Improving Adherence in Adolescents and Young Adults With Bipolar Disorder
Phase: NA
Conditions: Bipolar Disorder
Sponsor: Case Western Reserve University

Page 1 of 26
Title: Improving Adherence in Adolescents and Young Adults with Bipolar Disorder
Principal Investigator: Martha Sajatovic, MD (UHCMC/CWRU) & Melissa DelBello, MD (UC)
Co-Investigators: Jennifer Levin, PhD, Molly McVoy, MD, Avani Modi, PhD (UC), Farren Briggs, PhD 
Version Date: May 26, 2022
Background:
This project will build upon an evidence-based adherence enhancement approach in adult BD and optimize 
the intervention to meet the specific developmental needs of a population (Adolescents and Young Adults- AYA 
with BD) for which there are no currently accepted adherence interventions and for which adherence behavior 
mechanisms are poorly known. This project will use a step-wise approach to characterize the needs of the target 
population, refine the intervention, and test mechanistic and adherence-related outcomes. This study would be 
the first to modify and pilot test an intervention that targets adherence barriers in order to optimize adherence in 
AYAs with BD. Other novel elements include: 1) using iterative qualitative input to optimize a manualized 
intervention salient to AYAs with BD, 2) assessing the intervention in two geographically distinct sites, and 3) 
examining mechanisms of adherence behavior in AYAs. The resulting feasibility, acceptability and preliminary 
efficacy data will lay the groundwork for an RCT with the overarching goal of enhancing generalizability and 
scale-up.
There is no current standard-of-care for improving adherence in AYAs with BD. An expanding literature 
suggests that it may be possible to enhance treatment adherence in BD.1, 2-6 Multiple-strategy interventions are 
likely to be more effective than a generic single-strategy intervention.7-10 However, broadly-focused psychosocial 
interventions that address the full scope of BD problems are not consistently associated with improved 
adherence.1,11 Intensive psychosocial interventions are not practical in many clinical settings. Additionally, they 
are unlikely to be tolerated by non-adherent AYAs with multiple academic, employment and social 
commitments.12-14 Similar to the adult BD literature, existing care approaches in AYAs with BD do not specifically 
target adherence and may not be practical for clinical settings. Miklowitz and colleagues have successfully used 
family-focused treatment (FFT) for adolescents with BD.15, 16 However, FFT requires more than 20 sessions and 
a 9-month intervention duration, a time commitment that is not ideal for AYA, who tend to be oriented toward 
more immediate rewards. Thus, there is a clear need for brief interventions that are attractive to AYAs and which 
can rapidly facilitate key health behaviors.
Customized adherence enhancement is a novel intervention that works in BD. Findings from our group, as 
well as other adherence research 17,1,18,19,20,21-27 suggest that key modifiable adherence barriers in BD include an 
under-appreciation of illness severity/consequences of non-adherence, substance abuse and other high risk 
behaviors that impede appropriate medication-taking, difficulties with medication routines, and inadequate ability 
to communicate with prescribing clinicians regarding drug side-effect concerns. We developed CAE to address 
key barriers to medication adherence, specifically for non-adherent patients with BD.28, 29 Complementary and 
differing sources of qualitative data (focus groups, advisory board input, cognitive interviews) will optimize 
delivery of CAE to meet the needs of AYAs with BD. 
Research in AYAs with chronic health conditions suggests that addressing adherence barriers predicts 
outcomes: The Pediatric Self-Management Model (Figure 2),30 developed by Modi (co-I) and colleagues, 
highlights the individual, family, healthcare system, and community factors that influence disease management 
and how these processes in turn impact adherence and health outcomes. This model has been applied to a 
variety of chronic conditions and shares important targets for adherence interventions, including the specific 
focus on barriers in the current proposal. Modi and colleagues demonstrated that a greater number of adherence 
barriers correlates with and predicts worse adherence in AYAs with chronic health conditions.31, 32 Specifically, 
and aligned with the CAE intervention developed by Sajatovic and Levin, BD knowledge, communication with 
clinicians and support systems (e.g., family, peers), risk-taking (e.g. substance abuse, unprotected sex), and 
medication-taking routines appear to be key mechanisms to improve adherence in AYAs. However, there is a 
need to incorporate the unique issues relevant to AYAs with BD when targeting adherence barriers. Qualitative 
findings will inform modifications which may include remote technology-facilitated delivery methods (i.e. smart 
phone) to appeal to AYAs.

Page 2 of 26
Project Design:
Aim 1: 
In Phase 1, we will conduct focus groups in adolescents and young adults (AYAs) with bipolar disorder (BD), 
their parents/guardians/care partners, and healthcare providers to evaluate barriers & facilitators to adherence. 
We will use these data, as well as input from an advisory board, to modify an adult intervention that targets 
adherence barriers in order to optimize adherence, Customized Adherence Enhancement (CAE), with the goal 
of targeting our hypothesized mechanism, such that it is developmentally specific, appropriate and acceptable 
to AYAs with BD.
In Phase 2, we will conduct cognitive interviews (e.g., “think aloud”) with 6-8 of the AYAs with BD (ages 16-21 
years) to elicit feedback on the resulting CAE-AYA. 
Aim 2: In Phase 3, we will conduct a pilot randomized-controlled trial of CAE-AYA vs. enhanced treatment as 
usual (ETAU) to examine changes in medication adherence (primary outcome) in AYAs with BD.
Hypotheses 1: At 6 month follow-up, compared to ETAU, individuals in CAE-AYA will have greater improvement 
in adherence measured by the Tablets Routine Questionnaire (TRQ) and electronic adherence monitoring.
Hypotheses 2: We expect greater improvements in secondary outcomes, including health related quality of life 
and symptoms in CAE-AYA vs ETAU group. 
Aim 3: Exploratory analyses will investigate CAE-AYA mechanistic effects by evaluating whether adherence 
barrier change (BD knowledge, communication with clinicians/parents/guardians/care partners, medication 
routines and substance use/risky behaviors) is related to adherence change.
Hypotheses 3: Change in knowledge, communication with clinicians/parents/guardians/care partners, 
medication routines and substance use/risk-taking behaviors will mediate improved adherence.
Number of Study Participants
We plan to enroll a total of up to 82 participants across all 3 phases and both sites (see breakdown below):
Phase 1:  focus groups/advisory board (n=up to 54; all at CWRU)
Phase 2:  cognitive interviews (n=up to 8; all at CWRU)
Phase 3:  The total number of subjects that may be enrolled in to the RCT across both sites (CWRU and UC) is 
40. 
Inclusion and Exclusion Criteria
Phase 1 Focus Group/s and Advisory Board
We will conduct 2-3 focus groups in AYA with BD (6 individuals per focus group with a total of 12-18 individuals), 
2-3 focus groups of parents, legal guardians or care partners (e.g., spouse, grandparent, adult sibling, etc.) who 
are involved in the care of and live with an AYA with BD (6 individuals per focus group with a total of 12-18 
individuals), and 2-3 focus groups of healthcare providers that care for AYA with BD (6 individuals per focus 
group with a total of 12-18 individuals). AYA and parent/guardian/care partner focus group participants will be 
referred by clinicians or self-referred in response to IRB-approved advertisements.  To optimize generalizability, 
some of the prescribing healthcare providers will be community-based.
We will then convene an advisory board (AB) of AYAs with BD (n= up to 10), parents/guardians/care partner of 
AYAs with BD (n= up to 10), and a group of healthcare providers (e.g., physicians, therapists, pharmacists, and 
nurses) that care for AYAs with BD.  AYA and parent/guardian/care partner AB members will be a representative 
subset of the members of the focus groups. Healthcare provider AB participants will be physicians, therapists, 
pharmacists, and nurses that care for AYAs with BD.
Inclusion for AYA focus group and AB members
1.
Individuals between the age of 16 and 21 years old.

Page 3 of 26
2.
DSM-5 diagnosis of bipolar disorder (BD)
3.
If <18 years, able and willing to give written informed assent and have a legal guardian provide written 
informed consent. If > 18 years, able and willing to provide written informed consent.
4.
Fluent in English.
Inclusion for parent/guardian/care partner focus group and AB members
1.
Individuals of age 18 years or older.
2.
Parent, legal guardian or other person who is closely involved with the care of and lives with an 
adolescent/young adult who meets the study criteria.
3.
Willing/able to provide written, informed consent for their participation. 
4.
Fluent in English
Inclusion for provider focus group and AB members 
1.
Individuals of age 18 years or older.
2.
Physician, therapist, pharmacist, or nurse that cares for AYAs with BD.
3.
Willing/able to provide written informed consent for their participation. 
4.
Fluent in English
Exclusion for all focus groups and AB members
1.
Unable to receive care in the outpatient setting due to illness severity
2.
A DSM-5 diagnosis of an autism spectrum disorder or primary psychotic disorder.
3.
Documented or suspected IQ< 70. 
Phase 2 Usability testing and feedback:
In Phase 2, CAE-AYA will undergo usability testing and feedback with 6-8 AYAs with BD, representative of age, 
gender, and ethnicity. Participants will be referred by clinicians or self-referred in response to IRB-approved 
advertisements.  
Inclusion for Phase 2 participants
1.
Individuals between the age of 16 and 21 years old.
2.
DSM-5 diagnosis of bipolar disorder (BD), type I or II.
3.
Poor adherence defined as missing ≥ 20% of prescribed evidence-based BD medications, i.e., mood 
stabilizer (e.g., lithium, valproic acid, or carbamazepine) or second generation antipsychotics, on the 
TRQ at any point since being diagnoses with bipolar disorder. 
4.
If < 18 years, able and willing to give written informed assent and have a legal guardian provide 
written informed consent; if > 18 years, able and willing to provide written informed consent.
5.
Fluent in English. 
Exclusion for Phase 2 participants
1.
Unable to receive care in the outpatient setting due to illness severity.
2.
A DSM-5 diagnosis of an autism spectrum disorder or primary psychotic disorder.
3.
Documented or suspected IQ<70.
4.
Prior enrollment in CAE.
Phase 3 Randomized Clinical Trial:
Once a referral has been made, either by self or clinician referral, a research assistant will telephone the potential 
participant, give a brief description of the study, and invite them to an appointment to assess their eligibility. 
Individuals who provide informed consent (or assent with informed consent provided by their legal guardians if 
they are < 18 years old) will then proceed with screening and enrollment for the RCT.  
Inclusion for RCT participants 
1.
Individuals between the age of 13 and 21 years old.
2.
DSM-5 diagnosis of bipolar disorder (BD), type I or II as diagnosed by the Structured Clinical Interview 
for DSM-5 (SCID-5).

