Conditions: Bipolar Disorder Bipolar Depression Unipolar Depression
Keywords: bipolar disorder bipolar depression serotonin transporter serotonin receptors binding potential brain imaging unipolar depression
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 76
Healthy volunteers: yes

Brief summary:
The primary aims of this study are to:

1. Quantify serotonin transporter (5-HTT) binding potential (BP) in vivo in bipolar disorder patients (BPD) during a major depressive episode (MDE).
2. Assess the effect of lithium treatment of bipolar disorder on 5-HTT.
3. Assess the effect of lithium treatment of bipolar disorder on 5-HT1A BP.
4. Assess the effect of lamotrigine treatment of bipolar disorder on 5-HTT and 5-HT1A BP.
5. Assess the effect of lithium treatment of unipolar depression on 5-HTT BP.

Detailed description:
PET and MRI imaging will be used to investigate the aims described above in patients who have bipolar disorder or unipolar depression and are currently experiencing a depressive episode. Both healthy controls and depressed participants with bipolar disorder or unipolar depression will be recruited. Patients who are on medication before enrolling in the study will have a three week washout. At baseline, healthy controls and patients will have an MRI consisting of both structural and functional sequences. Psychological measures will also be obtained at baseline. Within one week of the MRI, both patients and healthy controls will have one CUMI and one DASB PET scan.

Following the baseline PET scans, patient participants will begin medication treatment with either lithium or lamotrigine, based on the clinical judgement of the treating psychiatrist. Psychological measures will be obtained every 2 weeks. After 6 weeks of medication treatment at a therapeutic dose, patients will be assessed for remission (defined as a 50% decrease in the HDRS score from baseline). If this criteria is met, patient participants will then have follow-up PET scans (one CUMI and one DASB). If this criteria is not met, the patient will be switched to the other medication under study and will be reevaluated after an additional 4 weeks of medication treatment. Patients who still do not demonstrate a 50% decrease in their HDRS will be considered non-responders and will have repeat CUMI and DASB scans.

Arms:
arm 1: Patients in this condition will receive lithium administered as follows: Day 1, 2 and 3, 300 mg bid; Days 4-7 lithium 300 qam and 600 qhs. Lithium level will be checked as close to Day 7 as possible and titrated to a therapeutic plasma level of 0.8-1.2 mEq/l. Subjects will not undergo lithium monotherapy if they have a documented history of at least two failed trials of lithium of at least 4 weeks duration with therapeutic blood levels for a major depressive episode arm 2: Patients who have not respond to adequate prior lithium treatment while depressed, or who refuse lithium, will be given lamotrigine. Lamotrigine will be started at 25 mg bid and increased to 50 mg bid after 2 weeks and again increased to 100 mg bid after an additional 2 weeks.

Interventions: intervention 1: Lithium intervention 2: Lamotrigine
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Official Title: PET and MRI Brain Imaging of Bipolar Disorder 
NCT: NCT01880957 
Document Date: 12/13/2019 


