Prediction of Clinical Response to SSRI Treatment in Bipolar Disorder Using Serotonin 1A Receptor PET Imaging
Phase: PHASE4
Conditions: Bipolar Disorder
Sponsor: New York State Psychiatric Institute

Official Title: Prediction of Clinical Response to SSRI Treatment in Bipolar Disorder using 
Serotonin 1A Receptor PET Imaging 
Research Protocol 
Last approved by Institutional Review Board: 11/27/2020 
Lay Summary of Proposed Research  
Bipolar disorder is associated with alterations of chemicals in the brain, including one named 
serotonin. Treatment of depression in bipolar disorder can be accomplished by increasing 
serotonin function by a type of medication named a selective serotonin reuptake inhibitor 
(SSRI). Serotonin signals in the brain occur through receptors in a way that is similar to a lock 
and key, where serotonin is a key and the receptor is a lock. One important receptor is the 
serotonin 1A (5-HT1A) receptor. This receptor has been found to be abnormal in bipolar 
disorder during periods of depression, as measured by a type of brain imaging called positron 
emission tomography (PET).  
The amount of brain 5-HT1A receptor measured by imaging has also been associated with how 
well depressed patients with major depressive disorder respond to an SSRI medication. This 
project will measure the 5-HT1A receptors in bipolar depressed individuals using PET with the 
radiotracer [11C]-CUMI-101 and will evaluate the ability of this brain imaging signal to predict 
how patients respond to SSRI treatment when added to a mood stabilizer.  
Background, Significance and Rationale  
Bipolar disorder (BD) is a common psychiatric condition characterized by episodes of mania and 
depression. It is one of ten leading causes of disability worldwide and carries a significantly 
elevated risk for suicide. The pathophysiology of the disorder remains largely unknown and 
there are no imaging or diagnostic tests for the disorder. BD depression is the mood state most 
associated with disability and suicide, and patients typically spend more time in this phase. BD 
depression remains difficult to treat, with only three medications approved for its treatment. 
Moreover, treatment can only be given in a trial and error manner. For these reasons, there is a 
need for more knowledge of the pathophysiology of BD depression in order to design and select 
better treatment options. Several randomized, placebo-controlled clinical trials have 
demonstrated the efficacy of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), when 
combined with an anti-manic agent, for BD depression. Clinical trials of other SSRI’s have not 
demonstrated a class effect of the medications, however, despite their common use and clinical 
guidelines recommending their use. Treatment with SSRI’s also carries risks. A test to 
determine which patient with BD depression will respond to SSRI treatment would therefore be 
clinically useful. Positron emission tomography (PET) imaging allows for the quantitation of 
serotonin receptor levels and affinity in the brain. The serotonin 1A (5-HT1A) autoreceptor 
regulates serotonin neuron firing and release, and thereby influences the function of brain 
serotonin signaling. Our group developed a novel PET radiotracer for the 5-HT1A receptor, 
[11C] CUMI-101. This radiotracer has a straightforward and reliable synthesis process and is a 
partial agonist and therefore represents a technical improvement over [11C]WAY-100635 that 
has been previously used to measure binding to the receptor. [11C] CUMI-101 should be able to 
detect both upregulation and an increase in the proportion of high affinity agonist binding in the 

autoreceptor. We found that PET imaging of the 5- HT1A receptor binding using [11C] WAY-
100635 in BD depression found that high autoreceptor binding was associated with clinical 
remission from the disorder after patients received 3 months of naturalistic treatment. PET 
imaging with this radiotracer also found high autoreceptor binding to be associated with clinical 
response to antidepressant treatment in subjects with major depressive disorder. This protocol 
aims to evaluate whether PET scanning with [11C] CUMI-101 of autoreceptors in patients can 
predict clinical outcome after a protocol-driven six week treatment.  
Specific Aims and Hypotheses  
This protocol aims to evaluate whether PET scanning with [11C] CUMI-101 in bipolar depressed 
patients can predict clinical outcome after a protocol-driven six week treatment with an SSRI 
medication when added to a mood stabilizer medication. We hypothesize that higher brainstem 
raphe binding of [11C] CUMI-101 in the brain (BP) will predict a better clinical response to 
treatment. This result would be consistent with the finding that higher BP within the brainstem 
raphe of a similar radiotracer [11C] WAY-100635 predicted clinical response to selective 
serotonin reuptake inhibitors in subjects with major depressive disorder. Our finding may be the 
first step to developing an imaging test to predict clinical response to SSRI treatment in BD 
depression.  
Specify subject population 
 
