Clinical trial NCT02845453
Conditions: Substance Use Disorders Bipolar Disorder Mood Disorders
Keywords: youth adolescent young adult substance use disorder bipolar disorder quetiapine mood dysregulation
Sponsor: Boston Medical Center
Start date: 2017-01-20; Completion date: 2021-04-07
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study proposes to use quetiapine as an adjunct treatment to treatment as usual to improve both substance use disorder (SUD) and mood symptoms in youth with SUD and severe mood dysregulation (SMD). This is a randomized, double blind placebo controlled parallel design study. Youth with symptoms of mood dysregulation and active substance use that meets criteria for a SUD will be randomized to adjunct treatment with quetiapine or placebo. The investigators hypothesize that treatment with quetiapine will lead to a reduction in substance use, improvement in mood, and lead to greater engagement in outpatient treatment.

Detailed description:

Arms: arm 1: Quetiapine arm 2: Placebo
Interventions: intervention 1: Quetiapine intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will be randomly assigned Quetiapine and will be titrated to the maximum daily dose over three weeks and then enter a dose maintenance phase for weeks 4 through 8 of the study. intervention 2: Participants will be randomly assigned to placebo and will be titrated to the maximum daily dose over three weeks and then enter a dose maintenance phase for weeks 4 through 8 of the study.

Protocol documents:
Prot_SAP_001.pdf: 
A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co-Occurring Substance Use Disorders (SUDs) 
and Severe Mood Dysregulation (SMD) 
 
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A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co-Occurring 
Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
 
ClinicalTrials.gov number: NCT02845453 
Protocol Version Number: 1.14 
Protocol Version Date: 2/19/2021 
Funding Mechanism:  American Academy of Child and Adolescent Psychiatry K12 DA000357-17 
 
Principal Investigator: Amy Yule, MD 
 
Phone: 617-414-1936 
 
E-mail: Amy.yule@BMC.org 
Study Contact Information: 
Phone: 617-699-5899 
E-mail: moodandsubstance@bmc.org 
 
 
 
 
Detailed Statistical Plan pages 32-34 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of Boston Medical Center. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorization 
from the study sponsor. 
 
 


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TABLE OF CONTENTS 
1 List of Abbreviations ................................................................................................................. 3 
2 Protocol Summary .................................................................................................................... 3 
3 Background/Rationale & Purpose ............................................................................................ 5 
3.1 
Background Information ................................................................................................. 5 
3.2 
Rationale and Purpose .................................................................................................... 9 
4 Objectives.................................................................................................................................. 9 
4.1 
Study Objectives .............................................................................................................. 9 
4.2 
Study Outcome Measures ............................................................................................. 10 
4.2.1 
Primary Outcome Measures ........................................................................... 10 
4.2.2 
Secondary Outcome Measures ....................................................................... 11 
5 Study Design............................................................................................................................ 11 
6 Potential Risks and Benefits .................................................................................................... 12 
6.1 
Risks ............................................................................................................................... 12 
6.2 
Potential Benefits .......................................................................................................... 14 
6.3 
Analysis of Risks in Relation to Benefits ........................................................................ 15 
7 Study Subject Selection ........................................................................................................... 15 
7.1 
Subject Inclusion Criteria ............................................................................................... 15 
7.2 
Subject Exclusion Criteria .............................................................................................. 15 
8 Study Intervention .................................................................................................................. 16 
9 Study Procedures .................................................................................................................... 16 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) ........................................... 25 
10.1 Definitions ..................................................................................................................... 25 
10.2 Safety Review ................................................................................................................ 26 
10.3 Reporting Plans ............................................................................................................. 28 
10.4 Stopping Rules ............................................................................................................... 28 
11 Data Handling and Record Keeping ........................................................................................ 29 
11.1 Confidentiality ............................................................................................................... 29 
11.2 Source Documents ........................................................................................................ 30 
11.3 Case Report Forms ........................................................................................................ 30 
11.4 Study Records Retention ............................................................................................... 32 
12 Statistical Plan ......................................................................................................................... 32 
12.1 Study Hypotheses .......................................................................................................... 32 
12.2 Sample Size Determination ........................................................................................... 32 
12.3 Statistical Methods ........................................................................................................ 33 
13 Ethics/Protection of Human Subjects ..................................................................................... 34 
14 Literature References ............................................................................................................. 35 
15 Appendix ................................................................................................................................. 39 


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1 
List of Abbreviations 
Abbreviation 
Abbreviation definition 
SUD 
Substance use disorder 
SMD 
Severe mood dysregulation  
DMDD 
Disruptive mood dysregulation disorder  
SGA 
Second Generation antipsychotic  
BD 
Bipolar Disorder  
M.I.N.I 7.0 
Mini-International Neuropsychiatric Interview 
KSADS-PL 
DMS-V Kiddie Schedule for Affective Disorders and Schizophrenia 
Present and Lifetime 
YMRS 
Young Mania Rating Scale 
AIMS 
Abnormal Involuntary Movement Scale 
CGI 
Clinical Global Impressions   
C-SSRS 
Columbia Suicide Severity Rating Scale 
GAF 
DSM-V Global Assessment of Functioning 
ASR 
Adult Self-Report 
YSR 
Youth Self-Report 
BRIEF 
Behavior Rating Inventory of Executive Function 
BDI-II 
Beck Depression Inventory-II 
PHQ-9 
Patient Health Questionnaire-9 
TLFB 
Timeline Followback of Substance Use 
AE 
Adverse event  
SAE 
Serious adverse event  
 
2 
Protocol Summary 
Title: 
A Randomized Controlled Trial of Quetiapine for the Treatment of 
Youth With Co-Occurring Substance Use Disorders (SUDs) and 
Severe Mood Dysregulation (SMD) 
Population: 
We plan to enroll 56 youth, ages 15 to 24, with SUD and SMD.   
Intervention: 
Drug name: Quetiapine 
Route of administration: Oral  
Dose: Quetiapine will be titrated to the maximum achieved dose as 
tolerated during the first three weeks of the trial. Study medication 
will be initiated at 50 mg twice daily and will be gradually up-
titrated by 100 mg per day (increasing by 50 mg twice daily) to a 
maximum dose of 150 mg twice daily. Titration of the study 
medication is flexible, guided by tolerability with the option for 
slower, lower, or hold titration.  If a participant prefers once daily 
dosing instead of twice daily dosing this will be allowed.   
 
Objectives: 
Specific Aim 1: To evaluate the effect of quetiapine on SUD in youth 
with SUD and SMD 


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Specific Aim 2: To evaluate the effect of quetiapine on SMD in 
youth with SUD and SMD.  
 
Specific Aim 3: To evaluate the effect of quetiapine on engagement 
in outpatient treatment in youth with SMD and SUD.  
 
Specific Aim 4: Assess the safety and tolerability of quetiapine in 
youth with SUD and SMD. 
 
Exploratory Aims: Evaluate whether substance use and mood 
symptoms are related and if so, examine the nature of the 
relationship. Evaluate whether scales that measure emotional 
regulation, the Emotional Control Subscale for the Behavior Rating 
Inventory of Executive Function and the Anxiety/Depression, 
Attention, and Aggression subscales of the Youth Self-Report or 
Adult Self-Report, predict treatment response and/or what specific 
components improve with treatment.  Evaluate whether the Patient 
Health Questionnaire-9 is a valid measure of mood symptoms in 
youth with co-occurring substance use and SMD. Examine the 
impact of quetiapine (versus placebo) on self-reported and 
objective measures of non-primary substances of use.  Evaluate 
whether differences exist in medication adherence, high-risk 
behaviors associated with HIV and Hepatitis C, and global 
functioning between the active treatment and placebo groups.  
Examine the impact of common psychiatric co-morbidities for youth 
with SUD and SMD on outcome and retention in the study.  
Evaluate whether youth’s reasons for substance use, motivation to 
change, and confidence in their ability to change impact response 
to treatment.  Assess whether level of engagement in self help and 
therapy impact response to treatment.  Evaluate whether peer 
substance use and exposure to substance use in the subject’s living 
environment impact response to treatment. 
 
Design/Methodology: 
To evaluate the effect of quetiapine on substance use, SMD, and 
engagement in care, we are proposing an 8-week randomized, 
double blind placebo controlled parallel design study for youth with 
SUD and SMD who are entering into or currently engaged in 
behavioral therapy.  Please refer to the Schedule of Events in the 
Appendix for a table of visits and assessments.  
Total Study Duration: 
Open for Data Analysis until May 2022 


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Subject Participation Duration: 10 weeks  
 
3 
Background/Rationale & Purpose 
 
3.1 
Background Information 
 
Substance use disorders (SUDs) in youth commonly co-occur with categorical and dimensional measures 
of psychopathology [1-4] including prominent dysregulation of mood and emotions found in severe 
mood dysregulation (SMD).  For clarity in this project, SMD includes bipolar spectrum disorders, 
disruptive mood dysregulation disorder, and mood disorder not otherwise specified.  While a growing 
literature suggests an important link between SMD and SUD [5] the relationship between SMD and SUDs 
has been best characterized in youth with SMD indicative of bipolar disorder (BD).  Specifically, among 
adolescents with SUD, 8% to 32% have been found to have BD. [1, 6-8] Conversely, clinical samples of 
adolescents with BD also have elevated rates of SUD, ranging from 9% to 39% when evaluated cross-
sectionally and followed prospectively.[9-14]  
 
SUD co-occurring with SMD is particularly concerning due to the morbidity associated with the co-
occurrence of both disorders.  For example, in BD we found that young people (mean age 21 years) with 
co-occurring SUD and BD had significantly higher rates of severe SUDs (13% had an opioid use disorder 
and 9% a cocaine use disorder) compared to similar aged non-mood disordered control peers.[15] Co-
occurring SUD and BD in youth has also been associated with increased morbidity when compared to 
youth with BD alone.  Compared to BD alone, youth with SUD and BD have higher rates of lifetime 
hospitalizations[15], increased lifetime prevalence of suicide attempts, and higher rates of past year 
legal difficulties, and more frequent unplanned pregnancies and abortions among females.[16] Delbello 
and colleagues [11] found that none of the adolescents with BD, attention deficit hyperactivity disorder 
(ADHD), and alcohol use disorder were adherent with medication during the year following 
hospitalization for a manic episode compared to 38% in similarly affected adolescents without an 
alcohol use disorder. Medication nonadherence was associated with a longer recovery period after 
initial hospitalization in this same sample of adolescents with BD.[11]  
 
Although less studied, evidence exists that SMD, such as observed in BD, may be driving SUD in some 
youth.[5, 17-19] For example, in a case controlled sample of BD, we reported that emotional 
dysregulation was significantly linked with an increased risk for SUD.[5] Lorberg and colleagues found 
that adolescents with BD and SUD were more likely than controls with SUD to start using their drug of 
choice to change their mood[18] Additionally, Goldstein and colleagues in a longitudinal sample of BD 
spectrum youth found a strong relationship between mood symptoms and substance use.[17] In 
adolescents with BD greater hypo/mania symptom severity was observed in the 12 weeks before they 
developed a SUD compared to other 12 week periods over four year follow up and compared to 
adolescents with BD who did not develop a SUD.  Since SMD may be associated with substance use it 
follows that treatments developed for SMD may be effective in reducing substance use in youth with co-


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occurring SUD and SMD.    
 
Despite the high prevalence and morbidity associated with SUDs and SMD in youth, there is a dearth of 
studies on the treatment of this comorbidity. Only one small randomized control trial (RCT) of lithium in 
SUD adolescents with or at high risk for BD (e.g. SMD) has been published. [20] In this study twenty-five 
adolescents were randomized to lithium with mean blood levels 0.9 mEq/L versus placebo and followed 
twice weekly during the six week trial.  Adolescents treated with lithium had significant improvement in 
their SUD and overall improved functioning compared to controls.[20] Interestingly, no change in mood 
scores was observed, and despite a strong signal in a relatively small sample that treatment with a mood 
stabilizer leads to a reduction in substance use in adolescents with co-occurring SUD and SMD, no other 
medication RCTs have been published in this high-risk group.   
 
Lithium’s usefulness for the treatment of youth with SUDs and SMD has been limited due to lithium’s 
narrow therapeutic index and concern regarding toxicity in patients with active substance use due to 
associated shifts in hydration and adherence to monitoring.[21, 22] Since Geller’s publication a new 
class of mood stabilizers, second generation antipsychotic (SGAs) medication, have been developed that 
appear to have less risk for acute toxicity.  A significant literature supports the effectiveness of SGAs for 
the treatment of SMD, specifically adolescent manic symptoms and DMDD.[23-26] A recent meta-
analysis suggested superior efficacy of SGAs for mania in adolescents compared to traditional mood 
stabilizers.[24] Several SGAs have FDA approval for use in adolescents with manic episodes associated 
with BD including: risperidone, olanzapine, quetiapine, and aripiprazole.[27] Furthermore, adolescent 
versus adult-onset manic symptoms appear more responsive to SGAs than traditional mood 
stabilizers.[28] Less information exists on the effectiveness of SGAs for the treatment of depressive 
symptoms in youth with BD. [29]  Given the efficacy associated with SGAs for SMD it is no surprise that 
SGAs are increasingly used in the treatment of SMD.[30, 31]  
 
Since excess dopamine is thought to mediate the reinforcing effect of substances of abuse in the reward 
circuitry system of the brain[32] dopamine antagonists and SGAs in particular have been investigated as 
a treatment for SUDs in adults.  Positive findings have been found for olanzapine, aripiprazole and 
quetiapine for various measures associated with substance use in adults with SUDs.  Both one dose of 
olanzapine and five days of daily olanzapine were shown to be effective in decreasing alcohol cravings 
when subjects were exposed to alcohol.[33, 34] Further work by Hutchinson et al in a 12-week RCT 
demonstrated olanzapine to be effective for decreasing cravings for alcohol and alcohol consumption in 
subjects with alcohol dependence who had a particular genetic polymorphism.[35] Aripiprazole was 
evaluated as a treatment for adults with alcohol dependence in a 12-week RCT.[36] While there was no 
difference between aripriprazole and placebo in percent days abstinent, the aripiprazole group reported 
significantly fewer drinks per drinking day and subjective improvement in their alcohol dependence.[36] 
In contrast, several RCTs of both olanzapine and risperidone did not show superior efficacy to placebo in 
decreasing cravings for cocaine[37-39] or cocaine use[37, 38, 40] in adults with cocaine use disorders. 
Open label treatment with quetiapine however was shown to be effective in decreasing cravings for 


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cocaine and days of cocaine use.[41] A retrospective review of males with alcohol dependence who 
were treated or not treated with quetiapine demonstrated treatment with quetiapine was associated 
with increased number of days abstinent and decreased number of hospitalizations.[42] Another 
retrospective review of patients with opioid use disorders engaged in outpatient opioid detoxification 
found that quetiapine was associated with decreased opioid cravings in 74% of patients.[43] Hence, the 
preponderance of data seems to suggest a role for SGAs in SUD; however, little is known about this 
treatment in youth with SUD. 
 
Research on the efficacy of SGA medication in RCTs for the treatment of adults with co-occurring SUD 
and a type of SMD, BD, has been mixed.  Quetiapine, approved by the FDA for both manic and 
depressive episodes associated with adult BD, has been the most extensively studied SGA for the 
treatment of adults with co-occurring SUD and BD. When compared to placebo as adjuvant treatment, 
quetiapine significantly decreased alcohol use and depressive symptoms in a subgroup of adult patients 
with heavy baseline levels of alcohol consumption who met criteria for an alcohol use disorder and 
BD.[44] Both quetiapine and risperidone were equally effective in improving mania, mixed, and 
depressive symptoms as well as drug cravings when compared in a RCT trial for the treatment of adults 
with co-occurring stimulant use disorders and BD.[45] An open label study of quetiapine for cocaine 
dependence and BD showed improvements in cravings for cocaine and measures of mood, with 
nonsignificant decreases in days per week of cocaine use.[46] Other studies that evaluated quetiapine as 
adjuvant medication and the primary medication for the treatment of co-occurring alcohol dependence 
and BD did not find significant differences between placebo.[47, 48] Although treatment trials of adults 
with co-occurring SUD and  BD provide some guidance on effective treatment strategies it is unclear if 
youth with co-occurring SUD and SMD would respond similarly to adults based on the different 
phenotypic descriptions of BD and medication treatment responses seen between youth and adults with 
BD.  
 
To our knowledge there have been no published papers to date specifically examining treatment of co-
occurring SUD and SMD in youth with SGAs.  Delbello reported on a RCT in adolescents with frequent 
cannabis use and BD with symptoms of mania (Young Mania Rating Scale (YMRS) score greater than 20) 
who were treated with quetiapine and randomized to topiramate or placebo.[49] Although quetiapine 
plus topiramate was more effective than quetiapine alone in reducing substance use, both treatment 
groups showed overall improvement in substance use and mood.  Substance use decreased by 10 joints 
per week (-72%) in the quetiapine only group and by 10.6 joints per week (-96%) in the quetiapine plus 
topiramate group. YMRS scores decreased by 16 in the quetiapine only group (ca -53%) and 14 (ca -47%) 
in the quetiapine plus topiramate group—these data suggest quetiapine could be a highly useful 
intervention for treatment of SUD co-occurring with BD when adolescents are experiencing symptoms 
of mania. Further research is warranted to determine if quetiapine would be more efficacious compared 
to placebo in decreasing both SUD and affective symptoms.   
 