IRB# 2012-1826-F
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PI: Chuan Huang, PhD
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1
COMMITTEES ON RESEARCH INVOLVING HUMAN SUBJECTS
Established 1971
Protocol Summary Form
Title: Pathophysiology and Treatment of Bipolar Disorder as Assessed by In Vivo Imaging
Principal Investigator: Chuan Huang, PhD
Co-Investigators:  Colleen Oliva, NP
Department: Psychiatry and Behavioral Science
A. Specific Aims
1.  Quantify serotonin transporter (5-HTT) binding potential (BP) in vivo in bipolar disorder patients (BPD) 
during a major depressive episode (MDE): Using an older PET ligand for 5-HTT, [11C]McN5652, we find 
lower 5-HTT BP1 in medication-free bipolar patients in many brain regions compared to healthy volunteers. 
[11C]DASB also offers better signal to noise than [11C]McN5652 (Frankle et al., 2004) permitting assay of 5-
HTT in the cortex.  We hypothesize that untreated bipolar depression will be characterized by lower BP in both 
subcortical (amygdala, hippocampus, midbrain, thalamus, putamen) and cortical (anterior cingulate and 
prefrontal cortex) regions as assessed by region of interest and voxel based analyses, reflecting a more 
widespread abnormality of the serotonergic system than in unipolar depression.
2. Assess the effect of lithium treatment of bipolar disorder on 5-HTT. We propose to rescan BPD patients with 
[11C]DASB 6-10 weeks from the time of therapeutic or highest tolerable dose of lithium monotherapy. We 
hypothesize that lithium will increase the low 5-HTT BP in BPD patients in the temporal, frontal, and 
entorhinal cortices towards ‘normal’ levels.  We will determine the relationship between BP change and 
antidepressant effect.
3. Assess the effect of lithium treatment of bipolar disorder on 5-HT1A BP. Chronic lithium in animal studies 
does not affect somatodendritic 5-HT1A Bmax in the dorsal raphe nucleus but decreases 5-HT1A Bmax in frontal 
cortex and hippocampus. We propose to perform baseline 5-HT1A scans with [11C]CUMI-101 or [18F]MeFWAY 
and repeat scans 6-10 weeks from the time of therapeutic or highest tolerable dose of lithium monotherapy. Our 
preliminary 5-HT1A data in bipolar subjects suggest that as a group they have slightly higher 5-HT1A BP than 
controls with a sex by diagnosis interaction.  We hypothesize that regardless of sex, 5-HT1A BP will 
downregulate in response to chronic lithium.
4.   Assess the effect of lamotrigine treatment of bipolar disorder on 5-HTT and 5-HT1A BP. We estimate based 
on our experience with bipolar subjects in our clinic that 50% of the subjects will not be eligible for lithium 
monotherapy. We propose to treat this group with lamotrigine. Lamotrigine, like lithium, alters 5-HT1A Bmax 
and also activity. There are no data regarding lamotrigine and its effects on 5-HTT.  We propose to explore the 
effect of lamotrigine on 5-HTT and 5-HT1A in order to determine if this medication also acts via alteration of 
these proteins. We will determine the relationship between BP change and antidepressant effect.
5. Assess the effect of lithium treatment of unipolar depression on 5-HTT BP. We will perform baseline and 
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post treatment [11C]DASB scans in 10 unipolar depressed subjects. We will determine if the effects of lithium 
treatment are specific to bipolar depression.
B. Background and Significance
Bipolar disorder is a brain disorder characterized by recurrent manic and major depressive episodes, the 
latter being clinically similar to those observed in unipolar or major depressive disorder.  The one year 
prevalence rate for Bipolar I or II is estimated at 1-2% for all ages.1 Bipolar disorder ranked 20th in terms of 
causes of loss of disability-adjusted life-years in 1999.2 Yet, its neurobiological underpinnings are poorly 
understood and most research has focused on functional brain abnormalities rather than alterations in 
neurotransmission.3 Pharmacotherapy development has focused on testing molecules that target neuroreceptors, 
transporters and heavily on serendipitous findings regarding lithium and anticonvulsants where the precise 
mechanism of therapeutic action is unknown. Further, treatments for bipolar depression show remission rates 
only modestly better than placebo.4 As a potential aid to rational drug development and to elucidate its 
pathophysiology, neurotransmission deficits present in bipolar depression require attention.
Our group has been interested in determining the role of key neurotransmitter receptors and transporters 
in both unipolar and bipolar depression. In unipolar depression this initial work has lead to a working model 
that incorporates 5-HT1A receptors, the 5-HTT, and genetic polymorphisms.9,21,22 In parallel with this work in 
unipolar depression we have started 5-HT1A and 5-HTT studies in bipolar disorder, preliminary data will be 
presented in Sections C.1 and C.2.  Our goal is to develop a neurotransmitter based model of bipolar disorder to 
complement important findings from fMRI and MR that will enhance understanding of the pathophysiology and 
the action of drugs with proven beneficial effects to accelerate development of more specific or novel treatment 
strategies.
There is very little in vivo neuroreceptor data in bipolar disorder.  The proposed studies would help in 
determining if there are abnormalities in the 5-HTT and 5-HT1A proteins in bipolar depressed subjects scanned 
during a major depressive episode.  Further, we propose to examine the mechanism of action of two approved 
medications for the treatment of bipolar depression (lithium and lamotrigine). We will also examine the 
diagnostic specificity of lithium response by studying 10 unipolar depressed subjects in an identical manner. 
Based on our preliminary data of 5-HTT and 5-HT1A in bipolar depression and unipolar depression, the 
preclinical evidence, and years of working with this patient population, we believe we are in a position to 
address these fundamental and critical questions in this devastating mental illness.
 [11C]WAY-100635 has been very well characterized and validated. It has high sensitivity and specificity for the 
5-HT1A receptor, and high correlation to the gold standard for receptor quantification, human post-mortem 
autoradiography. [18F]MeFWAY was developed to be a close structural analog of [11C]WAY-100635.40 Due to 
its 109-minute half-life, this tracer can be shipped to hospitals and research centers and would not require a 
cyclotron on site for synthesis.  This is the main advantage of using [18F]MeFWAY vs [11C]WAY-100635.  
Further, [18F]MeFWAY was developed to be relatively more stable to metabolism, be easily synthesized, and 
retain high affinity and selectivity for the 5-HT1A receptors. Also, placing a fluorine on a primary carbon (rather 
than a secondary carbon as in 18F-FCWAY) enhances the compound's stability toward defluorination in vivo. 40 
Data suggest that it is a feasible alternative PET tracer to quantify 5-HT1A  receptors. When necessary 
[18F]MeFWAY will be used to complete the aims of this study. 
Background for Optional Psychophysiological Assessment 
Event-related potentials (ERPs) have been widely utilized to determine differences between healthy individuals 
and patients with depression. Interestingly, some ERP tasks may be sensitive to monoaminergic activity. For 
example, the loudness dependence auditory evoked potential (LDAEP) is thought to correlate with serotonergic 
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activity, such that a high LDAEP reflects low serotonergic neurotransmission (Hegerl et al 1998; Juckel et al 
1999; Strobel et al 2003). It is thought that the neural generator of the LDAEP is the primary auditory cortex 
(Juckel et al 1997), which is a region that has a high concentration of serotonin (Azmitia & Ganno, 1986; Lewis 
et al 1986). In LDAEP studies, participants listen to an increasing sound intensity (usually between 60-100 dB) 
and the amplitude of specific ERP components (e.g. N1 and P2) should increase with each intensity increase. 
Although few studies have found significant effects of depression on the LDAEP (Brocke et al 2000), many 
have found increased LDAEP in responders to selective serotonin reuptake inhibitor (SSRI) treatment (Paige et 
al 1994; Linka et al 2004; Lee et al 2005; Mulert et al 2007). Interestingly, one study found that depressed 
patients with a high LDAEP did not respond to a norepinephrine reuptake inhibitor (NRI; Linka et al 2005). 
These studies support the notion that LDAEP may be sensitive to serotonergic changes that may result in 
psychopathological conditions that are thought to involve deficiencies in serotonin, such as depression. By 
including the LDAEP task in this proposal, we can 1) examine the relationship between the LDAEP (as a proxy 
of serotonergic neurotransmission) and 5-HT1A receptor binding (as measured by our PET scan using the 
CUMI tracer), and 2) examine if baseline LDAEP level is predictive of lamictal or lithium treatment response. 
C. Preliminary Studies
C.1. 5-HTT Binding in Bipolar 
Disorder:
Prior to the use of [11C]McN5652 in 
patient 
populations 
we 
carefully 
evaluated the ligand to determine the 
optimal data acquisition and analysis 
methods.7 Demographics of the 18 
subjects (10 female, 8 male) who met 
DSM-IV(1994) criteria for bipolar 
disorder with a major depressive 
episode 
(MDE) 
and 
41 
healthy 
volunteers (19 female, 22 male) who 
participated in this study are presented 
in  Table 1. Inclusion and exclusion 
criteria were evaluated by clinical 
history, 
chart 
review, 
Structured 
Clinical Interview for DSM IV (SCID 
I)133, Hamilton Depression Rating Scale 
for depression (HAM-D)134, review of 
systems, physical examination, routine 
blood tests, pregnancy test, and urine 
toxicology. 
The 
healthy 
volunteer 
group was free of lifetime psychiatric 
history and had no first-degree relatives 
with mood disorders.
Criteria for study entry for bipolar subjects included: 1) age 18 to 65 years; 2) DSM-IV Major 
Depressive Episode, bipolar disorder) 3) absence of alcohol or substance abuse or dependence in the prior 6 
months; 
4) 
absence 
of 
family 
history 
of 
schizophrenia 
5) 
absence 
of 
exposure 
to 
3,4-
methylenedioxymethamphetamine (MDMA, ecstasy); 6) absence of significant medical conditions; 7) absence 
Table 1. Demographics of the [11C]McN5652 Bipolar Study Groups
Healthy 
volunteers 
(N=41)
Depressed 
Bipolars 
(N=18)
t-test 2-test p-value
Male
22
8
Female
19
10
0.425 0.514
Age (years)
38.1  9.7
39.3  16.0
0.349
0.729
Bipolar I / Bipolar II
NA
10 / 8
HDRS-24 
0.61  0.89 23.72  6.27
15.57
9
<.001
BDI
1.5  2.1
28.9  10.1
16.71
1
<.001
GAS
89.5  4.7
48.7  10.1
21.26
2
<.001
1st Degree Relative with MDD
NA
16 (89%)
NA
1st Degree Relative with BD
NA
3 (17%)
NA
Age at first MDE (years)
NA
18.9  7.89
NA
Age at first Manic/Hypomanic 
Episode (years)
NA
28.59  11.36
NA
Previous Suicide Attempts
NA
9 (50%)
NA
5-HTTLPR Genotype (%)
          Ll
10 (25%)
8 (44%)
          Ls
19 (47.5%)
10 (56%)
          Ss
11 (27.5%)
0 (0%)
6.623 0.036
5-HTTLPR Allele Frequency
          L
39 (49%)
26 (72%)
          S
41 (51%)
10 (28%)
5.552 0.018
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of pregnancy; and 8) capacity to provide 
informed consent; 9) able to tolerate a washout of 
current 
psychotropic 
medications 
and 
be 
medication free for at least 2 weeks prior to the 
scans (6 weeks for fluoxetine, 3 weeks for oral 
neuroleptics), except benzodiazepines, which 
were discontinued 24 hours prior to the scan. 
Two (2, 11%) subjects had a remission of MDE 
during medication washout, but all subjects were 
scanned within a month of full MDE. Only five 
of the bipolar subjects had no previous exposure 
to psychiatric medication.
Study criteria for healthy volunteers were 
similar except for the absence of a psychiatric 
history, including alcohol and substance abuse 
and absence of mood or psychotic disorder in 
their first-degree relatives.  
The Institutional 
Review 
Boards 
of 
Columbia 
University 
Presbyterian Hospital and the New York State 
Psychiatric Institute approved the protocol.  
Subjects gave written informed consent after 
detailed explanation of the study.
Healthy volunteer and bipolar disorder 
groups were matched for age (range 18 to 65 
years; t =0 .35, p = 0.73) and sex (2 = 0.43, p = 
0.51).   Eight bipolar subjects met the criteria for 
Bipolar II disorder, 10 met criteria for Bipolar I 
disorder.  Other Axis I disorders included Binge 
Eating (2), Obsessive-Compulsive Disorder (3), 
Simple Phobia (1), Generalized Anxiety Disorder 
(1), Post-Traumatic Stress Disorder (PTSD, 2).  
Nine bipolar subjects had made suicide attempts 
(2.33 ± 1.87 lifetime attempts, range 1 - 7).  Bipolar subjects averaged 23.72  6.27 on the Hamilton depression 
rating scale (24 item), while the healthy volunteer group averaged 0.61  0.89.  Data from this healthy volunteer 
sample was reported in a previous study involving Major Depressive Disorder.9   The injected dose of 
[11C]McN5652 injected was not different between healthy volunteers (11.89  4.10 mCi) and bipolar subjects 
(12.79  4.85 mCi, Students’ t = -0.733, p = 0.466).   Specific activity (healthy volunteers = 0.97  0.69 
mCi/nmol, bipolar = 0.81  0.40 mCi/nmol, Students’ t = 0.921, p = 0.361) and injected mass (healthy 
volunteers = 70.45  69.10 mole, bipolar = 50.40  23.22 mole, Students’ t = 1.20, p = 0.236) also did not 
differ.
A linear mixed effects model of regional BP1, demonstrated that bipolar subjects had lower 5-HTT BP1 (F = 
5.41, df = 1, 58, p = 0.024) across all six brain regions examined (Figure 1): midbrain (27%), amygdala (26%), 
hippocampus (23%), thalamus (23%), putamen (16%), and anterior cingulate cortex (23%). There was no 
evidence that the deficit differed across regions (F = 1.34, df = 5, 285, p = 0.247) despite the seemingly uniform 
reduction in 5-HTT BP1 (Figure_2).   Moreover, this effect was independent of depression severity rated by 
either self-report or clinical assessment.  Results on the triallelic genotype (data not shown) are comparable to 
the biallelic genotype results (see Table 1).  There was no relationship between5-HTTLPR genotype based on 
functional classification and BP1 in the six regions considered in bipolar subjects.
0
5
10
15
20
25
30
35
40
MID
PUT
AMY
THA
HIP
ACN
Healthy Volunteers (N = 41)
Bipolar Subjects (N = 18)
5-HTT Binding Potential
1 (mL/g)
Figure 1: Lower [11C]McN 5652 BP1 to the serotonin 
transporter (5-HTT) in non-medicated bipolar subjects in 
six regions of interest (MID = midbrain; PUT = putamen; 
AMY = amygdala; HIP = hippocampus; ACN = anterior 
cingulate cortex; THA = thalamus) compared to healthy 
volunteers (F = 5.41, df = 1, 58, p = .024).  Bars represent 
the mean LEGA modeled BP1 (VT(region) – 
VT(cerebellum)) for each region +/- one standard deviation.
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In contrast to unipolar depressed 
subjects where BP1 was 16% lower in 
amygdala and midbrain, using the same 
methodology, depressed bipolar subjects 
showed 16% to 26% lower BP1 in all six 
brain regions examined: amygdala, midbrain, 
anterior 
cingulate 
cortex, 
hippocampus, 
putamen, and thalamus. The current findings 
suggest that lower 5-HTT binding is more 
pronounced and possibly more widespread in 
bipolar depression.
Cerebellar 5-HTT VT (V2) was higher 
in healthy volunteers than depressed bipolar 
subjects (21.49 ± 5.11 mL/g vs. 17.04 ± 2.58 
mL/g, Students’ t = 4.43, df = 56, p < .001), 
and therefore cannot explain our results.  
Such an effect leads to an underestimate of 
the 5-HTT BP1 in the regions of interest, with 
the effect being more pronounced in the 
healthy 
volunteers.  
Thus, 
observed 
differences in BP1 between healthy and 
depressed bipolar subjects are likely an 
underestimation of the actual physiological 
difference.  
Because of the difference in 
cerebellar VT, outcome measures that are 
more sensitive to this measure (BP2 = 
BP1/VT) show no difference between bipolar 
subjects and controls.  A major limitation of 
studies that do not utilize arterial sampling is 
that BP2 is the only outcome measure that can 
be obtained.
Whether lower 5-HTT BP1 observed 
in depressed bipolar subjects is due to 
primary deficits in the serotonin system or 
secondary 
to 
other 
neurochemical 
abnormalities and whether this abnormality is 
a trait or only present during the depressed 
state requires further inquiry.   
Studies 
examining 5-HTT binding during periods of 
mania or euthymia or measuring 5-HTT 
binding concomitantly with GABA or glutamate levels in brain may elucidate these issues.  Nonetheless, these 
findings, the first in vivo evidence of a brain abnormality of this magnitude in bipolar disorder, suggest that 
bipolar depression is associated with more extensive serotonergic dysfunction than unipolar depression and may 
be a more severe manifestation of illness along a spectrum of mood disorders.
C.2. 5-HT1A in Bipolar Disorder.
Figure 2: Maps of serotonin transporter (5-HTT) binding 
from a healthy volunteer (B) and a bipolar subject (C) whose 
midbrain BP1 was closest to the respective group mean. 
Subject maps were co-registered to the MRI (A) from the 
healthy volunteer. Each voxel intensity is a single BP1 
measurement.  The color-bar represents mL/g. 5-HTT BP1 
was significant lower in midbrain (1st/2nd column), amygdala 
(2nd/3rd column), thalamus (1st/3rd column), anterior cingulate 
cortex (1st column), hippocampus (2nd column), and putamen 
(not shown).
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Prior to the use of 
[11C]WAY-100635 
in 
patient populations we 
carefully evaluated this 
ligand to determine the 
optimal data acquisition 
and 
analysis 
methods.6,11,152,153 Twenty 
subjects who met DSM-
IV154 criteria for a bipolar 
disorder and a current 
major depressive episode 
and 41 control subjects 
have been scanned to date 
and are included in the data presented below. Inclusion criteria were assessed through history, chart review, 
Structured Clinical Interview for DSM IV (SCID I)133, review of systems, physical examination, routine blood
tests, pregnancy test, urine toxicology and EKG. The Beck Depression Inventory 
 (BDI)155, Hamilton Depression Rating Scale (HAMD)134, and Global Assessment Scale156 assessed subjective 
and objective depression severity and functional impairment, respectively.
Study criteria for bipolar subjects included: 1) age 18 to 65 years; 2) DSM-IV criteria for bipolar 
disorder and a current MDE; 3) absence of any psychotropic medications for at least 2 weeks (6 weeks for 
fluoxetine, 4 weeks for neuroleptics), except benzodiazepines, which were discontinued three days prior to the 
scan; 4) absence of lifetime history of alcohol or substance abuse or dependence; 5) absence of life-time 
exposure to 3,4-methylenedioxymethamphetamine (“ecstasy”); 6) absence of significant medical conditions; 7) 
absence of pregnancy; and 8) capacity to provide informed consent.
Study criteria for controls were similar except for the absence of medical, neurological and psychiatric 
history or a history of a mood or psychotic disorder in a first-degree relative.  The Institutional Review Boards 
of Columbia University Medical Center and the New York State Psychiatric Institute approved the protocol.  
Subjects gave written informed consent after an explanation of the study.
Data acquisition and analysis 
was identical to those previously 
described.9 
Briefly, 
a 
ten-minute 
transmission scan was acquired prior to 
the bolus injection of [11C]WAY-
100635.  Emission data were collected 
in frames of increasing duration for 110 
minutes. Image analysis was performed 
using 
MEDX 
software 
(Sensor 
Systems, Inc., Sterling, VA). Each of 
the 20 frames was coregistered to the 
eighth frame using FMRIB’s Linear 
Image 
Registration 
Tool 
(FLIRT) 
v5.0.142 
Mean 
PET 
images 
were 
coregistered to the corresponding MRI 
using FLIRT.  No attempt was made to 
correct 
for 
transmission 
emission 
mismatch in reconstruction. ROIs were 
traced based on brain atlases143 and 
published reports144 and verified by a 
0.00
20.00
40.00
60.00
80.00
100.00
RN
VPFC
MPFC
DLPFC
ACN
CIN
AMY
HIP
PHG
INS
TEM
PAR
OCC
Binding Potential (mL/g)
Control (n = 41)
Bipolar (n = 20)
Figure 3: No difference in 5-HT1A BP between controls and bipolar 
