Conditions: Bipolar Youth Treated With Second-generation Antipsychotics
Keywords: Bipolar disorder Second-generation antipsychotics Obesity Cardiometabolic risk
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 19
Healthy volunteers: no

Brief summary:
The investigators tested the hypothesis that long-chain omega-3 (LCn-3) fatty acid supplementation will attenuate the adverse cardiometabolic effects of second-generation antipsychotics exposure in first-episode adolescent manic patients.

Detailed description:
Following acute (6-week) open-label treatment with quetiapine, first-episode adolescent manic patients (ages 10-17 years) were randomized to double-blind adjunctive treatment with long-chain omega-3 (LCn-3) fatty acids or placebo for 24 weeks to investigate protective effects on the of adverse cardiometabolic events and weight gain during quetiapine maintenance therapy. They will have 6 visits over a 24-week period.

Arms:
arm 1: Patients will be randomized to EPA+DHA supplements (OmegaRx) at fixed dose of 3.0 g/day (EPA: 2.0 g, DHA: 1.0 g; 5 capsules/d) for 24 weeks. arm 2: Patients will be randomized to similar in shape an color placebo supplements (corn oil)

Interventions: intervention 1: Omega intervention 2: Placebo intervention 3: Quetiapine fumarate
Intervention descriptions: intervention 1: Omega-3 supplements intervention 2: Similar in shape and color to Omega supplements intervention 3: Prior to randomization to Omega/placebo, patients were started on 100 mg BID of quetiapine, and the dose adjusted based on tolerability and response. The quetiapine target dose is 400-600 mg.

Protocol document:
Prot_SAP_000.pdf: 
                                                                                                                               PI: McNamara, Robert K. 
 
Version Date:August 16 2017  
 
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TITLE: Risk and Protective Factors for SGA-Induced Metabolic Syndrome in Bipolar 
Youth 
 
SPONSOR: Investigator Initiated study with funding from National Institute of Diabetes and 
Digestive and Kidney Diseases 
 
 
 
 
Principal Investigator:  
Robert K. McNamara, Ph.D. 
 
 
 
 
 
 
Department of Psychiatry 
 
 
 
 
 
 
University of Cincinnati College of Medicine 
260 Stetson Street, Rm. 3306 
Cincinnati, OH 45219-0516 
PH: 513-558-5601 
FX: 513-558-2955 
EM: robert.mcnamara@uc.edu 
 
 
 
 
    Sub-Investigators:  
Melissa DelBello, MD 
Luis Rodrigo Duran Patino, MD 
Jeff Welge, PhD 
Laurie Moore (Study Coordinator) 
____________________________________________________________________________
A.  SPECIFIC AIMS  
The overall objective of this prospective surveillance and controlled intervention study is to test 
the hypotheses that (1) low long-chain omega-3 (LCn-3) fatty acid status increases risk for 
adverse cardiometabolic effects and weight gain in adolescent bipolar patients treated with 
second generation antipsychotic (SGA) medications by up-regulating stearoyl-CoA desaturase-
1 (SCD1), a lipogenic enzyme implicated in triglyceride biosynthesis, metabolic syndrome, and 
obesity, and (2) that increasing LCn-3 fatty acid status through dietary supplementation will be 
protective against the onset and progression of adverse cardiometabolic effects and weight gain 
in SGA-treated patients by suppressing SCD1 expression/activity. 
SPECIFIC AIM 1:  
To prospectively evaluate low LCn-3 fatty acid status as a risk factor for adverse 
cardiometabolic effects and weight gain in SGA-treated adolescent manic patients. Prediction 1: 
Low baseline RBC EPA+DHA levels will be associated with greater baseline-endpoint increases 
in BMI and triglyceride levels following acute (6-week) SGA treatment compared with high RBC 
EPA+DHA levels. Prediction 2: Baseline SCD1 expression/activity will increase significantly 
following 6-week SGA treatment. Prediction 3: The relationship between RBC EPA+DHA levels 
and SGA-induced elevations in BMI and triglyceride levels is mediated by elevations in SCD1 
expression/activity. 
SPECIFIC AIM 2:  
To prospectively evaluate the protective effects of increasing LCn-3 fatty acid status on the 
progression of adverse cardiometabolic effects and weight gain in SGA-treated adolescent 
manic patients. Prediction 4: LCn-3 fatty acid supplementation will be more effective than 
placebo for decreasing BMI and triglyceride levels in SGA-treated patients. Prediction 5: 
Reductions in BMI and triglyceride levels following LCn-3 fatty acid supplementation will be 
associated with reductions in SCD1 expression/activity and elevations in RBC EPA+DHA levels. 
Prediction 6: LCn-3 fatty acid supplementation will be more effective than placebo for improving 
SGA safety, tolerability, and efficacy. 


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B.  BACKGROUND AND SIGNIFICANCE  
Bipolar disorder is a common psychiatric illness that is characterized by recurrent 
episodes of mania and depression, as well as inter-episode periods of euthymia.71 In the United 
States (US), the life-time prevalence rates are 1.0% for bipolar I disorder (BD-I), 1.1% for BD-II, 
and 2.4% for subthreshold BD (4.4% total).72 The initial onset of mania, and by definition BD-I, 
most frequently occurs during childhood and adolescence.12-15 Outcome data indicate that 
bipolar youth have a relapsing and remitting illness course that is often associated with 
significant psychosocial morbidity73 and a 10-fold increased risk for suicide compared with 
general population estimates.74,75 Prior US studies have reported that 55%–75% of adult BD-I 
patients are overweight or obese, a rate that is approximately double the US national average 
(~30%).4,8,76-79 This is a major concern because obesity has been associated with a worsening 
of psychiatric outcomes in bipolar disorder, including shorter time to recurrence of mood 
episodes,28 poorer global functioning,80 and more frequent suicide attempts.29 Furthermore, 
excessive weight gain and obesity during childhood and adolescence strongly predict obesity, 
metabolic syndrome, hypertension, sleep apnea, osteoarthritis, type II diabetes, and 
cardiovascular morbidity and mortality in adulthood.81-88 Indeed, standardized mortality rates due 
to cardiovascular and circulatory disease in bipolar patients are approximately twice the age-
adjusted population norms.10,11 Health care costs for cardiometabolic conditions associated with 
obesity are over twice as high in bipolar patients compared with the general population.89 
Accordingly, there is an urgent and currently unmet need to identify modifiable risk and 
protective factors for metabolic disorder, obesity, and associated cardiovascular risk in patients 
with bipolar disorder.  
 
Second-generation antipsychotic (SGA) medications, including quetiapine, olanzapine, 
and risperidone, have been shown to be efficacious for the rapid treatment of acute manic and 
psychotic symptoms in pediatric and adolescent patients in controlled trials.16 These SGA 
medications are currently approved by the US FDA for the treatment of acute mania and 
psychosis in youth.17 The American Academy of Child and Adolescent Psychiatry (AACAP) 
endorses the use of SGA medications as optimal first-line agents for the treatment of acute 
mania, and recommend 12-24 months of maintenance therapy for the treatment of acute 
mania.18,19 Epidemiological data indicate that there has been a 6-fold increase in SGA 
prescription rates in pediatric and adolescent (<18 years of age) patients in US office-based 
medical practice during the past decade.20-22 However, several prospective studies indicate that 
SGA medications are associated with significant treatment-emergent weight gain and obesity, 
metabolic syndrome, and elevated cardiovascular risk factors in the majority of SGA-naïve first-
episode pediatric and adolescent patients.23-27 Our group reported that the prevalence of 
overweight among hospitalized children and adolescents with exposure to SGA medications 
was triple that of national norms.90 Another study found that more than 70% of youth exhibited 
significant weight gain after 12 week treatment with SGA medications.26  In one of the largest 
prospective studies conducted to date, pediatric and adolescent patients treated with SGA 
medications including quetiapine exhibited significant elevations in body weight, fat mass, waist 
circumference, and BMI after 4 week exposure, and these parameters as well as triglyceride 
levels continued to increase at 8 and 12 weeks.23  Our group similarly found that 8-week double 
blind treatment with the SGA quetiapine in adolescent (ages 12-17 years) bipolar patients 
resulted in a significantly greater increase in weight gain and fasting triglyceride levels 
compared with placebo.91 Although controversial,23 children and adolescents may be at greater 
risk than adult patients for SGA-induced weight gain.26 Together, these and other data suggest 
that exposure to SGA medications precipitate weight gain and lipid dysregulation in a large 
subset of pediatric and adolescent patients with bipolar disorder. Despite consensus and label 
recommendations for metabolic screening and monitoring for all patients receiving these SGA 
medications,92 the majority of youth starting SGA medications do not receive recommended 


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regular glucose or lipid screening/monitoring in clinical practice.93 Together, these data highlight 
an urgent and unmet met need to identify modifiable risk and protective factors for SGA-induced 
adverse cardiometabolic effects and weight gain to guide ameliorative and preventative 
strategies. 
 
