Nutrition, Exercise, and Wellness Treatment (NEW Tx) for Bipolar Disorder
Phase: PHASE1
Conditions: Bipolar Disorder
Sponsor: Massachusetts General Hospital

 
 
 
 
 
 
Nutrition, Exercise, and Wellness Treatment (NEW Tx) for Bipolar Disorder 
 
NCT01615367 
 
Date of document: 8/28/2014 

Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
 
1
NUTRITION, EXERCISE, AND WELLNESS TREATMENT (NEW TX) 
FOR PATIENTS WITH BIPOLAR DISORDER: 
A TWO-PHASE PILOT STUDY TO TEST FEASIBILITY AND ACCEPTABILITY 
 
Version Date: 8/28/14 
 
 
I. 
BACKGROUND AND SIGNIFICANCE 
Cardiovascular disease is the leading cause of morbidity and mortality among individuals with bipolar disorder (BD)1, 2. 
Diabetes, hypertension, hyperlipidemia, and obesity are among the most common diseases in BD and are also the leading 
risk factors for cardiovascular disease3-6 and subsequent mortality7-9. Individuals with BD are at high risk for medical 
comorbidity3-6 which leads to high rates of morbidity and mortality1, 2, medical visits and admissions10 as well as 
complicates treatment and course of BD11. The medical burden for BD appears to be worsening, perhaps due to increased 
use of medications that are associated with cardiovascular risk factors8, 12, 13. 
 
To further treatment development, the National Institute of Mental Health (NIMH) held a meeting in 2005 to discuss the 
impact of obesity, nutrition, and physical inactivity among those with mental disorders14. Experts in the field stated that 
“obesity among those with mental disorders has not received adequate research attention, and empirically-based 
interventions to address the increasing prevalence of obesity and risk of cardiovascular and metabolic diseases in this 
population are lacking”14. In 2006, another meeting was convened to develop a “plan of action” in managing medical 
comorbidity and psychiatric illness. The committee recommended “integrated models of care” to prevent and treat 
medical comorbidity in psychiatric populations with outcomes focused on enhancing individuals’ physical “health” and 
“quality of life” (p. 51815).  
 
Pharmacological treatment contributes to the risk of cardiovascular disease in BD16 and weight gain is a major cause of 
treatment noncompliance, completing a dangerous cycle of increased burden of illness and decreased treatment efficacy9, 
17. This medical burden is highlighted by the fact that individuals with BD have nearly three times more medical 
admissions than other behavioral health care diagnoses10. Although the phenomenology of the medical burden associated 
with BD is unclear, it has been recognized as a primary concern in the treatment of this population13, 18. Pharmacological 
strategies as adjunctive treatments for psychotropic-associated weight gain have been examined in overweight or obese 
outpatients with BD with limited benefit19. Even less promising data has been observed in pediatric bipolar samples20 and 
schizophrenia21. Thus, adjunct psychosocial interventions have become increasingly important in reversing the behavioral 
antecedents that lead to poor nutrition and overeating. Interventions aimed at increasing healthy, nutritious eating have 
produced better outcomes for both clinical22 and non-clinical populations23. Reducing the medical burden requires an 
integrated approach given that several factors (i.e., body mass index, exercise, food choices) impact BD individuals’ 
outcomes in a weight loss program24. 
 
Despite these multiple factors, very few integrated programs have been developed, and only a few have been developed 
for severe mental illness. The Lifestyle Challenge Program incorporated nutrition, weight-management and exercise 
strategies into weekly, group-based psychoeducational sessions25. Only 43% of participants completed the program, but of 
these participants, they reported improvements in health-related quality of life and depressive symptoms25. The Integrated 
Intervention Model is an individualized psychoeducational program on sleep/wake rhythms, nutrition, exercise, and time 
management in BD (n = 24) and improved overall functioning and reduced psychiatric hospitalizations, but did not 
examine risk factors for cardiovascular disease26. The medical care model for BD consists of four psychoeducational 
group-based, self-management sessions about cardiovascular disease and how to improve diet and increase exercise. The 
treatment group showed improvements in mental health-quality of life and may have buffered against further decline in 
their quality of life18. Other current treatments for co-morbid medical and psychiatric conditions focus on establishing co-
located general medical providers or treatment teams within mental health clinics27, 28. Although these approaches are 
targeting medical burden and enhance communication between providers, they tend to be costly, rely on an abundance of 
resources, or do not develop an individualized, integrated treatment. Without integrated treatments, one provider is not 
responsible for monitoring the patient which may limit observations of interactions between treatment and conditions15, 29.  
 
The nutrition, exercise, and wellness treatment program (NEW Tx) is designed to reduce medical burden by targeting 
three areas: poor nutrition/obesity, sedentary lifestyle, and unhealthy lifestyle choices: 

Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
 
2
i. 
Nutrition: Individuals with BD have poor eating and nutritional habits30, 31. Moreover, obesity is more prevalent 
in BD than the general population, with one study finding 38% of bipolar individuals are overweight and 29% are 
obese32. 
ii. 
Exercise: Sedentary lifestyle is associated with increased morbidity and mortality33 and exercise training has been 
demonstrated to improve a number of important risk factors of medical burden (i.e., weight, cholesterol, insulin 
level34, 35). Exercise may be dually beneficial for BD given that it has also been found to improve mood 36, 37. In a 
unipolar depressed sample, exercising 3 days/week for 45-min was as effective in reducing depressive symptoms 
as an antidepressant (i.e., sertraline)38, 39, with promising data for bipolar samples40. Given the duality of exercise 
benefit for mental health, interventions are needed to increase lifestyle activity.  
iii. 
Wellness: Individuals with BD make poor food choices31 and use maladaptive coping strategies for stress, such as 
smoking, that increase their medical burden. For example, smoking in BD populations has been shown to increase 
heart disease mortality41. Individuals with BD have dysregulated behavioral activation systems42 which may 
explain why they chose rewarding activities (i.e., cigarettes, caffeine), opposed to healthier coping skills. It is 
essential that an intervention reinforce the importance of making healthy lifestyle choices (i.e., food choices, 
lifestyle activity, reducing caffeine). 
 