subjects scanned during a major depressive episode.
Carson 
2004
Laruelle
199423
Carson
199724 
Relationship 
to receptor 
parameters
Equilibrium 
calculation
Kinetic 
calculation
Graphical 
calculation
BP
V3 
S’
Bmax/KD 
C3/C1f1 
K1k3/k2k4f1 
(VT - VREF)/f1 
BP1
V’3 
S 
f1Bmax/KD 
C3/C1 
K1k3/k2k4 
VT  - VREF 
BP2
V”3 
R 
f2Bmax/KD 
C3/C2 
k3/k4 
(VT/VREF) - 1 
Table 2: Adapted from 25.  Bmax = density of available binding sites; 1/KD = affinity of 
the radiotracer for available binding sites; f1 = radiotracer plasma free fraction; f2 = 
radiotracer intracerebral free fraction VREF = V2 = distribution volume of 
nondisplaceable (free and nonspecifically bound) compartment; K1 and k2 = rate 
constants for transit of the radiotracer between plasma and nondisplaceable 
compartment; k3 and k4 = rate constants for transit of the radiotracer between 
nondisplaceable and specific binding compartment; VT = total tissue distribution volume 
relative to total radiotracer concentration.
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neuroanatomist (VA).  ROIs included the ventral prefrontal cortex (VPFC), medial PFC (MPFC), dorsolateral 
PFC (DLPFC), anterior cingulate (ACN), cingulate cortex (CIN), amygdala (AMY), hippocampus (HIP), 
parahippocampal gyrus (PHG), insular cortex (INS), temporal cortex (TEM), parietal cortex (PAR), and 
occipital cortex (OCC). A fixed volume elliptical ROI (2 cm3) was placed on the raphe nuclei (RN) in the dorsal 
midbrain: a composite of mostly the dorsal and median raphe nuclei, on a mean PET image for each subject 
since the boundaries of this structure cannot be identified on MRI.  A cylindrical ROI was drawn in the 
cerebellar white matter.11 MRIs were segmented utilizing the exbrain v.2 utility145 and within the cortex only 
the voxels classified as gray matter were used to measure PET activity distribution.  Data analysts were blind to 
subject identity or group. Binding potential (BP) is equal to the product of the receptor density (Bmax, nM per g 
of tissue) and affinity (1/KD, nM per mL of brain water, Table 2.23,157  VT was defined as the total regional 
equilibrium distribution volume, equal to the sum of V2 and V3, distribution volumes of the second 
(nondisplaceable) and third (specific) compartments, respectively. Cerebellar VT from a one tissue (1T) 
compartment model was used as a constraint for the K1/k2 ratio in the two tissue (2T) kinetic modeling of the 
regions of interest.  Binding potential (BP) was calculated as (VT - V2)/f1 where f1 is the free fraction in plasma.
Statistical analyses performed included Student’s t-test, one way analysis of variance, and linear mixed 
models analysis with subject as the random effect. Model fitting was computed using both SPSS 11 for Mac 
OSX (www.spss.com) and R (www.R-project.org).  When multiple regions were considered in a single 
analysis, region was included as a fixed effect, 
and the analysis was performed on the natural log 
of BP, in order to account for heterogeneity of 
variances across regions.  
Significance was 
defined as p < 0.05 and p-values are reported 
without multiple comparison adjustment.  All 
tests were two-sided.  In all models, there were 
no interactions, first or higher order, therefore, 
the interaction terms were not included in the 
models.  Data are presented as mean ± standard 
deviation.
There was no difference in percentage of 
females between controls (56%) and bipolar 
subjects (60). They also did not differ in age 
(controls = 37.3 ± 14.5, BPD = 39.04 ± 10.0, p = 
0.640). The control population presented here is 
the same as in our previous publication.22
Across all regions there was slightly 
higher BP in BPD subjects scanned during a 
MDE compared to controls but this did not reach 
statistical significance (F = 0.592; df = 1, 54; p = 
0.444; Figure 3). We have previously reported 
that females have significantly higher 5-HT1A BP 
than men and that there is a correlation between 
lifetime aggression scores and BP.153 As this is 
preliminary data, we do not have lifetime 
aggression scores for all the subjects but when we 
include gender in the linear mixed effects model 
we get a significant gender by diagnosis 
interaction (F = 5.99; df = 1, 54; p = 0.018). In 
contrast to the our findings in unipolar 
depression, it appears that male bipolar subjects 
Males
0.00
20.00
40.00
60.00
80.00
100.00
RN
VPFC
MPFC
DLPFC
ACN
CIN
AMY
HIP
PHG
INS
TEM
PAR
OCC
Binding Potential (mL/g)
Control (n=18)
Bipolar (n=8)
Females
0.00
20.00
40.00
60.00
80.00
100.00
RN
VPFC
MPFC
DLPFC
ACN
CIN
AMY
HIP
PHG
INS
TEM
PAR
OCC
Binding Potential (mL/g)
Control (N = 23)
Bipolar (n = 12)
Figure 4: Trends for higher 5-HT1A BP in male bipolar 
patients and lower 5-HT1A BP in female bipolar patients.
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IRB# 2012-1826-F
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PI: Chuan Huang, PhD
Page 8 of 37
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have higher 5-HT1A BP compared to male controls while female bipolar patients have lower BP compared to 
female controls (Figure 4).  We have also shown that prior medication status has a major effect on 5-HT1A BP22 
however 90% of the bipolar subjects had been previously exposed to medication.
There is no compelling evidence of a differential response to lithium based on sex. In a review of 17 
studies and over 1500 patients, males and females responded equally well to lithium158, therefore we 
hypothesize that chronic lithium treatment will result in decreasing cortical but not somatodendritic 5-HT1A 
receptors in both males and females. If our preliminary data are correct, this would result in ‘normalizing’ 5-
HT1A BP in males and possibly lowering 5-HT1A BP in females below control levels. This significance of this 
can only be assessed in the larger context of the completed dataset.
D. Research Design and Methods
1. Rationale/Overview
Bipolar disorder is a brain disorder characterized by recurrent manic and major depressive episodes, the 
latter being clinically similar to those observed in unipolar or major depressive disorder.  The one-year 
prevalence rate for Bipolar I or II is estimated at 1-2% for all ages. Bipolar disorder ranked 20th in terms of 
causes of loss of disability-adjusted life-years in 1999. Yet, its neurobiological underpinnings are poorly 
understood and most research has focused on functional brain abnormalities rather than alterations in 
neurotransmission. Pharmacotherapy development has focused on testing molecules that target neuroreceptors, 
transporters and heavily on serendipitous findings regarding lithium and anticonvulsants where the precise 
mechanism of therapeutic action is unknown. Further, treatments for bipolar depression show remission rates 
only modestly better than placebo. As a potential aid to rational drug development and to elucidate its 
pathophysiology, neurotransmission deficits present in bipolar depression require attention.
Our group has been interested in determining the role of key neurotransmitter receptors and transporters 
in both unipolar and bipolar depression. In unipolar depression this initial work has lead to a working model 
that incorporates 5-HT1A receptors, the 5-HTT, and genetic polymorphisms. In parallel with this work in 
unipolar depression we have started 5-HT1A and 5-HTT studies in bipolar disorder.  Our goal with this study is 
to develop a neurotransmitter based model of bipolar disorder to complement important findings from fMRI and 
PET that will enhance understanding of the pathophysiology and the action of drugs with proven beneficial 
effects (lithium and lamotrigine) to accelerate development of more specific or novel treatment strategies.
We will use the radiotracer [11C]DASB to measure serotonin (5-HT) transporter binding and 
[11C]CUMI-101 to measure serotonin receptors in the brain of depressed or recently depressed bipolar subjects 
using Positron Emission Tomography (PET) before and after treatment with a mood stabilizer.  We propose to 
assess how the clinical responses to two types of mood stabilizer treatment relate to the state of the serotonin 
system.  The two treatments we intend to compare are lithium and lamotrigine. We propose to perform 
[11C]CUMI-101 and [11C]DASB in 38 medication free bipolar subjects during a major depressive episode and 
compare 5-HTT and 5-HT1A binding potential in 38 healthy volunteers. We will also examine the diagnostic 
specificity of lithium response by studying 10 unipolar depressed subjects in an identical manner.
We will obtain blood samples from all subjects in the protocol in order to be able to evaluate their 
genetic information.  We plan to analyze the DNA from the blood to assess for genome wide and single 
nucleotide polymorphisms and their associations with MRI and PET brain imaging measures.  For example, the 
effects of the C(-1019)G 5-HT1A promoter polymorphism has been shown to affect the binding of our 5-HT1A 
tracers in humans.  The genetic information may also be used to study the general pathophysiology of major 
depression, bipolar disorder or past suicidal ideation in the subjects. Blood RNA will also be evaluated because 
it tells us whether the gene variants are associated with altered gene expression. We expect gene variants with 
altered expression levels to be of greater pathophysiological consequence. 
2. Research Site
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IRB# 2012-1826-F
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PI: Chuan Huang, PhD
Page 9 of 37
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MRI scans, research interviews, clinical assessments and treatment will take place at Stony Brook University 
Medical Center. PET scans will take place at the Yale University PET Center in New Haven, CT.  
3. Study Sample
86 subjects in total are proposed. The power calculations are below.
Age range: 18-70
Total subjects: N = 86 (38 bipolar, 38 healthy volunteer, 10 unipolar)
Gender: Male and female representation are about equal.
No ethnic/racial/gender group is excluded.
4. Screening
All patients will be assessed clinically through history, chart review, Structured Clinical Interview for DSM IV 
(SCID I)133, review of systems, physical examination, routine blood tests, pregnancy test, urine toxicology and 
electrocardiogram.  The Beck Depression Inventory (BDI)155, Hamilton Depression Rating Scale (HDRS)134, 
and Global Assessment Scale156 will be used to assess  subjective and objective depression severity and 
functional impairment, respectively.  Patients who currently meet criteria for bipolar disorder, as assessed by the 
Structured Clinical Interview for DSM-IV (SCID I), and who have a 17-Item HDRS score of at least 15 or a 17-
Item HDRS score of 10 to 14 in conjunction with a BDI score of at least 29 will be recruited for this study. 
Patients who currently meet criteria unipolar depression and are in a current major depressive episode, as 
assessed by the Structured Clinical Interview for DSM-IV (SCID I), and who have a 17-Item HDRS score of at 
least 15 or a 17-Item HDRS score of 10 to 14 in conjunction with a BDI score of at least 29 will be recruited for 
this study.
Patients with prior antidepressant treatment will undergo a three-week medication washout prior to enrollment 
in the study. Although this is a relatively prolonged washout, we have shown that depressed patients who are 
washed out of antidepressants that they had failed to respond to do not worsen, rather report modest 
improvement in their symptoms.159
Normal controls are recruited to provide normative values on the clinical and brain imaging measures used.  
Subjects are screened for mental and physical health. Family history of psychiatric disorder is assessed using 
the Family Interview for Genetic Studies (FIGS). Urinary drug screen, physical examination and laboratory 
testing are performed prior to acceptance as a control subject. The normal control sample is selected to match 
the mean, variance and shape of the distributions across the clinical sample, at a group level.   Matching 
variables are age, gender, socioeconomic status, education, marital and employment status, and race.
BIPOLAR PATIENTS:
INCLUSION:
(1) Patients diagnosed with bipolar disorder. Patients on 
psychiatric medication will have failed their current 
regimen for the treatment of their depression: they 
will meet criteria for depression, be seeking 
treatment for it, and have been on an adequate dose 
of antidepressant or mood stabilizer (as defined by 
the Antidepressant Treatment Form—see Oquendo 
et al., 2003) for 4 weeks or more
As defined by the DSM-IV by 
means of the SCID
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(2) Of sufficient severity to score at least 15 on the first 
17 items of the Hamilton Depression Rating Scale or 
a score of 10 to 14 on the first 17 items of the 
Hamilton Depression Rating Scale in conjunction 
with a score of at least 29 on the Beck Depression 
Inventory
Hamilton Depression Rating Scale 
(HDRS), 
Beck 
Depression 
Inventory (BDI)
(3) Age range 18-70 years
Interview
(4) Able to stop all psychotropic and other types of 
drugs likely to interact with serotonin transporters 
and 5-HT1A receptors for at least 21 days before PET 
scans. Allowed short-acting benzodiazepines for 
distressing anxiety or insomnia (up to 24 hours prior 
to each PET scan). Able to be off neuroleptics for 3 
weeks and off fluoxetine for 6 weeks prior to study. 
Able to be off serotonin depleting drugs such as 
reserpine for 3 months.  
Able to be off anti-
coagulant/anti-platelet treatment such as Coumadin, 
with the exception of aspirin, for 10 days before PET 
scans.
History, chart and urine drug 
screen
(5) Willing to travel to Yale University for PET 
scanning
Interview
EXCLUSION:
(1) 
Other 
major 
psychiatric 
disorders 
such 
as 
schizophrenia, 
schizoaffective 
illness; 
Current 
substance abuse (within the past 2 months) or recent 
dependence (within the past 6 months) except for 
cannabis use disorders, which are not exclusionary; 
anorexia nervosa or bulimia nervosa, purging type in 
the past year, except for bulimia nervosa, non-
purging type plus a normal BMI, which is not 
exclusionary; IV drug use in the past 5 years or 
ecstasy (MDMA) use more than 15 times in the past 
10 years or any MDMA use in the past month.
SCID; Urine drug screen
(2) Significant active physical illness particularly those 
that may affect the brain or serotonergic system 
including 
blood 
dyscrasias 
lymphomas, 
hypersplenism, endocrinopathies, renal failure or 
chronic 
obstructive 
lung 
disease, 
autonomic 
neuropathies, peripheral vascular disease, diabetes, 
low hemoglobin and malignancy, significant anemic 
disease or blood loss and the lab parameters platelet 
count < 80,000
Medical history (by a physician), 
physical exam, screening lab tests 
(comprehensive metabolic panel, 
CBC with differential, thyroid 
function tests [TSH and free T4], 
PT/PTT, urine test for pregnancy, 
and 
urine 
drug 
screen) 
(approximately 15.2 ml of blood 
drawn) and an ECG. A physician 
will review lab findings to ensure 
that there are no anemia related 
contraindications to participation
(3) Lacks capacity to consent
Clinical interview 
(4) Actively suicidal-begins expressing a plan for suicide 
during the washout phase or develop suicidal 
Clinical interview
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IRB# 2012-1826-F
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Page 11 of 37
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ideation that warrants admission or requires 
medication or treatment intervention
(5) ECT within the past 6 months
History, chart review 
(6) Pregnancy, currently lactating; planning to conceive 
during the course of study participation or abortion 
in the past two months
HCG pregnancy test to rule out 
pregnancy or unwilling/unable to 
use a medically acceptable means 
of birth control through the course 
of the study.  Urine pregnancy test 
will be done at screening. A urine 
pregnancy test will be done on the 
day of the PET scan prior to 
scanning. In addition, each female 
subject must confirm that she is 
using an acceptable method of birth 
control for at least two weeks prior 
to the PET scan
(7) Metal implants, pacemaker or metal prostheses or 
orthodontic appliances, the presence of shrapnel
History
(8) Current, past or anticipated exposure to radiation, 
that may include:
      - being badged for radiation exposure in the 
workplace
      - participation in nuclear medicine procedures, 
including research protocols in the last year.*
1. Subjects will undergo a clinical 
interview, during which they will 
be asked whether or not they have 
worked with radioactive substances 
or have been badged in the past.  In 
addition, they are asked about any 
prior chemotherapy or radiation 
treatment.  2.  A research assistant 
will check our database to ensure 
that the subject has not participated 
in an imaging study within our 
department in the past year.  
(9) A neurological disease or loss of consciousness for 
more than a few minutes
Clinical interview
(10) Medicinal patch that cannot be removed**
Medical history (by a physician), 
physical exam.
(11)Patients who are responding satisfactorily to 
psychiatric medications, because they will not be 
washed-out for purposes of this study
History
(12) A documented history of a lack of response to a 
trial of adequate dose and duration of both lithium 
and lamotrigine defined as minimal clinical 
response to lamotrigine 200 mgs for at least 4 
weeks or lithium serum levels of at least 0.8 (or 
dose >= 900 mgs) for at least 4 weeks
History
(13) Patient is unlikely to be able to tolerate medication 
washout
Clinical interview
(14) Claustrophobia
Clinical interview
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IRB# 2012-1826-F
PSF 2/23/15
PI: Chuan Huang, PhD
Page 12 of 37
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(15) Blood donation within 8 weeks of the start of the 
study.
Clinical interview
(16) History of a bleeding disorder or are currently 
taking anticoagulants (such as Coumadin, Heparin, 
Pradaxa, Xarelto).
 History
* Subjects will be eligible 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 (see below)
** In case the subject does have a medicinal patch, they will be asked to remove it prior to the MRI scan 
session
HEALTHY VOLUNTEERS:
INCLUSION:
(1) No lifetime history of Axis I disorders other than 
specific phobia, social phobia, and/or adjustment 
disorder.
Structured Clinical Interviews I 
for DSM IV; clinical history and 
interview
(2) Age range 18-70 years.
Interview
(3) Willing to travel to Yale University for PET   
scanning.
Interview
EXCLUSION:
(1) Past or present alcohol/substance abuse or 
dependence except for cannabis use disorders, 
which are not exclusionary; IV drug use in the 
past 5 years; IV drug use in the past 5 years or 
ecstasy (MDMA) use more than 15 times in the 
past 10 years or any MDMA use in the past 
month.
SCID; Urine drug screen
(2) A first-degree relative with history of major 
depression if participant is less than 44 years old 
(median age of onset plus one quartile)174, 
schizophrenia, schizoaffective disorder, or suicide 
attempt; two or more first degree relatives with a 
history of substance dependence if the participant 
is less than 27 years old (median age of onset plus 
one quartile).174.
Clinical 
interview, 
Family 
Interview for Genetic Studies 
(FIGS)
(3) Significant active physical illness particularly 
those that may affect the brain or serotonergic 
system including blood dyscrasias lymphomas, 
hypersplenism, endocrinopathies, renal failure or 
chronic obstructive lung disease, autonomic 
neuropathies, 
peripheral 
vascular 
disease, 
diabetes, low hemoglobin and malignancy, 
significant anemic disease or blood loss, and the 
following lab parameters:
  platelet count < 80,000
Medical history (by a physician), 
physical exam, screening lab 
tests (comprehensive metabolic 
panel, CBC with differential, 
thyroid function tests [TSH and 
free T4], PT/PTT, urine test for 
pregnancy, 
and 
urine 
drug 
screen) (approximately 15.2 ml 
of blood drawn). A physician 
will review lab findings to ensure 
that there are no anemia related 
Approved: 12/13/2019
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Stony Brook University Human Subjects Committee (IRB)