The principal long-chain omega-3 (LCn-3) fatty acids, eicosapentaenoic acid (EPA, 
20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), can only be obtained through the diet, and 
membrane EPA+DHA composition modulates cellular signaling pathways involved in the 
regulation of lipid and metabolic homeostasis.96 Specifically, evidence suggests that low LCn-3 
fatty acid status is associated with elevated blood pressure,33-35 increased waist circumference, 
overweight and obesity,36-40 elevated fasting triglyceride levels,41-43 and elevated C-reactive 
protein (CRP) levels.44-48 Increasing LCn-3 fatty acid status is efficacious for lowering elevated 
triglyceride levels,42 and Lovaza (EPA+DHA, GSK) is currently approved by the US FDA for the 
treatment of very high triglyceride levels (500 mg/dl). Increasing LCn-3 fatty acid intake is 
thought to decrease triglyceride levels by reducing biosynthesis and promoting oxidation.161-163 
Moreover, there is now a substantial body of evidence implicating low LCn-3 fatty acid 
status,95,96 as well as elevated triglyceride levels,97-99 as risk factors for cardiovascular morbidity 
and mortality. Consistent with the storage of excess triglycerides in peripheral fat stores (i.e., 
adipocytes), a growing number of rodent studies have also found that increasing LCn-3 fatty 
acid status is also protective against diet-induced increases in adiposity and weight gain.118-121 
While there have been no clinical studies conducted to evaluate the protective effects LCn-3 
fatty acid against the initial onset and progression of weight gain, obesity is associated with 
LCn-3 fatty acid deficiency36-40 and preliminary intervention studies have observed reductions in 
total fat mass, subcutaneous adipocyte diameter, and BMI in adult overweight or obese patients 
following LCn-3 fatty acid supplmentation.164-166 Extant translational evidence therefore supports 
the proposition that low LCn-3 fatty acid status represents a candidate risk factor for 
hyperlipidemia and associated increases in adiposity and BMI.  
 
Red blood cell (RBC) membrane EPA+DHA composition represents a reliable index of 
habitual (1-2 months) dietary EPA+DHA intake and ‘omega-3 status’,100 and we recently 
reported that adult medication-withdrawn patients with bipolar disorder residing in the US exhibit 
robust RBC EPA+DHA deficits compared with healthy adults.101 The latter finding is consistent 
with prior case-control studies also finding that adult patients with bipolar disorder exhibit 
significantly lower RBC EPA+DHA levels relative to healthy adults.102,103 Importantly, our recent 
evidence further indicates that SGA-naïve first-episode adolescent manic patients also exhibit 
robust RBC EPA+DHA deficits compared with healthy adolescents (Section a.6.1). Moreover, 
dietary supplementation with EPA+DHA (fish oil) significantly increases RBC EPA+DHA levels 
in children and adolescents with bipolar disorder in association with significant reductions in 
manic and depressive symptom severity.104,105 We have also obtained preliminary evidence that 
12-week dietary supplementation with EPA+DHA (OmegaRx) significantly increases RBC 
EPA+DHA composition from in adolescent patients. Additionally, a preliminary open-label study 
found that 4-week EPA+DHA treatment significantly decreased elevated fasting triglyceride 
levels in schizophrenic patients treated with the SGA clozapine.106 Adjunctive LCn-3 fatty acid 
supplementation was also found to accelerate treatment response, improve tolerability, and 
permit a 20% reduction in SGA dose in first-episode psychotic patients,107 and to reduce relapse 
rates in predominantly medicated adult patients with bipolar disorder.108 Together, these data 
support our hypothesis that normalizing the low LCn-3 fatty acid status exhibited by bipolar 
youth will be protective against SGA-induced adverse cardiometabolic effects, and will have 
additional benefits for improving mood symptoms, tolerability, and adherence. 
 
While the mechanisms mediating SGA-induced adverse cardiometabolic effects are poorly 


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understood,109 recent evidence from in vitro, rodent, and clinical studies indicate that different 
SGA medications up-regulate the expression of stearoyl-CoA desaturase-1 (SCD1, delta9-
desaturase),65-70 a lipogenic enzyme implicated in triglyceride biosynthesis, metabolic syndrome, 
and obesity.54-64 Specifically, preclinical studies have demonstrated that mutation of the SCD1 
gene is associated with impaired triglyceride biosynthesis,54-57 increased insulin sensitivity,58 and 
reduced visceral adiposity and resistance to high-fat diet-induced obesity in mice.59 Similarly, 
selective pharmacological inhibitors of the SCD1 enzyme reduce elevated triglyceride and 
glucose levels in rodent metabolic disease models.60,61 We recently reported that chronic 
exposure to SGA medications significantly increase SCD1 activity indices in rats, and that this 
effect accounted for 56 percent of the variance in plasma triglyceride levels.67 In human 
subjects, elevations in the plasma product-precursor ratio of oleic acid to stearic acid 
(18:1/18:0), an index of SCD1 activity (the ‘desaturation index’), is positively correlated with 
human liver biopsy SCD1 mRNA expression,110 plasma triglycerides levels, insulin resistance, 
and obesity.54,62-64 Moreover, schizophrenic patients treated with the SGA olanzapine exhibit 
greater SCD1 mRNA expression in peripheral blood cells compared with drug-free patients.70 
Together, this body of translational evidence suggests that up-regulation of SCD1 may 
represent a mechanism through which SGA medications increase triglyceride levels, excess 
adiposity, and obesity. 
 
In contrast to SGA medications, LCn-3 fatty acids down-regulate SCD1 expression at the 
level of transcription and mRNA stability in vitro,50,51 and we recently reported that dietary-
induced LCn-3 fatty acid deficiency robustly up-regulates rat liver SCD1 mRNA expression, and 
that this effect is positively correlated with plasma triglyceride levels.53 Additionally, we found 
that normalization of LCn-3 fatty acid status through dietary supplementation normalized 
elevated liver SCD1 mRNA expression and plasma triglyceride levels. These data are 
consistent with prior findings that dietary LCn-3 fatty acid supplementation decrease SCD1 
activity in liver microsomes ex vivo111 and reduce liver triglyceride synthesis and/or secretion in 
different rodent models.112-116 Other studies have similarly found that EPA supplementation 
decreases mouse liver SCD1 mRNA expression and hepatic triglyceride content,117 and dose-
dependently decreases plasma triglyceride levels in schizophrenic patients treated with the SGA 
clozapine.159 We have recently obtained proof-of-concept evidence that dietary-induced 
EPA+DHA deficits robustly augment SGA-induced elevations in rat liver SCD1 
expression/activity and liver and plasma triglyceride levels in rats maintained on standard 
diets.160 Together, these translational data suggest that LCn-3 fatty acids and SGA medications 
have opposing effects on SCD1 expression/activity which may account for their opposing effects 
on triglyceride biosynthesis and weight gain.  
 
C.  PRELIMINARY STUDIES 
C.1. First-episode SGA-naïve manic youth exhibit LCn-3 fatty acid deficiency. In ongoing 
studies, we have found that SGA-naive first-episode pediatric/adolescent (10-18 yrs) manic 
patients (n=30, 15.2±1.6 years) exhibit RBC EPA+DHA levels that are significantly lower than 
those observed in age-matched healthy adolescents (n=30)(2.9±0.8 vs. 4.2±1.3 wt% total, 
p=0.0002). Importantly, 91% of first-episode manic patients exhibited an ‘omega-3 index’ 
(EPA+DHA) of 4.0% compared with 25% of healthy controls (2 p=0.001). Based on 
prospective observational studies finding that an omega-3 index of 4.0% confers a 10-fold 
greater risk for primary cardiac arrest compared with an omega-3 index of >8.0%,123 these data 
suggest that the majority of these first-episode manic patients are at increased risk for 
cardiovascular morbidity and mortality. Moreover, the RBC EPA+DHA levels observed in first-
episode pediatric/adolescent manic patients (2.9±0.8%) is similar to that previously observed in 
adult patients suffering acute coronary syndrome (3.4±1.6%),124 as well as adolescents at ultra-
high-risk for developing psychosis (3.1±1.2%).125 It is of note that the baseline BMI of first-


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episode manic patients (24.8±0.9 kg/m2) did not differ significantly from healthy 
pediatric/adolescent controls (24.0±1.0 kg/m2)(p=0.67), a finding consistent with prior 
prospective trials.23 This finding suggests that LCn-3 fatty acid deficiency alone is not sufficient 
to induce weight gain, but rather, increases risk for greater weight gain in response to a 
metabolic challenge (i.e., SGA-induced lipogenesis).  
 
