Conditions: Schizophrenia Bipolar Disorder
Keywords: D-cycloserine Glycine Psychosis Mutation GABA
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 2
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy of d-cycloserine (DCS) as an augmentation strategy in two psychotic patients with a triplication (4 copies) of the glycine decarboxylase (GLDC) gene. Subjects will first undergo an eight-week open-label arm of treatment with DCS (50 mg/d) followed by six 6-week double-blind placebo-controlled exposures to DCS or placebo. The length of each double-blind arm is limited to six weeks to minimize the length of symptom exacerbation experienced by the subjects when they are receiving placebo. The randomization scheme will allow two consecutive exposures to DCS, but will not allow two consecutive exposures to placebo, again to minimize the length of any symptom exacerbation. At the end of the open-label DCS trial, the following procedures will be carried out: structural MRI (3T), proton 1H MRS (4T), fMRI (3T), steady-state auditory evoked potentials, and electroretinogram recordings. In addition, 1H MRS (4T) for 2 hours after a single oral dose of a DCS will be assessed. Baseline data on all of these measures were previously obtained as part of a different study registered in clinical trials.gov - NCT01720316). 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. Pharmaceutical grade DCS) or placebo will be compounded and dispensed by the McLean Hospital Pharmacy.

The investigators hypothesize that mutation carriers will have reduced endogenous brain glycine and GABA levels and increased brain glutamate and glutamine levels. DCS administration will increase brain glycine in the two carriers compared to baseline and treatment with glycine (0.8g/kg).

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 DCS, but not placebo, will improve positive, negative and affective symptoms as well as neurocognitive function.

The investigators also hypothesize that DCS 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. 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.

There is an extensive literature on the effects of NMDA enhancing agents on positive, negative, and depressive symptoms and on neurocognitive function. Although many studies have reported positive results in at least one symptom domain, the results of other studies have been negative or ambiguous. 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 and individual differences in brain glycine uptake and metabolism . 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 DCS 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 DCS 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.

Arms:
arm 1: Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule for 8 weeks. arm 2: Randomized to DCS or placebo. Participants underwent double-blind placebo-controlled exposures to DCS for 6 weeks or placebo for 6 weeks. One participant received exposure to DCS for 6 weeks and then received placebo dosing for 6 weeks. The other participant received exposure to placebo dosing for 6 weeks and then DCS for 6 weeks. arm 3: Both participants received second open label exposures to D-cycloserine (seromycin), 50 mg/d capsule for 24 weeks.

Interventions: intervention 1: D-cycloserine intervention 2: DCS or placebo intervention 3: D-cycloserine
Intervention descriptions: intervention 1: Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks. intervention 2: Double-blind placebo-controlled exposures to DCS or placebo x 6 weeks. One participant received exposure to DCS x 6 weeks and then received placebo dosing x 6 weeks. The other participant received exposure to placebo dosing x 6 weeks and then DCS x 6 weeks. intervention 3: Both participants received second open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.

Protocol document:
ICF_000.pdf: 
Official Title: Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine (DCS) 
 
NCT number:  NCT02304432 
 
Document Date: 4/9/2015 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  October 2014 
 
 
 
 
Page 2 of 15 
 
Subject Identification 
Protocol Title: Targeting a Genetic Mutation in Glycine Metabolism with D-
cycloserine 
 
Principal Investigator: Deborah L. Levy, Ph.D. 
 
Site Principal Investigator: Deborah L. Levy, Ph.D. 
 
Description of Subject Population: Two carriers of a mutation affecting glycine 
metabolism  
 
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. 
 
Partners HealthCare System is made up of Partners hospitals, health care providers, and 
researchers.  In the rest of this consent form, we refer to the Partners system simply as 
“Partners.” 
 
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. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you.  At most, the Web site 
will include a summary of the results.  You can search this Web site at any time. 
 
Why is this research study being done? 
 
We are doing this research to investigate the effects of a specific genetic mutation on brain 
structure and metabolism and to determine whether a specific medication (d-cycloserine, or 
DCS) is helpful in reducing psychotic and mood symptoms and in improving cognition. 
 
DCS (seromycin) is an antibiotic. It is approved by the U.S. Food and Drug Administration (FDA) 
to treat tuberculosis. It is not approved by the FDA to treat psychotic conditions, but it has been 
used in several studies to enhance the effects of standard treatment in individuals with a 
diagnosis of schizophrenia.  


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Subject Identification 
 
We are asking you to take part in this research study because you have a genetic mutation that 
affects the metabolism of glycine and you previously participated in a study involving glycine. 
DCS may help to normalize the functioning of the glycine receptor in the brain. During this study 
you will receive DCS and at other times you will receive a placebo (a capsule that does not 
contain medicine). You will also receive one tablet of vitamin B complex daily throughout the 
study. 
 
Two people will take part in this research study. 
 
The National Institute of Mental Health is paying for this research to be done. 
 
How long will I take part in this research study? 
 
It will take about 50 weeks to complete this study. During this time, we will ask you to make one 
visit to the University of Minnesota and McLean Hospital. Details about the specific procedures 
and the length of each procedure are included in the next section. 
 
What will happen in this research study? 
 
Study Visits and Design 
 
Part I. If you are still taking a glycine supplement of your current psychiatric medications, you 
will stop taking glycine. You will receive a standard battery of clinical interviews every two weeks 
to assess the severity of any psychotic and mood symptoms. Each interview lasts about an 
hour. The interviews will be done over a “skype-like” connection with which you are already 
familiar. 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. If your symptoms get worse after stopping the glycine, you may receive the same clinical 
interview every week for a few weeks. Within approximately 6 weeks or less of discontinuing to 
take glycine, you will start taking a low dose of DCS (50 mg/d). DCS comes in the form of a 
capsule that you will take once a day for 8 weeks. You will be evaluated on the same clinical 
measures mentioned above every two weeks. In addition, you will be in weekly phone contact 
with Dr. Levy.  
 
Immediately prior to beginning to take DCS, you will have a physical examination and EKG from 
your own doctor. You will also have a blood test in which either 61 or 66 cc (approximately two 
ounces) of blood will be drawn. The same amount of blood will be drawn at the time of each 
subsequent blood test. For this and all blood tests, it is important that you have nothing to eat or 
drink and do not take any medications until after the blood test is over. You will also have a 
movement disorder exam using the same “skype-like” connection as in the interviews. The 
movement disorder exam takes about 5 minutes.  
 


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Subject Identification 
During the 8 weeks of DCS treatment, you will have your blood drawn and get weighed once a 
month. You will receive the same clinical interviews every two weeks to assess the severity of 
any psychotic and mood symptoms. You will also be in weekly phone contact with Dr. Levy.  
Although we do not anticipate that DCS will cause any symptoms to worsen, this possibility 
cannot be ruled out in advance. If your symptoms do show a substantial worsening, you will 
stop taking DCS and your participation in the study will be over. In such a case, it will be your 
option to begin taking glycine again as part of a separate research study so that your symptoms 
can be stabilized. 
 
If you develop significant side effects (such as worsening of mood or psychotic symptoms), 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. 
 
Part II. In the 7th week of DCS treatment, you will be flown to Minneapolis for tests of retinal 
function and to Boston for brain imaging procedures. In addition, the movement disorder 
examination, the neurocognitive battery you have had before (the MATRICS), the EEG you 
have had before, and a physical exam and EKG will be repeated. The procedures in 
Minneapolis and Boston will take about one week.  
 
The brain imaging procedures allow Dr. Levy and colleagues at McLean Hospital to study the 
effects of a specific genetic mutation on brain structure and metabolism. Three magnetic 
resonance imaging techniques will be used. 
 
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 that 
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. Magnetic 
resonance imaging and spectroscopy will also be used to measure brain glycine levels 
before and for 2 hours after your take your usual dose of DCS. This procedure will measure how 
your brain absorbs DCS. 
 
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, an EKG, a movement disorder 
examination, and blood tests. These procedures will take about 2 hours.  
 
On another day there will be a structural MRI (at 3.0 T), which takes 15 minutes, and a DTI 
scan, which takes about an hour.  
 
On a separate day, spectroscopy MRI at 4.0 T, which takes one hour, will be done. 
 
On a different day, there will be spectroscopy scans using a 4T scanner. The pre-DCS scan 
takes one hour. After you take your DCS dose, the scan will last 2 hours. 


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Subject Identification 
 
The neuropsychological tests (MATRICS) assess things like memory, attention, and planning 
and take 1 hour. 
 
The EEG involves having electrodes pasted to your scalp and recording brain waves while you 
listen to auditory stimuli. It takes about 1 hour. 
 