IRB# 2012-1826-F
PSF 2/23/15
PI: Chuan Huang, PhD
Page 13 of 37
13
contraindications to participation.
(4) Lacks capacity to consent
Clinical interview
(5) Pregnancy, currently lactating; planning to 
conceive during the course of study participation 
or abortion in the past two months
HCG pregnancy test to rule out 
pregnancy or unwilling/unable to 
use a medically acceptable means 
of birth control through the 
course of the study.  
Urine 
pregnancy test will be done at 
screening.  A urine pregnancy 
test will be done on the day of 
the PET scan prior to scanning. 
In addition, each female subject 
must confirm that she is using an 
acceptable 
method 
of 
birth 
control for at least two weeks 
prior to the PET scan.
(6) Metal implants, pacemaker or metal prostheses or 
orthodontic appliances, the presence of shrapnel
History
(7) Current, past or anticipated exposure to radiation, 
that may include:
    - being badged for radiation exposure in the   
workplace
    - participation in nuclear medicine procedures, 
including research protocols in the last year *
1. Subjects will undergo a 
clinical interview, during which 
they will be asked whether or not 
they 
have 
worked 
with 
radioactive substances or have 
been badged in the past.  
In 
addition, they are asked about 
any 
prior 
chemotherapy 
or 
radiation treatment.  
2.  
A 
research assistant will check our 
database to ensure that the 
subject has not participated in an 
imaging 
study 
within 
our 
department in the past year.  
(8) A neurological disease or loss of consciousness 
for more than a few minutes
Clinical interview
(9) Medicinal Patch that cannot be removed*
Medical history (by a physician), 
physical exam.
(10) Unable to stop drugs or medication that affect 
the serotonin system prior to the PET scans. 
History
(11) Claustrophobia
Clinical Interview
(12) Blood donation within 8 weeks of the start of the 
study.
(13) History of a bleeding disorder or are currently 
taking 
anticoagulants 
(such 
as 
Coumadin, 
Heparin, Pradaxa, Xarelto).
 History
Approved: 12/13/2019
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IRB# 2012-1826-F
PSF 2/23/15
PI: Chuan Huang, PhD
Page 14 of 37
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* Subjects will be eligible 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 (see below).
** In case the subject does have a medicinal patch, they will be asked to remove it prior to the MRI scan 
session.
UNIPOLAR PATIENTS:
INCLUSION:
(1) Unipolar patients suffering from a major depressive 
episode currently or recently (in the month prior to 
scanning).  Patients on psychiatric medication will 
have failed their current regimen for the treatment of 
their depression: they will meet criteria for 
depression, be seeking treatment for it, and have 
been on an adequate dose of antidepressant or mood 
stabilizer 
(as 
defined 
by 
the 
Antidepressant 
Treatment Form—see Oquendo et al., 2003) for 4 
weeks or more
As defined by the DSM-IV by 
means of the SCID
(2) Of sufficient severity to score at least 15 on the first 
17 items of the Hamilton Depression Rating Scale or 
a score of 10 to 14 on the first 17 items of the 
Hamilton Depression Rating Scale in conjunction 
with a score of at least 29 on the Beck Depression 
Inventory
Hamilton Depression Rating Scale 
(HDRS), 
Beck 
Depression 
Inventory (BDI)
(3) Age range 18-70 years
Interview
(4) Able to stop all psychotropic and other types of 
drugs likely to interact with serotonin transporters 
and 5-HT1A receptors for at least 21 days before PET 
scans. Allowed short-acting benzodiazepines for 
distressing anxiety or insomnia (up to 24 hours prior 
to each PET scan). Able to be off neuroleptics for 3 
weeks and off fluoxetine for 6 weeks prior to study. 
Able to be off serotonin depleting drugs such as 
reserpine for 3 months.  
Able to be off anti-
coagulant/anti-platelet treatment such as Coumadin, 
with the exception of aspirin, for 10 days before PET 
scans.
History, chart and urine drug 
screen
(5) Willing to travel to Yale University for PET 
scanning***
Interview
EXCLUSION:
(1) 
Other 
major 
psychiatric 
disorders 
such 
as 
schizophrenia, 
schizoaffective 
illness; 
Current 
substance abuse (within the past 2 months) or recent 
dependence (within the past 6 months) except for 
cannabis use disorders, which are not exclusionary; 
anorexia nervosa or bulimia nervosa, purging type in 
the past year, except for bulimia nervosa, non-
SCID; Urine drug screen
Approved: 12/13/2019
Expiration Date: 12/12/2020
Stony Brook University Human Subjects Committee (IRB)


