Clinical trial NCT02473250
Conditions: Bipolar Disorder
Sponsor: New York State Psychiatric Institute
Start date: 2015-01-01; Completion date: 2019-12-01
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is for subjects with a diagnosis of bipolar disorder who have depression at the time of recruitment. It involves brain imaging with an MRI (magnetic resonance imaging) and PET scan (positron emission tomography) and treatment with an antidepressant. The medication involves adding an SSRI (either celexa/citalopram or prozac/fluoxetine) to a mood stabilizer.

Detailed description:
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 medications named selective serotonin reuptake inhibitors (SSRI's). 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.

Arms: arm 1: Bipolar depressed subjects will have neuroimaging and treatment with fluoxetine in combination with a mood stabilizer (valproate)
Interventions: intervention 1: Fluoxetine intervention 2: Citalopram
Intervention descriptions: intervention 1: Bipolar depressed patients will be treated with fluoxetine in combination with a mood stabilizer (valproate). intervention 2: Bipolar depressed patients will be treated with citalopram in combination with a mood stabilizer (valproate) if fluoxetine is not clinically warranted.

Protocol documents:
Prot_SAP_001.pdf: 
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.  
References  
Amsterdam, J. D. and J. Shults (2005). "Comparison of fluoxetine, olanzapine, and combined 
fluoxetine plus olanzapine initial therapy of bipolar type I and type II major depression--lack of 
manic induction." J Affect Disord 87(1): 121-130.  
Beck, A. T., C. H. Ward, M. Mendelson, J. Mock and J. Erbaugh (1961). "An inventory for 
measuring depression." Arch Gen Psychiatry 4: 561-571.  
Buss, A. H. and A. Durkee (1957). "An inventory for assessing different kinds of hostility." J 
Consult Psychol 21(4): 343-349.  
Cohn, J. B., G. Collins, E. Ashbrook and J. F. Wernicke (1989). "A comparison of fluoxetine 
imipramine and placebo in patients with bipolar depressive disorder." Int Clin Psychopharmacol 
4(4): 313-322.  
Endicott, J., R. L. Spitzer, J. L. Fleiss and J. Cohen (1976). "The global assessment scale. A 
procedure for measuring overall severity of psychiatric disturbance." Arch Gen Psychiatry 33(6): 
766-771.  
Hamilton, M. (1960). "A rating scale for depression." J Neurol Neurosurg Psychiatry 23: 56-62.  
Kumar, J. S., M. S. Milak, V. J. Majo, J. Prabhakaran, P. Mali, L. Savenkova, J. J. Mann and R. 
V. Parsey (2012). "Comparison of high and low affinity serotonin 1A receptors by PET in vivo in 
nonhuman primates." J Pharmacol Sci 120(3): 254-257.  