Patients with bipolar disorder, currently in a major depressive episode 
Number of completers required to accomplish study aims 
25 
Projected number of subjects who will be enrolled to obtain required number of completers 40-
45 
Age range of subject population 
18-60  
Gender, Racial and Ethnic Breakdown  
The target composition will be 75% White or Caucasian, 20% Black or African American, 5% 
Asian. Approximately 15% will be Hispanic and 85% will be non-Hispanic. 60% will be female 
and 40% will be male.  
Describe settings where recruitment will occur  
Patients will be recruited through referrals from treating outpatient psychiatrists, or from clinics, 
inpatient units and emergency department (ED) at Columbia University. Advertisements will be 
placed through the Columbia University website, on advertising sites such as Craig’s List, social 
medial websites and in print newspapers such as AM New York. The study will be listed on 
Columbia's research study search engine, RecruitMe, and a website that describes the study 
will be created. Fliers will be posted around Columbia University Medical Center campus and 
the undergraduate campus at Morningside Heights. Outreach to mental health clinics, primary 
care clinics, support groups, community groups and facilities will be conducted in-person to best 
reflect the composition of the population in our city. Letters and fliers will be sent via mail or 

email to clinic directors of outpatient mental health clinics describing the study and asking for 
referrals. Messages will be posted on email list-serves of mental health clinicians describing the 
study and asking for referrals.  
How and by whom will subjects be approached and/or recruited?  
Study staff and investigators will contact subjects who respond to advertising efforts to screen 
and recruit eligible individuals. For patients in the ED or inpatient unit, only subjects who the 
clinical staff has identified as appropriate will be approached. The clinical staff will first ask the 
patient if he or she can be approached by research staff. Only if the subject agrees to be 
approached will the staff from this study do so. All potential subjects will be given the telephone 
number of the research coordinators who will discuss the purpose and procedures of the 
research and screen the subjects for potential eligibility.  
Inclusion criteria 
1. Ability to provide informed consent.  
2. Diagnosis of bipolar I disorder or bipolar II disorder and currently As defined by DSM-IV 
by means meet criteria for a major depressive episode.  
3. Patients who were on psychiatric medication at presentation will have failed that 
regimen, as defined as not achieving at least partial remission after an adequate dose of 
medication for at least six weeks. Benzodiazepines are allowed up to 24 hours before 
neuroimaging and hypnotics are permitted throughout the study.  
4. Depression of sufficient severity to score at least 16 on the first 17 Hamilton Depression 
Rating Scale items of the Hamilton Depression Rating Scale including the atypical 
depression items addendum  
5. Age range 18-60 years  
6. Females of child-bearing potential must be willing to use an acceptable method of birth 
control throughout the study. These include abstinence, birth control pill, male condom, 
IUD, depo-provera, Norplant, male sterilization, female sterilization  
7. Subject agrees to discontinue all psychotropic other than those in Clinical interview, 
chart and urine the PSF and other types of drugs likely to interact with the 5-HT1A 
receptors.  
8. Subject is likely to tolerate medication cross-taper to monotherapy Clinical interview and 
assessment with a mood stabilizer (valproate, lamotrigine or lithium),  
Exclusion criteria 
1. Diagnosis of any other major psychiatric disorders such as lifetime schizophrenia, 
schizoaffective disorder, current psychotic depression or current drug or alcohol abuse 
(within two months before the study) or recent drug or alcohol dependence (within six 
months before the study); anorexia nervosa or bulimia nervosa within the last year; 
ecstasy use more than three times. Meet DSM-IV criteria for a manic episode at the time 
of screening.  
2. Previous failed trial of fluoxetine and citalopram by themselves or in combination with an 
anti-manic agent, defined as at least six weeks of treatment at the dose of 20 mg per 
day or more. Failure of two trials of any SSRI or SNRI antidepressant medications.  
3. If the patients are discontinuing medications as part of the washout period or are starting 
valproate, previous failed trial of the mood stabilizer that they will take alone, such that 
the patient experienced clinically significant symptoms of mania or increased rates of 

