Clinical trial NCT03222570
Conditions: Depressive Disorder
Sponsor: University of Minnesota
Start date: 2018-02-26; Completion date: 2024-04-28
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the effectiveness of two adaptive treatment strategies (ATSs) for adolescent depression. The ATSs include delivery of an evidence-based psychotherapy (interpersonal psychotherapy for depressed adolescents, IPT-A), systematic symptom monitoring, and an empirically-derived algorithm that specifies whether, when, and how to augment IPT-A. Two hundred depressed adolescents (age 12-18) will be recruited to participate in a 16-week sequential multiple assignment randomized trial conducted in outpatient community mental health clinics. Adolescents will be randomized to the IPT-A ATS condition or the community clinic's usual care (UC). Adolescents in the IPT-A ATS condition who are insufficient responders will be randomized a second time to the addition of a selective serotonin reuptake inhibitor (SSRI) or more intensive IPT-A (delivered twice per week). Research assessments will be administered at baseline and at weeks 4, 8, 12, 16, and 36.

Detailed description:

Arms: arm 1: Adolescents begin with an initial treatment plan of 12 weekly sessions of interpersonal psychotherapy for depressed adolescents (IPT-A). Depressive symptoms will be assessed at week 4 and week 8 of therapy. If an adolescent demonstrates an insufficient response at either time point, the adolescent will be randomized a second time to either an increased dose of IPT-A (sessions scheduled twice per week for 4 weeks;16 sessions total) or the addition of a selective serotonin reuptake inhibitor (SSRI). arm 2: Therapists will implement therapy procedures that they usually use and believe to be effective in clinical practice. Therapists will use whatever methods they usually use to make decisions regarding the frequency of therapy sessions and whether to refer the adolescent to start an SSRI.
Interventions: intervention 1: Interpersonal Psychotherapy for Depressed Adolescents intervention 2: Selective Serotonin Reuptake Inhibitor intervention 3: Usual Care
Intervention descriptions: intervention 1: IPT-A is an evidence-based intervention that aims to decrease depressive symptoms by helping adolescents improve their relationships and interpersonal interactions. It addresses one or more of four interpersonal problem areas: grief, role disputes, role transitions, and interpersonal deficits. The primary treatment techniques in IPT-A include emotion identification/expression, linking interpersonal events to mood, communication analysis, communication skill building, decision analysis, role playing, and assignment of interpersonal experiments (i.e. homework). In clinical trials, depressed adolescents treated with IPT-A demonstrated fewer depressive symptoms and better psychosocial functioning post-treatment than adolescents in control conditions. intervention 2: Fluoxetine, escitalopram, citalopram, fluvoxamine, or sertraline intervention 3: Therapists will implement therapy procedures that they usually use and believe to be effective in clinical practice. Therapists will use whatever methods they usually use to make decisions regarding the frequency of therapy sessions and whether to refer the adolescent to start an SSRI

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL TITLE: An Adaptive Algorithm-Based Approach to Treatment for 
Adolescent Depression 
VERSION DATE: 09/05/2023 
 
 
 
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PROTOCOL TITLE: 
An Adaptive Algorithm-Based Approach to Treatment for Adolescent Depression  
 
PROTOCOL NUMBER: 25767 
 
PRINCIPAL INVESTIGATOR or FACULTY ADVISOR: 
Meredith Gunlicks-Stoessel, Ph.D., L.P. 
Department of Psychiatry, Division of Child and Adolescent Psychiatry 
612-273-9844 
mgunlick@umn.edu 
 
 
STUDENT INVESTIGATOR: 
None 
 
VERSION NUMBER/DATE: 
Version 27 (09/05/2023)  
 
 


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Table of Contents 
 
1.0 
Objectives ................................................................................................................ 5 
2.0 
Background .............................................................................................................. 5 
3.0 
Study Endpoints/Events/Outcomes ........................................................................ 15 
4.0 
Study Intervention(s)/Investigational Agent(s)...................................................... 16 
5.0 
Procedures Involved............................................................................................... 17 
6.0 
Data and Specimen Banking .................................................................................. 26 
7.0 
Sharing of Results with Participants ...................................................................... 26 
8.0 
Study Duration ....................................................................................................... 27 
9.0 
Study Population .................................................................................................... 27 
10.0 Vulnerable Populations .......................................................................................... 30 
11.0 Local Number of Participants ................................................................................ 31 
12.0 Local Recruitment Methods ................................................................................... 31 
13.0 Withdrawal of Participants .................................................................................... 40 
14.0 Risks to Participants ............................................................................................... 41 
15.0 Potential Benefits to Participants ........................................................................... 41 
16.0 Data Management .................................................................................................. 42 
17.0 Confidentiality ....................................................................................................... 51 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants .................... 48 
19.0 Provisions to Protect the Privacy Interests of Participants .................................... 49 
20.0 Compensation for Research-Related Injury ........................................................... 50 
21.0 Consent Process ..................................................................................................... 50 
22.0 Setting .................................................................................................................... 53 
23.0 Multi-Site Research ............................................................................................... 53 
24.0 Resources Available............................................................................................... 53 
25.0 References .............................................................................................................. 55 
 


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ABBREVIATIONS/DEFINITIONS 
 
• AE 
 
Adverse Event 
• ATA  
Adaptive Treatment Attitudes Questionnaire 
• ATA-T 
Adaptive Treatment Attitudes – Therapist Questionnaire 
• ATS 
 
Adaptive Treatment Strategy 
• BDI-II  
Beck Depression Inventory-II 
• CASA  
Child and Adolescent Services Assessment 
• CBQ  
Conflict Behavior Questionnaire 
• CDRS-R 
Children’s Depression Rating Scale-Revised 
• CGAS  
Children’s Global Assessment Scale 
• CSQ-8  
Client Satisfaction Questionnaire 
• C-SSRS 
Columbia Suicide Severity Rating Scale 
• CGI 
 
Clinical Global Improvement 
• DSMB  
Data and Safety Monitoring Board 
• EBPAS-36 
Evidence-Based Practice Attitude Scale-36 
• ET 
 
Expectations for Treatment 
• HRSD  
Hamilton Rating Scale for Depression 
• IC 
 
Issues Checklist 
• IE  
 
Independent Evaluator 
• IPPA Inventory of Parent and Peer Attachment 
• IPT-A  
Interpersonal Psychotherapy for Depressed Adolescents  
• ISM 
 
Independent Safety Monitor 
• K-SADS-PL  Schedule for Affective Disorders and Schizophrenia for School- 
aged Children – Present and Lifetime Version 
• ORCA  
Organizational Readiness to Change Assessment 
• SAE 
 
Serious Adverse Event 
• SASC  
Sociotropy-Achievement Scale for Children 
• SMART 
Sequential Multiple Assignment Randomized Trial 
• SOCQ  
Stages of Change Questionnaire 
• SSRI  
Selective Serotonin Reuptake Inhibitor 
• TP 
 
Treatment Preference 
• UC 
 
Usual Care  
 
 
 


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STUDY SUMMARY 
 
Study Title 
An Adaptive Algorithm-Based Approach to 
Treatment for Adolescent Depression 
Study Design 
Phase II Clinical Trial 
(Sequential Multiple Assignment Randomized Trial; 
SMART) 
Primary Objective 
Evaluate the effectiveness of the two adaptive 
treatment strategies (ATSs) as compared to usual 
care (UC) 
Secondary Objective(s) 
• Evaluate adolescents’ interpersonal functioning 
as a treatment target of Interpersonal 
Psychotherapy for Depressed Adolescents (IPT-
A) 
• Evaluate moderators of initial treatment and 
treatment augmentation strategies. 
• Conduct an implementation-focused process 
evaluation to identify barriers and facilitators 
that influenced ATS implementation. 
• Examine genetic variants, gene expression, and 
DNA methylation signatures in relationship to 
treatment response and symptoms 
Research 
Intervention(s)/Investigational 
Agents 
• Interpersonal Psychotherapy for Depressed 
Adolescents (IPT-A) 
• Selective Serotonin Reuptake Inhibitors (SSRIs) 
• Usual Care (UC) 
IND/IDE # (if applicable) 
N/A 
Investigational Drug Services 
# (if applicable) 
N/A 
Study Population 
• Adolescents (age 12-18) with a diagnosis of a 
depressive disorder and their parents 
• Clinic staff 
Sample Size (number of 
participants) 
• 200 adolescents and their parents 
• 50 clinic staff members 
Study Duration for Individual 
Participants 
36 weeks 
 
 
 


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1.0 
Objectives 
Adolescent depression is a prevalent and debilitating disorder that places youth at 
risk for suicidality, other psychiatric diagnoses, and functional impairment both 
during adolescence and into adulthood. There are a number of effective 
treatments; however, 30-50% of adolescents who receive these treatments do not 
respond. To improve response rates, practice parameters recommend routine 
systematic symptom assessment over the course of treatment to inform decisions 
regarding whether to switch or augment treatment. Unfortunately, routine 
symptom assessment in usual care for adolescent depression is extremely rare. In 
addition, for psychotherapy, which is the most frequent treatment for adolescent 
depression, there are currently no guidelines to direct therapists regarding how to 
use those symptom assessments to guide subsequent treatment decisions. 
Addressing this critical knowledge gap requires identifying (1) what symptoms or 
patient characteristics to assess, (2) when to administer those assessments, and (3) 
what subsequent treatment to provide, based on those assessments. Adaptive 
treatment strategies (ATSs) provide algorithms for guiding treatment decision 
making. These algorithms are based on patient characteristics and outcomes 
collected during the course of therapy, and they provide guidelines regarding 
when, how, and for whom midcourse changes in the treatment approach should be 
initiated. The purpose of the current study is to evaluate the effectiveness of two 
ATSs for adolescent depression. The ATSs include delivery of an evidence-based 
psychotherapy for adolescent depression (interpersonal psychotherapy, IPT-A), 
systematic symptom monitoring, and an empirically-derived algorithm that 
specifies whether, when, and how to augment IPT-A. Two hundred depressed 
adolescents (age 12-18) will be recruited to participate in a 16-week sequential 
multiple assignment randomized trial (SMART) conducted in outpatient 
community mental health clinics (PrairieCare Medical Group and Minnesota 
Mental Health Clinics). Adolescents will be randomized to the IPT-A ATS 
condition (N=134) or the community clinic’s usual care (UC) (N=66). The aims 
of this study are to: 
• Evaluate the effectiveness of the ATSs as compared to UC. 
• Evaluate adolescents’ interpersonal functioning as a treatment target of IPT-A 
• Evaluate moderators of initial treatment and treatment augmentation 
strategies. 
• Conduct an implementation-focused process evaluation to identify barriers 
and facilitators that influenced ATS implementation. 
• Examine genetic variants, gene expression, and DNA methylation signatures 
in relationship to treatment response and symptoms 
 
2.0 
Background 


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The Public Health Problem of Adolescent Depression:   
Depression is one of the most common psychiatric disorders in adolescents,1 with 
approximately 20% of adolescents experiencing a depressive episode at some 
point during their teenage years.2 It is associated with significant morbidity, 
mortality, and functional impairment3,4 and is the largest predictor of completed 
suicides among girls and the second largest predictor among boys.5 Adolescent 
depression imparts significant costs on families and society, including 
expenditures on health care services and lost work time for parents.6,7 In 
addition, the psychiatric and psychosocial sequelae have been found to persist into 
adulthood.8,9 Accordingly, the development of effective strategies for treating 
adolescent depression has significant implications for health and well-being both 
during adolescence and into adulthood.  
 
 
Improving Outcomes and Clinical Practice by Developing Adaptive Treatment 
Strategies: 
There are now a number of evidence-based treatments for adolescent depression 
including psychotherapy, antidepressant medication, and their combination.10 
Two psychotherapies have “well-established” empirical support: interpersonal 
psychotherapy (IPT-A) and cognitive behavioral therapy (CBT).11 A number of 
antidepressant medications also have demonstrated efficacy,12-16 and fluoxetine 
and escitalopram (both selective serotonin reuptake inhibitors, SSRIs) have 
approval by the Food and Drug Administration for use with adolescents. Despite 
progress in treatment development, approximately 30-50% of adolescents who 
receive these treatments do not respond.17,18 To address this problem, practice 
parameters recommend systematic and routine assessment and monitoring of 
depression symptoms over the course of treatment to inform treatment planning, 
including decisions regarding whether to switch or augment treatment.10,19 Several 
studies have shown that routine assessment improves treatment outcomes 
compared to no assessment conditions.20-26 Importantly, progress monitoring can 
be easily implemented in community practice by integrating it into patients’ 
electronic medical records (EMRs). EMRs can be programmed to alert clinicians 
to administer an assessment at a specified time point, the assessment data can be 
entered directly into the EMR, and the EMR can be programmed with the 
algorithms that guide subsequent treatment recommendations. This creates a user-
friendly data-based decision support system that provides feedback on treatment 
progress and guides treatment planning.27 Despite ample research support and 
available methods for implementation, routine symptom assessment in usual care 
for adolescent depression is extremely rare.28 A recent review of EMRs from 3 
large health care systems found that only 32% of depressed adolescents had 
documentation of symptom monitoring following the initial intake.28 In addition, 
for psychotherapy, which is the most frequent treatment for adolescent 
depression,28 there are currently no guidelines to direct therapists regarding how 
to use those symptom assessments to guide subsequent treatment decisions. As a 
consequence, if clinicians do decide to switch or augment treatment, they may do 


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so in a trial and error fashion, which could result in extended time to remission, 
unnecessary experience of side effects, or increased cost or other burdens.  
 
Developing a guideline to inform treatment planning requires evaluating (1) what 
symptoms or patient characteristics to assess, (2) when to administer those 
assessments, and (3) what subsequent treatment to provide, based on those 
assessments. Adaptive treatment strategies (ATSs) provide algorithms for guiding 
treatment decision making. These algorithms are based on patient characteristics 
and outcomes collected during the treatment process, and they provide guidelines 
regarding when, how, and for whom midcourse changes in the treatment approach 
should be initiated. They can, for example, operationalize when to determine that 
a patient is not likely to respond if a treatment strategy is continued, what the next 
treatment should be, and at what dose or intensity. The development of evidence-
based ATSs for adolescent depression not only has the potential to significantly 
improve treatment outcomes, but can also increase the efficiency and cost 
effectiveness of treatment by delivering treatments when and for whom they will 
do the most good.  
 
ATSs are developed and evaluated within the context of sequential multiple 
assignment randomized trials (SMARTs).29-31 In a SMART, subjects can be 
randomized multiple times, and these randomizations occur sequentially through 
time at selected critical decision points. The data collected in a SMART are used 
to infer the expected results under different treatment strategies and to determine 
the ATS leading to the most favorable outcomes. We propose to develop an 
algorithm-based ATS for adolescent depression that follows a stepped-care model 
of health care delivery. Stepped-care models recommend selecting an initial 
treatment that is the least restrictive among available empirically-based 
treatments.32 “Least restrictive” refers to all restrictions on the patient’s life and 
resources, including cost, physical effects of the treatment, and interference in the 
patient’s lifestyle. Treatments that are more restrictive (but potentially more 
effective) are reserved for patients who do not respond to the initial treatment. In 
this way, a stepped-care approach aims to achieve a positive treatment outcome 
with as little treatment as possible, which maximizes clinical benefits, minimizes 
burdens, and leads to more efficient and cost effective service delivery. Stepped-
care models have demonstrated feasibility and effectiveness in improving a 
variety of outcomes,33-35 including youth depression.36  
 
Stage 1 Treatment: 
We propose two ATSs that begin with psychotherapy. Psychotherapy does not 
carry a risk of adverse physical side effects, it is the most frequent treatment for 
adolescent depression,28 and many families report a preference for psychotherapy 
over medication.37-39 The psychotherapy provided will be interpersonal 
psychotherapy for depressed adolescents (IPT-A).40 IPT-A aims to address a key 
mechanism in the development and resolution of adolescent depression: 


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disruptions in interpersonal relationships (attachment/affiliation subconstruct of 
the Systems for Social Processes in the NIMH Research Domain Criteria (RDoC) 
matrix).41-43 IPT-A teaches skills that can address the relationship difficulties most 
closely related to the onset or maintenance of the adolescent’s depression. IPT-A 
has strong empirical support and has been implemented successfully in real-world 
settings.17,44,45 While CBT has been the focus of a greater number of empirical 
studies than IPT-A, the uptake of CBT in community practice has been 
underwhelming,46 and many challenges have been described in training 
community clinicians in CBT.47 The most frequently used therapy approaches for 
adolescent depression in community practice are family-based and 
psychodynamic.48 Given that the therapy approaches in IPT-A may be a bit more 
consistent with usual care, IPT-A may be an easier treatment approach to 
disseminate. The IPT-A treatment manual has been published by Guilford Press, 
and online training in IPT-A is also recently available via the Society of Clinical 
Child & Adolescent Psychology website (www.effectivechildtherapy.com), thus 
significantly increasing the feasibility of uptake of this intervention in community 
settings. 
 