Kumar, J. S., R. V. Parsey, S. A. Kassir, V. J. Majo, M. S. Milak, J. Prabhakaran, N. R. 
Simpson, M. D. Underwood, J. J. Mann and V. Arango (2013). "Autoradiographic evaluation of 
[3H]CUMI-101, a novel, selective 5-HT1AR ligand in human and baboon brain." Brain Res 1507: 
11-18.  
Kumar, J. S., J. Prabhakaran, V. J. Majo, M. S. Milak, S. C. Hsiung, H. Tamir, N. R. Simpson, R. 
L. Van Heertum, J. J. Mann and R. V. Parsey (2007). "Synthesis and in vivo evaluation of a 
novel 5-HT1A receptor agonist radioligand [O-methyl- 11C]2-(4-(4-(2-methoxyphenyl)piperazin-
1-yl)butyl)-4-methyl-1,2,4- triazine-3,5(2H ,4H)dione in nonhuman primates." Eur J Nucl Med 
Mol Imaging 34(7): 1050-1060.  
Lan, M. J., N. Hesselgrave, A. Ciarleglio, R. T. Ogden, G. M. Sullivan, J. J. Mann and R. V. 
Parsey (2013). "Higher pretreatment 5-HT1A receptor binding potential in bipolar disorder 
depression is associated with treatment remission: a naturalistic treatment pilot PET study." 
Synapse 67(11): 773-778.  
Lanzenberger, R. R., M. Mitterhauser, C. Spindelegger, W. Wadsak, N. Klein, L. K. Mien, A. 
Holik, T. Attarbaschi, N. Mossaheb, J. Sacher, T. Geiss-Granadia, K. Kletter, S. Kasper and J. 
Tauscher (2007). "Reduced serotonin-1A receptor binding in social anxiety disorder." Biol 
Psychiatry 61(9): 1081-1089.  
Milak, M. S., A. J. Severance, R. T. Ogden, J. Prabhakaran, J. S. Kumar, V. J. Majo, J. J. Mann 
and R. V. Parsey (2008). "Modeling considerations for 11C-CUMI-101, an agonist radiotracer for 
imaging serotonin 1A receptor in vivo with PET." J Nucl Med 49(4): 587-596.  
Milak, M. S., A. J. Severance, J. Prabhakaran, J. S. Kumar, V. J. Majo, R. T. Ogden, J. J. Mann 
and R. V. Parsey (2011). "In vivo serotonin-sensitive binding of [11C]CUMI-101: a serotonin 1A 
receptor agonist positron emission tomography radiotracer." J Cereb Blood Flow Metab 31(1): 
243-249.  
Miller, J. M., N. Hesselgrave, R. T. Ogden, F. Zanderigo, M. A. Oquendo, J. J. Mann and R. V. 
Parsey (2013). "Brain serotonin 1A receptor binding as a predictor of treatment outcome in 
major depressive disorder." Biol Psychiatry 74(10): 760-767.  
Montgomery, S. A. and M. Asberg (1979). "A new depression scale designed to be sensitive to 
change." Br J Psychiatry 134: 382-389.  
Neumeister, A., E. Bain, A. C. Nugent, R. E. Carson, O. Bonne, D. A. Luckenbaugh, W. 
Eckelman, P. Herscovitch, D. S. Charney and W. C. Drevets (2004). "Reduced serotonin type 
1A receptor binding in panic disorder." J Neurosci 24(3): 589-591.  
Nugent, A. C., P. J. Carlson, E. E. Bain, W. Eckelman, P. Herscovitch, H. Manji, C. A. 
Zarate, Jr. and W. C. Drevets (2013). "Mood stabilizer treatment increases serotonin type 1A 
receptor  
binding in bipolar depression." J Psychopharmacol 27(10): 894-902. 
Overall, J. E. and D. R. Gorham (1962). "The Brief Psychiatric Rating Scale." Psychological 
Reports 10(3):  


799-812. 
Parks, C. L., P. S. Robinson, E. Sibille, T. Shenk and M. Toth (1998). "Increased anxiety of mice 
lacking  
the serotonin1A receptor." Proc Natl Acad Sci U S A 95(18): 10734-10739.  
Parsey, R. V., M. A. Oquendo, N. R. Simpson, R. T. Ogden, R. Van Heertum, V. Arango and J. 
J. Mann (2002). "Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A 
receptor binding potential measured by PET using [C-11]WAY-100635." Brain Res 954(2): 173-
182.  
Rabkin, J. G., J. S. Markowitz, K. Ocepek-Welikson and S. S. Wager (1992). "General versus 
systematic inquiry about emergent clinical events with SAFTEE: implications for clinical 
research." J Clin Psychopharmacol 12(1): 3-10.  
Sullivan, G. M., R. T. Ogden, M. A. Oquendo, J. S. Kumar, N. Simpson, Y. Y. Huang, J. J. Mann 
and R. V. Parsey (2009). "Positron emission tomography quantification of serotonin-1A receptor 
binding in medication-free bipolar depression." Biol Psychiatry 66(3): 223-230.  
Tohen, M., E. Vieta, J. Calabrese, T. A. Ketter, G. Sachs, C. Bowden, P. B. Mitchell, F. 
Centorrino, R. Risser, R. W. Baker, A. R. Evans, K. Beymer, S. Dube, G. D. Tollefson and A. 
Breier (2003). "Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of 
bipolar I depression." Arch Gen Psychiatry 60(11): 1079-1088.  
Tondo, L., G. Vazquez and R. J. Baldessarini (2010). "Mania associated with antidepressant 
treatment: comprehensive meta-analytic review." Acta Psychiatr Scand 121(6): 404-414.  
Witte, A. V., A. Floel, P. Stein, M. Savli, L. K. Mien, W. Wadsak, C. Spindelegger, U. Moser, M. 
Fink, A. Hahn, M. Mitterhauser, K. Kletter, S. Kasper and R. Lanzenberger (2009). "Aggression 
is related to frontal serotonin-1A receptor distribution as revealed by PET in healthy subjects." 
Hum Brain Mapp 30(8): 2558- 2570.  
Young, R. C., J. T. Biggs, V. E. Ziegler and D. A. Meyer (1978). "A rating scale for mania: 
reliability, validity and sensitivity." Br J Psychiatry 133: 429-435.  
 