IRB# 2012-1826-F
PSF 2/23/15
PI: Chuan Huang, PhD
Page 15 of 37
15
purging type plus a normal BMI, which is not 
exclusionary; IV drug use in the past 5 years or 
ecstasy (MDMA) use more than 15 times in the past 
10 years or any MDMA use in the past month.
(2) Significant active physical illness particularly those 
that may affect the brain or serotonergic system 
including 
blood 
dyscrasias 
lymphomas, 
hypersplenism, endocrinopathies, renal failure or 
chronic 
obstructive 
lung 
disease, 
autonomic 
neuropathies, peripheral vascular disease, diabetes, 
low hemoglobin and malignancy, significant anemic 
disease or blood loss and the lab parameters platelet 
count < 80,000
Medical history (by a physician), 
physical exam, screening lab tests 
(comprehensive metabolic panel, 
CBC with differential, thyroid 
function tests [TSH and free T4], 
PT/PTT, urine test for pregnancy, 
and 
urine 
drug 
screen) 
(approximately 15.2 ml of blood 
drawn) and an ECG. A physician 
will review lab findings to ensure 
that there are no anemia related 
contraindications to participation
(3) Lacks capacity to consent
Clinical interview 
(4) Actively suicidal-begins expressing a plan for suicide 
during the washout phase or develop suicidal 
ideation that warrants admission or requires 
medication or treatment intervention
Clinical interview
(5) ECT within the past 6 months
History, chart review 
(6) Pregnancy, currently lactating; planning to conceive 
during the course of study participation or abortion 
in the past two months
HCG pregnancy test to rule out 
pregnancy or unwilling/unable to 
use a medically acceptable means 
of birth control through the course 
of the study.  Urine pregnancy test 
will be done at screening. A urine 
pregnancy test will be done on the 
day of the PET scan prior to 
scanning. In addition, each female 
subject must confirm that she is 
using an acceptable method of birth 
control for at least two weeks prior 
to the PET scan
(7) Metal implants, pacemaker or metal prostheses or 
orthodontic appliances, the presence of shrapnel
History
(8) Current, past or anticipated exposure to radiation, 
that may include:
      - being badged for radiation exposure in the 
workplace
      - participation in nuclear medicine procedures, 
including research protocols in the last year.*
1. Subjects will undergo a clinical 
interview, during which they will 
be asked whether or not they have 
worked with radioactive substances 
or have been badged in the past.  In 
addition, they are asked about any 
prior chemotherapy or radiation 
treatment.  2.  A research assistant 
will check our database to ensure 
that the subject has not participated 
in an imaging study within our 
department in the past year.  
Approved: 12/13/2019
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Stony Brook University Human Subjects Committee (IRB)