The Adaptive Treatment Algorithm: 
Using data from a previous clinical trial of IPT-A, we examined whether there 
were early indicators of IPT-A treatment response that could be used to guide 
decisions regarding whether and when to intensify or augment treatment. We 
found that depressed adolescents who begin treatment with IPT-A can be 
classified as likely or not likely to respond to a full course of IPT-A (12 sessions 
delivered over 16 weeks) at week 4 and at week 8 of treatment (Preliminary Study 
1).49 At week 4, a cutoff of a 20% reduction in symptoms on the Hamilton Rating 
Scale for Depression (HRSD)50 represented the best combined sensitivity and 
specificity for predicting response status post-treatment (week 16). At week 8, a 
40% reduction in symptoms was required to predict week 16 response. The 
HRSD has demonstrated feasibility and reliability in community settings.50 It 
provides standardized feedback to clinicians and decreases idiosyncrasies that 
occur when clinicians make treatment decisions without use of a standardized 
measure.  
 
Stage 2 Treatments: 
For insufficient responders to IPT-A, we propose to test two approaches to 
intensifying treatment during stage 2: the addition of an SSRI and more intensive 
IPT-A (delivered twice per week). Five studies have examined the efficacy of a 
combination of psychotherapy and medication in comparison to psychotherapy 
alone and/or medication alone.18,51-54 Three studies found that the combined 
treatment approach was significantly more efficacious than monotherapy,18,51,52 
whereas the other two did not.53,54 Thus, adding an SSRI to IPT-A may be an 
effective option for some adolescents, though research support is not unequivocal. 
Studies have also found that psychotherapy delivered on a twice a week basis is 


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an effective treatment approach for depression.55-58 Most insurance panels will 
permit billing for twice per week sessions. Given many families’ preference for 
psychotherapy over medication,37-39 intensifying the therapy rather than adding an 
SSRI may yield more promising results because it is a more patient-centered 
treatment approach for some families. Attending therapy twice per week does add 
additional burden to families; however, it is time limited (4 weeks), and in our 
pilot study (Preliminary Study 2), we developed some strategies for increasing 
motivation and problem-solving obstacles, which resulted in good session 
attendance. To summarize, there are two ATSs embedded in our trial design:  
 
ATS 1:  Psychotherapists initiate weekly IPT-A.17,40,59 If at week 4 the adolescent 
has shown at least a 20% reduction in depressive symptoms, continue IPT-A. If at 
week 8, the adolescent has shown at least a 40% reduction in symptoms, continue 
IPT-A (12 sessions total). If the adolescent has not shown a sufficient reduction at 
week 4 or week 8, refer the adolescents to a psychopharmacologist to add an SSRI 
and continue weekly IPT-A sessions (12 sessions total).  
 
ATS 2:  Psychotherapists initiate weekly IPT-A.17,40,59 If at week 4 the adolescent 
has shown at least a 20% reduction in depressive symptoms, continue IPT-A. If at 
week 8, the adolescent has shown at least a 40% reduction in symptoms, continue 
IPT-A (12 sessions total). If the adolescent has not shown a sufficient reduction at 
week 4 or week 8, increase dose of IPT-A by scheduling sessions twice a week for 
4 weeks; then return to weekly IPT-A (16 sessions total). 
 
Further Refinement of the ATSs, Including Evaluation of Treatment Target 
Engagement: 
In this study, we are hypothesizing that our adaptive treatment algorithm, based 
on change in depression at weeks 4 and 8, will produce significantly better 
outcomes than usual care, in which therapists make decisions about treatment 
planning using their usual methods. However, we also expect that incorporating 
assessment of other patient characteristics, in addition to depressive symptoms, 
into the decision of whether and how to change treatment will likely increase the 
response rates further. NIMH’s new focus on experimental therapeutics is highly 
relevant here.60,61 In the experimental therapeutics paradigm, intervention 
evaluation focuses first on whether the intervention has an impact on the 
intervention’s proposed mechanism of action or “treatment target,” and second, 
on whether “target engagement” produces the proposed clinical effect.60,61 
SMARTs are ideal clinical trial designs for this. They have the distinct advantage 
of providing the opportunity to examine the impact of treatment target 
engagement during the initial (stage 1) treatment on the effectiveness of the 
subsequent (stage 2) treatment approach in a treatment sequence. For IPT-A, 
whose purported mechanism of action is improvements in interpersonal 
relationships, we can examine degree of improvement in adolescents’ 
interpersonal relationships during stage 1 (i.e. degree of target engagement), as a 


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tailoring variable for selecting the subsequent stage 2 treatment. At stage 2 in the 
current study, insufficient responders are randomized to an increased dose of IPT-
A or the addition of an SSRI. In this way, we can evaluate, among the insufficient 
responders who did not demonstrate target engagement, the comparative 
effectiveness of intensifying psychotherapeutic work on interpersonal skills to 
attempt to better engage the treatment target versus adding a different treatment 
approach (SSRI) that will address a different treatment target. The advantage of 
the SMART design is that stage 2 treatment assignment is not confounded with 
the tailoring variable (due to randomization), making inference on the effect of 
tailoring treatment less prone to bias.  
 
In addition to measures of IPT-A target engagement, we will also explore 
additional moderators of stage 2 treatments for insufficient responders to further 
refine the ATSs. The moderators selected represent previously identified 
predictors of IPT-A specifically or treatment for depression generally, and 
include: patient treatment preference,62,63  expectation of treatment outcome,64 
sociotropy (a personality trait representing the degree to which one’s self-concept 
and well-being are dependent on the how things are going in one’s 
relationships),65 depression severity,17 comorbid diagnoses,66 and stage 1 
treatment attendance.67  
 
Genetic and Epigenetic Relationships with disease risk and treatment response: 
The causality of mood disorders is complex and involves the interplay between 
genetic predisposition and non-genetic biological, psychological, and social 
factors. Studies have shown that mood disorders such as major depressive 
disorder are highly heritable, with genetic factors contributing 31-42% of disease 
risk.68 Since the completion of the Human Genome Project, research has 
identified multiple candidate genes displaying variable contributions to the risk of 
depression. Due to the wide variability in therapeutic response to SSRIs in the 
treatment of depression, studies have also focused on identifying pharmacogenetic 
predictors of drug response which would aid in therapeutic and dosing selection 
currently performed in ‘trial and error’ approaches. Earlier studies utilizing a 
hypothesis-driven, candidate gene study design to assess the relationship between 
genetics and SSRI treatment response in patients with depression focused on 
genes of the serotonergic, dopaminergic, glutamatergic, monoaminergic, 
neurotrophic and hypothalamic-pituitary-adrenal (HPA) axis systems: COMT,69,70 
HTR2A,71-73 HTR1A,74_ENREF_74 CNR1,74_ENREF_75 SLC6A4,75 NPY,76 
MAOA,70,77 IL1B, 70,78 GRIK4,79 BDNF, 70,72 GNB3,70 FKBP5,72 and ABCB1.70,80 
In addition, studies investigating the wide variability in SSRI treatment response 
have also investigated multiple pharmacokinetic markers, namely three 
cytochrome P450 (CYP) hepatic enzymes CYP2C19, CYP2D6, and CYP3A4, 
involved in SSRI metabolism. Previous studies have shown that genetic 
differences in CYP2C19 and CYP2D6 have been associated with differing serum 
concentrations of SSRIs such as escitalopram as well as treatment response.73,81-83  


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Multiple studies have also utilized hypothesis-generating, genome-wide 
association study (GWAS) approaches,84-87 although this work has primarily 
focused on adult populations with a need for investigations in younger patients. 
Nevertheless, analysis of antidepressant response data using a mixed linear model 
approach to estimate the proportion of phenotypic variance explained by genome-
wide polymorphisms has shown that common genetic variants explain a 
considerable proportion of individual differences in antidepressant response 
which has thus prompted further pharmacogenomic studies.88 
Despite the relatively high heritability of depression, there is considerable 
discordance within monozygotic twin pairs, implicating a role for non-genetic, 
presumably environmental, factors.89 One mechanism by which external 
environmental stimuli can have an impact on individual development is via 
epigenetic changes to gene expression. Epigenetics refers to dynamic 
modifications of the DNA structure influencing gene regulation that do not 
involve altering the DNA sequence. Exposure to pharmaceuticals, nutrition, 
exercise, and stress are capable of producing positive and negative epigenetic 
modifications with lasting effects on human development, metabolism and 
health.90 To date, DNA methylation is the most studied epigenetic modification. 
Previous studies suggest that DNA methylation plays a role in stress-related 
psychiatric disorders and, more specifically, in the development and treatment of 
depression.91 Early epigenetic studies in rodents focused on the promoter region 
of the glucocorticoid receptor gene NR3C1 and showed that maternal behavior 
and environment alters methylation profiles in hippocampal tissue, and that 
environmental improvement removed the differences in epigenetic profiles and 
improved the impaired stress response.92 In terms of treatment of depression, 
studies have also indicated that multiple antidepressants and mood stabilizers may 
exert part of their therapeutic action through epigenetic modification of DNA 
methyltransferase I (DNMT1) or histone deacetylase inhibition, altering 
methylation levels and thus affecting gene expression.93 To date, the majority of 
epigenetic studies investigating relationships with antidepressant treatment 
response have used a targeted approach examining a limited number of DNA 
methylation sites within specific gene loci, including SLC6A4, BDNF, FKBP5, 
OXTR, IL11, and MAOA.89  
Though much research has been performed in assessing the relationships between 
genetic and epigenetic markers with risk of depression, symptom severity, and 
treatment response, the majority have focused on adult patients and SSRI 
treatment modalities. The current trial provides a unique opportunity to 
retrospectively investigate genetic and epigenetic signatures in a well-defined 
cohort of adolescents diagnosed with depression. Furthermore, this trial focuses 
on non-pharmacological treatment interventions, namely interpersonal 
psychotherapy for adolescents. Genetic and epigenetic research utilizing this 
cohort of patients may aid in identifying genetic markers (gene polymorphisms or 
expression) or epigenetic signatures (DNA methylation levels) that correlate with 
difference in response to non-pharmacological treatment interventions, or identify 


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individuals who would benefit from the addition of SSRI treatment. Utilizing 
saliva collected longitudinally over the treatment course also offers significant 
benefits due to the non-invasive nature and ease of collection as well as the ability 
to detect DNA methylation and gene expression changes over treatment time.  
 
Implementation: 
The primary aim of this study is to validate the algorithm that is the basis of the 
adaptive treatment strategies proposed in this project. We have designed the ATSs 
to maximize the potential for implementation in community practice by 1) using 
an intervention that is easily accessible to professionals, 2) basing our treatment 
algorithms on an assessment measure that is free and available for public use, and 
3) automating the treatment algorithm in a user-friendly web-based program. In 
addition, we propose to integrate some components of implementation research 
into our effectiveness study to inform and facilitate future dissemination and 
implementation of these ATSs into broad clinical practice. Following Curran et 
al,94 we will follow a hybrid type I effectiveness-implementation design that tests 
the effects of the ATSs on clinical outcomes, while also observing and gathering 
information on implementation. Hybrid type I studies focus on process 
evaluations of barriers and facilitators to uptake/adoption efforts, and on 
identifying tools and training that would facilitate future implementation. 
Information is collected not only from patients and providers, but also from 
clinical and organizational leaders who would be responsible for rolling out the 
clinical intervention. Our process evaluation is informed primarily by the RE-
AIM framework (Reach, Effectiveness, Adoption, Implementation and 
Maintenance).95,96 Reach refers to how many eligible patients agree to the 
intervention. Effectiveness evaluates the intervention’s clinical outcomes. 
Adoption refers to the decision of the leadership and staff at the targeted settings 
to implement the intervention. Implementation refers to whether the intervention 
is implemented with high fidelity and consistency, as well as the cost of the 
intervention. Maintenance (not assessed in this study) refers to whether the 
clinical intervention is sustained after implementation support is withdrawn. We 
also include two elements from the Promoting Action on Research 
Implementation in Health Services (PARIHS) framework: (1) Evidence: the 
extent to which providers and staff believe there is research evidence, as well as a 
clinical need for the new intervention, and (2) Context: provider and staff 
perception of the organization’s leadership culture, staff culture, leadership 
feedback, readiness to change, and resources to support to new intervention. The 
results of the process evaluation will be used to inform future implementation 
efforts.97,98 
Preliminary Data:  
1. Early Prediction of Treatment Response with IPT-A (Gunlicks-Stoessel & 
Mufson, 2011).49 These data support the selection of the time points and criteria 
for classifying adolescents who begin treatment with IPT-A as “likely to respond” 


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or “not likely to respond” by the end of a 16-week course of IPT-A. 34 
adolescents participating in an RCT of IPT-A versus treatment as usual in school-
based health clinics were randomized to receive 12 sessions of IPT-A delivered 
over 16 weeks.17 The HRSD99 was administered by blinded evaluators at weeks 4, 
8, 12, and 16. Receiver operating characteristic (ROC) analysis identified week 4 
and week 8 as the best time points for predicting post-treatment (week 16) 
response (week 4: AUC=.78, p=.01; week 8: AUC=.81, p=.00). At week 4, a 
cutoff of 20% reduction in HRSD from baseline represented the best combined 
sensitivity (72.7%) and specificity (71.4%) for predicting post-treatment response. 
At week 8, a cutoff of 40% reduction in HRSD from baseline represented the best 
combined sensitivity (72.7%) and specificity (83.3%).  
 