To this end, we aim to study the efficacy of a SGA, quetiapine, as treatment for active SUD, as well as 


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mood symptoms in youth with SUD and SMD in a naturalistic, outpatient treatment setting.  Quetiapine 
was selected as the SGA to target SUD and SMD since the adolescent and adult literature has suggested 
possible efficacy for treatment of SUDs and quetiapine is FDA approved for the treatment of adolescent 
BD.   
 
We propose to use quetiapine as an adjunct treatment to treatment as usual to improve both SUD and 
mood symptoms in a double blind, parallel design RCT over 8 weeks for youth with SUD and SMD who 
are in a comprehensive outpatient treatment program utilizing evidence based family and individual 
behavioral therapies.[50, 51] Our trial will examine a number of important variables including the 
impact of acute treatment with quetiapine on SUD, mood, and treatment engagement in youth with co-
occurring SUD and SMD.  Although this study cannot directly evaluate the relationship between 
substance use and mood symptoms and vice versa, we will closely monitor the trajectory of these 
symptoms. We will also explore whether scales that measure SMD—the Emotional Control Subscale for 
the Behavior Rating Inventory of Executive Function (BRIEF)[52] and the Anxiety/Depression, Attention, 
and Aggression (AAA) subscales of the Youth Self-report (YSR)[53] or Adult Self-Report (ASR)[54], which 
are self-report versions of Achenbach System of Empirically Based Assessments based on age—predict 
treatment response in youth with co-occurring SUD and SMD; as well as specific improvement in areas 
thereof that may be reflective of improved SUD.  We will explore the impact of quetiapine (versus 
placebo) on self-reported and objective measures of non-primary substances of use.  We also plan on 
exploring the impact of pharmacologic treatment on medication adherence, retention in treatment, 
high-risk behaviors associated with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), and 
overall global functioning.  Furthermore, we will examine the impact of common psychiatric co-
morbidities for youth with SUD and SMD, such as conduct disorder, attention deficit hyperactivity 
disorder (ADHD), and anxiety, on outcome and retention in the study.   
 
As noted earlier, quetiapine is FDA approved for the treatment manic episodes associated with bipolar 
disorder in adolescents, and the treatment of manic and depressive episodes associated with bipolar 
disorder in adults. An IND was not requested because this study is not intended to support a new 
indication for use, change in labeling for the drug, or change in the advertising of quetiapine. 
Furthermore, this study does not involve a change in route of administration or dosage level, use in a 
subject population, or other factor that significantly increases the risk associated with the use of 
quetiapine.  
 
This study was originally approved by the Partners Healthcare IRB on 09/14/2016 and has been taking 
place at the Massachusetts General Hospital (MGH). To date the study has completed 161 phone 
screens, scheduled 75 screening visits, consented 39 subjects, and randomized 19 subjects. Since the PI 
has changed employers from MGH to BMC this study is currently closed to recruitment at MGH and is 
being closed with the Partners IRB.  
 
This study will be conducted in compliance with the protocol, applicable regulatory requirements, and 
BMC/BU Medical Campus Human Research Protection policies and procedures. 


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3.2 
Rationale and Purpose  
 
Given the morbidity associated with SUDs and SMD there is a need to continue to evaluate strategies to 
stabilize SUDs when co-occurring with SMD in youth.  It is particularly important to evaluate treatment 
strategies in youth since delayed treatment of both SUDs and SMD in youth has been associated with a 
more complicated course of illness. [55, 56] The exclusion of youth with SUDs from treatment trials for 
BD has been a barrier to progress in this field.   
 
Increasing knowledge on effective ways to stabilize and engage this high-risk population in treatment 
will be of utility to the field by decreasing the morbidity associated with SUD and SMD in youth.  
Additionally, once treatments for acute stabilization have been established, the field can begin to 
evaluate maintenance treatment strategies and improve our understanding of the common relationship 
between substance use and mood longitudinally in youth with co-occurring SUD and SMD.   
 
 
 
4 
Objectives 
 
4.1 
Study Objectives 
 
Primary Objectives:  
Objective 1: Evaluate the effect of quetiapine on SUD on youth with SUD and SMD. 
Hypothesis 1A: Treatment with quetiapine will decrease self-reported substance use for primary 
substance of use (e.g. number of days of use past month, % abstinence past month).  Hypothesis 1B: 
Treatment with quetiapine will increase the number of toxicology specimens negative for primary 
substance of use Hypothesis 1C: Treatment with quetiapine will decrease drug craving for primary 
substance of use demonstrated by a reduction in the Weiss cravings scale. 
 
Objective 2: Evaluate the effect of quetiapine on SMD in youth with SUD and SMD. 
Hypothesis 2A: Treatment with quetiapine will result in a decrease in symptoms of mania demonstrated 
by reduction in Young Mania Rating Scale.  Hypothesis 2B: Treatment with quetiapine will result in a 
decrease in symptoms of depression demonstrated by reduction in the Beck Depression Inventory II. 
 
Objective 3: Evaluate the effect of quetiapine on engagement in outpatient treatment in youth with 
SUD and SMD. 
Hypothesis 3A: Treatment with quetiapine will lead to greater engagement in outpatient treatment as 
demonstrated by greater number of appointments attended in the active treatment group.   
 
Objective 4: Assess the safety and tolerability of quetiapine in youth with SUD and SMD. 
Exploratory Objectives:  


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Evaluate whether substance use and mood symptoms are related and if so, examine the nature of the 
relationship. Evaluate whether scales that measure SMD, the Emotional Control Subscale for the 
Behavior Rating Inventory of Executive Function and the Anxiety/Depression, Attention, and Aggression 
subscales of the Youth Self-Report or Adult Self-Report, predict treatment response and/or what specific 
components improve with treatment. Evaluate whether the Patient Health Questionnaire-9 is a valid 
measure of mood symptoms in youth with co-occurring substance use and SMD. Examine the impact of 
quetiapine (versus placebo) on self-reported and objective measures of non-primary substances of use.  
Evaluate whether differences exist in medication adherence, high risk behaviors associated with HIV and 
Hepatitis C, and global functioning between the active treatment and placebo groups.  Examine the 
impact of common psychiatric co-morbidities for youth with SUD and SMD on outcome and retention in 
the study. Evaluate whether youth’s reasons for substance use, motivation to change, and confidence in 
their ability to change impact response to treatment.  Assess whether level of engagement in self-help 
and therapy impact response to treatment.  Evaluate whether peer substance use and exposure to 
substance use in the subject’s living environment impact response to treatment.  
 
4.2 
Study Outcome Measures 
 
4.2.1 Primary Outcome Measures 
 
Outcome 1: SUD response to quetiapine for primary substance of use will be assessed by Timeline 
Followback of Substance Use to assess self-report of substance use, toxicology screens negative for 
substances for objective measurement of substance use, and the Weiss drug craving scale to assess 
cravings.  The Timeline Followback will be used to compare self-report of substance for the month prior 
to study entry versus the last month of the study.  Toxicology screens and the Weiss drug craving scale 
will compare values from baseline to endpoint.   
 
Outcome 2: SMD response to quetiapine will be assessed by the YMRS and BDI-II comparing values from 
baseline to endpoint.   
 
Outcome 3: The impact of treatment with quetiapine on outpatient treatment engagement will be 
monitored by collateral from the outpatient program regarding the percentage of scheduled 
appointments attended after randomization. 
 
Outcome 4: An EKG will be administered at study screening to screen for cardiac risk factors that would 
exclude subjects from participation. A blood draw will be completed at screening and completion; 
approximately 30 ccs of blood will be drawn from each subject over the course of the study. Safety and 
tolerability of quetiapine monotherapy will be monitored by a battery of blood tests, weight 
measurements (to calculate Body Mass Index (BMI)), and the AIMS at baseline and endpoint to monitor 
for extrapyramidal symptoms.  Weight, the AIMS, and urine HCG test will also be completed at 
midpoint.  Adverse events, suicidality (C-SSRS), the CGI-S and CGI-I for SUD and SMD will be monitored 
at every study visit. Vital signs will be monitored at screening, midpoint and endpoint. 


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4.2.2 Secondary Outcome Measures 
 
Exploratory Outcome Measures: Evaluate whether scales that measure emotional regulation, the 
Emotional Control Subscale for the BRIEF and the AAA subscales of the YSR or ASR predict treatment 
response and/or what specific components improve with treatment in youth with co-occurring SUD and 
SMD. The validity of the PHQ-9 as a measure of mood symptoms in youth with co-occurring substance 
use and SMD will be evaluated by administering the instrument in conjunction with the BDI-II at Week 0 
and every 2 weeks thereafter. The impact of treatment with quetiapine on medication adherence will be 
assessed with weekly pill counts, a medication diary, and the medication adherence rating scale. Non-
primary substances of use will be evaluated by Timeline Followback of substance use, toxicology 
screens, urine THC levels, and a questionnaire on nicotine use. Changes in high risk behaviors associated 
with HIV and HCV due to treatment with quetiapine will be assessed with the Risk Behavior Survey.  The 
effect of treatment with quetiapine on functioning will be assessed by the GAF. Psychiatric co-
morbidities will be assessed at baseline with specific, predetermined modules from the M.I.N.I. 7.0. For 
an objective measure of adherence, approximately 4 ccs of blood will be drawn to assess quetiapine 
levels. This blood will be frozen and analyzed for subjects randomized to Quetiapine at the completion 
of the study.  Changes in the subject’s motivation and confidence in their ability to change will be 
assessed with two questions about subjects’ confidence in staying sober and the importance of 
abstaining from their primary substance of use. 
 
5 
Study Design 
 
To evaluate the effect of quetiapine on substance use, SMD, and engagement in care, we are proposing 
an 8-week randomized, double blind placebo controlled parallel design study for youth with SUD and 
SMD who are entering into or currently engaged in behavioral therapy.  Youth with active substance use 
who meet criteria for a SUD with the exclusion of current methamphetamine use disorders and unstable 
opioid use disorders and have symptoms of SMD as quantified by the aggregate score from the 
Anxiety/Depression, Attention, and Aggression (AAA) of the Youth Self Report or Adult Self Report will 
be randomized to adjunct treatment with quetiapine or placebo. We define an unstable opioid use 
disorder as less than three months on medication assisted treatment, i.e. naltrexone extended release, 
buprenorphine, or methadone. We will be studying use of quetiapine up to 300 mg/day administered in 
daily or twice-daily dosing.  Subjects will be continued on existing medication if indicated (e.g. buspirone 
for anxiety). Subjects will be asked not to change their existing psychiatric medications while taking the 
study medication. Subjects will be excluded if they plan on modifying their psychiatric and/or non-
psychiatric medications during the study such that they would be increasing the dose of an existing 
medication that may prolong QTc interval and/or adding a new medication that may prolong QTc 
interval.  
 
See the Appendix for the Schedule of Events.  
 
 
 
 


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5.1 
Virtual Visits in the Context of COVID-19 
 
Due to public health concerns regarding the COVID-19 pandemic, we would like to minimize in person 
interaction as much as possible. Thus, study procedures may take place either in person at Boston 
Medical Center or remotely through BMC Zoom videoconferencing software. Zoom Video 
Communications is a remote conferencing services company that provides remote conferencing 
services, which combines video conferencing, screen sharing services, online meetings, chat, 
and mobile collaboration, with both audio and video communication options. We will use a 
BMC Zoom account which is HIPAA compliant. Participants can use zoom via their phone, 
computer, or tablet/iPad. Both the study clinician and study coordinator will be present during 
the virtual study visits and conduct the visit in a private and professional setting. 
 
Screening, midpoint and final visits (Weeks 99, 4 and 8) will always be held in person. All other 
study visits may take place virtually due to patient preference or health and safety concerns. 
During the consent process, participants will be informed that in person study visits may not be 
permitted and that remote study visits may be a possibility if they choose to enroll or continue.  
 
In the event that a subject is unable to make it to the office for an in-person visit, or is unable to join a 
Zoom videoconference, clinician and patient rated scales may be completed over the phone with a focus 
on safety, medication efficacy and tolerability. 
 
 
6 
Potential Risks and Benefits 
 
6.1 
Risks 
 
Confidentiality: There is a risk of loss of confidentiality in research. However, precautions will be taken 
to uphold subject privacy and confidentiality. A notation that the subject is taking part in the research 
study may be made in the subject’s electronic medical record. Subjects will be identified by code names 
and numbers and all research related records that reveal the subject’s identity will remain confidential 
except as may be required by law. We have a federal certificate of confidentiality. Information from the 
research that relates to the subject’s general medical care may be included in the record (for example, 
results of standard safety and monitoring blood labs done at the hospital laboratory). 
 
Structured Interview: Answering detailed questionnaires may create a mild degree of inconvenience or 
emotional upset for the subjects. We aim to minimize this risk by reminding subjects that they can 
choose to not answer questions that make them feel uncomfortable or upset.  
 
Blood draw: Some subjects may experience mild discomfort associated with blood draws and in rare 
cases a small arm bruise, clot, or infection may occur at the site of the blood drawing.  We aim to 
minimize this risk by having blood draws done by trained phlebotomists.  


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EKG: Some subjects may have a skin reaction to the adhesive used to apply the electrode on your skin. 
We aim to minimize this risk by cleaning the skin areas where the electrode was attached after the 
removal of the electrode.  
 
Risk/Discomforts of Study Medication: Consistent with good clinical practice, safety will be monitored 
by the Principal Investigator, and will reflect the oversight of study investigators. Adverse events will be 
recorded and reported according to institutional policies.  
 
Subjects will be given quetiapine throughout the study. The most frequently observed adverse reactions 
(incidence ≥ 5% and twice placebo) associated with the use of quetiapine include: somnolence, dry mouth, 
dizziness, pharyngitis, weight gain, constipation, lethargy, ALT increase, postural hypotension, 
hypertension, dyspepsia, fatigue, increased appetite, tachycardia, vomiting and asthenia. Serious adverse 
reactions associated with the use of quetiapine include: hyperglycemia, lipid elevations, hypothyroidism, 
neuroleptic malignant syndrome, seizures, diabetes mellitus, cataracts, QTc prolongation, and tardive 
dyskinesia. Tardive dyskinesia causes repetitive involuntary movements. The movements most commonly 
appear in the eyes, lips, tongue, and jaw. Although tardive dyskinesia is rare it can be irreversible.  
 
To minimize adverse reactions a baseline EKG will be completed to assess QTc length, and subject’s past 
medical history will be assessed for thyroid dysfunction, seizures, diabetes mellitus, and cataracts. 
Adverse reactions will be monitored during the study by assessing for adverse events, as well as vital signs 
including blood pressure, heart rate, and weight, blood testing (lipids, glucose, AST, ALT), and 
extrapyramidal symptoms including tardive dyskinesia (AIMS).    
 
Problems and side effects not listed above and not known at this time could occur. Subjects will be told 
of any changes in the way the study will be done and any newly discovered risks to which they may be 
exposed. 
 
Quetiapine has a black box warning for increased suicidality risk in adolescents and young adults largely 
due to co-administration in patients with major depressive disorder who are on antidepressants.  
Suicide risk is assessed at every study visit by the study physician (psychiatrist) during the mental status 
exam. After the first baseline screening visit (week 98) the Columbia Suicide Severity Rating Scale is 
formally administered by the study physician at each study visit. When the subject completes self-report 
scales that include questions regarding suicidality the study coordinator will review the subject's 
responses before the subjects leaves the study visit. If the subject endorses suicidality on the self-report 
scales this will be reviewed with the study physician before the subject leaves the study visit. The study 
physician will assess acute risk for suicide and will use clinical judgement to guide next steps. If the study 
physician feels the subject is at risk to acutely harm themselves by suicide, and the subject requires 


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further evaluation, a section 12 will be completed and the subject will be transported to the emergency 
room by hospital security. 
 
There are no medications with specific FDA approval for the treatment of co-occurring SUD and SMD in 
youth.  There are other medications approved for the treatment of mania associated with SMD such as 
second generation antipsychotics, specifically risperidone, olanzapine, and aripiprazole. 
 
As with any drug, an allergic reaction to Quetiapine could occur. Common symptoms of an allergic 
reaction are rash, itching, skin problems, swelling of the face and throat, or trouble breathing. Subjects 
will be informed to call 911 immediately if they are having trouble breathing.  
The effects of the study drug on an embryo or fetus, or on a breastfeeding infant, is unknown and may 
be harmful. Because of these unknown risks, the subject cannot take part in the study if she is pregnant. 
Furthermore, to participate in the study subjects must agree to use birth control and pregnancy tests 
are scheduled for weeks 99, 4, and 8. If the subject becomes pregnant during the study, she will be 
instructed to stop taking the study medication.  
Treatment with quetiapine may add to the hypotensive effects of antihypertensive agents. Alternately, 
quetiapine may antagonize the effect of levodopa and dopamine agents. Caution should be used when 
quetiapine is used concomitantly with drugs known to cause electrolyte imbalance, increase QT interval, 
or centrally acting drugs, and P450 3A inhibitors may decrease the clearance of quetiapine.  
Subjects will be given the contact information to reach the study investigator 24 hours a day, 7 days a 
week. The PI or designee will review any and all reports of adverse events. Subjects are repeatedly advised 
that they can discontinue participation in the study at any time. 
 
Subjects will be monitored for adverse events at each visit and all events will be recorded. After study 
completion (week 8), or if a subject withdraws early from the study, subjects will be offered up to 3 free 
clinical follow-up visits. The first follow-up visit will be offered within 2 weeks of the last study visit. If the 
subject would like to continue medication after the study they will be offered the choice of quetiapine 
and a prescription will be sent to the pharmacy. If a subject chooses to not continue quetiapine after the 
study there is no need to taper when the medication is discontinued.  
 