IRB# 2012-1826-F
PSF 2/23/15
PI: Chuan Huang, PhD
Page 16 of 37
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(9) A neurological disease or loss of consciousness for 
more than a few minutes
Clinical interview
(10) Medicinal patch that cannot be removed**
Medical history (by a physician), 
physical exam.
(11)Patients who are responding satisfactorily to 
psychiatric medications, because they will not be 
washed-out for purposes of this study
History
(12) A documented history of a lack of response to a 
trial of adequate dose and duration of lithium 
defined as minimal clinical response to lithium 
serum levels of at least 0.8 (or dose >= 900 mgs) for 
at least 4 weeks
History
(13) Patient is unlikely to be able to tolerate medication 
washout
Clinical interview
(14) Claustrophobia
Clinical interview
(15) Blood donation within 8 weeks of the start of the 
study.
Clinical interview
(16) History of a bleeding disorder or are currently 
taking anticoagulants (such as Coumadin, Heparin, 
Pradaxa, Xarelto).
History
* Subjects will be eligible 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 (see below)
** In case the subject does have a medicinal patch, they will be asked to remove it prior to the MRI scan 
session
*** In case the subject cannot travel to Yale, scans will be done at the Siemens Biograph mMR-System 
located at the Ambulatory Imaging Center at Stony Brook Medicine.
Screening Tests
All subjects will have a complete medical history and clinical examination to exclude significant physical 
illness as described above. Approximately 15.2  ml of blood will be drawn at the screening visit for laboratory 
testing. A urine sample will also be collected. The following tests will be performed before the study: 1) clinical 
blood count including differential; 2) metabolic panel (14) comprehensive (Alanine aminotransferase 
(ALT/SGPT); albumin:globulin (A:G) ratio; albumin, serum; alkaline phosphatase, serum; aspartate 
aminotransferase (AST/SGOT); bilirubin, total; BUN; BUN:creatinine ratio; calcium, serum; carbon dioxide, 
total; chloride, serum; creatinine, serum; globulin, total; glucose, serum; potassium, serum; protein, total, serum; 
sodium, serum); 3) thyroid function tests (TSH and free T4) 4) PT/PTT 5) drug screen; 6) and pregnancy test. 
Other tests will be performed if there are specific indications.
5. Procedures
Collection of Genetic Information
Approved: 12/13/2019
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IRB# 2012-1826-F
PSF 2/23/15
PI: Chuan Huang, PhD
Page 17 of 37
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Whole blood (approximately 8 ml) will be drawn for assays of candidate gene expression and polymorphisms 
(i.e., genetic polymorphism of tryptophan hydroxylase, serotonin transporter, etc.).
MRI Scan  
An MRI scan will be performed to localize anatomic regions of interest on the PET scan.  MRI scans will be 
performed at the Stony Brook University SCAN Center.  Participants will receive an array of structural and 
functional MRI scans  
(e.g. T1 and T2-weighted structural images, diffusion tensor imaging [DTI], 
pseudocontinuous arterial spin labeling [pCASL], etc.) over the course of approximately 1 to 1.5 hours. Patients 
will be monitored by the MRI technician and research assistant, who will be available at all times. A study 
physician will also be available if it is necessary. The procedure will be immediately stopped if subjects exhibit 
significant distress. 
Repeat MRI: patient participants will have a second MRI scan following their treatment period (scheduled 
approximately one week before or after the second set of PET scans). Control participants will be asked to 
return for a second MRI approximately 12 weeks after their initial MRI. This is optional for control participants. 
PET Studies
Approximately 8ml of blood will be drawn the day of the PET scans for female participants to assess their 
stage in the menstrual cycle. 
PET experiments will be conducted at the Yale University PET Center, 800 Howard Avenue, in New 
Haven, CT. [11C]CUMI-101 and [11C]DASB scans will be performed. Participants may have only one of 
these scans, depending on radiotracer availability. The PET scans will preferably be performed after the 
MRI scan, but the order may be reversed if needed. 
Participants will be provided with transportation from Stony Brook University to Yale University by a 
combination of taxi/car service, ferry, and/or train. Participants will be accompanied by a staff member 
while traveling to/from Yale University. Participants will arrive the night before the scheduled scan day(s) 
and be given accommodations at a nearby hotel at no cost to them. 
On the day of the scans, a urine pregnancy test will be done on females to ensure that pregnancy has not 
occurred between the time of the screening and the PET scans.  All participants will also have a urine drug 
screen. The preparation of the subject will include the placement of one venous lines (for radiotracer 
injection), a second venous line (for and blood sampling), and an arterial line (for blood sampling).  An 
experienced physician will place the arterial line after infiltration of the skin with 1% lidocaine.  A 
transmission scan is then obtained. Before injection of the radiotracer, approximately 8ml of venous blood 
will be collected. For the [11C]CUMI-101 scan, up to 20 mCi of [11C]CUMI-101 (mass dose of 5 µg or less) 
will be administered i.v. after the transmission scan. Emission data will be collected for up to 120 minutes.  
At the time of injection, arterial sampling will be initiated.  In order to demonstrate that the arterial and 
venous metabolites are the same for late time points, a 4 mL venous sample will be initiated at 60 and 90 
minutes. 90 ml or less will be collected during scan time. 
At the end of the scan, subjects will be provided with a light meal and be allowed to relax.  For the 
[11C]DASB scan, the subject will go back on the scanner table and an injection of up to 20 mCi of  
[11C]DASB, (mass dose of 10 µg or less) will be administered. Emission scan and arterial sampling will be 
resumed as described above.  A 4 mL venous sample will be initiated at 50 and 80 minutes. Thus, maximal 
blood sampling during the entire PET procedure will be approximately 180 ml (about 12 tablespoons). 
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The order of [11C]CUMI-101 and [11C]DASB administration may be reversed, or subjects may participate in 
only one scan (either [11C]CUMI-101 or [11C]DASB),.
In cases where the subject has a hemoglobin level less than 12 for males and less than 11 for females, we 
would forgo blood drawing for the [11C]DASB scan except for one sample to be taken at the 50 minute time 
point, as outlined in the simultaneous estimation (SIME) approach. Likewise, we would forego blood 
drawing for the [11C]CUMI-101 scan except for one sample at the 60 minute time point. We have recently 
confirmed that this provides an excellent estimate of the plasma parameters necessary for quantification and 
modeling of this radioligand. It involves drawing one 12 cc sample off the arterial line at the 50 min post-
radioligand injection time point. Therefore, instead of 120 cc being drawn during the DASB scan, we would 
reduce the blood drawn to 12 cc.
In the case that the two injections are planned but cannot be done on the same day once the PET procedures 
have been started, subjects may be asked to return on a separate day in order to complete the scans.  If the PET 
procedure has to be rescheduled and placement of another aline is required, subject consent will be sought.
 
After the acute treatment period, the patients who are on either lithium or lamotrigine will have a second PET 
scanning session that is identical to the first: up to 20 mCi or less of [11C]CUMI-101 and up to 20 mCi of 
[11C]DASB. Healthy volunteers will not have follow up scans.
Alternate Location and Tracer for PET Scans
Due to limited availability of PET scans at the Yale PET center, alternative arrangements will be made for 
subjects at Stony Brook Medicine. In cases where the subject cannot accommodate a trip to the Yale PET center 
or the Yale PET center cannot accommodate for enough scans due to decreased scan staff, PET/MRI scans may 
take place at the the Siemens Biograph mMR-System located at the Ambulatory Imaging Center using 
[18F]MeFWAY. Similar to the [11C]CUMI-101 scans being performed at the Yale PET center, [18F]MeFWAY also 
has the capability to examine 5-HT1A  binding. Only bipolar and unipolar patients will be scanned at Stony 
Brook, when Yale is unable to accommodate the number of scans necessary. Healthy controls will continue to 
be scanned at Yale PET Center. 
Participants will complete a metal screening form prior to procedure to ensure there are no MRI 
contraindications (e.g. pacemaker, non-MR safe metal implants). A pregnancy test will be performed on the day 
of the scan for female participants to confirm that pregnancy has not occurred. And we will also measure female 
hormones by blood samples to ensure if contraceptives were used and if not, the results of the hormone levels 
can be used as covariates for the data analysis. Preparation of the subject will include the placement of venous 
lines (for radiotracer injection and blood sampling), and an arterial line (for blood sampling only).  At the time 
of injection, blood sampling will be initiated.  120 mL or less (about 4 ounces or 1/2 cup) will be collected 
during each scan. The wrist scanner will also be placed around the subject’s wrist. 
Participants will be asked to urinate in a cup to determine the validity of the dosimetry for future studies. 
Bolus Protocol:  For each scan, participants will receive a venous injection (bolus delivery) of no more than 
2.5 mCi of the radiotracer [18F]MeFWAY, as per RDRC protocol. 
Simultaneous MRI Scan:  An MRI scan will be performed simultaneously with the PET scan.  Participants 
will receive an array of structural and functional MRI scans  (e.g. T1 and T2-weighted structural images, 
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diffusion tensor imaging [DTI], pseudocontinuous arterial spin labeling [pCASL], etc.) The anatomical image 
(T1) will be used to localize anatomic regions of interest on the PET scan.  During this time, subjects will be 
monitored by the MRI technician.  During the rest of the PET acquisition, participants will receive an array of 
structural and functional MRI scans. 
Structural scans may include: 
Diffusion Tensor or Spectrum Imaging to measure white matter tracts.  These sequences are used to 
evaluate orientation and diffusion characteristics of white matter (WM) and, by inference, WM 
microstructure.85 Fractional anisotropy (FA), or the disorganization of water molecules, is a common measure 
used in DTI to determine integrity of WM fibers. Characteristics of healthy WM include parallel organization of 
white matter fibers and myelination, which leads to reduced movement of water. FA values range from zero 
(isotropic diffusion) to one (anisotropic diffusion), with higher values denoting greater WM microstructure 
integrity.86 In the past several years, FA measures have been used to study the correlation between WM 
microstructure and mood disorders.87,88,89,90 A 2009 meta-analysis of DTI studies demonstrated that, in 21 of the 
27 studies, subjects with mood disorders had significantly lower fractional anisotropy in the frontal and 
temporal lobes and tracts.91
Arterial Spin Labeling (ASL) to measure cerebral blood flow.  In a previously published correlation of 
HAM-D scores and regional blood flow in depressed subjects, correlation coefficients between 0.69 and 0.84 
were observed.92  
Functional scans may include:
Resting-state functional MRI (fMRI) reveals the network of the brain active when a subject is not 
performing a task.  During this functional task, the subject will be asked to keep their eyes open and try to clear 
their mind, fixate on an image of cross-hairs on a screen.  Analysis of functional MR images indicates that some 
brain regions are more active during rest, and that these same regions have routinely decreased activity during 
the performance of tasks.93,94 This led to the hypothesis that there is a “default mode” of the brain that remains 
active in a structured fashion when the brain is at rest.94,95 Further, it has been shown that this default mode 
network is disrupted in MDD. 179-186
Optional Psychophysiological Assessment
We will ask participants if they would be willing to participate in a brief optional electroencephalograph EEG 
procedure at baseline and follow-up. For patient participants, the baseline EEG would be before they begin 
medication treatment. 
The EEG assesses brain electrical activity through surface recording disks (electrodes) which are placed near 
the participant's head. The electrodes transmit the signals, which are then amplified and stored on a computer.  
The procedure is entirely non-invasive.
A custom designed 32-electrode Lycra cap will be placed on the participant's head.  In order to record the 
brain's activity, these disks need to be filled will a gel which allows the electrodes to better record brain activity 
at the scalp.  Therefore, the participants in this study will need to clean their hair after participation.  The gel is 
completely water soluble, and the procedure is painless.  The laboratory has sinks and towels, and the 
investigators will help to make sure the participant has thoroughly rinsed all the gel from their hair.  After an 
accurate signal is assured, the signal derived from the electrode cap is then amplified, transmitted to a computer, 
and stored for later analysis.  
In addition to the EEG recording, skin conductance, heart rate, and muscle activity from around the eyes will be 
recorded from the participants.  Skin conductance is recorded by placing two recording sensors on the 
participant’s forefinger and middle finger; the procedure is entirely non-invasive and painless.  Heart rate is 
recorded by placing a sensor on the participant’s pinky finger. This procedure is completely non-invasive and 
painless.  Muscle activity from the face and around the eyes is recorded by small sensors that will be placed 
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above and below the participant’s right eye, as well as on the outer canthi (just below the eyebrow) of each eye, 
and above the eye.
Tasks
1. Loudness dependence auditory evoked potential (LDAEP)
The LDAEP will be performed in accordance with Linka et al (2007). Participants will be presented with 
binaural 1000-Hz tone bursts lasting 80 ms (including a 10 ms rise and 10 ms fall time). The tone bursts will be 
presented at one of five intensity levels: 60, 70, 80, 90 and 100 dB (presented in random order). There will be 
an interstimulus interval randomized between 500-900 ms. Participants will be instructed to attend to the sounds 
that are being presented. All participants will first perform a practice block of 10 trials; the actual experiment 
will consist of 2 blocks of 500 trials (1000 trials). Between blocks, participants will be able to take a short 
break. The actual experiment will last approximately 10 minutes. 
Optional Adult Attachment Interview
We will ask controls if they would be willing to participate in an adult attachment interview. The interview is 
approximately 45-75 minutes long and can be completed over the phone or in person. The interviews are audio 
recorded and transcribed. The recorded interviews are kept confidential with a participant number. There are no 
risks or benefits associated with this optional interview. 
Treatment Procedures
Site of Treatment
 Patients will be treated on an outpatient basis at Stony Brook University Medical Center. Patients may visit the 
Clinical Research Center or a LabCorp collection site for sample collection, if needed on rare occasions. 
Treatment Choice
 At baseline, patients will have a [11C]CUMI-101 and [11C]DASB PET scan. All patients will then receive 
outpatient pharmacologic treatment with lithium administered as follows: Day 1, 2 and 3, 300 mg bid; 
Days 4-7 lithium 300 qam and 600 qhs.  A blood sample will be drawn (approximately 8.5 ml) to check the 
lithium level as close to Day 7 as possible. The lithium level will be titrated to a therapeutic plasma level of 
0.8-1.2 mEq/l; the lithium level will be checked weekly via a blood sample of approximately 8.5 ml until 
this level is reached. Patients may have additional blood samples drawn to check the lithium level after 
reaching this level, if needed. Patients will not undergo lithium monotherapy if they have a documented 
history of at least two failed trials of lithium of at least 4 weeks duration with therapeutic blood levels for a 
major depressive episode.  If they have not responded to adequate prior lithium treatment while depressed 
or refuse lithium, they will be given lamotrigine. Lamotrigine will be started at 25 mg bid and increased to 
50 mg bid after 2 weeks and again increased to 100 mg bid after an additional 2 weeks.
After 6-10 weeks from the time of therapeutic or highest tolerable dose of treatment with either agent they will 
have repeat [11C]CUMI-101 and [11C]DASB PET scans. Blood levels of the lithium will be measured at the 
time of the repeat scan.  At 6 weeks, if patients have not shown at least a 50% improvement in their HDRS 
score from the baseline interview they will be switched to lamotrigine. Similarly, if patients cannot tolerate 
treatment, they will be switched to lamotrigine and we will repeat both [11C]CUMI-101 and [11C]DASB  scans 
4-10 weeks after subjects are on therapeutic levels of lamotrigine. If subjects cannot tolerate either treatment, or 
if the subject scores a CGI-I (severity of illness) score of 4 (“moderately ill”) or more after the week 4 visit for 
two visits in a row, and/or a CGI-II (global improvement) score of 6 (“much worse”) or 7 (“very much worse”) 
for 2 visits in a row, the subject will be considered a non-responder and will receive the repeat [11C]CUMI-101 
and [11C]DASB scans. They will then receive open treatment in our clinic.
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Neither lithium nor lamotrigine is approved by the FDA for acute treatment of depressive episodes in patients 
with bipolar disorder, and neither drug is approved for treatment of unipolar depression.  Thus, the use of both 
drugs as treatment for depression in this study is off-label.  Nevertheless, both drugs represent reasonable 
treatment options for depression which has failed to respond to traditional antidepressants in either bipolar or 
unipolar depressive disorders.  There have been several reports of the efficacy of lithium and lamotrigine in 
both bipolar and unipolar depression (175-178). In this study, unipolar depressed patients will only be treated 
with lithium.
Subjects will be offered up to 6 months of outpatient treatment and one month of medication at no cost. If the 
lithium or lamotrigine treatment is effective, it will be continued; if not, the subjects will be switched to open 
treatment with other drugs or other modalities. If subjects should still need additional treatment beyond the 
allotted time, they will be given referrals for continuing treatment elsewhere. In order to monitor renal and 
thyroid function, subjects taking lithium will have blood drawn (approximately 12.5 ml) for a comprehensive 
(14) metabolic panel, CBC with differential and Thyroid function tests (TSH and free T4) as well as an ECG 
after 3 months and 6 months from the start of treatment.
Clinical Monitoring
Personnel
Patients will be treated and monitored by psychiatrists in the Stony Brook Department of Psychiatry.
Frequency of clinical evaluations 
For the initial 4 weeks of medication treatment, patients will see a psychiatrist in person at least once/week, 
and more frequently if clinical conditions warrant. If it is not possible to schedule an in-person visit every 
week, weekly phone contact may be substituted. Depending on each individual's clinical status, additional 
initial contact by the treating clinician may be either in person or by phone.  
After 4 weeks, frequency of visits will be every two weeks up until the follow up PET scan, depending on 
combined evaluation of treatment response, and side effect issues. At minimum, all patients in active treatment 
will be seen monthly.
It should be noted that this outlines the minimum contact that each patient will have with their physician. In the 
course of the initial phases of treatment, patients may have multiple other contacts with clinically licensed 
personnel in the research program, such as psychologists, who will be involved in the conduct of this labor-
intensive protocol. These staff members will be in frequent direct contact with treating physicians and will, 
therefore, constitute an extension of clinical monitoring.
Side effects
Side effects will be monitored in standard clinical fashion. MDs will interview patients about possible side 
effects at each contact and patients will be encouraged to call with any questions which may arise at any time. 
Response to side effects will depend on the circumstance. Doses may be titrated or patients may have 
medication discontinued, if clinically indicated.
Instruments 
A battery of assessments will be administered to assess mood, suicidality, and character traits. Ratings will 
be collected at multiple time points, including at baseline (2 hours), biweekly during medication treatment 
(1/2 hour), within one week of an MRI/PET scan (or at the conclusion of a mood-stabilizer trial), (1/2 
hour), and at designated follow-up time points (2 hours). Patients may be video or audio-recorded with 
their consent during the administration of these scales.
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Examples of measures that will obtained include: 