Page 4 of 26
3.
Poor adherence defined as missing ≥ 20% of prescribed evidence-based BD medications, i.e., mood 
stabilizer (e.g., lithium, valproic acid, or carbamazepine) or second generation antipsychotics, on the 
TRQ for the past week or past month.
4.
If < 18 years, able and willing to give written informed assent and have a legal guardian provide 
written informed consent. If > 18 years, able and willing to provide written informed consent.
5.
Fluent in English. 
Exclusion for RCT participants
1.
Unable to receive care in the outpatient setting due to illness severity. 
2.
A DSM-5 diagnosis of an autism spectrum disorder or primary psychotic disorder.
3.
Documented or suspected IQ< 70.
4.
Have recently (in the past month) started a new psychotherapy/behavioral intervention
Special/Vulnerable Populations: 
Minors
The CAE-AYA intervention is meant to be an adjunct to routine clinical care. The AYA with BD participant 
and their legal guardians (if < 18 years) will be informed and it will be understood that acceptance or refusal to 
participate in any phase of the study will not influence their ability to receive clinical care at any affiliated hospital 
or clinic setting or elsewhere, and that they are free to withdraw from study participation at any time. The informed 
consent/assent process will be documented for each participant. Specifically, for all participants, it will be 
documented that information was provided regarding the risks, benefits, and alternatives to study participation.
Consistent with the Federal guidelines, all participants/guardians will be informed, verbally and in the written 
consent/assent form, of the federally mandated reporting laws for child abuse and neglect. Specifically, the 
consent form will read, “the state of Ohio, mandates all those working with children report suspected incidents 
of abuse or neglect. In addition, research records, just like hospital records may be subpoenaed by a court order. 
If some information about abuse is revealed that must be reported, or if a court order to release the reports is 
received, an attempt will always be made to inform you before the Department of Human Services or any other 
agency is consulted.  Within the bounds of confidentiality permitted by the law, no information about you (or your 
child) will be shared with any individual or agency without your prior consent.” Thus, except under circumstances 
covered under the mandated child abuse reporting laws, and/or situations in which the adolescent/young adult 
and/or a family member is judged to be a danger to him- or herself or others, no information about the 
adolescent/young adult or family will be shared with any individual or agency without prior consent. 
Students/Employees 
UHHS or CWRU employees or students will not specifically be recruited for this study, however, they will be 
allowed to participate if they fit the inclusion criteria and do not directly report to the Psychiatry Department. 
Students and employees may directly benefit from participation. Anyone with an employment or academic 
relationship to CWRU or UH will be informed that their participation in the study or refusal to do so, will in no way 
influence their grades, employment, or subsequent recommendations. Employees will never be made to feel that 
their job, promotion, salary, or status in any way depends on participation in the research study. The Principal 
Investigator or any other coinvestigator will not be responsible for directly recruiting and/or obtaining informed 
consent from any person under his or her direct supervision/employee.
Setting:
1) Research will be conducted at the Research offices of the PIs, Dr. Sajatovic in Cleveland and Dr. DelBello in 
Cincinnati.  
2) Participants will be referred by local clinicians who have been informed of the study by study staff, by self-
referral in response to IRB flyers, and by email as described in the Recruitment section. 
3) The Cleveland offices are in the W.O. Walker Center, 10524 Euclid Ave., Cleveland, OH 44106.
The consent process may be conducted remotely via video conferencing, using either UH Zoom, CWRU 
restricted Zoom, Zoom for Healthcare or WebEx, and REDCap (individual link emailed directly to the 
participant/guardian) if necessary. All other study procedures may also be conducted remotely via telephone or 

Page 5 of 26
via video conferencing, using UH Zoom, CWRU restricted Zoom, Zoom for Healthcare or WebEx and REDCap 
(individual link emailed directly to the participant/guardian), if necessary.
Recruitment Methods 
Participants will be recruited for Phases 1 & 2 of the study at CWRU. It is expected that most participants will 
be referred from the child, transitional care and the general adult psychiatry clinics in the Department of 
Psychiatry at CWRU/UH or (for Phase 2) be self-referred in response to IRB-approved flyers advertising the 
study which will be posted with permission of staff at Community Mental Health Clinics, physician offices, and 
other organizations serving this population.  Healthcare providers will also be recruited by email for focus groups 
and advisory boards. Follow-up methods will include both email and phone calls.
Participants for Phase 3 of the study will be recruited from CWRU/UH and child and adult clinics in Cincinnati.  
Once a potential participant has been identified by their clinician, the clinician will ask if they are interested in 
hearing more about the study and ask permission for someone from the study team to call them.  Potential 
participants may also self-refer in response to IRB-approved flyers advertising the study which will be posted 
with permission of staff at Community Mental Health Clinics, physician offices, and other organizations serving 
this population.  Once the referral has been made, either by self or clinician referral, a research assistant will talk 
with the potential participant over the phone, give a brief description of the study, and invite them to an 
appointment to assess their eligibility. 
At the CWRU site, we will recruit participants through their clinicians from the Department of Psychiatry at 
UHCMC, the Division of Child and Adolescent Psychiatry at UHCMC, and affiliated community mental health 
centers. The CWRU site will also recruit using ResearchMatch. social media ads, Google search ads and bus 
ads. Social media ads will be posted on Facebook originating from the main UH Facebook page. Bus ads will 
run on the RTA bus system. Social media ads, Google search ads and bus ads are being done in coordination 
with UH Marketing & Communications and Brokaw ad agency. We will also query TriNetX to identify potential 
participants. Address, phone numbers and email addresses will be collected so that parents/guardians/potential 
participants can be contacted (by letter or email, followed by a phone call).  The letters will mention specifically 
that individuals can opt out of the follow up phone call. Potential participants/their parents/guardians who do not 
opt out of the follow-up phone will be contacted and, if they express interest in the study, a screening visit will be 
scheduled.  Up to 4 attempts will be made to contact the potential participant.  Research personnel will leave a 
voicemail if the person does not answer.  For those participants who cannot be contacted, refuse participation, 
or otherwise do not qualify for the study, only aggregate numbers will be retained to keep track of recruitment 
efforts. The personal information will only be kept for as long as necessary (i.e. until the participant is enrolled or 
documented as a pre-screen failure).  We will request a partial waiver of HIPAA to be able to collect PHI for 
recruitment purposes.
In Cincinnati we will recruit participants from The Mood Disorders Clinic at the University of Cincinnati Medical 
Center, The Division of Child and Adolescents Psychiatry at Cincinnati Children’s Medical Center, and the 
Central Clinic Community Mental Health Center. The UC site will also recruit using ResearchMatch. We will also 
run an electronic medical record query at this site as well, using the same method as described above for the 
CWRU site. 
Clinicians at the above mentioned clinics will be given information about the research study and will be asked 
to consider referring AYA patients of theirs with BD and ask them if they would be interested in hearing more 
about a research study.  The research assistant will then call patients who have agreed to being called, give 
them a brief description of the study, and prescreen them for basic inclusion/exclusion criteria over the phone.  
If patients are still interested, an appointment will be made to meet with the RA in person to consent the 
participant and complete the screening visit.
The CWRU outpatient clinics from which we will recruit provided care to 2,212 unique individuals in 2018 
who were between the ages of 14-20. Patients are seen for follow-up every 1-3 months.
The University of Cincinnati (UC) outpatient clinics from which we will recruit patients provide care to 
approximately 3,500 unique individuals annually.  Typically, patients are seen for follow-up every 1-3 months. 
Research will be conducted at the Research offices of the PIs, Dr. Sajatovic in Cleveland and Dr. DelBello 
in Cincinnati. Participants will be referred by local clinicians who have been informed of the study by study staff, 
by self-referral in response to IRB flyers, and by email as described in the Recruitment section. The Cleveland 
offices are in the W.O. Walker Center, 10524 Euclid Ave., Cleveland, OH 44106.

Page 6 of 26
Consent Process
At the CWRU site, the consenting will take place at the PI’s research offices within the Department of 
Psychiatry in the W.O. Walker Center. The consent process may also be conducted remotely over video 
conferencing, using either UH Zoom, CWRU restricted Zoom, Zoom for Healthcare or WebEx, and via 
REDCap/electronic written consent (individual link emailed directly to the participant/guardian) if necessary. 
Before enrollment in the study, an authorized member of the investigational staff will explain to potential 
participants the aims, methods, reasonably anticipated benefits, and potential hazards of the study, and any 
discomfort participation in the study may entail. The research staff will present the consent form in detail, and 
make sure the participants understand the study by encouraging them to ask any questions they may have, and 
asking them to explain what the study will involve in their own words.  The participant and their parent/guardian 
(if applicable) will be given sufficient time to read the informed consent form and the opportunity to ask questions. 
Participants or their parent/guardian (if applicable) will also be asked to sign a Photograph, Image and Audio 
Release Form.
The consent process will begin when the research assistant first talks on the phone with the potential 
participant and explains the study to them.  If possible, potential participants (if > 18 years old), will be given a 
copy of the consent form ahead of time by mail or email and they will be asked to read it carefully.  RCT 
participants will be allowed to take the consent/assent form home to think it over and schedule another time to 
come back to finish the screening visit if they wish.
The research staff will present the consent form in detail, and make sure the participants understand the 
study by encouraging them to ask any questions they may have, and asking them to explain what the study will 
involve in their own words. Once the researcher has confirmed the identity of the subject, the researcher, subject 
and their parent/guardian (if applicable) sign either a physical copy of the consent form or an electronic version 
of the consent form in REDCap. For those consenting via e-consent, identity will be confirmed by asking the 
potential participant to show his/her driver’s license or if not available, any state or government-issued picture 
identification card. If they do not have picture identification available, they will be asked to provide the last four 
digits of the social security number, their date of birth and one of the following: account number, street address, 
insurance carrier name, insurance policy number, medical record number, birth certificate or insurance card.
At each visit the participant will be asked if they want to continue with the study. The research assistant who 
consents the participants will not be in any way involved with their clinical care.  The AYA with BD participant 
and their legal guardians (if < 18 years) will be informed and it will be understood that acceptance or refusal to 
participate in any phase of the study will not influence their ability to receive clinical care at any affiliated hospital 
or clinic setting or elsewhere, and that they are free to withdraw from study participation at any time.
Research Participants who are not yet adults (children and teenagers) will parental permission be obtained 
from one parent even if the other parent is alive, known, competent, reasonably available, and shares legal 
responsibility for the care and custody of the child. Signed consent form will be documenting the 
parental/guardian permission. If a participant has a legal guardian, they will be allowed to sign consent for the 
participant. Participants who are 14-17 years old will sign the consent form and their parent will countersign it. 
Participants who are 13 years old will sign the assent form and informed consent from participant’s parent will 
be obtained and documented using an IRB-approved consent.
Waiver of Written Consent for Clinicians
We will be asking the clinicians of subjects who participate in the RCT portion of the study to complete a 
questionnaire giving their impressions of the intervention their patient received and asking them what types of 
adherence improvement or support approaches are used in their clinic. When participants enroll in the study, 
they are asked to sign a release of information so we may talk to their treating clinician. Study staff will use that 
contact information to reach out to clinicians to complete this questionnaire. Clinicians will be sent a survey link 
via REDCap. The initial page of the RedCap survey will include an electronic consent form. Consent will be 
implied by completion of the survey. Alternatively, the clinician may complete their questionnaire over the 
phone or by having it mailed to them for them to mail back to the study site. In those cases, study staff will 
review with them in detail the language in the consent form  that explains the purpose of the study, the 
procedures involved, potential risks and benefits, how to withdraw from the study, confidentiality, and informs 
respondents that participation is voluntary. A copy of the informed consent may be sent to the potential subject 
for them to review prior to consent should they request this. After reviewing the consent form with the clinician 
and answering any questions they may have, verbal consent will be obtained over the phone from the clinician. 