 
II. 
SPECIFIC AIMS 
The purpose of this research is to develop and test the feasibility and acceptance of a theoretically integrated treatment to 
address the impact of medical comorbidity of individuals with BD, while exploring its efficacy, whether it improves 
overall functioning and symptoms, as well as examine a potential moderator and mediator of treatment response. NEW Tx 
is a proposed solution to this problem as it builds upon previous empirical studies in healthy populations as well as the 
limited literature on lifestyle modification with serious mental illness. NEW Tx also integrates and modifies treatment 
strategies, such that it can be administered by a sole provider who is skilled in intervention and assessment of medical 
comorbidity and BD. NEW Tx is not intended to replace the need to collaborate with other providers, and strongly 
encourages such support as needed, but is a first-line, adjunct treatment to reduce the medical burden in individuals with 
BD. 
 
A. Primary Aims 
i. 
Aim 1: Feasibility and Acceptance of NEW Tx in the Nonrandomized Trial (N=6). Hypothesis 1a: A preliminary 
study of whether NEW Tx will be feasible with regards to recruitment, retention, blinded assessments, and 
therapist adherence to NEW Tx43. Hypothesis 1b: Participants will report high satisfaction with the treatment 
(CSQ-8) and acceptability (NEW Tx Scale) over the study duration (i.e., 20-weeks) in a nonrandomized trial (n = 
6). 
ii. 
Aim 2: Feasibility and Acceptance of NEW Tx and its Evaluation in the Randomized Pilot Trial (n = 40). 
Hypothesis 2a: A pilot study of whether NEW Tx will be feasible with regards to recruitment, randomization, 
retention, blinded assessments, and therapist adherence to NEW Tx43. Hypothesis 2b: Participants will report high 
expectations for the treatment (CEQ) and high satisfaction and acceptability with the treatment (CSQ-8; Post-Tx 
Questionnaire; NEW Tx Scale) in a 20-week nonrandomized trial (n = 6). 
B. Exploratory Aims 
i. 
Aim 3a: Reducing Medical Burden in the Randomized Pilot Trial. Pilot test (n = 40) the efficacy of NEW Tx in 
improving medical burden using the Framingham Risk Score (FRS). Hypothesis 3a: Over the course of 20-weeks 
(18 sessions) the NEW Tx group will have a lower FRS compared to treatment as usual (TAU) in the randomized 
pilot trial. 
ii. 
Aim 3b: Symptoms and Functioning in the Randomized Pilot Trial. Examine the efficacy of NEW Tx in 
improving functioning and symptoms of BD. Hypothesis 3b: Over the course of 20-weeks (18 sessions) the NEW 
Tx group will improved functioning (LIFE-RIFT) and symptoms (YMRS, MADRS) compared to TAU in the 
randomized pilot trial. 
iii. 
Aim 3c: Moderator and Mediator of NEW Tx in the Randomized Pilot Trial. Investigate a potential moderator 
and mediator of treatment response. Hypothesis 3c.1: Individuals with higher baseline BMI (>30) will moderate 
the between treatment effect size for medical burden (FRS) in the randomized pilot trial, such that of NEW Tx 
will have lower FRSs. Hypothesis 3c.2: Mastery of the diet (food diaries) and exercise (exercise duration from 
Exercise Questionnaire) modules of NEW Tx will mediate the association of NEW Tx and improvement in 
medical burden (FRS). 

Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
 
3
 
 
III. 
INTERVENTION MODULES AND OVERVIEW 
NEW Tx is a flexible modular treatment such that modules are selected based on the needs of the individual to increase its 
generalizability across patients, settings, and providers as well as its acceptability to patients. The three modules of the 
intervention are as follows: 
 
A. Nutrition/Weight Loss Module 
To enhance nutrition, we review nutritious foods (e.g., high in vitamins and minerals, low in fat) in each of the food 
groups as well as teach participants how to calculate serving size to enhance portion control. We discuss the importance of 
a “balanced diet” as well as having essential vitamins and minerals, particularly ones that may be beneficial for mood 
disorders. Finally, we review food that may be unhealthy and why. Weight loss is tracked as needed  and food diaries are 
used as needed (at minimum at baseline, week 10, and week 20) to monitor participants’ daily foods consumed and 
calories. Participants, with guide from their NEW Tx therapist, will determine a daily goal for caloric intake to assist in 
identifying healthy and realistic weekly weight loss goal. We utilize Cognitive Behavioral Therapy (CBT) strategies to 
challenge negative thoughts about changing food choices44. We also include a session on emotional eating, or eating to 
cope with negative affect, by evaluating the accuracy of thoughts associated with the craving. We discuss positive coping 
strategies, or distraction activities, to replace food as a way to improve mood or “comfort” oneself. We also utilize the 
philosophy from Brownell’s LEARN program45 that there are no “forbidden foods” as evidence suggests that this may 
increase cravings for these foods as well as negative thoughts about the module46. We use psychoeducational materials to 
enhance adherence. We specifically discuss the impact of “psychological factors” and review research studies of diet 
programs that have had positive outcomes in severe mental illness. Finally, we employ behavioral strategies in NEW Tx, 
such as positive reinforcement, to enhance adherence through the use of reward charts. We then collaboratively set 
homework and weekly goals each session.  
 