6.2 
Potential Benefits 
 
This study will examine the efficacy of quetiapine for treating youth with co-occurring SUD and SMD. 
Youth with co-occurring SUD and SMD enrolled in this study may benefit from an improvement in their 
SUD and/or severe mood symptoms if they are randomized to receive quetiapine. Findings from the 
study could lead to increased knowledge on effective ways to quickly stabilize and engage this high-risk 
population in treatment that may decrease the morbidity associated with these co-occurring illnesses.  


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These data may also help elucidate the important mechanistic connection between SMD and SUD in 
youth. 
 
6.3 
Analysis of Risks in Relation to Benefits 
 
All efforts are made to minimize risks to subjects. Risks are minimized by careful subject selection, 
including only subjects that are appropriate. This protocol is designed to ensure that safety 
measurements are completed prior to initiation of medications and that the subject’s response is closely 
monitored. All procedures used are consistent with sound research design and do not unnecessarily 
expose subjects to risk.  
 
7 
Study Subject Selection 
 
7.1 
Subject Inclusion Criteria 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
-Male or female age 15 to 24 
-Meet DSM-5 criteria for a substance use disorder 
-Substance use ≥ 14 days of past 28 days (i.e. use ≥ 50% of days in the past 28 days) 
-If subject in restricted setting/care (e.g. detox or residential treatment) for ≤ 2 weeks, then use ≥ 50% of 
days while outside of restricted setting (e.g. 7 days of substance use out of 14 days in unrestricted 
setting) 
-Subjects need to have been in an unrestricted setting for at least 2 weeks prior to screening 
-Meets DSM-5 criteria for bipolar disorder or disruptive mood dysregulation disorder or DSM IV criteria 
for mood disorder NOS  
-Symptoms of SMD: YSR or ASR AAA ≥180 
-Stable to be treated in outpatient level of care 
-Access to internet and the ability to utilize Zoom videoconferencing software 
 
7.2 
Subject Exclusion Criteria 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
-Current methamphetamine use disorder 
-Current unstable opioid use disorder (i.e. < 3 months on medication assisted treatment for an opioid 
use disorder) 
-Pregnant or breastfeeding 
-Placement in a restricted setting (e.g. detox or residential treatment) for ≥ 2 weeks out of past 28 days 
prior to screening visit, or placement in a restricted setting at anytime during study participation 
-Unwilling or unable to use effective birth control 
-Unwilling or unable to sign release of information for the treatment program providing behavioral 
treatment to coordinate care (e.g. study visit and treatment attendance and any safety concerns) 


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-For participants >17 years—unable or unwilling to identify emergency contact 
-Medical or psychiatric condition likely to make participation unsafe as judged by the clinical investigator 
-EKG shows a QTc>450 or arrhythmia or the subject has a family history of malignant arrhythmia or 
sudden death 
-Current treatment with a CYP3A4 inhibitor (e.g. clarithromycin, fluconazole) 
-AST or ALT greater than three times normal 
-BMI > 35 
-Poor command of the English language 
-Current treatment with quetiapine, or an allergy to quetiapine 
-No internet access or the inability to utilize Zoom videoconferencing software 
- Planning to change any psychiatric and/or non-psychiatric medications during the study such that they 
would be increasing the dose of an existing medication that may prolong QTc interval and/or adding a 
new medication that may prolong QTc interval 
 
8 
Study Intervention 
 
The study drug will be acquired from, stored by, and distributed by the BMC research pharmacy. After 
the week 99 visit, a two week supply of medication will be mailed to the participant’s preferred address. 
After the week 1 visit, another two week supply will be mailed to the participant. The rest of the 
medication will be provided to the participant in person at the Week 4 visit. 
 
Pill counts will be conducted at each visit. During virtual visits, study participants will be asked 
to count remaining pills with study staff over videoconference call. During in-person visits 
(week 4 and week 8), study participants will be asked to return any unused study medication. Unused 
study medication will be counted by study staff and disposed of per the investigational pharmacy’s 
protocol.  
 
 Dosage will range from 50 MG to 300 MG as tolerated by the study participant. The study medication is 
titrated to full dose tolerated by the study participant during the first four weeks of the study. 
Quetiapine will be administered orally.  
 
Capsules of 50 mg and 100 mg dosages of quetiapine or placebo will be dispensed. Capsules of 
quetiapine will be created with quetiapine powder.  
 
9 
Study Procedures 
 
9.1 
Recruitment 
 
We plan to primarily recruit subjects from the referral pool of both new and existing patients from the 
Center for Addition Treatment for Adolescents/ Young Adults who use Substances (CATALYST), the Child 
Outpatient Psychiatry clinic, and the Adult Outpatient Psychiatry clinic at Boston Medical Center.  The 
CATALYST program is a multidisciplinary SUD treatment program for young people under 26 years of age 


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that is based in the adolescent and young adult medical home. Possible study participants from 
CATALYST will be identified by clinical staff primarily during a weekly meeting that all clinicians attend 
where new evaluations and current patients in the program are discussed regularly. Clinical staff from 
CATALYST may also contact study staff outside of this meeting. The Child and Adult Outpatient 
Psychiatry Clinics are housed at Boston Medical Center as well. Research staff will present the study at 
clinical meetings for the Child Outpatient team, Adult Outpatient team and Integrated Behavioral Health 
team. Possible study participants will be identified by clinical staff during these meetings. Clinical staff 
from outpatient psychiatry departments may also contact study staff outside of this meeting. 
 
We will also use BMC Quest reports to identify potentially eligible participants. We will pull BMC 
Appointment Reports for visits to Child Outpatient Psychiatry, Adult Outpatient Psychiatry, and 
Integrated Behavioral Health departments. We will then filter these reports to look for patients aged 15-
24 who have a diagnosis of Bipolar Disorder or Mood Disorder not otherwise specified. We will use 
information from the report, such as patient name, date of birth, age, MRN, provider, and clinic, to 
reach out to the patient’s clinician.  
 
The medical record for patients identified by clinical staff at CATALYST or Outpatient Psychiatry Clinics 
with symptoms of SMD, or patients identified by pulled Quest Reports, will be reviewed by study staff, 
with a focus on encounter notes, problem lists, medications, and allergies. If the patient appears to 
meet eligibility criteria the patient’s name, the name of the provider the patient is scheduled to see, and 
the date of the patient’s next appointment will be recorded. Study staff will discuss with the clinician 
who the patient will see at the next appointment and the best strategy to connect the patient with 
study staff for more information about the study (e.g. IRB-approved flyer provided to the patient, verbal 
permission obtained for study staff to call patient, and/or meet briefly with study staff after the 
appointment to discuss the study). If study staff meet/are introduced to the patient in-person the phone 
screen would be done in person instead of over the phone. 
 
In addition to the BMC psychiatry clinics, we will also contact participants who are referred from 
another study on which PI Dr. Amy Yule is an investigator. This study, H-40668: Does Treating Young 
Persons Psychopathology Prevent the Onset of Opioid and other Substance Use Disorders?, is a multisite 
study that takes place at Mass General Brigham and Boston Medical Center. Participants who indicate 
interest in being contacted for other studies during informed consent for study H-40668 will be referred 
to our study staff after a brief introduction by their research assistants. Our study staff will then contact 
the potential participant for a phone screen.  
 
We may also recruit in the community with IRB-approved flyers. We may advertise at therapeutic high 
schools in the area, but only in the event that the school administrator provides written authorization to 
do so beforehand. We will provide the school administrator with information about the study and a 
document for him/her to sign if he/she wishes to provide the written authorization. We will also contact 
colleges and universities in the area to ask if they would be willing to advertise our study to their 


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students. This will entail the distribution of our study flyer in digital settings such as the school website 
or student newsletters. Schools may also decide to include a short summary of our study when they 
distribute the flyer. Flyers will include a study phone number and email address which potential 
participants may call, text, or email if interested in the study.  
 
In addition to flyers in the community, we will work closely with the BMC Communications team to 
advertise our study on Facebook and Instagram. Potential participants can click on the advertisement to 
learn more about the study. Clicking the ad will take them to a REDCap page where they can read about 
the study in more detail. If they are interested, they can call, text or email us with the provided contact 
information. They also have the option to fill out a short form to indicate their interest in which we will 
contact the participant to discuss the study in more detail and complete a phone screen. The contact 
information collected by the REDCap webpage will be deleted if the participant is not eligible after the 
phone screen. If the participant seems eligible after the phone screen, their name and phone number 
provided on the REDCap webpage will be saved in the phone screen log. 
Texting and email are offered so that the young target population may contact us more easily with their 
preferred means of communication. Texting and email are to be used solely for assessing interest in the 
study and for scheduling the initial screening over the phone. Thus, once contacted, study staff will then 
work with potential participants to schedule a time for a phone screening. In our responses, we will 
acknowledge that texting/email might not be the most secure form of communication and thus we 
would prefer to speak by phone.  A response to a text or email from potential participant will look 
similar to the following message: “Thank you for being in touch! To protect your privacy, we would like 
to continue communication over the phone. Could you provide a good time for us to reach you for a 
phone screen?” Responses will not include research staff’s personal or contact information except for a 
first name. 
Potential participants will be first screened by phone to ensure that basic inclusion/exclusion criteria are 
met. Specifically, we will ask questions regarding primary substance of use, and frequency of use. We 
will also query for past psychiatric diagnoses, current mood status, and psychiatric or substance related 
hospitalizations within the past month. We will also ask potential participants to self-report their height 
and weight so that we can calculate BMI. If potential subjects are not taking quetiapine at the time of 
the phone interview, are not allergic to quetiapine, have a BMI less than or equal to 35, and have a 
sufficient level of substance use and mood symptoms, they will be invited to meet with a study doctor.  
 
9.2 
Informed Consent  
 
IRB-approved informed consent will be obtained from each subject prior to initiation of any study 
procedures. Parents will provide written, informed consent for their adolescent.  All adolescents will be 
provided with an age-appropriate explanation of the purpose, nature, risks and benefits of the study and 
will provide written assent to study procedures. Youth over age 17 will provide written informed 
consent. Informed consent may also be obtained over Zoom videoconference call, in which case an 


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electronic signature will be obtained through DocuSign. Informed consent documents will be provided 
to the potential subject prior to the informed consent discussion.  
 
The informed consent document will be used to explain, in simple terms, the purpose, procedures, risks 
and benefits of study participation to the subject and his or her parent (if applicable). Per IRB guidelines, 
the informed consent document includes a section on receiving unencrypted text messages detailing the 
possible associated security risks and fees. Consent will be obtained by a licensed MD investigator on 
study staff in a private office or over Zoom videoconference. The subject and his or her parent will be 
encouraged to ask questions pertaining to participation in the study and the subject and his or her 
family may take as much time as they feel is necessary to consider participation in the study as well as 
consult with family members and/or the subject’s physician. Some subjects may be recruited from the 
investigators’ own patients. Under no circumstances will the physician investigator complete informed 
consent with her own, ongoing patients. Interested and eligible patients will be consented by a 
colleague physician who is on study staff. The investigator will reinforce that participation is voluntary, 
that they do not have to participate, and the decision not to participate will not affect their care, now or 
in the future. Participation in this study is voluntary and the subject may withdraw at any time. The IRB-
approved consent document will be signed, physically or electronically, and dated by the subject (and 
parent if applicable) and the investigator obtaining consent. Signed consent forms will be saved to a 
password-encrypted folder on the BMC secure network. A copy of the signed consent form will be given 
to the subject and the parent/guardian.  As part of the consent process, all participants will be aware of 
HIPAA policies as they apply to research data collected. Participants will also be informed that in person 
study visits may not be permitted and that remote study visits may be a possibility if they choose to 
enroll or continue. 
 
After consent has been obtained, all subjects will complete a clinical diagnostic interview with a study 
clinician to assess medical, psychiatric and substance use history, and potential eligibility.  
 
9.3 
Screening and Study Visits 
 
Clinical characterization at the screening visit will consist of a thorough psychiatric and medical 
evaluation, and the completion of participant rated questionnaires and scales. A clinical interview will be 
conducted supplemented by modules from the M.I.N.I. 7.0 and the KSADS-PL where applicable. The 
Timeline Followback of Substance Use over the past month and the YSR or ASR will also be completed at 
screening to assess eligibility. Additional information regarding participants’ past psychiatric 
/psychotropic history, past/current suicidal ideation, suicide attempts, and past/current delusions will 
be gathered through clinical interview and the Columbia Suicide Severity Rating Scale (C-SSRS). The 
Weiss adherence interview will be completed at the screening visit to assess baseline patterns of 
adherence and past reasons for nonadherence.  Participants will also complete the Emotional Control 
Subscale of the BRIEF to assess emotional regulation.  The risk behavior survey will be completed to 
assess high-risk behaviors associated with HIV/HCV. Participants will also answer questions about 
reasons for their alcohol/substance use, reasons for coming to treatment, family opinions on their 
alcohol/substance use, and friends drinking/drug use behaviors. 


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All participants will be required to complete a breathalyzer test and give a urine sample to screen for 
certain types of drugs. This includes prescription drugs, illegal drugs (street drugs), and controlled 
substances (substances that may be habit forming) that may affect behavior and that may be regulated 
by law. The breathalyzer test and urine sample will be collected by study staff during screening, 
midpoint, and final visits (in-person visits). Results of the drug screen will be conveyed to the participant 
by the study clinician. For all other virtual visits, the participant will self-administer the urine drug test 
before the virtual study visit. These drug tests will be given to the participant at the previous in-person 
visit. The participants will then share and discuss their results with the clinician over Zoom 
videoconference call. In addition, female subjects of childbearing potential will complete a urine 
pregnancy test at the screening, midpoint, and final study visits. If a participant has a positive urine 
pregnancy test, she will not be able to take part in the study. The study doctor will inform the 
participant of any positive test results. The decision whether to inform the subject’s parent/guardian of 
these results will be made by the study doctor based on the participant's age, risk level associated with 
substance use, administration route of substance use, and maturity level.   
 
The medical evaluation at screening will include a clinical interview, vital signs, and laboratory tests 
focused on assessing for medical conditions that would be contraindications for a trial with quetiapine 
and for assessing changes at endpoint. Subjects will complete physical assessment measures (height, 
weight, BMI, heart rate, blood pressure), and a 15 cc blood draw for blood tests measuring both AST/ALT 
levels, and the presence of Hepatitis C or HIV. If the participant has a BMI between 30 and 35 at screening, 
we will monitor their weight at every visit instead of just midpoint and endpoint visits. We will ask 
participants to self-report their weight, and provide a scale if they do not own one at home. If their weight 
increases such that their BMI increases by ≥1, the participant will be withdrawn from the study. An EKG at 
the screening visit will be administered to screen for cardiac risk factors that would exclude subjects 
from participation. The screening process may take place over multiple days, as necessary. 
 
Before receiving study medication, the healthy lifestyle behavior recommendations developed by Correll 
and Carlson to prevent and minimize weight gain on SGAs will be reviewed with all eligible subjects. 
Participating youth with active SUD and SMD will be randomized to treatment or placebo in a 1:1 ratio.  
Randomization lists will be generated by the investigational pharmacy for each age block (e.g. 15-17; 18-
24 years).  Throughout the 10-week study participants will be encouraged to engage in treatment as 
usual which includes evidence based behavioral therapies through the Center for Addition Treatment for 
Adolescents/ Young Adults who use Substances (CATALYST) at Boston Medical Center.   
 
Subjects will be sent appointment reminders via text before their study visits. Reminders will be sent 
from a cell phone designated for this study’s purposes and will only contain the date, time, and location 
of the appointment. No personal/health information will be shared over text.  
 
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Clinician rated assessments: 
• 
Mini-International Neuropsychiatric Interview (M.I.N.I. 7.0)[57]: The M.I.N.I is a short, 
structured, diagnostic interview with an administration time of approximately 15 minutes that is 
the structured interview of choice for psychiatric outcome tracking in clinical 
psychopharmacology trials. Specific, predetermined modules will be completed to assess for 
DSM-V mood disorders, disruptive disorders, SUDs and anxiety disorders (will be administered 
at screening). The suicidality, lifetime panic disorder and optional assessment measures to track 
changes over time including cross cutting measures and disability/functional impairment will not 
be utilized in the study. The M.I.N.I KID will be administered in subjects under the age of 18. In 
these interviews the suicidality, separation anxiety disorder, Tourette’s disorder, adjustment 
disorder and autism spectrum disorder modules will also not be utilized in the study. 
• 
DMS-V Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime (KSADS-
PL) module for DMDD[58]: The KSADS-PL is a semi-structured assessment of current and lifetime 
psychopathology in children under 18. The DMDD module has been selected to supplement 
clinician assessment of children under 18 who have not been diagnosed with bipolar disorder. 
The assessment is composed of 2 items, rated using a 0 – 3 point scale, and will take 
approximately 10 minutes to administer.  
• 
Weiss Adherence Interview[59]: will be completed at the screening visit to assess patterns of 
medication adherence and past reason for nonadherence prior to subject enrollment (will be 
collected at screening). 
• 
Adverse Experiences and Concomitant Medications: (will be collected at all study visits). 
• 
Young Mania Rating Scale (YMRS)[60]: The YMRS is composed of 11 items, and each question is 
rated with a likert rating scale. It is designed to capture symptoms over the prior 48 hours, with 
total scores ranging from 0 to 60: (will be completed at screening, baseline, and every 2 weeks 
thereafter). 
• 
Abnormal Involuntary Movement Scale (AIMS)[61]: The AIMS is used to record the occurrence 
of tardive dyskinesia (TD) in patients receiving neuroleptic medications. It is a 12-item anchored 
scale that requires raters to assess for movement in the face, lips, jaw, tongue, upper 
extremities, lower extremities, and trunk (it will be administered at screening, midpoint and 
final study visit). 
• 
Clinical Global Impressions (CGI)[62] scale for SUD and SMD. The CGI is a measure of illness 
severity, improvement, and efficacy of treatment (will be collected at all study visits). 
• 
Columbia Suicide Severity Rating Scale (C-SSRS)[63]: The C-SSRS is a suicidal ideation rating scale 
used to evaluate and monitor suicidality. It rates an individual’s degree of suicidality on a 
continuum ranging from passive suicidal ideation to active suicidal ideation with specific intent 
and plan (will be administered at all study visits).  
• 
DSM-V Global Assessment of Functioning (GAF) scale: The GAF will assess global functioning 
using a scale from 1 (worst) to 100 (best); (this will take place at the baseline, midpoint, and the 
final study visits).  
 