Page 7 of 26
Those who enroll via mail will be mailed a copy of the consent form along with their questionnaire. Clinician 
participation involves the completion of an online survey and involves no more than minimal risk. A survey 
such as this, conducted outside of the research context would not require written consent.
Study Design/Procedures
Phase 1: Investigation of AYA Needs in Adherence Promotion:  Adaptation of CAE and development of new 
content will be guided by focus groups and key informant interviews with a representative advisory board (AB) 
of AYAs with BD (n= up to 10), their parents/guardians/care partners (n= up to 10), and a group of healthcare 
providers (e.g., physicians, therapists, pharmacists, and nurses) that care for AYAs with BD.  To optimize 
generalizability, some of the prescribing providers will be community-based. Focus groups and AB meetings 
may take place in person or via a video conferencing platform with optional telephone call-in if needed.
Prior to the first AB meeting, we will conduct 2-3 focus groups in AYA with BD (6 individuals per focus group 
with a total of 12-18 individuals), 2-3 focus groups of parents, legal guardians or care partners who live with an 
AYA with BD (6 individuals per focus group with a total of 12-18 individuals), and 2-3 focus groups of healthcare 
providers that care for AYA with BD (6 individuals per focus group with a total of 12-18 individuals) to assess 
perceived adherence barriers and facilitators. Focus groups will be organized, conducted, and analyzed in the 
format described by Morgan and Krueger. 34 All focus group participants will complete a demographics form that 
should take no more than 5 minutes to complete. This form will be completed either on paper or in REDCap via 
a survey link sent to the participants email address. The focus groups and AB will be convened at CWRU and 
led by Sajatovic & Levin. All focus groups and AB meetings will be video or audio-recorded and transcribed 
verbatim (any reference to names or other PHI will be removed/coded to ensure deidentification) to undergo 
thematic analysis and reviewed by the members of the study team at CWRU, UC, Cincinnati Children’s Hospital 
Medical Center (CCHMC), and University of Florida (UF).  In the event that a participant agrees to be in a focus 
group, but is unable to attend the focus group because of scheduling or other problems, the study team may 
conduct an individual interview (either in person or by phone) following the same set of questions that would 
have been administered in the focus group.
Following the focus groups, the AB will meet twice. At the first meeting, we will present a summary of the 
perceived barriers/facilitators from focus groups and present a first draft of the CAE-AYA intervention. We will 
elicit additional suggestions on barriers/facilitators and receive input on the CAE-AYA draft. In the second AB 
meeting, we will present a revised draft and solicit input for a final product. Those participating in the AB who did 
not participate in a focus group portion of phase 1 will be asked to complete a demographics form that should 
take no more than 5 minutes to complete The resulting intervention will combine CAE elements and focus on 
adherence barriers within a development framework 33 that articulates the involvement of support networks (e.g., 
family, peers, and clinicians), acknowledges the presence and variability of support network stress, engagement 
in risk-taking behaviors, and is sensitive to the needs of AYAs with BD.
Phase 2: Intervention Refinement Based on Patient Input: CAE-AYA will undergo usability testing and 
feedback 
with 
6-8 
AYAs 
with 
BD, 
representative of age, gender, and ethnicity. 
AYA will all have self-reported difficulties with 
adherence (missing > 20% of BD medication 
at any point since being diagnosed with 
bipolar disorder). We will determine usability 
by systematically observing AYAs under 
controlled conditions to detect issues that can 
lead to lack of engagement.35 Specifically, we 
will 
evaluate 
the 
acceptability, 
comprehensibility, and relevance of each CAE 
module. Each participant will undergo a 1-
hour session of testing to minimize the burden 
of the evaluation and to ensure that each 
module is reviewed by 2-3 AYAs with BD. 
After brief explanation by a trained facilitator, participants will be asked to ‘think aloud’ as they work through one 

Page 8 of 26
module, thus allowing us to evaluate the thought processes of the AYA as he/she works through the modules.36 
Sessions will be video recorded, and notes will be taken by the facilitator. Modifications will be made after each 
AYA completes testing, as they play a crucial role in developing the intervention content and materials. The 
recordings may be transcribed verbatim (any reference to names or other PHI will be removed/coded to ensure 
deidentification) and reviewed by the members of the study team at CWRU, UC, CCHMC, and UF. These 
sessions may take place in person or via a video conferencing platform with optional telephone call-in if needed
Phase 3: Pilot Testing of CAE-AYA: Once the CAE-AYA treatment manual is completed, we will conduct a 6-
month, prospective, 2-site pilot RCT testing the effects of CAE-AYA (N=20) vs. enhanced treatment as usual 
(ETAU) (N=20). Participants will be consented/assented, screened for inclusion/exclusion, and receive their 
electronic monitoring device. One week later, those who meet screening criteria and complete baseline 
evaluation will be randomized to Control (Enhanced Treatment as Usual; ETAU) or Treatment (CAE-AYA). 20 
AYAs with BD will receive CAE-AYA and 20 AYAs with BD will receive ETAU, with 10 of each group at each site. 
Participants will be in the study for a total of 6 months and measures will be completed at Screening, Baseline, 
and Weeks 8, 12 and 24 as noted in Figure 4 and Table 2. Study visits may take place in person or via a video 
conferencing platform with optional telephone call-in if needed
Treatment Randomization: Individuals will be randomized on a 1:1 basis to participate in either CAE-AYA or 
ETAU. Block randomization with block sizes ranging randomly between 3-5 consecutive patients will ensure 
equal numbers of CAE-AYA and ETAU patients balanced on demographic and clinical characteristics. The 
randomization list will be computer-generated by CWRU personnel who are not members of the study staff. We 
will stratify by site (UC vs. CWRU) and age (13-17 vs. 18-21 years old). 
Measures and Assessments
Table 2 shows the measures to assess outcomes, symptoms, barriers, mechanisms, and visits at which the 
measures are given. All scales have been used successfully with AYAs. Phase 3 participants will be evaluated 
for DSM-5 diagnoses using the Structured Clinical Interview for DSM-5 (SCID-5)37 and the separation anxiety 
module of the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS)88, administered by a trained 
rater with established diagnostic reliability. All comorbid psychiatric diagnoses determined by the SCID-5 and K-
SADS, including ADHD, will be recorded and considered in analyses. Both sites have extensive experience 
administering the structured diagnostic interviews and clinical symptom and self-report assessments that will be 
used in the proposed study. 
Demographic variables will include age, sex, race/ethnicity, living situation, parental education level, 
educational/school, and socioeconomic status. The primary outcome measures include two adherence 
measures: TRQ and electronic monitoring via the SimpleMed pillbox. Participants will be encouraged to be as 
candid as possible in reporting adherence, although we acknowledge that some individuals might over-report 
adherence. In the proposed study, there will be a hierarchical plan for determining adherence in which the TRQ 
will be the primary measure and SimpleMed pillboxes will be used to validate these adherence data. The TRQ 
evaluation will include adherence data for each BD drug. 
The SimpleMed boxes can assess adherence for multiple medications and we will examine adherence for 
each BD drug. Participants will be instructed on the use of the pillbox and will be given a handout with simple 
instructions.  Participants load their weeks’ worth of medication into the pillbox each week.  When it is time to 
take their medication, the participant removes the dose for that day/time.  SimpleMed sends the data about 
whether or not the compartment was opened via an internal cellular modem which only requires a battery that is 
rechargeable.  The data is linked only to the SimpleMed ID and kept in the SimpleMed cloud portal that the study 
staff can access.  The link to the participant study ID will be kept separate with the study’s secure documents.  
A dose will be counted as “taken” if the cell on the pillbox is opened within two hours of the prescribed time. 
Using the TRQ, we will collect information on the type and number of prescribed BD drugs, dosing frequency 
and adherence. We will also collect information on drugs prescribed for psychiatric comorbidity, including drug 
name/class, dose, dosing frequency and TRQ.  We will assess prior treatment duration for each medication.  For 
follow-up, we will inquire about any drug changes. For the primary outcome, we will calculate an average TRQ 
based on TRQ scores for each BD drug, but also plan to explore differences across BD drugs and drug classes 
in additional exploratory analyses. Data from 35 AYA with BD prescribed 2 medications in our prior study suggest 
that of the 19 (54%) were non-adherent to either medication, and most of those who were poorly adherent (n=16, 

Page 9 of 26
84%) were non-adherent to both medications. Analyses will also consider medication changes, number of 
medications, and medications prescribed for psychiatric comorbidity as possible variables that impact outcomes. 
The adult CAE RCT demonstrated that TRQ scores by blinded vs. un-blinded raters were similar, likely because 
the TRQ is a self-report measure. However, the SimpleMed data will be analyzed by staff blind to intervention 
assignment. In the event a subject’s SimpleMed box is not working or the subject does not wish to use the 
SimpleMed Box for any period of time, the subject will track their medication compliance using a paper form. 
Adverse effects will be collected systematically at each study visit using open-ended questions. Severity and 
duration and its relation to BD medications and/or CAE-Y will be evaluated and recorded by a study clinician. All 
adverse events will be reviewed by the DSMB biannually.

Page 10 of 26
Study Timeline: 
Phase 3 RCT Schedule of Events
Screen
Baseline
W1-W7
W8/V1
W12/V2
W24/V3
Estimated time requirement of visit
90-120 
minutes
60-90 
minutes
45-60 
minutes 
60-90 
minutes
60-90 
minutes
60-90 
minutes
Informed Consent
X
Structured Clinical Interview for DSM-5 37
Separation anxiety module of the Kiddie Schedule for 
Affective Disorders and Schizophrenia88
X
Family History 
X
Demographics Form 
X
BIPOLAR SYMPTOMS
Young Mania Rating Scale56 
X
X
X
X
Clinical Global Impression (CGI)-Severity Scale57  CGI-
Improvement Scale57 
X
X
X
X
The Columbia Suicide Severity Rating Scale58 *
X
X
X
X
X
Suicide Risk Assessment
X
Hamilton Depression Rating Scale (HAM-D)55 
X
X
X
X
PRIMARY OUTCOMES
Tablets Routine Questionnaire 59, 60 ***
X
X
X
X
X
SimpleMed Boxes (Vaica) / Compliance log
X
X
X
X
SECONDARY OUTCOMES
Quality of Life Inventory (PedsQL)61,62 
X
X
X
X
Longitudinal Interval Follow-up Evaluation (LIFE) -modified 
mental health, medical and crisis service utilization.63, 64
X
X
X
ADHERENCE BARRIERS
Oxford Bipolar Knowledge Questionnaire65 
X
X
X
X
Adolescent Patient-Provider Interaction Scale66
X
X
X
Self-Report Habit Index67
X
X
X
X
Bipolar Disorder Routines Questionnaire (adapted from 
Asthma Routines Questionnaire)68
X
X
X
X
Teen-Addiction Severity Index (Chemical Use section only) 69
X
X
X
X
Rule Breaking Subscale of the Antisocial Behavior 
Questionnaire70, 71
X
X
X
X
DEVELOPMENTAL MECHANISM
Attitudes Towards Mood Stabilizers Questionnaire, a 
modification of the Lithium Attitudes Questionnaire72
X
X
X
X
Transition Readiness Assessment Questionnaire (TRAQ) 73
X
X
X
X
Global Decision-Making Scale 74
X
X
X
X

Page 11 of 26
Conflict Behavior Questionnaire - 2075 
X
X
X
X
Inventory of Parent and Peer Attachment76 
X
X
X
X
FEASIBILITY, ACCEPTABILITY, AND SATISFACTION OF TREATMENT
Patient & Clinician Acceptability & Satisfaction 
Questionnaires (W8)
X
Attendance Tracking Sheet (W1-W8)
X
Evaluation of adherence with scheduled routine mental health 
care appointments (no shows) and number of routine mental 
health care appointments in past 6 months
X
X
Table 2: Assessment Strategy for Phase 3
Questionnaire/Assessment 
# of items/Description/Reliability-Validity 
DSM-5 DIAGNOSIS
Structured Clinical Interview for DSM-537, 
Family History & separation anxiety module of 
the Kiddie Schedule for Affective Disorders 
and Schizophrenia88
Structured Clinical Interview for DSM-5 and separation anxiety module 
of the Kiddie Schedule for Affective Disorders and Schizophrenia will 
be administered by a trained rater with established diagnostic 
reliability (diagnostic kappa > 0.9). Family History will be assessed by 
asking the subject if they have any immediate family members (parent, 
grandparent, aunt/uncle, siblings ) with bipolar depression, anxiety 
disorder, PTSD, schizophrenia, substance use/abuse or other 
psychiatric illness, and if so, who has them.
BIPOLAR SYMPTOMS
Depression
Hamilton Depression Rating Scale (HAM-D)55 
17-item observer-rated questionnaire to assess depressive symptoms 
with excellent reliability and validity
Mania
Young Mania Rating Scale56 
11-item observer-rated questionnaire to assess manic symptoms with 
high reliability and validity
Illness Severity & 
Illness Improvement
Clinical Global Impression (CGI)-Severity 
Scale57  CGI-Improvement Scale57 
A well-established observer-rated 7-point scale to assess overall 
illness severity and change from baseline
Suicidality
The Columbia Suicide Severity Rating Scale58 
Suicide Risk Assessment****
Assessment for suicidality. If any subject experiences worsening 
suicidality, the Child/Adolescent mental health clinician on the study 
team will evaluate them and determine the most appropriate course of 
action, referral and/or management. The study team has established 
high inter-rater reliability with all rating scales (ICC >0.85)
PRIMARY OUTCOME 
Tablets Routine Questionnaire 59,60 ***
Self-report measure noted to be reliable for use in BD and shows a 
high correlation with lithium levels.62, 63 For individuals who are on 
more than one medication, an average TRQ for each medication will 
be calculated. 
Adherence 
SimpleMed Boxes (Vaica) / Compliance log
Daily objective adherence data of BD medications are captured in real 

