. 
 
Oral glycine has been widely used to augment standard psychotropic drug treatment and is well 
tolerated. By using a weight-adjusted maximum dose of 0.8 g/kg (based on the subjects’ 
weights at date of initial screening) 
administered on a TID schedule, the dose will be well within the range of a glycine dose that is 
tolerated without undue adverse effects. If necessary, the dose can be lowered to minimize GI 
side effects. The subjects will be monitored closely by the research team and by their own 
psychiatrists. Blood chemistries, including liver/kidney function tests, will be monitored at 
baseline and at the end of each treatment arm.   
 
Glycine Augmentation Clinical Trial: Pharmaceutical grade glycine (Ajinomoto) will be used. 
Glycine powder-water mixtures (dissolved as a 20% solution) will be prepared by the McLean 
Hospital pharmacy. The dose of glycine will be slowly titrated until a TID maximum dose of 0.8 
g/kg of body weight (based on the subjects’ weights at date of initial screening) (administered 
after meals) is reached. This dose is well within the range of doses that were well tolerated in 
previous patient studies (Goff et al. 1999; Heresco-Levy et al. 1996, 1999, 2004). The most 
common side effect is mild gastrointestinal distress, which is reversible upon discontinuation, 
should that be necessary. At a mean dose similar to that proposed here, 82% and 95% of 
patients, respectively, completed the clinical trial (Heresco-Levy et al. 1999, 2004). No adverse 
effects on kidney, liver, hematology or blood chemistry values were observed over a 6-week 
period. If necessary, the dose can be lowered to minimize GI side effects. The subjects will be 
monitored closely by the research team and by their own psychiatrists. Blood chemistries, 
including liver/kidney function tests, will be monitored at baseline.   
 
The titration schedule is based on that of Heresco-Levy et al. 2004. For someone who weighs 
99 kg (217.8 pounds), the approximate expected weight of one subject, the expected maximum 
daily dose would be 79.2 g/d. For someone who weighs 85 kg (187 pounds), the approximate 
expected weight of the other subject, the expected maximum daily dose would be 68 g/d. The 
maximum dosage ranges used in two previous studies, based on the same maximum dosage of 
0.8g/kg/d of body weight, were 40-90 g/d (Heresco-Levy et al. 1999) and 40-80 g/d (Heresco-
Levy et al. 2004). The estimated maximum doses we are proposing to use are within these 
ranges. 
 
Periodic blood samples and the IV involve the slight discomfort of a needle stick and the small 
risk of a bruise. Every attempt is made to have the subject feel comfortable and at ease with the 
environment and the staff.  
 
Other than the paste used to adhere ERPs/EEGs electrodes to the scalp, no discomforts or 
risks should be incurred from these procedures, which are quite routine.  
 


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Risks to privacy and confidentiality are minimal. All subjects are assigned a random4-digit ID 
number, which is used to code all material.  
 
VIII. Potential Benefits 
The general goal of this study is to clarify the neurobiology of a mutation in glycine mutation and 
to determine whether carriers of this mutation may preferentially benefit from glycine 
augmentation of their medication regimen. Although subjects receive no immediate benefit from 
the brain imaging and ERP/EEG procedures beyond contributing to important research and 
reasonable monetary compensation for the time commitment, the potential scientific yield could 
have a major impact on identifying causal mechanisms in psychotic disorders. If the glycine 
augmentation is beneficial, these two subjects may experience a significant reduction in 
psychotic symptoms and improvement in neurocognition, which may also help other subjects 
with mutations impacting the glycine metabolic pathway. 
 
IX. Monitoring and Quality Assurance 
Data safety monitoring is carried out to ensure and maintain the scientific integrity of research 
projects involving human participants and to protect the safety of the participants. Safety 
monitoring is any process during a study that involves the review of accumulated outcome data 
for groups of participants to determine if any of the study procedures should be altered or 
stopped. The plan includes details of how the data collections are monitored and how adverse 
events are detected and reported. The safety data include all imaging procedures, ERPs/EEGs, 
then neurocognitive function battery, as well as the double-blind placebo-controlled and open-
label glycine augmentation trials. Efficacy data includes all glycine-related procedures.  
 