C.2. Omega-3 fatty acid supplementation increases RBC EPA+DHA levels in adolescent 
patients. While the etiological factors contributing to LCn-3 fatty acid deficiency observed in 
bipolar youth are poorly understood and likely multifactorial, dietary EPA+DHA insufficiency 
plays a key role.126 Specifically, studies have found that pediatric and adolescent bipolar patients 
consume less preformed EPA+DHA in their diet compared with healthy controls,127 and that 
dietary EPA+DHA (fish oil) supplementation significantly increases RBC EPA+DHA composition 
in bipolar youth.104,105 In a pilot study of adolescent patients with MDD (n=30, 15.2±3.5 years), 
we found that 12-week open-label EPA+DHA (OmegaRx) supplementation (2.4 g/d) significantly 
increased RBC EPA+DHA composition from 3.10.3% at baseline to 7.51.2% at study 
endpoint (+49%, p<0.0001). Based on prospective observational studies, the level of EPA+DHA 
observed in these patients following 12-week EPA+DHA treatment would confer a ~10-fold 
reduced risk for primary cardiac arrest compared with their baseline values.123 Consistent with 
prior studies,104,128 we found that baseline depressive (CDRS) symptom severity scores (primary 
outcome measure) declined significantly following 12-week EPA+DHA supplementation (-18%, 
p=0.01). Importantly, in this and other LCn-3 fatty acid supplementation trials conducted in 
children and adolescents,104,105,128 adverse events (predominantly gastrointestinal-related) were 
few and rated as mild by patients. Together, these preliminary findings suggest that dietary 
EPA+DHA supplementation is efficacious and well-tolerated for increasing LCn-3 fatty acid 
status in pediatric and adolescent patients, and provide preliminary evidence for beneficial 
effects for mood symptoms.  
 
C.3. LCn-3 fatty acids and SGAs have opposing effects on SCD1 mRNA expression in rat 
liver. As discussed above, emerging evidence suggests that stearoyl-CoA desaturase-1 (SCD1) 
is required for de novo triglyceride synthesis,54,56,57 and that SCD1 is negatively regulated by 
omega-3 fatty acids in vitro.51,52 To evaluate this mechanism in vivo, we have been investigating 
the effects of dietary-induced LCn-3 fatty acid deficiency, as well as subsequent repletion, on 
young adult rat liver SCD1 mRNA expression and activity indices (liver 16:1/16:0 & 18:1/18:0 
ratios), and determined relationships with postprandial plasma triglyceride levels. Compared 
with controls, rats fed the omega-3-deficient diet exhibited significantly lower RBC and liver 
EPA+DHA compositions, which were highly correlated, and both were normalized in repleted 
rats. Liver SCD1 mRNA expression (+82%, p=0.001) and activity indices (18:1/18:0: +60%, 
p<0.0001; 16:1/16:0: +75%, p<0.0001) were significantly greater in omega-3 deficient rats 
compared with controls. Consistent with a prior human liver biopsy study,110 liver SCD1 mRNA 
expression was positively correlated with liver 18:1/18:0 (r = +0.90, p≤0.0001) and 16:1/16:0 (r = 
+0.93, p≤0.0001) ratios, supporting the validity of these measures as indices of SCD1 activity.54 
Plasma triglyceride levels were significantly greater in omega-3 fatty acid deficient rats 
compared with controls (+30%, p=0.02), and liver SCD1 mRNA expression and activity indices 
were positively correlated with plasma triglyceride levels. Importantly, normalization of omega-3 
fatty acid status corrected elevations in liver SCD1 expression and activity as well as elevated 
plasma triglyceride levels observed in omega-3 deficient rats. In contrast to the negative 
regulatory effects of LCn-3 fatty acid on SCD1 expression and activity, recent translational 
studies have found that different SGA medications robustly up-regulate SCD1 expression and 
activity.65-70 Of direct relevance to the current proposal, we recently reported that dietary-induced 
EPA+DHA deficits robustly augment risperidone-induced elevations in rat liver SCD1 
expression/activity and triglyceride levels in rat liver and plasma.160 Together, these translational 


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data provide preliminary support for our hypothesis that SGA medications and LCn-3 fatty acids 
have opposing effects on SCD1 expression and activity.  
 
C.4. SGA-induced weight gain and hypertriglyceridemia in adolescent bipolar patients: 
Our group previously reported that 12-week open-label treatment with the SGA quetiapine 
resulted in a statistically significant increase in body weight in 20 adolescents at ultra-high risk 
for developing bipolar disorder (i.e., have a mood disorder diagnoses other than bipolar I 
disorder and a first-degree relative with bipolar I disorder).129 In a subsequent double-blind 
placebo-controlled 8-week trial in adolescents (ages 12-17 years) with bipolar disorder, we 
observed a statistically significant between-group difference in baseline-endpoint change in 
fasting triglyceride levels (mean change in quetiapine: +30 mg/dL vs. placebo: +14 mg/dL, 
p=0.003), and that a greater number of subjects in the quetiapine group (24%) than in the 
placebo group (0%) exhibited a shift from normal to abnormal triglyceride levels. Subjects in the 
quetiapine group also gained more weight (mean increase: 2.3 kg) than those in the placebo 
group (0.9 kg), and the increase in BMI was greater for the quetiapine group (mean increase: 
0.9 kg/m2) than the placebo group (0.3 kg/m2).91 These data and are entirely consistent with 
larger prospective studies finding treatment-emergent weight gain in youth with bipolar disorder 
following sub-chronic exposure to quetiapine,23 and demonstrate our experience in 
administering quetiapine to adolescent patients.  
 
D.  INVESTIGATOR EXPERIENCE 
Dr. McNamara is Associate Professor of Psychiatry and Behavioral Neuroscience, 
Division of Bipolar Disorders Research, at the University of Cincinnati College of Medicine, and 
is Director of the Lipidomics Research Program (LRP). Dr. McNamara has been studying the 
pathophysiology of bipolar disorder for over 15 years, and has an active translational research 
program investigating the role of bioactive lipids in the pathoaetiology and treatment of 
psychiatric disorders. Dr. McNamara has specific expertise in lipid analytical tecnhiques as well 
as gene expression (i.e., qPCR) procedures outlined in this proposal. He has also been PI on 
prior and current omega-3 fatty acid intervention trials in pediatric and adolescent subjects. Dr. 
McNamara will be responsible for the overall scientific conduct of the study, providing 
conceptual, managerial, and administrative direction. Dr. DelBello is Associate Professor of 
Psychiatry, Pediatrics, and Psychology and Co-Director of the Division of Bipolar Disorders 
Research at the University of Cincinnati College of Medicine (UCCOM), is Director of Research 
Training and Education for the Division of Psychiatry at Cincinnati Children’s Hospital Medical 
Center (CCHMC), and is Co-Director of the Mood Disorders Clinic at CCHMC. Dr. DelBello is a 
child and adolescent psychiatrist with extensive expertise in the field of pediatric and adolescent 
bipolar disorder. She has been studying the pharmacology and neurobiology of bipolar disorder 
for over 20 years. Dr. DelBello has several publications characterizing the effects of SGA 
medications on mood and metabolic parameters in adolescents with bipolar disorder. Dr. 
DelBello will coordinate subject recruitment and will assist with patient assessment, and will 
supervise training and reliability of the personnel performing diagnostic and rating instruments. 
Dr. DelBello will serve as the medically responsible physician for the present study. Dr. Patino is 
a child and adolescent psychiatrist in the Division of Bipolar Disorders Research (DBDR) at the 
University of Cincinnati College of Medicine. Dr. Patino has worked within the DBDR for the past 
year, and is currently participating in several clinical trials of children and adolescents with mood 
and cognitive disorders. He has extensive experience with, and has demonstrated excellent 
inter-rater reliabilities for, all of the proposed diagnostic and rating scales (kappa and ICCs > 
0.8). Dr. Patino will assist with the clinical care and diagnostic and symptom and safety ratings 
for study participants. He has extensive experience with, and has demonstrated excellent inter-
rater reliabilities for, all of the proposed diagnostic and rating scales (kappa and ICCs > 0.8), 
and will assist with the day-to-day management of the research visits and patient care. Dr. 