The retinal function tests in Minneapolis consist of two parts: a routine eye exam, including 
dilation of your pupils, and a more detailed exam of your retinas (the part of the eye that 
receives visual images and transmits them to the brain). Eye drops will be used during part of 
the detailed eye exam, which will numb your eyes to make you comfortable during the 
procedures. You should feel minimal or no discomfort. During the exam, recordings will be 
made from your retina, using a contact lens. There will also be a small flexible fiber placed just 
inside your lower eyelid, so it is in contact with your tears. This fiber relays information about the 
test. The fiber will be held in place by 2 sticky pads applied to your skin. There will be four 
additional small fibers placed on your skin near the outer corner of your eye(s), earlobe(s), 
forehead or on your forearm/hand. Photographs will be taken of your eyes. The exam will take 
about 3 hours; breaks are included. 
 
Part III. If you complete the 8-week DCS trial, you will be randomized to receive DCS-placebo-
DCS-placebo-DCS or to receive placebo-DCS-placebo-DCS-placebo, each for 6 weeks in a 
double-blind design. The McLean Hospital research pharmacist will determine the 
randomization and will know whether you are receiving drug or placebo, but you and all other 
study staff will not know. In case of an emergency, the study doctor can find out if you are taking 
DCS or placebo. There will be a total of five 6-week trials with DCS or placebo. In between each 
6-week period, there will be one week of neither DCS nor placebo. The length of each double-
blind arm is limited to six weeks to minimize the length of any symptom worsening you may 
experience when you are receiving placebo. After these five 6-week periods, you will receive 
DCS for 6 weeks.  
 
Throughout this time, you will have your blood drawn and get weighed once a month. You will 
also receive the same clinical interviews every two weeks to assess the severity of any 
psychotic and mood symptoms. You will also be in weekly phone contact with Dr. Levy.  
 
The total amount of blood that will be drawn over the course of the study will be 854 ml (about 
58 tablespoons) or 896 ml (about 61 tablespoons). Both amounts are well within safe guidelines. 
You are asked not to donate blood during the course of the study. 
 
At the end of all of these six 6-week periods, the following procedures will be repeated in your 
city of residence: the movement disorder examination (by Dr. Levy), the neurocognitive battery 
(the MATRICS, by Dr. Levy), and a physical exam and EKG (by your doctor). 
 
Partners Alert System. Partners has an electronic system that lets your study doctors 
know if you are admitted to a Partners Hospital, or if you visit a Partners Hospital 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  October 2014 
 
 
 
 
Page 6 of 15 
 
Subject Identification 
Emergency Department.  We want to make sure the study doctors know about any 
possible problems or side effects you experience while you are taking part in the study. 
 
Reasons for and procedures for early withdrawal from the study. Although we do not anticipate 
that DCS will cause any symptoms to worsen substantially, this possibility cannot be ruled out in 
advance. If your symptoms do show a substantial worsening, you will stop taking DCS and be 
withdrawn from the study. You may also be withdrawn if there are significant changes in your 
kidney or liver function. If you are withdrawn from the study you should contact your treating 
psychiatrist to discuss treatment options.  You also have the option to begin taking glycine again 
as part of a separate research. 
 
Should you become suicidal during the study, you must immediately notify Dr. Levy (617-855-
2854), Dr. Bodkin (617-855-3186) and your psychiatrist, and call 911 if the situation is an 
emergency. If you are suicidal, we will recommend a course of action. This will include notifying 
your psychiatrist and internist, notifying a member of your family, and possibly calling the local 
EMTs to take you to a hospital if needed. You will be given a separate release form in which you 
will provide written consent for Dr. Levy and/or her designees to contact your psychiatrist, 
internist, and a designated family member.   
 
Sending data/specimens to research collaborators outside Partners. Some of the blood 
samples will be processed either in a clinical lab in the city in which you live or by the clinical lab 
affiliated with McLean Hospital. Other blood samples will be sent to the Nathan Kline Institute 
(NKI) in Orangeburg, NY, where they will be analyzed for various amino acid levels (for 
example, glycine, serine). By signing this consent form, you give permission for Dr. Raymond 
Sukow and the Nathan Kline Institute permission to provide Dr. Levy and her colleagues with 
the results of any blood samples that are analyzed at NKI. 
 
Storing Samples and Health Information at McLean Hospital and NKI for Future Use. We 
would like to store some of your samples and health information for future research related to 
psychiatric illnesses.  We will label your samples and health information with a code instead of 
your name.  The key to the code connects your name to your samples and health information.  
Dr. Levy will keep the key to the code in a password-protected computer. 
 
Do you agree to let us store your samples and health information for future research related to 
psychiatric illnesses? 
 
 Yes 
 No 
Initials___________ 
 
If later you change your mind and want your samples destroyed, contact Dr. Levy. 
 
Study Information Included in Your Electronic Medical Record. A notation that you are 
taking part in this research study may be made in your electronic medical record.  Information 
from the research that relates to your general medical care may be included in the record (for 
example, list of allergies, results of standard blood tests done at the hospital labs. 
 


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Subject Identification 
Please ask Dr. Levy if you have any questions about what information will be included in your 
electronic medical record. 
 
Voluntary Participation. 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. Dr. Levy and her colleagues 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. 
 
What are the risks and possible discomforts from being in this research 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) 


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Subject Identification 
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. 
 
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 that of 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. 
 
We are doing the 4T MRI scan in this study to answer research questions, not to give you 
medical care.  The information created by this study will not usually become part of your hospital 
record.  This 4T MRI scan is not the same as one that your own doctor would order.  It may or 
may not show problems that would be found on a standard clinical radiological test.  If we do 
see something that looks like a medical problem, we will ask a radiologist (a doctor who 
specializes in x-rays / scans / test results of this sort) to review the results.  If the radiologist 
thinks there might be a problem, we will tell you and help you get follow-up care.  If the 
radiologist thinks that you might have a medical problem, but it turns out that you don't, we may 
have caused you to worry needlessly about your health. 


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Subject Identification 
 
In rare cases, a very slight, uncomfortable tingling of the back 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: Not applicable. 
 
Blood tests 
You may receive a bruise at the site of the needle insertion. 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). 
 
DCS-Placebo Treatment 
During the open label-DCS treatment period and the DCS-placebo treatment periods: When 
you are taking DCS, you may experience a modest and time-limited worsening of “negative” 
symptoms (withdrawal, lack of motivation), but this is unlikely. When you are taking placebo, 
you may experience a worsening of psychotic, negative, and mood symptoms that had 
improved on DCS. If you experience these or any other 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). 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) or Dr. Dost Ongur at 617-
855-3922 M-F 9-5 (can also be paged through 617-855-2000). 
 
DCS at high doses can cause B12 and folate deficiency. You will be taking a low dose of DCS, 
so these side effects are unlikely. To make sure that you do not develop either deficiency, you 
will be given vitamin B complex tablets to take daily (1/day) throughout the study. 
 
You will have periodic blood tests to monitor your kidney and liver function to make sure that 
you can safely continue to take DCS. 
 
Neuropsychological Test Procedures 
No adverse effects of the neuropsychological procedures are expected, but the testing may be 
tiring. 
 
EEG 
The paste that is used to stick the electrodes to your scalp is a clear gel. It may make your hair 
feel greasy and can be washed out. 
 


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Subject Identification 
Eye Exams 
 
Eye drops will be used during part of the detailed eye exam, which will numb your eyes to make 
you comfortable during the procedures. You should feel minimal or no discomfort. Your eyes will 
be dilated for each part of the exam, so it will take a few hours before you can read easily and 
you will need to wear sunglasses outside during the day. 
 
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. 
 
There may be risks that are currently unknown from taking DCS or undergoing the various 
research procedures. 
 
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 help 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 DCS may reduce your psychotic and 
mood 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, DCS, may be available to you through 
prescription and preparation by a compounding pharmacy without taking part in this study. 
 
 
Can I still get medical care within Partners 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 Partners 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. 
 
 


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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. 
 
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  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? 
 
You can receive up to $2,200 if you complete all study visits. You will be paid $1,000 by check 
for participating in the open-label DCS study and the procedures during weeks 7-8. You will be 
paid an extra $200 for the retinal function tests in Minneapolis. You will be paid an additional 
$1,000 by check for the six 6-week periods during the randomized DCS-placebo part of the 
study. If you do not complete all of the procedures, you will be paid a pro-rated amount based 
on the proportion of the study that was completed. For example, if you complete 80% of the 
procedures during the open-label DCS study, you will be paid $800. If you incur transportation-
related expenses related to your participation, such as gas or taxis, you will be reimbursed up to 
$500 in the first year of the study and up to $300 in the second year of the study, based on 
submitted receipts. 
 
If you do not complete the study, we will pay you a pro-rated portion for the part of the study that 
you did complete. 
 
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. If you incur expenses, such 
as parking or gas costs, you will be reimbursed. 
 
What happens if I am injured as a result of taking part in this research 
study?
 
If you are injured as a direct result of taking part in this research study, we will assist you in 
obtaining the medical care needed to treat the injury. This means arranging for (but not paying 
for) transportation to an acute care center for treatment of the injury.  McLean Hospital is a 
psychiatric care facility and does not provide general health care services. 
 