Drs. Levy, Kaufman, Öngür, and Bodkin will be responsible for monitoring the safety of this 
study, executing the DSMP, and complying with the reporting requirements to the McLean 
Hospital Institutional Review Board (IRB).  The investigators are very familiar with these 
responsibilities and Dr. Kaufman serves as Vice-Chair of the McLean Hospital IRB. All adverse 
events will be promptly reported to the McLean IRB, NIMH, and the FDA as appropriate. 
 
The research will be altered or stopped if subjects have adverse reactions to any of the 
procedures (e.g., claustrophobia in the scanners) or significant side effects to glycine. The dose 
of glycine in the glycine loading study (0.4g/kg of body weight on the day of the scan) will not 
exceed 30 grams, a dose that is unlikely to cause significant side effects in our experience.  
 
The dose of glycine used in the augmentation trials (a maximum of 0.8 g/kg/d (based on the 
subjects’ weights at date of initial screening) using a TID dosing schedule after meals) is well 
tolerated and is a standard dose used in clinical trials with minimal, if any, side effects. The PI 
will be in touch with the subjects by phone on a weekly basis or more often as needed. Both 
subject’s psychiatrists will also be monitoring their clinical states and side effects throughout the 
study. Their local internist will be informed when each arm of the glycine-placebo and open-
label glycine begins (sample letter informing the internist has been uploaded). In addition, at the 
end of the first week of glycine or placebo, and at the end of weeks 3, 5, 9, 11, and 13 (more 
often if needed) the subjects will also be called by a study physician (Dr. Bodkin) to assess how 
they are reacting to the glycine or placebo. During the open-label glycine trial, side effects will 
also be assessed at the end of weeks 1, 3, and 5, or more often as needed. The subjects will 
also be monitored weekly during the two weeks post-drug.  
 
The subjects will also be given emergency contact numbers for Drs. Levy, Bodkin, Ongur, and 
Kaufman. The subjects will also be told to go the nearest emergency room if they experience 
any acute side effects (e.g., vomiting). Dr. Javitt, a consultant on this project, has a great deal of 


Version 6_10_17_2012 
experience in using glycine to augment the therapeutic effects of antipsychotic medication and 
will be available to advise the study team about any needed changes (i.e., slower titration, dose 
reduction, discontinuation) based on side effects.  It is conceivable that subjects may 
experience more side effects as the dose is increased, requiring either temporary 
discontinuation and/or dose reduction and/or slower titration. It may also be necessary to lower 
the maximum daily dose or to extend each arm of the study for several weeks in order to 
accommodate a longer titration period up to the therapeutically optimal dose.  Decisions about 
how best to proceed will be made in consultation among Drs. Levy, Bodkin, (Ongur if Dr. Bodkin 
is not available), Javitt, and the McLean pharmacist. Based on Dr. Javitt’s extensive experience 
using doses of glycine comparable to those proposed here and the fact that the dose is being 
titrated upward more slowly in this study, it is very unlikely that it will be necessary to 
discontinue the trial altogether. Should there be changes in any arm of the study, such as 
temporary discontinuation, a need for slower titration, extending the time period, the IRB will be 
notified. If subjects develop side effects that make them too uncomfortable or that make it 
medically necessary to discontinue the study, the study will be stopped. This level of oversight 
for subjects who are not local seems reasonable for monitoring subjects taking a dietary 
supplement that has been widely and safely used as an augmentation strategy. As stated 
above, we have purposefully included the flexibility to slow the titration schedule if needed and 
to lengthen each treatment arm to accommodate individual differences in metabolism. 
 
The PI has talked all of the people involved in the study (Drs. Kaufman, Ongur, Bodkin, Javitt, 
Visschers, and Vukovic; Mr. Rosen) about the adequacy of the plan to provide medical and/or 
psychiatric monitoring of these patients while they are taking a novel compound. With the 
exception of Mr. Rosen, who has been on medical leave, they have agreed that the proposed 
plan is acceptable. 
 
The PI will monitor the validity and integrity of the data and ensure that all appropriate forms 
(e.g., consent forms) have been thoroughly completed and that all blood samples are collected 
and shipped in accordance with the approved protocol. Monitoring will be done on an ongoing 
basis in close collaboration with the co-investigators.  
 
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