Page 12 of 26
time via GMS connectivity. Features to enhance adherence, including 
reminders and alerts will be activated for those in CAE as part of the 
Routines module while those in ETAU will use the system as a simple 
pill box.
SECONDARY OUTCOME
Quality of Life
Quality of Life Inventory (PedsQL)61, 62 
23 items representing physical, emotional, social, and school 
functioning and a total score for Teen (13-18 years) and Young Adult 
(18-25) versions will be used. Scores range from 0-100 and reliability 
for scales approach or exceed α= 0.70. 
Mental Health & Medical 
Service Utilization 
Longitudinal Interval Follow-up Evaluation 
(LIFE) -modified mental health, medical and 
crisis service utilization.63, 64
A systematic assessment recording week by week use of psychiatric 
medications. 
ADHERENCE BARRIERS
Bipolar Knowledge
(Module 1)
Oxford Bipolar Knowledge Questionnaire65
40-item self-report questionnaire used to assess knowledge of BD 
management on a 3-point Likert scale from agree to disagree131
Communication
(Module 2)
Adolescent Patient-Provider Interaction 
Scale66
9-item self-report measure of adolescent patient-provider interaction 
which demonstrates good internal consistency (Cronbach’s alpha = 
.75) and construct validity and has been used in 15-21 year olds. 
Self-Report Habit Index67
12-item self-report questionnaire on a 5-point Likert Scale from agree 
to disagree that measures habit strength can be used with both 
adolescents and emerging adults and will be administered regarding 
the habit of taking medication
Medication Routines 
(Module 3)
Bipolar Disorder Routines Questionnaire 
(adapted from Asthma Routines 
Questionnaire)68
Factor analysis identified two distinct dimensions to the original scale, 
Medication Routines and Routine Burden. Medication Routines is 
associated with both medication adherence and health care utilization 
while Routine Burden is associated with quality of life. Alphas are 
adequate for each scale. 
Teen-Addiction Severity Index69
Semi-structured interview developed as a standardized instrument for 
periodic evaluation of substance abuse. This is an age-appropriate 
modification of the Addiction Severity Index. It yields 70 ratings in 
seven domains: substance use, school status, employment/support 
status, family relations, peer/social relationships, legal status, and 
psychiatric status. It has established validity and inter-rater reliability. 
78, 69  We will ony be using the chemical use section in this study. 
Risk Behaviors 
(Module 4) 
Rule Breaking Subscale of the Antisocial 
Behavior Questionnaire70, 71 
Self-report measure used to assess rule-breaking behavior commonly 
seen in AYA 13 to 21 years of age. Eleven rule-breaking behaviors are 
assessed on a 5-point Likert Scale with a Cronbach’s alpha calculated 
at .78.
DEMOGRAPHICS

Page 13 of 26
Participant demographics
Demographics Form 
The questionnaire will assess basic demographic data, including age, 
sex, race/ethnicity, living situation, school status, and socioeconomic 
status. 
DEVELOPMENTAL MECHANISMS
Medication Attitudes
Attitudes Towards Mood Stabilizers 
Questionnaire, a modification of the Lithium 
Attitudes Questionnaire72
19-item self-report questionnaire grouped into 7 subscales: Opposition 
to Prophylaxis, Denial of Therapeutic Effectiveness, Fear of Side 
Effects, Difficulty with Medication Routines, Denial of Illness Severity, 
Negative Attitudes toward Drugs in General, and Lack of Information 
about Medications. Test-retest reliability is good to excellent. 
Self-Management
Transition Readiness Assessment 
Questionnaire (TRAQ) 73
The 20-item TRAQ assesses the degree to which AYAs demonstrate 
the self-management skills necessary to transition from pediatric to 
adult healthcare across conditions. It has good internal consistency 
and criterion validity.
Decision Making Style
Global Decision-Making Scale 79
A 25-item questionnaire measuring five decision-making styles:  
rational, intuitive, dependent, avoidant, and spontaneous. Within an 
adolescent sample, the scale showed good reliability, factorial 
stability, and convergent validity 80
Parent-AYA 
Communication and 
Conflict
Conflict Behavior Questionnaire - 2075 
A 
20-item 
self-report 
questionnaire 
assessing 
perceived 
communication and conflict with a parent during the past 2 weeks. The 
questionnaire assess both the AYA’s evaluation of the parent’s 
behavior and AYA’s dissatisfaction with parent’s behavior.75 The scale 
shows good reliability and has been used in a number of studies 
evaluating the efficacy of interventions for AYA’s with bipolar 
disorder.81 
Parent and peer supportive 
communication
Inventory of Parent and Peer Attachment76 
The parent and peer communication subscales assess the perceived 
quality of supportive communication with parents and peers when 
discussing personal problems, issues, or concerns. The 9-item parent 
subscale and 11-item peer subscale (one of three subscales in the 
IPPA) has demonstrated reliability and validity with AYA samples. 
While the IPPA assess relationships with both mother and father, we 
will only query AYAs about 1 parent. 
FEASIBILITY, ACCEPTABILITY, AND SATISFACTION OF TREATMENT
Acceptability & 
Satisfaction
Patient Acceptability & Satisfaction 
Questionnaire 
Participant opinion regarding the format, content, length, and 
convenience of the intervention
Attendance 
Attendance Tracking Sheet
Participants will be tracked for their attendance to all intervention and 
phone sessions
Provider perceptions of 
acceptability and 
satisfaction with CAE AYA
Clinician Acceptability & Satisfaction 
Questionnaire
Clinician opinion regarding their impression of the intervention
Evaluation of adherence 
Mental Health Care Appointments 
Participants will be asked how many mental health clinic visits that had 

Page 14 of 26
with scheduled routine 
mental health care 
appointments/number of 
routine mental health care 
appointments in past 6 
months
Attendance Tracking Sheet
in the last 6 months at baseline and in the last 3 months at week 12 
and week 24, as well as how many mental health visits they scheduled 
but were unable to attend in the last 6 months at baseline and in the 
last 3 months at week 12 and week 24,(including  those they cancelled 
and those that they did not cancel, but in the end were unable to 
attend)
*** Parents or caregivers will be asked about medication adherence at baseline and at 6 months (V3)
**** Suicidality is clinically assessed by the interventionist during each CAE/EDU session

Page 15 of 26
Intervention 
TREATMENT GROUP - Customized Adherence Enhancement for Adolescents and Young Adults (CAE-
AYA): CAE-AYA participants will have 4 core sessions (45-60 minutes each) spaced about 1 week apart over a 
period of approximately 4 weeks and one “booster” session approximately 4 weeks after completion of the 4 core 
sessions (total of up to 5 in-person sessions spaced out over 8 weeks). These CAE sessions may take place in 
person or via a video conferencing platform with optional telephone call-in if needed. There will be one follow-up 
phone call with a study interventionist, approximately 6 weeks post-baseline (timed half-way between completion 
of the core sessions and the “booster” session; Figure 4). Given that in the CAE RCT, the majority (63%) of 
participants were assigned all 4 modules, all AYAs will receive all 4 modules, with the content within each module 
being customized to developmental stage and behavioral experience. Within each module, there will be a range 
of material based on relative difficulty with the barrier experienced and developmental stage. Low endorsement 
of barriers will elicit sessions focused on anticipatory guidance while high-level endorsement of barriers will elicit 
sessions focused on problem-solving around the immediate barriers with the goals of becoming more 
independent and engaging in behaviors which encourage adherence and BD self-management. Module 
customization will be determined based on baseline scores on measures of BD knowledge, communication with 
providers, family members, and support systems (e.g., peers), difficulties with routines, and risk-taking behaviors 
(e.g., substance use, unprotected sex or other risk behaviors). Coaching in problem-solving skills will be 
integrated into all modules. 

MODULE 1 - Psychoeducation on BD Medications: Psychoeducation approaches BD as a biological 
disorder that can be managed by appropriate medication in conjunction with coping strategies.39 
Psychoeducation improves medication adherence.40,41 This module uses a modified Life Goals Program 30,42-
44. Educational materials will be refined to meet the developmental needs of AYAs. For example, if AYAs 
have high levels of knowledge, more detailed and extensive knowledge will be provided. If AYAs have low 
levels of knowledge, more basic skills and education will be provided. Notably, problem-solving skills will also 
be taught in this initial session as it will serve as the foundation for future modules. The following approach 
to teach problem-solving skills will be used: 1) Coach the AYA to identify an adherence barrier (Problem 
Definition), 2) Teach AYA to generate several creative solutions (Generating Alternative Solutions), 3) 
Systematically evaluate potential solutions by the AYA and support system (Decision-Making), 4) AYA 
selects one solution for implementation (Implementation of New Solution), and 5) Detailed solution is 
reviewed with specifics regarding the who, when, where, and how the solution will be attempted.

MODULE 2 - Communication with Providers & Caregivers: This module focuses on improving 
communication using principles from collaborative care and a patient-focused, patient-directed approach.45-
47 Individuals will explore key components of treatment planning including expectations for medication and 
feared/experienced side effects. Content will focus on communication with a treatment support team, which 
may be comprised of family, friends, and other individuals within their network of support. For AYAs engaged 
in good communication styles, anticipatory guidance will be provided about how to transition from a triadic 
partnership for care to a dyadic one, with more focus on transition elements. For AYAs with more problematic 
communication styles, basic communication skills will be emphasized, including optimal ways to 
communicate with their support network, issues of disclosure, allocation of treatment responsibility, and initial 
stages of transition. The communication with providers CAE intervention module was also designed to 
specifically address patient-perceived medication burden. This includes both experienced side effects as well 
as side effect concerns. A focus of CAE is helping patients learn to communicate with clinicians about 
medication burden vs. benefit and ideally determine, in collaboration with their clinician, a treatment plan that 
balances benefit vs. burden in a way that is acceptable to AYA. The CAE intervention uses a detailed manual 
with forms that are completed in collaboration between patients and interventionists, which will be translated 
to CAE-AYA. Specifically, this module uses a form to identify care access/delivery problems and ideally 
empower patients to problem-solve and/or discuss adherence impediments with their providers. These forms 
will be collected at the end of each CAE-AYA session to identify whether access issues appear to be a main 
driver of poor adherence. 

MODULE 3 - Medication Routines: Complex medication regimens may interfere with adherence.47 Using 
principles from interpersonal and social rhythm therapy for BD,48 a key activity is the focus on daily routine 
with respect to medication-taking (when, where, and how medications are taken) and problem-solving 
regarding identified challenges. This module emphasizes the use of prompts/reminders and self-

Page 16 of 26
monitoring/self-regulation to maximize and maintain adherence. Tools to improve routines including 
pillboxes, alarms or use of other technology available to the participant (e.g., smart phone apps) will be 
introduced and evaluated. For participants interested in using apps, we will provide a one-page handout 
providing an overview of 4 apps that are well-utilized and receive positive reviews for medication 
management (i.e. MyMedSchedule Mobile, Mango Health, MedCoach Medication Reminder, and MediSafe 
Meds and Pill Reminder). App information will be provided on the handout (see Figure 5 as an example). All 
participants will be asked, if they want to use an app, which app they will try. Unfortunately, there are no 
electronic ways to track app usage on phones. As such, we will be relying on self-reported use of apps. 
Features of the SimpleMed pillbox, such as alarms and visual reminders, can be turned on and off. These 
features can further reinforce the use of organization tools and will be part of the intervention for the CAE-
AYA treatment group only. The SimpleMed pillbox will serve as a passive monitoring tool for the control group 
but will serve as both a monitoring device and as an active intervention around medication routines for the 
treatment group. Phase 1 input will inform embedding additional technology elements into this module. The 
medication routines module includes a form that identifies impediments (e.g. access) to medication-taking, 
and will allow the study team to identify whether access issues appear to be a main driver of poor adherence.