The care provider may bill your insurance company or other third parties, if appropriate, for the 
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payment of any deductibles and co-payments required by your insurer. 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  October 2014 
 
 
 
 
Page 12 of 15 
 
Subject Identification 
 
For the blood draws at Bozeman-Deaconess Hospital, McLean Hospital will not be involved in 
mitigation of any injuries that may occur. 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
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If you think you have been injured or have experienced a medical problem as a result of taking 
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If I have questions or concerns about this research study, whom can I 
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You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
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Dr. Deborah Levy, Ph.D., is the person in charge of this research study.  You can call her at 617-
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Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  October 2014 
 
 
 
 
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Subject Identification 
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General Template 
Version Date:  October 2014 
 
 
 
 
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Subject Identification 
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Version Date:  December 2008 
 
 
 
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Consent Form Version:  4/9/2015 
 
 

SAP_002.pdf: 
Official Title: Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine (DCS) 
 
NCT number:  NCT02304432 
 
Document Date: 2/27/2015 


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2
DETAILED PROTOCOL 
 
 
 
 
Principal Investigator: Deborah L. Levy, Ph.D. 
 
Protocol Title: Targeting a Genetic Mutation in Glycine Metabolism with D-cycloserine 
 
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 rearranged 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 NMDAR modulators 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 the therapeutic potential of augmenting agents in 
these individuals. 
 


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3
In previous work Kaufman and colleagues have shown that 14 days of oral Gly increases brain 
Gly compared with baseline 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).  This protocol includes magnetic resonance spectroscopy 
(MRS).  It is possible to obtain J-resolved proton 1H MRS that 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. 
 
In a separate IRB-approved protocol (Neurobiology of a Mutation in Glycine Metabolism in 
Psychotic Disorders), we treated two carriers of the GLDC triplication with oral glycine using a 
double blind placebo-controlled cross over design, followed by open-label glycine. During both 
active treatment arms, the subjects experienced substantial improvement in clinical symptoms. 
The clinical gains that were achieved during Gly treatment were lost during the placebo arm and 
when the open-label treatment period ended. We obtained an administrative supplement from 
NIMH to continue to treat the subjects with open-label glycine for six months. The six-month 
extension is approved by the IRB. Due to the high doses of Gly required for therapeutic effects 
(~0.8 g/kg), it cannot be administered in capsule(s) without producing an osmotic load resulting 
in vomiting. As a result, the glycine powder (~60 g/d) has to be mixed with soft food or a drink, 
ingested slowly after each meal, and taken on a TID schedule, making it a cumbersome long-
term treatment.  
 
D-cycloserine (DCS) is a reasonable, and much less cumbersome, alternative. There are three 
reasons why DCS may be particularly advantageous in treating the mutation carriers. First, at 
the low dose (50 mg) we will use, DCS acts as a partial agonist at the glycine modulatory site 
(GMS); the GLDC mutation impacts glycine homeostasis. DCS has 40-70% of the potency of 
Gly to potentiate excitation of the NMDAR (Emmett et al. 1991; Henderson et al. 1990; Hood et 
al. 1989 McBain et al. 1989; Watson et al. 1990). Although the lower potency of DCS might 
reduce its efficacy, DCS crosses the blood brain barrier more readily than Gly (Morton et al. 
1955-1956). In addition, the magnitude of the augmentation needed to normalize Gly 
homeostasis in our subjects was substantially lower than anticipated - the maximum tolerated 
Gly dose was lower (~0.7 g/kg) than what is thought to be optimally therapeutic (0.8 g/kg) and 
the clinical benefits began at doses well below the maximum dose used. Second, DCS inhibits 
the formation of kynurenic acid (KYNA), a glutamate receptor antagonist with a particularly high 
affinity for the GMS, as least in in vitro studies (Baran & Kepplinger, 2014). Schwarcz was 
unable to replicate this effect in live rats, however (personal communication). Whether this is a 
difference between in vitro and in vivo effects or whether effects in rats generalize to humans is 
unclear.  Unbeknownst to us when we designed the original Gly study, our subjects have 
unusually high levels of KYNA. Elevated KYNA may potentiate the deleterious effect of the 
GLDC triplication at the GMS and may have attenuated the magnitude of the clinical effects we 
observed with Gly. If the Baran and Kepplinger findings hold up in people, it is conceivable that 
DCS may normalize KYNA, which Gly did not. Third, low dose DCS enhances learning and 
memory in animals, at least acutely (Watson et al., 1990; Collingridge, 1987; Monahan et al. 
1989; Quartermain et al. 1994), and in SZ patients, but is time-limited (Goff et al. 2008, 2012; 
Gottlieb et al. 2011). Gly produced no change in neurocognition in our subjects; conceivably, the 
combination of GMS agonism and KYNA inhibition may result in greater neurocognitive benefit. 
Whether these effects are sustainable is an empirical question. This tripartite rationale for using 
DCS in these specific subjects outweighs the relatively sparse and variable data on the clinical 
efficacy of DCS (Goff et al. 1999a, b, 2005, 2008; Duncan et al. 2004; van Berckel et al. 1999; 


Version  3 2_27_2015 
4
Rosse et al. 1996; Heresco-Levy et al. 1998, 2002). Of note, when DCS works, the effect size is 
large (0.8) (Goff et al. 1999b).  
 
DCS has been widely used as an anti-tubercular drug at doses substantially higher (500-2000 
mg) than the 50 mg dose we plan to use. At high doses, DCS acts as an antagonist at the GMS 
(Emmett et al. 1991) and can cause seizures, anxiety and psychosis (Kendig et al. 1956; Crane, 
1959). Some studies suggest that 50 mg of DCS selectively worsens negative symptoms in 
patients being treated with clozapine (Goff et al. 1996, 1999a, b), but improves negative 
symptoms when used in conjunction with typical antipsychotics (Goff et al. 1995, 1999b). At the 
low dose we plan to use, the only reported side effect was a modest and time-limited worsening 
of negative symptoms in a small minority of patients who were taking clozapine; this effect may 
be related to having a high DCS plasma level (Goff et al. 1996, 1999a, b). Interestingly, this mild 
worsening was not “particularly distressing to patients or clinicians” (Goff et al. 1999a).  
 
NMDAR modulatory agents have generally not shown therapeutic efficacy in patients taking 
CLZ (Tsai et al. 1999, 2010; Evins et al. 2000;), but there are exceptions (Heresco-Levy et al. 
1996; Tsai et al. 2010). Both of our patients will continue to take clozapine during the DCS 
study, as they did during the Gly study. One possible reason why they benefited from Gly 
despite being treated with clozapine is that the GLDC triplication is likely to cause unusually low 
levels of brain glycine. In such a situation, clozapine alone may not normalize synaptic levels of 
glycine in the presence of the accelerated degradation caused by the mutation. We will be 
monitoring DCS plasma levels every month as part of the monthly blood tests (see schema). 
Only one of the two carriers has negative symptoms and we will be following both of them 
closely (see below), as we did in the previous study.  
 
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; Cirak 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. 
 
The rationale for including the ophthalmological and pattern evoked electroretinogram (PERG) 
exam is as follows: Dr. Robert Miller at the University of Minnesota has shown that NMDA 
receptors in retinal ganglion cells require d-serine to function normally. He has been studying 
schizophrenic patients and shown abnormalities in the pattern evoked electroretinogram 
(PERG) consistent with NMDA hypofunction. A similar pattern is observed in serine racemase 
mice. We know from work that we have done to date that the two carriers have multiple indices 
of NMDAR hypofunction (reduced serine; increased kynurenine and kynurenic acid and 
quinolinic acid all of which are consistent with glycine dysregulation).  In light of this evidence, 
there is a compelling scientific justification for studying their PERGs during the open-label DCS 
augmentation arm. Although it would be interesting to obtain the PERG data after chronic DCS 
treatment, there are two reasons why we will not do so: 1) because of the blind, we would have 
to repeat the PERG procedures at least twice more, and 2) the procedure is rather arduous 


Version  3 2_27_2015 
5
since it takes 2 hours, involves having the pupils dilated, and would mean two trips to 
Minneapolis. 
 
d. Overview of Design 
The design is shown in the schema. If subjects are using glycine, this will be discontinued.   All 
of their other psychotropic medications will remain unchanged. They will be evaluated clinically 
every two weeks during the washout to establish the point at which they show a 25% worsening 
on the BPRS and/or when their CGI severity scores change from borderline mentally ill (their 
current ratings) to moderately mentally ill (a worsening of 2 severity points). These assessments 
are carried out by Dr. Levy and Mr. Coleman, both of whom have over 30 years of experience 
with psychotic patients and who know the symptom profiles of these patients quite well. Dr. 
Bodkin is kept fully informed about changes in clinical symptoms. When the subjects have 
returned to their baselines, Dr. Bodkin will assess the subjects as well to confirm that he is in 
agreement. This will establish a new clinical baseline (time point 0). Based on our previous 
experience with glycine discontinuation, we anticipate that this worsening will occur within about 
one month. Once notable clinical changes have started to occur, the formal clinical ratings will 
be carried out every week until the criteria for a new baseline have been met. Note that subjects 
are in at least weekly contact with the PI to monitor symptoms and side effects independent of 
completing the clinical scales, so the need for a change in the frequency of the formal clinical 
assessments can be readily ascertained. 
 