2. A Pilot SMART of 4 ATSs Beginning with IPT-A (Gunlicks-Stoessel et al., 
2016).38 These data support the feasibility, acceptability, and preliminary efficacy 
of the two proposed ATSs. Forty adolescents with a depression diagnosis enrolled 
in a 16-week SMART, with an initial treatment plan of 12 sessions of IPT-A. 
Adolescents were randomized to a week 4 or a week 8 decision point for 
identifying potential non-responders.  Adolescents who were classified as 
sufficient responders (> 20% reduction in HRSD99 at week 4 or > 40% reduction 
in HRSD at week 8) continued the initial treatment plan of 12 IPT-A sessions. 
Adolescents who were classified as insufficient responders were randomized a 
second time to the addition of fluoxetine (FLX) or an additional 4 IPT-A sessions 
scheduled twice a week (increase from 12 to 16 sessions). The SMART study 
procedures and ATSs were feasible and acceptable to families and therapists. 
   
a. Subject Recruitment, Adherence, and Retention. 145 adolescents were pre-
screened by telephone, 63 signed consent/assent, and 40 were randomized. These 
rates are comparable or better than other published clinical trials of treatments for 
adolescent depression.18,36,100,101 Adherence and retention were high (see below): 
 
Stage 2 
Treatment 
Number who 
Initiated Stage 
2 Treatment 
Randomized 
Treatment Plan 
Mean (SD) Session 
Attendance 
Completed 
Treatment 
No Change  
(n = 17) 
17/17 
12 IPT-A sessions 
11.2 (1.8) 
14/17 
Add Medication  
(n = 11) 
10/11 
12 IPT-A sessions 
6-8 medication 
sessions 
11.7 (1.4) IPT-A 
5.3 (2.6) medication 
9/11 
Increase IPT-A 
(n = 11) 
10/11 
16 IPT-A sessions 
15.4 (.9) 
8/11 
* One adolescent dropped out prior to determination of stage 2 treatment 
 
b. Therapist Fidelity. Twelve therapists, eleven of which had no prior experience 
delivering IPT-A, delivered the ATSs in this study. Therapists were adherent to 


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VERSION DATE: 09/05/2023 
 
 
 
Page 14 of 66 
 
implementation of the ATSs. 100% of therapists administered HRSD at 
appropriate session and initiated and communicated the appropriate stage 2 
treatment to families. Interrater reliability of the HRSD (Pearson’s r) was .82. 
Therapists’ HRSD ratings at week 4 and 8 were correlated with Independent 
Evaluators’ CDRS-R ratings (week 4: r = 78, p = .00; week 8: r = .63, 
p=.00).Therapists also implemented IPT-A with a high level of adherence (mean 
adherence = 3.30 on scale of 1 to 4).  
 
c. ATS Acceptability. Adolescents’ and parents’ treatment satisfaction (CSQ-8) was 
high (adolescents: M = 27.2, SD = 3.9; parents: M = 27.0, SD = 4.0).   
 
d. Parents’ and Adolescents’ Attitudes Regarding Medication and More Intensive 
Therapy.  These data support (1) parents’ preferences for a stepped-care model of 
treatment that begins with therapy only, and (2) parents’ preference for 
augmenting treatment for insufficient responders by increasing the dose of IPT-A.  
Prior to treatment, adolescents and parents reported their attitudes regarding the 
possible type of change to the treatment plan for insufficient responders. They 
also reported their attitudes right after they were informed of the change to 
treatment and at week 16. Prior to treatment, many parents reported negative 
attitudes regarding adding medication (37% neg, 33% neu, 30% pos) and were 
more positive about the possibility of increasing the dose of IPT-A (70% pos, 
22% neu, 7% neg). Among parents of insufficient responders who were 
randomized to add medication, most parents reported feeling negative about 
adding medication right after they were informed of the change (60% neg, 20% 
neu, 20% pos). By post-treatment, 50% felt positive, 25% felt negative, and 25% 
felt neutral. All parents of adolescents randomized to increased IPT-A felt 
positively about the change both right after they were informed of the change and 
post-treatment. Most adolescents reported feeling positive about both treatment 
augmentation strategies at both pre-treatment (add meds: 46% pos, 31% neu, 23% 
neg; increase IPT-A: 54% pos, 23% neu, 23% neg) and post-treatment (add meds: 
71% pos, 14% neu, 14% neg; increase IPT-A: 80% pos, 20% neu, 0% neg).  
 
e. Treatment Outcomes. It was better to begin assessing for insufficient response and 
altering the treatment plan at week 4 rather than waiting until week 8 to make to 
first assessment and possible treatment change. Outcomes for insufficient 
responders randomized to add FLX or increase the dose of IPT-A are below: 


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Page 15 of 66 
 
 
 
Week 4 
M (SD) 
Week 8 
M (SD) 
ES 
(d) 
Insufficient 
Responder:  
Add FLX   M 
(SD) 
Insufficient 
Responder: 
Increase IPT-A  
M (SD) 
ES 
(d) 
Children’s Depression 
Rating Scale 
   Baseline 
   Week 16 
 
55.90 (10.36) 
34.76 (13.29) 
 
55.25 
(10.99) 
41.06 (8.19) 
 
 
.57 
 
58.00 (11.00) 
38.10 (10.51) 
 
56.45 (9.06) 
37.75 (9.02) 
 
 
.04 
Children’s Global 
Assessment Scale 
   Baseline 
   Week 16 
 
50.35 (5.17) 
66.41 (15.28) 
 
51.65 (6.92) 
60.44 (6.37) 
 
 
.51 
 
   50.73 (6.48) 
62.50 (14.70) 
 
49.64 (5.28) 
63.25 (8.71) 
 
 
.06 
Clinical Global 
Improvement 
   Week 16 
 
2.25 (.97) 
 
2.80 (.95) 
 
.57 
 
2.64 (1.03) 
 
2.45 (.69) 
 
.22 
 
3. Feasibility of the Service Setting (Bloomquist, et al., in press).102 Twenty-eight 
depressed adolescents participated in a pilot study of CBT adapted for delivery 
within an intensive outpatient program. Treatment involved 24 hours of CBT 
skills training for youth and 12 hours of CBT information/support for parents 
delivered in groups over six weeks. Out of 24 days delivered over six weeks, 
adolescents attended at high rates (mean 18.7 days or 78%; median 20 days or 
83%) with a majority of parents attending the information parent groups. Fidelity 
indicators of program delivery derived from intermittent live research technician 
observations showed acceptable to high levels of fidelity (teen skills: adherence 
82%, quality of delivery 85%; parent skills: adherence 70%, quality 98%). 
Adolescents demonstrated significant reductions in depressive symptoms  (pre-
treatment BASC-2:103 M = 62.90, SD = 18.60, post-treatment: M = 55.50, SD = 
12.78).  
 
3.0 
Study Endpoints/Events/Outcomes 
Primary Endpoint/Event/Outcome: Children’s Depression Rating Scale-Revised 
(CDRS-R)104  
Secondary Endpoint(s)/Event(s)/Outcome(s): Beck Depression Inventory-II (BDI-
II),105 Clinical Global Improvement (CGI),106 Conflict Behavior Questionnaire 
(CBQ); Inventory of Parent and Peer Attachment (IPPA),107 Issues Checklist 
(IC),108 adolescents’ and parents’ perceptions of their interpersonal behaviors 
during a conflict negotiation task,109,110 cost effectiveness, qualitative findings 
from the implementation-focused process evaluation, genetic variants, gene 
expression, DNA methylation levels. 


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4.0 
Study Intervention(s)/Investigational Agent(s) 
Description:  
Interpersonal Psychotherapy for Depressed Adolescents (IPT-A).40 IPT-A is an 
evidence-based intervention that aims to decrease depressive symptoms by 
helping adolescents improve their relationships and interpersonal interactions. It 
addresses one or more of four interpersonal problem areas: grief, role disputes, 
role transitions, and interpersonal deficits. The primary treatment techniques in 
IPT-A include emotion identification/expression, linking interpersonal events to 
mood, communication analysis, communication skill building, decision analysis, 
role playing, and assignment of interpersonal experiments (i.e. homework). In 
clinical trials, depressed adolescents treated with IPT-A demonstrated fewer 
depressive symptoms and better psychosocial functioning post-treatment than 
adolescents in control conditions.17,59,111 
Selective Serotonin Reuptake Inhibitors (SSRIs). Fluoxetine, escitalopram, 
citalopram, fluvoxamine, and sertraline have demonstrated efficacy, with 
response rates of 40-60%.12-16 Fluoxetine will be the first choice SSRI, given the 
literature supporting its efficacy and tolerability, and its FDA approval. 
Escitalopram will be the second choice since it has acquired FDA approval for 
adolescents. The psychopharmacologist may choose to select escitalopram first if 
clinically indicated when there is a previous history of intolerance to fluoxetine, 
based on family history or preference, and inability to achieve an adequate 
fluoxetine dose. Citalopram, fluvoxamine, and sertraline may also be selected first 
if clinically indicated, as above. 
 
Usual Care (UC). UC psychotherapists will implement therapy procedures that 
they usually use and believe to be effective in clinical practice. The clinic 
directors characterize the psychotherapy currently provided in the clinics as 
“eclectic,” with a combination of psychodynamic, client-centered, family-
focused, and cognitive behavioral approaches utilized. Therapy will continue until 
the therapist and/or family decides to terminate services. Therapists will use 
whatever methods they usually use to make decisions regarding the frequency of 
therapy sessions (weekly, twice per week, every other week, etc) and whether to 
refer the adolescent to start an SSRI. If an adolescent is referred for medication 
management, the psychopharmacologist will follow the medication management 
procedures that they usually use and believe to be effective in clinical practice.   
Drug/Device Handling:  
The psychopharmacologist will give the adolescent a prescription for the SSRI 
that they will then fill with a licensed pharmacy.  
IND/IDE: N/A 
Biosafety: N/A  
 


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5.0 
Procedures Involved 
Study Design:  
Two hundred adolescents who present for treatment for depression at community 
mental health clinics (PrairieCare and Minnesota Mental Health Clinics) will be 
recruited to participate in a sequential multiple assignment randomized trial 
(SMART; see Figure 1). Subjects will be initially randomized using a 2:1 
allocation ratio to IPT-A ATS or UC. Subjects randomized to IPT-A AST who are 
insufficient responders at week 4 or 8 will be re-randomized using a 1:1 allocation 
ratio to the addition of an SSRI or increased dose of IPT-A. Subjects will be block 
randomized using randomly permuted blocks of 2 and 4. The first randomization 
will be stratified by clinic site, CDRS-R (< 55 and > 55), and CBQ strata (< 9 and 
> 9).108,112 The second randomization will be stratified by clinic site, HRSD (< 20 
and > 20), and CBQ strata (< 9 and > 9). Assessments will be administered by 
evaluators who are blind to treatment condition at baseline and weeks 4, 8, 12, 16, 
and 36. 
 
 
 
Study Procedures:  
IPT-A Adaptive Treatment Strategies (IPT-A ATSs).  Adolescents randomized to 
the IPT-A AST condition will begin IPT-A with an initial treatment plan of 12 
weekly sessions. Therapists will be staff therapists already employed by 
PrairieCare and Minnesota community mental health clinics. Therapists are 
masters level clinicians (LPCC, LICSW, LP). Therapists will be trained and 
supervised in IPT-A and the AST procedures by Dr. Gunlicks-Stoessel (Project 
Director, Kristina Reigstad, PsyD, LP, may provide supervision at times when Dr. 
Gunlicks-Stoessel is not available. Dr. Reigstad has been previous trained in IPT-


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VERSION DATE: 09/05/2023 
 
 
 
Page 18 of 66 
 
A by Dr. Gunlicks-Stoessel). As part of treatment, therapists will administer the 
HRSD at weeks 1, 4, and 8. Therapists will enter the scores into a secure HIPAA-
compliant web application (Research Electronic Data Capture; REDCap). 
REDCap will be programmed to calculate the percent change in HRSD from 
week 1 to week 4, and from week 1 to week 8, as well as the algorithm for 
specifying the stage 2 treatment decision. If the adolescent has demonstrated < 
20% reduction on the HRSD at week 4, REDCap will trigger the randomized 
stage 2 treatment: increase dose of IPT-A or add SSRI. If the adolescent has 
demonstrated > 20% reduction in depression on the HRSD at week 4, REDCap 
will trigger the therapist to inform the family that no change in treatment will be 
made and the adolescent will continue the initial treatment plan of 12 IPT-A 
sessions. If an adolescent who was a week 4 sufficient responder continues to be a 
week 8 sufficient responder (> 40% reduction in depression on the HRSD), 
REDCap will trigger the therapist to inform the family that no change in treatment 
will be made and the adolescent will continue the initial treatment plan of 12 IPT-
A sessions. If an adolescent who was a week 4 sufficient responder becomes a 
week 8 insufficient responder (< 40% reduction in depression on the HRSD), 
REDCap will trigger the randomized stage 2 treatment: increase dose of IPT-A or 
add SSRI. If an adolescent misses the week 4 or week 8 session, the HRSD will 
be completed at  the next attended session and the decision regarding stage 2 
treatment will occur at that session. Adolescents randomized to increase IPT-A 
will receive an additional four IPT-A sessions scheduled twice a week (16 
sessions total). Adolescents randomized to add SSRI will be referred to a 
psychopharmacologist to start an SSRI in addition to completing the remainder of 
their 12 IPT-A sessions.  
 
Selective Serotonin Reuptake Inhibitors (SSRIs). Adolescents randomized to 
receive an SSRI at stage 2 will be prescribed an SSRI by a staff 
psychopharmacologist already employed by the mental health clinics. 
Psychopharmacologists will be psychiatrists and/or psychiatric nurse 
practitioners. They will receive training in the medication protocol from co-
investigator, Kathryn Cullen, MD. Dr. Cullen will also provide quarterly 
consultation. Fluoxetine will be the first choice SSRI. Escitalopram will be the 
second choice. The psychopharmacologist may choose to select escitalopram first 
if clinically indicated when there is a previous history of intolerance to fluoxetine, 
based on family history or preference, and inability to achieve an adequate 
fluoxetine dose. Citalopram, fluvoxamine, and sertraline may also be selected first 
if clinically indicated, as above. The medication management protocol will follow 
standard clinical practices. Prior to initiation of the SSRI, all female patients will 
be asked, “Is it possible that you could be pregnant?” and “Have you recently or 
are you currently having any unprotected sex?”. If a female patient endorses 
either of these questions, they will be counseled on the risks of taking an SSRI 
and encouraged to practice safe sex practices. If the patient believes that she may 
be pregnant, she will be instructed to take a pregnancy test before beginning 


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medication. If a patient is pregnant, medication management will not be initiated. 
If a female adolescent who is taking an SSRI becomes pregnant over the course of 
the trial, her psychopharmacologist will provide council on the potential risks and 
benefits of continuing the medication. If the patient and psychopharmacologist 
decide to discontinue the medication, the patient can continue to receive IPT-A 
and continue to participate in the study assessments. Medication sessions will be 
scheduled weekly for the first two weeks, biweekly for the subsequent 6 weeks, 
and monthly thereafter. Sessions will include assessment of vital signs, adverse 
effects, safety, and symptomatic response. The medication dosing will follow 
published guidelines.10,113 Psychopharmacologists will be advised to decrease the 
dose as necessary at any point to address tolerability problems. Adolescents will 
be asked to bring back the bottle of pills to each appointment to track adherence. 
_ENREF_10_ENREF_113 
 
 
 
 
 
 
 
Usual Care (UC). Adolescents randomized to UC will receive care as usual, as 
described above in Section 4 
Assessments. Assessments will be administered by independent evaluators who 
will remain blind to treatment condition. They will be required to have at least a 
Master’s degree and one year experience administering clinical interviews, and 
they will be trained in the study measures by Dr. Gunlicks-Stoessel and Dr. 
Reigstad. Participants will consent to their assessment sessions being audio 
recorded. The recordings are for fidelity monitoring. Participants will not be able 
to opt out of the audio recording. 
The baseline research assessment will take approximately 5 hours (split into two 
visits), the week 4 and week 8 assessments will each take approximately 2 hours, 
the week 12 assessment will take approximately one hour, and the week 16 and 
week 36 assessments will take approximately 3 hours each.  
 
Saliva Collection. During each assessments point (Baseline, Week 4, Week 8, 
Week 16), a study staff member will provide the adolescent participant with 
written step-by-step instructions for the collection of a saliva sample using the 
Oragene DISCOVER saliva self-collection kit (DNA Genotek, Ottawa, ON, 
Canada, Catalog number OGR-500) and ask the participant to not eat, drink, 
smoke or chew gum for 30 minutes before giving a saliva sample. The total 
amount of saliva collected is approximately 2 milliliters (about half a teaspoon) 
and will take approximately 5 minutes to complete.  
SSRI Titration Schedule 
Medication 
Starting
Increments
Effective
Maximum
 
mg/d 
  mg 
mg 
mg 
Citalopram 
10 
10 
20 
60 
Fluoxetine 
10 
      10–20 
20 
60 
Fluvoxamine 
50 
50 
150 
300 
Sertraline 
25 
12.5–25 
50 
200 
Escitalopram 
5 
5 
10 
20 


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Nucleic Acid (DNA and RNA) Extraction. Collected saliva samples will be stored 
in the laboratory of Dr. Jeffrey R. Bishop at the University of Minnesota (516 
Delaware Street S.E. Phillips-Wangensteen Building room B150 Minneapolis, 
MN 55455). Saliva samples will be processed for both DNA and RNA using the 
prepIT extraction kit following the manufacturer’s standard protocol (DNA 
Genotek, Ottawa, ON, Canada, catalog number PT-L2P-5). Extracted DNA will 
be quantified by the Quant-iT™ PicoGreen™ dsDNA Assay Kit (Invitrogen, 
Waltham, MA USA, Catalog number P7589) using the Synergy HTX mult-imode 
plate reader (BioTek Instruments, Winooski, VT, USA). Extracted RNA will be 
quantified by the Quant-iT™ RiboGreen™ RNA Assay Kit (Invitrogen, 
Waltham, MA USA, Catalog number R11490) using the Synergy HTX mult-
imode plate reader. 
 