 
 
 
 
 
 


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. 
 
 
 
 
 

ICF_000.pdf: 
 
                                                                                                         
IRB #7056, Version Date 10/25/2019, Page 1 of 8 
 
 
 
 
 
 SUMMARY COVER SHEET 
Serotonin 1A Receptor Binding in Bipolar Depression Determined by PET Imaging:  
Prediction of Clinical Response 
Principal Investigator: Dr. Martin Lan (646-774-7610) 
 
Overview: This outline is meant to be a guide for you to use while considering the study and 
reading the consent form.  The consent form contains detailed information about the study and 
about the risks, which you will need to consider before making your decision.  You are being 
asked to participate in research that looks at chemicals in the brain that are thought to be 
involved with bipolar disorder by having scans called MRI and PET.  After the scans, for 6 
weeks you will also receive medication treatment for depression that uses a selective serotonin 
reuptake inhibitor, either fluoxetine (Prozac) or citalopram (Celexa) added to mood stabilizer(s) 
(valproate, lithium, or lamotrigine).  The goal is to determine whether “pictures” from PET scans 
can predict how effective the treatment will be. 
 
Participation is Voluntary:  As with all research, this is a voluntary study, and you do not have 
to participate if you do not want to.  Also, you may stop participating at any time. 
 
Alternatives: The alternative to participating in this study is to receive treatment with a 
physician outside of this study.  Other medications used for depression in bipolar disorder 
include quetiapine (Seroquel), fluoxetine and olanzapine combination (Symbyax) or lurasidone 
(Latuda).  You can also refuse treatment altogether. 
 
Procedures 
§ 
Your medications will be changed so that you are on only mood stabilizers (either valproate, 
lithium, or lamotrigine).  If you are not on any of these medications, valproate will be started 
and adjusted so that the levels in the blood are in the appropriate range; this will require 
drawing your blood several times over the course of about a week and treatment with this 
dose for three weeks. 
§ 
An MRI scan will use radiowaves and a large magnet to take a picture of the brain 
§ 
A PET scan will take a picture in the brain.  It uses a small dose of a radioactive substance 
called [11C]CUMI-101 that is given through a catheter (IV) placed with a needle into a vein.  
[11C]CUMI-101 is an investigational drug approved by the FDA only for research use.     
§ 
After the scans, fluoxetine or citalopram will be added to the mood stabilizer(s) for six weeks 
of combination treatment.  You will meet with a clinician regularly, and your mood and 
anxiety will be assessed during this time. 
§ 
You can receive free office visits with a psychiatrist for six months from starting the study 
 
Risks 
§ 
Delay in starting antidepressant: During the delay before the study antidepressant is started, 
and when your current medications may be changed or stopped, there is a chance that your 
depression will worsen, including having new or more intense suicidal thoughts.   
§ 
MRI Scan: Metal implants or medicinal patches can dangerously interact with the machine. 
§ 
PET Scan: Exposes you to radiation but within limits set by FDA, a government regulatory 
agency.  Intravenous (IV) line is needed and can cause discomfort, bruising or rarely 
bleeding or infection.   
§ 
Valproate side effects: You may experience headaches, weakness, nausea, vomiting, 
diarrhea, dizziness, weight gain, double or blurry vision.  Rarely, liver or pancreas damage. 
§ 
Fluoxetine or citalopram side effects: You may experience nausea, sexual dysfunction, 
weight loss or gain, nervousness and/or difficulty sleeping, diarrhea or dry mouth.  
Fluoxetine or citalopram may not help your depression or may cause manic symptoms. 
 
Benefits: This research study will not be of benefit to you. 
 
Questions: Please contact the study doctors, Dr. Martin Lan at (646)774-7610 with any 
questions. You can also contact the physician on call at (646)774-7650 with any questions. 