B. Exercise Module 
The goal of this module is to exercise 5 days/week, for at least 30 min each day, of moderate intensity 47. Participants 
complete the Exercise Questionnaire each session to track their exercise. We begin this module by discussing the 
importance and rationale for exercise. We review evidence that exercise is particularly important in enhancing mood. We 
also discuss ways of increasing lifestyle activity (i.e., taking the stairs, standing instead of sitting, walking to the store). In 
this way, we approach exercise as a task not requiring sustained or extreme energy, concentration, and motivation, but a 
more casual experience, which can last for a relatively short period of time and still be helpful. This paradigm shift in 
conceptualizing exercise as lifestyle activity is very important for individuals who have a vulnerability to think negatively 
about themselves, their world, and their future. We utilize CBT strategies to challenge negative thoughts about exercising, 
which for individuals with BD is often their most significant obstacle44, 48. We also set weekly exercise goals and discuss 
participants’ obstacles to adhering to these goals. Many exercise programs encourage participants to find a “work out 
partner”45. This can be especially problematic for individuals with BD who tend to isolate when depressed or have 
interpersonal problems when manic48. Given that social support is still a very important motivator and can buffer against 
future episodes49, 50, we discuss the concept of “structured, group lifestyle activities.” Feedback from our pilot groups 
suggests that this is immensely helpful, even participants with anxiety report that they can tolerate structured groups as 
they do not feel pressure “to perform” or “to interact with others.” Some participants from our pilot group have noted that 
exercising when manic helps them to stay focused and keep their energy level down, while others have reported the 
opposite effect. Similarly, some participants reported choosing to exercise in the evening as it helps them to relax and 
sleep, while others report needing “wind down time” after exercising. By including individuals with manic symptoms, we 
will learn more about the association of exercise and mania. 
 
C. Wellness Module 
This module is integrated throughout the first two modules as it reinforces the importance of making healthy decisions 
(e.g., food choices, exercise, increasing behavioral activation) and helps to problem solve obstacles to making these 
choices. This module is reflected in the use of CBT-based strategies that focus on increasing adherence to the nutrition 
and exercise modules as well as other healthy choices (e.g., reduction of caffeine, smoking, substance use). For example, 
we discuss that having 5 to 6 smaller meals throughout the day is an ideal meal plan as it is healthier and enhances their 
routine and energy level, opposed to using caffeine or smoking as stimulants. We focus on these other lifestyle choices as 
exercise reduces the craving for smoking51 and substance use52 as well as seems to buffer against substance abuse53. 

Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
 
4
Similarly, we encourage participants to choose a feasible time every other day to exercise and to use positive rewards 
when meeting exercise and diet goals. In this module, we also discuss important aspects of behavioral activation, such as 
balancing mastery and pleasurable tasks and setting appropriate mood-dependent schedules. An important aspect of 
enhancing healthy lifestyle choices is accounting for mood-specific shifts in their activation. For example, during 
(hypo)manic episodes bipolar individuals tend to be impulsive and overly energetic, and thus their lifestyles often become 
chaotic and erratic. In contrast, during depressive episodes, bipolar individuals lose this behavioral activation and thus, 
tend to isolate or withdraw. In this module, we stress the importance of having two feasible choices or plans: one for 
elevated moods and one for depressed moods. Both plans emphasize structure and healthy coping behaviors, but the 
activities vary. We also use reward charts to reinforce healthy decisions and challenge self-defeating thoughts (e.g., “I 
can’t change”). This module also incorporates motivational interviewing techniques which are effective in helping 
individuals gain insight into their unhealthy behaviors and the need for change54.  
 
 
 
IV. 
RESEARCH DESIGN AND METHODS 
 
A. Overview  
Currently there are no theoretically integrated treatments for the medical burden associated with BD. This is enormously 
problematic given the increased risk that this medical burden poses for this population’s course of illness, functioning, and 
morbidity. Given the scope of the problem and lack of treatments, leaders in the field have called for further treatment 
development 14, 15. Proposed as 18 sessions (45-60 minutes each) over 20 weeks in an individual therapy format, NEW Tx 
is composed of the following treatment modalities: Nutrition/weight loss, Exercise, and Wellness treatment. A blinded 
independent evaluator will be used to administer assessments (see Table 1) and an unblinded study coordinator will 
oversee recruitment and scheduling. As will be described in detail in the following sections, the research study will utilize 
the intervention modules in two distinct pilot samples:  
i. 
Phase I: In the first phase of the study, we will test NEW Tx in a nonrandomized, open trial (n = 6). This pilot 
group for NEW Tx will be used to test the feasibility of the treatment as determined by participant attendance, 
therapist adherence to the procedures, and client feedback. All participants in this initial sample will be treated by 
the Principal Investigator (PI). 
ii. 
Phase II: In this phase, we will pilot test the NEW Tx methods compared to TAU (n = 60) to further examine 
feasibility, to estimate an effect size, and to explore its efficacy for reducing medical burden. TAU will be the 
control group in the Phase II pilot study as it is the standard treatment in the Massachusetts General Hospital 
(MGH) Bipolar Clinic and Research Program. Participants randomized to TAU who complete the first 20 weeks 
of the study will have the option to receive NEW Tx. TAU participants who chose to receive NEW Tx (the 
waitlist group) will follow the same procedures as the NEW Tx group over an additional 20 weeks such that they 
will have assessments at Weeks 30, (mid-treatment), 40 (post-treatment), and 52 (follow-up) (see Table 2). For 
TAU, medication and dosage changes are allowed as needed as long as the change is recommended based on the 
guidelines and participants remain on a mood stabilizer. Medication changes will be monitored with the Clinical 
Monitoring Form Medication Module. All participants will have a three-month follow-up visit during which post-
treatment measures and assessments will be repeated.  Participants will be recruited with the same criteria as the 
nonrandomized trial, but will be randomized using a 1:1 allocation ratio with a blocking strategy. The assessments 
will be similar to those used in Phase I. In addition to the study staff utilized in Phase I, clinicians with training in 
CBT and mood disorders will be added as NEW Tx therapists. 
 