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Welge, Research Assistant Professor of Psychiatry and Biostatistics and Director of the Division 
of Quantitative Methods in the Department of Psychiatry UCCOM, has extensive expertise in 
the area of psychiatry and biostatistics. Dr. Welge has specific expertise in multivariate 
regression mixed models and will oversee all aspects related to database design and data 
management, and will lead the proposed statistical analyses. Mrs. Nasrallah will be responsible 
for completing and maintaining regulatory documents for this study and will also serve as liaison 
with local and federal study monitors.  
 
E. EXPRIMENTAL DESIGN & METHODS 
a. Methods and Procedures 
Study Overview: We are proposing a two-phase study design (see Fig. 1) to first prospectively 
investigate the relationship between baseline LCn-3 fatty acid status and treatment-emergent 
adverse cardiometabolic events and weight gain in response to acute (6-week) quetiapine in 
adolescent manic patients (ages 10-17 years)(Phase I, SA1). During Phase II (SA2), patients 
from Phase I will be randomized (stratified by BMI of 30 kg/m2) to double-blind adjunctive 
treatment with LCn-3 fatty acids or placebo for an additional 24 weeks to investigate protective 
effects on the progression and resolution of adverse cardiometabolic events and weight gain 
during quetiapine maintenance therapy. Patients will be recruited from the inpatient psychiatric 
units and outpatient clinics at Cincinnati Children’s Hospital Medical Center (CCHMC). The 
attending physicians and then the legal guardians of adolescents with a manic or mixed mood 
episode and who have a diagnosis of bipolar disorder, type I, will be approached by research 
staff for potential study participation. Once permission is obtained from their inpatient 
psychiatrist and legal guardians, adolescents will be approached about study participation. If 
agreeable, research staff will obtain written informed consent and assent for study participation 
from the legal guardian and adolescent, respectively. Patients will be discharged from 
hospitalization when they are clinically stable at the discretion of their attending psychiatrist 
(typically after 7 days).  Following initiation of double blind treatment, patients will have regularly 
scheduled visits at which time metabolic parameters (i.e., lipid profile, glucose, insulin), 
anthropomorphic measures (i.e., BMI), and mood symptom ratings (CDRS, YMRS) will be 
obtained. Primary outcome measures for both study Phases are BMI and fasting triglyceride 
levels. Following the completion of the 24-week Phase II study procedures (or early 
termination), patients will transition care to a community clinician so that there is no lapse in 
treatment. Patients will be recruited from the inpatient units and less commonly outpatient clinics 
affiliated with University and Cincinnati Children’s Medical Center Hospitals. Our program, the 
Division of Bipolar Disorders Research, has successfully recruited hundreds of patients from 
these units during the past 5 years, and is therefore well-positioned to carry out the proposed 
study. Study visits will take place in the department of Psychiatry, Division of Bipolar Disorders 


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Research, University and Cincinnati College of Medicine.  
 
 
 
 
 
 
 
 
 
 
 
 
 
OUTCOME MEASURES 
We will obtain the following anthropomorphic, metabolic, safety, and mood symptom 
measures at selected visits during the 6 week Phase I component and the 24 week Phase II 
component (Table 1). 
Table 1.  Schedule of Assessments 
ASSESSMENT
  PHASE I
BASELINE 
PHASE I
WEEKS 1,2,3,4,5 
PHASE I     
(ENDPOINT) 
PHASE II     
BASELINE
PHASE II
WEEKS 4,8,12,16,20
PHASE II
  ENDPOINT 
  (WEEK 24) 
WASH-U KSADS and WASI (IQ)
X 
 
 
 
 
Young Mania Rating Scale (YMRS) 
X 
X 
X 
X 
X 
Children’s Depression Rating Scale-Revised 
(CDRS) 
X 
X 
X 
X 
X 
Clinical Global Impression-Severity (CGI-S) 
X 
X 
X 
X 
X 
Columbia Suicide Severity Rating Scale 
 
 
X 
X 
X 
Addiction Severity Index (ASI) 
X 
 
X 
 
X 
Prior medical and treatment history (con-meds) 
X 
X 
X 
X 
X 
Tanner scale 
X 
 
 
 
 
3 d food record/Omega-3 Questionnaire   
 
 
X  
X (wk 12 & 20 
only)
 
Urine toxicology screen, urine pregnancy test 
X 
X (wks 1 & 6 
only)
X 
 
 
Serum laboratory tests (renal profile, complete 
blood count, & liver tests) 
X 
 
X 
X (wk 12 only) 
X 
Vital signs: body weight, BMI, waist circumference, 
blood pressure. 
X 
X 
X 
X 
X 
Physical exam 
X 
 
 
 
 
Metabolic/lipid panel: fasting lipids [TAG, LDL-C,    
HDL-C], glucose, and insulin (HOMA-IR)  
X 
 
X 
X  
X 
Adiponectin, TSH, hsCRP, leptin 
X 
 
X 
X (wk 12 only) 
X 
Platelet function assay (PFA) 
 
 
X 
X (if indicated) 
X 
RBC/Plasma fatty acid analysis (GC) 
X 
 
X 
X (wk 12 only) 
X 
WBC SCD1 mRNA expression 
X 
 
X 
X (wk 12 only) 
X 
ECG (QTc) 
X 
 
X 
  
X 
Adverse events (SEFCA)  
  
 
X 
X 
X 
Demographics 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
Med accountability sheet 
 
X 
X 
X 
X 
                            Total duration of appointment: 
2-3 hrs 
2 hrs 
2 hrs 
2 hrs 
2 hrs 
 
Anthropomorphic and metabolic measures: We will obtain the following anthropomorphic 
measures: body mass index (BMI, calculated as weight in kilograms (to the nearest 0.1 kg) 
divided by height (to the nearest 0.1 cm) in meters squared, kg/m2), incidence rates of clinically-
BD-I - OL Quetiapine + DB Placebo
Refer 
to TAU
Phase 2 Endpoint 
Assessments
Phase I Endpoint    
Phase 2 Screening/Baseline
Assessments
Visit #     1                  2-6                     7                                         
8-12                                                       13
OL=Open-Label; DB=Double-blind; TAU=Treatment as usual.
First-episode mania
Quetiapine
Phase I - 6 weeks
BD-I - OL Quetiapine + DB Omega-3
Phase 1 Screening
Informed Assent/Consent
Baseline Assessments
Phase II - 24 weeks
6 Weeks
Fig. 1
Phase 2 Midpoint 
Assessments


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significant weight gain of 7% from baseline, waist circumference (measured at the level of both 
superior iliac crests and umbilicus, using the point of largest abdominal circumference), and 
sitting systolic and diastolic blood pressure. Fasting (>8 hour) venous blood (approximately 15 
cc) will be collected for determination of lipids (total cholesterol, low-density lipoprotein (LDL) 
cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides), glucose, insulin, TSH, 
adiponectin, leptin, and hsCRP. The homeostasis model assessment of insulin resistance will 
be calculated [HOMA-IR: fasting insulin umol × glucose mmol/22.5]. White blood cells 
(lymphocytes, leukocytes, myeloid cells) will be isolated from whole blood to measure gene 
expression (i.e., SCD1 mRNA) by qPCR as previously described.53,67,160 Red blood cell fatty acid 
composition will be determined as previously described.101,143 
 
Dietary assessments: We will request that subjects maintain their current diet over the course 
of their study participation. During the course of the trial we will obtain 3-day food records at 
scheduled visits to obtain estimates of average total energy intake (kJ/kg/d) and other dietary 
macronutrients (i.e., fat (g/d), carbohydrate (g/d), and protein (g/d). Additionally, the Omega-3 
Dietary Intake Questionnaire, an 11-item scale, will be administered at each Phase II visit to 
specifically assess omega-3 fatty acid intake. The Omega-3 Dietary Intake Questionnaire has 
been validated, and questionnaire scores (mg EPA and mg DHA per day) are positively 
correlated with EPA and DHA status.130 The Addiction Severity Index (ASI) will also be 
administered to collect data regarding drug use (including nicotine and alcohol) at the Phase I 
baseline visit and at Phase II baseline and endpoint visits. 
 
Mood symptom ratings: Symptom ratings will be obtained using the Young Mania Rating 
Scale (YMRS),131-133 an 11-item scale to assess manic symptoms; the Children’s Depression 
Rating Scale-Revised (CDRS-R), a 17-item observer-rated questionnaire, to assess depressive 
symptoms.134,135  Subjects will also be rated using the Clinical Global Impression-Severity Scale 
(CGI-S), a clinician-rated 7-point scale (1=normal to 7=extremely ill) to assess overall illness 
severity.136 A potential new manic episode will be identified when patients present with a YMRS 
score >16, and a depressive episode will be identified when patients present with a CDRS score 
>24 and YMRS score <10. Per DSM-IV criteria, two weeks of depressive symptoms or one 
week of manic symptoms are required to define a new episode.  
 