cycling between mood states while taking a clinically therapeutic regimen in terms of 
dose and length of treatment.  
4. Experienced intolerable side effects of both citalopram and fluoxetine in the past. Clinical 
interview If subject is not on medications, intolerable side effects of valproate in the past.  
5. History of clinical deterioration when any of the medications that the patient is taking at 
presentation have been discontinued in the past with the exception of any of the 
medications that will be continued during the research protocol (eg. valproate, lithium or 
lamotrigine).  
6. A first-degree family history of schizophrenia if the subject is less than 33 years old  
7. Significant active physical illness, including blood dyscrasias, lymphomas, 
hypersplenism, endocrinopathies, renal failure, chronic obstructive lung disease, 
autonomic neuropathies, peripheral vascular disease, malignancy  
8. Actively suicidal, as defined by expressing ideation with a plan for suicide or develops 
suicidal ideation that requires immediate medication or treatment intervention.  
9. Pregnancy, abortion or miscarriage in the two months prior to enrollment or plans 
Clinical interview and serum pregnancy to conceive during the course of study 
participation  
10. Lactating women  
11. ECT within the past 6 months  
12. Subjects who endorse a history of prior head trauma and score 1.5 standard deviations 
below the mean on Trailmaking A & B will be excluded from study participation.  
13. Metal implants, pacemaker, metal prostheses, metal orthodontic appliances or shrapnel 
in the body  
14. Current, past or anticipated exposure to radiation, including:  
• 
Having been badged for radiation exposure in the workplace  
• 
 Participation in nuclear medicine protocols in the last year*.  
*Subjects will be eligible, however, if the injected dose and dosimetry of the radiotracer 
are known and the cumulative annual exposure of the previous study and this study is 
lower than the annual limit for research subjects defined by the FDA (21 CFR 361.1)  
15. History of claustrophobia that would prevent the participation in imaging scans  
16. Obesity with weight >350 lbs or inability to fit into the MRI scanner**  
** If there are doubts that the MRI scanner can accommodate the physical dimensions of 
the participant, the subject’s circumference may be measured to determine if it is less 
than the MR scanner limit, 55 cm. The subject may also be brought to the MRI center 
and the MRI technologist will assess whether the subject will be able to fit into the MRI 
scanner. Metal screening and urine pregnancy testing will be done in this circumstance 
before the subject enters the MRI area.  
Research Procedures 
Valproate trial and medication washout: If patients are eligible to participate in the study, and if 
they are taking psychiatric medications at the time of recruitment, they will have all medications 
tapered off besides mood stabilizers indicated for the maintenance treatment of bipolar disorder 
(specifically, either lithium, lamotrigine or valproate). If the subject is on a combination of any of 
these three mood stabilizers, they will continue with this combination for the study. The doses of  

the mood stabilizers will be changed as needed so that for one week before starting the SSRI 
medication one of the mood stabilizers will be in the therapeutic range - either serum level of 
lithium >0.6 mg/ml, serum level of valproate >40 mg/ml, or dose of lamotrigine greater or equal 
to 200 mg daily. If the subject is on no medications, valproate will be initiated. In that case, 
patients will be receive valproate monotherapy and have an effective anti-manic dose (serum 
level >40 mg/ml) for at least one week before starting SSRI medication. Benzodiazepines will be 
permitted up to 24 hours before the PET scan or MRI scan, and hypnotics will be permitted 
throughout the study. The patients will be off of all medications besides the mood stabilizer(s) 
for three weeks before PET scanning. This monotherapy treatment period is necessary to obtain 
imaging and clinical outcome data that are not significantly influenced by previous medications. 
This design also will allow us to measure the clinical response to an SSRI that is independent 
from a clinical response to starting valproate. Patients will meet with their psychiatrist at least 
weekly via phone or in person during this time. A CGI, HAM-D, YMRS and CSSRS will be 
performed at least weekly to detect new onset manic symptoms or clinical deterioration. Only 
patients who still meet the inclusion criterion of HAM-D>15, including the atypical depression 
items addendum, at the clinical appointment one week before the scheduled PET scan will 
continue. Patients who no longer meet inclusion criteria at the end of the period, including those 
that are no longer sufficiently depressed, will not continue with imaging and will be offered up to 
6 months of open label outpatient treatment.  
Frequency of clinical visits: Throughout the study, outpatients will meet with a treating MIND 
psychiatrist at least once a week either in-person or on the phone. This meeting will be in-
person at least once every other week. Subjects will do the washout on the 4 Center or 5 South 
unit if clinically warranted. Inpatients will be evaluated by their physician at least three times 
weekly. In addition, all inpatients are monitored at intervals on an around-the-clock basis by 
ward clinical staff. During the wash-out period, inpatients will generally see a psychiatrist daily, 
except for weekends and holidays.  
MRI/fMRI scans: All subjects will have an MRI of the brain prior to fluoxetine treatment to obtain 
information on brain structure and function. This information will help understand how brain 
structure, function and serotonin mechanism are inter-related. MRI scans will be obtained at the 
NYSPI MRI facility using a 3.0 Tesla GE scanner. Females of child bearing potential will have a 
urine hcg test within 24 hours of the scan. Subjects will have the option of visiting the MRI suite 
before the scan to enter a mock (fake) MRI scanner. The mock MRI scanner has the same 
dimensions as the real scanner so it allows participants to experience what it is like to be inside 
the actual magnet. The purpose of this is to have the subject be as comfortable as possible 
before the actual scan.  
Patients will receive a combination of structural and functional MRI scanning lasting not more 
than 90 minutes. Structural scans will include T1-weighted, T2-weighted FLAIR and diffusion 
tensor imaging sequences. Resting state fMRI and arterial spin labeling MRI will be obtained to 
assess baseline brain activity while patients relax and focus their attention on a cross-hair in the 
field of view. The procedure will be immediately stopped if the subjects report significant 
distress. If the NYSPI MRI facility is unavailable, the Neurological Institute’s MRI Center will be 
used.  
PET imaging: Each subject will undergo a PET scan with [11C]-CUMI-101 at the Kreitchman 
PET Center, 722 West 168th Street, New York, NY 10032. A urine pregnancy test will be done 
on females on the morning of the PET scan before the scan to assure that pregnancy has not 
occurred between the time of laboratory tests at screening, during which a serum pregnancy 