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• 
Reproductive Potential Form is used to assess whether or not the patient is able to reproduce. If 
the patient is female and of childbearing years, a urine pregnancy test is applicable (pregnancy 
screening will occur at the screening, midpoint, and final study visits if applicable). 
 
Subject/Parent rated scales: 
• 
Socioeconomic Status/Background: A brief demographic interview will be conducted after 
subjects have signed consent, as part of the screening procedures. This interview will be used to 
estimate socioeconomic status, as well as collect information about any educational 
accommodations, and past head injuries and trauma. For youths aged 15-17, this interview will 
be conducted with the parent. 
 
• 
Youth Self-Report (YSR)[53] and Adult Self-Report (ASR)[54]: Several self-report, parent-report, 
and informant-report scales have been developed by the Achenbach System of Empirically 
Based Assessment (ASEBA)[64]. Due to the age range of our study population (ages 15-24), we 
will administer different versions depending on the subject’s age. For 15-17 year olds, we will 
administer the YSR to the subject, and parents may fill out the Child Behavior Checklist 
(CBCL)[65] if they are present and willing, although it will not be required. Similarly, for 18-24 
year olds, we will administer the ASR to the subject, and an informant may fill out the Adult 
Behavior Checklist (ABCL)[54] if they are present and willing, although it will not be required. All 
versions of the above scales contain questions to address problematic areas in an individual’s 
functioning scored on a Likert scale (0=Not True, 1=Sometimes True, 2 = Often True). We will be 
primarily concerned with cumulative scores on the Anxiety/Depression, Attention, and 
Aggression (AAA) subscales (completed at the screening and final study visits). For this reason, 
we will only ask subjects/parents/informants to complete pages 3 and 4 of the aforementioned 
scales. If parents/informants are unable to complete the CBCL/ABCL at screening, they may 
complete it at the subject’s baseline visit. 
 
• 
Behavior Rating Inventory of Executive Function (BRIEF)[52]: Several self-report, parent-report, 
and informant-report versions of the BRIEF exist. Due to the age range of our study population 
(ages 15-24), we will administer different versions of the 10-item emotional control subscale 
depending on the subject’s age. For 15-17 year olds, we will administer the BRIEF-Self Report to 
the subject, and parents may fill out the BRIEF-Parent if they are present and willing, although it 
will not be required. Similarly, for 18-24 year olds, we will administer the self-report BRIEF-Adult 
to the subject, and an informant may fill out the BRIEF-Informant if they are present and willing, 
although it will not be required. The BRIEF emotional control subscale will be completed at 
screening and final study visit. If parents/informants are unable to complete the BRIEF-
Parent/BRIEF-Informant at screening, they may complete it at the subject’s baseline visit. 
 
• 
Beck Depression Inventory-II (BDI-II)[66]: The BDI-II assesses depressive symptomatology over 
the 2 weeks prior to administration. It is a 21-item scale with each question rated with a likert 
rating scale from 0 to 3, and the total score representing a summation of all responses ranging 
from 0 to 63 (will be administered at baseline and every 2 weeks thereafter). The scale will be 
administered by the research coordinator who will review question 9 (regarding suicidality) prior 


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to visit completion. If the subject answers question 2 or 3 on question 9 or makes any 
spontaneous remarks expressing suicidality the research coordinator will immediately inform 
the licensed study clinician. 
 
• 
Patient Health Questionnaire-9 (PHQ-9)[67]: A 9-item instrument with each item rated with a 
likert scale from 0 (not at all) to 3 (nearly every day) used to assess symptoms of depression 
upon which the diagnosis of DSM-IV depressive disorders is based. The total score represents a 
summation of all responses ranging from 0 to 27 (will be administered at baseline and every 2 
weeks thereafter). The scale will be administered by the research coordinator who will review 
question 9 (regarding suicidality) prior to visit completion. If the subject answers question 2 or 3 
on question 9 or makes any spontaneous remarks expressing suicidality the research 
coordinator will immediately inform the licensed study clinician. 
 
• 
Weiss Craving Scale[68]: A 3-item scale with each question rated with a likert scale from 0 (no 
desire/likelihood of use) to 9 (strong desire/likelihood of use), and the total score representing 
the summation of all responses ranging from 0 to 27. Subjects will be asked to rate cravings for 
their drug of choice (will be administered at baseline and every 2 weeks thereafter).   
 
• 
Fagerström Tolerance Questionnaire for Adolescents: A 7-item scale used to determine 
dependence on nicotine. Calculating the total points determines whether a patient is dependent 
on nicotine. Two additional questions about electronic cigarette use (“vaping”) and frequency of 
use will also be added that will not be factored into the total score. This scale will be completed 
at baseline, week 4, and final study visit.  
 
• 
Timeline Followback of Substance Use (TLFB)[69]: Measure used to quantify self-reported 
alcohol and drug use. It will be administered at initial screening visit to assess use during the 
month prior to evaluation, and will also be administered weekly over the course of the study to 
quantify use in the week between subsequent visits. Although all substance use will be queried, 
the primary focus will be response to quetiapine assessed by evaluating changes in subjects’ use 
of drug of choice.  
 
• 
Risk Behavior Survey[70]: Will be used to assess the effect of quetiapine treatment on changes 
in high risk behaviors associated with HIV and HCV (will be administered at baseline, midpoint 
and final study visit). 
 
• 
Supplemental Substance Use Questionnaire: Will be used at screening to assess reasons for 
alcohol/substance use, reasons for coming to treatment, family opinions on subjects' 
alcohol/substance use, and friends' drinking/drug use behaviors. 
 
Assessments collected at virtual visits may be administered by study staff or sent to participants via 
REDCap survey. REDCap surveys will be sent via secure email. If emails are sent to external email 
addresses, the subject line will contain the word “secure.” This creates a secure messaging system 
where the participant will create a login/password to access the email. Study staff will be with 
participants to troubleshoot the process if needed.  


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9.4 
Medication Management  
 
Quetiapine will be titrated to the maximum achieved dose as tolerated during the first three weeks of 
the trial.  Dose titration phase: Study medication will be initiated at 50 mg twice daily and will be 
gradually up-titrated by 100 mg per day (increasing by 50 mg twice daily) to a maximum dose of 150 mg 
twice daily. Titration of the study medication is flexible, guided by tolerability with the option for slower, 
lower, or hold titration.  If a participant prefers once daily dosing instead of twice daily dosing this will 
be allowed.   
 
As noted earlier, safety and tolerability of quetiapine monotherapy will be monitored by a battery of 
blood tests (30 cc of blood drawn over the duration of the study for fasting glucose and fasting lipids, 
AST, ALT, Hepatitis C and HIV testing), urine tests, height and weight measurements (to calculate Body 
Mass Index (BMI)), and the AIMS at screening and endpoint (completion/drop visit).  Weight, the AIMS, 
and urine HCG test will also be completed at midpoint. As previously described, weight may also be 
monitored at every visit if the participant’s BMI at screening is between 30 and 35. If the participant has 
a BMI under 30 at screening, but between 30 and 35 at midpoint, we will monitor their weight for the 
remainder of their visits. We will ask participants to self-report their weight, and provide a scale if they 
do not own one at home. If their weight increases such that their BMI increases by ≥1 from their 
midpoint BMI, the participant will be withdrawn from the study. Adverse events, C-SSRS, and the CGI-S 
and CGI-I for SUD and SMD will be monitored at every study visit. Vital signs will be monitored at 
screening, midpoint and endpoint visits. During the final study visit an additional 4 ccs of blood will be 
drawn to test the quetiapine level. The quetiapine level will only be tested for subjects who were 
randomized to Quetiapine. Hence, blood samples will be frozen and stored until the study is complete 
and unblinded. 
 
9.5 
Participant Cost and Compensation  
 
All study visits are at no cost to the subjects. Participating individuals will receive between $10 and $50 
deposited on a ClinCard for each study visit they complete. The remuneration schedule is as follows: 
Screening (week 98): $25; Screening (week 99): $25; Week 0: $15; Week 1: $10; Week 2: $15; Week 3: 
$10; Week 4: $15; Week 5: $10; Week 6: $15; Week 7: $10; Week 8: $50. In addition, participants will 
receive an additional $3.50 at each visit that they bring back their medication in the medication bottle. 
Participants will also receive payment for transportation to Boston Medical Center if they use public 
transit or park in the hospital garage during study visits. A participant who uses public transportation to 
get to and from a study visit will receive an additional $5 deposited on their ClinCard for that visit. A 
participant who parks in the hospital garage during a study visit will receive a parking coupon. 
 
Please see the Appendix for the Schedule of Events. 
 
9.6 
Health and Safety Procedures for In-Person Visits 


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In addition to reducing the number of in-person visits, health and safety measures will be taken to 
reduce the risk of spread of COVID-19. Two research staff (PI and research coordinator) will be present 
for all in person visits. The visits will take place in the Psychiatry Research Center at Boston Medical 
Center, which will operate at reduced capacity, including study participants and staff. Research teams 
will coordinate times for their study visits to ensure that the capacity is not exceeded.  
 
All research study areas will be sanitized by research staff at the beginning of the day before the first 
research participant arrives and sanitized again after each participant. Sanitizing methods will include 
the use of germicidal cleaning wipes and/or spray. In addition to sanitizing the study areas, research 
staff and participants must wear a mask at all times. The research team will provide sufficient masks for 
each participant. Research staff will also take the participants temperature with an infrared 
thermometer before entering the research area.  
 
Physical distancing will not be possible during certain study procedures including an EKG, blood draw, 
vital signs (weight, blood pressure, and heart rate), as well as brief assessment of upper extremity 
muscle tension for the assessment of abnormal involuntary movement exam. However, all other 
procedures that need to be completed during these visits can be done virtually through zoom with the 
participant on a computer in one office and research staff in another office.  
 
Finally, screening questions for COVID-19 exposure/illness will be asked will be asked throughout the 
study, starting at Week 98. Study staff will also contact participants by phone the day prior to any in-
person visit to ask these screening questions. The screening questions will always be asked at the 
beginning of each in person (weeks 99, 4 and 8). Responses to these screening questions will be 
recorded only at Week 98, 99, 4, and 8. (See attached “COVID-19 Screening Questions” CRF for more 
details.) 
 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) 
 
10.1 Definitions 
 
The following definitions will be used in the assessment of safety: 
 
Adverse Event (AE) is any untoward or unfavorable medical occurrence in a human subject, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research. 
 
Serious Adverse Event (SAE) is any adverse event that  
(1) results in death; 
(2) is life-threatening; 


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(3) results in inpatient hospitalization or prolongation of existing hospitalization; 
(4) results in a persistent or significant disability/incapacity; 
(5) results in a congenital anomaly/birth defect; or 
(6) based upon appropriate medical judgment, may jeopardize the subject's health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition 
(examples of such events include allergic bronchospasm requiring intensive treatment in the 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse).  
 
Life-threatening means that the event places the subject at immediate risk of death from the event as it 
occurred.  
 
Unanticipated Problem is defined as an event, experience or outcome that meets all three of the 
following criteria:  
• 
is unexpected; AND 
• 
is related or possibly related to participation in the research; AND 
• 
suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
 
Possibly related means there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the procedures involved in the research 
 
Unexpected means the nature, severity, or frequency of the event is not consistent with either: 
• 
the known or foreseeable risk of adverse events associated with the procedures involved in the 
research that are described in (a) the protocol–related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as product labeling and 
package inserts; or 
• 
the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for the 
adverse event. 
 
10.2 Safety Review 
 
Both the risks listed in Section 4.1 and unknown risks will be monitored as follows:  
 
Safety monitoring 
The Principal Investigator will be responsible for ensuring that adverse events are reported to the local 
Institutional Review Board in compliance with requirements. Any changes to the protocol will be made 
in accordance with local IRB policies. The Principal Investigator will supervise all study activities, 
including those of the research coordinators and co-investigators, and will be available 24 hours by 
page. The physician investigators will review all laboratory results and adverse events. 
 


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General safeguards will be in place for all subjects enrolled in the study.  All subjects will have access to 
24 hours a day, 7 days a week coverage provided by the PI or designated substitute by pager for 
emergencies.  The PI will be responsible for monitoring the safety of the study and complying with the 
reporting requirements. Continuous, close monitoring of participant safety will include prompt and 
frequent reporting of safety data (i.e., adverse/serious adverse events) to the Boston Medical Center 
Institutional Review Board and/or appropriate study staff with oversight responsibility. Serious adverse 
events and unanticipated problems will be reviewed by the PI within 24 hours of the study team 
knowing about the AE/UP.  Unanticipated Problems (UPs) will be reported to the Data Safety and 
Monitoring Board (DSMB) chair within 24 hours of the PI learning of the event and to the IRB within 7 
days. Non-serious adverse events will be reviewed by the PI within 7 days of a study visit. A summary of 
serious adverse events and AEs will be reviewed by the PI every 6 months during progress reports as 
well as during the written report required by the IRB as part of the annual IRB renewal process.   
 
Data Safety and Monitoring Board (DSMB) 
We have established a DSMB board which includes the following members: 
-Thomas J. Spencer M.D.; Child Psychiatrist, Researcher; Massachusetts General Hospital 
-Gagan Joshi M.D.; Child Psychiatrist, Researcher; Massachusetts General Hospital 
-Martha Kane Ph.D.; Child and Addiction Psychologist, Addictionologist, member of the MGH 
QI/QA committee; Massachusetts General Hospital 
-MaryKate Martelon M.P.H.; Statistician; Massachusetts Department of Public Health, and 
Massachusetts General Hospital 
  
The DSMB will meet once per year during the active study and most recently met on 09/10/2019. The 
DSMB will be provided with unblinded data from the study so as to examine whether the study should 
be stopped because the drug interventions are either clearly beneficial or harmful to participants.  In 
addition to the IRB, the K12 PI, and the NIH project officer, the DSMB chair will be informed of any 
unanticipated problems that occur during the trial.  The primary concern of the investigators of this 
study is the safety of the subjects. 
 
Adverse Event Reporting: Consistent with good clinical practice, safety will be monitored by study staff 
at each study visit. A study clinician will supervise all study activities including ratings, reported adverse 
events, lab results and vital signs, and the Principal Investigator, Dr. Amy Yule, will be available for 
further review. Should any study activities require urgent attention, the PI and study clinicians will be 
available 24 hours a day by page.  All procedures have been designed to minimize subject discomfort, 
and no subject will be asked to engage in research procedures not outlined in the consent form. 
Subjects will be monitored for adverse events at each visit.  All adverse events (including unexpected 
and serious AEs) will be recorded and reported in accordance with Boston Medical Center Institutional 
Review Board guidelines.  We will follow and adhere to all guidelines as defined and outlined on the 
Boston Medical Center Institutional Review Board website: 
http://www.bumc.bu.edu/irb/files/2019/06/Reporting_Requirements.pdf 


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Data Monitoring 
The PI will be responsible for ongoing quality control.  This includes all aspects of the study related to 
safety, but also data integrity and protocol compliance.  Quality control will include self-audits of data 
collection and storage as well as compliance with the informed consent procedure.  The review of data 
and procedures may result in early termination of the study, amendment of the protocol or data 
collection plans, or amendment of study forms.  The IRB will be notified and all amendments approved 
prior to study implementation.  In addition, the participants will be notified of any significant new 
findings that develop during the course of research (e.g., other potential risks) that may affect their wish 
to continue participation in the study.   
 
The study clinicians, research coordinator, and Principal Investigator will monitor study progress 
including enrollment, adherence to inclusion/exclusion criteria and study protocol, as well as any 
adverse events. The Principal Investigator will be responsible for ensuring that adverse events are 
reported to the local Institutional Review Board in compliance with local and federal requirements. Any 
changes to the protocol will be made in accordance with local IRB policies. The Principal Investigator will 
supervise all study activities, including those of the research coordinator and co-investigators, and will 
be available 24 hours a day by page. 
For quality control purposes, audio of clinician-administered measures completed during the visits may 
be recorded, with subjects’ permission. These recordings will be used to monitor quality control and inter-
rater reliability in this study by the PI. Each audio file will be coded with subject initials and number to 
maintain confidentiality. These recordings will be de-identified and stored in a password-protected file. 
 
10.3 Reporting Plans 
 
The Principal Investigator at BMC/BU Medical Campus will report Unanticipated Problems, safety 
monitors’ reports, and Adverse Events to the BMC/BU Medical Center IRB in accordance with IRB 
policies: 
• 
Unanticipated Problems occurring at BMC/BU Medical Campus will be reported to the IRB within 7 
days of the investigator learning of the event. 
• 
Reports from safety monitors with recommended changes will be reported to the IRB within 7 
days of the investigator receiving the report.  
• 
Adverse Events (including Serious Adverse Events) will be reported in summary at the time of 
continuing review, along with a statement that the pattern of adverse events, in total, does not 
suggest that the research places subjects or others at a greater risk of harm than was previously 
known. 
• 
Reports from safety monitors with no recommended changes will be reported to the IRB at the 
time of continuing review.  
 