Safety and tolerability assessments: A complete medical and treatment history, vital signs, a 
physical examination, and serum laboratory tests (including a renal profile, complete blood 
count, liver function tests) will be performed at select visits during Phases I and II. Additionally, 
electrocardiograms (ECGs) will be performed at selected visits to assess QTc interval. Adverse 
events will also be assessed at selected visits using a clinical interview as well as a structured 
side effect interview, the Side Effects Form for Children and Adolescents (SEFCA).138 The 
SEFCA measures the frequency and severity of specific cardiovascular, gastrointestinal, central 
nervous system, ocular, mouth and nasal, genitourinary, dermatological, and musculoskeletal 
side effects. Because LCn-3 fatty acid treatment may be associated with increasing bleeding 
time, we added the following four questions to the SEFCA: “Bruising”, “Nosebleeds”, “Longer 
than usual bleeding”, and “Heavy bleeding associated with menstruation”. Additionally, the 
Platelet Function Assay (PFA), a sensitive measure of blood clotting, will be measured at Phase 
II baseline and endpoint. If a study participant answers positively to any of the bleeding items on 
the SEFCA, a PFA will be performed at that point. Patients will be discontinued from study 
participation if their PFA values are outside the reference range (PFA-EPI: 75.0-199.0 and PFA 
ADP: 68.0-112.0) on two consecutive visits and provided with follow-up care. An adverse event 
will be defined as a symptom that was not present at or worsened in severity from baseline. The 
Columbia Suicide Severity Rating Scale (C-SSRS)139 will be administered at each Phase II visit 
as a measure of suicidality. We have extensive experience and established high inter-rater 


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reliability with these instruments (ĸ & ICCs >0.7 and typically >0.9 for most ratings).  
 
TREATMENTS: 
Quetiapine: Quetiapine fumarate (Seroquel) is approved by the FDA for the treatment of acute 
mania in pediatric and adolescent patients (ages 10-17 years), and is currently among the most 
frequently prescribed SGA in children and adolescents in outpatients clinics in the US.21 
Importantly, we have considerable experience administering quetiapine to pediatric and 
adolescent patients,91,129,140-142 and prior prospective studies including our own have found that 
quetiapine, like other SGA medications, is associated with treatment-emergent elevations in our 
primary outcome measures (i.e., BMI, triglyceride levels) in pediatric and adolescent 
patients.23,91,129,140-142 For the proposed Phase I component, acutely manic patients with limited 
prior SGA exposure (3 months) will be treated with quetiapine for 6-weeks. Patients will be 
started on 25 mg per day of quetiapine QHS, and the dose adjusted based on tolerability and 
response. The quetiapine target dose is 400-600 mg, with most subjects in the range of 200-500 
mg. In our prior studies, the mean quetiapine dose was 400 mg/day.91,140 Quetiapine will be 
dispensed at each visit by the investigational pharmacist, and we will monitor patient 
compliance by pill counts at weekly visits by patient/parental reports. During Phase I, every 
effort will be made to achieve an effective, well tolerated, and stable maintenance dose by 
Week 6. If patients are unable to tolerate therapeutic doses, they will be removed from the study 
and referred for alternate treatment. While it is anticipated that patients will be maintained on 
this dose during the 24-week double blind component (Phase II), we will permit dose 
adjustments if clinically indicated.  
 
   Risks of Quetiapine 
Side Effect
Percentage of children and adolescents who have 
experienced this side effect in previous clinical trials 
Somnolence
53%
Dizziness
18%
Fatigue
11%
Increased appetite
9%
Nausea
8%
Vomiting
8%
Tachycardia
7%
Dry mouth
7%
Weight gain
6%
 
LCn-3 fatty acid supplements: For the Phase II intervention trial, patients will be randomized 
to EPA+DHA supplements (OmegaRx) or placebo (safflower oil). Safflower oil was selected for 
the placebo because it does not contain omega-3 fatty acids, including -linolenic acid (found in 
olive oil), and to minimally alter the fatty acid composition of the typical American diet. All 
capsules will be stored atroom temperature (60-75⁰F) , and EPA+DHA content determined upon 
initial receipt and every 90 d by gas chromatography to assure consistency across the trial. 
Omega-3 and placebo capsules will be dispensed at each visit by the investigational 
pharmacist. Placebo and OmegaRx capsules are identical in caloric content (~9 kcal/capsule), 
size, shape, and color to protect the blind. To test the integrity of the study blind, we will ask 
study participants to separately identify their treatment as placebo or omega-3 fatty acids at the 
end of their study participation. We will also ask the raters for that subject to complete a 
questionnaire asking to which group (omega-3 fatty acids or placebo) they thought the subject 


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had been assigned. All responses will be placed in a sealed envelope and after the last subject 
completes the study, will be compared with actual assignments using Fisher exact tests.  
 
  
We have previously confirmed that each OmegaRx capsule contains 400 mg EPA and 
200 mg DHA. Subjects will be randomized to OmegaRx or placebo at a fixed dose of 3.0 g/day 
(EPA: 2.0 g, DHA: 1.0 g; 5 capsules/d). This fixed dose was selected based on American Heart 
Association recommendations to consume between 2.0-4.0 g/d for triglyceride reduction in 
individuals with hypertriglycerolaemia,145 controlled dose-response studies finding that similar 
fixed doses (2.0-4.0 g/d) are efficacious in lowering elevated triglyceride levels,42 a one month 
open-label intervention study finding that 3.0 g/day EPA+DHA significantly reduced fasting 
plasma triglyceride levels in patients treated with the SGA clozapine,106 and findings that similar 
EPA+DHA doses (1.9-2.6 g/d) are efficacious for reducing manic and depression symptom 
severity in medicated bipolar adolescents.104,105 The US FDA considers EPA+DHA doses up to 
3.0 g/d to be ‘generally regarded as safe’ (www.cfsan.fda.gov/~dms/ds-ltr11.html). Treatment 
adherence will be encouraged at each visit and adherence monitored by subject interview, 
capsule counts, legal guardian interviews, and a capsule adherence diary. Subjects with > 50% 
non-adherence during 2 contiguous weeks will be discontinued from the study and provided with 
recommendations for follow-up care. Subjects in the placebo group will be required to take 5 
pills per day to match the OmegaRx group. Patients will be advised to take 2 capsules during 
their morning meal and 3 capsules during their evening meal. In our previous studies we have 
found that this approach is effective and does not reduce compliance as evidenced by capsule 
counts and self-reports.  
 
   Risks of LCn-3 fatty acid 
Side Effect
Percentage of children and adolescents
who have 
experienced this side effect in a previous clinical trial105 
Gastrointestinal Distress 
25%
Cold/Flu/Allergies/Infection
20%
Headache
15%
Decreased Appetite
10%
Sleep Problems
10%
Skin Disturbance
10%
Agitation/Activation
5%
Respiratory Side Effects
5%
Tics
5%
Anxiety
5%
 
Concomitant Medications: Subjects diagnosed with ADHD and taking a stable dose of 
stimulants for the previous month will be permitted to continue if it is determined necessary by 
the subject, primary caregiver, and treating clinician report in conjunction with the study 
physician. In general, patients will be instructed to contact study staff prior to taking any 
concomitant medications during their study participation to minimize the adverse effects that 
might occur with medications as well as to accurately record the reason for concomitant 
medication use. 
 
b. Data analysis and Data Monitoring:  
Data management and analyses will be organized and performed under the direction of 
Dr. Welge, Director of the Division of Biostatistics in the Department of Psychiatry at the 
University of Cincinnati, who has participated in the development of this analytic plan. The 
research coordinator will be responsible for managing study flow, maintaining case report forms, 


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and entry of data into a database. All data will be double entered and compared every six 
months to ensure the integrity of the information. The principal investigator will maintain a 
secure database of all raw data which will be password protected. Demographic and clinical 
data will be managed in a database using Microsoft Access® and stored in an IBM compatible 
PC connected to other PCs within the Division of Bipolar Disorder Research with a LAN that is 
password protected and coded to meet HIPAA requirements. Backups are performed weekly to 
protect against data loss. 
 