test is conducted, and the PET scan. The subject will have one intravenous line placed for 
radiotracer injection and one for obtaining two venous blood samples, one before radiotracer 
injection to determine radiotracer protein binding, one at 60 minutes to determine metabolite 
correction factor. Patients will have vital signs measured before radiotracer injection and after 
the PET scan is complete. Patients will have a urine pregnancy test conducted within 2 weeks 
of PET scanning.  
The subject will be placed in a supine position on the camera bench. A head holder will be used 
to decrease head movement during the scan. A low dose computer tomography scan will be 
used to obtain data for attenuation correction. 16mCi or less of [11C]CUMI-101 will be 
administered I.V. The emission scan will be initiated at the time of injection and emission data 
will be obtained for 120 minutes or less. If the patients need to get up from the scanner for any 
reason, the low dose computer tomography scan will be repeated once only per PET scan. 
Patients will have a clinical check in with a study physician within 48 hours of the PET scan for 
safety evaluation that will include an administration of the CSSRS.  
Selective serotonin reuptake inhibitor treatment: After imaging, patients will have baseline 
clinical rating scales. They will be started on fluoxetine or citalopram 20 mg PO daily. Fluoxetine 
will be the first choice of SSRI treatment due to more clinical trial evidence of its efficacy in 
bipolar depression than citalopram. Clinical judgement will be used to determine if fluoxetine is 
not appropriate. After two weeks, the dose can be increased to 40 mg PO daily if the patient has 
not had a response to treatment at that time. If the dose is increased to 40 mg, the dose can be 
decreased again to 20 mg PO daily if the patient experiences side effects including any 
symptoms of hypomania. They will receive a clinical check-in with a research psychiatrist 
weekly throughout the valproate optimization/medication washout and treatment phases. At 
each appointment, the clinician will administer the clinical global impression scale-I, the 
SAFETEE-GI and the CSSRS. If subjects receive a CGI-I of 6 or higher at any visit, their clinical 
status will be evaluated by the clinical team for suitability to continue the treatment algorithm or 
the need to change the treatment in some other way such as medication adjustment. Subjects 
will receive Montgomerey Asberg Depression Rating Scale (MADRS), Beck Depression 
Inventory (BDI), Hamilton Anxiety Rating Scale (HAM-A), questions of BPRS related to 
psychotic symptoms, and Young Mania Rating Scale (YMRS) at weeks 0, 2, 4, 6. If subjects 
have no response in depression by week 4 of the study, the treating clinician will re-assess the 
plan to continue the research treatment protocol. Subjects will also have valproate or lithium 
levels checked at either weeks 1, 2 or 4 and will have fluoxetine or citalopram levels checked at 
either week 4 to check for adherence. Patients will be asked about the number of pills of 
fluoxetine or citalopram left each week to assess adherence. Patients without alcohol or 
benzodiazepine use disorders may receive benzodiazepines for insomnia or anxiety/agitation 
(maximum dose equivalent to 4 mg of lorazepam per day). All patients may also receive 
zolpidem or diphenhydramine for insomnia or agitation.  
The medications that are started as part of study procedures (citalopram, fluoxetine or 
valproate) and all laboratory tests will be provided for free of charge to the participant. Patients 
will receive  
six months of free outpatient treatment including the treatment obtained through this protocol, 
with treatment visits at least monthly. All outpatient follow-up visits and clinical assessments will 
be performed by Dr. Martin Lan unless coverage is needed.  