Genotyping and DNA methylation detection. DNA extracted from saliva 
specimens will be standardized to a working concentration of either 10ng/µl prior 
to genotyping or 25ng/µl prior to DNA methylation assessment. Targeted gene 
variants will be genotyped using either TaqMan SNP Genotyping assays and the 
Applied Biosystems 7500 Real Time PCR system (Applied Biosystems, Foster 
City, CA, USA), or Restriction Fragment Length Polymorphism (RFLP) 
performed by fragment analysis on the 3730 Genetic Analyzer (Applied 
Biosystems). Genome-wide scale genotyping will be performed using the 
Infinium PsychArray that includes 265,000 proven tag SNPs found on the 
Infinium Core-24 BeadChip, 245,000 markers from the Infinium Exome-24 
BeadChip, and 50,000 additional markers associated with common psychiatric 
disorders (Illumina, San Diego CA, USA) or a comparable alternative depending 
on price and availability. For methylation detection studies, DNA extracted from 
saliva specimens will be bisulfite-converted using the EZ DNA Methylation Kit 
(Zymo Research, Irvine, CA, USA). Bisulfite-modified DNA will be PCR-
amplified using primers designed to cover target gene regions for CpG site DNA 
methylation detection, and sequenced using the Illumina MiSeq system following 
a standardized protocol at the University of Minnesota Genomics Core facility 
(UMGC). Genome-wide methylation assessments will be performed using the 
Infinium MethylationEPIC BeadChip Kit (Illumina) (or comparable alternative) 
which interrogates over 850,000 methylation sites quantitatively across the 
genome at single-nucleotide resolution.  
 
Gene Expression Studies. RNA extracted from saliva specimens will be 
standardized to a working concentration of 200ng/µl prior to gene expression 
analysis. Expression analysis of target genes will be performed using the 
following: 1) TaqMan® Gene Expression Assays and the Applied Biosystems 
7500 Real Time PCR system (Applied Biosystems, Foster City, CA, USA), and 2) 
nCounter® expression panels (neuropathology, inflammation, immunology, and 
miRNA) and the NanoString nCounter Analysis System (NanoString 


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Technologies, Seattle, WA) available through the Univeristy of Minnesota 
Genomics Core Center (UMGC). Genome-wide gene expression analysis will be 
performed using a next-Generation sequencing approach of double-stranded 
cDNA generated by reverse-transcription of RNA, known as RNA-Seq, which has 
become the standard method for genome-wide gene expression analysis. Strand-
specific RNA-Seq library preparation and NGS using the Illumina MiSeq System 
will be performed at the UMGC.    
 
Demographic, Medical, and Social History 
• Demographics Form collects information regarding demographics, family 
constellation, and school functioning. 
• Medical History collects comprehensive medical and developmental information 
about the adolescent.  
• NDA Information Form collects information regarding legal name (according to 
birth certificate) and municipality of birth, as is required to report for the NIMH 
data archive. 
• Pronouns Information Form collects information regarding participants’ preferred 
pronouns. 
• Impact of COVID-19 assesses parents’ and adolescents’ perceptions of how 
COVID-19 has impacted their family’s financial situation, stress, emotional well-
being, physical well-being, and relationships and modes of communication with 
others.  
 
Adolescent Psychiatric Symptoms & Diagnoses 
• Beck Depression Inventory-II (BDI-II)105 is a self-report measure that assesses the 
severity of depressive symptoms. 
• Children’s Depression Rating Scale-Revised (CDRS-R) 104 is a clinician-
administered semi-structured interview conducted with adolescents and parents 
that assesses depressive symptoms. 
• Clinical Global Improvement (CGI)106 is used in clinical trials to track change in 
patients’ clinical status with treatment.   
• Children’s Global Assessment Scale (C-GAS)114 is used in clinical trials to track 
change in general (global) functioning for youth under age 18. 
• Columbia Suicide Severity Rating Scale (C-SSRS)115 is a clinician-administered 
standardized suicidal rating system that is based on definitions of suicidality 
derived from empirical findings on the phenomenology of suicidality and 
identified predictive and risk factors.   
• Hamilton Rating Scale for Depression (HRSD)99,116 is a clinician-administered 
semi-structured interview assessing depressive symptoms. It is widely used with 
adolescents.117 
• Schedule for Affective Disorders and Schizophrenia for School-aged Children – 
Present and Lifetime Version (K-SADS-PL)118 is a clinician-administered semi-


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structured interview conducted with adolescents and parents that assesses present 
episode and lifetime history of DSM psychiatric diagnoses.  
• Side Effects Form for Children and Adolescents119 is a commonly used measure 
of treatment-related adverse events and side effects observed in children and 
adolescents receiving pharmacological treatment.   
 
Assessment 
Informant 
Base-
line 1 
Base-
line 2 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
36 
Demographic, Medical, and Social History 
Demographics 
Parent 
Adolescent 
 
X 
 
 
 
 
 
Medical History 
Parent 
 
X 
 
 
 
 
 
Preferred 
Pronouns 
Adolescent 
 
X 
 
 
 
 
 
NDA 
Information 
Parent 
 
X 
 
 
 
 
 
Impact of 
COVID-19 
Parent 
Adolescent 
 
X 
X 
X 
X 
X 
X 
Adolescent Psychiatric Symptoms & Diagnoses 
 BDI-II 
Adolescent 
 
X 
X 
X 
X 
X 
X 
CDRS-R 
Adolescent 
Parent 
X 
 
X 
X 
X 
X 
X 
CGI 
Adolescent 
 
X 
X 
X 
X 
X 
X 
C-GAS 
Adolescent 
X 
 
X 
X 
X 
X 
X 
C-SSRS 
Adolescent 
X 
 
X 
X 
X 
X 
X 
HRSD*  
Adolescent 
 
X 
X 
X 
 
 
 
K-SADS-PL  
Adolescent 
Parent 
X 
X 
 
 
 
X 
X 
Side Effects 
Adolescent 
 
X 
X 
X 
X 
X 
 
Interpersonal Processes 
CBQ 
Adolescent 
Parent 
 
X 
X 
X 
X 
X 
X 
IPPA 
Adolescent 
 
X 
X 
X 
X 
X 
X 
P-A Conflict 
Task    
Adolescent 
Parent 
 
X 
X 
X 
 
X 
 
Candidate Treatment Moderators 
ET 
Adolescent 
Parent 
 
X 
X 
X 
X 
X 
X 
SASC  
Adolescent 
 
X 
 
 
 
 
 
SOCQ  
Adolescent 
 
X 
X 
X 
 
 
 
COVID-19 Measures 
Impact of 
COVID-19 
Adolescent 
Parent 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Implementation-Focused Process Evaluation 
ATA 
Adolescent 
Parent 
 
X 
 
 
 
X 
 
CSQ-8 
Adolescent 
Parent 
 
 
 
 
 
X 
 
Satisfaction 
with Telehealth 
Adolescent 
Parent 
 
 
 
 
 
X 
 
ATA-T 
Therapists 
 
 
 
 
 
X 
 


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Interpersonal Processes 
• Conflict Behavior Questionnaire (CBQ)120 is a self-report measure that assesses 
parent-child communication, conflict, and relationship functioning. The CBQ will 
be completed by adolescents and parents. 
• Inventory of Parent and Peer Attachment (IPPA_ENREF_107)107 is a self-report 
measure of adolescents’ degree of mutual trust; communication quality; and anger 
and alienation with their mother, father, and a close peer.    
Parent-Adolescent Conflict Task. Issues Checklist (IC)108 consists of 50 typical 
topics of parent-adolescent conflict. For each issue, adolescents and parents 
indicate whether it was a topic of discussion during the last month and the 
intensity of the discussion. It has frequently been used as a means of identifying a 
topic for observational assessments of parent-adolescent interactions. Conflict 
Negotiation Task. Using the IC, a topic that both the parent and adolescent rated 
as a source of frequent and moderately heated discussions will be identified. 
Parents and adolescents will spend 15 minutes describing the issue and attempting 
to resolve the problem.121 Participants will consent to their conflict discussion 
being videotaped. Participants will not be able to opt out of the video recording. 
In response to Covid-19, video recording will be completed using Zoom, a 
HIPAA-compliant web-based platform. The option of recording to the cloud is 
disabled, and instead the recording will save to the research staff’s hard drive. 
The recording will then be uploaded to Box Secure Storage and promptly 
deleted off the hard drive to maintain HIPAA compliance. Video-Recall 
Procedure.109,110 At Baseline and Week 16 appointments, adolescents and parents 
will view the videotape twice. First they will rate on a 5-point Likert scale the 
extent to which their own behaviors were supportive, conflictual, humorous, 
submissive (giving in), and sarcastic. After each 15-second portion of the video, a 
computer will pause the tape for 15 seconds, and the adolescents and parents will 
complete the rating scales, considering the full 15-second segment of the 
discussion. They will rate 32 segments, for a total of 8 minutes of interaction. 
Subsequently, parents and adolescents will view the same 8-minute portion of 
videotape again and repeat the procedure, this time rating the extent to which the 
behaviors of the other person indicated support, conflict, humor, submission, and 
misunderstanding. Adolescents’ and parents’ ratings for themselves and for each 
other will be separately aggregated for a total score for each behavior. At 
Staff 
Background 
Information 
Therapists & 
Clinic staff 
 
Therapists: At start of study 
participation 
Staff: At the end of the study 
EBPAS-36 
Therapists & 
Clinic staff 
 
Therapists: at start and end of study 
participation 
Staff: At the end of the study 
ORCA 
Therapists & 
Clinic staff 
 
Therapists: at end of study 
participation 
Staff: At the end of the study 
Implementation 
interview 
Therapists & 
Clinic staff 
 
Therapists: at end of study 
participation 
Staff: At the end of the study 
 
*completed as part of treatment; not a research measure 


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Baseline, Week 4, Week 8, and Week 16 appointments, adolescents and parents 
will also complete a shortened version of this task. They will rate on a 5-point 
Likert scale the extent to which their own behaviors were supportive, conflictual, 
humorous, submissive (giving in), and sarcastic, considering the entire duration of 
the conflict discussion. Subsequently, they will then repeat the procedure this time 
rating the extent to which the behaviors of the other person indicated support, 
conflict, humor, submission, and misunderstanding, considering the entire 
duration of the conflict discussion. Electrocardiograms.  
 
Candidate Treatment Moderators  
• Expectations for Treatment (ET)122 assesses adolescents’ and parents’ 
expectations of how successful and suitable they think their treatment will be. 
• Sociotropy-Achievement Scale for Children (SASC)123 is a self-report measure 
that assesses sociotropy (the degree to which one values his/her interpersonal 
relationships) and achievement-orientation (the degree to which one values 
achievement and goal attainment). 
• Stages of Change Questionnaire (SOCQ)124,125 is an assessment of an individual’s 
awareness of life problems and readiness to make changes in their behavior to 
address these problems. It provides scores for the four stages of readiness to 
change: precontemplation, contemplation, action, and maintenance. It has been 
adapted for use with adolescents.124 
 
Cost Effectiveness 
• Clinic Record Review. All treatment providers will keep detailed records on study 
patients, following their clinic’s protocol. Records will include type of treatment 
(psychotherapy, medication management), treatment duration, session attendance, 
no-shows/cancellations, telephone contacts, and other data required for service 
and cost documentation.  
• The Child and Adolescent Services Assessment (CASA)126 is a reliable and valid 
measure that will be used to assess services received by the youth during and 
following the intervention.  
 
Treatment Fidelity and Characterization 
• Recordings of Therapy Sessions. Participants will consent to their treatment 
sessions being recorded. The recordings are for fidelity monitoring and to code 
and characterize the usual care condition. Participants will not be able to opt out 
of the recording.  
• ATS Implementation Checklist is an ATS fidelity measure that includes a 
checklist of procedures to be implemented (administers the HRSD, communicates 
the correct stage 2 treatment, etc.) and a likert scale score of effectiveness in 
communicating the stage 2 treatment (e.g. effectively addresses questions, “sells” 
the treatment to increase engagement). It is completed based on the audiotape of 
each therapy session. 


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• IPT-A Supervision Checklist127 is a IPT-A fidelity rating scale based on the 
audiotape of each therapy session.  
• Therapy Process Observational Coding System for Child Psychotherapy-Revised 
Strategies Scale (TPOCS-RS)128 is a psychotherapy coding system. It consists of 
five theory-based subscales (Cognitive, Behavioral, Psychodynamic, Family, and 
Client-Centered) along with eight items that represent interventions that are 
considered to play a meaningful role in child therapy but are not associated with a 
specific subscale (e.g., homework). The TPOCS-RS has been shown to have 
strong reliability and validity.129 
• Psychiatric Medication Log tracks all psychiatric medications received by the 
adolescent during the course of the study.  
 
Implementation-Focused Process Evaluation: 
• Adaptive Treatment Attitudes (ATA)38 assesses adolescents’ and parents’ 
attitudes regarding changing the adolescents’ treatment plan and the type of 
treatment change for insufficient responders.  
• Client Satisfaction Questionnaire (CSQ-8)130 is a self-report instrument used to 
assess adolescents’ and parents’ satisfaction with treatment.   
• Satisfaction with Telehealth assesses adolescents’ and parents’ satisfaction with 
receiving services via telehealth. It was adapted from the Telehealth Usability 
Questionnaire (TUQ).  
• Adaptive Treatment Attitudes – Therapists (ATS-T)38 assesses therapists’ 
attitudes regarding changing the adolescents’ treatment plan and the type of 
change to the treatment plan for insufficient responders.  
• Clinic Staff Background Information assesses previous work experience, 
educational background, demographic characteristics, and approach to therapy. 
•  and attitudes about different treatment approaches.  
• Evidence-Based Practice Attitude Scale-36 (EBPAS-36)131 is a brief and 
pragmatic measure of attitudes to evidence-based practices. 
• Research Team Observational Log will document interactions that research staff 
have with patients, treatment providers, other clinic staff, or members of the 
leadership that provide information regarding attitudes about the ATSs or 
perceived barriers or facilitators to their adoption, implementation, and 
maintenance.  
• Post-Treatment Interviews with Treatment Providers and Leadership will include 
assessment of opinions regarding the intervention and the impact of the 
intervention on the clinic, providers’ interactions with patients, and staff 
workload. They will be asked about barriers and facilitators to adopting and 
implementing the intervention as part of the clinic’s standard care. Suggestions 
will be elicited regarding resources, tools, and training that would be needed to 
deliver the intervention and integrate it into regular practice. 
• Organizational Readiness to Change Assessment (ORCA) Evidence Scales132 
assesses clinic staff opinions of the intervention based on their perception of its 


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research evidence, their clinical experience, and their perception of patient 
attitudes. It also assesses their perceptions of colleagues’ opinions. 
• ORCA Context Scales132 assesses clinic staff perceptions of the organization’s 
leadership culture, staff culture, leadership feedback, readiness to change, and 
resources to support practice changes. 
 
Follow-Up: Assessment schedule and measures are described above. 
Individually Identifiable Health Information: This research will involve the use of 
individually identifiable health information. We will have all participants 
complete a HIPAA authorization form. We will follow UMN Privacy Office 
Policies  
Use of radiation: N/A  
Use of Center for Magnetic Resonance Research: N/A 
6.0 
Data and Specimen Banking 
Storage and Access: All data resulting from the proposed project will be shared 
via the National Database for Clinical Trials (NDCT). Qualified researchers can 
request access to shared data in NDCT. Researchers can view summary-level 
data, or can request access to query and download subject-level data. Researchers 
who would like to access shared must complete a Data Use Certification (DUC) 
form and submit it for review by a Data Access Committee. There are three 
criteria researchers must meet to be eligible to request access: (1) the researcher 
must have a research-related need to access the data, (2) the researcher must be 
associated with an NIH-recognized research institution, defined as an institution 
registered in the NIH electronic research administration system (eRA Commons) 
and have the approval of an authorized signatory official of that institution, and 
(3) the researcher’s institution must have an active Federalwide Assurance 
(FWA.) 
Biological specimens: All biological specimens (saliva, DNA, and RNA) 
collected through this protocol will be stored in the laboratory of Dr. Jeffrey R. 
Bishop at the University of Minnesota (516 Delaware Street S.E. Phillips-
Wangensteen Building room B150 Minneapolis, MN 55455). All specimens will 
be labeled and stored with a de-identified study specimen number, not with any 
personal or protected health information. 
Data: All data will be de-identified via the use of a Global Unique Identifiers 
(GUIDS) and shared. We will work with the NIMH to create data dictionaries that 
are relevant to the research. 
Release/Sharing: The researchers will work with the NIMH to determine an 
appropriate schedule for sharing the data with the research community. 
7.0 
Sharing of Results with Participants 


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No individual results will be shared with participants or others (e.g., participants’ 
primary care physicians).  
 