B. Participant Selection and Recruitment 
Participants (n = 6 for the open trial phase; n = 60 for the randomized phase) will be recruited from within as well as 
outside the MGH Bipolar Clinic and Research Program, and we plan to recruit 1 participant per month for the Phase I 
open trial and 2 participants per month for the Phase II randomized trial. Some subjects will be self-referred, whereas 
others will be referred by MGH or community clinicians. Some subjects may be obtained from media advertisements. 
Potential participants will not be identified through medical records, and the researchers will not contact potential 
participants without their permission. If a clinician feels that one of his or her patients would be potentially appropriate for 
this study, the patient will be encouraged to contact the PI or the research assistant directly. Alternatively, the clinician 
may ask the patient to give permission to be contacted over the phone by either the PI or the research assistant. Written 
IRB approved informed consent will be obtained from all patients before protocol-specified procedures are carried out. 

Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
 
5
Patients may be referred to the study by their treating clinicians in the MGH Bipolar Clinic and Research Program, and 
will be recruited according to the following criteria: 
i. 
Inclusion Criteria 
□ Diagnosis of Bipolar Disorder (Type I or II), which is the primary focus of treatment 
□ Ability to give informed consent 
□ Currently ill (CGI-BP ≥ 3)  
□ Age > 18 years and < 65 years 
□ Overweight individuals (BMI > 25); those with BMI of 25-30 must also have high rate of percentage of 
body fat (greater than or equal to 32% for women and 25% for men) 
ii. 
Exclusion Criteria 
□ Unwilling/unable to comply with study procedures 
□ Endorsed item, confirmed by patient’s physician, on the PAR-Q 
□ Euthymic (CGI-BP < 3) 
□ Diagnosis of anorexia nervosa or bulimia nervosa in the past month 
□ Diagnosis of substance dependence in the past month 
□ Active suicidality (MADRS item 9 score > 4) 
□ Pregnant (as analyzed by a urine pregnancy test) 
□ Exercising regularly (i.e., 5 days per week for 30 min) 
□ Neurologic disorder or history of head trauma 
□ Contraindications to exercise or diet interventions (e.g., co-morbid nutritional and metabolic diseases, 
physical injuries)  
 
An EKG will be required for participants over the age of 40, if clinically indicated, to further minimize potential risks 
associated with exercising. For clinical monitoring and assessment of adverse events, a fasting blood draw will be 
conducted at Week 0, Week 10, and Week 20. For the waitlist group (i.e., TAU participants who choose to receive NEW 
Tx after 20 weeks), fasting blood draws will be conducted at Weeks 30, Week 40, and Week 52, in addition to the 
aforementioned draws. Drug screens will not be required; however, administration of drug screening as part of ongoing 
treatment is at the discretion of the treating physician at any time after consultation with the participant.  
 
C. Diagnostic and Clinical Assessments 
i. 
Extended Mini-International Neuropsychiatric Interview (MINI57) will be used to establish DSM-IV 
diagnoses including BD, substance use, and eating disorders.  
ii. 
Demographics, Medical History, and Psychiatric History forms will assess any pertinent medical or psychiatric 
conditions that may impact the participants’ eligibility or treatment in this study. 
iii. 
Montgomery Asberg Depression Rating Scale (MADRS58) is a 10-item clinician-rated measure of depression 
that assesses the presence and severity of patient’s current depressive symptoms.  
iv. 
Young Mania Rating Scale (YMRS59) is an 11-item, clinician-rated measure that assesses the presence and 
severity of patient’s current symptoms of mania.  
v. 
Clinical Global Impression-Bipolar Illness (CGI-BP60) is a one item illness severity score that is a widely 
accepted, reliable, and valid assessment of global illness in BD61. The CGI-BP is a modified version of the CGI 
designed specifically for use in assessing global illness severity in patients with BD. This version assigns ratings 
for mania, depression, overall severity, and side effects. 
vi. 
Clinical Monitoring Form (CMF) Medication Module62 will track medication and dosage changes and whether 
the subject is taking medications for blood pressure (used to calculate the FSR score).   
vii. 
Food Diaries or a self-report record of foods and calories consumed will be completed by participants between 
study visits as needed. Selected food diaries will be reviewed by a dietician (as needed). 
viii. 
Exercise Questionnaire (EQ) is a modified version of the Exercise History and Attitude Questionnaire which has 
been used in a wide variety of settings63, 64. It is typically administered to healthy populations; thus, some items 
were excluded that were not likely to pertain to BD. This questionnaire assesses baseline (i.e., past) exercise 
history as well as ongoing exercise duration and frequency at follow-up study visits65.  
ix. 
LIFE- Range of Impaired Functioning Tool (LIFE-RIFT66, 67) assesses the extent to which medical burden has 
impacted current functioning.  
x. 
Framingham Risk Score (FRS) will be used to estimate medical burden as it is designed to estimate risk in 
adults (age > 20) to predict 10-year risk for myocardial infarction and coronary death. The FRS is calculated 

Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
 
6
based on six indices: age, gender, total cholesterol, HDL cholesterol, smoker (Y/N), systolic blood pressure, and 
medications to treat high blood pressure (Y/N). It is one of the most widely validated and cited clinical prediction 
scores, and although several modifications have been proposed, a recent review of over 1900 studies found that 
these studies had “flaws in their design, analyses, and reporting that cast some doubt on the reliability of the 
claims for improved prediction”68. The Medical History form will collect the patient data necessary to calculate 
the FRS score.   
xi. 
Physical Activity Readiness Questionnaire (PAR-Q69) is a seven-item, self-report questionnaire to screen 
individuals for starting an exercise program. In addition to the PAR-Q, an EKG will be required for participants 
over the age of 40, if clinically indicated, to further minimize potential risks associated with exercising.  
xii. 
Credibility/Expectancy Questionnaire (CEQ70) is a 6-item, self-report questionnaire to assess patients’ 
perceptions of and expectations for treatment before the study begins. 
xiii. 
Client Satisfaction Questionnaire-8 (CSQ-871) is a reliable and valid self-report of participants’ acceptability of 
treatment. This is an assessment of client/patient satisfaction with their care and perceived quality and tolerability 
of NEW Tx.  
xiv. 
NEW Tx Scale is a 10-item scale to assess participants’ acceptability of NEW Tx. This scale also includes a 
comments section to solicit unstructured feedback from participants on NEW Tx.  
xv. 
Post-Treatment Questionnaire is an open-ended, 3 question measure that asks participants to identify aspects of 
the treatment that were helpful or not helpful and that could be improved. 
xvi. 
Intent to Attend72 is a single item that measures participants’ intent to attend the next study visit which will be 
used in part to inform the extent to which attrition is ignorable73. 
xvii. 
DXA scans measure total body composition and fat content using low-dose x-rays. 
xviii. 
University of Rhode Island Change Assessment Scale (URICA) is a 32-item, self-administered measure that is 
a reliable and valid measure of motivation and intention to change at entrance to treatment. 
xix. 
Metabolic Cart Assessment—Metabolic Cart Assessment—A metabolic cart is an electronic medical tool that is 
used to measure basal metabolic rate and can be used by medical professionals to determine someone’s overall 
health condition. his test indirectly measures how much energy a person’s body uses at rest by measuring 
the amount of oxygen a person consumes versus the amount of carbon dioxide a person expends. 
Table 1. Schedule of Assessments for the NEW Tx and TAU groups 
Weeks 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
16 
18 
20 
32 
 
 
Pre 
 
 
 
 
 
 
 
 
 
 
Mid 
 
 
 
 
 
 
 
Post/
ET 
Follow
-Up 
MINI 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
Hx 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric 
Hx 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demograp
hics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PAR-Q 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-BP 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
Blood 
Draw** 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
Vitals  
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
DXA scan 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
CMF 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
MADRS 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
YMRS 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
LIFE-RIFT 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
NEW 
Tx 
Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
CEQ 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSQ-8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
URICA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Met Cart  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Post-Tx 
Questionn
aire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 

Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
 
7
EQ 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Intent-to-
Attend† 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Food 
Diaries† 
x 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x 
x1 
x1 
x1 
x1 
x1 
x1 
x 
x1 
 
ET= Early Termination. Vitals = Height (at Week 0 and Week 20), weight, waist circumference, blood pressure, pulse, and Dual X-Ray Absorptiometry 
(i.e., body composition). ** Includes lipid profile (i.e., cholesterol, triglycerides), metabolic panel (i.e., blood urea nitrogen (BUN), creatinine (Cr), 
electrolytes, blood glucose level), complete blood count (CBC), and thyroid stimulating hormone (TSH). C reactive protein (CRP) and inflammatory 
marker panels (Human TH1/TH2 10-Plex (IFN-g, IL-1b, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13, TNF-a)) will be included at pre- and post-treatment 
visits. A urine pregnancy test will be administered at Week 0 to determine eligibility. An EKG will be completed at Week 0 for participants > 40-years-old, 
if clinically indicated. 
1 As needed. 
†For the TAU group, will only be collected at Weeks 0, 10, and 20 
 
 
T
able 
2. 
Schedule 
of 
Assessme
nts for the 
Waitlist 
Group 
(TAU 
participan
ts 
who 
choose to 
receive 
NEW 
Tx)Week
s 
2
1 
2
2 
2
3 
2
4 
2
5 
2
6 
2
7 
2
8 
2
9 
30 
3
1 
32 
3
3 
3
4 
3
5 
3
6 
3
7 
3
8 
3
9 
40 
52 
 
 
 
 
 
 
 
 
 
 
Mid-tx  
 
 
 
 
 
 
 
 
 
Post-tx 
Follo
w-up  
CGI-BP 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
Blood 
Draw** 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
Vitals  
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
DXA scan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
CMF 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
MADRS 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
YMRS 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
LIFE-RIFT 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
NEW 
Tx 
Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
CSQ-8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
URICA 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Met Cart 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Post-Tx 
Questionn
aire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
EQ 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Intent-to-
Attend 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Food 
Diaries 
x
1 
x
1 
x
1 
x
1 
x
1 
x
1 
x
1 
x
1 
x
1 
x1 
x
1 
x1 
x
1 
x
1 
x
1 
x
1 
x
1 
x
1 
x
1 
x1 
x1 
 