The primary outcome of the study will be whether subjects have a greater than or equal to 50% 
change in MADRS score from baseline at any point in the six week trial. Subjects who achieve 
this will be considered “responders” and those that do not will be considered “non-responders”.  
Eventually, “responders” will be compared to “non-responders” to evaluate differences in [11C] 
CUMI-101 binding potential in the brain. Scores of anxiety on the HAM-A and manic symptoms 
on the YMRS will also be evaluated for correlation with [11C] CUMI-101 BP in an exploratory 
manner.  
Emergency procedures  
A research psychiatrist will be available by cell phone at all times during the study. Patients 
requiring urgent admission at the time of a study visit will be brought to the CUMC Emergency 
Department by the study physician and if necessary, security assistance will be provided. The 
treating psychiatrist will arrange non-urgent hospital admissions, preferably to the NYSPI 5-
South unit. If patients refuse hospitalization but the clinical team determines that this is needed, 
the team will arrange all necessary interventions including contacting the local crisis team, 
family or Emergency Medical Services  
Patients lost to follow-up  
Upon enrollment, patients will be asked to provide the name and phone number of at least two 
persons who will likely know their future whereabouts. These people will be contacted if the 
subject is lost to follow up.  
Criteria for Early Discontinuation  
1) Intolerable side effects of medications 
2) Refusal to continue regimen and willingness to receive open treatment  
3) DSM-IV criteria for a manic episode or score > 12 on the YMRS  
4) During the washout/valproate monotherapy period, if subjects score a six (much worse) or 
seven (very much worse) on the CGI-I, the protocol will be discontinued. If the patients do not 
tolerate the washout because of marked agitation, severe anorexia such as inability to drink 
adequate amount of fluids or suicidal ideation or behavior with plan or intent, the protocol will be 
discontinued. In these cases, subjects will be offered open clinical treatment.  
5) During the SSRI treatment phase, if there is clinical reason to change to open treatment, 
such as onset of psychotic symptoms, active suicidal ideation or a score on the CGI-I of 5 or 6 
on two consecutive visits, the clinical team will evaluate whether the risks outweigh the benefits 
of continuing protocol.  
6) If the patient requests withdrawal for any reason.  
7) The PI judges that it is medically unwise to continue in the study, for example if the subjects 
are unable to comply with the study procedures and rules.  
Clinical treatment alternatives  

The proposed treatment is considered standard treatment. Several treatment guidelines for 
depression in bipolar disorder suggest a trial of either the olanzapine-fluoxetine combination pill 
or quetiapine before this regimen, however. Other anti-manic agents also exist that could be 
used in place of valproate, including lithium, carbamazepine or atypical antipsychotics. 
Valproate was chosen primarily because it has few effects on the serotonin signaling system, 
the scientific focus of the study.  
Risks that could be encountered during the study period  
1. Valproate initiation and washout period: Valproate has not been found to be effective on its 
own in treating depression in bipolar disorder. This medication needs to be started for patients 
not on any medications at the time of screening to limit the risks of precipitating mania or manic 
symptoms with SSRI treatment. It is possible that medications that patients are taking at the 
time of consent and that need to be tapered off as part of the research procedures are having a 
psychiatric treatment benefit. During this phase of changing medications to a mood stabilizer 
monotherapy, therefore, patients are at risk for worsening of the their depression or 
experiencing manic symptoms during the medication changes.  
2. Discomfort during scanning (MRI and PET): It may be uncomfortable to lie motionless in the 
PET or MRI scanners and may cause some subjects to have anxiety.  
3. MRI Scan: The MRI scanner takes images of the brain using a large magnet (3.0 Tesla). It is 
not associated with any known medical risks unless subjects have a heart pacemaker or metal 
in their body (ie. shrapnel or surgical prostheses) that can be affected by the magnet; medicinal 
patches can also cause burns in the magnet. There are no known risks associated with 
pregnancy but no one who is known to be pregnant will be scanned. Changes in the magnetic 
field of the scanner can stimulate peripheral nerves and sometimes cause sensations that are 
described as “tingling” or “twitching”, and can rarely cause a painful sensation. Some people 
feel nervous or claustrophobic feelings due to the scanner’s small space.  
4. PET scan: There are some risks of exposure to radiation during the scan. For the [11C]CUMI- 
101 compound, the single study exposure to the critical organ (pancreas in males) is 18.93 mGy 
(males) with the maximum proposed dose of 16 mCi (592 MBq). This is below the 5 Rem (50 
mGy) single dose limit under the FDA guidelines 21CFR361.1. There is also a smaller exposure 
of radiation from the attenuation CT scan before the PET acquisition, significantly below the 
single dose limit under the FDA guidelines 21CFR361.1. The attenuation CT scan may have to 
be repeated only once if the subject leaves the scanner for any reason during the PET scan. In 
that scenario, the single study exposure will remain below the single dose limit under the FDA 
guidelines 21CFR361.1.  
Maximum Proposed Dose of Radiation per PET scan and FDA Dose Limit per Single Study 
Exposure  
 