10.4 Stopping Rules 
 


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A subject will be withdrawn from the study if they:  
• 
Develop an adverse event despite dose adjustments that is determined to be intolerable based 
on clinician judgment. An intolerable event is any side effect or worsening of SMD or SUD 
symptoms that are determined by the investigator to be excessive in severity or in duration 
• 
Have worsening SMD or SUD symptoms (as determined by clinician judgment indicated through 
scores ≥5 on the CGI Global Improvement scale on two consecutive weeks) that warrants an 
early termination 
• 
Have new onset of severe SUD (e.g. intravenous, intentional/unintentional overdose) 
• 
Have unstable mental health (new onset SI/HI with intent and/or plan) 
• 
Become incarcerated 
• 
Demonstrate severe noncompliance with medication dosing or study procedures 
• 
Become pregnant during the study 
• 
Modify their psychiatric and/or non-psychiatric medications such that they would be increasing 
the dose of an existing medication that may prolong QTc interval 
• 
Add a new medication that may prolong QTc interval 
• 
Gain weight such that their BMI increases by ≥1 point if 1) their starting BMI is between 30-35 or 
2) their starting BMI is < 30 but BMI at midpoint is between 30-35 
 
In case of an emergency, the investigator will be able to contact the Boston Medical Center research 
pharmacy for emergency unblinding 24 hours a day. The blinded information is to be broken only when 
knowledge of such treatment may have an impact on future treatment decisions or aid in the 
emergency treatment of the subject. This decision can only be made by Dr. Yule or designee. Any subject 
for whom the blind is broken will be discontinued from the study. If an SAE occurs, the principal 
investigator, Dr. Yule or designee, should be informed of the event within 24 hours so appropriate 
actions may be taken. 
 
11 Data Handling and Record Keeping 
 
11.1 Confidentiality 
 
All research related records initiated as a result of a subject’s participation in this study that reveal the 
subject’s identity will remain confidential except as may be required by law. Data obtained from this 
study will not identify the subjects individually. Subjects will be assigned code names and ID numbers. 
Biospecimens will be stored securely in a locked room only accessible to study staff. Data obtained from 
our studies may be published, but published data will not identify individual participants. Original 
research-related records may be reviewed by the Boston Medical Center Institutional Review Board and 
regulatory authorities for the purpose of verifying clinical trial procedures and/or data. Information will 
be held and processed on a computer, but access to these computerized records will be password 
protected and restricted to study staff. At the onset of an initial clinical encounter, subjects will be 
informed of Federal privacy guidelines that pertain to them under the Healthcare Insurance Portability 
and Accountability Act. Results of urine drug or pregnancy testing will not become part of the subject’s 
medical record.  Subjects will only be contacted regarding future studies if they indicate that they are 


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interested in being contacted by initialing in the specific section of the consent form. Information may 
be held and processed on a computer.  Access to these computerized records will be password 
protected and restricted to study staff.  
 
Data Use Agreements and Material Transfer agreements will be filed with the appropriate offices 
regarding receiving identified data and biospecimens from Massachusetts General Hospital.  
 
11.2 Source Documents 
 
Structured diagnostic and psychosocial interviews will be collected from youth and parents when 
available.  Biological samples of blood will be collected to measure hepatic function, test for hepatitis C 
and HIV, and monitor glucose and lipid levels during treatment.  Urine samples will be collected to 
measure drug toxicology and detect pregnancy.  For a full list of data records, please see the Schedule of 
Events in the Appendix.  
 
Data generated by the methods described in the protocol will be recorded in the subjects' medical 
records and/or special research files, one per subjects, which will be identified by an ID number that will 
not identify the subject in any way. Data may be transcribed legibly on hard copy CRFs supplied for each 
subject or directly inputted into REDCap—an electronic data management system. Any hard copy 
material including the names of subjects or other identifying information (consent/assent forms, paper 
records) will be kept in locked filing cabinets in a locked room or scanned and uploaded to a password-
encrypted folder on the BMC secure network. Documentation linking subjects’ names and numbers will 
be kept in a password-protected electronic file on a BMC networked drive only accessible by the project 
coordinator and primary investigator (PI) on a password-protected computer located behind a secure 
and maintained firewall.  Blood sample collection, analysis and disposal will be managed by the BMC lab.  
Urine sample collection, analysis, and disposal will be managed by study staff and samples will not 
contain identifying information.  Data will be transmitted only in pooled form, and subjects will be 
identified by ID numbers.  Any publications of study findings will be reported so that no person can be 
identified individually.  These issues will be clearly stated in consent forms and discussed with 
participants during the informed consent process, prior to any study related procedures. 
 
 
11.3 Case Report Forms 
 
The study case report forms (CRF) will be the primary data collection instruments for the study. All data 
requested on the CRFs will be recorded. All missing data will be explained. If a space on the CRF is left 
blank because the procedure was not done or the question was not asked, “N/D” will be written. If the 
item is not applicable to the individual case, “N/A” will be written. All entries will be printed legibly in 
black ink. If any entry error has been made, to correct such an error, a single straight line will be drawn 
through the incorrect entry and the correct data will be entered above it. All such changes will be 


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initialed and dated.  There will be no erasures or white-out on CRFs.  For clarification of illegible or 
uncertain entries, the clarification will be printed above the item, then initialed and dated.  
 
See the Appendix for the following CRFs:  
Clinician rated assessments (stored in patient files/ REDCap): 
• 
Mini-International Neuropsychiatric Interview (M.I.N.I. 7.0) 
• 
DMS-V Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime (KSADS-
PL) module for DMDD  
• 
Weiss Adherence Interview 
• 
Adverse Experiences and Concomitant Medications 
• 
Young Mania Rating Scale (YMRS) 
• 
Abnormal Involuntary Movement Scale (AIMS) 
• 
Clinical Global Impressions (CGI)[62] scale for SUD and SMD 
• 
Columbia Suicide Severity Rating Scale (C-SSRS)  
• 
DSM-V Global Assessment of Functioning (GAF) scale 
• 
Reproductive Potential Form  
 
Subject/Parent rated scales (stored in patient files/REDCap): 
• 
Socioeconomic Status/Background 
• 
Youth Self-Report (YSR) and Adult Self-Report (ASR)  
• 
Behavior Rating Inventory of Executive Function (BRIEF)  
• 
Beck Depression Inventory-II (BDI-II)  
• 
Patient Health Questionnaire-9 (PHQ-9)  
• 
Weiss Craving Scale 
• 
Fagerström Tolerance Questionnaire for Adolescents 
• 
Timeline Followback of Substance Use (TLFB)  
• 
Risk Behavior Survey 
• 
Supplemental Substance Use Questionnaire 
 
Other CRFs (stored in patient files/REDCap): 
• 
Laboratory tests: Drug screen (urine and breathalyzer), Urine HCG  


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• 
Safety/reliability procedures: EKG, Heart Rate, Blood Pressure, Height, Weight 
• 
Chart Note  
• 
Adverse Events Log  
• 
Concomitant Medication Log  
• 
COVID-19 Screening Questions 
 
Other CRFs stored in patient Medical Record and patient files/REDCap  
• 
Laboratory tests: AST/ALT, Hepatitis C, HIV, Fasting Lipids, Fasting Glucose, Urine THC, 
Creatinine  
 
11.4 Study Records Retention 
 
All study records will be retained for at least seven years after the completion of the study, per Boston 
Medical Center Research Center requirements. These records include informed consent documents for 
all subjects.  
 
12 Statistical Plan 
 
12.1 Study Hypotheses 
 
Primary Aim 1: Evaluate the effect of quetiapine on SUD. Hypothesis 1A: Treatment with quetiapine 
will decrease self-reported substance use for primary substance of use (e.g. number of days of use past 
month, % abstinence past month).  Hypothesis 1B: Treatment with quetiapine will increase number of 
toxicology specimens negative for primary substance of use Hypothesis 1C: Treatment with quetiapine 
will decrease drug craving for primary substance of use. 
 
Primary Aim 2: Evaluate the effect of quetiapine on SMD. Hypothesis 2A: Treatment with quetiapine 
will result in a decrease in symptoms of mania demonstrated by reduction in Young Mania Rating Scale.  
Hypothesis 2B: Treatment with quetiapine will result in a decrease in symptoms of depression 
demonstrated by reduction in the Beck Depression Inventory II. 
 
Primary Aim 3: Evaluate the effect of quetiapine on engagement in outpatient treatment. Hypothesis 
3A: Treatment with quetiapine will lead to greater engagement in outpatient treatment as 
demonstrated by greater number of appointments attended in the active treatment group.   
 
12.2 Sample Size Determination 
 
Since there have not been any published studies to date on quetiapine for the treatment of SUD co- 


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occurring with SMD in young people, we are estimating the effect size of quetiapine for the treatment of 
youth with co-occurring SUD and SMD based on Delbello and colleagues’ preliminary report on a sample 
of 75 patients with frequent cannabis use and BD who were treated with quetiapine and randomized to 
topiramate or placebo.[49] The quetiapine plus placebo group had improvements in both substance use 
and mood.  Cannabis use decreased from an average of 14 joints per week to 4 joints per week 
representing a 72% decrease.  In this study, the YMRS decreased by 16 (from approximately 30 to 14) 
indicating a 53% improvement in mood.  These expected improvements in SUD associated with mood 
are reminiscent of those of Geller et al using lithium for youth with SUD and SMD (effect size of ca 1.0). 
[20]  
 
Power Analysis: To achieve 90% power using a two-tailed test with 5% significance level to detect a 
difference in measures of substance use we will need 22 subjects per group.  To detect similarly 
powered differences in measures of mood we will need 10 subjects per group.  Clinical trials for 
quetiapine in adolescents with BD have a 75 to 80% completion rate.[71, 72] We therefore estimate we 
may have 20% attrition and aim to recruit 28 subjects per group for a total of 56 subjects. 
 
12.3 Statistical Methods 
 
All analyses will be modified intention to treat, which will be defined by completing at least one week of 
study medication.  We will analyze group differences across demographics using Pearson’s Chi Squared 
tests for binary outcomes and student t tests or linear regression models for continuous outcomes.  To 
assess our main outcomes, we will use generalized estimating equations that estimate the main effects 
of drug and time as well as any interactions (time X drug).  We will evaluate our primary outcome 
measures hierarchically in the following order for SUD: Timeline Followback of substance use, urine drug 
screen, and Weiss craving scale.  For binary outcomes, logistic regression models will be fit with Poisson 
family and log link, and for normally distributed data, linear regression models will be fit with the 
Gaussian distribution and the identity link.  Exploratory aims will be examined using models similar to 
the main outcomes.  All statistical tests will be performed using STATA 13.0.  The statistical significance 
will be set at 5% and all tests will be two-tailed. 
 
To evaluate hypotheses 1A, 1B and 1C, we will monitor SUD response to quetiapine for primary 
substance of use by way of the Timeline Followback of Substance Use (TLFB). Specifically, the TLFB will 
be used to compare self-report of substance for the month prior to study entry versus the last month of 
the study.  We will use weekly toxicology screens negative for primary substance of abuse as an 
objective measurement of decrease in substance use severity. The Weiss Craving Scale will be used to 
assess the effect of quetiapine treatment on cravings for primary substance of use. Values for all three 
measures (TLFB, toxicology screens, and Weiss Craving Scale) will be compared between baseline and 
endpoint.   
 
To evaluate hypotheses 2A and 2B, we will assess SMD response to quetiapine by way of comparing 


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values from baseline to endpoint on the YMRS and BDI-II.   
 
To evaluate hypothesis 3A, the impact of treatment with quetiapine on outpatient treatment 
engagement will be monitored by collateral from the outpatient program regarding the percentage of 
scheduled appointments attended after randomization. 
 
To evaluate exploratory aims, we plan to administer scales that measure emotional regulation, including 
the Emotional Control Subscale for the BRIEF (BRIEF-Self-Report, BRIEF-Adult, BRIEF-Parent, BRIEF-
Informant) and the AAA subscales of the Achenbach Assessments (Youth Self-Report, Adult Self-Report, 
Child Behavior Checklist, Adult Behavior Checklist) to determine if they predict treatment response 
and/or what specific components improve with treatment in youth with co-occurring SUD and SMD. The 
impact of treatment with quetiapine on medication adherence will be assessed with weekly pill counts, 
a medication diary, and the medication adherence rating scale.  Non-primary substances of use will be 
evaluated by TLFB and toxicology screens.  Changes in high risk behaviors associated with HIV and HCV 
due to treatment with quetiapine will be assessed with the Risk Behavior Survey.  The effect of 
treatment with quetiapine on functioning will be assessed by the GAF.  Psychiatric co-morbidities will be 
assessed at baseline with specific, predetermined modules from the M.I.N.I. 7.0.  Youth’s reasons for 
substance use and peer substance use will be assessed with a supplemental substance use 
questionnaire at screening. Motivation to change, confidence in their ability to change, level of 
engagement in therapy, and exposure to substance use in the subject’s living environment will be 
assessed with additional questions added to the Weiss Craving Scale but not factored into the total 
score. The validity of the PHQ-9 will be evaluated by administering the instrument in conjunction with 
the BDI-II at Week 0 and every 2 weeks thereafter 
 
13 Ethics/Protection of Human Subjects 
 
This study is to be conducted according to applicable US federal regulations and institutional policies 
(which are based in federal regulations, guidance, and ICH Good Clinical Practice guidelines). 
 
This protocol and any amendments will be submitted to the Boston Medical Center and Boston 
University Medical Campus IRB, for formal approval of the study conduct. The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator  
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. The 
consent form will be submitted with the protocol for review and approval by the IRB. The consent of a 
subject, using the IRB-approved consent form, must be obtained before that subject is submitted to any 
study procedure. Consent will be documented as required by the IRB.   
 
 
 
 


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14 Literature References 
 
1. 
Wilens, T.E., et al., Clinical characteristics of psychiatrically referred adolescent outpatients with 
substance use disorder. J Am Acad Child Adolesc Psychiatry, 1997. 36(7): p. 941-7. 
2. 
Kandel, D.B., et al., Psychiatric disorders associated with substance use among children and 
adolescents: Findings from the methods for the epidemiology of child and adolescent mental 
disorders (MECA) study. J Abnorm Child Psychol, 1997. 25: p. 122-132. 
3. 
Hovens, J.G., D.P. Cantwell, and R. Kiriakos, Psychiatric comorbidity in hospitalized adolescent 
substance abusers. Journal of the American Academy of Child and Adolescent Psychiatry, 1994. 
33(4): p. 476-483. 
4. 
Bukstein, O.G., et al., Practice parameter for the assessment and treatment of children and 
adolescents with substance use disorders. J Am Acad Child Adolesc Psychiatry, 2005. 44(6): p. 
609-21. 
5. 
Wilens, T.E., et al., Difficulties in emotional regulation and substance use disorders: A controlled 
family study of bipolar adolescents. Drug Alcohol Depend, 2013. 
6. 
Stowell, R. and T.W. Estroff, Psychiatric disorders in substance-abusing adolescent inpatients: A 
pilot study. Journal of the American Academy of Child and Adolescent Psychiatry, 1992. 31: p. 
1036-1040. 
7. 
Bukstein, O.G., L.J. Glancy, and Y. Kaminer, Patterns of affective comorbidity in a clinical 
population of dually diagnosed adolescent substance abusers. Journal of the American Academy 
of Child and Adolescent Psychiatry, 1992. 31(6): p. 1041-1045. 
8. 
Subramaniam, G.A. and M.A. Stitzer, Clinical characteristics of treatment-seeking prescription 
opioid vs. heroin-using adolescents with opioid use disorder. Drug Alcohol Depend, 2009. 101(1-
2): p. 13-9. 
9. 
Goldstein, B.I. and O.G. Bukstein, Comorbid substance use disorders among youth with bipolar 
disorder: opportunities for early identification and prevention. J Clin Psychiatry, 2010. 71(3): p. 
348-58. 
10. 
Findling, R.L., et al., Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I 
disorder. Bipolar Disord, 2001. 3(4): p. 202-10. 
11. 
Delbello, M.P., et al., Twelve-month outcome of adolescents with bipolar disorder following first 
hospitalization for a manic or mixed episode. Am J Psychiatry, 2007. 164(4): p. 582-90. 
12. 
Geller, B., et al., Child bipolar I disorder: prospective continuity with adult bipolar I disorder; 
characteristics of second and third episodes; predictors of 8-year outcome. Arch Gen Psychiatry, 
2008. 65(10): p. 1125-33. 
13. 
West, S.A., et al., Phenomenology and comorbidity of adolescents hospitalized for the treatment 
of acute mania. Biological Psychiatry, 1996. 39: p. 458-460. 
14. 
Strober, M., et al., Recovery and relapse in adolescents with bipolar affective illness: A five-year 
naturalistic, prospective follow-up. Journal of the American Academy of Child and Adolescent 
Psychiatry, 1995. 34(6): p. 724-731. 
15. 
Wilens, T.E., et al., Further Evidence for Smoking and Substance Use Disorders in Youth With 
Bipolar Disorder and Comorbid Conduct Disorder. J Clin Psychiatry, 2016. 77(10): p. 1420-1427. 
16. 
Goldstein, B.I., et al., Substance use disorders among adolescents with bipolar spectrum 
disorders. Bipolar Disord, 2008. 10(4): p. 469-78. 