 
                                                                                                         
IRB #7056, Version Date 10/25/2019, Page 2 of 8 
 
 
 
 
 
 
 
Columbia-Presbyterian Medical Center 
New York State Psychiatric Institute 
 
Informed Consent for Participation in Research 
 
Serotonin 1A Receptor Binding in Bipolar Depression Determined by PET Imaging:  
Prediction of Clinical Response 
Dr. Martin Lan (646 774 7610) 
 
 
Patient Name: ____________________________                                   
 
Purpose and Overview 
 
Fluoxetine (Prozac) and citalopram (Celexa) are antidepressant medications that can treat 
depression in people with bipolar disorder.  They work, in part, by increasing a chemical in the 
brain called serotonin.  Brain scans using positron emission tomography (PET) take “pictures” 
that give information on the activity of serotonin.  These “pictures” seem to predict how well 
antidepressant medications like fluoxetine (Prozac) or citalopram (Celexa) work in patients with 
depression.  We are trying to find out whether these “pictures” can predict how well the 
antidepressants work in bipolar disorder.  You are being asked to participate in this study 
because you are depressed at this time, you have a diagnosis of bipolar disorder, you are 
between the ages of 18 and 60 years old, and you have agreed to be a part of a different study 
(IRB #4815).  If you agree to participate in this study, and you are not currently taking a mood 
stabilizer (either lamotrigine, lithium, or valproate), you will first start valproate (Depakote), to 
prevent mania.  After the mood stabilizer dose(s) is adjusted properly, and there is a period of 
time of treatment with just that medication, about three weeks altogether, you will receive 
imaging scans of the brain.  After the scans, you will start either fluoxetine (Prozac) or 
citalopram (Celexa) to treat your depression. This antidepressant treatment will be for six 
weeks.  There will be regular monitoring and follow-up of your mood, and especially depression, 
to determine the antidepressant effect.  You can receive up to six months of free office visits 
after starting the research procedures with a psychiatrist at New York State Psychiatric institute.  
You will be responsible for the costs of your medications if they are not started as part of the 
research procedures.  This study is funded by a grant from the National Institute of Mental 
Health. 
 
Voluntary 
 
Participation in this research study is voluntary.  If you decide not to participate, or if you later 
decide to stop participating, you will not lose any benefits to which you are otherwise entitled.  A 
decision not to participate or withdraw your participation will not affect your current or future 
treatment at the New York State Psychiatric Institute or Columbia University. If you experience 
side effects of the medications that you cannot tolerate, you can stop participation in the study 
and will be able to receive other treatments.  
 
You will be notified of any significant findings that may relate to your willingness to participate. 
 
Alternative Treatments/Alternatives to Participation  
 


 
                                                                                                         
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The alternative to participating in this study is to receive psychiatric treatment elsewhere right 
away, without undergoing the procedures of this research protocol.  The scans and other 
procedures will not help guide your treatment and will not provide information that will be used 
by the doctors caring for you.  The tests are designed to learn more about bipolar disorder, not 
you, your diagnosis or which medications will help you. 
 
The FDA approved approaches for treating depression in bipolar disorder include quetiapine 
(Seroquel), fluoxetine in combination with olanzapine (Symbyax) or lurasidone (Latuda).  A 
variety of other medications and combinations of medications may be useful for bipolar 
depression.  If your manic symptoms have never been severe in the past, and therefore you 
have a diagnosis of bipolar 2 disorder, using valproate in addition to either fluoxetine or 
citalopram may not be needed.  Valproate is used here for bipolar 2 patients in part for scientific 
reasons, so that all people in the study receive the same medication treatment. 
 
Procedures 
  
Your psychiatric medications will first be changed to either one or a combination of mood 
stabilizers (valproate, lithium or lamotrigine).  If you are not on any of these medications, 
valproate (Depakote) will be started and the dose will be changed so that the levels of the 
medication in the blood are within the correct range.  This will require blood tests to measure the 
level of the medication every few days.  Your other medications will be decreased and stopped 
gradually, a process that usually takes about a week.  You will be treated with the correct dose 
of the mood stabilizer alone for about three weeks before the imaging.  If you are still depressed 
at that time you will have imaging performed.  It is important that you contact your study 
physician right away if your depression worsens, if you develop new or more intense suicidal 
thoughts, or if you have significant side effects. 
 