MODULE 4 - Targeting Risky Behavior via Modified Motivational Enhancement Therapy (MET): MET 
is adapted from an evidence-based intervention for dual diagnosis.43, 49-52 We have successfully used this 
technique in AYA with BD and substance use in prior studies.53 For AYAs with BD, it is expected that 
substance use will be considered within the general context of risk behavior and protective factors associated 
with the occurrence of these behaviors will similarly be addressed. For those using drugs or alcohol, the 
module will be similar to that in CAE. For those who are not using, anticipatory guidance about patterns of 
risky behavior that impact BD self-management such as staying out late will be emphasized.
Delivery and Fidelity to CAE-AYA: The CAE-AYA intervention will be delivered by social workers or equivalent 
with mental health experience and at least some experience in working with AYAs with BD. We will randomly 
assign social workers to be designated as either the CAE-AYA or ETAU interventionist once interventionist staff 
are hired and oriented to the project. The format will closely follow the original CAE intervention, although the 
content will be refined based on Phase 1 and 2 data. All CAE-AYA sessions will be held in outpatient clinical 
settings. Interventionists will participate in monthly teleconferences supervised by a senior interventionist at the 
UH/CWRU site to discuss implementation issues. For the CAE-AYA intervention, we will use training and fidelity 
procedures similar to the adult CAE RCT. A senior interventionist at the UH/CWRU site  will lead the 
interventionists in intensive protocol training with mock intervention sessions using the standardized protocol until 
100% protocol fidelity is achieved. Fidelity will be assessed by video or audio-recording all CAE-AYA sessions 
and 20% of randomly selected sessions will reviewed using a standardized check-list to evaluate that content 
and format has been administered appropriately. Fidelity evaluations will be done by a senior interventionist at 
the UH/CWRU site. If there are any omissions/deviations, Dr. Levin will conduct additional training/support to 
ensure fidelity. This method of assessing fidelity is easily implemented in community practice settings.
CONTROL GROUP - Enhanced Treatment as Usual (ETAU): ETAU will consist of usual clinical care with 
prescribing clinicians and therapists, augmented by written materials specific to BD for AYAs and 6 follow-up 
telephone calls to briefly review the materials and be available for questions (weekly in the first month, then at 
Weeks 6 and 8) by social workers with mental health experience and at least some experience in working with 
AYA with BD. In order to ensure that there is not treatment contamination, different trained interventionists will 
be used for CAE and eTAU. Therapists will briefly review the materials and be available for questions during the 
phone calls. Materials will cover general self-management in BD. The calls will be relatively brief (maximum of 
20-30 minutes). ETAU  sessions will be video or audio-recorded and fidelity evaluations will be the same as for 
CAE-AYA and will be done by a senior interventionist at the UH/CWRU site. eTAU will not vary across sites. The 
“enhanced” elements include the use of an electronic monitoring of medication, which may in and of itself 
increase adherence, written materials specific to BD for AYAs and 6 phone calls to briefly review the written 
materials and be available for questions about the materials. Thus, participants in both arms will have a similar 
number of sessions. 
Data Analysis:
Study data will be collected and managed at each site using REDCap,77 a secure, web-based application 

Page 17 of 26
designed to support data capture for research studies. Each site (CWRU and UC) will use their own institutions’ 
REDCap. When the study is over, UC will send their de-identified data to the CWRU site where it will be combined 
with CWRU data and analyzed as outlined below. Consistent with the developmental nature of the R34 
mechanism, we will evaluate feasibility, acceptability and satisfaction of the interventions using the feasibility 
evaluation noted in section C.3 e. and C.3f., attendance tracking, and an exit interview that includes Likert scales 
to evaluate perceived benefit vs. burden as well as open-ended/write-in suggestions. PIs at each of the proposed 
study sites will be responsible for overseeing data input and quality and, working with Dr. Tatsuoka, will oversee 
the data analytic procedures. For the primary RCT outcome, we will adopt Type I error level of 0.05. Multiple 
comparisons adjustment will be applied for barrier variable analyses. We propose to enroll 40 AYAs with BD who 
are randomized to either CAE-AYA (N=20) or to ETAU (N=20). Based on our prior studies,28, 29 we expect up to 
30% of participants will discontinue study participation during the 24-week study period.  
As outlined in Aim 2, the primary statistical outcome measure will be change in adherence behavior as 
measured by past month TRQ. Adherence rates will be calculated for TRQ as well as the SimpleMed as follows: 
the number of days with a missed dose will be divided by the number of days in the time period and then 
multiplied by 100 with higher number indicating worse adherence. 
For the primary intent-to-treat analysis in Aim 2, we will use longitudinal mixed-effects modeling to evaluate 
the treatment-by-time interaction of adherence levels between CAE-AYA and ETAU. Significant interaction would 
indicate that the treatments (i.e., CAE-AYA vs. ETAU) have different trajectories of adherence. We will adjust for 
site and consider covariates such as age, gender, SES, psychiatric comorbidity (e.g. ADHD), mood state (e.g. 
(hypo) manic vs. euthymic vs. depressed) and symptom ratings (e.g. HAM-D and YMRS scores), and/or family 
history. We will consider representing scores as binary outcomes, indicating whether or not an adherence 
threshold has been met (e.g., 80% adherent), particularly if adherence levels are highly skewed. We will thus 
consider generalized linear mixed models for binary outcomes (SAS PROC GLIMMIX).  Adherence barriers, 
symptom rating scales and HRQoL scores will also be modeled by through longitudinal mixed models. In 
addition, we will compare corresponding TRQ and SimpleMed pillbox adherence levels. Correlation between the 
measures will be estimated and Bland-Altman plots will be generated82. 
In Aim 3, it is hypothesized that reductions in adherence barriers (e.g. BD knowledge, medication routines, 
communication with clinicians and parents/guardians, and substance use/risk behaviors) will be associated with 
changes in adherence.  We will regress respective changes in adherence levels upon changes in barrier variable 
values. We will also compare difference values in barriers by treatment arm, and include treatment indicator 
variables in regression models.  Modeling assumptions will be thoroughly assessed, and transformations will be 
considered. In a similar manner, we will also examine whether improvements in adherence behaviors correlate 
with improvements in symptoms and HRQoL. These analyses will support the clinical interpretability of effect sizes 
in adherence change for future studies.  Barrier variables with change values that appear to be associated with 
change in adherence levels and that appear to differ by treatment will be considered further as mediator 
variables, following as in MacKinnon (2008)83 and Preacher and Hayes (2008).84  This will involve single mediator 
analyses as well as exploring multiple mediator models.  These analyses will involve the treatment variable and 
change in adherence values. Associated standard errors of estimated indirect effects will be derived through 
bootstrapping, using the M-Plus software. 
Missing Data:  
Data that remain missing despite our retention efforts will be accommodated in our analyses and their impact 
evaluated through sensitivity analyses. The models we propose can be estimated without bias under the missing 
at random (MAR) assumption85 and provide valid analysis as long as auxiliary covariates associated with 
missingness (if any) are included in the analysis model.  To assess which covariates may be associated with 
missing outcome data, we will create binary indicators of whether the outcome was missing (=1) or not (=0). If a 
covariate is correlated with missingness at r >0.40 and is correlated at r >0.40 with the original response variable, 
it will be included in the analysis as an auxiliary correlate.86 We will conduct preliminary assessment of the 
missing at random (MAR) assumption by pattern mixture models that relax the missing at random assumption.  
We will also consider selection models to assess sensitivity to MAR in a Bayesian Markov Chain Monte Carlo 
framework,87.

Page 18 of 26
Power: 
As a reference, for the projected sample size of 40 subjects with up to 30% attrition, given two-sided Type I 
error of 0.05, two-sample t-tests will have power of 0.70 for effect sizes of at least 0.975.  Tests for non-zero 
correlation will have power of 0.70 for correlations with magnitude of at least 0.438.  Note that we are associating 
change in adherence with change in clinical outcomes, to better calibrate clinical significance in adherence effect 
sizes related to the target population for future studies.
Confidentiality of Data
To maintain the confidentiality of the data, a unique study identifier to code individual’s identifiable data and 
will store the master list separate from the study data. The key will be stored in a password protected document 
that only the study staff will have access to. When the study is closed with the IRB (after primary outcomes data 
has been analyzed), we will delete the file that contains identifiable information and will be securely shred any 
paper documents containing identifiable information. Electronic data will be stored in CWRU Redcap, CWRU 
Box, and UH Secure Network Drive. University Hospital PHI will only be stored on the UH Secure Network not 
on CWRU REDCap or CWRU Box. Paper research data and documents will be stored in a double-locked secure 
environment in the PI’s research offices in the Psychiatry Department at the W.O. Walker Center.
Data Sharing Plan 
The deidentified transcriptions will be shared with the study personnel at UC, CCHMC, and UF.  The UC site 
will also send deidentified quantitative data from Phase 3 to CWRU for analysis.  Deidentified qualitative and 
quantitative data will be shared via CWRU Box or email.
The ability for research communities to share data as soon as it is available adds to the ability for discovery 
to translate into useable innovation and adds value to the research. Therefore, we will adhere to the NIH Grants 
Policy on Availability of Research Results: Publications, Intellectual Property Rights, and Sharing Biomedical 
Research Resources. Sharing of data generated by the RCT portion of this project (Phase 3) will be carried out 
in several different ways. In addition to the report we will submit to NIMH, we intend to make emerging results 
available both to the community of scientists interested in understanding our research, but especially to those in 
the community who can use these behavioral techniques to possibly assist their patients.
Data entered into the NIMH National Database: If this proposal is funded we will collaborate with our project 
office to determine the best mechanism to ensure that our Phase 3 data is entered into the common informatics 
platform by NIMH, called the National Database for Clinical Trials Related to Mental Illness 
(http://ndct.nimh.nih.gov, NDCT).  We will work with NIMH to transform the data we collect into relevant 
information using the suggested consent form language, NIMH software that will create global unique identifiers 
and a useful data dictionary as much as we are able in order to deposit data into the National Database allowing 
other researchers and NIMH to use available data. NIMH can use its substantial resources for dissemination of 
the “go or no-go” results via its website, e-newsletters, internal government communications to other agencies 
and more. 
Department and University, CTSA websites and newsletters: As our academic health centers are two of 
many Centers of Clinical and Translational Science around the country, our findings and strategies may be 
disseminated quickly through the network of CTSA’s. 
Peer-reviewed presentations: at national scientific meetings. From the project, we expect to submit 
presentations to regional, national and international meetings. 
Peer-reviewed publications: We anticipate that the project will result in several peer-reviewed publications 
each year. 
In addition to the above, we will also post study results on www.clinicaltrials.gov and will make de-identified 
data available to other qualified investigators in the research community.  In all cases, data will be shared as 
soon as it is available and for as long as the format allows. Publications and presentations will use de-identified 
data in order to preserve confidentiality. In line with accepted data sharing practices and ethical principles, we 
will share de-identified raw data with other researchers attempting to replicate our findings or including our 
findings in subsequent projects. Researchers will be able to contact us by telephone or email to request these 
data, which we will provide in a timely manner. We will not release any data that are considered identifying or 
protected by IRB, HIPAA, or federal regulations unless that researcher and the PI of the current project have 
obtained proper administrative agreements or participation in the NIMH national database.