Data Analysis: Demographic and clinical variables (e.g. sex, race, age, baseline BMI, 
quetiapine dose, dietary energy intake) will be included as covariates in the model in a stepwise 
manner if they are associated with primary outcome measures using a liberal p-value of <0.2. 
We will use independent, 2-tailed t-tests for continuous variables and χ2 tests for categorical 
variables, and adjust for multiple comparisons as appropriate. For the Phase II DBPC 
component, analyses will be performed using data from the intent-to-treat (ITT) sample (all 
subjects receiving at least one dose of omega-3 fatty acid or placebo). All tests of hypotheses 
will be done at the 5% level of significance, unless otherwise specified. Prior to data analysis, 
the distribution of all dependent variables will be examined for normality. We will transform or 
apply alternative statistical models for dependent variables that are not normally distributed. 
Specifications for temporal correlation and random effects will be selected using AIC criterion. 
All analyses will be performed using the Statistical Analysis System (SAS) (SAS Institute, Cary, 
NC, 2002) by Dr. Welge.  
 
Prediction 1: Low baseline RBC EPA+DHA levels will be associated with greater elevations in 
BMI and triglyceride levels in response to acute (6-week) SGA treatment compared with high 
RBC EPA+DHA levels. The relationships between baseline-endpoint change in BMI and 
triglyceride levels and baseline RBC EPA+DHA composition will be evaluated with a linear 
regression model. We will evaluate potential covariates (i.e., baseline BMI) as described above. 
We will also generate odd ratios and 95% confidence intervals to estimate relative risk in 
different quartiles of RBC EPA+DHA composition.  
 
Prediction 2: Baseline SCD1 expression/activity will increase significantly following 6-week 
SGA treatment. We will use an unpaired t-test (one-tail) to compare change from baseline to 
week 6 (or endpoint) in SCD1 mRNA expression and SCD1 activity index (plasma 18:1/18:0). 
We will evaluate potential covariates and confounds as described above.  
 
Prediction 3: The relationship between RBC EPA+DHA levels and SGA-induced elevations in 
BMI and triglyceride levels is mediated by elevations in SCD1 expression/activity. We predict a 
mediated effect in which low RBC EPA+DHA levels are associated with elevated SCD1 mRNA 
expression and SCD1 activity (plasma 18:1/18:0), which in turn increase baseline-endpoint 
change in BMI and triglyceride levels. For the prediction of a mediated effect to be supported, 
two conditions must be met: a significant association between RBC EPA+DHA levels and SGA-
induced elevations in BMI and triglyceride levels (Prediction 1), and a significant association 
between RBC EPA+DHA levels and SCD1 expression/activity (Prediction 2). If there is no 
residual relationship between RBC EPA+DHA levels and weight and metabolic parameters, 
then the relationship between these measures will be inferred to exist solely through the 
mediating effect of SCD1 expression/activity. Path analysis,157 an extension of linear regression 
to systems of simultaneous linear regression equations, will be used to analyze the fit of the 
proposed mediation model. This method allows for the same variable to serve as an 
independent variable in some of the regressions and a dependent variable in others. In this 
analysis, baseline-endpoint changes in BMI and triglyceride levels will serve as the final 
outcome measure, with changes in SCD1 expression/activity as the mediator and RBC 


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EPA+DHA level as the independent variable. Estimation of path coefficients and bootstrap 
computation of associated significance levels (=0.05) will be carried out using SAS macros.158 
The relationship between baseline-endpoint change in baseline RBC EPA+DHA composition, 
and baseline-endpoint change in BMI and triglyceride levels will be evaluated with multiple 
regression models.  
 
Prediction 4: LCn-3 fatty acid supplementation will be more effective than placebo for 
decreasing BMI and triglyceride levels in SGA-treated bipolar patients. A mixed effects model 
repeated measures (MMRM) approach will be used to compare change over time in BMI and 
triglyceride levels between treatment groups (placebo, omega-3). The model will contain terms 
for group (2 levels), time, and group-by-time interaction. Covariates will be included as 
described above. We will also compare treatment group differences in change from baseline to 
endpoint in BMI and triglyceride levels using an analysis of variance (ANOVA). This analysis will 
provide information without the necessary assumptions of the MMRM model regarding missing 
data and fitting the regression.  
 
Prediction 5: Reductions in BMI and triglyceride levels following LCn-3 fatty acid 
supplementation will be correlated with reductions in SCD1 expression/activity and increases in 
RBC EPA+DHA levels. The relationship between baseline-endpoint change in BMI and 
triglyceride levels and baseline-endpoint change in SCD1 mRNA expression and SCD1 activity 
index (plasma 18:1/18:0) will be evaluated with a simple linear regression model. We will 
evaluate potential covariates and confounds as described above.  
 
Prediction 6: LCn-3 fatty acid supplementation will be more effective than placebo for 
improving SGA tolerability and efficacy (i.e., lower relapse and discontinuation rates). For 
tolerability, a MMRM approach will be used to compare change over time adverse events 
(SEFCA) and extrapyramidal symptoms (SAS) between treatment groups (placebo, omega-3). 
We will additionally measure the duration of time to exit double-blind treatment because of 
tolerability issues. For efficacy, we will use a MMRM approach to compare change over time in 
mood symptom severity (CDRS, YMRS). We will also compare treatment group differences in 
change from baseline to endpoint in CDRS and YMRS scores using an analysis of variance 
(ANOVA). A Kaplan-Meier with Mantel-Cox log-rank statistic will be used to compare duration of 
remission in the 2 treatment groups controlling for baseline symptom severity. 
 
Data and Safety Monitoring plan 
The data and safety monitoring plan for the proposed study will include monitoring of 
efficacy and safety data by an independent Data Safety Monitoring Board (DSMB) and 
monitoring of tolerability data, including adverse events and serious adverse events, by the 
study investigators as well as the independent DSMB and the University of Cincinnati College of 
Medicine Institutional Review Board (IRB). The DSMB will consist of non-study related faculty 
with research related experience and will include a statistician, a psychiatrist with expertise in 
omega-3 fatty acids, and a child and adolescent psychiatrist. The DSMB will meet a minimum of 
every 6 months during the course of the study and will formally review tolerability, safety and 
efficacy data. Drs. McNamara and Patino will be responsible for providing updated efficacy and 
tolerability data to the DSMB. The DSMB will assess the risks and benefits of study participation 
to all subjects. Based on this assessment the DSMB will provide a written report of their 
analyses and recommendation as to whether the study should continue or modification to the 
study as needed. Drs. McNamara, Patino, and DelBello, in conjunction with the DSMB, will be 
responsible for making certain that the DSMB files their report to the IRB. The DSMB will also 


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provide the investigator with a summary of their report that will include their recommendations.  
 
c. Data Storage and Confidentiality  
Every effort will be made to maintain the confidentiality of study records. Agents of the 
University of Cincinnati Medical Center Institutional Review Board and the University of 
Cincinnati Division of Bipolar Disorders Research may be allowed to inspect records related to 
this study. The data obtained from the study may be published; however, participants will not be 
identifiable in such publications.  Participant identity will remain confidential unless disclosure is 
required by law. The records of this research study will be kept confidential and will not be given 
to anyone who is not helping conduct this study unless specifically requested and waived by the 
participant. To further ensure confidentiality, study records will be kept in locked file cabinets 
and/or in computers with passwords, all in locked rooms here at the University of Cincinnati 
Department of Psychiatry. Additionally, participant identification is coded with letters and 
numbers to de-identify individuals. As required, this study will be in full compliance of HIPAA. 
 
d. Setting - The offices of the Division of Bipolar Disorders Research (260 Stetson St., ML 
0516, Cincinnati, OH  45219-0516) is the setting for this protocol.  
 
e. Laboratory Methods & Facilities - Red blood cell fatty acid composition will be determined 
in a blinded manner by gas chromatography in the laboratory of Dr. McNamara in the 
Department of Psychiatry, Division of Bipolar Disorders Research (260 Stetson St., ML 0516, 
Cincinnati, OH  45219-0516). The proposed metabolic/lipid panels and labs will be performed by 
LabCorp, the Platelet Function Assay (PFA) by CCHMC, and adiponectin, leptin, and hsCRP by 
the GCRC Biochemistry Laboratory. 
 
f. Estimated Period of Time to Complete the Study - The following is a timeline for the 60-
month period of the proposed study: Months 1-2: Train study personnel, Months 3-56: recruit an 
average of 2 patients per month; Months 57-60: Complete subject participation, data entry, 
checking and analyses. 
 