There will be two days for brain imaging, one for an MRI and one for a PET scan.  The MRI will 
happen at the New York State Psychiatric Institute (NYSPI).  The MRI takes about 60 minutes. 
If the NYSPI MRI is not available, the MRI will be performed at another MRI facility at Columbia 
University Medical Center.  In that case, the MRI will be only 30 minutes. The PET scan will take 
place at the Columbia Kreitchman PET Center (722 West 168th Street, New York, NY).  A 
research assistant will meet you before the scans and will stay with you during the entire time 
you are there.  The PET scan will take about 2 hours but may be shorter.  In total, you will 
spend up to 3 hours in the PET suite to prepare for the scan and have the scan done. 
 
The MRI (which stands for magnetic resonance imaging) takes a picture of the brain using a 
large magnet and radiowaves.  It does not use X-rays.  Before starting the test, you will be 
asked to take off any medicinal patches, metal or magnetized objects (like keys or credit cards) 
and change into a hospital gown.  You will be asked to lie on a table that slides into a camera 
that is about 25 inches wide and 6 feet long.  You will be asked to stay still for about 60 minutes.  
You will hear some loud banging noises.  You may also feel tingling in your fingers or toes that 
can rarely be painful, sharp sensations.  Within a month of the MRI, the scan will be read by a 
neuroradiologist for evidence of any obvious irregularities requiring follow-up.  You or a 
physician of your preference will be informed if any significant abnormalities are detected.  If you 
wish, we can also inform you if there are no obvious findings.  Because of the research design 
of the scan, the lack of a finding does not mean that one is definitely not there.  
 
On the day of the PET scan, you will be able to eat and drink as usual.  Any women that have 
the potential of being pregnant will have a urine pregnancy test on the day of the PET scan to 
make sure that pregnancy has not occurred since the first screening visit.  An IV catheter 
(intravenous) will be put into a vein in each arm using a needle.  One IV will be used to inject the 


 
                                                                                                         
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“tagged” tracer and the other will be used to take two blood samples as part of the scan.  A 
“tagged” tracer is a chemical that has radioactivity that allows the PET scanner to take pictures 
of where in the brain the chemical goes.  A total of 2 blood samples (half of a teaspoon) will be 
taken during the PET scan. 
 
You will be helped onto the scanner table and a plastic head support will be placed that helps to 
keep your head from moving during the scan.  The scanner table will slide into the large 
doughnut shaped scanner machine.  At the beginning of the scan, you will be injected with a 
tagged chemical named [11C]-CUMI-101 and you will rest quietly on a table for two hours or 
less. To help you feel as comfortable as possible while lying still in the PET scanner or to help 
with any anxieties, our staff will be available the whole time during the scan to provide support.  
After the PET scan is done, we will take out the IV catheter and the head support. You will be 
asked to drink some extra fluids and urinate normally to decrease any exposure to radioactivity.  
You will be checked briefly and then you will be able to go home.  You will have a clinical check-
in with your treating doctor within 48 hours of the PET scan. Within two weeks of the PET scan, 
you will have another urine pregnancy test performed to be sure that no pregnancy was present 
during the PET scan. 
 
After the PET and MRI scans are completed, you will start the antidepressant fluoxetine 
(Prozac) or citalopram (Celexa) at 20 mg per day.  This dose will be increased to 40 mg per day 
after three weeks if you continue to be depressed.  If you develop some side effects from the 
fluoxetine (Prozac) or citalopram (Celexa) at the 40 mg dose, the dose can be lowered back to 
20 mg per day.   
 
The levels of either valproate or lithium will also be measured at weeks 1, 2 and 4 while taking 
the fluoxetine (Prozac) or citalopram (Celexa) to make sure it is at the proper level to prevent 
mania from occurring.  The level of fluoxetine (Prozac) or citalopram (Celexa) will also be 
measured at week 4.  In total, there will be approximately 9 teaspoons of blood drawn for the 
laboratory tests in the study. 
 
The treatment with either fluoxetine (Prozac) or citalopram (Celexa) will continue for a total of 
six weeks.  You will meet each week with a study doctor during this treatment. Your mood and 
anxiety will be monitored with questionnaires every two weeks during the study.  These will take 
about 90 minutes to complete.  Valproate and either fluoxetine (Prozac) or citalopram (Celexa) 
will both be provided to you free of charge. 
 
During the treatment, you will be able to take medications for sleep or anxiety, although these 
medications will not be paid for by our team. 
 