Page 19 of 26
Risks to Research Participants
The CAE-AYA intervention is an adjunct to standard clinical care that participants receive, and is not 
expected to impact ongoing clinical care beyond the fact that some individuals may become more adherent to 
their prescribed medication regimen and some participants may become more engaged in their own care as a 
result of CAE-AYA or ETAU. Patients will not be compelled to participate in any way in the activities of the project. 
Participants will be free to withdraw from any phase of the study at any time without penalty. This study involves 
either participating in focus groups, advisory board meetings, and possible cognitive interviews or participating 
in the pilot study of up to 5 therapy sessions, using SimpleMed Pillboxes, and completing a set of self-report 
instruments. All instruments have been utilized in outpatient research settings by the PIs and are not associated 
with risks to patients. The behavioral intervention is intended to enhance adherence attitudes, remove adherence 
barriers, and ultimately, improve adherence behaviors, mood symptoms and HRQoL, and will be adapted from 
an existing therapy that is not generally known to increase risk to individuals. The participants are not at 
increased risk from participating in this study, other than finding that talking about some matters may be 
uncomfortable. However, AYA with BD are at risk for other medical and psychiatric complications because of 
their underlying condition.
Participants may exhibit worsening of their mood symptoms (depression or mania) during the study. They 
may also exhibit worsening or the onset of suicidal ideation or homicidal ideation. 
Because of the nature of group interactions in Phase 1, participant confidentiality cannot be guaranteed for 
this phase; however, the importance of respecting other group members’ privacy will be stressed to all 
participants. There is also a risk of loss of confidentiality for participants in Phases 2 and 3, however, precautions 
against this risk will be taken as described below. 
Consistent with the Federal guidelines, participants will be informed of the federally mandated reporting laws 
for child abuse and neglect, verbally and in the written consent form. Therefore, if abuse or neglect is suspected 
the Department of Human Services will be called. Risks associated with this include embarrassment, legal 
consequences, and removal of the child from the parents’/legal guardians’ home. 
In summary, based on the previously described considerations, we believe the risks are minimal for 
participants who are involved in this study.
To maximize safety, at any time during study participation, if it is the opinion of the participant/legal guardian, 
any of the investigators, or their non-study related clinician, that because of exacerbation of mood or other 
psychiatric symptoms (defined either by clinical assessment or a CGI-I > 5) or a lack of improvement in any 
mood or behavioral symptoms, it is not in the best interest of the participant to continue treatment, then the 
participant will be discontinued from study participation and all endpoint procedures will be performed. If at any 
time during study participation mood or any psychiatric symptoms worsen for any study participant, a study 
clinician will immediately assess the participant to evaluate whether they are safe to continue in the study and/or 
whether an immediate referral to the psychiatric emergency department is necessary. Additionally, at Screening, 
participants (or legal guardians if participants are < 18 years old) will be asked to provide a release of information 
so that study staff are permitted to communicate with their non-study clinicians. If at any point during study 
participation an AYA experiences worsening of symptoms or is felt to be a risk to themselves or others, their 
legal guardian (if < 18 years old) and their non-study clinician will be contacted to discuss a treatment plan. The 
informed consent/assent will describe that for participants < 18 years old, legal guardians will be informed of 
worsening of psychiatric symptoms and/or suicidal or homicidal ideation during a participant’s study participation 
and study clinicians will discuss any necessary clinical follow-up with participants and their legal guardians. For 
participants > 18 years old, their non-study clinician will be informed of any worsening of symptoms or suicidal 
or homicidal ideation if a release of information to contact that clinician was obtained. 
For any phase of the study, if an individual who is suicidal or homicidal is identified during the screening 
process or at any time during the study, the study staff interacting with the individual will immediately notify 1) 
the participant’s non-study clinician (if a release of information has been obtained), 2) the site PI, who is a 
practicing licensed psychiatrist, and 3) if the participant is < 18 years old, their legal guardian, so that all available 
and appropriate measures may be taken to ensure the prompt safety and most appropriate care setting for the 
participant. If at any point during the study a patient has active suicidal behavior on the C-SSRS; an increase 
from baseline in suicidality, as measured by the C-SSRS, or appears to the investigator to pose a risk of self-
harm or a harm to others, guardians will be informed and the participant will be referred to appropriate clinical 

Page 20 of 26
care. Individuals who are at immediate risk of harm to themselves or others will be taken to the psychiatric 
emergency department located in close proximity to where the proposed study will be conducted at both sites.  
Additionally, participants/legal guardians will be informed during the informed consent/assent process that if 
the participant/legal guardian experiences any suicidal ideation, intent, or plan (as measured by the C-SSRS or 
clinical assessment) during a focus group, advisory board meeting, cognitive interview, a CAE-AYA or ETAU 
session, or a rating scale interview they will be evaluated immediately by a study clinician and referred to the 
appropriate clinical follow-up. Specifically, if a participant is judged to be a danger to themselves or others, the 
participant will be taken to the psychiatric emergency department for further evaluation. As described, If the 
participant is < 18 years old, their legal guardian will be informed of any suicidal or homicidal ideation and of any 
necessary treatment referrals or further evaluation (e.g., assessment at the psychiatric emergency room).
Provisions to Protect the Privacy Interests of Research Participants
Complete confidentiality cannot be assured due to the nature of group interactions in the focus groups and 
advisory board, although we will request that participants in these groups maintain other participants’ 
confidentiality. Confidentiality of the research data will be protected in several ways. Paper assessment forms 
and other study records will be stored in the locked research offices of the site PIs and/or study staff.  Participants 
will be identified by a separate study ID number on all study records. The lists that link study ID codes with 
participant names, and all electronic study records will be stored on password-protected, encrypted computers 
or secure servers. Only aggregate data will be presented or published, and will be presented such that individual 
patients cannot be identified. The proposed project’s research personnel who will have access to participant 
identities are the study PIs, co-investigators, and the study research assistants, interventionists and data analyst. 
All study personnel will be required to be certified in the protection of human subjects throughout the study. The 
focus groups, advisory board, and therapy sessions will be recorded and reviewed by study staff for fidelity. The 
recorded sessions will be stored on a secure server, and will be destroyed at the end of the study, after all data 
analyses have been completed.
The identifiable information will not be reused or disclosed to any other person or entity outside UHC other 
than those identified in the protocol, except as required by law, for authorized oversight of this research study, 
or as specifically approved for use in another study by an IRB.
Potential Benefit to Research Participants 
Potential benefits include a thorough psychiatric evaluation performed by study staff with expertise in the 
diagnosis and treatment of bipolar disorder, and the chance to contribute to a scientific investigation, which may 
be of benefit to patients with similar illnesses in the future. Participants may also benefit from participating in the 
sessions and may find it helpful to talk about their conditions and challenges in adherence. There is no guarantee 
of benefits to any participant.  However, the goal of this project to develop a contribution to knowledge, which 
can be useful in improving the understanding and management of poor adherence in AYA with BD. It will be 
explained to participants and legal guardians that participation in the study may not benefit them in any way but 
may be of benefit to other patients in the future. Overall, the risks associated with this study are minimal to the 
participants and they may receive direct benefit from their study participation as previously described. Therefore, 
in the opinion of the investigators, the benefits associated with this study outweigh the risks.
Withdrawal of Research Participants
Individuals will be discontinued from the protocol prior to 24 weeks if they wish to withdraw for any reason at 
any time.  Since the intervention is an addition to their regular treatment and does not include medication, there 
is no need for follow-up with the research team.
Should the need arise to discontinue a patient from the study because of symptom worsening (as defined 
previously) or for any other reason, including patient/legal guardian withdrawal of consent, we will collaborate 
with the patient/legal guardian, and their non-study related clinician to determine treatment options for that patient 
following study discontinuation.
Cost to participants
Participants and their insurance will not be charged for any study visits. Subjects may incur costs such as 
travel, parking, and meals. These are reasonable costs that a subject will incur as a result of going to study 
visits. Subjects are compensated for these costs as outlined below.

Page 21 of 26
Research Participant Compensation 
Phase 1 focus group and advisory board participants will each receive for $20 for each meeting they attend.
Phase 2 participants will receive $30 for each usability session they attend.
Phase 3 RCT participants ages 13-21 will receive $25 per assessment visit for attending the 5 assessment 
visits and an additional $10 at the V3 visit for returning the SimpleMed box. Throughout the CAE-AYA 
intervention sessions, small token items of insignificant value (e.g., $5 gift card, pens, notebooks, key tags, 
lanyards, mini calendars, etc.) may be given and will not be used as a contingency for study participation.
At the UH/CWRU site stipends will be paid by check mailed to the participant’s home or in some cases, in 
cash at the visit if cashing a check would be burdensome on the participant, or via gift card/e-gift card. At the 
UC site, subjects will be paid in the form of a prepaid debit card or gift card.
Participants in all 3 phases will be offered a bus pass or parking pass for any meetings, sessions, and 
assessment visits.  In some circumstances other transportation (i.e., taxi or Uber/Lyft) will be arranged and the 
cost will be covered by the study if necessary. 
Provisions to Monitor the Data to Ensure the Safety of Research Participants 
The study PIs, Drs. Sajatovic and DelBello, will monitor the study to ensure data integrity and the safety of 
the participants. The CWRU site Data Coordinator, will review the data for discrepancies on a regular basis and 
will review the study records for compliance with IRB requirements and verification of source documents.  The 
PIs will hold regular weekly meetings across sites via teleconference with all study staff to review study progress 
and any issues that may come up regarding data integrity and completeness.
Data and Safety Monitoring Board or Committee 
For Phase 3, we are proposing that a DSMB be comprised of experts in the following fields: a behavioral 
psychiatrist/psychologist, expert in BD, and biostatistician. These experts, from outside the departments of either 
PI, will review and evaluate the accumulated data for participant safety, adverse events, study conduct and 
progress every 6 months. The DSMB will make recommendations to the appropriate regulatory agencies (IRB, 
NIH) concerning continuation, modification or termination of the study.  DSMB members will be identified before 
the start of the clinical trial in Phase 3 of the project.
Alternatives to Participation
The alternative is for research subjects not to participate.