F. HUMAN SUBJECTS 
a. Description of Subjects 
This is a total of 30-weeks divided into Phase I (6-weeks quetiapine) and Phase II  (24-weeks 
double-blind adjunctive treatment with LCn-3 fatty acids or placebo) for the treatment of manic 
bipolar adolescents (ages 10-17 years)(Total N=94). Patient selection will be done by the 
research staff, in consultation with and with permission from Dr. DelBello and the attending 
physician of that patient. Inclusion and exclusion criteria are listed below. 
 
b. Sample Size  
Up to 100 patients will be enrolled in this study at the University of Cincinnati Medical Center 
over a total of 60 months.  As this is an investigator-initiated protocol, there are no other sites 
associated with this submission. 
 
c. Inclusion/Exclusion Criteria 
Phase I - Inclusion Criteria:  
 
DSM-IV-TR criteria for bipolar disorder, type I, manic or mixed episode, diagnosed by the 
Washington University in St. Louis Kiddie Schedule for Affective Disorders and 


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Schizophrenia (WASH-U-KSADS) 
 
Baseline YMRS score > 20  
 
Ages 10-17 years 
 
Tanner scale stages II-V 
 
No prior long-term (3 month) exposure to SGA medications 
 
Fluent in English 
 
Provision of written informed consent by a legal guardian and written assent by the subject 
 
Manic or depressive symptoms do not result entirely from acute medical illness or acute 
intoxication or withdrawal from drugs or alcohol as determined by medical evaluation and 
rapid symptom resolution 
 
If female and of child bearing potential, agrees to use one of the following method of birth 
control: complete abstinence from sexual intercourse, barrier (diaphragm or condom), or 
oral/injectable contraceptive.  
 
Phase II, additional Inclusion criteria:  
 
Receiving a stable therapeutic dose of quetiapine for a minimum of 1 week (i.e., patients 
who achieved remission (YMRS total score 12 during Phase I) 
 
Not requiring concomitant use of antidepressant or mood-stabilizer medications. 
 
Exclusion Criteria: 
 
IQ < 70, as determined by The Wechsler Abbreviated Scale of Intelligence (WASI) 
 
A positive pregnancy test (to avoid teratogenesis) 
 
A history of major cardiovascular or neurological illness 
 
Any current DSM-IV-TR substance use disorder (nicotine dependence is permitted) 
 
A lifetime DSM-IV-TR diagnosis of any pervasive developmental disorder 
 
Phase II, additional Exclusion criteria:  
 
Any history of a hematological disorder in themselves or a first-degree relative will be 
excluded (since omega-3 fatty acids may be associated with anti-thrombotic effects). 
Similarly, concomitant use of medications with anticoagulant effects (e.g. aspirin) will be 
prohibited 
 
Allergy to fish/seafood 
 
Currently taking omega-3 fatty acid supplements. 
 
d. Intended Demographics 
Patients will be adolescents (ages 10-17 years) diagnosed with bipolar disorder. Patients from 
all available ethnic groups will be recruited at rates that reflect the demographics of the 
University Hospital Catchment Area. Consequently, we expect approximately 60% of the 
sample being White, 35% African-American and the remainder from other ethnic backgrounds. 
Because prior treatment with SGA medications would be anticipated to influence our primary 
outcome measures, we will recruit only patients with limited prior SGA exposure. 
 
e. Study population source 
Patients will be recruited from the inpatient units and less commonly, outpatient clinics affiliated 
with University and Cincinnati Children’s Medical Center CCHMC Hospitals. Dr. DelBello is 
Director of Research Training and Education and Co-Director of the Mood Disorder Clinic at 
CCHMC, which will facilitate recruitment of potential subjects.  
 
f. Recruitment Plans 
Adolescents will be recruited primarily through infrastructure originally established for Dr. 


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Delbello’s ongoing research study (R01MH080973-PI-Dr. DelBello) investigating the effects of 
6-week quetiapine treatment on mood and neuroimaging measures. Since the initiation of this 
trial, n=73 patients who would be eligible for participation in the proposed study (i.e., they were 
SGA-naïve and diagnosed with DSM-IV-TR criteria for bipolar disorder, type I, manic or mixed 
episode) have been randomized (an average of 3 patients per month). This rate of recruitment 
is sufficient to meet the proposed enrollment goals of an average of 2 subjects/month. 
Nevertheless, we will periodically assess our recruitment and retention rates and adjust 
recruitment efforts accordingly.  
 
Specifically, recruitment will be performed by study staff in consultation with CCHMC (inpatient) 
and UC (outpatient) physicians. Inpatients will be identified as potential study candidates by 
study staff with CCHMC privileges.  Physicians of those identified will be asked if they deem 
such inpatients suitable for this research study.  If so, study staff will also ask the same 
physician if it is permissible to approach the inpatient and their family about the research study. 
 
G.  RISK TO SUBJECTS  
a. Level of Risk Description  
Potential risks from study participation include possible risks from treatments, as well as 
other risks associated with any study participation (e.g. loss of confidentiality and fatigue and 
frustration from repeated evaluations). Possible risks of the proposed study design include 
the potential for symptom exacerbation. For the proposed study, all participants will be 
treated with quetiapine fumarate (Seroquel) which is the standard of care. All subjects and 
their legal guardians will be informed about the potential risks associated with quetiapine 
during the informed consent/assent process. Quetiapine is approved by the United States 
Food and Drug Administration for the treatment of acute mania in children and adolescents 
(ages 10-17 years) and is commonly prescribed for adolescents with bipolar disorder. All 
adolescents will be receiving quetiapine for 30 weeks total, which presently is a standard 
treatment for children/adolescents with acute mania.18,19 As with any SGA medication there is 
a risk that quetiapine will precipitate adverse metabolic side-effects, and the principle 
objective of the proposed study is to elucidate risk and protective factors associated with 
SGA-induced adverse cardiometabolic side-effects and weight gain. Additionally, subjects 
who exhibit worsening of mood symptoms (they have a 9 point increase in CDRS-R score (1 
point increase in > 50% of the 17 CDRS-R items) or a > 6 point increase in YMRS score (1 
point increase in > 50% of the 11 YMRS items) from baseline at any two consecutive visits) 
will be discontinued from study participation. If in the clinical judgment of the study physician 
a patient exhibits increased suicidality from Phase I baseline at any two consecutive visits, 
he/she will be discontinued from study participation. Other adverse events may include 
extrapyramidal symptoms. To minimize this risk, we will permit concomitant medications (e.g. 
propranolol or anticholinergics) for extrapyramidal syndromes that develop. Additionally, all 
subjects and their legal guardians will be informed about the potential risks associated with 
omega-3 fatty acids during the informed consent/assent process. Patients will be informed of 
potential omega-3 fatty acid side-effects including nausea, diarrhea, gastrointestinal reflux, 
and of less common side effects, such as vomiting and increased bleeding time. We will 
routinely monitor for all of these side effects with clinical interviews (i.e., SEFCA), vital signs, 


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and laboratory measures. 
 
In general, patients for whom further treatment with quetiapine or omega-3 fatty acids is 
contraindicated, either as a result of exacerbation of psychiatric symptoms or exceeding 
criteria for clinically-significant adverse cardiometabolic symptoms, will be terminated from 
the study and final study procedures performed if feasible. We will also instruct patients (and 
their legal guardians) to contact study staff 24 hours/day, 7 days/week, if any concerns arise 
during their study participation. Following study discontinuation, study physicians (Drs. 
DelBello and Patino) will provide clinical care to address urgent safety issues and will actively 
facilitate clinical referral for individualized treatment to ensure that there is no lapse in care. 
Alternative medication options will be discussed with the patient and their family if 
discontinuation is necessary.  
In an effort to minimize risks associated with medication interactions, a complete history 
of prior medications will be obtained from the patient and their legal guardian, as well as, 
their treating clinician (after a release of information is obtained) by an experienced physician 
investigator. To minimize the potential risk associated with the screening period, patients will 
be monitored by study staff for worsening of mood symptoms. Patients will be evaluated in 
person as needed. Additionally, the screening period may be shortened at the discretion of 
the study physician. Patients and their families will have access to a study physician 24 
hours/day, 7 days/week. The screening period is necessary to ensure the accuracy of the 
diagnosis. We have successfully used this approach during the screening period to maximize 
the safety of hundreds of adolescents with disruptive behavior and/or mood disorders in more 
than 20 prior studies. Subjects who, in the opinion of the investigator, are in need of inpatient 
hospitalization for suicidal or homicidal ideation will be excluded from study participation. 
Nevertheless, The Columbia Suicide Severity Rating Scale (C-SSRS), will be administered at 
each Phase II visit to measure of suicidality.  
 