We temporarily suspended the glycine augmentation, because the TID dosing had become so 
burdensome that the subjects asked to stop, at least temporarily, after 16 weeks of 
augmentation, even though they both recognized that they were substantially better.  Both 
subjects have now resumed taking glycine due to a recurrence of symptoms. Assuming that 
they continue to take it until this protocol is approved, they will both undergo the washout 
described above. If one or both discontinue taking glycine before this protocol is approved, they 
may already have returned to their baseline. 
 
After the discontinuation period is completed, the subjects will receive open-label DCS (50 
mg/d) for 8 weeks. Subjects will be formally evaluated on all of the clinical measures (see below 
and schema) every two weeks but will be in weekly phone contact with the PI throughout. 
Although we do not anticipate that DCS will cause a worsening of their symptoms, we cannot 
rule out this possibility in advance. If the BPRS shows an additional 25% worsening or severity 
of specific symptoms changes by two additional points (compared to their new baseline), that 
subject will be discontinued. Dr. Bodkin will review the clinical data before a subject is 
discontinued.  . Subjects who complete the open label DCS trial will be randomized to DCS or 
placebo for 6-week periods in a double-blind design. The McLean Hospital research pharmacist, 
Laura Godfrey, will determine the randomization and will not be blind to drug or placebo 
condition, but the subjects and all other study staff will be. There will be a total of four 6-week 
double-blind exposures to DCS or placebo, each followed by one week of washout. A one-week 
washout is more than sufficient for both a behavioral and biochemical washout (half-life of DCS 
is 10 hours, so technically, two days should be sufficient). The two possible randomization 
schemas are: DCS-placebo-DCS-placebo or placebo-DCS-placebo-DCS, to be determined by 
the research pharmacist. We are limiting the length of each double-blind arm to six weeks to 
minimize the length of symptom exacerbation experienced by the subjects when they are 
receiving placebo. These four double-blind exposures (two each for DCS and placebo) will be 
followed by a 6-week single-blind exposure to DCS (subjects and the person doing the clinical 
assessments will not know if they are getting DCS or placebo, but Drs. Levy, Bodkin, and Ongur 
will know that they are getting DCS). After a one-week washout, this single-blind exposure will 


Version  3 2_27_2015 
6
be followed by 6 weeks of open-label DCS. Subjects will be aware of the design and thus will 
know that if they experience a worsening of symptoms in any clinical arm, it will be time-limited.  
 
II. Specific Aims 
 
a. Objectives/hypotheses 
 
The broad specific aims of this study are 1) to treat the carriers of this mutation with an NMDAR 
modulatory compound that can be administered as a pill, D-cycloserine (DCS), and 2) to 
compare the clinical and neurobiological changes achieved with DCS to those achieved with 
Gly. If the subjects experience similar clinical benefits, DCS augmentation could potentially be a 
long-term treatment for these individuals. 
 
Specific Aim 1: To assess the acute (8 weeks) effects of open-label DCS augmentation on 
positive, negative, and mood symptoms and on neurocognition. Hypothesis: Improvement 
during acute and chronic treatment, but not during placebo. Greater improvement on DCS than 
on Gly. To assess changes in the same clinical and cognitive dimensions just mentioned during 
discontinuation of DCS and DCS treatment (6 weeks/arm). 
 
Specific Aim 2: To assess the acute (8 weeks) effects of DCS augmentation on brain structure 
(3.0 Tesla) and chemistry using magnetic resonance spectroscopy (MRS, 4.0 Tesla). 
Hypothesis: Normalization of brain Gly level, decreased baseline GABA and increased baseline 
glutamate (Glu). Greater normalization on DCS than on Gly. 
 
Specific Aim 3: To assess the acute (8 weeks) effects of DCS augmentation on auditory evoked 
response potentials (ERPs). Hypothesis: Greater normalization of P50, mismatch negativity 
(MMN), P300, gamma oscillations on DCS than on Gly. 
 
Specific Aim 4: To assess the acute (8 weeks) effects of DCS augmentation on NMDAR in 
retinal ganglion cells. Hypothesis: Pattern electroretinogram amplitudes will increase more (i.e., 
greater saturation) on DCS than on Gly. 
 
Specific Aim 5: To assess the acute (8 weeks) and subsequent (6 weeks) effects of DCS 
augmentation or placebo on amino acid levels and other metabolites (e.g., kynurenic acid, 
KYNA). Hypothesis: Serine and Gly levels will increase, and KYNA levels will decrease, more 
on DCS than on Gly, and more on DCS and Gly than on placebo.  
 
III. Subject Selection 
Inclusion Criteria: Subjects will be selected on the basis of having a triplication of GLDC and a 
psychotic disorder and having participated in the protocol entitled Neurobiology of a Mutation in 
Glycine Metabolism in Psychotic Disorders (2012P001597). Exclusion criteria: meeting inclusion 
criteria but having a creatinine clearance less than 50 mL/min.  Prior to beginning the study, 
subjects will be called by the PI and all of the procedures and time frames will be reviewed. 
Written informed consent will be obtained by the PI and Dr. J. Alexander Bodkin, a licensed 
physician who is medical back-up for the study. 
 
IV. Subject Enrollment 
The total projected sample size is two individuals who are carriers of the 9p24.1 
duplication/triplication. One has a diagnosis of bipolar disorder with psychotic features and the 
other has a diagnosis of schizo-affective disorder. They will be recruited as outpatients. Their 


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7
current ages are 33 (male) and 61 (female). The total projected sample size is two individuals 
who are carriers of the 9p24.1 duplication/triplication.  
 
At the present time, the subjects are taking the following medications: 
 
5459: clozapine (62.5 mg/d); lithium (600 mg/d); gabapentin (300/d); cymbalta (120/d), mirapex 
(0.3 mg/d) 
 
3363: Clozapine (100 mg/d); abilify (15 mg/d); celexa (40 mg/d) 
 
V. Study Procedures 
1) Baseline procedures previously completed at McLean prior to the glycine augmentation study 
that will not be repeated at baseline for this study: The previously collected data will be used for 
comparison with data collected during the open-label DCS treatment arm. 
 
Physical exam/EKG/weight (by Dr. Ongur). 
Structural MRI (3T - 15 minutes), proton 1H MRS (4T) for GABA levels (MEGAPRESS - 1 hour); 
Proton 1H MRS (4T-J-Resolved) for glycine and glutamate and GABA levels (1 hour). All 
scan procedures were approved by the McLean IRB. Dr. Ongur will continue to be 
responsible for medical oversight of the imaging components of the study.   
Auditory evoked response data (by Dr. Hall). 
 
2) Baseline procedures that will be collected at time point 0 (defined above and below), the new 
baseline, even if they were previously obtained as part of the glycine study. 
 
Movement disorders exam (extrapyramidal side effects, tardive dyskinesia - AIMS/SAS) (Guy, 
1976; Simpson 
 & Angus, 1970) (by Dr. Levy, in person). 
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., 
using a secure skype-like connection – vidyo – see below). Dr. Bodkin will confirm that 
the subject meets criteria for a new baseline (a 25% worsening on the BPRS and/or 
when their CGI severity scores worsen by 2 severity points). 
Neurocognitive testing (MATRICS Consensus Cognitive Battery-MCBB (Kern et al. 2011) (by 
Dr. Levy, in 
person). 
Physical Exam/EKG/Weight: These procedures will be carried out by the subjects’ internist, Dr. 
Colette  
Kirchhoff, in Bozeman MT. 
 
Fasting blood tests for amino acid levels, psychotropic drug levels, DCS levels, and routine 
clinical labs [comprehensive metabolic profile (CMP), lipid panel, GGT, uric acid, CBC with 
differential, CRP-hs]: Blood will be drawn at the Clinical Lab of Bozeman-Deaconess Hospital. 
Centrifuged plasma will be frozen for later analysis of amino acid, psychotropic drug, and DCS 
levels at Nathan Kline Institute. Blood for routine clinical labs and one subject’s lithium level will 
be processed by the Clinical Lab of Bozeman-Deaconess Hospital on the day the sample is 
obtained. 
 