Page 22 of 26
References
1.
Berk L, Hallam KT, Colom F, Vieta E, Hasty M, Macneil C, Berk M. Enhancing medication adherence in 
patients with bipolar disorder. Human psychopharmacology. 2010;25(1):1-16. Epub 2009/12/31. doi: 
10.1002/hup.1081. PubMed PMID: 20041478.
2.
Riley WT, Velligan D, Sajatovic M, Valenstein M, Safren S, Lewis-Fernandez R, Weiden P, Ogedegbe G. 
Adherence to Psychiatric Treatments. Current Medical Literature: Psychiatry. 2009;20(4):89-96.
3.
Velligan DI, Weiden PJ, Sajatovic M, Scott J, Carpenter D, Ross R, Docherty JP. The expert consensus 
guideline series: adherence problems in patients with serious and persistent mental illness. The Journal of 
clinical psychiatry. 2009;70 Suppl 4:1-46; quiz 7-8. Epub 2009/08/25. PubMed PMID: 19686636.
4.
Sajatovic. Psychosocial intervention to enhance treatment attitudes.  American Psychiatric Association 
Annual Meeting2005.
5.
Kilbourne AM, Biswas K, Pirraglia PA, Sajatovic M, Williford WO, Bauer MS. Is the collaborative chronic care 
model effective for patients with bipolar disorder and co-occurring conditions? Journal of affective disorders. 
2009;112(1-3):256-61. Epub 2008/05/28. doi: 10.1016/j.jad.2008.04.010. PubMed PMID: 18504059.
6.
Gonzalez-Pinto A, Gonzalez C, Enjuto S, Fernandez de Corres B, Lopez P, Palomo J, Gutierrez M, 
Mosquera F, Perez de Heredia JL. Psychoeducation and cognitive-behavioral therapy in bipolar disorder: an 
update. Acta psychiatrica Scandinavica. 2004;109(2):83-90. Epub 2004/01/17. PubMed PMID: 14725587.
7.
Aagaard J, Vestergaard P, Maarbjerg K. Adherence to lithium prophylaxis: II. Multivariate analysis of clinical, 
social, and psychosocial predictors of nonadherence. Pharmacopsychiatry. 1988;21(4):166-70. Epub 
1988/07/01. doi: 10.1055/s-2007-1014670. PubMed PMID: 3205885.
8.
Osterberg L, Blaschke T. Adherence to medication. The New England journal of medicine. 2005;353(5):487-
97. Epub 2005/08/05. doi: 10.1056/NEJMra050100. PubMed PMID: 16079372.
9.
Byrne MK, Deane FP, Lambert G, Coombs T. Enhancing medication adherence: clinician outcomes from the 
Medication Alliance training program. The Australian and New Zealand journal of psychiatry. 2004;38(4):246-
53. Epub 2004/03/25. doi: 10.1111/j.1440-1614.2004.01344.x. PubMed PMID: 15038804.
10. Newell SA, Bowman JA, Cockburn JD. A critical review of interventions to increase compliance with 
medication-taking, obtaining medication refills, and appointment-keeping in the treatment of cardiovascular 
disease. Preventive medicine. 1999;29(6 Pt 1):535-48. Epub 1999/12/22. doi: 10.1006/pmed.1999.0579. 
PubMed PMID: 10600435.
11. Gaudiano BA, Weinstock LM, Miller IW. Improving treatment adherence in bipolar disorder: a review of 
current psychosocial treatment efficacy and recommendations for future treatment development. Behavior 
modification. 2008;32(3):267-301. Epub 2008/04/09. doi: 10.1177/0145445507309023. PubMed PMID: 
18391049; PMCID: 3691269.
12. Colom F, Vieta E, Martinez-Aran A, Reinares M, Goikolea JM, Benabarre A, Torrent C, Comes M, Corbella 
B, Parramon G, Corominas J. A randomized trial on the efficacy of group psychoeducation in the prophylaxis 
of recurrences in bipolar patients whose disease is in remission. Archives of general psychiatry. 
2003;60(4):402-7. doi: 10.1001/archpsyc.60.4.402. PubMed PMID: 12695318.
13. Clarkin JF, Carpenter D, Hull J, Wilner P, Glick I. Effects of psychoeducational intervention for married 
patients with bipolar disorder and their spouses. Psychiatric services (Washington, DC). 1998;49(4):531-3. 
doi: 10.1176/ps.49.4.531. PubMed PMID: 9550248.
14. Miklowitz DJ, George EL, Richards JA, Simoneau TL, Suddath RL. A randomized study of family-focused 
psychoeducation and pharmacotherapy in the outpatient management of bipolar disorder. Archives of 
general psychiatry. 2003;60(9):904-12. Epub 2003/09/10. doi: 10.1001/archpsyc.60.9.904. PubMed PMID: 
12963672.
15. Miklowitz DJ, Schneck CD, George EL, Taylor DO, Sugar CA, Birmaher B, Kowatch RA, DelBello MP, 
Axelson DA. Pharmacotherapy and family-focused treatment for adolescents with bipolar I and II disorders: 
a 
2-year 
randomized 
trial. 
The 
American 
journal 
of 
psychiatry. 
2014;171(6):658-67. 
doi: 
10.1176/appi.ajp.2014.13081130. PubMed PMID: 24626789; PMCID: PMC4083000.
16. Goldstein BI, Goldstein TR, Collinger KA, Axelson DA, Bukstein OG, Birmaher B, Miklowitz DJ. Treatment 
development and feasibility study of family-focused treatment for adolescents with bipolar disorder and 
comorbid 
substance 
use 
disorders. 
Journal 
of 
psychiatric 
practice. 
2014;20(3):237-48. 
doi: 
10.1097/01.pra.0000450325.21791.7e. PubMed PMID: 24847999; PMCID: PMC4142596.

Page 23 of 26
17. Gonzalez-Pinto A, Mosquera F, Alonso M, Lopez P, Ramirez F, Vieta E, Baldessarini RJ. Suicidal risk in 
bipolar I disorder patients and adherence to long-term lithium treatment. Bipolar Disord. 2006;8(5 Pt 2):618-
24. doi: 10.1111/j.1399-5618.2006.00368.x. PubMed PMID: 17042834.
18. Sajatovic M, Biswas K, Kilbourne AK, Fenn H, Williford W, Bauer MS. Factors associated with prospective 
long-term treatment adherence among individuals with bipolar disorder. Psychiatric services (Washington, 
DC). 2008;59(7):753-9. Epub 2008/07/01. doi: 10.1176/appi.ps.59.7.753. PubMed PMID: 18586992.
19.  Sajatovic M, Blow FC, Kales HC, Valenstein M, Ganoczy D, Ignacio RV. Age comparison of treatment 
adherence with antipsychotic medications among individuals with bipolar disorder. International journal of 
geriatric psychiatry. 2007;22(10):992-8. doi: 10.1002/gps.1777. PubMed PMID: 17323327.
20.  Sajatovic M, Davies M, Bauer MS, McBride L, Hays RW, Safavi R, Jenkins J. Attitudes regarding the 
collaborative practice model and treatment adherence among individuals with bipolar disorder. Compr 
Psychiatry. 2005;46(4):272-7. PubMed PMID: 16175758.
21. Mander AJ, Loudon JB. Rapid recurrence of mania following abrupt discontinuation of lithium. Lancet. 
1988;2(8601):15-7. PubMed PMID: 2898622.
22. Svarstad BL, Shireman TI, Sweeney JK. Using drug claims data to assess the relationship of medication 
adherence with hospitalization and costs. Psychiatric Services. 2001;52(6):805-11. doi: DOI 
10.1176/appi.ps.52.6.805. PubMed PMID: WOS:000169066800013.
23. Sajatovic M, Chen PJ, Dines P, Shirley ER. Psychoeducational approaches to medication adherence in 
patients with bipolar disorder. Disease Management & Health Outcomes. 2007;15(3):181-92. doi: Doi 
10.2165/00115677-200715030-00006. PubMed PMID: WOS:000249150800006.
24. Zeber JE, Copeland LA, Good CB, Fine MJ, Bauer MS, Kilbourne AM. Therapeutic alliance perceptions and 
medication adherence in patients with bipolar disorder. J Affect Disord. 2008;107(1-3):53-62. doi: 
10.1016/j.jad.2007.07.026. PubMed PMID: WOS:000254546000007.
25. Maarbjerg K, Aagaard J, Vestergaard P. Adherence to lithium prophylaxis: I. Clinical predictors and patient's 
reasons for nonadherence. Pharmacopsychiatry. 1988;21(3):121-5. Epub 1988/05/01. doi: 10.1055/s-2007-
1014662. PubMed PMID: 3406049.
26. Sajatovic M, Jenkins JH, Safavi R, West JA, Cassidy KA, Meyer WJ, Calabrese JR. Personal and societal 
construction of illness among individuals with rapid-cycling bipolar disorder: A life-trajectory perspective. 
American Journal of Geriatric Psychiatry. 2008;16(9):718-26. doi: DOI 10.1097/JGP.0b013e3180488346. 
PubMed PMID: WOS:000258852200003.
27. Clatworthy J, Bowskill R, Rank T, Parham R, Horne R. Adherence to medication in bipolar disorder: a 
qualitative study exploring the role of patients' beliefs about the condition and its treatment. Bipolar disorders. 
2007;9(6):656-64. Epub 2007/09/12. doi: 10.1111/j.1399-5618.2007.00434.x. PubMed PMID: 17845282.
28. Sajatovic M, Levin J, Tatsuoka C, Micula-Gondek W, Fuentes-Casiano E, Bialko CS, Cassidy KA. Six-month 
outcomes of customized adherence enhancement (CAE) therapy in bipolar disorder. Bipolar disorders. 
2012;14(3):291-300. Epub 2012/05/03. doi: 10.1111/j.1399-5618.2012.01010.x. PubMed PMID: 22548902; 
PMCID: 3342843.
29. Sajatovic M, Levin J, Tatsuoka C, Micula-Gondek W, Williams TD, Bialko CS, Cassidy KA. Customized 
adherence enhancement for individuals with bipolar disorder receiving antipsychotic therapy. Psychiatric 
services (Washington, DC). 2012;63(2):176-8. Epub 2012/02/04. doi: 10.1176/appi.ps.201100133. PubMed 
PMID: 22302337.
30. Modi AC, Pai AL, Hommel KA, Hood KK, Cortina S, Hilliard ME, Guilfoyle SM, Gray WN, Drotar D. Pediatric 
self-management: a framework for research, practice, and policy. Pediatrics. 2012;129(2):e473-85. doi: 
10.1542/peds.2011-1635. PubMed PMID: 22218838.
31. Modi AC, Monahan S, Daniels D, Glauser TA. Development and validation of the Pediatric Epilepsy 
Medication 
Self-Management 
Questionnaire. 
Epilepsy 
& 
Behavior. 
2010;18(1-2):94-9. 
doi: 
10.1016/j.yebeh.2010.03.009. PubMed PMID: WOS:000280018500015.
32. Loiselle K, Rausch JR, Modi AC. Behavioral predictors of medication adherence trajectories among youth 
with newly diagnosed epilepsy. Epilepsy & Behavior. 2015;50:103-7. doi: 10.1016/j.yebeh.2015.06.040. 
PubMed PMID: WOS:000361186300023.
33. Guralnick M. Connections between developmental science and intervention science. Zero to Three. 
2001;21(5):24-9.
34. Morgan DL, Krueger RA, King JA. Analyzing and reporting focus group results.: Sage; 1998.
35. Nielsen J. Fundamentals of Human-Computer Interaction. Behav Inform Technol. 1986;5(3):291-8.

Page 24 of 26
36. Ericsson KA, Simon HA. Protocol analysis: Verbal reports as data. Cambridge, MA: Bradford Books/MIT 
Press; 1984.
37. First MB, Gibbon M, Spitzer RL, Williams JB. User’s Guide for the Structured Clinical Interview for DSM-IV-
TR Axis I Disorders - Research Version - (SCID-I for DSM-IV-TR, November 2002 Revision): Biometrics 
Research; 2002.
38. Birmaher B, Axelson D, Monk K, Kalas C, Goldstein B, Hickey MB, Obreja M, Ehmann M, Iyengar S, 
Shamseddeen W, Kupfer D, Brent D. Lifetime Psychiatric Disorders in School-aged Offspring of Parents With 
Bipolar Disorder The Pittsburgh Bipolar Offspring Study. Arch Gen Psychiat. 2009;66(3):287-96. doi: DOI 
10.1001/archgenpsychiatry.2008.546. PubMed PMID: WOS:000263765600007.
39. Vieta E. The package of care for patients with bipolar depression. J Clin Psychiatry. 2005;66 Suppl 5:34-9. 
PubMed PMID: 16038600.
40. Sajatovic M, Jenkins JH. Is antipsychotic medication stigmatizing for people with mental illness? International 
Review 
of 
Psychiatry. 
2007;19(2):107-12. 
doi: 
10.1080/09540260701278911. 
PubMed 
PMID: 
WOS:000246664400002.
41. Vieta E, Colom F. Psychological interventions in bipolar disorder: From wishful thinking to an evidence-based 
approach. Acta Psychiatr Scand. 2004;110:34-8. doi: DOI 10.1111/j.1600-0447.2004.00411.x. PubMed 
PMID: WOS:000224297000004.
42. Bauer MS, McBride L, Williford WO, Glick H, Kinosian B, Altshuler L, Beresford T, Kilbourne AM, Sajatovic 
M. Collaborative care for bipolar disorder: part I. Intervention and implementation in a randomized 
effectiveness trial. Psychiatr Serv. 2006;57(7):927-36. Epub 2006/07/04. doi: 10.1176/ps.2006.57.7.927. 
PubMed PMID: 16816276.
43. Ziedonis DM, Smelson D, Rosenthal RN, Batki SL, Green AI, Henry RJ, Montoya I, Parks J, Weiss RD. 
Improving the care of individuals with schizophrenia and substance use disorders: consensus 
recommendations. J Psychiatr Pract. 2005;11(5):315-39. PubMed PMID: 16184072; PMCID: PMC2599914.
44. Bauer M, McBride L. Structured Group Psychotherapy for Bipolar Disorder: The Life Goals Program. 2nd ed. 
New York: Springer Publications; 2003 2003.
45. Moore LG, Wasson JH. An introduction to technology for patient-centered, collaborative care. J Ambul Care 
Manage. 2006;29(3):195-8. PubMed PMID: 16788351.
46. Wagner EH, Austin BT, Von Korff M. Organizing care for patients with chronic illness. The Milbank quarterly. 
1996;74(4):511-44. Epub 1996/01/01. PubMed PMID: 8941260.
47. Bauer MS, Biswas K, Kilbourne AM. Enhancing multiyear guideline concordance for bipolar disorder through 
collaborative care. Am J Psychiatry. 2009;166(11):1244-50. doi: 10.1176/appi.ajp.2009.09030342. PubMed 
PMID: 19797436.
48. Frank E, Kupfer DJ, Thase ME, Mallinger AG, Swartz HA, Fagiolini AM, Grochocinski V, Houck P, Scott J, 
Thompson W, Monk T. Two-year outcomes for interpersonal and social rhythm therapy in individuals with 
bipolar I disorder. Arch Gen Psychiatry. 2005;62(9):996-1004. doi: 10.1001/archpsyc.62.9.996. PubMed 
PMID: 16143731.
49. Miller WR. Motivational interviewing: research, practice, and puzzles. Addict Behav. 1996;21(6):835-42. 
PubMed PMID: 8904947.
50. McCambridge J, Strang J. The efficacy of single-session motivational interviewing in reducing drug 
consumption and perceptions of drug-related risk and harm among young people: results from a multi-site 
cluster randomized trial. Addiction. 2004;99(1):39-52. PubMed PMID: 14678061.
51. Orellana ER, Picciano JF, Roffman RA, Swanson F, Kalichman SC. Correlates of nonparticipation in an HIV 
prevention program for MSM. AIDS Educ Prev. 2006;18(4):348-61. doi: 10.1521/aeap.2006.18.4.348. 
PubMed PMID: 16961451.
52. Peterson PL, Baer JS, Wells EA, Ginzler JA, Garrett SB. Short-term effects of a brief motivational intervention 
to reduce alcohol and drug risk among homeless adolescents. Psychol Addict Behav. 2006;20(3):254-64. 
doi: 10.1037/0893-164X.20.3.254. PubMed PMID: 16938063.
53. Heffner JL, Anthenelli RM, DelBello MP, Stahl L, Strakowski SM. Mood management and nicotine patch for 
smoking cessation in adults with bipolar disorder. Nicotine & tobacco research : official journal of the Society 
for Research on Nicotine and Tobacco. 2013;15(11):1805-6. doi: 10.1093/ntr/ntt076. PubMed PMID: 
23766341; PMCID: PMC3790632.