Dosimetry Table for [C-11]CUMI-101 Exposure  

 
* Critical organs  
Summary Dosimetry Table for Entire Study  
 
* Critical organs  
5. Vascular access during PET scan: There is a small risk of infection or bleeding associated 
with intravenous catheters. A vasovagal reaction, which can include light-headedness, dizziness 
or more rarely, syncopy can occur with venous line placement. Syncopy is estimated to occur in 
<1% of phlebotomy procedures, but we have not found reports in the literature of its incidence 
for catheterization specifically.  
6. Side effects of medications initiated as part of study procedures  
a. Fluoxetine or citalopram: Potential side effects include nausea, sexual dysfunction 
(decreased sexual desire, anorgasmia or abnormal ejaculation), weight loss or gain, 
nervousness and/or insomnia, diarrhea or dry mouth. There is some risk that the SSRI will 
induce hypomania, mania or a mixed state.  

b. Valproate: Potential side effects include headache, weakness, nausea, vomiting, diarrhea, 
somnolence, tremor, dizziness, weight gain, double or blurred vision or flu-like symptoms.  
Valproate also has risk for rare but more serious reactions of hepatic failure, pancreatitis, 
thrombocytopenia, hyperammonemia and multi-organ hypersensitivity reactions. Valproate is 
also teratogenic and is contraindicated in pregnancy.  
c. Zolpidem: Potential side effects include diarrhea, dizziness, drowsiness, a drugged feeling 
and dry mouth  
d. Lorazepam: Potential side effects include dizziness, drowsiness, a drugged feeling and some 
potential for tolerance or withdrawal symptoms  
e. Diphenydramine: Potential side effects include dizziness, drowsiness, a drugged feeling and 
dry mouth  
7. Interviews  
Psychiatric interviews can be distressing at times, but some people find talking to a physician or 
psychologist helpful. All interviews will be performed by experienced clinicians.  
8. Blood drawing: Drawing of blood will be performed with routine venipuncture procedures. 
These do carry minimal risk of physical discomfort, bleeding or bruising.  
9. Pregnancy: Treatment with valproate is associated with teratogenicity and is considered 
contraindicated in pregnancy. For this reason, pregnancy is considered an exclusion criterion 
and will be evaluated at screening with a serum pregnancy test.  
Describe procedures for minimizing risks  
1. MRI scan: Subjects will have a screening interview before their scan with questions of 
whether they have a pacemaker or other metal in their body. Subjects will be asked to remove 
any medicinal patches from their body prior to scanning to avoid burns. Women of childbearing 
age will have a pregnancy test performed at the day of scanning. If the subject reports 
unpleasant sensations or feels uncomfortable during the scan, the MR technologist will stop the 
scan  
immediately. Our research staff will be present at all times and a staff psychologist or 
psychiatrist will be available at all times should they be needed to comfort or treat the patient. 
From our experience, no subjects have had abnormal sensations that have persisted after 
stopping the scan. Because the MRI scan is designed for research purposes, it may not show 
problems that would be found on a clinical brain MRI scan ordered by a doctor for clinical 
purposes. However, the T1-weighted and T2-FLAIR images acquired in this study, will be 
examined by an appropriate qualified radiologist. These scans may demonstrate gross 
structural abnormalities such as the presence of mass effects or hydrocephalus. Upon request, 
results will be shared with research subjects or a physician designated by them.  
2. PET imaging: To limit the risks of radiation exposure, subjects with radiation exposure in a 
research study in the previous year will only be included if the injected dose and dosimetry of 