ET= Early Termination. Vitals = weight, waist circumference, blood pressure, pulse, and Dual X-Ray Absorptiometry (i.e., body composition). ** Includes 
lipid profile (i.e., cholesterol, triglycerides), metabolic panel (i.e., blood urea nitrogen (BUN), creatinine (Cr), electrolytes, blood glucose level), complete 
blood count (CBC), and thyroid stimulating hormone (TSH). C reactive protein (CRP) and inflammatory marker panels (Human TH1/TH2 10-Plex (IFN-g, 
IL-1b, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13, TNF-a)) will be included at pre- and post-treatment visits. A urine pregnancy test will be administered 
at Week 0 to determine eligibility.  
1 As needed. 
 
 

Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
 
8
 
D. Independent Evaluator Training 
The independent evaluators will receive instructions and observe the other trained independent evaluators in the BCRP, 
who have extensive experience in administering the study assessments. 
 
E. Clinician Training 
New therapists utilized in Phase II of the study will be trained by the PI. The therapists will be required to demonstrate 
understanding of the theoretical rationale for each module of NEW Tx, knowledge of BD, and proficiency in the strategies 
and techniques used to achieve treatment goals. Specific training components will include: (1) reviewing the procedures 
with PI; (2) role playing NEW Tx techniques; and (3) ongoing weekly supervision with the PI to review their sessions.  
 
Some treatment sessions will be taped to ensure treatment integrity.  The PI will review selected audio files and give 
feedback to the NEW Tx therapists.  Audio recording is optional, so participants may opt out and still participate in the 
study.  Audio files will be recorded with a microphone connected to a Partners computer.  Files will be uploaded and 
saved directly to the BCRP secure network, they will not be saved as hard copies.  Audio files will be labeled with the 
subjects’ study IDs and not their names.  Files will be sent to the PI through Partners Secure File Transfer 
(http://rc.partners.org/sFTP).   
 
F. Targeted Enrollment 
We expect to recruit a representative sample of Boston, MA, the location of our research site (see Table 3 and Table 4)74. 
We expect that our sample will resemble the general population given that current studies in the MGH Bipolar Clinic and 
Research Program are meeting or exceeding this minority representation. 
 
Table 3. Minority Representation in Boston, MA 
Racial/Ethnic Category 
Boston, MA*  
Race 
 
    White 
76.1% 
    Black or African American 
14.4% 
    American Indian and Alaska Native 
0.4% 
    Asian 
7.8% 
    Native Hawaiian and Other Pacific  
    Islander 
0.1% 
Ethnicity 
 
   Hispanic or Latino 
10.5% 
   White Persons, 
   Not Hispanic/Latino 
68.1% 
  Other 
21.4% 
*Suffolk & Norfolk Counties 
 
Table 4. Expected Enrollment by Race, Ethnicity and Gender 
TARGETED/PLANNED ENROLLMENT for Phase I and II Studies (n = 60) 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown or 
Not Reported       Total 
Hispanic or Latino 
6 
6 
 
12 
 
Not Hispanic or Latino 
18 
18 
 
36 
 
Unknown (individuals not reporting ethnicity) 
6 
6 
 
12 
 
Ethnic Category: Total of All Subjects 
30 
30 
 
60 
 
Racial Categories 
 
American Indian/Alaska Native  
0 
0 
 
0 
 

Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
 
9
Asian  
3 
3 
 
6 
 
Native Hawaiian or Other Pacific Islander  
0 
0 
 
0 
 
Black or African American  
4 
4 
 
8 
 
White  
23 
23 
 
46 
 
More Than One Race 
 
 
 
2 
 
Unknown or Not Reported 
 
 
 
6 
 
Racial Categories:  Total of All Subjects 
30 
30 
 
60 
 
 
 
V. 
POTENTIAL BENEFITS 
Participants may be reimbursed for up to $20/visit for travel-related costs as needed. Additionally, at two points during the 
20 week treatment (one around midway and one around the end) participants will receive $10, for a total of $20, as part of 
their work with NEW Tx therapists to set and achieve treatment-related goals. 
 
The proposed research study involves an intervention that holds the potential for direct individual benefit. This research 
will further our knowledge about medical burden in BD and the feasibility of psychosocial treatment to reduce this 
burden. Risks of discomfort associated with NEW Tx should be offset by the potential physical and mental health 
benefits. Thus, this study has the potential to not only improve the treatment of BD patients, but also advance the field by 
developing a treatment that can be used in future treatment studies of BD. 
 
VI. 
RISKS AND DISCOMFORT  
The risks that the Phase I and II trials pose to participants are reasonable in relation to the anticipated benefits because BD 
is associated with a disproportionately high medical burden as well as chaotic mood swings and a high rate of functional 
impairment. As the NEW Tx represents an augmentation of standard treatment with an experimental psychosocial 
intervention, the additional risk is small, justifiable given the potential benefits, and is at least as favorable as alternative 
approaches.  
 