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and Severe Mood Dysregulation (SMD) 
 
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17. 
Goldstein, B.I., et al., Predictors of first-onset substance use disorders during the prospective 
course of bipolar spectrum disorders in adolescents. J Am Acad Child Adolesc Psychiatry, 2013. 
52(10): p. 1026-37. 
18. 
Lorberg, B., et al., Do adolescents with Bipolar disorder use addictive substances for Self-
medication? . Am J Addict, 2010. 
19. 
Cheetham, A., et al., The role of affective dysregulation in drug addiction. Clin Psychol 
Rev, 2010. 30(6): p. 621-34. 
20. 
Geller, B., et al., Lithium for prepubertal depressed children with family history predictors of 
future bipolarity:  A double-blind, Placebo-controlled study. Journal of Affective Disorders, 1998. 
51(2): p. 165-75. 
21. 
Okusa, M.D. and L.J. Crystal, Clinical manifestations and management of acute lithium 
intoxication. Am J Med, 1994. 97(4): p. 383-9. 
22. 
Stern, T.A., et al., Massachusetts General Hospital: Comprehenisve Clinical Psychiatry. Second 
Edition ed. 2016, New York, NY: Elsevier. 
23. 
Goldstein, B.I., R. Sassi, and R.S. Diler, Pharmacologic treatment of bipolar disorder in children 
and adolescents. Child Adolesc Psychiatr Clin N Am, 2012. 21(4): p. 911-39. 
24. 
Liu, H.Y., et al., Pharmacologic treatments for pediatric bipolar disorder: a review and meta-
analysis. J Am Acad Child Adolesc Psychiatry, 2011. 50(8): p. 749-62 e39. 
25. 
Geller, B., et al., A randomized controlled trial of risperidone, lithium, or divalproex sodium for 
initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Arch 
Gen Psychiatry, 2012. 69(5): p. 515-28. 
26. 
Krieger, F.V., et al., An open-label trial of risperidone in children and adolescents with severe 
mood dysregulation. J Child Adolesc Psychopharmacol, 2011. 21(3): p. 237-43. 
27. 
Pfeifer, J.C., R.A. Kowatch, and M.P. DelBello, Pharmacotherapy of bipolar disorder in children 
and adolescents: recent progress. CNS Drugs, 2010. 24(7): p. 575-93. 
28. 
Correll, C.U., E.M. Sheridan, and M.P. DelBello, Antipsychotic and mood stabilizer efficacy and 
tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, 
randomized, placebo-controlled trials. Bipolar Disord, 2010. 12(2): p. 116-41. 
29. 
Cosgrove, V.E., D. Roybal, and K.D. Chang, Bipolar depression in pediatric populations : 
epidemiology and management. Paediatr Drugs, 2013. 15(2): p. 83-91. 
30. 
Alexander, G.C., et al., Increasing off-label use of antipsychotic medications in the United States, 
1995-2008. Pharmacoepidemiol Drug Saf, 2011. 20(2): p. 177-84. 
31. 
Olfson, M., M. King, and M. Schoenbaum, Treatment of Young People With Antipsychotic 
Medications in the United States. JAMA Psychiatry, 2015. 72(9): p. 867-74. 
32. 
Volkow, N.D., G.F. Koob, and A.T. McLellan, Neurobiologic Advances from the Brain Disease 
Model of Addiction. N Engl J Med, 2016. 374(4): p. 363-371. 
33. 
Hutchison, K.E., et al., Olanzapine reduces urge to drink after drinking cues and a priming dose of 
alcohol. Psychopharmacology (Berl), 2001. 155(1): p. 27-34. 
34. 
Hutchison, K.E., et al., Olanzapine reduces craving for alcohol: a DRD4 VNTR polymorphism by 
pharmacotherapy interaction. Neuropsychopharmacology, 2003. 28(10): p. 1882-8. 
35. 
Hutchison, K.E., et al., The effect of olanzapine on craving and alcohol consumption. 
Neuropsychopharmacology, 2006. 31(6): p. 1310-7. 
36. 
Anton, R.F., et al., A randomized, multicenter, double-blind, placebo-controlled study of the 
efficacy and safety of aripiprazole for the treatment of alcohol dependence. J Clin 
Psychopharmacol, 2008. 28(1): p. 5-12. 


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Page 37 of 40 
37. 
Kampman, K.M., et al., A pilot trial of olanzapine for the treatment of cocaine dependence. Drug 
Alcohol Depend, 2003. 70(3): p. 265-73. 
38. 
Loebl, T., et al., A randomized, double-blind, placebo-controlled trial of long-acting risperidone in 
cocaine-dependent men. J Clin Psychiatry, 2008. 69(3): p. 480-6. 
39. 
Smelson, D.A., et al., A double-blind placebo-controlled pilot study of risperidone for decreasing 
cue-elicited craving in recently withdrawn cocaine dependent patients. J Subst Abuse Treat, 
2004. 27(1): p. 45-9. 
40. 
Grabowski, J., et al., Risperidone for the treatment of cocaine dependence: randomized, double-
blind trial. J Clin Psychopharmacol, 2000. 20(3): p. 305-10. 
41. 
Kennedy, A., et al., Quetiapine for the treatment of cocaine dependence: an open-label trial. J 
Clin Psychopharmacol, 2008. 28(2): p. 221-4. 
42. 
Monnelly, E.P., et al., Quetiapine for treatment of alcohol dependence. J Clin Psychopharmacol, 
2004. 24(5): p. 532-5. 
43. 
Pinkofsky, H.B., et al., Reduction of opioid-withdrawal symptoms with quetiapine. J Clin 
Psychiatry, 2005. 66(10): p. 1285-8. 
44. 
Brown, E.S., M. Garza, and T.J. Carmody, A randomized, double-blind, placebo-controlled add-on 
trial of quetiapine in outpatients with bipolar disorder and alcohol use disorders. J Clin 
Psychiatry, 2008. 69(5): p. 701-5. 
45. 
Nejtek, V.A., et al., Do atypical antipsychotics effectively treat co-occurring bipolar disorder and 
stimulant dependence? A randomized, double-blind trial. J Clin Psychiatry, 2008. 69(8): p. 1257-
66. 
46. 
Brown, E.S., et al., Quetiapine in bipolar disorder and cocaine dependence. Bipolar Disord, 2002. 
4(6): p. 406-11. 
47. 
Stedman, M., et al., A double-blind, placebo-controlled study with quetiapine as adjunct therapy 
with lithium or divalproex in bipolar I patients with coexisting alcohol dependence. Alcohol Clin 
Exp Res, 2010. 34(10): p. 1822-31. 
48. 
Brown, E.S., et al., A randomized, double-blind, placebo-controlled trial of quetiapine in patients 
with bipolar disorder, mixed or depressed phase, and alcohol dependence. Alcohol Clin Exp Res, 
2014. 38(7): p. 2113-8. 
49. 
DelBello, M. Topiramate Plus Quetiapine Cut Cannabis Use in Bipolar Teens. in the American 
Academy of Child and Adolescent Psychiatry. 2011. Toronto. 
50. 
Wilens, T.E., J. McKowen, and M. Kane, Transitional-Aged Youth and Substance Use: Teenaged 
Addicts Come of Age. Contemp Pediatr, 2013. 30(11): p. 24-30. 
51. 
Abuse, N.I.o.D., Principles of Adolescent Substance Use Disorder Treatment: A Research-Based 
Guide. 2014, National Institute on Drug Abuse (NIDA). 
52. 
Gioia, G., et al., BRIEF: Behavior Rating Inventory of Executive Function. Psychological 
Assessment Resources, Inc. 2000, Odessa, FL. 
53. 
Achenbach, T.M., Manual for the Youth Self-Report and 1991 Profile. 1991, Burlington, VT: 
University of Vermont. 
54. 
Achenbach, T.M., Manual for the Young Adult Self-Report and Young Adult Behavior Checklist. 
1997, Burlington, VT: University of Vermont Department of Psychiatry. 
55. 
Wittchen, H.U., et al., What are the high risk periods for incident substance use and transitions 
to abuse and dependence? Implications for early intervention and prevention. Int J Methods 
Psychiatr Res, 2008. 17 Suppl 1: p. S16-29. 


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56. 
Nery-Fernandes, F., et al., Is there an association between suicide attempt and delay of initiation 
of mood stabilizers in bipolar I disorder? J Affect Disord, 2012. 136(3): p. 1082-7. 
57. 
Sheehan, D.V., et al., The Mini-International Neuropsychiatric Interview (M.I.N.I.): the 
development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-
10. J Clin Psychiatry, 1998. 59 Suppl 20: p. 22-33;quiz 34-57. 
58. 
Kaufman, J., et al., Schedule for affective disorders and schizophrenia for school-age children-
present and lifetime version (K-SADS-PL): Initial reliability and validity data. Journal of the 
American Academy of Child and Adoelscent Psychiatry, 1997. 36(7): p. 980-988. 
59. 
Weiss, R.D., et al., Medication compliance among patients with bipolar disorder and substance 
use disorder. J Clin Psychiatry, 1998. 59(4): p. 172-4. 
60. 
Young, R., et al., A rating scale for mania:  Reliability, validity and sensitvity. British Journal of 
Psychiatry, 1978. 133: p. 429-435. 
61. 
W., G., Abnormal Involuntary Movement Scale (AIMS), in ECDEU Assessment Manual for 
Psychopharmacology: Revised (DHEW publication number ADM 76-338). E.a.W. US Department 
of Health, Public Health Service, Alcohol, Drug Abuse and Mental Health Administration, NIMH 
Psychopharmacology Research Branch, Division of Extramural Research Programs, Editor. 1976: 
Rockville, MD. p. 534-537. 
62. 
Aman, M.G., et al., Psychometric characteristics of the aberrant behavior checklist. Am J Ment 
Defic, 1985. 89(5): p. 492-502. 
63. 
Posner, K., et al., The Columbia-Suicide Severity Rating Scale: initial validity and internal 
consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry, 
2011. 168(12): p. 1266-77. 
64. 
Achenbach, T.M., The Achenbach System of Empirically Based Assessemnt (ASEBA): 
Development, Findings, Theory, and Applications. 2009, University of Vermont Research Center 
for Children, Youth, & Families: Burlington, VT. 
65. 
Achenbach, T.M. and L.A. Rescorla, Manual for the ASEBA School-Age Forms and Profles; Child 
Behavior Checklist for Ages 6-18. 2001, University of Vermont, Research Center for Children, 
Youth and Families: Burlington, VT. 
66. 
Beck, A.T., R.A. Steer, and G.K. Brown, Manual for the Beck Depression Inventory-II. 1996, San 
Antonio, TX: Psychological Corporation. 
67. 
Kroenke, K., R.L. Spitzer, and J.B. Williams, The PHQ-9: validity of a brief depression severity 
measure. J Gen Intern Med, 2001. 16(9): p. 606-13. 
68. 
Weiss, R.D., et al., The relationship between cocaine craving, psychosocial treatment, and 
subsequent cocaine use. Am J Psychiatry, 2003. 160(7): p. 1320-5. 
69. 
Sobel, L.C. and M.B. Sobel, Timeline follow-back:  A technique for assessing self-reported alcohol 
consumption, in Measuring alcohol consumption: Psychosocial and biochemical methods. 2006, 
Humana Press: Totowa, NH. p. 41-72. 
70. 
Community Research Branch, N.I.o.D.A., Risk Behavior Assessment. 3rd ed. 1993, Rockville, MD: 
NIDA. 
71. 
Pathak, S., et al., Efficacy and safety of quetiapine in children and adolescents with mania 
associated with bipolar I disorder: a 3-week, double-blind, placebo-controlled trial. J Clin 
Psychiatry, 2013. 74(1): p. e100-9. 
72. 
Delbello, M.P., et al., A double-blind, randomized, placebo-controlled study of quetiapine as 
adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry, 2002. 41: p. 
1216-1223. 


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15 Appendix 
 
1. Schedule of Events  
2. DSMB Charter 
3. Case Report Forms (CRFs) 
a. Urine Drug and Breathalyzer 
b. Adverse Events  
c. CBCL 
d. MARS 
e. AIMS  
f. BDI-II 
g. Craving Scale  
h. ABCL 
i. 
Concomitant Medications 
j. 
Reproductive Potential 
k. Fagerstrom Tolerance Questionnaire  
l. 
Chart Notes (Week 98 & 99, Week 0, Weeks 1-8) 
m. KSADS DMDD Module  
n. Electronic Cigarette Use Questionnaire  
o. GAF  
p. Supplemental Substance Use Questionnaire  
q. BRIEF-Subscale Adult  
r. BRIEF- Subscale Parent  
s. BRIEF- Subscale Informant 
t. BRIEF-Subscale Self-Report 
u. Demographics Facepage  
v. Lifetime Weiss Adherence Interview  
w. ASR  
x. CSSR-S 
y. YSR 
z. CGI SMD 
aa. YMRS 
bb. PHQ9 
cc. Risk Behavior Survey  
dd. MINI Adult 7.0 
ee. MINI Kid 7.0 
ff. CGI SUD  
gg. Timeline Followback Forms (2020, 2021) 
hh. COVID-19 Screening Questions 
4. Data Management Plan 
5. Informed Consent  
6. Recruitment Flyer  
7. Medication Diary  
8. Deviation Exception Log  


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9. Healthy Lifestyle Behaviors  
10. Dosing Instructions 
11. Recruitment Email 
12. Telephone Script 
13. Quetiapine package insert 

ICF_002.pdf: 
 A Randomized Controlled Trial of Quetiapine for the Treatment of Youth  
With Co-Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
NCT02845453 
ICF Date  2-22-2021


Page 1 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
BOSTON MEDICAL CENTER AND THE 
BOSTON UNIVERSITY SCHOOLS OF MEDICINE, 
PUBLIC HEALTH AND DENTAL MEDICINE 
RESEARCH CONSENT FORM 
Basic Information 
Title of Project: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
IRB Number: submission H-39577 
Principal Investigator: Amy Yule, MD 
E-mail: Amy.yule@BMC.org
PI/study mailing address: 720 Harrison Ave Suite 915, Room 910 Boston, MA 02118
Study-Related Phone Numbers: Regular business hours: 617-699-5899, 24 hours: 617-414-1990
Overview
We are asking you to allow your child to be in a research study. A research study is an organized way of 
collecting information about scientific questions. This form will tell you what you and your child should 
expect if you agree to allow your child to be in the study. There are programs in place to make sure that 
investigators fulfill their obligations listed in this form. 
It is your decision whether or not to allow your child to join the study. We are doing the research to find 
out if a medication called quetiapine (also known as Seroquel) can help youth with substance use 
disorder (SUD) and severe mood dysregulation (SMD). If you agree, your child will take either quetiapine 
or placebo for 8 weeks. They will also be encouraged to engage in behavioral therapy through the 
Boston Medical Center clinical program, CATALYST, if they are not already engaged in therapy 
elsewhere. Your child will be in the study for 10 weeks if you and your child decide that your child will 
stay for the whole study. You will find more information about what will happen in this study later in this 
form. 
The main risks of being in the study are from the side effects of the study drug and your child will be 
asked to disclose sensitive, personal information. You will find more information about risks later in this 
form. 
Your child might benefit from being in the study because their SUD and/or severe mood symptoms may 
improve. You will find more information about benefits later in this form. 
Your child could get these benefits without being in the study by engaging in therapy or psychiatric care. 
You will find more information about alternatives later in this form. 
Your child’s doctor may also be an investigator in this research study. Being an investigator means your 
child’s doctor is interested in both your child and the study. Your child may want to get another opinion 
about being in the study. You and your child can do so now or at any time during the study. A doctor 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 2 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
who is not part of this study could give you and your child their opinion about being in the study. You 
and your child do not have to agree to be in this study even though it is offered by your doctor. 
Purpose 
We are doing this research study to find out if a medication called quetiapine (also known as Seroquel) 
can help youth with SUD and co-occurring SMD. SMD includes bipolar spectrum disorders, disruptive 
mood dysregulation disorder, and mood disorder not otherwise specified. We want to find out if 
quetiapine is beneficial in reducing substance use and mood symptoms in individuals with SUD and 
SMD. 
The U.S. Food and Drug Association (FDA) has approved quetiapine to treat mania in bipolar disorder in 
adolescents, as well as depression and mania in adults. However, quetiapine is not approved by the FDA 
to treat co-occurring SMD and SUDs in youth. This is what we intend to study in the current 
investigation. 
We will compare quetiapine to a placebo. The placebo will look exactly like the quetiapine capsules, but 
will contain no quetiapine. During this study, your child may get a placebo instead of quetiapine. 
Placebos are used in research studies to see if the study results are due to the study drug or due to 
other reasons. Your child will be continued on your current medication if it has been helpful to them. 
However, we ask that your child does not change their medication during the duration of the study. We 
will also encourage your child to engage in behavioral therapy through the Boston Medical Center 
clinical program, CATALYST, while they are participating in the study, if they are not already engaged in 
therapy elsewhere. 
This is a pilot study. Pilot studies are done on a small group of subjects to learn if a larger study would 
be useful. 
We are asking your child to take part in this research study because they have been diagnosed with SUD 
and SMD. About 56 people will take part in this research study. The American Academy of Child and 
Adolescent Psychiatry is paying for this study to be done through a grant from the National Institutes of 
Health-National Institute on Drug Abuse (NIH-NIDA). 
What Will Happen in This Research Study 
If your child is aged 15-17 and chooses to take part in this study, we will ask them to sign a consent form 
in addition to the consent form we ask you to sign. If your child turns 18 during the study, we will ask 
them to sign another consent form before continuing with the study. We will give you and your child a 
copy for your records. 
Because of COVID-19, some study visits will happen virtually using Zoom Videoconferencing software. 
Your child can use Zoom on their phone, computer or tablet. By signing this form, you and your child 
agree to take part in both in-person and virtual study visits. In case of scheduling conflicts, or in the 
event that your child is unable to use Zoom, they will have the option to complete some visits over the 
phone. The study doctor will speak with your child over the phone and ask them the same questions 
that he/she would ask if they came to the office. 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 3 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
SCREENING PERIOD 
 
Screening Visit (Visit 1) 
 
Visit 1 will take place at virtually using Zoom videoconferencing. It will take about 1.5 hours to complete 
this visit. At this visit, we will ask your child questions regarding your mood and substance use to see if 
they qualify to take part in the study. If they do not qualify, the study doctor will tell them why. 
 