8.0 
Study Duration 
• 
Duration anticipated for an individual participant’s participation in the 
study: 36 weeks 
• 
Duration anticipated to enroll all study participants: 4 years 
• 
Duration anticipated to complete all study procedures and data analysis: 5 
years 
9.0 
Study Population 
Adolescent Inclusion Criteria:  
1) Male and female adolescents (ages 12-18)  
2) meet DSM-V criteria for a primary diagnosis of Major Depressive Disorder, 
Persistent Depressive Disorder, or Depressive Disorder NEC (based on the K-
SADS118);  
3) demonstrate symptoms of depression (CDRS-R104 > 36); and 
4) demonstrate impairment in functioning (CGAS114 < 65) during a baseline 
evaluation conducted by an IE.  
Adolescent Exclusion Criteria:  
1) Non English-speaking 
2) Meet criteria for bipolar disorder, psychosis, anorexia nervosa (other eating 
disorders will be included), substance use disorder (substance use will be 
included), autism spectrum disorder, or intellectual disability disorder (based on 
school placement information).  
3) Depressed adolescents who are actively suicidal with a plan and/or intent who 
are assessed to need a higher level of care than outpatient treatment due to safety 
risk will be referred for appropriate level of stabilization (inpatient, partial 
hospitalization, intensive outpatient). Once stabilized, the adolescent can be re-
evaluated for eligibility to participate in the study.  
4) Adolescents will be excluded if they are already receiving treatment for 
depression or if they are taking medication for a psychiatric diagnosis other than 
ADHD. Adolescents with comorbid ADHD who are on a stable dose of stimulant 
medication (> 3 months) will be eligible. Interested families with adolescents 
currently taking psychiatric medication may, if desired, undergo a medication 
washout process to participate in the study. With the approval and oversight of 
their prescribing clinician, adolescents may choose to stop their medication. The 
prescribing clinician will determine with the families how to best wean off the 
medication. After 2 weeks completely off the medication, adolescents may be re-


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considered for study eligibility. If the adolescent is taking fluoxetine, the required 
washout period will be 3 weeks rather than 2 weeks. 
 
Parent/Caregiver Inclusion Criteria: 
1) Parent/caregiver of an adolescent enrolled in the study 
Parent/Caregiver Exclusion Criteria: 
1) Non English-speaking 
 
Therapist Inclusion Criteria: 
 
1) Therapist at PrairieCare  or Minnesota Mental Health Clinics who agrees to 
provide psychotherapy to an adolescent enrolled in the study 
 
Clinic Staff Inclusion Criteria: 
 
1) Treatment providers, other clinic staff, and members of the leadership team at 
PrairieCare and Minnesota Mental Health Clinics 
 
Screening:  
PrairieCare has two screening pathways: 
(1) PrairieCare offers free psychiatric needs assessments for families who are 
unsure if they are in need of services or are unsure what level of service is needed 
(e.g. outpatient, partial hospitalization, inpatient). If the clinician determines that 
the adolescent has a depression diagnosis and outpatient level of care is 
appropriate, the clinician will provide information about the study to the 
adolescent and parents.  
(2) Some families call PrairieCare’s outpatient clinic directly to initiate outpatient 
services. If families’ initial call with an intake coordinator is regarding an 
adolescent aged 12-18 years, the intake coordinator will inform the families that 
they can schedule a screening appointment with the University of Minnesota team 
to obtain a diagnostic evaluation and, if eligible, hear about participation in the 
study as an option.  
Minnesota Mental Health Clinics has two screening pathways: 
(1) Families who call the clinics to initiate outpatient services speak with an 
intake coordinator to schedule an appointment. If families’ initial call with an 


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intake coordinator is regarding an adolescent aged 12-18 years, the intake 
coordinator will provide information about the study to the family.  
(2) Therapists in the clinic who meet with a family with an adolescent (age 12-18) 
for an intake and/or ongoing therapy can provide information about the study to 
the family. 
Additional screening pathway for both sites: 
Some families will be directed to the study through recruitment sources other than 
PrairieCare and Minnesota Mental Health Clinics. Families who are referred from 
other organizations that serve youth (e.g., pediatric clinics) will complete a 
permission to contact form which will be faxed to the research team, indicating 
parents’ permission to be contacted by research staff. Parents may either (a) 
participate in a structured telephone screen with study staff that asks about mood, 
medical history, and current and prior treatment. If a parent completes the phone 
screen and the adolescent appears eligible, they will be asked to meet with an 
independent evaluator (IE) to learn more about the study, provide consent/assent, 
and complete the baseline assessments to determine eligibility. Or (b) schedule an 
in-person screening appointment with the University of Minnesota team to obtain 
a diagnostic evaluation and, if eligible, hear about participation in the study as an 
option.  
If the parent opts to schedule the screening appointment, parent and adolescent 
will complete screening consent/assent forms. They will then complete the 
“assessment of current symptoms” in the screening module of the K-SADS-PL, as 
well as any supplements that may determine eligibility/ineligibility if symptoms 
are endorsed during the screening module (affective, psychotic, substance use, 
eating disorders, and autism spectrum disorders supplements). Parent and 
adolescent will also complete the CDRS-R, C-GAS, and C-SSRS, as well as the 
Brief Screen Additional Information form. If parent and adolescent are deemed 
eligible, study staff will describe the study. If the family is interested in 
participating in the study, study staff will proceed to schedule them for the 
Baseline visit to complete the study consent and remaining Baseline measures. If 
families are ineligible or are eligible and decide not to participate in the study, 
they will be referred to services at PrairieCare, Minnesota Mental Health Clinics, 
or other services. Based on the needs of patients and availability of providers, 
some families will be directed to study treatment options outside of PrairieCare 
and Minnesota Mental Health Clinics. 
Reassessment of eligibility if there is a delay in starting treatment:  
If there is a > 2 week, but < 6 week delay between the eligibility evaluation and 
starting treatment, the following measures will be re-administered to re-assess 
eligibility and re-establish baseline scores, as the measures only capture 
symptoms in the previous 1-2 weeks: CDRS-R, BDI-II, CGI.  


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If there is a > 6 week delay between the eligibility evaluation and starting 
treatment, all baseline measures will be re-administered.  
If an adolescent is found to be ineligible at re-assessment, referrals to PrairieCare, 
Minnesota Mental Health Clinics, or other services will be made, as described 
above.  
 
 
10.0 Vulnerable Populations 
☒ Children 
☐ Pregnant women/Fetuses/Neonates 
☐ Prisoners 
☒ Adults lacking capacity to consent and/or adults with diminished 
capacity to consent, including, but not limited to, those with acute 
medical conditions, psychiatric disorders, neurologic disorders, 
developmental disorders, and behavioral disorders 
☐ Approached for participation in research during a stressful situation such 
as emergency room setting, childbirth (labor), etc. 
☐ Disadvantaged in the distribution of social goods and services such as 
income, housing, or healthcare 
☐ Serious health condition for which there are no satisfactory standard 
treatments 
☐ Fear of negative consequences for not participating in the research (e.g. 
institutionalization, deportation, disclosure of stigmatizing behavior) 
☐ Any other circumstance/dynamic that could increase vulnerability to 
coercion or exploitation that might influence consent to research or 
decision to continue in research 
☐ Undervalued or disenfranchised social group 
☐ Members of the military 
☐ Non-English speakers 
☐ Those unable to read (illiterate) 
☐ Employees of the researcher 
☐ Students of the researcher 
☐ None of the above 
Adults lacking capacity to consent and/or adults with diminished capacity to 
consent: 
The study sample includes adolescents up through 18 years of age. The sample 
consists solely of adolescents because adolescence has been identified as a critical 
period for the treatment of depression, given that it is characterized by a 
significant rise in the rates of depressive symptoms and diagnoses.133  


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This population represents the least degree of impairment compatible with the 
aims of this study. We are not enrolling participants during hospitalizations. We 
are also not enrolling adolescents who are actively suicidal with a plan and/or 
intent who are assessed to need a higher level of care than outpatient treatment. 
Once stabilized, the adolescent can be re-evaluated for eligibility to participate in 
the study. 
• 
The MacArthur Competence Assessment Tool for Clinical Research 
(MacCAT-CR) will be used to assess capacity to consent.  
• 
If we encounter a participant 18 years of age or older with 
diminished/fluctuating capacity to consent, we will ask this participant 
to sign the assent form and their LAR to sign the main consent form. 
• 
Criteria for study withdrawal are described below in section 13  
• 
Procedures to minimize risks are described below in section 14 
Additional Safeguards 
Parents will provide consent for their child to participate and adolescents will 
provide assent. This research team has considerable experience and expertise 
conducting research with adolescents and will train all research staff in the ethical 
conduct of research with adolescents. 
 
11.0 Local Number of Participants 
Local Number of Participants to be Consented: We expect to consent 
approximately 240 adolescents and parents/caregivers in order to reach a target 
sample of 200 participants who meet eligibility criteria to enroll in the trial. We 
expect to consent approximately 50 Minnesota mental health clinic staff 
members. 
 
12.0 Local Recruitment Methods 
Recruitment Process:  
Recruitment from PrairieCare: 
(1) PrairieCare offers free psychiatric needs assessments for families who are 
unsure if they are in need of services or are unsure what level of service is needed 
(e.g. outpatient, partial hospitalization, inpatient). If the clinician determines that 
the adolescent has a depression diagnosis and outpatient level of care is 
appropriate, the clinician will provide information about the study to the 
adolescent and parents. If families are interested in learning more about the study, 
clinic staff will document permission to be contacted by research staff on a 
“consent to contact” form that will be faxed to the research team. The clinic staff 
will also have the option to complete the “consent to contact” form via a link to a 
secure, HIPAA compliant, REDCap database. 


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(2) Some families call PrairieCare’s outpatient clinic directly to initiate outpatient 
services. If families’ initial call with an intake coordinator is regarding an 
adolescent aged 12-18 years, the intake coordinator will inform the families that 
they can schedule a screening appointment with the University of Minnesota team 
to obtain a diagnostic evaluation and, if eligible, hear about participation in the 
study as an option. If families are interested in learning more about the study, 
clinic staff will document permission to be contacted by research staff on a 
“consent to contact” form that will be faxed to the research team. The clinic staff 
will also have the option to complete the “consent to contact” form via a link to a 
secure, HIPAA compliant, REDCap database. 
Recruitment from Minnesota Mental Health Clinics: 
(1) Families who call the clinics to initiate outpatient services speak with an 
intake coordinator to schedule an appointment. If families’ initial call with an 
intake coordinator is regarding an adolescent aged 12-18 years, the intake 
coordinator will provide information about the study to the family. If families are 
interested in learning more about the study, the intake coordinator will document 
permission to be contacted by research staff on a “consent to contact” form that 
will be faxed to the research team. The intake coordinator will also have the 
option to complete the “consent to contact” form via a link to a secure, HIPAA 
compliant, REDCap database. 
(2) Therapists in the clinic who meet with a family for an intake and/or ongoing 
therapy can provide information about the study to the family. If families are 
interested in learning more about the study, therapists will document permission 
to be contacted by research staff on a “consent to contact” form that will be faxed 
to the research team. The therapist will also have the option to complete the 
“consent to contact” form via a link to a secure, HIPAA compliant, REDCap 
database. 
Additional recruitment methods: 
(1) The research team will recruit from pediatric clinics, mental health clinics, 
schools, and community centers that are proximal to PrairieCare and Minnesota 
Mental Health Clinics (sites which may serve individuals that are likely to seek 
services at PrairieCare or Minnesota Mental Health Clinics). At sites that serve 
low income and/or minority populations, the team will also offer to provide 
psychoeducational workshops for treatment providers and families who are 
interested in learning more about adolescent depression and its treatment. 
Information about the study will be provided. This effort will ensure a more 
diverse, representative sample.  
(2) Study information will also be on display at the UMN Department of 
Psychiatry recruitment display board.  
(3) Posters will be posted around the Twin Cities metro area in businesses and 
public spaces.  


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(4) Advertisements will be aired on local radio stations and published on digital 
platforms.   
Source of Participants: Adolescents seeking treatment for depression, as described 
above. 
Identification of Potential Participants: See ‘Recruitment Process’ Section above. 
Recruitment Materials: PrairieCare and Minnesota Mental Health Clinic staff will 
use the study brochure and Permission to be Contacted form to introduce the 
family to the study. Research staff will use the introductory informational letter to 
offer to provide psychoeducational workshops at pediatric clinics, mental health 
clinics, schools, and community centers that serve low income and/or minority 
populations. A psychoeducational article will be given with pediatric clinics, 
mental health clinics, schools, and community centers to share with their clients. 
The Department of Psychiatry recruitment display board will include contact 
cards and a poster briefly detailing the study. Contact cards and study posters or 
postcards will also be used for recruitment at PrairieCare, Minnesota Mental 
Health Clinics, and pediatric clinics, mental health clinics, schools, and 
community centers that are proximal to PrairieCare and Minnesota Mental Health 
Clinics. Posters with removable contact information tabs will be posted around 
the Twin Cities area in businesses and public spaces. Radio ads will be aired on 
local stations with study team contact information. Advertisements with an 
informative graphic and a link to the study website will also be published on 
social media and digital platforms (e.g., Facebook, Craigslist). The study website 
will be hosted on Discovery Partners. 
Individuals who want to be contacted about the study will complete contact 
information via a link to a secure, HIPAA compliant, REDCap database. Only the 
study coordinator and Principal Investigator, Meredith Gunlicks-Stoessel, will 
have access to the secure database. A link and quick response code (QR) for the 
contact form will be used on paper and digital materials. Individuals will provide 
their name and a preferred method of communication, such as an email address 
and/or phone number. We will use the approved screening script and form when 
contacting potential participants. 
Payment: Adolescents will be compensated $70 for the baseline, week 4, week 8, 
week 16, and week 36 assessments, and $25 for the week 12 assessment. Parents 
will be compensated $30 for the baseline, week 4, week 8, week 16, and week 36 
assessments, and $15 for the week 12 assessments. Total compensation for 
adolescent participation in the study will be up to $375. Total compensation for 
parents will be up to $165. If a particular assessment is deemed too time-intensive 
for completion in a single visit, it may be preemptively split into two 
appointments; the allocated payment for that assessment will be split evenly and 
distributed accordingly after the completion of each partial visit (i.e., an 
assessment with a compensation value of $70 would be distributed in two $35 
payments). If research interviews still exceed the scheduled time and an additional 


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appointment is required to complete the interview, participants (either parents or 
adolescents) will be compensated an additional $20. Therapists will be paid $20 
for completing measures at the start of their participation in the study and $40 for 
completing the measures at the end of their participation in the study. Clinic staff 
will be paid $40 for completion of measures.   
Payment will be made using a pre-paid debit card called Greenphire ClinCard. 
This system functions like a bank debit card; participants will receive a debit card, 
and each time they receive a payment for participation in this study, the money 
will be added to the card after each completed visit. 
 
Participants may use this card at any store that accepts MasterCard or can use a 
bank machine to remove cash. There may be fees drawn against the balance of the 
card for cash withdrawals (ATM use) and inactivity (no use for 3 months). 
Participants will be provided with the ClinCard Frequently Asked Questions 
information sheet that answers common questions about the debit card. They will 
also receive letters with additional information on how they can use these cards 
and who to call if questions arise. 
 
The debit card system is administered by an outside company. The company, 
Greenphire, will be given participant names. This information will be used only as 
part of the payment system. This information will not be used for any other 
purposes and will not be given or sold to any other company. Greenphire will not 
receive any information about participants’ health statuses or the study in which 
they are participating. 
 