After the six-week clinical trial, you will be offered up to 6 months of treatment with a 
psychiatrist, primarily involving medications, at the New York State Psychiatric Institute. Your 
doctor appointments will be free of charge during this time, but you will be responsible for the 
cost of your medications.  This is different from the period of time during the research phase 
when your medications are paid for by the research team.  If you do participate in this six 
months of treatment, and you still need treatment when this period ends, you will be given 
referrals for continuing treatment elsewhere. 
 
Risks and Inconveniences 
 
Delay to starting antidepressant: If you are not on one of the mood stabilizer medications, some 
time will be needed to adjust the dose of valproate until it is within the dose range that has been 
found to be effective at preventing manic symptoms.  Medications other than the mood stabilizer 


 
                                                                                                         
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medications will need to be tapered off.  These changes usually take about 1 week. There will 
then be about three weeks of treatment with just the mood stabilizer(s) before the scanning. 
Valproate does not have a significant antidepressant effect, so there may be a delay before your 
depression improves.  If you are currently taking psychiatric medication, there is a chance that it 
is helping your mood even though you are depressed.  Therefore, there is a risk that your 
condition will worsen when your medication is changed to just valproate, with more depressive 
symptoms, new or worse suicidal thoughts or manic symptoms.  
 
 
MRI Scan: Some people have reported feelings such as “tingling” or “twitching” (or very rarely a 
painful sensation) that are caused by the large magnet used to take pictures of the brain 
affecting the nerves in your body.  If you do have these sensations, and feel that they are 
uncomfortable, you can tell the MR technologist and the scan will be stopped right away.  Some 
people have felt nervous or claustrophobic because of the scanner’s small space.  If you have 
any discomfort, you can also tell the MR technologist and he or she will stop the scan right 
away.  From our experience, no one has had sensations from the scanning that did not stop as 
soon as the scan stopped. We know of no health risks from the MRI scan besides problems with 
pacemakers or other types of metal in the body.  There is also a risk of burns from medicinal 
patches during the MRI, so you will be asked to take off any patches before the scan starts.  
Lying still in an enclosed space can also be uncomfortable for some people.  The MRI scanner 
used here is considered to be experimental, but the FDA has determined that is a non-
significant risk device that poses no more than minimal risk to humans.  An MRI should not be 
done during pregnancy, however, because of possible risk to the fetus. 
 
Radiation Exposure from PET scan: The PET scan involves exposure to imaging radiation with 
a substance or imaging agent called [11C]-CUMI-101.  It is a research drug that is approved by 
the Food and Drug Administration for use only in research studies.  [11C]-CUMI-101 will be given 
intravenously (IV) during the PET scan at very low doses.  It has been tested in animals at 100 
times the dose used in people and has been used in about 60 research subjects in our group 
without significant symptoms occurring.  However, it is still possible that mild or even serious 
unknown side effects may occur.  We will watch you closely during the study in the unlikely 
event that you may have an adverse reaction.  If this does occur, we will treat you appropriately.  
The procedures involving radiation in this research study will expose you to a very small amount 
(3.16 mSv) of radiation in addition to the amount that you might receive from your normal 
medical care.  There may be an increase in the chance of your developing cancer many years 
after this study.  The additional risk from this research study is less than 0.0634%, or 1:1577.  At 
this very low level, scientists are uncertain as to the actual risk from research and there may be 
no risk at all.  Health hazards from such low amounts of radiation have never been shown.  
Radiation risk is cumulative over a lifetime, though, and any additional exposure should be 
carefully considered.  Everyone is exposed to natural background radiation from sources such 
as radon, food, water and the sun’s rays.  To compare the amount of radiation exposure in this 
research study, the amount of radiation you get in one PET scan will be less than the amount 
you would receive in one year of natural background sources. It is not possible to tell whether 
the small additional radiation that you get through participating in this study will increase your 
long-term risk for diseases such as cancer.  
 
To make sure that you do not receive more radiation than the maximum allowed for research 
purposes, you will be asked about any past radiation exposures including past CT scans or x-
rays.  In addition, we will check the records from our group to make sure you have not been a 
part of an imaging study using radiation here in the past year.  Because we are only able to 
check our divisional database, you must inform the research staff of any other known radiation 
exposures (PET scans, CT scans, x-rays).  Also, you should not take part in any other research 


 
                                                                                                         
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studies that use ionizing radiation for at least 12 months after you complete this study, unless it 
is approved by the appropriate regulatory authorities. 
 