Prior to the beginning of the open-label arm (within three days) and at the end of each of the six 
double-blind placebo controlled treatment arms fasting blood tests will be done for the following:  


Version  3 2_27_2015 
8
 
Both subjects: 
6 cc - tryptophan plasma level;  
6 cc - small neutral/excitatory amino acid plasma levels;  
4 cc – GABA plasma level;  
6 cc- homocysteine plasma level; 
7 cc – KYNA plasma level, KYN plasma level, and quinolinic acid plasma levels  
5 cc – DCS level 
1 cc – comprehensive metabolic profile (CMP); 
1 cc - lipid panel 
1 cc - GGT 
1 cc – uric acid 
4 cc  - CBC with differential 
1 cc – CRP-hs 
Subtotal: 43 cc 
 
Subject 5459: 
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.  
Subtotal: 23 cc 
Thus, for this subject a total of 66 cc will be drawn at each time point.  
 
Subject 3363: 
6 cc- clozaril steady state plasma level;  
6 cc – abilify steady state plasma level;  
6 cc – celexa steady state plasma level, all prior to AM dose.  
Subtotal: 18 cc 
Thus, for this subject a total of 61 cc will be drawn at each time point.  
 
If a subject’s medications change prior to the initiation of the DCS study, plasma levels for 
specific dugs may change. If this results in a change in the amount of blood required, the IRB 
will be informed. 
 
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 
total amount of blood that will be drawn over the course of the entire 50 weeks of the study will 
be 854 cc (about 58 tablespoons) for one subject and 896 cc (about 61 tablespoons) for the 
other. 
 
The personal physician of the two subjects has been informed about their planned participation 
in a study that involves exposure to DCS and has agreed to its safety (physician ok has been 
uploaded). Before the study begins, the internist will be notified in writing (sample letter to 
practitioner has been uploaded). 
 
3) Glycine Washout. Glycine augmentation will be discontinued and subjects will be monitored 
clinically every week (at least once a week). During the washout all other psychotropic 
medications will remain unchanged. The subjects will receive clinical ratings (see above) every 
two weeks to establish the point at which they show a 25% worsening on the BPRS and/or 
when their CGI severity scores change from borderline mentally ill (their current ratings) to 


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9
mildly or moderately mentally ill (a worsening of 1-2 severity points) (new clinical baseline). 
Based on our previous experience with glycine discontinuation, we anticipate that this 
worsening will occur within about one month. Once notable clinical changes have started to 
occur, the clinical ratings will be carried out every week until the criteria for a new baseline have 
been met. Note that subjects are in at least weekly contact with the PI to monitor symptoms and 
side effects independent of completing the formal clinical scales, so the need for a change in the 
frequency of the formal clinical assessments can be readily ascertained. The end of the glycine 
washout will be equivalent to week 0. 
 
4) Open-label DCS (daily dose of 50 mg) for 8 weeks – Treatment Arm A: Product Description 
of DCS (seromycin), has been uploaded with the application.  
 
Dr. Bodkin will be responsible for medical oversight of the DCS 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. Both psychiatrists agreed to the DCS 
study before the DCS grant was submitted to NIMH. Copies of those letters have been 
uploaded. 
 
The McLean Hospital Pharmacy will order pharmaceutical grade DCS from The Chao Center. 
The DCS will be stored at room temperature in closed containers in a dry area in the McLean 
Hospital Pharmacy, avoiding humidity, sunlight and high temperature.  
 
DCS is supplied in 250 mg capsules. The McLean Research Pharmacy will compound   DCS 50 
mg double-blind capsules and Placebo double blind capsules for dispensing to subjects.  
Although unlikely at the low dose of DCS (50 mg) that will be used, to ensure that subjects do 
not develop B12 or folate deficiency, they will be prescribed one vitamin B-complex tablet per 
day. Prescriptions for DCS 50 mg/Placebo double blind capsules and vitamin B-complex tablets 
will be dispensed by the McLean Hospital Research Pharmacy and shipped by Fed Ex to 
subjects in 4-6 week supplies.  
 
B-Complex vitamins will be procured and dispensed to subjects by the McLean Hospital 
Research Pharmacy in the following USP approved formulation:  Nature Made Super B 
Complex® Tablets (UPC # 031604027278).   
 
It is anticipated that all of the DCS that is ordered will be used. However, if there is any unused 
DCS, we will collect and dispose of all unused study medications.  After documenting the return 
and de-identifying the product, non-controlled study medication is destroyed with biohazard 
waste and documented as such by the McLean Hospital Pharmacy. 
 
Subjects will keep a daily log to mark the time each dose was taken (sample log has been 
uploaded). 
 
Weekly 
Monitoring of clinical changes and side effects weekly (or more often as needed). 
 
At the end of weeks 2, 4, 6, and 8: 


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10 
Clinical ratings using “skype-like” video conferencing (see below for details on measures that 
will be taken to ensure confidential and secure connections under the auspices of Partners 
Collaborative Media).  
 
During week 4: 
a) Weight measurement 
b) Blood work (66 cc and 61 cc)  (drawn in the Clinical Laboratory at Bozeman-Deaconess 
Medical Center; frozen plasma for amino acid and psychotropic blood levels will shipped to the 
Analytical Psychopharmacology Laboratory at the Nathan Kline Institute (NKI) for processing. 
Routine laboratory tests, such as CBC with differential, etc as well as DCS levels will be 
performed by Clinical Laboratory at Bozeman-Deaconess Medical Center. 
 
At the end of week 7 (on the way to Boston for week 8 procedures detailed below): 
Ophthalmology and Electroretinogram Exams at the University of Minnesota: 
 
The subjects will be flying through Minneapolis to get to Boston for their week 8 procedures 
during the open-label DCS treatment arm. For reasons explained above, this is a unique 
opportunity to collect data related to NMDA receptor function. The procedures are routine and 
do not pose significant risk to the subjects. The details of the eye exam are described below and 
in the consent form. The eye exam will be carried out in collaboration with Dr. Robert F. Miller, 
3M Bert Cross Professor of Visual Neuroscience, Professor in Neuroscience and 
Ophthalmology Department of Neuroscience, University of Minnesota Medical School. He 
currently has IRB approval to carry out these procedures in schizophrenia patients at the 
University of Minnesota and is revising the protocol to include bipolar patients. Copies of his 
currently approved consent form and IRB approval have been uploaded.  Both subjects have 
completed these procedures uneventfully twice.  
 
There are two components to the eye exam, both of which were previously approved by the 
McLean IRB: 
 
Component I is a routine clinical eye exam to evaluate the health of the eyes.  A board certified 
ophthalmologist shines a light into the eyes and views them through a magnifying lens to 
examine internal structures of the eyes. This procedure requires dilated using a standard 
dilation eye-drops (phenlyephrine and tropicamide). The exam will also include photography of 
the inside of the eyes with a specialized camera.  This, too, is a routine procedure and will be 
conducted by a trained photographer. The subject will sit in front of a camera that is equipped 
with a head rest and chin rest for comfort.  The subject will be asked to look at a visual target 
while the photographer takes the picture. Both procedures (exam and photography) take only a 
few minutes to complete and should involve no physical discomfort. The camera is non-contact, 
FDA-approved, and there are no known risks associated with them other than the dilation.   
 
Component II involves four tests that measure physical and functional features of the retina.  
Three of the tests are electroretinogram (ERGs).  The fourth test is called OCT. The three types 
of ERGs are the 1) Pattern ERG, 2) Full Field ERG, and 3) Multifocal ERG.  Collectively, these 
tests will measure how well different parts of the retina work.  For these tests, anesthetic eye-
drops are administered to make the subject comfortable during the procedures (the subject 
should feel minimal or no discomfort. Short breaks can be taken if necessary). For the full field 
ERG, multifocal ERG and the OCT test, the pupils will be fully dilated using standard dilation 
eye-drops (phenlyephrine and tropicamide).    
 
Below is a more detailed description of the ERG and OCT procedures:  


Version  3 2_27_2015 
11 
 
Pattern ERG (pERG) and Fullfield ERG (ffERG):  The pERG provides information about the 
ganglion cell in the retina. The Full Field ERG (ffERG) is a standard clinical test that looks at the 
overall function of the retina. For both tests, a flexible conducting fiber will be placed just inside 
the margin of the lower eyelid so it comes in contact with the tear film of the eye.  The 
conducting fiber will be held in place by 2 sticky pads on the skin.  Four additional conducting 
fibers (two for each eye recording) will be placed on the skin near the outer corner of the eye, on 
the earlobe, on the forehead or on the forearm/hand. For the pERG, subjects will have a vision 
test and wear corrective lenses if necessary.   Both eyes will be tested at the same time.  
Subjects will be asked to look at black and white checkerboard images as part of the task.  This 
procedure should last between 45 and 75 minutes, which includes the time required for the 
vision test.   For the ffERG, each eye is tested separately.  Subjects will sit in a dark room for 
about 15 minutes prior to the beginning of the procedure in order to dark-acclimate.  During the 
testing, subjects will place their chins on a chin rest and forehead against a headrest and look 
straight ahead, while lights of that differ in brightness are flashed in front of their eyes.   Next, 
subjects will sit in a more brightly lit room and view the flashes as before.   This procedure 
should last between 45 and 60 minutes.  
 