A. Potential Risks to Subjects 
There is a possibility that study patients will not improve from this treatment. During the study assessments, subjects may 
also experience some discomfort from discussing personal material and completing self-report questionnaires. Subjects 
may also experience some discomfort from the blood draw. Participants will be exposed to radiation from two DXA 
scans.  The total amount of radiation exposure is equal to a whole body exposure of approximately 16 microSieverts. A 
microSievert is a unit of radiation dose.  This amount of radiation is about the same as you would normally 
receive in 2 days from natural background sources from the earth and the sky. Participants will also participate 
in a metabolic cart assessment, in which a clear plastic canopy will then be fitted over the head and upper chest 
of the participants to collect the air the participant exhales for 15 minutes. Participants may experience some 
discomfort or anxiety. 
 There is a risk of breach of confidentiality and loss of privacy, which great care will be taken to prevent.  
 
B. Protection Against Risks 
We will take precautions to ensure that potential risks are minimized. All treatments will be provided by at least master-
level mental health professionals with experience in CBT and mood disorders. NEW Tx therapists will be closely 
supervised by the PI. In the case of an emergency, the NEW Tx therapist will page the PI. If the PI is unavailable, the 
covering clinician will be paged. If immediate assistance is required, the participant will be directed to call 911 or go to 
the MGH Acute Psychiatric Service. The following procedures will also ensure participant safety: 
i. 
All participants who fail to respond to treatment or withdraw prematurely will be referred for alternative 
treatment. If withdrawal from the study is necessary, we will provide appropriate referrals for other treatment. The 
PI, or the covering clinician, will be available to discuss the study, alternative treatments, or any concerns about 
the study with subjects if requested by the participant, therapist, or independent evaluator. 

Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
 10 
ii. 
Ratings on the MADRS suicide item will be monitored during the open trial (Phase I) and the randomized trial 
(Phase II). Participants’ with a suicidality score greater than 4 at Week 0—for either trial—will be excluded from 
the study.  
iii. 
Participants’ NEW Tx therapists will be available to them to discuss any concerns throughout the treatment 
period. The PI, or a covering clinician from the MGH Bipolar Clinic and Research Program, will make every 
effort to be available at all times to study participants in the event of a clinical emergency. However, if immediate 
assistance is required, the participant will be directed call 911 or go to the MGH Acute Psychiatric Service which 
is open and staffed 7 days a week, 24 hours a day. Participants will be withdrawn from either the open trial (Phase 
I) or the pilot study (Phase II) if their clinical condition deteriorates substantially. Participants may also be 
withdrawn if, in the judgment of the study investigators, remaining in the study poses a substantial risk to the 
participant or a higher level of care is needed. 
 
C. Ensuring Confidentiality 
To ensure protection of confidential information, all data will be coded and stored in locked files in the MGH Bipolar 
Clinic and Research Program. Names will not be included in computerized data files or in any published reports. Case 
records will be reviewed only by study personnel or, if necessary, by institutional, state, or federal regulatory personnel. 
All research personnel will have completed the Collaborative Institutional Training Initiative (CITI) Program on-line 
training and final exam, be well versed in Health Insurance Portability and Accountability Act (HIPAA) regulations and 
procedures, and be approved as study staff by the IRB. All HIPAA guidelines will be followed and all research personnel 
will be educated about the importance of strictly protecting participants' rights to confidentiality.  
 
 
VII. 
DATA COLLECTION 
All data collection will adhere to HIPAA regulations. Data will be obtained specifically for research purposes and 
managed using the REDCap system. Data on feasibility and satisfaction of NEW Tx as well as medical burden, BD 
symptoms, and functioning will be collected via patient self-report, clinician- and rater-administered assessments. These 
data will be used to evaluate treatment feasibility and acceptability, treatment integrity, efficacy, and possible mechanisms 
of change. Data assessing safety and adverse events will be collected through blood analysis.  
 
 
A. Safety and Monitoring 
There will be a Data Safety and Monitoring Board (DSMB) for this study composed of three investigators who have 
experience in clinical research, clinical treatment of BD, and specifically overseeing the safety of participants in bipolar 
trials. This DSMB will monitor safety issues, including the review of adverse events, the PI’s quarterly report of the 
study’s progress, all IRB amendments, the adequacy and integrity of accumulating data, and the capability of the Phase I 
and II trials to test the hypotheses. The purpose of this process is to assess scientific integrity and patient safety issues, and 
ensure the ethical conduct of the trials. The DSMB will approve the initiation of the study and subject enrollment, and 
determine if study procedures should be altered or stopped due to evidence of benefit or harm to trial subjects that may be 
attributable to NEW Tx or reasons related to scientific integrity. The PI will submit quarterly reports to the DSMB 
detailing any study changes, adverse events, subject recruitment and retention, reasons for early termination, and ongoing 
data reports. The PI will also respond to all DSMB issues and queries. 
 
B. Adverse Events 
Any serious adverse events (e.g., death, suicide attempt, hospitalization) will be reported within 24 hours to the IRB and 
the NIMH program officer. A full written report of the event will be sent to the above entities within 10 working days of 
the event's occurrence. All adverse events will be assessed for the events’ severity/intensity, expectedness, relatedness to 
NEW Tx, clinical outcome, and any action taken due to the event. Any adverse event (e.g., causing interference with usual 
activities or requiring treatment) and which appears definitely, probably, or possibly related to study participation will be 
tracked and reported to the IRB at the yearly continuing review. Any serious adverse events will be summarized in the 
NIMH, DSMB, and IRB annual progress reports. We will also inform the NIMH, DSMB and the IRB of actions, if any, as 
a result of their continuing review. 
 