Page 25 of 26
54. Lavori PW, Keller MB, Endicott J. Improving the Validity of Fh-Rdc Diagnosis of Major Affective-Disorder in 
Uninterviewed Relatives in Family Studies - a Model Based Approach. J Psychiat Res. 1988;22(4):249-59. 
doi: Doi 10.1016/0022-3956(88)90034-9. PubMed PMID: WOS:A1988R380100002.
55. Hamilton M. A rating scale for depression. Journal of neurology, neurosurgery, and psychiatry. 1960;23:56-
62. PubMed PMID: 14399272; PMCID: 495331.
56. Young RC, Biggs JT, Ziegler VE, Meyer DA. Rating-Scale for Mania - Reliability, Validity and Sensitivity. Brit 
J Psychiat. 1978;133(Nov):429-35. doi: DOI 10.1192/bjp.133.5.429. PubMed PMID: ISI:A1978FV44600006.
57. Guy W. Clinical Global Impressions. ECDEU Assessment Manual for psychoparmacology. Rockville, MD: 
US Department of Health, Education, and Welfare (DHEW); 1976.
58. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill 
L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency 
findings from three multisite studies with adolescents and adults. The American journal of psychiatry. 
2011;168(12):1266-77. Epub 2011/12/24. doi: 10.1176/appi.ajp.2011.10111704. PubMed PMID: 22193671; 
PMCID: 3893686.
59. Scott J, Pope M. Nonadherence with mood stabilizers: prevalence and predictors. J Clin Psychiatry. 
2002;63(5):384-90. PubMed PMID: 12019661.
60. Peet M, Harvey NS. Lithium maintenance: 1. A standard education programme for patients. Br J Psychiatry. 
1991;158:197-200. PubMed PMID: 1707323.
61. Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQL 4.0 as a pediatric population health measure: 
feasibility, reliability, and validity. Ambul Pediatr. 2003;3(6):329-41. PubMed PMID: 14616041.
62. Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. 
Medical care. 1999;37(2):126-39. PubMed PMID: 10024117.
63. DelBello MP, Hanseman D, Adler CM, Fleck DE, Strakowski SM. Twelve-month outcome of adolescents with 
bipolar disorder following first hospitalization for a manic or mixed episode. American Journal of Psychiatry. 
2007;164(4):582-90. doi: DOI 10.1176/appi.ajp.164.4.582. PubMed PMID: ISI:000245402600012.
64. Keller MB, Lavori PW, Friedman B, Nielsen E, Endicott J, Mcdonaldscott P, Andreasen NC. The Longitudinal 
Interval Follow-up Evaluation - a Comprehensive Method for Assessing Outcome in Prospective 
Longitudinal-Studies. Arch Gen Psychiat. 1987;44(6):540-8. PubMed PMID: WOS:A1987H528500007.
65. Bilderbeck AC, Atkinson LZ, McMahon HC, Voysey M, Simon J, Price J, Rendell J, Hinds C, Geddes JR, 
Holmes E, Miklowitz DJ, Goodwin GM. Psychoeducation and online mood tracking for patients with bipolar 
disorder: A randomised controlled trial. Journal of affective disorders. 2016;205:245-51. doi: 
10.1016/j.jad.2016.06.064. PubMed PMID: 27454410.
66. Woods ER, Klein JD, Wingood GM, Rose ES, Wypij D, Harris SK, Diclemente RJ. Development of a new 
Adolescent Patient-Provider Interaction Scale (APPIS) for youth at risk for STDs/HIV. The Journal of 
adolescent health : official publication of the Society for Adolescent Medicine. 2006;38(6):753 e1-7. doi: 
10.1016/j.jadohealth.2005.08.013. PubMed PMID: 16730606.
67. Verplanken B, Orbell S. Reflections on past behavior: A self-report index of habit strength. J Appl Soc 
Psychol. 
2003;33(6):1313-30. 
doi: 
DOI 
10.1111/j.1559-1816.2003.tb01951.x. 
PubMed 
PMID: 
WOS:000185760500011.
68. Fiese BH, Wamboldt FS, Anbar RD. Family asthma management routines: Connections to medical 
adherence and quality of life. Journal of Pediatrics. 2005;146(2):171-6. doi: 10.1016/j.jpeds.2004.08.083. 
PubMed PMID: WOS:000226846300007.
69. Kaminer Y, Bukstein O, Tarter RE. The Teen-Addiction Severity Index: rationale and reliability. Int J Addict. 
1991;26(2):219-26. PubMed PMID: 1889921.
70. Gullone E, Moore S. Adolescent risk-taking and the five-factor model of personality. Journal of adolescence. 
2000;23(4):393-407. doi: 10.1006/jado.2000.0327. PubMed PMID: 10936013.
71. Burt SA, Donnellan MB. Development and validation of the Subtypes of Antisocial Behavior Questionnaire. 
Aggressive behavior. 2009;35(5):376-98. doi: 10.1002/ab.20314. PubMed PMID: 19618380.
72. Harvey NS. The development and descriptive use of the Lithium Attitudes Questionnaire. Journal of affective 
disorders. 1991;22(4):211-9. Epub 1991/08/01. PubMed PMID: 1939930.
73. Scott SG, Bruce RA. Decision-Making Style: The Development and Assessment of a New Measure. 
Educational and Psychological Measurment. 1995;55(5):818-31.
74. Schwartz SJ, Hardy SA, Zamboanga BL, Meca A, Waterman AS, Picariello S, Luyckx K, Crocetti E, Kim SY, 
Brittian AS, Roberts SE, Whitbourne SK, Ritchie RA, Brown EJ, Forthun LF. Identity in young adulthood: 

Page 26 of 26
Links 
with 
mental 
health 
and 
risky 
behavior. 
J 
Appl 
Dev 
Psychol. 
2015;36:39-52. 
doi: 
10.1016/j.appdev.2014.10.001. PubMed PMID: WOS:000350514700005.
75. Moos RH. Conceptual and empirical approaches to developing family-based assessment procedures: 
resolving the case of the Family Environment Scale. Fam Process. 1990;29(2):199-208; discussion 9-11. 
PubMed PMID: 2373215.
76. Armsden GC, Greenberg MT. The Inventory of Parent and Peer Attachment - Individual-Differences and 
Their Relationship to Psychological Well-Being in Adolescence. J Youth Adolescence. 1987;16(5):427-54. 
doi: Doi 10.1007/Bf02202939. PubMed PMID: WOS:A1987L401400002.
77. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture 
(REDCap)-A metadata-driven methodology and workflow process for providing translational research 
informatics support. Journal of biomedical informatics. 2009;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010. 
PubMed PMID: WOS:000264958800018.
78. McLellan AT, Luborsky L, Woody GE, O'Brien CP. An improved diagnostic evaluation instrument for 
substance abuse patients. The Addiction Severity Index. The Journal of nervous and mental disease. 
1980;168(1):26-33. PubMed PMID: 7351540.
79. Schwartz SJ, Hardy SA, Zamboanga BL, Meca A, Waterman AS, Picariello S, Luyckx K, Crocetti E, Kim SY, 
Brittian AS, Roberts SE, Whitbourne SK, Ritchie RA, Brown EJ, Forthun LF. Identity in young adulthood: 
Links 
with 
mental 
health 
and 
risky 
behavior. 
J 
Appl 
Dev 
Psychol. 
2015;36:39-52. 
doi: 
10.1016/j.appdev.2014.10.001. PubMed PMID: WOS:000350514700005.
80. Baiocco R, Laghi F, D'Alessio M. Decision-making style among adolescents: relationship with sensation 
seeking 
and 
locus 
of 
control. 
J 
Adolesc. 
2009;32(4):963-76. 
Epub 
2008/10/10. 
doi: 
10.1016/j.adolescence.2008.08.003. PubMed PMID: 18848722.
81. Detke HC, DelBello MP, Landry J, Usher RW. Olanzapine/Fluoxetine combination in children and 
adolescents with bipolar I depression: a randomized, double-blind, placebo-controlled trial. Journal of the 
American Academy of Child and Adolescent Psychiatry. 2015;54(3):217-24. doi: 10.1016/j.jaac.2014.12.012. 
PubMed PMID: 25721187.
82. Altman D, Bland J. Measurement in medicine: the analysis of method comparison studies. Statistician. 
1983;32:307-17.
83. MacKinnon DP. Introduction to statistical medication analysis. New York: Lawrence Erlbaum & Associates; 
2008.
84. Preacher KJ, Hayes AF. Asymptotic and resampling strategies for assessing and comparing indirect effects 
in multiple mediator models. Behav Res Methods. 2008;40(3):879-91. PubMed PMID: 18697684.
85. Rubin DB. Inference and missing data. Biometrika. 1976;63:581-92.
86. Graham JW. Adding missing-data-relevant variables to FIML-based structural equation models. Struct Equ 
Modeling. 
2003;10(1):80-100. 
doi: 
Doi 
10.1207/S15328007sem1001_4. 
PubMed 
PMID: 
WOS:000181322400004.
87. Ten Have T, Kunselman A, Pulkstenis E. Mixed effects logistic regression models for longitudinal binary 
response data with informative drop-out. Biometrics. 1998;54:367-83.
88. Chambers WJ, Puig-Antich J, Hirsch M, Paez P, Ambrosini PJ, Tabrizi MA, Davies M. The assessment of 
affective disorders in children and adolescents by semi-structured interview: test-retest reliability of the 
Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present Episode version. Arch 
Gen Psychiatry 985 Jul;42(7):696-702