Side effects of Fluoxetine and Citalopram: You may experience side effects from fluoxetine 
(Prozac) or citalopram (Celexa).  Side effects may include nausea, sexual dysfunction 
(problems with sexual desire, orgasm or ejaculation), weight loss or weight gain, nervousness, 
inability to sleep well, diarrhea or dry mouth. There is a small risk that either fluoxetine or 
citalopram will induce hypomania, mania or a mixed state, but it is thought that taking a mood 
stabilizer will decrease this risk.  There is also some risk that fluoxetine (Prozac) or citalopram 
(Celexa) will not be effective in treating your depression and there is some risk that it may make 
things worse.  
 
The FDA has warned that antidepressant medications may increase suicidal thoughts or actions 
in some children, teenagers, and young adults when the medicine is first started. You should 
pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, 
or feelings, especially when either fluoxetine (Prozac) or citalopram (Celexa) is first started or 
when the dose is changed. Call your doctor right away to report any new or sudden changes in 
mood, behavior, thoughts or feelings. Keep all scheduled follow-up appointment with your 
doctor. Call your doctor between visits if you have any concerns about symptoms. Do not stop 
taking your antidepressant medicines without consulting your doctor. 
 
Side effects of valproate:  Side effects may include headache, weakness, nausea, vomiting, 
diarrhea, sleepiness, tremor, dizziness, weight gain, double or blurred vision or flu-like 
symptoms. Please tell your doctor if any of these do arise.  Treatment with valproate also has 
risk for rare but more serious reactions of liver or pancreas damage, low blood cells called 
platelets and high levels of a chemical called ammonia in the blood that can cause medical 
problems, and a rare allergy-type reaction that affects multiple organs. Valproate is also known 
to cause birth defects (teratogenic) and is not safe in pregnancy. 
 
Please tell your doctor if any of these side effects occur.  Do not stop taking the medications 
without consulting your doctor first. 
 
Clinical visits and interviews: Psychiatric interviews can be upsetting at times, but some people 
find talking to their physician or psychologist to be helpful.  During the research procedures, you 
may meet with your clinician more regularly and for longer periods of time than you would in 
typical treatment. The rating scales that assess your symptoms will take about 90 minutes to 
complete at each visit.  This schedule has the potential to cause inconvenience.  If you have no 
response in your depression by week 4 of the study, your clinician will reassess your clinical 
treatment course at that time. 
 
Blood drawing and intravenous catheter: As a necessary part of treatment with valproate, 
venipuncture (drawing a blood sample) for routine blood laboratory tests is needed. These carry 
minimal risk of physical discomfort, bleeding or bruising. Putting in intravenous catheters can be 
briefly painful. Sometimes there is a bruise at the site after removal.  A risk of catheter 
placement and blood drawing is feeling dizzy or light-headed.  While rare, it is possible that you 
could pass out.  Please let us know if you have experienced any reactions like this in the past 
while having blood drawn or having a catheter placed. 
  
Pregnancy: Treatment with valproate is associated with birth defects and is therefore not safe in 
pregnancy.  Studies involving radiation should also not be conducted during pregnancy due to 
possible risk to the fetus.  To participate in this study, women of child-bearing potential must 
agree to use an effective form of birth control such as: not having sexual intercourse, using 


 
                                                                                                         
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either birth control pills or another form of medication for birth control (Depo-Provera or 
Norplant), male condoms, an intra-uterine device (an implanted form of birth control), male 
sterilization or female sterilization.  If female, you will also be required to have a blood 
pregnancy test at the time of medical screening, and urine pregnancy tests on the day of the 
PET and MRI scans.  Within two weeks of the PET scan, you will have another urine pregnancy 
test. You will not be charged for the pregnancy tests.  It is important to understand that even if 
your pregnancy test result is negative, you could still be pregnant because a urinepregnancy 
test cannot detect very early pregnancies (that is, within the first few days after conception),  
This study may convey risk to men because it is unknown if this radiation is harmful to sperm. 
 
Benefits  
 
This study has the potential for a benefit to the general public, as it may allow for better 
treatment of people who suffer from bipolar disorder in the future.  The medications used in this 
study are standard medications for depression in bipolar disorder and may therefore help your 
depression.  Because the MRI is designed for research purposes, you are not expected to 
benefit from the scan.  You are not expected to benefit from the PET scan. 
 