Hamilton Depression Rating Scale (15 min)

Hamilton Anxiety Scale (15 min) (at baseline and repeat PET scan)

Beck Depression Inventory (10 min)

GAS (2 min) (administered by treating physician during clinical check-ins)
Data Analysis 
PET data will be reconstructed into images using the appropriate software, coregistered to the MRI and regional 
time activity curves will be measured.  The arterial input function will be used to derive the regional density of 
5-HT transporters and 5–HT1A receptors with kinetic modeling. 
E. Statistics
Power Analyses
A power analysis was conducted to determine required sample size for detecting a difference in populations 
with 80% probability using a linear mixed-effect model with region and diagnosis as fixed effects and subject as 
random effect.  This was accomplished by means of a simulation study for a variety of sample sizes.  The noise 
level, the subject effect variance, and mean levels for each region were extracted from the linear mixed-effect 
model fitted to preliminary DASB studies.  The diagnosis effect was taken from the 5-HTT data in bipolar 
disorder.  To stabilize variance among regions, analysis will be performed on the log-transformed BP data.  
Results of the analysis indicate that 80% power will be achieved with 38 bipolar subjects and 38 controls and 10 
unipolar subjects.  Note that these results are for the simplest analysis – comparing bipolar patients with normal 
controls over six regions.  If genotype or other covariates are found to have an effect, then including these 
factors in the model can be reasonably expected to control more of the variance and thus increase power of 
testing for a diagnosis effect.
To assess the impact of lithium on the neuroreceptor measures we conservatively use the higher test/retest 
variability of the [11C]DASB compound and assume a 20-25% change in both 5-HT1A and 5-HTT after chronic 
lithium based on preclinical data. 14,16-18  Assuming 50% of the subjects complete the lithium treatment and 
repeat scans and this degree of change, we have a power of between 79% and 90% as this is a paired analysis.
Estimated outcome measures will be analyzed for all ROIs and all patients in a linear mixed model with patient 
as random effect and ROI and remission status as fixed effects.  Our previous studies have demonstrated that 
the standard deviation of BP across patients increases approximately linearly with the mean of the region, and 
so the BP values are first log-transformed in order to satisfy the assumptions of the modeling (constant variance 
across regions).  For the pre/post imaging of the non-remitters, a linear mixed model will again be used with 
ROI and condition (before/after) as fixed effects and with two levels of random effects -- a patient effect and a 
study within patient effect.  Many potential covariates will also be measured for each patient and will be 
included in the model when appropriate.  Modeling will be done using R software (www.r-project.org).
F. Funding Status, Details
The study is currently funded through the National Institutes of Health (NIH) through May 31,  2017.
Grant Title: Lithium’s Molecular Mechanism of Action and the Pathology of Bipolar Disorder
G. Human Subjects Research Protection from Risk
1. Risk to Subjects and 2. Adequacy of Protection Against Risks
Risks associated with participation in this study are related to 1) Drug-free interval; 2) placement of intra-
arterial catheter; 3) blood sampling; 4) discomfort during scanning (PET and MRI); 5) MRI scan; 6) 
radiation exposure; 7) toxicology (idiosyncratic reaction to the tracer); 8) genetic testing/confidentiality; 9) 
pregnancy and 10) risks associated with lithium/lamotrigine use.
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1. Drug-free interval
There is a risk that drug washout will result in a worsening of the patient’s condition which could include 
worsening of depression of induction of a manic episode. During the medication washout, we employ 
either inpatient supervision or outpatient supervision by a psychiatrist.  If the responsible physician 
(inpatient or outpatient) determines that treatment cannot be delayed safely or the patient withdraws from 
the study, all necessary treatment is offered. Patients on a mood stabilizer are excluded unless they are 
medication non-responsive. Patients are offered up to 3mg of Ativan daily to relieve symptoms during this 
phase. If the subject clinically deteriorates (worsening depression or mania) in the course of the drug 
washout to the extent that they feel they cannot tolerate the washout, or they are observed objectively to 
become significantly more depressed, manic, or develop suicidal ideation such that admission to hospital or 
medication is required clinically, we will drop them from the protocol and commence immediate 
appropriate treatment.
2. Intra-arterial catheter
Radial arterial catheterization is needed for repeated arterial blood samples to construct tracer input curves. 
Arterial sampling may be associated with mild-to-moderate pain, hematoma, inflammation, bleeding, or 
bruising at the puncture site. If this occurs, signs and symptoms will dissipate over time, usually 24 to 72 
hours after the event.  Certain individuals may feel light-headed during arterial catheter placement. 
In rare instances blocking of the artery, tearing of the artery, arterial leakage, poor healing, or infection at 
the catheter insertion site may occur. In a review of the literature between 1978-2001, Scheer21 found that 
among 19,617 radial artery catheterizations, temporary and benign occlusion occurred in 19.7% of patients. 
Thrombosis persisted as a major complication in just 0.09% of the cases. Septic complications occurred in 
0.13% of cases. In studies conducted at Columbia University/NYSPI we have found that of 1,132 arterial 
lines in 924 subjects, there was 1 instance of symptomatic thrombotic occlusion (0.09%), documented by 
Doppler ultrasound in a depressed female patient. There was no associated ischemic damage, and the 
condition resolved over a period of weeks without intervention.22 There has never been a serious adverse 
event related to an arterial line. In some cases, hematomas have formed after removal or the arterial line.  
But in all cases of hematoma formation this has occurred during the period immediately following removal 
of the line and after the routine several minutes of pressure applied by the physician removing the line.  In 
all these cases, pressure was immediately reapplied and the hematoma stabilized after release of the 
pressure.  No incidents or adverse events related to arterial line placement occurred in any of the subjects 
after leaving the Columbia University/NYSPI PET suite. 
In the proposed study, arterial catheters will remain in place no more than 12 hours.  The risks of radial 
artery cannulation are minimized by having the procedure performed by an experienced physician. Pain is 
minimized by local anesthesia. Bleeding is prevented by local pressure applied for a minimum of 15 
minutes after catheter removal. Subjects will have their hand and finger blood supply examined after 
arterial cannulation and again following catheter removal.  Also, subjects will be asked to abstain from 
aspirin and other NSAIDs for 7-10 days prior to arterial line insertion and 7-10 days following arterial line 
removal.Subjects will be provided a 24 hour emergency physician telephone number to call if they 
encounter pain, discoloration, numbness, tingling, coolness, hematoma, inflammation, or any other unusual 
symptoms in the wrist or hand, or fever, chills or drainage from the vascular puncture sites, following the 
procedure.  In addition, if an emergency arises at the time of cannulation or scanning, 911 will be called, 
and the subject will be sent to the Emergency Department for evaluation and treatment. Nurses will provide 
the subjects an instruction sheet documenting problems to watch for and procedures to follow should such 
problems occur. Infection is avoided by adequate cleansing of the skin prior to intravascular line insertion.
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Moreover, the physician will do no more than 3 arterial punctures in each arm, including the successful 
insertion of the catheter.  Before each attempt, the subject will be assessed for pain/discomfort and asked if 
they are amenable to another attempt. At anytime they can decline to proceed.  In the case that the arterial 
line has to be placed another time due to rescheduling of the scan, the subject will be reminded of the risks 
associated with the procedure.
In the event that an arterial line cannot be placed, we will use the simultaneous estimation (SIME) 
approach as discussed in the PET scan procedure section. This involves drawing one 12 cc sample via an 
arterial stick at 50 min post-radioligand injection for DASB, and at the 60 min post-radioligand injection 
timepoint for CUMI. This approach reduces the risk and burden to patients as it does not involve placing an 
indwelling catheter, but rather drawing a single blood sample. If the SIME approach fails, we will only 
draw from the venous line at the 50 and 80 time points for DASB and the 60 and 90 min time points or 
CUMI as described in the PET scan section.
3.  Blood sampling & IV line insertion 
Drawing blood and inserting an intravenous line (IV) into an arm vein are safe and standard medical 
procedures. Sometimes a bruise will occur at the puncture site and rarely, a blood clot or infection will 
occur in the vein. Certain individuals may feel light-headed during venipuncture. The volume of blood 
collected during the PET scans, will be approximately 16 tablespoons at most. At screening, 15.2ml will be 
drawn. An additional 8.5ml of blood will be drawn weekly until Lithium levels are therapeutic. This is not 
expected to have any serious negative effects on a study participant.
The risks of bruising, clotting, and infection will be minimized by having venipuncture performed by 
trained and experienced personnel using aseptic technique. To avoid injury due to fainting, the antecubital 
vein catheter will be inserted when the subjects are recumbent. The blood draws during PET scanning 
sessions will be obtained from the already inserted catheter, to minimize discomfort. 
For patients who have low hemoglobin levels, possible adverse effects of blood sampling will be 
minimized by using the SIME approach. No additional risks are introduced by the simultaneous estimation 
(SIME) approach.
4. Discomfort during scanning (PET and MRI)
It may be uncomfortable to lie motionless in the cameras (both PET and MRI) and it may cause some 
subjects to feel anxious.  Our staff will be available to provide support, reduce anxiety, optimize the 
comfort of the subject and remove the subject from the machine if requested. 
5. MRI/fMRI Scan
MRI: While there have been no reports of any ill long-term effects caused by magnets of the same or even 
higher strength, the long-term effects of being placed in a magnet of this strength are unknown.  The MRI 
scanner uses a large magnet to take pictures of the brain and is not associated with any known medical risks, 
except for persons who have a heart pacemaker, or have metal in their body (e.g. shrapnel or surgical 
prostheses) which may be affected by the magnet.  Patients will be asked to notify us if this is the case.  There is 
also the risk of burns from medicinal patches during the MRI; therefore, subjects will be asked to remove any 
patches prior to the scanning session.  Also, although there are no known risks associated with pregnancy, we 
will not scan someone who is pregnant. Some people have reported sensations during the MRI scan, such as 
"tingling" or "twitching" (or, very rarely, a painful sensation), which are caused by changes in the magnetic 
field that can stimulate nerves in the body.  If the subject experiences sensations and feels uncomfortable, the 
MR technologist will stop the scan immediately.  Occasionally, some people experience nervousness or 
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claustrophobic feelings due to the scanner's small space. Despite these sensations, in our experience, no one has 
had sensations from the scanning that did not stop as soon as the scanning stopped. The MRI scan is not painful, 
but having to lie still in the enclosed space of the scanning table is uncomfortable for some people.
fMRI: The risks associated with the fMRI due to the magnet strength are exactly the same as the risks 
associated with the MRI.
6. Radiation Exposure (PET)
The Yale-New Haven Hospital Radiation Safety Committee (RSC) will review the use of radiation in this 
research study, and no subjects will be enrolled until RSC approval is obtained. This research study involves 
exposure to radiation from [11C]CUMI-101 and [11C]DASB PET scanning. This radiation exposure is not 
necessary for medical care and is for research purposes only.
The targeted amount of radiation an individual subject will receive in this study per year is from up to 2 
injection(s) of ≤ 20 mCi from [11C]CUMI-101 and from up to 2 injection(s) of ≤ 20 mCi from [11C]DASB plus 
transmission scans. 
Although each organ will receive a different dose, the maximum amount of radiation exposure subjects will 
receive per year from this study is equal to an effective dose equivalent of 2.4 rem for a total of 2 injection(s) of 
up to 20 mCi of [11C]CUMI-101 and 2 injection(s) of up to 20 mCi of [11C]DASB.
The amount of radiation subjects will receive in this study is below the dose guidelines established by the FDA 
and monitored by the Yale-New Haven Hospital Radiation Safety Committee for research subjects. This 
guideline sets an effective dose limit of 5 rem per year.
The dosimetry tables below provide the absorbed radiation dose calculation for [18F]MeFWAY based on a 
dosimetry studies in humans.187 [18F]MeFWAY dosimetry estimates101,102 are shown in Table 4.  By voiding the 
urinary bladder at 90 minutes, as recommended by a recent human [18F]MeFWAY dosimetry study, 187the 
radiation dose is expected to be halved. By emptying the bladder at 90 minutes, the single study exposure to the 
critical organ (urinary bladder) with the minimum dose of 2.0 mCi and maximum dose of 2.5 mCi, as per Stony 
Brook RDRC protocol, results in radiation dosage of up to 1.9 Rad (Rem) for males and 2.46  Rad (Rem), 
which is under the 5 Rem single dose limit under the FDA 21 361.1.  
For the maximum number of scans (3), the dose to the critical organ would be 5.7 Rad (Rem) for males and 
7.38 Rad (Rem) for females, which is less than the 15 Rem annual dose limit under FDA 21 361.1. 22.8. It will 
be necessary to void the urinary bladder at 90 minutes. Each scan will be about 120 minutes or less, however, 
all participants will be required to void at 90 minutes. The scan will not continue if they cannot void their 
urinary bladder. We will encourage fluids including coffee, tea, and water intake. The half-life of 
1[8F]MeFWAY is 109 minutes and at least half of the radioactivity from the radiotracers, is expected to 
disappear by voiding the urinary bladder at 90 minutes.  The rest of the tracer will be excreted through general 
dissipation and from urine from the body within 24 hours. Because the radiation dosage is close to the 
maximum annual radiation dose limit, we will ask about the participant’s prior radiation exposure during the 
initial evaluation to ensure the radiation dose they are receiving from all research studies is less than the annual 
dose limit. 
 Table 3 shows the absorbed radiation dose calculation for [11C]CUMI-101 based on our human dosimetry data 
(MIRDOSE calculation based on baboon data).  Similarly, Table 3 provides the absorbed radiation dose 
calculation for [11C]DASB based on the dosimetry study of [11C]DASB in humans (Lu et al., 2004). The critical 
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organ is the testes in males and bladder wall in females for [11C]CUMI-101, and the lungs for [11C]DASB.  The 
exposure after a single injection of [11C]CUMI-101 and [11C]DASB is below the single dose limit under the 
FDA 21 361 dose limits for research subjects (3 rem per injection, 5 rem annually for whole body, active blood 
forming organs, lens of the eye and gonads and 5 rem per injection, 15 rem annually for other organs).
Single Study Limit
 [11C]CUMI-101: For the [11C]CUMI compound, the single study exposure to the critical organ (testes in males, 
bladder wall in females) with the maximum dose of 20 mCi, is 2.4 rem (males) and 1.5 rem (females) is below 
the 3(testes)/5(bladder wall) rem single dose limit under the FDA 21 361.1.
[11C]DASB: Table 3 provides the absorbed radiation dose calculation for [11C]DASB.  The dose estimates 
indicate that the maximum permissible single study dosage of [11C]DASB in human subjects remain below the 
21 CFR 361.1 dose limit for research subjects which is 20 mCi (i.e., calculation based upon the lung as the 
critical organ; 3 rads per single study for the whole body, active blood forming organs, lens of the eyes and 
gonads; 5 rads for other organ per single study limit).
[18F]MeFWAY  
While no adverse events have been observed to date in human research with this drug, since fewer than 15 
individuals have been injected with [18F]MeFWAY worldwide, even common and serious effects may not be 
known yet.
Yearly Cumulative Exposure
The radiation exposure table indicated that the total exposure resulting from the study will remain well below 
the FDA 21 361.1 dose limits for yearly cumulative exposure to research subjects (dose limits of 5 rads per year 
for whole body, active blood forming organs, lens of the eye and gonads; 15 rads per year for other organs).  
Each subject will receive up to 4 injections, (up to 2 [11C]DASB and up to 2[11C]CUMI-101 scans).  The 
cumulative exposure due to four injections remains below the FDA annual limits.
Table 3 (Human Data)
Organ
11C-CUMI-
101 
Single 
Study 
maximal 
exposure
 (20 mCi)
DASB 
Single Study 
maximal 
exposure 
(20mCi)
Cumulative Exposure 
(1 DASB + 1 CUMI)
Units
mGy/MBq
mGy/MBq
mrem/Year
%of limit
Adrenals
3.71E-03
3.16E-03
5.08E+02
3.4
Brain
1.04E-02
5.77E-03
1.20E+03
8.0
Breasts
1.79E-03
2.36E-03
3.07E+02
2.0
Gallbladder 
Wall
3.65E-03
9.27E-03
9.56E+02
6.4
LLI Wall
1.27E-03
2.11E-03
2.50E+02
1.7
Small Intestine
1.61E-03
2.18E-03
2.80E+02
1.9
Stomach Wall
2.58E-03
2.46E-03
3.73E+02
2.5
ULI Wall
1.74E-03
2.21E-03
2.92E+02
1.9
Heart Wall
2.51E-03
8.21E-03
7.93E+02
5.3
Kidneys
9.86E-03
9.28E-03
1.42E+03
9.4
Liver
1.84E-02
6.41E-03
1.84E+03
12.2
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Lungs
8.60E-03
3.28E-02
3.06E+03
20.4
Muscle
1.95E-03
2.09E-03
2.99E+02
2.0
Pancreas
3.20E-02
3.03E-03
2.59E+03
17.3
Red marrow
1.77E-03
2.33E-03
3.03E+02
6.1
Osteogenic 
Cells
1.57E-03
2.25E-03
2.83E+02
1.9
Skin
1.50E-03
1.60E-03
2.29E+02
1.5
Spleen
1.45E-02
7.40E-03
1.62E+03
10.8
Testes
1.52E-03
1.74E-03
2.41E+02
4.8
Thymus
2.08E-03
2.98E-03
3.74E+02
2.5
Thyroid
4.55E-03
2.06E-03
4.89E+02
3.3
Urinary Bladder 
Wall
1.90E-03
1.20E-02
1.03E+03
6.9
Lens of the Eye
0.00E+00
N/A
N/A
Total Body
0.00E+00
2.75E-03
2.04E+02
mSv/MBq
mSv/MBq
mrem/Year
Effective Dose 
Equivalent
0.00E+00
8.01E-03
5.93E+02
Effective Dose
5.33E-03
6.98E-03
9.11E+02
18.2
Note: The effective dose (ED) as a consequence of exposure to typical transmission scans on ECAT 
EXACT HR+ scanner is 2.7 x 10-4 mSv/MBq X h (Almeida et al, 1998).  There are 3 Ge68 rod sources on 
HR+ (<5mCi each). The transmission scan for this study is 10 minutes, which would result in a total 
additional ED of 2.7 X 10-4/MBq x (5x3x37) MBq x 10/60 hr = 0.025 mSv = 2.5 mrem per scan.
The dose of radiation will be submitted for approval to the Yale-New Haven Hospital Radiation Safety 
Committee (Y-NHH RSC). All scans will be done in the presence of medical supervision and trained staff 
in an institution specifically designed to support imaging studies. In the event of serious medical 
complications, the PET scan facilities have immediate access to or consultation with specialized medical 
units at the Yale-New Haven Hospital. Preparation of radiopharmaceuticals and performance of PET scans 
will be by radiochemists, physicians, and technologists of the Department of Diagnostic Radiology, Yale 
University School of Medicine. These professionals are qualified by training and experience in the safe use 
and handling of radiopharmaceuticals.
Subjects will be asked about their previous radiation and those who have had research exposure within the 
past year will be excluded if cumulative annual exposure (including the present study) exceeds FDA limits.   
The information on the previous radiation exposure of study subjects will be notified to the study doctor. 
No PET studies will be performed on pregnant or potentially pregnant women, as confirmed by pregnancy 
testing during evaluation and on each scan day before initiation of any scan procedures. If subjects are 
breastfeeding they will not be able to participate in this research study.
Table 4: Human Dosimetry of [18F]MeFWAY101,102
 