 
To guard against the side effects of omega-3 fatty acids and quetiapine, we will first 
check baseline laboratory tests as described and will perform vital signs, a physical exam 
and an ECG to ensure that the subject is physically healthy. We will then initiate dose titration 
with quetiapine. To maximize safety during the 24-week double blind study phase (Phase II), 
body weight and fasting triglyceride and glucose levels will be obtained at selected visits, and 
a patient will be discontinued from study participation if they meet criteria for clinically-
significant increases in body weight (7% from baseline) and/or clinically-significant 
increases in fasting triglyceride (450 mg/dL) and/or fasting glucose (125 mg/dL) on two 
consecutive visits during study participation. Patients and their legal guardians will also be 
told to contact study staff immediately if they experience any of the following; allergic 
reactions like skin rash, itching or hives, swelling of the face, lips, or tongue, anxiety, 
nervousness, changes in mood or behavior, chest pain, fast, irregular heartbeat, fever, or 
hot, dry skin, high blood pressure, muscle twitching, or uncontrollable head, mouth, neck, 
arm, or leg movements. Additionally, to minimize the gastrointestinal adverse events 
associated with quetiapine or omega-3 fatty acids, we will instruct subjects and their legal 
guardians to take their study pills with meals. To minimize difficulties associated with taking 5 
capsules, patients will be advised to take two capsules during their morning meal and 3 
capsules during their evening meal. We have considerable experience administering omega-
3 capsules to pediatric and adolescent patients, and have found that this approach is 
effective and does not reduce compliance as evidenced by capsule counts and self-reports. 
To minimize the side effects of quetiapine, we will encourage patients to take quetiapine in 
the evening and we will give them the minimum effective dosage. To minimize the risk of 
other adverse effects from study treatment, at each study visit following baseline, study 
physicians (Drs. DelBello or Patino) will carefully monitor all patients for adverse effects using 


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a clinical interview as well as a standardized structured side effects questionnaire, the 
SEFCA. To maximize safety we will specifically monitor for bleeding abnormalities, and have 
added four questions to the SEFCA that are associated with increased bleeding time: 
“Bruising”, “Nosebleeds”, “Longer than usual bleeding”, and “Heavy bleeding associated with 
menstruation”. Additionally, the Platelet Function Assay (PFA), a sensitive measure of blood 
clotting. If a study participant answers positively to any of the bleeding items on the SEFCA, 
a PFA will be performed at any point during study participation. Patients will be discontinued 
from study participation if their PFA values are outside the reference range (PFA-EPI: 75.0-
199.0 and PFA ADP: 68.0-112.0) on two consecutive visits and provided with follow-up care. 
We will advise all participants and their legal guardians about potential anti-coagulant effects 
of omega-3 fatty acids and will prohibit concomitant use of medications that have 
anticoagulant effects (e.g. aspirin or non-steroidal anti-inflammatory drugs, NSAIDs). Study 
related adverse events will be defined as a symptom that was not present at or worsened in 
severity or frequency from baseline. Patients also will be instructed to contact study staff prior 
to taking any concomitant medications during their study participation to minimize the 
adverse effects that might occur with medications as well as to accurately record the reason 
for concomitant medication. Moreover, rates of adverse and serious adverse events will be 
monitored by a Data Safety Monitoring Board (see Data and Safety Monitoring Plan) that will 
meet every six months to review study tolerability and efficacy measures and determine 
whether the study should continue.  
 
 
Additionally, should the need arise to discontinue a patient from the study because of 
symptom worsening (as defined previously) or for any other reason, including patient/legal 
guardian withdrawal of consent, we will collaborate with the patient, their legal guardian, and 
their non-study related physician to determine treatment options for that patient following study 
discontinuation. At the beginning of each subject’s study participation, we will make appropriate 
referrals for all patients who do not have preexisting clinicians so that follow-up care will be in 
place at the completion of their study participation. If a study participant discontinues study 
participation and is not able to have an immediate appointment with the clinician to whom they 
are being referred, a study related physician, in consultation with their treating clinician or the 
clinician to whom they are being referred, will initiate appropriate treatment for the patient until 
they are seen by a non-study clinician. The study clinician will discuss treatment options with the 
patient (and their legal guardians) as well as discuss whether they would like to continue to take 
quetiapine. Nonetheless, following study discontinuation, the study clinician will begin treatment 
as indicated in collaboration with non-study related clinicians if applicable and the study 
participant (and their legal guardian), to maximize the safety of the study participant. Study 
clinicians will manage the care of study participants until appropriate follow-up treatment is in 
place. We have been successfully using this approach to manage patients following study 
participation for more than 15 years and in most situations patients receive follow-up care with a 
non-study related clinician within 30 days following study participation.  
 
To minimize the risks associated with blood draws, only staff that is trained and certified in 
phlebotomy will draw blood. To guard against frustration and fatigue, interviewers will be 
carefully selected and trained. When necessary, assessments will be divided into separate 
interviews to decrease the time of a single session. To guard against loss of confidentiality, 
all subject information will be kept in locked file cabinets and in the computer system locked 
in the research suite. A password will be required to access computer information, and will be 
available only to the principal investigator and research team members who are directly 
involved in entering and analyzing the data. Subjects will be identified by code numbers, and 
the principal investigator will emphasize to the research team the responsibility of maintaining 
confidentiality and the seriousness of accidental or willful disclosure of confidential 


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information. Similarly, in the event of data sharing all information will be de-identified and no 
individual subject will be identifiable. Additionally, all study staff will be certified in Good 
Clinical Practice (GCP), which refers to a set of international ethical and scientific quality 
standards for designing, conducting, recording, and reporting studies that involve human 
subjects. No subject will be identifiable in any publication that should arise from this work. 
Furthermore, collateral persons who are contacted regarding any subject will be provided 
with a signed release of information from the legal guardian, and will typically be limited to the 
subject’s primary clinician(s). Subjects can withdraw from this study at any time, at which 
point contact with collateral sources will end. Subjects will be told that agents of the 
University of Cincinnati Medical Center Institutional Review Board, the National Institutes of 
Health, and the Food and Drug Administration will be allowed to inspect sections of their 
medical and research records related to this study if requested. By utilizing the previously 
described procedures we feel the risks to subjects will be minimized.   
 
 
We will attempt to minimize the risks associated with reporting of suspected abuse or 
neglect, by attempting to inform the family prior to contacting any state/county agency. All 
suspected abuse or neglect will be reported to the PI or if she is unavailable, one of the other 
study physicians, so that the situation can be further investigated by experienced clinicians. 
In addition, should the need for reporting arise, the adolescents and legal guardians will be 
provided with supportive clinical services from the study staff until referrals to appropriate 
agencies are made. Following termination of study participation all patients who do not have 
an existing treating clinician will be given appropriate referrals for treatment. Every effort will 
be made so that all subjects have an appointment with a non-study treating physician prior to 
their last study visit so that a follow-up medication plan can be in place at the end of the 
study. If the appointment does not occur prior to the subject’s study termination visit, and if 
clinically indicated and agreeable to subjects and their legal guardians, subjects will continue 
treatment with their medication and monitored until their follow-up appointment. We have 
used this approach with prior studies and typically patients are seen by a child and 
adolescent psychiatrist within one month of termination of study participation.    
 
To protect against potential coercion or undue influence, all study procedures will be 
carefully explained to the subject and the subject's parent/legal guardian by research staff. 
Research staff will inform patients that it is ok if they do not want to participate in the study 
and that they can stop being in the study at any time. Patient’s will be advised that they can 
take time to think about whether they want to participate in the study and that they can sign 
the assent at a later time. If agreeable research staff will obtain written informed consent and 
assent for study participation from the legal guardian and adolescent, respectively. 
 
 
b. Anticipated Benefit Justifies the Risk - Potential benefits include a thorough psychiatric 
evaluation and monitoring performed by investigators with expertise in the diagnosis and 
treatment of mood disorders, and the chance to contribute to a scientific investigation, which 
may be of benefit to patients with similar illnesses in the future. Additionally, study 
participants may also benefit from treatment with the quetiapine (and potentially omega-3 
fatty acid treatment) that they receive free of charge during study participation in that it may 
reduce their mood symptoms. If requested by any study subject or their legal guardian, 
information obtained from this study will be available to that subject’s primary clinician. 
Overall, the risks associated with this study are minimal to the participants and they may 


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receive direct benefit from their study participation as previously described. Thus, in the 
opinion of the investigators, the benefits associated with this study outweigh the risks.  
 
Anticipated Benefit as Favorable as Alternative Approaches – An alternative to study 
participation is not participating and receiving standard of care treatment as directed by a 
physician of that participant’s choosing.  Since this study proposes standard of care 
treatment, the investigators believe participation is as favorable to participants as that of the 
alternative approach. 
 
H. PAYMENT 
Subjects will be reimbursed $20 for each of 13 visits for their time and inconvenience. 
 
I. SUBJECT COSTS 
Patients are expected to provide for clinical care that is not part of this research protocol (e.g., 
hospitalization costs) through standard health care payment procedures. Subjects will have no 
costs associated with research participation. 
 
J. CONSENT/ASSENT FORMS 
See attached. 
 
K. LITERATURE CITED 
 
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