At this visit, we will: 
 
 
Review your child’s medical and psychiatric history and ask them questions about their symptoms of 
SUD and SMD. 
 
Ask your child questions about their substance use and mental health. The interview is in a “yes or 
no” format and covers questions about mood and substance use. 
 
Ask your child questions about their height and weight to calculate their Body Mass Index (BMI). 
 
Ask your child questions about their manic and depressive symptoms. 
 
Ask your child questions about their race, ethnicity, and family history. 
 Ask your child to complete a questionnaire about their type of substance use and frequency over the 
course of the past month. 
 Ask your child to complete a questionnaire about their mood 
 
Ask your child to sign a release of information for the treatment program where they are/will be 
receiving behavioral therapy to coordinate their treatment. 
 Ask you questions about your child’s socioeconomic status, educational accommodations, and past 
head injuries/trauma. 
 We may ask you to fill out two questionnaires about your child’s mood. 
 Ask your child screening questions for COVID-19 exposure/illness. 
 
Screening Visit (Visit 2) 
 
The second screening visit will take about 2 hours and will be completed at Boston Medical Center. The 
second screening visit will take place between 1 and 14 days after the first screening visit. At the second 
visit, we will do some tests and procedures on your child to gather more information and ensure their 
safety while participating in the study. The study doctor will review the results of these tests and 
procedures and inform your child if it is unsafe for them to participate. 
 
 
Measure your child’s vital signs (blood pressure, pulse). 
 
Measure your child’s height and weight to confirm their Body Mass Index (BMI). 
 Do a urine drug test with your child for certain types of drugs and breathalyzer for alcohol. The urine 
drug test includes prescription drugs and illegal drugs like marijuana, cocaine, PCP, and sedatives 
(habit-forming drugs that make you sleepy and calm). 
 Give your child 4 drug tests to administer at home over the next 4 visits and provide an explanation 
on how to do so. 
 Do a urine pregnancy test with your child if they are female and have started their periods 
(menstrual cycle). Pregnant women cannot take part in the study. 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 4 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
If your child is 16 or 17 years old, we will tell you the result if your child agrees to let us tell you. 
Even if your child does not agree, the study doctor may decide, based on their age, maturity, or 
medical condition, to tell you this information. 
 
Draw blood from your child for laboratory safety tests. This includes tests for HIV and Hepatitis C, 
tests of how well the liver is working, and tests of blood sugar levels and lipid (fat) levels. We will 
draw a total of about 2 tablespoons of blood during the entire course of this research study. We 
may ask your child to fast for several hours before drawing their blood for these tests. Hepatitis and 
HIV results will become part of their hospital medical record. We will refer your child for medical 
care if we find they have these infections. By law, healthcare providers must report positive test 
results for infectious diseases to public health authorities, including the Massachusetts Department 
of Public Health. These reports are required to identify your child by name. 
 
Perform an EKG on your child to screen for cardiac disease. An EKG is a test that measures the 
electrical activity of a heartbeat. Electrodes with stickers are placed on your child’s chest, arms, and 
legs for about 10 minutes. 
 
Ask your child questions about how they took their medications in the past. 
 Ask your child questions about your reasons for using alcohol/substances and coming to treatment, 
their family members’ opinions on your alcohol/substance use, and their friends’ drinking/drug use. 
 Ask your child to complete 2 questionnaires about their mood. 
 We may ask you to fill out a questionnaire about your child’s mood. 
 
Ask your child questions about their mental health. The interview is in a “yes” or “no” format and 
covers questions about anxiety and attention. 
 We will ask your child about any involuntary (unintentional) muscle movements they experience, 
and the study doctor will perform some tests to examine any possible involuntary movements they 
may experience. 
 Ask your child about their current place of residence where we can mail their study medication. 
 Ask your child screening questions for COVID-19 exposure/illness. Take your child’s temperature 
using a no-contact thermometer. 
 
Blood Test Results 
We will compare your child’s beginning test results, before they have taken the study drug, to the blood 
test results at the end of the study to see if there are any changes. During the study, these tests will help 
us know if your child can continue to take part in the study safely. The results of the blood tests will be 
placed in your child’s Boston Medical Center medical record. 
 
Assignment to Study Group 
If your child qualifies to take part in the study, we will assign your child by chance (like the flip of a coin) 
to the quetiapine or to the placebo group. Your child and the study doctor cannot choose your study 
group. Your child will have an equal chance of being assigned to either group. You, your child and the 
study doctor will not know which study group your child is in, but the study doctor can find out if 
necessary. 
 
STUDY DRUG PERIOD 
 
If your child qualifies to take part in the study, we will ask your child to attend a study visit once per 
week for 8 weeks. Two of these visits will take place in person at Boston Medical Center. The remaining 
6 visits will take place over Zoom videoconference. 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 5 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
Visit 3 
 
This visit will take about 1 hour and will be completed virtually. During the Week 0 visit (Visit 3) we will: 
 
 Review healthy lifestyle behavior suggestions. 
 
Ask your child to complete a urine drug test for certain types of drugs and discuss the results of the 
test. 
 Ask your child about their symptoms of SUD and SMD, their overall functioning, and any other 
symptoms they may be having. 
 Ask your child about risky behavior including details about substance use, and sensitive questions 
regarding their sexual activity. 
 Ask your child to fill out 4 questionnaires about their SUD and SMD symptoms. 
 Ask your child to weigh themselves if their Body Mass Index was between 30 and 35 at Visit 2. 
 
Taking the Study Drug 
The study doctor will explain to your child how to take the study drug. Your child will need to take the 
study drug either once or twice a day. If your child takes the study drug twice a day, your child will take 
one dose of the study drug in the morning and one dose in the evening. Please call the study doctor if 
you or your child have any questions or are ever unsure about how much study drug your child should 
be taking. 
 
We will mail the study medications to your child in two week supplies until their next in person visit. At 
that visit we will give your child the remaining 4 weeks supply. Your child will be asked to bring any 
unused study drug to Boston Medical Center at every in-person visit. We will count the leftover pills at 
each in-person study visit and ask your child to count the leftover pills during each virtual visit to make 
sure your child is taking the study drug properly. 
 
The Study Drug Diary 
We will give your child a study diary to fill out at home each day. Your child will write down the date and 
time they take the study drug and any other medications, as well as the dose they are taking. We will ask 
your child to bring this diary with them to each study visit (in-person or virtual), so we can track their 
progress. 
 
Visits 4, 6, 8, 10 
 
These visits will take about 30 minutes, and will all take place virtually. At these visits we will: 
 
 Ask your child to complete a urine drug test for certain types of drugs and discuss the results of the 
test. 
 Ask your child about their symptoms of SUD and SMD, their overall functioning, and any other 
symptoms they may be having. The study doctor will also ask if your child is having any side effects 
and if they have taken any other medication during the week. 
 Ask your child to fill out 1 questionnaire about their SUD symptoms. 
 Count unused study drug from the previous week. 
 Ask your child to weigh themselves if their Body Mass Index was between 30 and 35 at Visit 2 or Visit 
7. 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 6 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
Visits 5 and 9 
 
These visits will take about 45 minutes, and will all take place virtually. At these visits we will: 
 
  Ask your child to complete a urine drug test for certain types of drugs and discuss the results of the 
test. 
 Ask your child about their symptoms of SUD and SMD, their overall functioning, and any other 
symptoms they may be having. The study doctor will also ask if your child is having any side effects 
and if they have taken any other medication during the week. 
 Ask your child to fill out 4 questionnaires about their SUD and SMD symptoms. 
 Ask your child to weigh themselves if their Body Mass Index was between 30 and 35 at Visit 2 or Visit 
7. 
 
Visit 7 
 
This visit will take about 45 minutes, and will take place at Boston Medical Center. At this visit we will: 
 
 
Measure your child’s vital signs (heart rate, blood pressure). 
 
Measure your child’s weight to confirm their Body Mass Index (BMI). 
 Do a urine drug test with your child for certain types of drugs and breathalyzer for alcohol. 
 Ask your child about their symptoms of SUD and SMD, their overall functioning, and any other 
symptoms they may be having. The study doctor will also ask if your child is having any side effects 
and if they have taken any other medication during the week. 
 Ask your child to fill out 4 questionnaires about their SUD and SMD symptoms. 
 Ask your child to fill out 2 additional questionnaires about their SUD and SMD symptoms. 
 Ask your child about risky behavior including details about substance use, and sensitive questions 
regarding their sexual activity. 
 Do a urine pregnancy test with your child if they are female, and have started their periods. 
 Collect all unused drug from the past few weeks. 
 Collect all medication diaries from the past few weeks. 
 Give your child a new supply of the study drug. 
 Give your child 4 drug tests to administer at home over the next 4 visits. 
 Ask your child screening questions for COVID-19 exposure/illness. 
 Take your child’s temperature using a no-contact thermometer. 
 
Visit 11 (Final Visit) 
 
This visit will take about 2 hours and will take place at Boston Medical Center. During the final 
medication study visit, we will: 
 
 Measure your child’s vital signs (heart rate and blood pressure). 
 
Measure your child’s weight to confirm their Body Mass Index (BMI). 
 Do a urine drug test with your child for certain types of drugs and breathalyzer for alcohol. 
 Do a urine pregnancy test with your child if they are female and have started your periods. 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 7 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
 Ask your child about their symptoms of SUD and SMD, their overall functioning, and any other 
symptoms they may be having. The study doctor will also ask if your child is having any side effects 
and if they have taken any other medication during the week. 
 Ask your child about risky behavior including details about substance use, and sensitive questions 
regarding their sexual activity. 
 Ask your child to fill out 7 questionnaires about their SUD and SMD symptoms. 
 We may ask you to fill out 2 questionnaires about your child’s mood. 
 Draw a blood sample from your child. One vial of blood will be stored until the end of the study to 
test for quetiapine levels. The blood will be stored in a locked room only accessible by study staff. 
 Collect all unused study drug. 
 Collect all medication diaries from the past few weeks. 
 Ask your child screening questions for COVID-19 exposure/illness. 
 Take your child’s temperature using a no-contact thermometer. 
 
COVID-19 Safety 
For you and your child’s safety, study areas will be sanitized with germicidal cleaning wipes and/or spray 
before any in-person visit. In addition, research staff will wear a mask at all times. Your child (and you if 
you attend) must also wear a mask at all times. Your child may bring their own mask or we will provide 
them with a disposable face mask. 
 
Physical distancing will not be possible during certain study procedures like vital signs. However, all 
other procedures that need to be completed during these visits can be done virtually through zoom with 
your child on a computer in one office and research staff in another office. 
 
In addition to asking COVID screening questions at Visit 1 and in-person visits, we will also ask your child 
these questions the day before in-person visits by phone. Questions will ask about possible symptoms, 
travel, contact with someone who may have had COVID-19 and if you have been confirmed or suspected 
to have COVID-19. 
 
Audiotape Recordings 
We may make audiotape recordings while you and your child are answering some of our study questions 
during the study. These recordings will help us check the way that study staff members ask questions in 
this study. Each recording will be labeled with your child’s initials and an identification number and not 
their name in order to maintain confidentiality. We will store these recordings on a computer protected 
by a password. 
 
Text Message Reminders 
Text messages by mobile/cell phones are a common form of communication. This research study 
involves sending your child text messages to remind them of their scheduled appointments. Texting over 
mobile/cell phones carries security risks because text messages to mobile/ cell phones are not 
encrypted. This means that information your child sends or receives by text message could be 
intercepted or viewed by an unintended recipient, or by your child’s mobile/ cell phone provider. Since 
texting is not the most secure method of communication, we remind you and your child not to use 
texting as a method of communication other than for scheduling appointments. 
 
Below are some important points about texting in this research study. 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 8 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
 
Text messages are not encrypted, and therefore carry security risks. This research study and 
Boston Medical Center are not responsible for any interception of messages sent through 
unencrypted text message communications. 
 
 
Your child will be responsible for all fees charged by your carrier’s service plan for text 
messaging. This research study and Boston Medical Center are not responsible for any 
increased charges, data usage against plan limits or changes to data fees from the research 
texts. 
 
 
Text messages will only be read during regular business hours. Texts sent on nights or weekends 
will not be read until the next business day. 
 
 
Text messaging should not be used in case of an emergency. If your child experiences a medical 
emergency, call 911 or go to the nearest hospital emergency department. 
 
 
Your child may decide to not send or receive text messages with staff associated with this research 
study at any time. They can do this in person or by sending the research number a text message 
that says “Stop Research Text.” 
 
 
Your child’s agreement applies to this research study only. Agreeing to other texts from Boston 
Medical Center, for example appointment reminders, is a separate process. Opting out of other 
texts from Boston Medical Center is a separate process as well. 
 
 
It is your child’s responsibility to update your mobile/cell phone number with this research study in 
the event of a change. 
 
By signing this document, you agree that you have had the chance to ask questions about texting with 
staff associated with this research study, you have been informed of the risks and other information 
covered above, and you consent to the use of unencrypted text communications associated with this 
research study. 
 
Leaving the Study Early 
Your child can stop taking part in this study at any time. We may stop this study or remove your child 
from the study at any time if it is necessary and/or in your child’s best interest. We may stop your 
child from taking part in this study for any of the following reasons: 
 
 If your child does not feel well on the study drug. 
 If there is new information on the safety of the study drug. 
 If your child becomes pregnant during the study. 
 If your child’s drug use or mood symptoms escalate to the point where a more structured level of 
care is more appropriate. 
 If your child does not follow study guidelines, misses appointments, or does not return unused study 
drug. 
 If your child’s weight increases such that their Body Mass Index increases by 1 if… 
1) their Body Mass Index was above 30 at Visit 2 OR 
2) their Body Mass Index was under 30 at Visit 2 but above 30 at Visit 7 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 9 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
If your child leaves the study early, we will ask your child to complete all the procedures that are done 
during the final study visit (Visit 11). We will tell your child how to stop taking the study drug safely. It is 
important that your child return any remaining study drug if they leave the study. If you want, we will 
refer your child to another doctor or group in your area. If you would like us to release information to 
your child’s new doctor, you must sign a release of health/medical information form. 
 
Optional Follow-Up Visits (After you complete the study) 
After your child finishes the study or if they withdraw early from the study for any reason, we will offer 3 
clinical follow-up visits. Your child does not need to come to these follow-up visits; they are optional. 
During these follow-up visits, the study doctor will ask your child about their symptoms of SUD and 
SMD. The study doctor will also ask about your child’s overall health, and offer treatment guidance. 
These visits will last about 30 minutes each. These follow-up visits are not part of the study. We offer 
these follow-up visits to help your child find long-term care for their symptoms of SUD and SMD. We will 
not charge you for these appointments. However, you will be responsible for the cost (including any 
insurance co-payment) of medication if it is prescribed. 
 
Medical Records 
A notation that your child is taking part in this research study may be made in your child’s electronic 
medical record. Information from the research that relates to your child’s general medical care may be 
included in the record (for example, results of standard blood tests done at the hospital labs). Please ask 
the study doctor if you have any questions about what information will be included in your child’s 
electronic medical record. 
 
The ways we will protect you and your child’s privacy and confidentiality are described in a separate 
section later in this form. 
 
The research measurements we make are not necessarily the same as tests done by your doctor. We are 
collecting information on many people to answer our research questions. Not everyone doing the 
research tests is a doctor or a nurse. Your child or your doctor should not rely on the research 
measurements to make any diagnosis, treatment, or health planning decisions. If your child or your 
doctor decides that follow-up tests and treatments are necessary, then your child or their insurance will 
be billed for the costs. 
 
You will be one of approximately 37 subjects who will be asked to be in the study. 
 
Risks and Discomforts 
Taking part in this study may involve risks, some of which are listed below. There may also be other side 
effects that are not known at this time. 
 
Risks of Taking Quetiapine 
The risks of being in this study include the side effects of the study drug. Complications and side effects 
from the study drug that are unknown at this time could also occur. 
 
Common side effects (incidence more than 5 out of every 100 individuals, and twice the rate of placebo) 
associated with the use of quetiapine include: 
 Dry mouth 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 10 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
 
Drowsiness (somnolence) 
 Dizziness 
 
Sore throat (pharyngitis) 
 Weight gain 
 Alanine aminotransferase (ALT) increase (liver problems) 
 Liver problems (an increase in Alanine aminotransferase or ALT on your lab results) 
 Feeling lightheaded when you stand up quickly (postural hypotension) 
 Indigestion (dyspepsia) 
 Fatigue (extreme tiredness) 
 Increased appetite 
 Increased blood pressure (hypertension) 
 Fast heart rate (tachycardia) 
 Vomiting 
 Lack of energy 
 
Less common but serious side effects of quetiapine include: 
 High blood sugar (hyperglycemia) 
 Lipid elevations 
 Hypothyroidism 
 Malignant Neuroleptic Syndrome (muscle rigidity, fever, or changes in your thinking such as 
confusion or problems concentrating) 
 Seizures 
 Diabetes mellitus 
 Blurry vision (cataracts) 
 Heart problems (QTc prolongation) 
 Restless or involuntary muscle movements including tardive dyskinesia. The involuntary 
movements caused by tardive dyskinesia most commonly appear in the eyes, lips, tongue, 
and jaw. Although tardive dyskinesia is rare it can be irreversible. 
 