 
 
VIII. 
DATA ANALYSIS 

Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
 11 
Baseline demographic and clinical characteristics will be examined by the PI in collaboration with Steve Farone, Ph.D., 
Professor of Biostatistics. Measures of central tendency and variability will be estimated on each continuous measure; 
proportions estimated for categorical variables. Transformations will be used when distributional assumptions are not 
fulfilled for inferential tests. Dropouts and completers will be compared on baseline variables using Mann-Whitney or chi-
square tests.  
 
A. Data Management: REDCap 
To ensure the quality of electronic data capture (EDC) and management, the data management team will use the REDCap 
EDC system. The REDCap Consortium is comprised of 135 active institutional partners and it supports two secure, web-
based applications (REDCap and REDCap Survey) designed to support data capture for research studies. The REDCap 
application is currently in production use or development build-status for more than 2990 studies with over 9540 end-
users spanning numerous research focus areas across the consortium, and the REDCap Survey application is now being 
adopted rapidly by consortium partners. Both REDCap and REDCap Survey provide a process for building a database or 
online survey, an interface for collecting data, data validation, and automated export procedures for data downloads to 
statistical packages (SPSS, SAS, Stata, R). 
 
REDCap allows users to design and implement study scales to collect, store, retrieve, and manipulate data electronically. 
The REDCap platform for EDC that streamlines data collection and management, and the system is a study management 
tool used to monitor visit timing and completion in real-time, thus helping to minimize missing data. REDCap is already 
used at MGH for treatment studies and has proved extremely useful for conducting and managing studies. It obviates the 
need for data entry by staff, thus minimizing cost and human error. Furthermore, because data quality control checks can 
be built into the logic of the online measures, problems can be identified in real-time, thereby improving data quality and 
consistency.  
 
Research staff will enter scale and assessments responses into the REDCap electronic assessment forms. Using 128 bit 
RSA Secure Socket Layer (SSL) encryption, approved users will be logged-in to machines using secured browsers behind 
the Partners Healthcare Systems IS corporate firewall or the RIH firewall. Staff will have a unique identifying key that 
will link them to the electronic study forms. This unique ID will be used in addition to a randomly generated secure 
password that only the staff person will have. Additional confidentiality procedures are detailed in the Human Subjects 
section.  
 
B. Statistical Analyses Plan for Research Aims 
Each of the statistical tests below will use a two-tailed alpha-level of 0.05. 
i. 
Aim 1: Feasibility in Nonrandomized Trial (Phase I). Hypothesis 1a: Descriptive statistics will be used to 
report the number of intervention sessions attended (we expect > 80%), number of participants recruited per 
month, and therapist adherence to NEW Tx (average adherence score ≥ 6). Hypothesis 1b: Participants will report 
high satisfaction (total CSQ-8 score, M > 2475) with the treatment and acceptability (total NEW Tx Scale score, 
M<25, or at least an average score of “agree” on half of the items).  
ii. 
Aim 2: Feasibility in Randomized Trial (Phase II). Hypothesis 2a: Descriptive statistics will be used to report 
the number of intervention sessions attended (we expect > 80%), number of participants recruited per month, 
randomization rate (number randomized/number consented), number of assessment sessions attended (we expect 
> 80%), and retention (number of study completers/number randomized) (we expect > 80%, which is conservative 
for diet and exercise interventions for severe mental illness25, 76-78) and therapist adherence to NEW Tx (average 
adherence score ≥ 6). Hypothesis 2b: Participants will report high expectations (CEQ score) for the treatment and 
high satisfaction and acceptability (CSQ-8, Post-Tx Questionnaire, NEW Tx Scale).  
iii. 
Aim 3: Exploratory Aims (Phase II). Hypotheses 3a and 3b: Between treatment group effects sizes (and 95% 
CI) will be calculated. To supplement this, Mann-Whitney tests will compare treatment groups on medical burden 
(as measured by FRS) (Hypothesis 3a) and on improvement in symptoms (MADRS, YMRS) and functioning 
(LIFE-RIFT) (Hypothesis 3b) based on change from baseline. Hypothesis 3c.1: We will investigate baseline BMI 
as a potential moderator of treatment response. The focus will be on the magnitude of the effect, not on 
significance testing. The between treatment group effect sizes (i.e., FRS, MADRS, YMRS, LIFE-RIFT) will be 
compared with those who have high baseline BMI (> 30) versus low BMI (< 30). Hypothesis 3c.2: Mastery of the 
diet (Nutrition Data System score of food diaries) and exercise (weekly exercise duration from Exercise 
Questionnaire) modules will mediate the association of NEW Tx and improvement in medical burden (FRS). The 

Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
 12 
dependent variable will represent change in the FRS score from time of completion of respective module. The 
mediators will be tested separately. Differential between treatment group effect sizes for those who did and did 
not master the modules will provide evidence of a mediator of treatment. 
 
C. Rate of Attrition 
Some attrition (i.e., 20%) is expected and this can result in bias and reduce power, precision and generalizability79. 
Consistent with the Intent to Treat principle80, we will continue with the assessments for the study duration, even among 
those who fail to comply with the treatment81. As one aspect of the feasibility study, we will assess the likelihood to attrite 
using the “Intent to Attend” measure72. 
 
D. Power Analysis 
The sample sizes for the Phase I and II trials are based primarily on the fundamental aim of this project: feasibility. The N 
is not based on what is needed for inferential analyses as they are not a fundamental aspect of the design. Power analyses 
are not indicated for the proposed exploratory analyses. We acknowledge that we will not have sufficient power to detect 
large effects (e.g., d = .80). 
 
 
 
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Principal Investigator: Louisa Grandin Sylvia, Ph.D.                                  
 
 
 
 
 
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