Costs and Compensation 
 
You will not need to pay any costs associated with this research.  You will receive monetary 
compensation of up to $400 for expenses in undergoing all the scans and interviews.  If you do 
not complete the study, you will be given a partial payment that will relate to the amount that you 
participated in the study ($250 for PET scan session, $150 for the MRI).  Payment is by check 
and arrives via mail about 4-6 weeks after completing the last scan.  You will need to provide a 
W-9 form with your social security number in order for us to request the check that will be sent 
to you.  
 
You will also be offered medication-based treatment for the six months from the beginning of the 
study.  Medications will be provided by the research team during the research procedures, but 
you will be responsible for the costs of the medications after the research procedures are over. 
 
Confidentiality  
 
Your records will be kept in locked files and access will be allowed only to members of the 
research team or institutional personnel as part of a routine audit. Records may also be 
reviewed by state or federal regulatory agencies and their personnel (who may review records 
as part of routine audits). 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 your consent. 
 
Once you are enrolled in the project, your records are given a code number which is used for 
subsequent data and/or lab forms. This de-identified data may be shared with other researchers 
within our division only for research purposes. The code list and names of participants as well 
as all other data are kept in locked files with access limited to those directly responsible for 
maintenance of these files by the research team. Your name and other personal identifying 
information will be stored in an electronically secure database at New York State Psychiatric 
Institute protected by a “firewall” requiring a password. 
Your MRI report will be maintained as part of the clinical database at the New York State 
Psychiatric Institute or Columbia’s Neurological Institute along with your name. Your PET 


 
                                                                                                         
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report will be maintained as part of the clinical database at the Columbia Kreitchman PET 
Center along with your name. These reports will only be accessible by clinicians and your 
psychiatric diagnosis will not be part of the reports. 
 
In Case of Injury 
 
Federal regulations require that research participants be informed about our institution’s policies 
with regard to the provision of treatment and compensation for research related injuries. If you 
believe that you have sustained injury as a result of participating in a research study, you may 
contact the Principal Investigator, Dr. Martin Lan at 646-774-7610 so that you can review the 
matter and identify the medical resources which may be available to you. Please be aware that: 
• 
The New York State Psychiatric Institute, Columbia University and New York 
Presbyterian Hospital will furnish that emergency medical care determined to be 
necessary by the medical staff of this hospital  
• 
You will be responsible for the cost of such care, either personally or through your 
medical insurance or other form of medical coverage.  
• 
No monetary compensation for wages lost as a result of injury will be paid to you by the 
New York State Psychiatric Institute, Columbia University or by New York Presbyterian 
Hospital.  
• 
By signing this consent form, you are not waiving any of your legal rights to seek 
compensation through the courts.     
  
Questions 
 
The physician who has reviewed this consent form with you will answer to the best of his or her 
ability any questions that you may have now or in the future about the research procedures, or 
about your response to the procedures.  You can also contact Dr. Martin Lan (646) 774-7610, 
the principal investigator of the study, with any questions. 
 
If you have any questions about your rights as a research participant, want to provide feedback, 
or have a complaint, you may call the NYSPI Institutional Review Board (IRB). (An IRB is a 
committee that protects the rights of participants in research studies). You may call the IRB 
Main Office at (646) 774-7155 during regular office hours.  
 
You will be given a copy of this signed consent form to keep. 
 


 
                                                                                                         
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Documentation of Consent  
 
I voluntarily agree to participate in the research study described above. 
 
 
Participant print name: ________________________________ 
 
 
Participant signature: ___________________________________ 
 
 
Date: _______________________ 
 
MRI Results 
 
Initial “Yes” or “No” below: 
 
_____ YES, tell me my MRI results even if there are no significant abnormalities 
 
_____ NO, do not inform me of my MRI results if there are no significant abnormalities 
 
Physician Documentation of Consent 
 
I have discussed the proposed research with this participant including the risks, benefits, and 
alternatives to participation (including the alternative of not participating in the research).  The 
participant has had an opportunity to ask questions and in my opinion is capable of freely 
consenting to participate in this research.  
 
 
Researcher Print Name: _________________________________ 
 
 
Researcher Signature: ____________________________________ 
 
 
Date: _____________________