mSv/MBq
mRad/2.5mCi
Organ
Female
Male
Female
Male
Adrenals
1.59E-02
1.25E-02
147.25
116
Brain
8.58E-03
5.79E-03
79.25
53.5
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Breasts
7.96E-03
5.99E-03
73.75
55.5
Gallbladder Wall
2.04E-02
1.68E-02
188.5
155
LLI Wall
2.32E-02
1.90E-02
215
176
Small Intestine
1.67E-02
1.44E-02
154.25
133.25
Stomach Wall
1.18E-02
9.23E-03
109.5
85.5
ULI Wall
1.58E-02
1.25E-02
146.25
115.75
Heart Wall
1.25E-02
7.43E-03
115.25
68.75
Kidneys
3.36E-02
4.95E-02
310
457.5
Liver
7.54E-02
5.23E-02
697.5
485
Lungs
2.28E-02
1.32E-02
210.5
122
Muscle
1.20E-02
9.74E-03
110.75
90
Ovaries
2.29E-02
N/A
211.5
N/A
Pancreas
1.51E-02
1.19E-02
139.75
110.25
Red marrow
1.45E-02
1.22E-02
133.75
113.25
Osteogenic Cells
1.75E-02
1.29E-02
162
119.5
Skin
7.68E-03
6.19E-03
171
57.25
Spleen
1.10E-02
8.85E-03
102
81.75
Testes
N/A
1.36E-02
N/A
125.75
Thymus
9.43E-03
7.01E-03
87.25
64.75
Thyroid
7.64E-03
6.36E-03
70.75
58.75
Urinary Bladder Wall*
5.32E-01
4.10E-01
4925
3800
Uterus
3.67E-02
N/A
340
N/A
Lens of the Eye
N/A
N/A
N/A
N/A
Total Body
N/A
N/A
N/A
N/A
*For the urinary bladder wall, by voiding the bladder at 90 minutes, the radiation dose is expected to decrease to 
1.9 Rem for males and 2.46 Rem for females, which is under which is under the 5 Rem single dose limit under 
the FDA 21 361.1 as mentioned above.  
7.  Toxicology of Drugs and Radiotracers
[11C]CUMI-101: We have performed 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.
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All animals survived until their scheduled necropsy.  Male and female rats in the 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.  Rats in the low dose group at 44.05 µg/kg 
(264.3 µg/m2, 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 44.05 µg/kg (264.3 µg/m2) 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 8 human volunteers with two doses of the tracer given to each 
subject. No adverse effects were observed and the tracer gives a very reliable finding outcome measure with 
less than 10% CV on test retest. It has also been tested by Robert Innis at the NIH in 8 human volunteers with 
no adverse effects.
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. 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 the RDRC & IRB at Stony Brook University.
[11C]DASB: The dose of [11C]DASB (equal or below 10 µg) will be administered at tracer levels.  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, as specified in 21 CFR 361.1 (d8).
The dose of radiation for [18F]MeFWAY has been submitted for approval to the Stony Brook Hospital 
Radiation Safety Committee and the Stony Brook Radioactive Drug Research Committee (RDRC).  All scans 
will be done in the presence of trained staff in an institution specifically designed to support imaging studies. In 
the event of serious medical complications, the PET scan facilities have immediate access to or consultation 
with specialized medical units at Stony Brook Hospital, as well as the responsible study physician, Dr. Kunkel. 
Preparation of radiopharmaceuticals and execution of PET scans will be performed by radiochemists and 
technologists of Stony Brook University, including the Director of Radiochemistry, Dr. Peter Smith-Jones and 
authorized users Drs. Dinko Franceschi and Robert Matthews. These professionals are qualified by training and 
experience in the safe use and handling of radionuclides. Subjects will be asked about their previous radiation 
exposure, and those who have had research exposure within the past year will be excluded if their cumulative 
annual exposure (including the present study) exceeds FDA limits.  According to the CFR Title 21, part/section 
361.1 “Radioactive drugs for certain research uses”, single dose for whole body, active blood-forming organs, 
lens of the eye, and gonads should not exceed 3 Rems and annual and total dose commitment should not exceed 
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5 Rems.  For the current proposal, the estimated single study exposure to these organs is below 0.423 Rem (423 
mrem).  For the maximum number of scans (3), the dose to these organs is below 1.27 Rem (1,270 mrem), 
which is less than the 5 Rem annual dose limit. As for the other organs, Rems should not exceed 5 Rems for a 
single dose and 15 Rems for annual and total dose commitment. For the current proposal, the estimated single 
study exposure to all other organs is below 1.27 Rem (1,270 mrem).  For the maximum number of scans (3), the 
dose to all other organs is below 3.81 Rem (3,810 mrem), which is less than the 15 Rem annual dose limit. 
Further, the radiation dose is expected to be halved when the participant voids at 90 minutes. The scan will not 
continue if the participant does not void at 90 minutes.
8. Genetic samples and confidentiality
Samples will be de-identified and coded only with a number; no personal identifying or clinical information is 
provided to the testing laboratories.  Therefore, the risk of a breach in confidentiality is remote.  
9. Pregnancy
Studies involving radiation are contraindicated during pregnancy because of possible risk to the fetus.  
Women of child-bearing age will be required to have a urine pregnancy test administered on the evaluation 
day as well as on the day of the PET session prior to scanning. Subjects will not be charged for the 
pregnancy test.  In addition, nursing mothers will also be excluded from the study.
10. Other Risks Associated with Lithium and Lamotrigine Use
Lithium: possible side effects include diarrhea, vomiting, shakiness, drowsiness, slowed thinking, weakening of 
muscles, difficulty concentrating, acne, weight gain, change in thyroid function and increased urination. 
Because of the possibility of becoming sleepy, patients will be told to be cautious about driving especially when 
the medication is started or the dose is raised.  Patients will be told to tell their doctor if they develop any of 
these symptoms.   Patients will also be told not to take pain medications such as ibuprofen (Advil, Motrin, or 
Naproxen [Anaprox]) while on lithium. Diuretics (water pills) such as thiazide or furosemide (Lasix) should not 
be taken with lithium.  Lithium may react with other medications. While taking lithium, before adding another 
medication patients will be asked to check with their doctor to be sure it is safe.
Lamotrigine: Possible side effects include serious rashes that may need to be treated in a hospital or cause 
permanent disability or death; fever; swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower 
legs; hoarseness; difficulty breathing or swallowing; upset stomach; extreme tiredness; unusual bruising or 
bleeding; lack of energy; loss of appetite; pain in the upper right part of the stomach; yellowing of the skin or 
eyes; flu-like symptoms; pale skin; headache; dizziness; fast heartbeat; weakness; shortness of breath; sore 
throat, fever, chills, and other signs of infection; dark red or cola-colored urine; muscle weakness or aching; or 
painful sores in the mouth or around the eyes. Patients will also be told not to take valproic acid (Depakene) or 
divalproex (Depakote) while on lamotrigine.
11. Risks of optional EEG procedure
Potential risks include psychological distress and fatigue from performing the tasks. Participants may take short 
breaks between the various tasks. During the EEG recording, there is a small possibility of mild skin redness 
where the electrode contacts the skin.  This, however, is rare and usually temporary.
3. Potential Benefits of Proposed Research to the Subjects and Others
There will be potential benefit to the patients in terms of free clinical and diagnostic assessments. Patients will 
get a thorough psychiatric and medical work-up and then a free inpatient or outpatient initial treatment course of 
a mood stabilizer.  The benefits to society and to future patients may be considerable if enhanced understanding 
of biology of bipolar disorder and the action of mood stabilizers is gained.
Approved: 12/13/2019
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IRB# 2012-1826-F
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PI: Chuan Huang, PhD
Page 31 of 37
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4. Importance of the Knowledge to be Gained
Bipolar disorder is a major health problem in which the serotonin system may play a role in pathogenesis and/or 
treatment. An urgent need exists for a reliable biochemical test for bipolar disorder. Therefore, study of the 
serotonergic system should be conducted in the untreated depressed state where these measures may have 
potential as diagnostic tools as well as providing important information about the pathogenesis of bipolar 
disorder and biochemical heterogeneity of depressive disorders.  Repeating these tests after treatment will assist 
in determining the mechanism of action of mood stabilizers, the potential of this type of PET scan as a 
biochemical monitor of clinical response as well as help to determine whether alterations in function are state or 
trait-dependent.  Such studies can also improve knowledge regarding the mechanism of action of mood 
stabilizers, and may lead to the design of better medications.
H. Data Safety Monitoring Plan (for more than minimal risk studies)
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.
Once a patient enrolls in the project they are given a code number which 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.
Subjects whose history is obtained through the collection of family history information (from the interviewee) 
are also considered research subjects. They are subjected to minimal risk because all information is confidential. 
There are procedures to safeguard confidentiality of the information gathered about them from other family 
members, including names or identifying information kept on the family history form or in the records. All hard 
copies of records are kept in locked files. Computer files will be stored in a database which is password 
protected. The database is stored on a secured server.  Only essential staff will be allowed access to this 
information.  The study could not be completed without this information.
Blood samples for genetic testing will be de-identified and coded only with a number; no personally identifying 
or clinical information will be stored with the samples or provided to testing laboratories. 
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Approved: 12/13/2019
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PI: Chuan Huang, PhD
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SAP_001.pdf: 
Official Title: PET and MRI Brain Imaging of Bipolar Disorder 
 
NCT: NCT01880957 
 
Document Date: 11/14/2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Proposed Statistical Plan for [11C]-DASB (5-HTT) & [11C]-CUMI-101 (5-HT1A) from Parsey 
Bipolar Study 
 
 
Outcomes 
DASB: VT/fp + bootstrap ROI error 
CUMI: BPF + bootstrap ROI error (BPND ??) 
 
A priori ROIs 
DASB: acn, amy, midbrain, gcirc 
CUMI: acn, amy, cin, dlPFC, parahippocampal gyrus, hippocampus, raphe 
 
Statistical methods: 
Linear mixed models with subject fit as random variable 
LMM also with DASB & CUMI reference regions and fp  
Key outcomes: p-values for main effects/interactions; overall model R2 & p-value; standardized & 
unstandardized β’s, 95% CIs, p-values for post-hocs 
 
Covariates 
DASB: age 
CUMI: age, sex, previous med status (dichotomous – w/n 4 years) 
 
 
================================================================================= 
================================================================================= 
Post-Treatment 
Sample: HC, pre BPD, post BPD 
___________________________________________________________________________________________ 
Question 1: Do post-treatment BPD levels of DASB or CUMI differ from pre-treatment levels and HCs? 
 
 
 
Interactions of interest: 
Group (relationship btw brain & Group across all regions) 
Group*ROI (ROI-specific relationship btw brain & Group)  
 
================================================================================= 
================================================================================= 
Treatment Effects 
Sample: pre/post BPD pairs 
 
Tx response: % change in HDRS-24 (continuous) and remitter/non-remitter (dichotomous) 
_________________________________________________________________________________________ 
Question 2: Is the % change in DASB or CUMI associated with the treatment outcome? 
 
 
 
 
Interactions of interest: 
 
 
 
ΔHDRS (relationship btw brain & Tx outcome across all regions) 
 
 
 
ΔHDRS*ROI (ROI-specific relationship btw brain & Tx outcome) 
Dichotomous 
 
 
Interactions of interest: 
 
 
 
Remission (relationship btw brain & Tx outcome across all regions) 


 
 
 
Remission*ROI (ROI-specific relationship btw brain & Tx outcome) 
 
 
================================================================================= 
================================================================================= 
Predicting Treatment Outcome 
Sample: pre BPD with pre HDRS-24 + >7-week HDRS-24 
 
Tx response: % change in HDRS-24 (continuous) and remitter/non-remitter (dichotomous) (responder ??) 
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Question 3: Do pre DASB or CUMI in any of the a prioris predict treatment response? Are the a prioris 
independent predictors of treatment response? 
 
Interactions of interest: 
 
PET_roi (pre-treatment PET in ROI predicts treatment response) 
 
Interactions of interest: 
PET_roi (any significant ROIs are independent predictors of Tx response (over and above the other 
ROIs)) 
 
Same models fit with dichotomous remission status 
 
Additional question: Do pre DASB & CUMI together predict more of the variance in treatment response than 
either method alone? 
Change in overall model R2 from models with pre DASB & CUMI alone to combined 
model (If R2 increases with both methods, tracers are predicting unique properties 
of Tx response) 
 
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Question 4: With what accuracy does pre DASB or CUMI predict treatment response? 
 
Penalized logistic regression models 
 
Additional question: With what accuracy do pre DASB & CUMI together predict treatment response 
 
 
Metrics of interest: 
 
Accuracy, AUC, sensitivity, specificity, NPV, PPV, model factor importance ranking or 
% of variance explained with each factor 
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