the radiotracer are known and the cumulative annual exposure of the previous study and this 
study is lower than the annual limit for research subjects defined by the FDA (21 CFR 361.1, 
see below).  
We have performed a number of studies to evaluate the safety of [11C] CUMI-101 including the 
FDA required toxicity study (intravenous) of CUMI-101 (CUNBID-101) in Sprague-Dawley rats 
sponsored by National Institute of Mental Health (NIMH) in the Toxicology Laboratory of SRI 
International. We proposed a total human dose of 10 microgram per injection and based on this 
dose male and female Sprague-Dawley rats (10/sex/group) were given a single iv dose of 
CUMI- 101 at 881 μg/kg (5286 μg/m2 , 1000 times the human dose, Group 2) or at 88.1 μg/kg 
(528.6 μg/m2, 100 times the human dose, Group 4), or 44.05 μg/kg (264.3 μg/m2, 50 times the 
human dose, Group 5) on Day 1 or twice a day at 440.5 μg/kg/injection (2643 μg/m2/injection, 
500 times the human dose; total dose 881 μg/kg and 1000x human dose, Group 3). A control 
group (10/sex), Group 1, was given a single iv dose of vehicle, 5% ethanol in sterile saline, at an 
equivalent volume on Day 1. Animals were sacrificed on Day 3 or Day 15 (interim and terminal 
necropsy, respectively). The following parameters were evaluated for the toxicity evaluation: 
mortality/morbidity, clinical observations, body weights, food consumption, clinical pathology 
(hematology and serum chemistry), organ weights, and, at necropsy, macroscopic observation 
and microscopic histopathology. All animals survived until their scheduled necropsy. mid and 
high dose groups (Groups 2-4) displayed slight to moderate hypoactivity on Day 1 immediately 
after dose administration. The severity of the hypoactivity appeared to be dose dependent, with 
the highest severity observed in the high dose group (Group 2). The animals recovered quickly 
from the hypoactivity within a few hours and appeared normal by the last time point clinical 
observations were performed on Day 1. μg/kg (264.3 μg/mMale and female rats in the Rats in 
the low dose group at 44.05 2, 50x human dose) and the control group did not exhibit 
hypoactivity after dose administration. No drug-related effects were found for body weights, food 
consumption, organ weights, and macroscopic and microscopic evaluations. In conclusion, iv 
administration of CUMI-101 to male and female Sprague-Dawley rats for a single or twice a day 
administration did not produce overt biologically or toxicologically significant adverse effects 
except hypoactivity in the mid and high dose groups, which is not considered to be a dose 
limiting toxic effect. No adverse effects were observed in the low dose group. The no observed 
adverse effect level (NOAEL) is considered to be μg/kg (264.3 μg/m44.05 2) for a single iv dose 
administration. The maximum tolerated dose (MTD) is considered to be at least 881 μg/kg (5286 
μg/m2) for a single iv dose administration. Although the groups with 1000-100 times human 
dose based on a 10 microgram showed only slight hypoactivity, we reduced the maximum 
injected mass of CUMI-101 to human subjects as 5 microgram per dose considering the no 
hypoactivity for a 50 times dose. Based on this dose the group 5 is now 100 times dosage 
based on a 5 microgram human dose and tolerate well in the toxicology studies. CUMI-101 has 
been successfully tested by us in more than 58 human volunteers, with >10 subjects receiving 
two doses of the tracer. No adverse effects were observed and the tracer gives a very reliable 
finding outcome measure with less than 10% CV on test retest. The total dose of [11C]CUMI-
101 used for the scan in this study is below 5 μg which is negligible and has no pharmacological 
effect. The safety of [11C]CUMI-101 in humans is supported by SRI International Toxicology 
Report. Given a molecular weight of 371 g/mole, an injection of 13.0 to 20 mCi of [11C]CUMI-
101with specific activity of ~1 to 2 Ci/μmol would be 2.4- 7.4 μg. The risk of an idiosyncratic 
reaction is acknowledged in the consent form. A physician will be present at the time of each 
injection of the radiotracer. Any adverse reaction to the radioactive drug (radiation related or 
not) will be reported to the IRB and JRSC at Columbia, as specified in 21 CFR 361.1 (d8) and 
the NYPSI IRB. 16 mCi is the maximum dose and based on reviewing the quality of data from 