13.0 Withdrawal of Participants 
Withdrawal Circumstances: Five conditions that may lead to a decision to 
terminate treatment prematurely are: (a) the adolescent’s primary problem 
changes during treatment in a way that warrants changes in treatment priority 
(e.g., adolescent begins to use dangerous drugs); (b) parent and/or adolescent 
request a change of treatment focus or approach; (c) evidence of a deterioration 
with treatment; (d) evidence of a non-response to treatment at week 8 or week 12 
evaluation time points; or (e) evidence of serious suicide risk.  
An Independent Safety Monitor (ISM) will provide independent clinical 
consultation to the study team and treating clinicians, particularly in situations 
where there are concerns about the appropriateness of the subject continuing in the 
trial in the assigned arm of the treatment studies: 1) a suicide attempt, 2) serious 
suicidal ideation (with a plan) and refusal to contract for safety, 3) psychiatric 
hospitalization, 4) possible need for psychiatric hospitalization, 5) significant 
worsening of depressive or other clinical symptoms (CDRS-R > 76 or CGI 
improvement score > 5), 6) a non-response to treatment (CGI improvement score 
= 4 at week 8 or week 12), and 6) the need for alternative treatment outside of 


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protocol. Adolescents will be removed from the study treatment immediately 
following formal review if the ISM deems that the subject requires treatment 
outside of study protocols or if the treatment provided in the study is 
contraindicated. 
Participants will not be withdrawn from the study assessments unless they 
withdraw consent or unless the ISM deems that continued participation in the 
assessments is causing harm to the participant. 
Withdrawal Procedures: Participants who are withdrawn from the study treatment 
will be referred for alternative treatment at PraireCare, Minnesota Mental Health 
Clinics, or in an alternative community setting. Participants can continue to 
participate in the assessment procedures if they continue to provide consent/assent 
and the ISM deems participants safe to continue in the assessments. Data from the 
medical record regarding ongoing treatment (as described above in Section 5 
above) will continue to be collected unless the parent withdraws consent.  
Termination Procedures: Participants and the treating providers will be informed 
of termination within 24 hours following ISM review. Data will continue to be 
used after termination. 
 
14.0 Risks to Participants 
Foreseeable Risks: (1) During the assessments, subjects (adolescents and parents) 
could become upset, angry, or sad when completing the assessments. (2) During 
the interventions, feelings could arise that are upsetting to the participating 
individuals (adolescents and parents) and could lead to temporary feelings of 
anger, sadness, or being upset. (3) Adolescents could experience suicidal ideation 
or a deterioration with treatment. (4) Adolescents randomized to receive SSRI 
treatment could experience adverse effects of medications. While SSRIs are 
generally well tolerated, side effects do occur. The most commonly reported side 
effects are: nausea, tremor, overstimulation, headache, and gastrointestinal 
symptoms. There is also some indication that some children treated with 
antidepressant medications are at elevated risk for suicidal ideation and 
behavior.134 (5) Risk of identifying adolescent abuse/maltreatment during an 
assessment or treatment session. Risks 2-5 will not be different than risks 
normally seen in standard clinical practice. Additional risks include the potential 
risk of loss of confidentiality. 
 
Protections Against Risk:     
Risk of becoming upset during the assessment. All clinical measures will be 
conducted by experienced, trained IEs. The IEs will be master’s level clinicians. 
The PI and study Project Director, Kristina Reigstad, PsyD, LP, will provide 
detailed training and supervision to the IEs in the administration of all measures. 
In the instance of any adolescent or parent becoming upset when completing any 


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of the measures, including the parent-adolescent conflict negotiation task, the IE 
will attempt to debrief and council the adolescent or parent. Parents and 
adolescents who are upset following the conflict negotiation task will also be 
offered the opportunity to take a break before completing other assessments. If 
needed, the IE will contact the PI or Dr. Reigstad, who will assess the situation, 
and as necessary, will counsel the adolescent and/or the parent.  
 
Risk of becoming upset during the intervention. UC and IPT-A therapists will be 
masters or doctoral level clinicians (LPCC, LICSW, LP) currently employed by 
PrairieCare or Minnesota Mental Health Clinics. Pharmacotherapy will be 
delivered by psychopharmacologists (child psychiatrists and nurse practitioners) 
also already employed by PrairieCare or Minnesota Mental Health Clinics. 
Treatment providers will handle all clinical issues in the way they are generally 
handled at PrairieCare or Minnesota Mental Health Clinics. At PrairieCare, the 
Chief Psychotherapy Officer and the Chief Medical Officer will oversee the 
services by supervising and providing support and assistance to the treatment 
providers implementing the interventions. At Minnesota Mental Health Clinics, 
oversight will be provided by the Clinic Director. Furthermore, additional 
strategies will be implemented to minimize risk to research subjects. First, the 
IPT-A therapists will be trained and supervised by the PI. Second, the PI will 
closely monitor subjects throughout the course of treatment and will review all the 
assessments to identify any adolescent who may be at-risk.  
 
Risk of suicide or deterioration with treatment. Rescue procedures will follow the 
standard suicide prevention procedures as outlined in the AACAP Practice 
Parameters on Suicidal Behavior,135 including risk assessment, identification and 
modification of precipitants, and contracting for safety. All study staff will be 
trained to follow these parameters. Subjects will be educated about depression and 
signs of suicidal crisis. Subjects will receive PrairieCare’s or Minnesota Mental 
Health Clinic’s 24 hour on-call phone number. Subjects may fail to appear for 
treatment or assessment appointments. We will obtain locator information and 
obtain permission to contact three identified family members or friends in the event 
of a no-show for an assessment or therapy appointment. All subjects will be closely 
monitored with regard to suicidality on a frequent and regular basis (during 
treatment sessions and IE-administered assessments). Subjects who show 
deterioration in depression, mania, psychosis, or level of suicidality will be 
monitored closely. Subjects who are at risk may need to be psychiatrically 
hospitalized. If the treatment provider or IE is concerned about current suicide risk, 
the provider will follow the procedures that are consistent with the standard suicide 
prevention procedures as outlined in the AACAP Practice Parameters on Suicidal 
Behavior. The provider or IE will discuss these cases with the clinic leadership at 
the respective clinics, as well as the PI. Based on the information from various 
sources, the provider, PI, and clinic leadership at the respective sites will evaluate 
suicide risk and decide what level of care is sufficient. Subjects will be referred for 


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hospitalization if: a) his/her condition is unstable-as manifested by suicidal ideation 
with inability to agree to a safety plan, psychosis, mania, rapid cycling or mixed 
state; and b) there is a lack of sufficient environmental support and structure to 
guarantee the subject’s safety.  
 
For adolescents who are assessed to be safe to go home and are not referred for 
hospitalization, a safety plan will be established in collaboration with the subject 
and parents. The safety plan will include the adolescent’s/parent’s commitment to 
utilize a list of strategies that can help keep the adolescent safe in a suicidal crisis. 
The strategies will be individualized to each adolescent. The adolescent’s safety 
plan will include: (a) strategies that the adolescent can employ with the help of 
others (adult that the adolescent can contact), and (b) strategies that the adolescent 
can use by him/herself without the help of others (emotion regulation skills). The 
parent’s safety plan will include strategies that the parent can use to keep the 
adolescent safe. The parent’s safety plan will also include calling 911 or going to 
the Emergency Room should any safety concerns arise, and will include 
procedures for limiting the adolescent’s access to means of self-harm (e.g., 
medications, knives).  
 
Also, as described in Section 13, an ISM will provide independent clinical 
consultation to the study team and treating clinicians, particularly in situations 
where there are concerns about the appropriateness of the subject continuing in the 
trial in the assigned arm of the treatment study. The adolescent will be removed 
from the study treatment if the ISM deems that the subject requires treatment 
outside of study protocols or if the treatment provided in the study is 
contraindicated. 
       
Risk of side effects with SSRIs. While SSRIs are generally well tolerated, side 
effects do occur. Safety of the medication treatment will be monitored closely. 
The psychopharmacologists will be able to contact Dr. Cullen with any concerns 
or questions. The psychopharmacologists will review with families the following 
potential SSRI-related adverse events:  gastrointestinal complaints (nausea, pain, 
diarrhea, and constipation) (frequency: 4-29%), dizziness (frequency 2-11%), 
allergic reactions (frequency: rare), increased anxiety or irritability(frequency: 3-
15%), increased activation/restlessness (frequency: 2%), sleep changes (increased 
or decreased) (frequency: 5-30%), sexual side effects (frequency: 1-11%), 
appetite changes (increased or decreased) (frequency: 4-17%), unusual thoughts 
(frequency: rare), sweating (frequency: 2-9%), fatigue (frequency: 5-17%), 
suicidal ideation/attempts/and or behaviors (frequency: 4%). In addition to these 
issues, the psychopharmacologists will make the adolescents and their families 
aware of the Food and Drug Administration advisory that the use of 
antidepressants like the SSRIs may lead to suicidal thinking/attempts in depressed 
youths and that the FDA has placed product warning label with information 
highlighting the need for close observation for worsening of depression and the 


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emergence of suicidality in children treated with these medications. This 
information will be a part of the consent process for the study so that families are 
aware of these issues when considering participation in the study. Adolescents 
will be instructed to call the treatment provider with any concerns. PrairieCare 
and Minnesota Mental Health Clinics have a 24 hour on-call service for urgent 
matters that develop outside of regular business hours.  
 
To monitor potential risks, clinicians will carefully assess for any significant 
changes in mood, thinking, behaviors, physical symptoms, and suicidality, 
especially early in treatment. In the event of minor side effects (e.g., mild 
headaches), the medication may be maintained at the current dose levels or 
reduced. If any adverse medication reactions do occur, the medication will be 
withdrawn and clinical staff will follow the patient closely until the adverse 
reaction remits. Also, if a patient shows a worsening of symptoms, including 
suicidality, or develops exclusionary criteria described above, rescue procedures 
described above will be implemented and the patient will be evaluated by the ISM 
who will follow the procedures described above.  
 
Risk of identifying adolescent abuse/maltreatment. The PI and Dr. Reigstad will 
provide training to the project staff in requirements and procedures for following 
up on and collecting information about child maltreatment. In any case where the 
possibility of maltreatment arises, the project staff involved will collect the 
information and will immediately confer with the PI or Dr. Reigstad, and 
mandated reporter requirements will be followed closely. The research team will 
also discuss these cases. 
 
Risk of loss of confidentiality. The PI will emphasize the critical importance of 
subject confidentiality in the training of all project staff, and will reiterate this 
point as opportunities arise in handling of such material. All interviews and 
therapy sessions will take place in private rooms. All off-site communication 
between research staff and participants will occur by telephone or by email using 
the University’s email encryption system to ensure security. At two points in the 
study participants will be given the option to request that the research team does 
not send encrypted emails using the University encryption system using a request 
form for communication via unencrypted email. The first opportunity to request 
unencrypted email communication will occur at first contact of interest with study 
participation. The second opportunity will occur during the consent meeting. Both 
opportunities have unencrypted email authorization forms collected via REDCap 
for electronic signatures. This form will disclose risks of communicating via 
unencrypted email and will require a participant signature to take effect. 
Participants will also be given the option to request that the research team uses 
text messaging to schedule and confirm appointments using a consent for text 
message correspondence form. This form will disclose risks of and parameters for 
communicating via text message and will also require a participant signature to 


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take effect. Text messages will only be sent from a password-protected university-
owned device. In order to safeguard the confidentiality and security of data files, 
participants (adolescents and parents) will be assigned a coded identification 
number that will be used on all datacollection measures, including biological 
specimens. To minimize the risk of loss of confidentiality, the data collected in 
this study will be protected by the use of separate data files. The first will include 
the subject consent forms, names, addresses, telephone numbers, date of birth, and 
subject ID. Other databases will include the questionnaire data from the project, 
and subject ID numbers will be the only unique piece of information linking the 
data files to the consent file. The collected materials will be used only for research 
purposes; participants’ records with identifying information will not be released to 
anyone without participants’ written permission. Genetic and epigenetic 
information will be for research purposes only and will not be included in 
participants’ medical records. Genetic and epigenetic data obtained from this 
study will be de-identified by the use of subject ID numbers. 
Data for this study will be entered into a REDCap database, which uses a MySQL 
database via a secure web interface with data checks used during data entry to 
ensure data quality. REDCap includes a complete suite of features to support 
HIPAA compliance, including a full audit trail, user-based privileges, and 
integration with the institutional LDAP server. The MySQL database and the web 
server will both be housed on secure servers operated by the University of 
Minnesota Academic Health Center’s Information Systems group (AHC-IS). The 
servers are in a physically secure location on campus and are backed up nightly, 
with the backups stored in accordance with the AHC-IS retention schedule of 
daily, weekly, and monthly tapes retained for 1 month, 3 months, and 6 months, 
respectively. Weekly backup tapes are stored offsite. The AHC-IS servers provide 
a stable, secure, well-maintained, and high-capacity data storage environment, 
and both REDCap and MySQL are widely-used, powerful, reliable, well-
supported systems. Access to the study's data in REDCap will be restricted to the 
members of the study team by username and password. If participants are unable 
to complete a visit at the research site or complete a home visit, study staff 
members may send a hyperlink to participants to complete REDCap 
questionnaires remotely online. 
If participants are unable to complete a visit at the research site or complete a 
home visit, study staff members may also use Zoom Video Conferencing to video 
chat with participants and complete interviews, questionnaires, and research tasks. 
Zoom is a communications software that allows video conferencing, online 
meetings, chat, and mobile collaboration. Zoom is HIPAA (signed BAA) and 
PIPEDA/PHIPA compliant with complete end-to-end 256-bit AES encryption. 
Zoom does not have access to identifiable health information and encrypts all 
audio and video data. The study team will not record audio or video through 
Zoom software; instead, recordings will be captured on a secure independent 


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device (i.e., audio recorder), uploaded to Box Secure Storage, and promptly 
deleted off the device to maintain HIPAA compliance. The exceptions are during 
the Baseline assessment, week 4, week 8, and week 16 appointments, which 
requires recording the 15 minute Conflict Negotiation Task. The recording will be 
done via Zoom software, uploaded to Box Secure Storage, and promptly deleted 
off the device to maintain HIPAA compliance. 
Therapists will record their weekly sessions with participants to 1) ensure 
reliability for therapists assigned to the IPT-A condition and 2) identify 
characteristics of therapeutic orientation for therapists assigned to the usual care 
condition. Therapists will record their sessions using a digital audio recorder. 
Therapists will upload these audio recordings onto secure work computers at 
PrairieCare or Minnesota Mental Health Clinics and then transfer recordings into 
cloud-based storage platform Box Secure Storage. Box offers HIPAA and 
HITECH-compliant storage for all its users, and holds a signed HIPAA Business 
Associate Agreement (BAA) with the University of Minnesota. The storage 
platform demonstrates compliance through encrypting all uploaded data, both in 
transit and in storage, restricting physical access to production servers, and 
providing strict administrative controls which customers to configure user 
authorization to edit, download, password-protect, etc. An evaluation report 
(HIPAA AUP) issued by an independent third-party auditor detailing Box’s 
HIPAA compliance is available upon request to Box customer services. Upon 
uploading audio files to Box, therapists will delete the audio file from their secure 
computer and from the recording device. The research team may then access the 
files for review through Box Secure Storage through secure UMN servers. 
In circumstances when it is not feasible for the therapist to use a digital audio 
recorder (e.g. the therapists is conducting the therapy session via telehealth and 
needs to wear headphones), the therapist will use Zoom to record the therapy 
sessions. Zoom saves the video and audio data in separate files on the therapist’s 
secure work computer. Therapists will upload only the audio file to Box. Upon 
uploading the audio file to Box, therapists will delete both the audio and video 
files from their secure computer.   
 
Other study databases will be password protected and the database password will 
be changed on a regular basis. The UMN computing systems are protected from 
outside access. All staff members will be required to close password-protected 
applications or lock their workstations when they are away from their desks. All 
paper forms will be kept in locked file cabinets at UMN. During data analysis, all 
identifying information, with the exception of the subject ID is removed from the 
data. No information about identities of the study participants will be published or 
presented at conferences.  
 