For medications that may pose a serious risk to those taking them, the FDA issues a “black box warning.” 
The FDA has issued a black box warning for quetiapine which may increase suicidality risk in some 
adolescents and young adults. However, there is reason to believe this warning arose largely due to co- 
administration in patients with major depressive disorder who were on antidepressants. 
 
Because it is possible that quetiapine could make your child feel tired, your child should not drive or 
operate machinery until they know how quetiapine affects their functioning. 
 
Risks of Allergic Reactions 
As with any drug, an allergic reaction can occur. Allergic reactions can be mild or serious, and can even 
result in death in some cases. Common symptoms of an allergic reaction are rash, itching, skin problems, 
swelling of the face and throat, or trouble breathing. If you think your child is having an allergic reaction, 
call the study doctor right away. If your child is having trouble breathing, call 911 immediately. 
 
You should notify the study doctor immediately if your child develops a rash, illness or disease that they 
did not have at the start of the study. If your child becomes pregnant, have an injury or side effect, or 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 11 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
develop an unusual health problem during the study, contact your study doctor, Amy Yule, MD, 
immediately. 
 
Risks of Drug Interactions 
It is possible that taking quetiapine with your child’s regular medications or supplements may change 
how quetiapine works, or how your child’s regular medications or supplements work. It is very 
important that your child tells the study doctor about all prescriptions and over-the-counter 
medications or supplements your child is taking during the study. 
 
For your child’s safety during this study, call their study doctor BEFORE your child takes any: 
 New medications prescribed by their own doctor (for example, antibiotics) 
 Other medications sold over-the-counter without a prescription 
 Dietary or herbal supplements 
 
Your child may be excluded from participating in the study if they are planning to change any of their 
current medications (psychiatric and/or non-psychiatric) that are known to cause heart problems (QTc 
prolongation). 
 
Also, your child may be withdrawn from the study if they have to change any of their current 
medications (psychiatric and/or non-psychiatric) that are known to cause heart problems (QTc 
prolongation). 
 
Risks of Pregnancy 
If your child is female and gets pregnant while in this study, it could be bad for the fetus/baby. Your 
daughter must use birth control if she has sex with men while in this study. She should also keep using 
birth control for one week after the study ends. Only some birth control methods work well enough to 
be safe while your daughter is in this study. These methods are oral contraceptives (the pill), 
intrauterine devices (IUDs), contraceptive implants under the skin, contraceptive rings or patches or 
injections, diaphragms with spermicide, and condoms with foam. Your daughter should not be in this 
study if she has sex with men and cannot use one of these birth control methods. 
 
Risks of Sharing Sensitive Information 
Your child will be asked to disclose sensitive, personal information, such as pregnancy or drug use. 
There is a risk of discomfort in answering these sensitive, personal questions. In addition, it is 
possible that your child may be inconvenienced by the time required to answer all of our questions. 
 
Risks of Blood Draw 
Your child may have a bruise (a black and blue mark) or pain where we take the blood samples. There is 
also a small risk of feeling lightheaded, fainting, or infection. Blood samples will be stored in a locked 
room only accessible by study staff. 
 
Risks of the EKG 
Your child may have a skin reaction to the adhesive used to apply the electrode on their skin. 
 
Risks of Completing Study Questionnaires 
Both you and your child will be asked to complete some study questionnaires. There is a risk you/ your 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 12 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
child may feel uncomfortable or anxious while doing some of the computer tests or questionnaires. We 
hope that you and your child will try to complete all the study questionnaires, but you/your child can 
skip any questions you all do not want to complete. We will use a study code instead of your child’s 
name on these questionnaires. However, we cannot guarantee absolute confidentiality of this 
information 
 
There may be unknown risks or discomforts involved. 
 
Potential Benefits 
 
Your child may not benefit from taking part in this research study. It is possible that your child’s SUD 
and/or severe mood symptoms may improve while in the study if you are randomized to receive 
quetiapine. The results of this study may benefit other people with SUD and co-occurring SMD in the 
future. 
 
Alternatives 
 
Your child does not need to be in this study to get treatment for their SUD and SMD. There are no 
medications approved for the treatment of co-occurring SUD and SMD, but there are medications 
approved to treat the disorders individually. For SUD, the medications ReVia® (naltrexone) and 
Campral™ (acamprosate) can reduce the desire to drink alcohol in adults. For bipolar disorder 
Risperidal® (risperidone), Abilify® (aripiprazole) and Geodon® (ziprasidone) are among the medications 
approved to treat manic episodes. There are also non-medication treatments available for the 
management of SUD or SMD, such as cognitive behavioral therapy, group counseling and motivational 
interviewing. Your child’s primary care doctor or psychiatrist may prescribe these drugs for your child 
and/or refer your child to these therapies without them taking part in this study. 
 
Talk with the study doctor if you have questions about any of these interventions. 
 
Costs 
 
Study funds will pay for study-related items and services. There are no additional costs to you or your 
child for being in the study. Items and services done only for study purposes will be provided at no cost 
to your child. They won’t be billed to your child’s health insurance either. You or your child’s health 
insurance will be billed for all costs that are part of your child’s normal medical care. These costs include 
co-payments and deductibles. You can ask any questions now about insurance coverage for this study or 
about the research activities paid for by the sponsor. You can also ask the investigator later, using the 
number on the first page of this form. 
 
Payment 
 
Your child will receive between $10 and $50 for each study visit they complete which will be deposited 
on a ClinCard. The remuneration schedule is as follows: Visit 1 (screening visit 1): $25; Visit 2 (screening 
visit 2): $25; Visit 3: $15; Visit 4: $10; Visit 5: $15; Visit 6: $10; Visit 7: $15; Visit 8: $10; Visit 9: $15; Visit 
10: $10; Visit 11: $50. In addition, your child will receive a $3.50 at each visit that they bring back their 
medication in the medication bottle. 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 13 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
You will also receive payment for transportation to Boston Medical Center if you/your child use(s) public 
transit, or parking in the hospital garage during study visits if you/your child drive(s) to Boston Medical 
Center. An additional $5 will be deposited on the ClinCard for each visit that you/your child take public 
transit to and from the hospital. If you/your child park(s) in the hospital garage during a study visit, 
you/your child will receive a parking coupon. 
 
Compensation will be provided by Boston Medical Center and your child will receive incremental 
amounts at the end of each completed visit. In order to be paid for taking part in this research study, we 
will need to collect your child’s Social Security Number (SSN) or Individual Taxpayer Identification 
Number (ITIN). This will be stored in a locked location and will be maintained separately from your 
child’s other study information and documents. If your child does not wish to provide their SSN or ITIN, 
they can still participate in this study, but we will not be able to pay them. 
 
Confidentiality 
 
We must use information that shows your child’s identity to do this research. Information already 
collected about your child will remain in the study record even if your child later withdraws. 
 
We will store your child’s information in ways we think are secure. We will store biological samples 
taken from your child’s body (blood) in a locked room only accessible by study staff. We will store paper 
files in a locked research office. We will store electronic files in computer systems with password 
protection and encryption. However, we cannot guarantee complete confidentiality. 
 
This study is covered by a Certificate of Confidentiality (CoC) from the National Institutes of Health. All 
studies funded by the National Institutes of Health that involve identifiable information or biological 
samples are covered by a CoC. The CoC provides how we can share research information or biological 
samples. Because we have a CoC, we cannot give out research information or biological samples that 
may identify you or your child to anyone that is not involved in the research except as we describe 
below. Even if someone tries to get your child’s information or biological samples in connection with a 
legal proceeding, we cannot give it to them. The CoC does not prevent you or your child from sharing 
your child’s own research information. 
 
We will record information from this study in your child’s medical record, such as information related to 
your child’s medical care. A notation that your child is taking part in this research study will be made in 
their electronic medical record at Boston Medical Center. Information from the research that relates to 
your child’s general medical care may be included in the record (for example: list of allergies, results of 
standard blood tests done at the hospital labs). Please ask us if you have any questions about what 
information will be included in your child’s medical records. You should know that once information has 
been put into your child’s medical records, it is not covered by the CoC. However, information in your 
child’s medical records is protected in other ways. 
 
If you agree for your child to be in the study and sign this form, we will share information and biological 
samples that may show your and your child’s identity with the following groups of people: 
 
People who do the research or help oversee the research, including safety monitoring. 
 
People from Federal and state agencies who audit or review the research, as required by law. 
Such agencies may include the U.S. Department of Health and Human Services, the Food and 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
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IRB APPROVAL DATE: 02/22/2021 
 
 
 
Drug Administration, the National Institutes of Health, and the Massachusetts Department of 
Public Health. 
 
People who see your child’s medical records. 
 
Any people who you give us separate permission to share your child’s information. 
 
You should know that we are required to report information to a public health or public safety authority, 
or with specific individuals who may be at risk of harm, if we learn information that could mean harm to 
you, your child, or others. When state mandatory reporting statues would require us to disclose 
information, including about child or elder abuse, we will voluntarily disclose that information. 
 
If your child is in immediate danger of hurting themselves at any time in the study, the study team will 
try to work with you/your child on a plan to keep you safe. Because study staff will be trying to protect 
your child, it is possible that your information will be shared with others as part of a plan for safety. 
 
We will share research data where we have removed anything that we think would show your child’s 
identity. There still may be a small chance that someone could figure out that the information is about 
your child. Such sharing includes: 
 
Publishing results in a medical book or journal. 
 
Adding results to a Federal government database. 
 
Using research data in future studies, done by us or by other scientists. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time. 
 
Use and Sharing of Your Child’s Health Information 
 
The research team has to use and share your child’s health information to do this study, including 
information that may identify you or your child. By agreeing to allow your child to be in this study and 
signing this form, you are giving us your permission where needed to use and share your child’s health 
information as described in this form. 
 
Health information that might be used or shared during this research includes: 
 
Information that is in your child’s hospital or office health records. The records we will use or 
share are those related to the aims, conduct, and monitoring of the research study. 
 
Health information from tests, procedures, visits, interviews, or forms filled out as part of this 
research study. 
 
The health information specifically includes: 
o Mental health communications (with a psychiatrist, psychologist, clinical nurse specialist, 
marriage-, family-, rehabilitation-, or mental-health-counselor, or educational psychologist) 
o Social work communications 
o HIV/AIDS information 
o Sexually transmitted disease information 
o Communicable disease information 
o Alcohol or drug use disorder treatment records 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
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BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
The reasons that your child’s health information might be used or shared with others are: 
 
To do the research described here. 
 
To make sure we do the research according to certain standards set by ethics, law, and quality 
groups. 
 
To comply with laws and regulations. This includes safety-related information. As we explained 
above, we also have to share any information from you/ your child about: child abuse, elder 
abuse, or harm to others. 
 
To protect your child. As we explained above, if your child is in immediate danger of hurting them 
self, it is possible that your child’s information will be shared with others as part of a plan for 
safety. 
 
The people and groups that may use or share your child’s health information are: 
 
Researchers involved in this research study from Boston Medical Center, Boston University, 
and/or other organizations 
 
Other people within Boston Medical Center and Boston University who may need to access your 
child’s health information to do their jobs such as for treatment, research administration, 
payment, billing, or health care operations 
• 
People or groups that the researchers use to help conduct the study or to provide oversight for 
the study 
• 
The Institutional Review Board that oversees the research and other people or groups that are 
part of the Human Research Protection Program that oversees the research 
• 
Research monitors, reviewers, or accreditation agencies and other people or groups that oversee 
research information and the safety of the study 
 
Public health and safety authorities who receive our reports about child abuse, elder abuse, or 
harm to others. 
 
Other care providers and public safety authorities who may be involved in helping to protect your 
child if your child expresses thoughts about hurting them self. 
 
We ask anyone who gets your child’s health information from us to protect the privacy of your child’s 
information. However, we cannot control how they may use or share your child’s health information. 
We cannot promise that they will keep it completely private. 
 
The time period for using or sharing your child’s health information: 
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your health information. 
 
Your privacy rights are: 
 
You have the right not to sign this form that allows us to use and share your child’s health 
information for research. If you do not sign this form, your child cannot be in the research. This is 
because we need to use the health information to do the research. Your decision not to sign the 
form will not affect any treatment, health care, enrollment in health plans, or eligibility for 
benefits for you or your child. 
 
You have the right to withdraw your permission to use or share your child’s health information in 
this research study. If you want to withdraw your permission, you must write a letter to the 
Principal Investigator at the address listed on the first page of this form. If you withdraw your 
permission, you will not be able to take back information that has already been used or shared 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
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BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
with others. This includes information used or shared to do the research study or to be sure the 
research is safe and of high quality. If you withdraw your permission, your child cannot continue 
to be in the study. 
 
When the study has been completed for everyone, you have the right to request access to the 
health information that we used or shared to make your child’s treatment or payment decisions. If 
you ask for research information that is not in your child’s medical record, we might not give it to 
you, but we will explain why not. You may use the contact information on the first page of this 
form to find out how to get your child’s health information. You may also contact the HIPAA 
Privacy Officer at Boston Medical Center at DG-privacyofficer@bmc.org. 
 
Compensation for Injury 
 
If you think that your child has been injured by being in this study, please let the investigator know right 
away. Use the phone number on the first page of this form. Your child can get treatment for the injury at 
Boston Medical Center, or at any healthcare facility you choose. There is no program to provide 
compensation for the cost of care for research related injury or for other expenses. Other expenses 
might be lost wages, disability, pain, or discomfort. You or your child’s insurance will be billed for the 
medical care your child receives for a research injury. You are not giving up any of your legal rights by 
signing this form. 
 
 
Re-Contact 
 
We would like to ask your permission to contact you and your child again in the future. This contact 
would be after the study has ended. Please initial your choice below: 
 
  
Yes  
No You may contact me and my child again to ask for additional information 
related to this study 
 
  
Yes  
No You may contact me and my child again to let us know about a different 
research study 
 
Subject’s Rights 
 
By giving permission for your child to be in this study, you do not waive any of your or your child’s legal 
rights. Giving permission means that you have been given information about this study and that you 
agree to have your child participate in the study. Giving permission also means that you agree to allow 
your child to participate in virtual study visits. You will be given a copy of this form to keep. 
 
If you or your child do not agree for your child to be in this study or if at any time your child withdraws 
from this study, you or your child will not suffer any penalty or lose any benefits to which you or your 
child are entitled. Your child’s participation is completely up to you and your child. Your decision and 
your child’s decision will not affect your or your child’s ability to get health care or payment for your or 
your child’s health care. It will not affect your or your child’s enrollment in any health plan or benefits 
you or your child can get. 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 17 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
During this study, we may find out something that might make you or your child not want to have your 
child stay in the study. If this happens, we will tell you and your child as soon as possible. 
 
We may decide to have your child stop being in the study even if you and your child want to stay. Some 
reasons this could happen are if staying in the study may be bad for your child, or if the study is stopped. 
 
Questions 
 
The investigator or a member of the research team will try to answer all of your questions If you have 
questions or concerns at any time, contact Amy Yule at 617-414-1936. Also call if you need to report an 
injury to your child during this research Dr. Yule is available 24 hours a day/7 days a week by calling 617- 
414-1990. 
 
You may also call 617-358-5372 or email medirb@bu.edu if you have questions or concerns. You will be 
talking to someone at the Boston Medical Center and Boston University Medical Campus IRB. The IRB is 
a group that helps monitor research. You should call or email the IRB if you want to find out about your 
child’s rights as a research subject. You should also call or email if you want to talk to someone who is 
not part of the study about your questions, concerns, or problems. 
 
 
 
Child Subject:   
 
Printed name of subject 
 
By signing this permission form, you are indicating that 
 
you have read this form (or it has been read to you) 
 
your questions have been answered to your satisfaction 
 
you voluntarily agree to allow your child to participate in this research study 
 
you permit the use and sharing of information that may identify you or your child as described 
including your child’s health information. 
 
 
 
Printed name of parent/legal guardian 
 
 
 
Signature of parent/legal guardian 
Date 
 
 
By signing below, you are indicating that you have read this form, that your questions have been 
answered, and that you voluntarily agree to participate in this research study. 
 
 
 
Signature of child 
Date 


Project Title: A Randomized Controlled Trial of Quetiapine for the Treatment of Youth With Co- 
Occurring Substance Use Disorders (SUDs) and Severe Mood Dysregulation (SMD) 
Principal Investigator: Amy Yule, MD 
Page 18 of 18 
BMC and BU Medical Campus IRB 
IRB NUMBER: H-39577 
IRB APPROVAL DATE: 02/22/2021 
 
 
 
 
Researcher:   
 
Printed name of person conducting consent discussion 
 
 
I have personally explained the research to the above-named child and to the parent/legal guardian and 
answered all questions. I believe that they understand what is involved in the study and freely agree to 
participate. 
 
 
 
Signature of person conducting consent discussion 
Date 
 
 
 
To be completed by witness if researcher reads this form to the parent/legal guardian 
This permission form was read to and apparently understood by the parent/legal guardian in my 
presence. 
 
 
Printed name of witness (a person not otherwise associated with the study) 
 
 
 
Signature of witness 
Date