scans with lower doses, given the requirement to have enough counts for reliable quantifications 
in lower binding regions, we seek an average dose of around 15 mCi.  
3. Vascular access during PET scan: Placement of IV’s will be by trained physician or nurse. 
Any bleeding or hematoma formation will be treated with standard first aid procedures including 
application of pressure to the region. To reduce the risk of a vasovagal response, intravenous 
catheterization will be performed with subjects placed in a supine position, and subjects will be 
asked about a history of vasovagal responses with previous catherizations and blood draws.  
4. Valproate optimization period: If the treating physician determines that treatment cannot be 
delayed safely, the patient will not be enrolled in the study.  
5. Side effects of medications: Patients will be encouraged to report side effects of medications 
to their physicians. A rating scale for somatic symptoms, the SAFETEE-GI, will be administered 
regularly by the treating physician to monitor for these side effects systematically. If the dose of 
fluoxetine or citalopram is increased to 40 mg, the dose can be decreased again to 20 mg PO 
daily if the patient experiences any symptoms of hypomania. If patients have a YMRS >12 or 
meet DSM-IV criteria for a manic episode, they will be discontinued from the study and will be 
given appropriate anti-manic treatment.  
6. Interviews: Patients will be informed prior to the interviews of the risks and the option of 
skipping particularly difficult interviews will be considered.  
7. Blood drawing: Standard procedures for obtaining blood samples will be followed.  
8. Pregnancy: Patients must agree at the time of consent to use a reliable form of birth control 
and to inform their treating psychiatrist if they become pregnant during the study. Pregnancy will 
be ruled out with a serum pregnancy test at screening. If the patient becomes pregnant during 
the study, they will not have imaging performed and all medications will be discontinued 
according to standard clinical practice, weighing the risks and benefits with the patient. Women 
will have a urine pregnancy test conducted on the day of the MRI scan to ensure pregnancy has 
not occurred since the screening. Women will also receive a urine pregnancy test at the time of 
PET scan to avoid radiation exposure in pregnancy and teratogenic effects of valproate. Women 
will also have a urine pregnancy test conducted within 2 weeks of PET scanning.  
Describe methods to protect confidentiality  
Access to research data will be allowed only to members of the research team or institutional 
personnel as part of a routine audit. Records may be reviewed by state or federal regulatory 
agencies and their personnel. Research records, like other medical and clinical records, will be 
kept confidential to the extent permitted by law. There are legal advocacy organizations that 
have the authority under state law to access otherwise confidential subject records, though they 
cannot disclose this information without the subject’s consent. All hard copies of records are 
kept in locked files. Coded computer files will be stored in a database which is password 
protected and behind an institute and department firewall. In addition, subject names and other 
personal identifying information will be stored in an electronically secure database at New York 
State Psychiatric Institute, the R2Net system for registration and tracking of research 
participants in the outpatient clinics. If information is transmitted electronically, it will be 
encrypted.  

Once a patient enrolls in the project he/she is given a code number that is used for all 
subsequent computer data and/or lab forms. The code list and patient names as well as all data 
are kept in locked files in locked offices with access limited to those directly responsible for 
maintenance of these files by the research team. We will not apply for a Certificate of 
Confidentiality for this protocol.  
The MRI report will be maintained as part of the clinical database at the New York State 
Psychiatric Institute or Neurological Institute along with the subject’s name and will be 
accessible to clinicians. For patients (only), their psychiatric diagnosis will not be part of the 
report. All subjects will receive feedback  
about their scans. All results will be shared with research subjects in a manner that is consistent 
with the acuity and certainty of the finding, and will be communicated by an appropriately 
qualified member of the research team in the form of a letter approved by the IRB and will be 
contacted by telephone if there is evidence of an abnormality. Results will be shared with the 
subject or a physician designated by the subject.  
Compensation and/or Reimbursement 
$250 for participation in the PET scan and $150 for participation in the MRI scan. Payment 
procedures are initiated at the time of completion of the scans. Payment is in the form of a 
check, usually received in the mail about 4-6 weeks after the research procedures.  
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Statistical Analysis Plan 
Statistics: Binding measures were analyzed first for the RN by fitting a linear model with 
log(BPF) as outcome, using equal weighting of values.  Predictors included relevant 
pretreatment clinical variables.  Age and sex were considered as covariates, and they were 
removed from the model if they were not significant.  For analysis of data from multiple 
regions, a similar modeling strategy was taken, but fitting linear mixed effect models with 
participant as the random effect, and region also included as a fixed effect.   Prediction of 
clinical response was modeled linearly with MADRS score as outcome, controlling for initial 
MADRS score, and imaging or clinical predictors.  Demographic or clinical differences between 
clinical groups were calculated with student t-test or Fisher’s exact test.  Associations between 
outcome measure components and clinical variables were calculated using Pearson Correlation.  
Significance was defined as p value less than 0.05 and all tests were two sided.  SPSS 12 for Mac 
OSX (www.spss.com) or R (www.R-project.org) were used for calculations.