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Procedures for minimizing risks of audiotaping/videotaping. Digital audio files of 
treatment and assessment sessions, and digital video files of the parent-adolescent 
communication task will be coded by subject identification number, date, and the 
study name. Recorders will be kept in a locked box in the Research Coordinator’s 
office until transferred to an electronic file. Digital recordings will be transferred 
to an electronic, password protected file within three days. Once the recording is 
transferred to an electronic file, it will be deleted from the recorder or computer. 
These files will all be accessible to only a limited number of project personnel. 
The University of Minnesota’s computing system is protected from outside 
access. Only study IDs will be used to link audio/video files to questionnaire data.   
Disclosure of health risk behaviors by the adolescent. All subjects will be 
informed during the consent process that their information will be kept strictly 
confidential unless information is revealed suggesting that the subject or someone 
else is in danger (e.g., prostitution, IV drug use, child abuse (see below), 
suicidality, homicidality). Prior to eliciting this information, the child will be fully 
informed that the clinician may need to report such information. Before parents 
will be made aware of this information, our procedure will be to first talk with the 
child and explain what information will be disclosed to parents.   
Reporting of child abuse. Because information relating to abuse will be assessed (an 
item in the PTSD section of the K-SADS-PL),118, participants will be informed of 
the need to report child abuse prior to eliciting this information. All staff will follow 
federal and state child abuse reporting requirements.   
Reproduction Risks: The impact of SSRIs on fetuses is currently unclear. Prior to 
initiation of the SSRI, all female patients will be asked by the 
psychpharmacologist, “Is it possible that you could be pregnant?” and “Have you 
recently or are you currently having any unprotected sex?” If a female patient 
endorses either of these questions, they will be counseled on the risks of taking an 
SSRI and encouraged to practice safe sex practices. If the patient believes she 
may be pregnant, she will be instructed to take a pregnancy test before beginning 
medication. If a patient is pregnant, medication management will not be initiated. 
If a female adolescent who is taking an SSRI becomes pregnant over the course of 
the trial, her psychopharmacologist will provide council on the potential risks and 
benefits of continuing the medication. If the patient and psychopharmacologist 
decide to discontinue the medication, the patient can continue to receive IPT-A 
and continue to participate in the study assessments. 
Risks to Others: N/A 
 
15.0 Potential Benefits to Participants 
Potential Benefits: The benefit of participation in this study is receiving an active 
treatment (IPT-A with or without an SSRI or UC). IPT-A is an evidence-based 


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treatment that is not currently available in most community settings. The 
participants that are randomized to the treatment condition that includes IPT-A 
will be getting access to an evidence-based treatment that is not currently 
available at PrairieCare or Minnesota Mental Health Clinics.  
 
16.0 Data Management 
Data Analysis Plan: The proposed trial design of adaptive interventions is similar 
to a factorial design.31,136-138 All analyses will be by intention-to-treat.  
Aim 1. Hypotheses 1a and 1b: We will compare the average 16-week change in 
depressive symptoms (CDRS-R) and interpersonal functioning between 
adolescents compliant with ATS1 (cells 1 and 3) and UC (cell 4) and between 
adolescents compliant with ATS2 (cells 1 and 2) and UC (cell 4) using weighted 
t-tests. Secondary analyses will compare these groups using weighted regression 
adjusting for baseline characteristics such as age, gender, and depression severity. 
The measure of interpersonal functioning will be constructed from a latent factor 
analysis of changes in IPPA, IC, and parent-adolescent conflict behaviors. Note 
that the (unweighted) sample mean of adolescents in cells 1 and 2 contains an 
underrepresentation from adolescents with an insufficient response (compared to 
the population in which all adolescents followed ATS1) because half of the 
insufficient responders are re-randomized into subgroup 2 whereas the responding 
adolescents are not re-randomized. We can correct for this underrepresentation by 
weighting insufficient responders by 2.139-141  
Hypothesis 1c: Incremental cost-effectiveness ratios between the two contrast 
pairs (ATS1 vs. UC and ATS2 vs. UC) will be calculated from the weighted mean 
scores for the change in costs and QALYs, and adjusted mean scores, based on 
weighted regression analysis (weights described above). Probabilistic sensitivity 
analysis will be conducted to account for uncertainty in the parameters. 
Bootstrapping with replacement will be used to construct cost-effectiveness 
scatter plots and cost-effectiveness acceptability curves. Following the 2nd Panel 
guidelines,142 the analysis will be conducted from both a healthcare sector and 
societal perspective, and an Impact Inventory will be provided. 
Aim 2: We will fit a linear regression model for change in depressive symptoms 
including a term for 4-week change in interpersonal functioning, first-stage 
treatment, and other confounders of the mediator-outcome relationship and a 
model for change in relationship functioning with first-stage treatment and other 
covariates as predictors. The controlled direct effect can be estimated using the 
regression coefficient for first-line treatment in the adjusted outcome model and 
the indirect effect can be estimated as the product of the coefficient for first-line 
treatment in the outcome and mediator models.  
 


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Aim 3: We will first test the effect of baseline relationship functioning as a 
moderator of stage 1 treatment (IPT-A vs. UC) by fitting a regression model for 
16-week change in depression symptoms with baseline relationship functioning 
and an interaction between stage 1 treatment and baseline relationship functioning 
as covariates. Similarly, to assess the effect of 4-week change in relationship 
functioning and other possible covariates listed in the assessment section as 
moderators of second-stage treatment assignment, we will fit a regression model 
for change in depressive symptoms among insufficient responders among those 
initially randomized to IPT-A and include a term for 4-week change in 
relationship functioning and other covariates, second stage treatment (increased 
IPT-A vs. SSRI), and their interaction.  
 
Secondary Analyses: In addition to modeling the change in depressive symptoms 
at 16 weeks, we will also use linear mixed-effect models (growth curve models) 
to model the depressive symptoms over time (up to 36 weeks) within each of the 
2 embedded ATSs.  Importantly, the data collected as part of this trial will also 
permit us to explore how to tailor the interventions based on an individual’s 
characteristics, such as age, depression severity, or interpersonal functioning 
through the use of Q- and A-learning.143,144,145,146,147,148,149,150,151,152,153 
 
Aim 4: Descriptive results regarding subject consent and the demographics for 
those who consented and declined will be reported as percentages. Chi-square 
tests will compare the proportion of subjects consented based on diagnostic and 
demographic characteristics. Adolescents’, parents’, and therapists’ attitudes 
regarding the ATSs will be reported as mean scores and standard deviations on 
the CSQ-8 and ATA. Clinic staff members’ attitudes regarding the evidence for 
the ATSs and the clinics’ organizational readiness will be reported as mean scores 
and standard deviations on the ORCA Evidence and Context scales. Research 
team members will independently read transcripts of the treatment provider and 
leadership interviews and Research Team Observational Log, meet to discuss 
observed themes, and code the transcripts and logs.154 Structural coding will 
assign similar responses to a broad common code. Initial development of the 
coding list will focus on particular domains of interest, such as attitudes towards 
the ATSs, barriers to implementation, facilitators of implementation, and 
recommendations for improvement. As new ideas are identified in subsequent 
transcripts, new codes will be assigned. When coding is completed, the code list 
will be collapsed into categories that will yield descriptive overarching themes. 
Coding will be conducted using Atlas.ti qualitative software. 
Genetic and epigenetic association testing with treatment response phenotypes: 
We will use the Illumina PsychChip which contains the relevant candidate genes 
for study. Dr. Bishop has experience with this array155,156 and will use standard 
genotyping and QC procedures prior to analysis. Genes selected for candidate 
gene studies are based on a range of ­omic studies. Therefore, we will conduct 
set­based analyses using PLINK157 or Golden Helix SNP Variation Suite software 


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(GoldenHelix SVS) to generate permutation­adjusted gene­based p­values from 
models containing relevant covariates. In order to assess methylation across the 
entire genome, this study will use the Infinium MethylationEPIC Array which 
quantitatively measures DNA methylation at 850K sites across the genome. 
Samples from subjects receiving the different treatments will be evenly 
distributed across the arrays to minimize batch effects. Two non­study controls 
will be placed on each array for QA/WC. The variables of interest are % 
methylation calculated from the ratio of a methylated probe relative to the sum of 
methylated and unmethylated probes ranging from 0 (unmethylated) to 1 (fully 
methylated). After obtaining % DNA methylation data, we will filter out low 
quality samples and probes based on call rates and QC parameters provided by the 
manufacturer. Additionally, as we have done in previous studies, we will remove 
probes that may cross­hybridize to multiple genomic regions, as well as probes 
that contain common SNPs (MAF≥0.01).158 We will remove any experimental 
batch effects using a standard approach.159 Cell­composition effects will be 
controlled for using established bioinformatic methods.160 Association studies will 
examine mean methylation across specific regulatory regions for each candidate 
gene covered by the array in relation to treatment response status. 
Analyses of SNP and methylation predictors define response categorically 
according to the HRSD assessment at week 4 (non-responders show < 20% 
improvement) or week 8 (non-responders show <40% improvement). Genetically 
defined race (PCA), sex, and age will be included in all models as we have done 
previously.158,161 Covariates to be included in analysis include current medications 
which may influence methylation, particularly mood stabilizers,162 sex, and 
smoking status.163 Univariate assessments of intervention type (ATS1, ATS2, and 
UC), evidence of early trauma, lifetime trauma load, depressive symptoms, 
substance use exposures, medication utilization (antidepressants, anticonvulsants, 
antipsychotics, etc) will be examined to determine whether these variables require 
inclusion into our statistical models. Based on logistic regression models 
identifying significant predictors of clinical improvement, we may also create 
propensity scores which will be used as covariates in the analyses. We will 
compare % methylation at the pre­treatment time point in those who went on to 
respond versus those who did not, using analysis of covariance. Secondary 
analyses will examine HRSD and CDRS-R scores over multiple time points using 
mixed regression models (growth curve models) to examine the effect of % 
baseline methylation on symptom levels over time (baseline, wk4, wk8, wk16, 
wk32). Intercept and slopes will be fitted as random terms in the models of 
intraindividual change. We will be testing for a significant interaction between % 
baseline methylation and symptom change over time. We will use mixed 
regression models to examine the relationship between changes in HRSD and 
CDRS-R scores with % methylation changes longitudinally to identify whether 
change in methylation is correlated with HRSD and CDRS-R change scores. We 
will examine methylation changes from baseline to 8wks and 16wks in relation to 
responder status. We will first identify methylation changes that occur in 


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responders but not non­responders. Finally we will model % baseline methylation 
as a continuous outcome in relation to HRSD and CDRS-R scores across multiple 
time points. We will apply an unsupervised clustering approach to identify 
self­organizing maps164 defining clusters of individuals with similar trajectories 
over time. Using the identified clusters, we will test for markers with baseline 
methylation level specific to these groups. Genes associated with response will be 
evaluated for pathway enrichment via Gene Ontology, as well as representation in 
biological network clusters with Ingenuity Pathway Analysis IPA® (QIAGEN 
Redwood City, www.qiagen.com/ingenuity) for enrichment of regulatory 
pathways. For HPA­axis, inflammation, and neuroendocrine pathways implicated 
a priori, we will test specifically for over enrichment in those pathways using a 
hypergeometric distribution test. 
Power Analysis: The proposed trial is powered for a comparison of average 
change in depressive symptoms (Hypothesis 1a) and interpersonal functioning 
(Hypothesis 1b) between ATS1 & UC and ATS2 & UC. The power calculation 
for Hypotheses 1a and 1b is similar to a standard two-arm intervention trial with 
subject or case weights due to over- or under-sampling certain subgroups.165,166 
Table 2 gives the power for Hypotheses 1a and 1b assuming a total sample size of 
200 and 2:1 allocation under different assumptions of the effect size (ES) 
(Cohen’s d) between the ATSs beginning with IPT-A and UC. We consider an ES 
of 0.50 to be of interest; previous studies of IPT-A alone versus non-adaptive 
treatment as usual demonstrated similar ESs and we believe that similar ESs will 
be obtained comparing the ATSs with UC (which may be adaptive).17 Pilot data 
of these ATSs have demonstrated that approximately 50% of subjects will be 
responders and we demonstrate that adequate power is achieved across a range of 
plausible proportion of responders to IPT-A. 
Although the trial was powered to test the hypotheses for the primary aim, we 
demonstrate that we have adequate power to test for mediators (Hypothesis 2) and 
moderators of the first-line treatment effect (Hypothesis 3a) under plausible 
scenarios. Dietz et al. found that approximately 55% of the effect of family-based 
IPT-A on depressive symptoms was mediated by changes in interpersonal 
functioning.167 If we assume that 4 week changes in interpersonal functioning 
mediates between 30-50% of the total effect, we will have between 78% and 
99.5% power to detect a significant indirect effect. For ease of power estimates, 
we dichotomized the moderator (e.g. interpersonal functioning) into two groups 
with ~50% of the population in each group. If the overall effect size between 
those randomized initially to IPT-A versus UC is between 0.45 and 0.5 and the 
effect size among those with high baseline relationship functioning is between 0.0 
- 0.1,168 we will have 75%-95% power to detect a significant interaction effect 
between first-line treatment and interpersonal functioning assuming a two-sided 
Wald-type test using a 90% significance level. Treating interpersonal functioning 
as a continuous covariate would increase the power to detect a significant 
interaction. 


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Table 2. Power to test a difference in the average 16-week change (e.g., 
depressive symptoms, interpersonal functioning) between one of the IPT-A 
ATSs and UC. Power calculations assume total N=200, a 2:1 allocation 
ratio, and the use of a two-sided weighted t-test with a 95% significance 
level. 
    
 
 
 
 
 
Data Integrity: Participant self-report, parent-report, and clinician report measures 
will immediately checked upon completion by a research assistant to identify 
unintentionally missing data. Paper measures will be entered into a de-identified 
electronic database, and entry will be double checked for accuracy by a second 
research assistant. Scoring will also be double checked for accuracy by a second 
research assistant.   
 
17.0 Confidentiality 
Data Security: The PI will emphasize the critical importance of subject 
confidentiality in the training of all project staff, and will reiterate this point as 
opportunities arise in handling of such material. All interviews and therapy 
sessions will take place in private rooms. All off-site communication between 
research staff and participants will occur by telephone or by email using the 
University’s email encryption system to ensure security. If text messaging or 
unencrypted email is used to communicate between research staff and 
participants, it will only be used after participants provide consent and complete 
the appropriate authorization forms. In order to safeguard the confidentiality and 
security of data files, participants (adolescents and parents) will be assigned a 
coded identification number that will be used on all data collection measures. To 
minimize the risk of loss of confidentiality, the data collected in this study will be 
protected by the use of separate data files. The first will include the subject 
consent forms, names, addresses, telephone numbers, date of birth, and subject 
ID. Other databases will include the questionnaire data from the project, and 
subject ID numbers will be the only unique piece of information linking the data 
files to the consent file. The collected materials will be used only for research 
purposes; participants’ records with identifying information will not be released to 
anyone without participants’ written permission.  
Data for this study will be entered into a REDCap database, which uses a MySQL 
database via a secure web interface with data checks used during data entry to 
  
Effect Size 
Proportion of 
Responders 
0.45 0.50 0.55 
0.3 
77% 85% 91% 
0.5 
79% 87% 92% 
0.7 
82% 88% 94% 


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ensure data quality. REDCap includes a complete suite of features to support 
HIPAA compliance, including a full audit trail, user-based privileges, and 
integration with the institutional LDAP server. The MySQL database and the web 
server will both be housed on secure servers operated by the University of 
Minnesota Academic Health Center’s Information Systems group (AHC-IS). The 
servers are in a physically secure location on campus and are backed up nightly, 
with the backups stored in accordance with the AHC-IS retention schedule of 
daily, weekly, and monthly tapes retained for 1 month, 3 months, and 6 months, 
respectively. Weekly backup tapes are stored offsite. The AHC-IS servers provide 
a stable, secure, well-maintained, and high-capacity data storage environment, 
and both REDCap and MySQL are widely-used, powerful, reliable, well-
supported systems. Access to the study's data in REDCap will be restricted to the 
members of the study team by username and password. 
Therapists will record their weekly sessions with participants to 1) ensure 
reliability for therapists assigned to the IPT-A condition and 2) identify 
characteristics of therapeutic orientation for therapists assigned to the usual care 
condition. Therapists will record their sessions using a digital audio recorder. 
Therapists will upload these audio recordings onto secure work computers at 
PrairieCare or Minnesota Mental Health Clinics and then transfer recordings into 
cloud-based storage platform Box Secure Storage. Box offers HIPAA and 
HITECH-compliant storage for all its users, and holds a signed HIPAA Business 
Associate Agreement (BAA) with the University of Minnesota. The storage 
platform demonstrates compliance through encrypting all uploaded data, both in 
transit and in storage, restricting physical access to production servers, and 
providing strict administrative controls which customers to configure user 
authorization to edit, download, password-protect, etc. An evaluation report 
(HIPAA AUP) issued by an independent third-party auditor detailing Box’s 
HIPAA compliance is available upon request to Box customer services. Upon 
uploading audio files to Box, therapists will delete the audio file, and any video 
files, from their secure computer and from the recording device. The research 
team may then access the files for review through Box Secure Storage through 
secure UMN servers. 
 
In circumstances when it is not feasible for the therapist to use a digital audio 
recorder (e.g. the therapists is conducting the therapy session via telehealth and 
needs to wear headphones), the therapist will use Zoom to record the therapy 
sessions. Zoom saves the video and audio data in separate files on the therapist’s 
secure work computer. Therapists will upload only the audio file to Box. Upon 
uploading the audio file to Box, therapists will delete both the audio and video 
files from their secure computer. 
   