Multifocal ERG (mfERG):  The mfERG looks the functioning of different areas of the retina.  The 
procedure will require fully dilated eyes using drops commonly used in an ophthalmology clinic 
(phenylephrine and tropicamide).  Each eye will be tested separately.  A contact lens, which is 
attached to a flexible conducting fiber, will be used to record biological signals from the retina.    
The upper and lower eyelids will be held open by a special device.  A thick artificial tear drop 
(Goniosol) will be placed between the contact lens and the surface of your eye for comfort 
during data collection.  Subjects will be asked to view black and white hexagon patterns and to 
minimize eye movement in order to avoid irritating the eye.  The total duration of this procedure 
is approximately 45-60 minutes (and includes testing both eyes).  
 
Optical coherence tomography (OCT): The OCT test uses light to measure structures in the 
eye.  This machine also takes a picture of the inside of the eyes with a specialized camera.  A 
trained photographer will conduct this test.   The subject will sit in front of the OCT machine and 
be asked to look at a target.  The head and chin will rest against a head rest and chin rest.  The 
OCT machine will shine a light into the eye and a photograph will be taken.  The test takes 
about 1-2 minutes per eye.  This procedure is non-contact, FDA approved, and no risks are 
known to be associated with it other than the dilation.   
 
Dilation drops may need to be applied to the eyes twice in each visit if the dilation effects wear 
off before all procedures are completed.  There should be no additional risk associated with a 
second application of dilation drops. 
 
During week 8: 
 
a) Weight measurement 
b) Repeat physical exam and EKG (Dr. Ongur, at McLean) 
c) Blood work (66 cc and 61 cc)  (drawn in the Clinical Laboratory at McLean Hospital; frozen 
plasma for amino acid and psychotropic blood levels will shipped to the Analytical 
Psychopharmacology Laboratory at the Nathan Kline Institute (NKI) for processing (routine 
laboratory tests, such as CBC with differential, etc as well as DCS levels will be performed by 
North Shore Medical Center).  
d) Movement disorders assessment (extrapyramidal side effects, tardive dyskinesia - AIMS/SAS 
– by Dr. Levy or Dr. Bodkin, in person at McLean) 


Version  3 2_27_2015 
12 
 
e) MCCB (MATRICS) - by Dr. Levy, in person. 
f) EEG – Dr. Hall, at McLean 
 
f) Structural MRI (3T - 15 minutes), proton 1H MRS (4T) for GABA and glutamate levels 
(MEGAPRESS - 1 hour); Proton 1H MRS (4T-J-Resolved) for glycine levels (1 hour). All scan 
procedures are approved by the McLean IRB. All of these are brain imaging scans that were 
previously performed at McLean Hospital as part of the glycine study baseline procedures.   
 
Subjects will first receive an occipital cortex echo time averaged (TEAV) MRS scan; an MRS 
technologist will provide oversight.  Head and MRS voxel position coordinates at will be 
determined using brain structural landmarks and will be recorded.  
 
In addition, since both subjects will be taking DCS during the open-label phase, they will receive 
one MRS scan for glycine levels prior to their dose of DCS (above), followed by a scan shortly 
after taking the daily dose (50 mg) (90 minutes). We will be able to compare brain uptake after 
an acute dose (baseline) and after chronic treatment, including uptake immediately after dosing.  
 
Subjects will first receive a baseline occipital cortex echo time averaged (TEAV) MRS scan; an 
MRS technologist will provide oversight.  Head and MRS voxel position coordinates at will be 
determined using brain structural landmarks and will be recorded. After their DCS dose, 
subjects will be re-positioned in the scanner for the brain and blood measurements over the 
next two hours, as described above. 
 
Clinical Oversight: 
The subjects are well known to the PI and study staff, 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. Dr. Levy will inform Dr. Bodkin and Dr. Ongur immediately if 
any side effects or clinical changes are reported that warrant medical follow-up.   
 
At the end of the first week of DCS, 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 DCS. The subjects will also be given emergency contact numbers for Drs. Levy, Bodkin, and 
Ongur. The subjects will also be told to call Dr. Levy immediately if they experience any acute 
side effects (e.g., exacerbation of psychotic or negative symptoms).  
 
Week 9 will be a washout week during which neither DCS nor placebo will be administered. 
 
5) 6 Weeks on DCS (50 mg/d) or Placebo (weeks 10-15) – Treatment Arm B. 
 
The McLean Pharmacy will prepare and label prescriptions for DCS capsules, Placebo 
capsules, and vitamin B-12 Complex tablets, which will be FedEx’ed in 4-6-week supplies. The 
placebo is supplied in opaque gelatin capsules filled with microcrystalline cellulose. The McLean 
Hospital Pharmacy will provide the placebo. 
 
Subjects will keep a daily log to mark the time each dose was taken.  
 
At the end of weeks 11, 13, and 15:  
 
Clinical ratings as described above using “skype-like” video conferencing.  
 


Version  3 2_27_2015 
13 
At the end of week 12: 
Blood work as described above. 
Weight measurement. 
 
An assessment of movement disorders (extrapyramidal side effects, tardive dyskinesia - 
AIMS/SAS - Dr. Levy, by “skype.”  
 
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 DCS or placebo (week 10), and at the end of weeks 12 and 14, 
the subjects will be called by a study physician (Dr. Bodkin) to assess how they are reacting to 
the DCS or placebo. The subjects will also be told to call Dr. Levy immediately if they 
experience any acute side effects (e.g., exacerbation of psychotic or negative symptoms).  
 
Week 16 will be a washout week during which neither DCS nor placebo will be administered. 
 
6) 6 Weeks on DCS (50 mg/d) or Placebo (weeks 17-36) – Treatment Arms C-E. 
 
Procedures identical to those described above in section 5 (and at corresponding time points) 
will be administered except for the MATRICS battery, which will not be re-administered until 
week 50 (see 8 below).  
 
Weeks 23, 30, and 37 will be washout weeks during which neither DCS nor placebo will be 
administered. 
 
7) 6 weeks of DCS: Single-blind (weeks 38-43) – Treatment Arm F. 
Subjects will receive 50 mg/d of DCS. Subjects and the person doing the clinical assessments 
will not know if they are getting DCS or placebo, but Drs. Levy, Bodkin, and Ongur will know that 
they are getting DCS. 
 
Procedures identical to those described above (and at corresponding time points) will be 
administered. 
Week 44 will be a washout week during which neither DCS nor placebo will be administered. 
 
8) 6 weeks of DCS: Open-label (weeks 45-50) – Treatment Arm G. 
Procedures identical to those described above (and at corresponding time points) will be 
administered. 
The MATRICS battery will be re-administered in week 50. 
 
9) Processing of Amino acid levels. The consent forms contain a provision for subjects to give 
permission 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 are 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 


Version  3 2_27_2015 
14 
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. 
 
10) Total Amount of Blood Drawn: The total amount of blood drawn at each scheduled time 
point is 66 cc and 61 cc for each of the two non-mutation carriers, respectively. The total 
amount of blood will not exceed 550 cc in any 8-week period. The subjects will be advised not to 
donate blood for at least one month after completing the study.  
 
11) 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.  
Material on the MATRICS battery has been uploaded. 
 
12) 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. 
 
A technical statement from PCM about how the secure connection is implemented has been 
uploaded.  
 
VI. Biostatistical Analysis 
All data acquisition and processing will be carried out blind to mutation status. The McLean 
investigators have extensive imaging databases involving controls and patients with psychotic 
disorders. Thus, we are well positioned to compare 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 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). 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 DCS vs placebo. This is not a population study; it is 
designed to provide mechanistic insights about the effects of this mutation in the brain. Dr. Miller 
has PERG data on other patients and on controls. 
 
VII. Risk and Discomforts 


Version  3 2_27_2015 
15 
 
The imaging procedures have been used extensively at McLean 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.   
 
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).  Subjects will be allowed to leave the 
scanner between scans and can be re-positioned for the next scan, as described in the 
application. Both subjects have successfully completed imaging procedures. 
 


Version  3 2_27_2015 
16 
DCS has been widely used to augment standard psychotropic drug treatment and is well 
tolerated. The daily dose of 50 mg is low enough to be a partial agonist of the GMS and has no 
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.   
 
Periodic blood samples 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.  
 
The eye exam procedures are routine and should cause minimal or no discomfort. 
 
Risks to privacy and confidentiality are minimal. All subjects are assigned a random 4-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 DCS augmentation 
of their medication regimen. Although subjects receive no immediate benefit from the brain 
imaging 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 DCS 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 and NMDA receptor function. 
 
IX. Monitoring and Quality Assurance 
The scientific integrity of the study and protection of participant safety will be monitored by the 
investigators using an Adverse Event Tracking Log, including the detection and reporting of 
adverse events. The safety data include all imaging procedures, the neurocognitive function 
battery, as well as the double-blind placebo-controlled and open-label DCS augmentation trials. 
Efficacy data includes all DCS-related procedures.  
 
All adverse events will be promptly reported to the Partners Human Research Committee 
(PHRC) and NIMH as appropriate. At a minimum, the investigators will review all adverse 
events at the end of each treatment arm, but more often if needed. Unanticipated problems 
involving risks to subjects or others including adverse events will be reported to the PHRC in 
accordance with PHRC unanticipated problems reporting guidelines. 
At a minimum, the investigators will review all adverse events at the end of each treatment arm, 
but more often if needed. 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 DCS.  
 
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, diarrhea). Dr. Goff, a consultant on this project, has a 
great deal of experience in using DCS to augment the therapeutic effects of antipsychotic 
medication and will be available to advise the study team about any needed changes (i.e., dose 
reduction, discontinuation) based on side effects or changes in clinical state.  Decisions about 
how best to proceed will be made in consultation among Drs. Levy, Bodkin, (Ongur if Dr. Bodkin 
is not available), Goff, and the McLean pharmacist. Based on Dr. Goff’s extensive experience 


Version  3 2_27_2015 
17 
using this dose of DCS, 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 
or 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 compound that has been safely used as an augmentation strategy.  
The same procedures were used in the initial glycine augmentation study and the current 
extended glycine trial and have worked effectively. 
 
The PI has talked all of the people involved in the study (Drs. Kaufman, Ongur, Bodkin, Goff, 
Visscher, and Vuckovic; Ms. Godfrey) about the adequacy of the plan to provide medical and/or 
psychiatric monitoring of these patients while they are taking a novel compound; they have 
agreed that the proposed plan is acceptable. Dr. Visscher is the psychiatrist for one of the 
subjects and Dr. Vuckovic is the psychiatrist for the other. Blood work results are faxed to them 
and they are kept apprised of any notable developments (e., beginning and end of any phase of 
the study, worsening of clinical state, improvement in clinical state). They, in turn, contact the PI 
if they become concerned about changes in clinical state or side effects. 
 
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.  
 
X. 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. 
 
Baran H, Kepplinger B. D-cycloserine lowers kynurenic acid formation - New mechanism of 
action. Eur Neuropsychopharmacol 2014;24:639-644. 
 
Bennett J, Ashtari M, Wellman J, Marshall KA, Cyckowski LL, Chung DC, McCague S, Pierce 
EA, Chen Y, Bennicelli JL, Zhu X, Ying G-S, Sun J, Wright JF, Auricchio A, Simonelli F, Shindler 
KS, Mingozzi F, High KA, Maguire AM. AAV2 gene therapy readministration in three adults with 
congenital blindness. Sci Translational Med 2012;4:120ra15. 
 
Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets 
G, Burton EA, Wong B, Tsang G, West BL, Powell B, Shellooe R, Marimuthu A, Nguyen H, 
Zhang KYJ, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D’Andrea D, Koehler A, Stumm 
M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, Chapman 
PB, Flaherty KT, Xu X, Nathanson KL, Nolop K. Clinical efficacy of a RAF inhibitor needs broad 
target blockade in BRAF-mutant melanoma. Nature 2010;467:596-599. 
 
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 
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Prot_001.pdf: 
Official Title: Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine (DCS) 
 
NCT number:  NCT02304432 
 
Document Date: 4/9/2015 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
2 
 
Answer all questions accurately and completely in order to provide the PHRC 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 
Targeting a Genetic Mutation in Glycine Metabolism with D-cycloserine 
 
FUNDING 
NIMH 
 
VERSION DATE 
4/9/2015 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
We propose to (1) to target a triplication of GLDC by trying to normalize brain glycine levels 
using D-cycloserine augmentation of usual psychotropic drug treatment, and (2) to characterize 
the neurobiology of this mutation using neurocognitive and electrophysiology measures and 
studies of brain structure and function. 
 
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 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. 
 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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 Partners 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 Partners will be limited to 
adults although the sponsor’s protocol is open to both children and adults.”
 
The total projected sample size is 2, consisting of two carriers of the 9p24.1 mutation, both of 
whom participated in the protocol entitled Neurobiology of a Mutation in Glycine Metabolism in 
Psychotic Disorders (2012P001597). The two carriers have diagnoses of bipolar disorder with 
psychotic features and schizo-affective disorder and will be recruited as outpatients.  The age 
range is 33-64 and includes one male and one female. Inclusion is restricted to these carriers of 
this specific mutation. This is a private mutation, present only in these two individuals. Exclusion 
criteria: meeting inclusion criteria but having a creatinine clearance less than 50 mL/min. 
 
Design of the study:  
Open-label DCS (daily dose of 50 mg) for 8 weeks – Treatment Arm A, followed by four 6-week 
periods of double-blind DCS or placebo with one week of washout in between. Subjects will be 
randomized to DCS-placebo-DCS-placebo or to placebo-DCS-placebo-DCS by the McLean 
Hospital research pharmacist, Laura Godfrey.  These four double-blind exposures (two each for 
DCS and placebo) will be followed by a 6-week single-blind exposure to DCS (subjects and the 
person doing the clinical assessments will not know if they are getting DCS or placebo, but Drs. 
Levy, Bodkin, and Ongur will know that they are getting DCS). After a one-week washout, this 
single-blind exposure will be followed by 6 weeks of open-label DCS. The length of each 
double-blind arm is limited to six weeks to minimize the length of symptom exacerbation 
experienced by the subjects when they are receiving placebo. 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. Both the DCS (source: The Chao 
Center) and the placebo will be dispensed by the McLean Hospital Pharmacy. Throughout the 
study, subjects will take one vitamin-B complex tablet per day. 
 
Dr. Bodkin will be responsible for medical oversight of the d-cycloserine (DCS) augmentation 
component of the study. Dr. Ongur will serve as his back-up. Dr. Ongur will be responsible for 
medical oversight of the imaging components of the study. 
 
 
Briefly describe study procedures.  Include any local site restrictions, for example, 
“Subjects enrolled at Partners will not participate in the pharmacokinetic portion of the 
study.”  Describe study endpoints.
Before beginning the study, subjects will have an EKG and physical exam performed by their 
personal physician. This will be repeated at week 8 and week 44 at the end of the study. Blood 
work will be done at the same time and consist of the following tests: comprehensive metabolic 
profile (CMP), lipid panel, GGT, uric acid, CBC with differential, CRP-hs. Blood will also be 
drawn for large and small amino acid levels and psychotropic drug levels. 
 
Periodic blood tests and weight checks, clinical ratings (PANSS, Clinical Global Impression 
scale, Brief Psychiatric Rating Scale, Young Mania Rating Scale, HAM-D), side effect 
monitoring, movement disorder assessments (AIMS and SAS) and neurocognitive testing 
(MATRICS) – see schema for details. 
 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
4 
At the end of week 7 of open-label DCS, subjects will undergo electroretinograms at the 
University of Minnesota. During week 8 of open-label DCS they will have a structural MRI, 
Proton 1H MRS for brain GABA, glutamate, and glycine levels, the MATRICs neurocognitive 
battery, and an EEG. 
 
For studies involving treatment or diagnosis, provide information about standard of care 
at Partners (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.
Standard care usually does not involve augmentation with DCS. Otherwise, their 
pharmacological treatment is consistent with the standard of care. 
 
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.
 
Subjects who meet the inclusion criteria specific above but have a creatinine clearance less 
than 50 mL/min will be excluded. 
 
DCS Augmentation has been used to augment standard psychotropic drug treatment and is well 
tolerated. At 50 mg/day, DCS is a partial agonist. It crosses the blood brain barrier readily and 
should facilitate excitation of the NMDA receptor to compensate for the accelerated degradation 
of glycine caused by the mutation. Both patients will be taking clozapine; in some patients DCS 
results in either no clinical effects or a slight worsening of negative symptoms in clozapine-
treated patients. The same applies to glycine. The fact that both patients derived considerable 
clinical benefit from glycine would suggest that DCS should have a similar therapeutic effect.  
The subjects will be monitored closely by the research team and by their own psychiatrists.  
 
The clinical assessment every two weeks includes an evaluation of suicidality (HAMS and C-
SSRS. In addition, there is an at least once-weekly call with Dr. Levy to monitor changes in 
symptoms. Should any suicidal ideation emerge, Mr. Coleman and Dr. Levy would review the 
symptoms and their acuteness with Dr. Bodkin (or Dr. Ongur). Dr. Bodkin (or Dr. Ongur) would 
talk with the subject. We would then have a conference call involving Dr. Levy, Mr. Coleman, 
and Dr. Bodkin (Dr. Ongur should Dr. Bodkin not be available) to discuss the best disposition: 
determining whether a subject need to be hospitalized, whether the subject should be 
discontinued from the study; whether emergency services (911) should be notified. We would 
confer with the subject's psychiatrist and notify the internist.  We would discuss with the subject 
what we feel is the best plan going forward and facilitate whatever disposition seems best. The 
subject's family would be informed (with written permission from the subject obtained in the 
informed consent) to help ensure prompt compliance with the disposition. 
 