Other study databases will be password protected and the database password will 
be changed on a regular basis. The UMN computing systems are protected from 


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outside access. All staff members will be required to close password-protected 
applications or lock their workstations when they are away from their desks. All 
paper forms will be kept in locked file cabinets at UMN. During data analysis, all 
identifying information, with the exception of the subject ID is removed from the 
data. No information about identities of the study participants will be published or 
presented at conferences.  
 
Procedures for minimizing risks of audiotaping/videotaping. See Section 14.   
Disclosure of health risk behaviors by the adolescent. See Section 14. 
Reporting of child abuse. See Section 14.  
  
No research study information, including copies of consent forms, will be placed 
in the participants’ medical, employment, or educational records. 
 
18.0 Provisions to Monitor the Data to Ensure the Safety of 
Participants 
Data Integrity Monitoring. Research team members will meet regularly to discuss 
study progress, ensure data integrity, and that the study is conducted, recorded, 
and reported in accordance with the protocol, standard operating procedures, and 
applicable regulatory requirements. Study team members will be instructed to 
bring any identified protocol violations to the PI in a timely fashion and team 
members will be re-trained, if needed. 
Data Safety Monitoring. The PI’s monitoring of data will be ongoing throughout 
the project. Information regarding symptom severity, adverse events, and 
suicidality will be collected by IEs during the assessments. Any adverse events or 
suicidality that is reported to therapists during psychotherapy or 
psychopharmacology sessions will also be recorded, and treatment providers will 
report to the PI any serious or unexpected adverse events, unexpected problems 
that involve risk to the participants or others, and any breaches of confidentiality. 
Therapists will report on the progress of their cases during weekly supervision 
with the PI. The PI will monitor all data and will be available to study staff.  
Data and Safety Monitoring Board. The PI will convene a Data and Safety 
Monitoring Board (DSMB). The DSMB will include a biostatistician with 
expertise in randomized clinical trial methodology, a researcher with expertise in 
adolescent depression, and a clinical psychologist or psychiatrist. The members of 
the DSMB will not be involved in this project and will not be collaborators on any 
other of the investigators’ projects nor in their employ. DSMB members will 
provide the NIMH with qualifications and a COI statement indicating that they 
have no direct involvement with the study or COI with the investigators or 
institutions conducting the study. They will meet annually to 1) monitor the 
safety, quality and conduct of this study and 2) decide whether adequate subject 


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safeguards are in place. The DSMB will review: 1) the progress of the proposed 
study, including assessments of data quality and participant recruitment, accrual 
and retention; 2) outcome and adverse event data to determine whether there is 
any change to the anticipated benefit-to-risk ratio of study participation and 
whether the study should continue, be changed, or terminated; 3) external factors 
or relevant information (e.g., pertinent scientific literature reports or therapeutic 
developments, results of related studies) that may have an impact on the safety of 
study participants or the ethics of the research study;  and 4) study procedures 
designed to protect the privacy of the research subjects and the confidentiality of 
their research data. The biostatistician will be responsible for generating a 
deidentified annual report of key events that will be reviewed as part of the safety 
monitoring of the protocol. The tentative list of key events will include serious 
adverse events and more specifically: 1) suicide behaviors, 2) hospitalization, 3) 
school drop-out, 4) arrests, 5) pregnancies, 6) premature drop-out from treatment, 
7) depression symptoms, and 8) medication adherence and medication side 
effects. The key events will be reviewed at the first meeting of the DSMB to 
obtain the 3 DSMB members’ input into the list and to add any other events or 
measures that they feel would be relevant to include for evaluating the safety and 
conduct of the clinical trial.  
 
Reporting. All investigators will report unexpected serious adverse events (SAEs) 
or unanticipated problems involving risks to subjects to the IRB and to the 
assigned NIMH PO. Reports will be made to the (DSMB, as detailed above. If 
DSMB notes serious and unexpected adverse events, or unanticipated problems 
involving risks to subjects or others which are related to the study, the PI and IRB 
will be notified. This will be done via a letter from the DSMB 
Chair/Administrator to the PI for distribution to the institutional official, sponsor, 
and IRB. The PI will also submit an annual progress report to the IRB 
summarizing the data and safety monitoring activities and outlining 1) whether 
participants’ safety, privacy and confidentiality has been consistently assured, 2) 
whether research instruments have been administered in a uniform manner and in 
a way that protects participants’ privacy, 3) progress towards recruitment goals, 
quality of data collection (e.g., appropriate completion of forms), and participant 
retention/ attrition rates, and 4) a review of new scientific literature pertinent to 
the safety of participants or the ethics of research participation. 
The PI will report to the IRB and the assigned NIMH PO within the following 
timeframe: (1) IRB/ISM/DSMB suspensions or terminations (within 3 business 
days), (2) deaths related to study participation (within 5 business days), (3) 
unexpected serious adverse events (within 10 business days), (4) unanticipated 
problems involving risks to subjects or others (within 10 business days), (5) 
serious or continuing noncompliance (within 10 business days), (6) adverse 
events deemed expected or unrelated to the study (with annual progress report), 
and (7) protocol violations (with annual progress report). 
19.0 Provisions to Protect the Privacy Interests of Participants 


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Protecting Privacy: All consent procedures, assessments, and study activities will 
be conducted in private rooms by trained personnel. Dr. Gunlicks-Stoessel, a child 
psychologist, or trained psychology practicum students will administer all 
psychiatric diagnostic interviews and measures. Participants will be repeatedly 
reminded that sharing of information and completion of study tasks are voluntary. 
Assessment of participant comfort will occur on an ongoing basis; research staff 
will ask the youth how they are feeling and if they are comfortable with 
starting/continuing a study activity. Parents and children will be given the 
opportunity to separately discuss concerns or responses to questions with research 
staff. Since we are working with minors, we will inform participants and their 
parent(s) that we are required to report if the subject is a danger to themselves or 
others or if they report child abuse/neglect. 
Access to Participants: Accessing the participant’s medical record to obtain 
information regarding treatment history will be described in the consent form 
signed by the participant. Participants will be informed that they may withdraw 
this consent at any time. 
20.0 Compensation for Research-Related Injury 
Compensation for Research-Related Injury: The following statement is included 
in the consent form: “In the event that this research activity results in an injury, 
treatment will be available, including first aid, emergency treatment and follow-
up care as needed. Care for such injuries will be billed in the ordinary manner, to 
you or your insurance company. If you think that you have suffered a research 
related injury let the study physicians know right away.” 
Contract Language: N/A 
21.0 Consent Process 
Consent Process (when consent will be obtained) for Adolescents and Parents: 
Potential participants who learn about the study from PrairieCare or Minnesota 
Mental Health Clinic staff will call University of Minnesota research staff to 
express interest in participating in the study. Research staff will also directly 
contact potential participants if they have signed a Permission to Contact form. 
The researchers will schedule an appointment for the consent process to occur. 
For participants recruited via PrairieCare, Minnesota Mental Health Clinics, or 
referred from partnering organizations who opt to schedule a screening 
appointment: Families will schedule a brief screening assessment to confirm 
eligibility. Prior to completing this screening, parents and adolescents will 
complete “consent/assent to screen” forms indicating their willingness to 
participate in the screening process. Upon the completion of the screening 
process, eligible participants interested in the study will schedule a subsequent 
baseline assessment; at the baseline appointment, the study team will conduct 
informed consent for participation in the study.  


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For participants self-referred or participants referred that opt out of the scheduled 
screening option: Families will complete a “consent to contact form” which will 
be faxed to the research team, indicating parents’ permission to be contacted by 
research staff. Potential participants may also call University of Minnesota 
research staff to express interest in participating in the study. Parents will 
participate in a structured telephone screen with study staff that asks about mood, 
medical history, and current and prior treatment. If the adolescent appears eligible 
on the phone screen, they will be asked to meet with an independent evaluator 
(IE) to learn more about the study, provide consent/assent, and complete the 
baseline assessments to determine eligibility. 
Only members of the University of Minnesota research team will conduct the 
informed consent. During the consent meeting, the study will be explained; the 
consent forms will be reviewed in detail; any questions will be answered; and 
ability to understand will be assessed. Research staff will reiterate that the 
participants’ agreeing or declining to participate will have no bearing on their care 
at their chosen mental health clinic. Consent and assent forms will be signed if the 
parent and adolescent choose to participate. For participants who are not able to 
come to the University of Minnesota or are unable to do a home visit, the consent 
procedure will be conducted via a secure web-conferencing platform (Zoom). A 
member of the research team will review the consent form over Zoom and a copy 
will be available to participant via REDCap to electronically sign.  
Consent Process for Therapists and Other Clinic Staff: Clinic staff at PrairieCare 
or Minnesota Mental Health Clinics will be informed about participation in the 
study by members of the clinic’s leadership team. Clinic staff who are interested 
in participating will contact University of Minnesota research staff to indicate 
interest in participating in the study. Only members of the University of 
Minnesota research team will conduct the informed consent. During the consent 
meeting, the study will be explained; the consent forms will be reviewed in detail; 
any questions will be answered; and ability to understand will be assessed. 
Research staff will reiterate that the participants’ agreeing or declining to 
participate will have no bearing on their employment at their clinic. Consent 
forms will be signed if the individual chooses to participate. 
Waiver or Alteration of Consent Process (when consent will not be obtained): 
N/A 
 
Non-English Speaking Participants:  
N/A 
 
Participants Who Are Not Yet Adults (infants, children, teenagers under 18 years 
of age):  


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For adolescents younger than 18 years of age, the permission to contact form must 
be signed by their parent or legal guardian. Subsequent contact with these youth 
and their parent or guardian will include both consent and assent processes. Only 
one parent will be required to give consent. Research staff may accept signed  
consent from legal guardians if they provide documentation of their authority to  
consent to the youth’s general medical care. Assent will be required for all  
adolescents younger than 18 years of age. Youth assent will be documented by 
their signature on the Youth Assent Form. 
 
Cognitively Impaired Adults, or adults with fluctuating or diminished capacity to 
consent:  
• 
For adolescents 18 years of age, research staff conducting the consent 
meeting will administer the MacArthur Competence Assessment Tool 
for Clinical Research (MacCAT-CR) to assess capacity to consent. 
• 
During study visits, the independent evaluators conduct semi-
structured interview assessments of depression symptoms and 
psychosocial functioning. If during these assessments, they observe 
responses or behavior that suggest impaired competence, they will 
ensure that a qualified staff administer the MacCAT-CR to determine 
if capacity to consent has changed and requires permission from the 
legally authorized representative in order to continue participation in 
the study. The legally authorized representative will be notified and 
permission will be sought with the main study consent form if the 
LAR has not already provided consent. The LAR will be involved in 
the entire consent process each time capacity to consent is re-
evaluated. 
• 
Participants that are 18 years old or older during study participation 
will be asked to document their wishes regarding future study 
participation in the event that their capacity to consent fluctuates. 
Documentation will be part of the participant’s consent records for 
reference, but the legally authorized representative’s permission is still 
required in the event that the participant does not have capacity to 
consent. 
• 
To avoid seeking consent during periods of greater than normal 
impairment, we are not enrolling participants during hospitalizations. 
We are also not enrolling adolescents who are actively suicidal with a 
plan and/or intent who are assessed to need a higher level of care than 
outpatient treatment. Once stabilized, the adolescent can be re-
evaluated for eligibility to participate in the study. 
 


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Adults Unable to Consent:  
• 
For adolescents 18 years of age or older with diminished/fluctuating 
capacity to consent, we will ask this participant to sign the assent form 
and their LAR to sign the main consent form. 
 
22.0 Setting 
Research Sites: The treatment delivered in this study will be provided at 
PrairieCare and Minnesota Mental Health Clinics by treatment providers already 
employed by the clinics. The research assessments will be administered either at 
the mental health clinic or at the University of Minnesota. If a family is unable to 
complete an assessment at the community mental health clinic or at the University 
of Minnesota, research staff will travel to the family’s home and conduct the 
research assessment there (in this case, EEG data will not be collected). For the 
week 4, week 8, week 12, week 16, and week 36 assessments, if the family is not 
able to complete the assessment at the community mental health clinic or at the 
University of Minnesota, and the family is also not able to do a home visit, 
research staff will attempt to collect interview and questionnaire measures by 1) 
telephone, 2) Zoom Video Conferencing, and/or 3) hyperlinks to online REDCap 
questionnaires.  
 
23.0 Multi-Site Research 
N/A 
 
24.0 Resources Available 
Resources Available:  
Feasibility of Recruitment: PrairieCare completes over 4,000 psychiatric needs 
assessments per year and provides treatment to approximately 1000 depressed 
adolescents annually. Last year, over 300 adolescents with a diagnosis of 
depression initiated psychotherapy services in the outpatient clinics. This will be 
sufficient to recruit and enroll 200 participants over the course of 4 years.  
Minnesota Mental Health Clinics provided services to over 700 adolescents with a 
diagnosis of depression in the past year.  
 
The proposed time period for this research is 5 years. 
 
Facilities:  
 
Research Office Space: The investigators have adequate faculty office space and 
resources in their respective departments (Psychiatry, Biostatistics, and Health 
Policy & Management) to conduct the proposed research activities.  Office space 


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in the University’s Institute for Translational Research in Children’s Mental 
Health (ITR) will be utilized to house the Project Director, Research Coordinator, 
and Evaluators. Space in ITR will also secure (per HIPAA and IRB standards) all 
incoming and processing of data. In addition to daily research activities, training 
and staff meetings will be held at this location. This space will be capable of 
maintaining the required number of staff, technological, storage and training 
amenities to maximally perform the duties outlined in this grant. 
 
Research Laboratory Space: All biological specimens (saliva, DNA and RNA) 
collected through this protocol will be stored in the laboratory of Dr. Jeffrey R. 
Bishop at the University of Minnesota (516 Delaware Street S.E. Phillips-
Wangensteen Building room B150 Minneapolis, MN 55455). Dr. Bishop’s 
laboratory is within the College of Pharmacy’s Department of Experimental and 
Clinical Pharmacology Pharmacogenomics Laboratory located at B-150 Phillips-
Wangensteen Building.  It contains office space for twelve additional researchers 
(students/fellows/staff).  It is comprised of over 3,000 square feet of main 
laboratory space, plus auxiliary lab rooms and conference space. The 
pharmacogenomics laboratory is designed for targeted genotyping and functional 
characterization studies. This new, state of art laboratory is functionally divided 
into several work areas including those for molecular genetics, biochemical 
analysis, cell culture and analytical analysis. There is a dedicated biological safety 
cabinet for human biospecimen processing. The laboratory specializes in the 
isolation of nucleic acids (DNA, RNA, protein) from various biospecimen types 
such as serum, plasma, whole blood, isolated PBMCs, fresh/frozen/paraffin 
embedded (FFPE) tissue, saliva, and buccal swabs using validated and 
standardized protocols, and is capable of high capacity biospecimen storage. The 
laboratory also houses a 365 square-foot in-vitro cell culture room containing four 
biological safety cabinets, two stacked incubators, and one HERAcell 150i CO2 
incubator for functional characterization studies utilizing multiple cell modeling 
techniques.   
Computers: All investigators and research staff have adequate computer and 
software resources to meet the demands of the study. The investigative team 
benefits from several computer and server resources provided by the University of 
Minnesota, including a sophisticated data protection and back-up system. 
 
 
 
 
Treatment Sites: Treatment providers will deliver services at PrairieCare or 
Minnesota Mental Health Clinics outpatient clinic sites. They have adequate 
space to carry out participant programming activities, as well as record, store and 
maintain confidential client files per HIPAA and IRB protocols.  
 
Medical or psychological resources that participants might need as a result of any 
anticipated or unanticipated consequences of the research are available at 
PrairieCare, Minnesota Mental Health Clinics, and University of Minnesota 
Medical Center. 


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Research staff and mental health clinic staff who are involved in recruiting and 
treating participants will be trained in the protocol, procedures, and their 
respective duties and functions by the PI or Co-Investigators. If any future 
revisions are made to the protocol or study procedures, research staff and mental 
health clinic staff will be promptly trained in the revised procedures. Research 
staff and their training dates will be documented on the Delegation Log in the 
study regulatory binder.  
 
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