The imaging procedures have been used extensively at McLean without complications. Both 
subjects will be carefully screened again for the safety of the imaging procedures. Both subjects 
have had multiple brain scans at McLean in the recent past. Baseline imaging data collected in 
the glycine study will serve as baseline data in this study. 
 
The PI has talked with all of the people involved in the study (Drs. Ongur, Bodkin, Goff, 
Visscher, Vuckovic; Mr. Coleman, Ms. Godfrey) 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. Dr. Bodkin is the primary medical back-up; Dr. Ongur is back-up 


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5 
if Dr. Bodkin is unavailable. Dr. Goff is an unpaid consult with expertise in using DCS. Drs. 
Visscher and Vuckovic are the treating psychiatrists of the subjects. Mr. Coleman is performs all 
clinical assessments. Ms. Godfrey is the research pharmacist. 
 
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.
 
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 
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. The McLean imaging center is very experienced with MRI 
scanning and has an impeccable safety record. The effects of MRI on the fetus are not well 
characterized, but are irrelevant in this study, because the female patient has had a 
hysterectomy. 
 
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, 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
6 
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).  The DCS uptake scan requires multiple 
scans over a two 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. Both 
subjects have successfully completed imaging procedures. 
 
DCS Augmentation Clinical Trial: Pharmaceutical grade DCS (The Chao Center) will be used. 
The dose will be 50 mg/d, which is well within the range of doses that were well tolerated in 
previous patient studies (Goff et al. 1999a, b, 2005, 2008; Heresco-Levy et al. 1998, 2002). No 
adverse effects on kidney, liver, hematology or blood chemistry values have been reported. 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 monthly 
during the open-label DCS treatment arm as well as every 6 weeks after that. As mentioned 
above, at the low dose of DCS that we plan to use, the only reported psychiatric side effect was 
a modest and time-limited worsening of negative symptoms in a small minority of patients who 
were taking clozapine; this effect may be related to having a high DCS plasma level (Goff et al. 
1996, 1999a, b). Interestingly, this mild worsening was not “particularly distressing to patients or 
clinicians” (Goff et al. 1999a). Subjects will also take one vitamin B-complex tablet/day to ensure 
that they do not develop B12 and folate deficiency. These are unlikely at the low dose of DCS 
(50 mg) that will be used. 
 
Periodic blood samples 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. 
 
Risks to privacy and confidentiality are minimal. All subjects are assigned a random 4-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 metabolism 
and to determine whether carriers of this mutation may preferentially benefit from DCS 
augmentation of their medication regimen. Although subjects receive no immediate benefit from 
the brain imaging procedures beyond contributing to important research, the potential scientific 
yield could have a major impact on identifying causal mechanisms in psychotic disorders. If the 
DCS augmentation is beneficial, these two subjects may experience a significant reduction in 
psychotic symptoms and improvement in neurocognition, which may also help other subjects 


Partners Human Subjects Research Application Form  
 
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Version Date:  October 15, 2014 
 
  
7 
with mutations impacting the glycine metabolic pathway. Since both subjects responded well to 
glycine, which is a cumbersome to use and an unrealistic long-term treatment, DCS, which is 
available in a once daily pill would be a helpful long-term clinical adjunct if it is shown to be 
effective.  
 
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 DCS augmentation. All other subjects are excluded. Therefore, the only 
eligible participants at the present time are two carriers of this specific genetic mutation who 
also have a diagnosis of a psychotic disorder and have participated in the Neurobiology of a 
Mutation in Glycine Metabolism in Psychotic Disorders (2012P001597) protocol. To our 
knowledge, this is a private mutation although different mutations in the same gene have been 
reported in other individuals with psychotic disorders and with autism spectrum disorders. These 
individuals may be potentially eligible for a similar augmentation intervention. 
 
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 
 
For guidance, refer to the following Partners policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
          https://partnershealthcare-public.sharepoint.com/ClinicalResearch/Non-
English_Speaking_Subjects.1.10.pdf
 
 
 
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 will be selected on the basis of having a triplication of the GLDC gene, a mutation 
involving an abnormality in glycine metabolism that may be implicated in psychotic disorders, a 
psychotic disorder, and having participated in the Neurobiology of a Mutation in Glycine 
Metabolism in Psychotic Disorders (2012P001597) protocol. Prior to beginning the study, the PI 
will call the subjects and review all of the procedures and time frames. The subjects will be 
flown to Boston for the McLean procedures and to Minneapolis for the UMN procedures. Other 
procedures will be carried out in the subjects’ city of residence. The procedures will be 
scheduled well in advance to minimize inconvenience to the subjects and to optimize successful 
data collection at McLean.  


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
8 
 
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 subject will be paid $1,000 for completing the open-label DCS study and $1,000 for 
completing the entire double-blind DCS-placebo study. They will each be paid $200 for the 
UMN procedures. The imaging, electrophysiology procedures will involve at least 1 week 
away from work 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. Subjects will be paid a pro-rated amount if unable to complete all procedures based 
on the proportion of the study that was completed. For example, if a subject completes 80% 
of the procedures, that subject would be paid $800. Any additional expenses related to 
participation, such as gas or taxis, up to $500.00 in year 1 and up to $300 in year 2, will be 
reimbursed based on submitted receipts. 
 
For guidance, refer to the following Partners policies: 
          Recruitment of Research Subjects 
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Recruitment_Of_Research_Subjects.pdf
 
          Guidelines for Advertisements for Recruiting Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Guidelines_For_Advertisements.1.11.pdf
 
          Remuneration for Research Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Remuneration_for_Research_Subjects.pdf
 
 
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 
subjects are to be enrolled from among the investigators’ own patients, describe how 
the potential for coercion will be avoided.
The PI and Dr. J. Alexander Bodkin, a licensed physician who provides medical back-up for the 
study, will obtain written informed consent after reviewing the purposes of the study, detailing 
the procedures and explaining the informed consent documents. The subjects will have several 
weeks to consider participation. The subject will be given an opportunity to ask questions after 
which written informed consent is obtained. Competence to give informed consent will be 
determined by the PI 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 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
9 
Subjects of Research and/or Research Involving Individuals with Impaired Decision-
making Capacity, available on the New Submissions page on the PHRC website: 
      https://partnershealthcare.sharepoint.com/sites/phrmApply/aieipa/irb 
 
For guidance, refer to the following Partners policy: 
     Informed Consent of Research Subjects:
     https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Informed_Consent_of_Research_Subjects.pdf
 
 
 
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. 
 
The scientific integrity of the study and protection of participant safety will be monitored by the 
investigators using an Adverse Event Tracking Log, including the detection and reporting of 
adverse events. The safety data include all imaging procedures, the neurocognitive function 
battery, as well as the double-blind placebo-controlled and open-label DCS augmentation trials. 
Efficacy data includes all DCS-related procedures.  
 
All adverse events will be promptly reported to the Partners Human Research Committee 
(PHRC) and NIMH as appropriate. At a minimum, the investigators will review all adverse 
events at the end of each treatment arm, but more often if needed. Unanticipated problems 
involving risks to subjects or others including adverse events will be reported to the PHRC in 
accordance with PHRC unanticipated problems reporting guidelines. 
 
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 DCS. The dose of 
DCS used in the augmentation trials (50 mg/d) is well tolerated and is a standard dose used in 
clinical trials. Dr. Goff, a consultant on this project, has a great deal of experience in using DCS 
to augment the therapeutic effects of antipsychotic medication. Dr. Goff will be available to 
discuss ongoing clinical states, side effects, and to address any relevant management issues. 
At least once every week, the subjects will receive a phone call from Dr. Levy to discuss how 
they are feeling and to review side effects. At the end of the first week of DCS, the subjects will 
also be called by a study physician (Dr. Bodkin) to assess how they are reacting to the DCS 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).  
 


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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. 
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. 
 
A technical statement about how the secure connection will be implemented has been 
uploaded. 
 
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 Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  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 Partners Human Research Committee guidelines for Adverse Event 
Reporting
 
Subjects will be discontinued from the study if the BPRS shows a 25% worsening or severity of 
specific symptoms changes by two additional points (compared with baseline). Any adverse 
events will be immediately reported to the IRB. 
 
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 Partners policies: 
          Data and Safety Monitoring Plans and Quality Assurance
            https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/DSMP_in_Human_Subjects_Research.pdf  


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
11 
          
          Reporting Unanticipated Problems (including Adverse Events)
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Reporting_Unanticipated_Problems_including_Adverse_E
vents.pdf
 
 
 
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.
 
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, Ongur, or Bodkin. Computer databases are password protected.   
 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, 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 
Partners 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.
N/A 
 


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Version Date:  October 15, 2014 
 
  
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RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
When specimens or data collected by research collaborators outside Partners will be 
sent to Partners investigators, indicate from where the specimens/data will be obtained 
and whether the specimens/data will contain identifiers that could be used by Partners 
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