Treatment for anxiety: Mindfulness meditation versus escitalopram (TAME): Design of a randomized, controlled non-inferiority trial

Journal Pre-proof Treatment for anxiety: Mindfulness meditation versus escitalopram (TAME): Design of a randomized, controlled noninferiority trial

Elizabeth A. Hoge, Eric Bui, Mihriye Mete, Samantha R. Philip, Caroline Gabriel, Meredith J. Ward, Rebecca Suzuki, Mary Ann Dutton, Naomi M. Simon PII:

S1551-7144(20)30043-4

DOI:

https://doi.org/10.1016/j.cct.2020.105965

Reference:

CONCLI 105965

To appear in:

Contemporary Clinical Trials

Received date:

22 October 2019

Revised date:

29 January 2020

Accepted date:

17 February 2020

Please cite this article as: E.A. Hoge, E. Bui, M. Mete, et al., Treatment for anxiety: Mindfulness meditation versus escitalopram (TAME): Design of a randomized, controlled non-inferiority trial, Contemporary Clinical Trials(2020), https://doi.org/10.1016/ j.cct.2020.105965

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

© 2020 Published by Elsevier.

Journal Pre-proof

Treatment for Anxiety: Mindfulness Meditation versus Escitalopram (TAME): Design of a Randomized, Controlled Non-Inferiority Trial

of

Elizabeth A. Hogea,* [email protected], Eric Buib, c, Mihriye Metea,d, Samantha R. Philipa , Caroline Gabriel a , Meredith J. Wardb, Rebecca Suzuki e , Mary Ann Duttona , Naomi M. Simone a Department of Psychiatry, Georgetown University Medical Center, Washington D.C., USA b Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA c Harvard Medical School, Boston, MA, USA d MedStar Health Research Institute, Hyattsville, MD, USA e Department of Psychiatry, NYU Langone Health, New York University School of Medicine, New York, NY, USA * Corresponding author at: Associate Professor of Psychiatry, Georgetown University Medical Center, 2115 Wisconsin Ave, NW, Washington, DC 20007, USA

ur

na

lP

re

-p

ro

Abstract Anxiety disorders (generalized anxiety disorder, social anxiety disorder, panic disorder, and agoraphobia) are common, distressing, and impairing. While pharmacotherapy and psychotherapy are first-line treatment strategies for anxiety disorders, many patients are reluctant to take psychiatric medication, and many prefer to avoid any kind of mental health treatment due to stigma or distrust of traditional medical care. We present the trial protocol for the first study comparing first-line medication treatment with Mindfulness-Based Stress Reduction (MBSR), a popular mindfulness meditation training program, for the treatment of anxiety disorders. We will use a non-inferiority, comparative effectiveness trial design, in which individuals with diagnosed anxiety disorders will be randomized to either pharmacotherapy with escitalopram or MBSR for 8 weeks of treatment. Treatment outcome will be based on gold standard symptom severity measures assessed by trained independent evaluators blind to treatment allocation. Secondary outcomes will include key symptom and function measures, as well as tolerability and satisfaction with treatment. Findings will provide crucial information to inf orm decision making about the relative benefits of MBSR versus a first line medication for anxiety disorders by patients, medical care providers, healthcare insurers and other stakeholders.

1. Introduction

Jo

Keywords: Anxiety, Anxiety Disorder, Mindfulness Meditation, Escitalopram, Social Anxiety, Worry

Anxiety disorders, including generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), and agoraphobia, are the most frequent psychiatric conditions in the US, with a lifeti me prevalence of approximately 30% [1, 2]. Anxiety disorders are associated with significant distress and impairment in functioning [3, 4] and increased risk for suicide [4]. Antidepressant medication and psychotherapy are considered first-line treatments, with a recent meta-analysis finding that overall medication has a slightly higher effect size than psychotherapy [5].

Journal Pre-proof Selective serotonin reuptake inhibitor antidepressants (SSRIs) are considered first-line medication treatment options for anxiety disorders [6, 7]; however, they are only partially effective, with approximately half of patients failing to reach long-term recovery from anxiety and many more not adhering to their prescribed drug regimen [8-11]. For example, one antidepressant adherence study found that only about half of patients who initiated an SSRI accessed their first prescription refill [12].

of

Cognitive-Behavioral Therapy (CBT) is the most well-supported psychotherapy for anxiety disorders, but

ro

it can be difficult to access and even unavailable in some geographic regions due to a lack of trained

-p

providers [13]. Even when available, patients do not always follow up -- in a study on anxiety disorders that examined pre-treatment attrition rates, approximately 30% of patients who were referred to CBT

lP

re

by doctors did not end up undergoing treatment [14].

In addition, the above treatments are typically provided in a mental health treatment setting such as a

na

psychiatric clinic which unfortunately may be associated with stigma [15]. Approximately 10-20% of

ur

adult patients report stigma as a reason for not pursuing mental health treatment [16, 17]. Thus, it is

Jo

important to explore alternatives that are offered outside of a mental health context and therefore may have better acceptability for some patients.

Mindfulness-Based interventions (MBI’s) have become increasingly popular and are employed for a variety of psychological and physical complaints including stress and anxiety [18]. Mindfulness meditation practice involves focusing on current thoughts, feelings, and physiological sensations, and trains a person to act consciously rather than react unconsciously [19]. This helps the individual stay focused on (and increase acceptance of) present experience rather than getting absorbed in worries about the future [20]. Mindfulness meditation training has been manualized in a group format called

Journal Pre-proof Mindfulness-Based Stress Reduction (MBSR) [21, 22]. Several studies have demonstrated promising findings for MBI’s in patients with anxiety [23, 24]. In a tightly-controlled randomized GAD trial, in which over a third of patients also had another co-morbid anxiety disorder, MBSR yielded greater symptom reduction compared to an attention control condition [25]. Therefore, the next logical step is to compare the effectiveness of MBSR to a first-line treatment for anxiety disorders such as antidepressant

of

treatment.

ro

This paper describes the procedures and methodology of the first non-inferiority randomized, controlled

-p

trial comparing the effectiveness of MBSR to the antidepressant escitalopram for anxiety disorders. Results from this study will inform the field about the potential relative value of MBSR as an evidence-

lP

re

based treatment option for anxiety disorders compared to first-line pharmacotherapy with an SSRI.

Jo

ur

2.1. Participants

na

2. Materials and Methods

Inclusion criteria were selected to reflect a generalizable treatment seeking sample of adults with a primary psychiatric diagnosis of an anxiety disorder including: GAD, SAD, PD, or agoraphobia according to the Diagnostic and Statistical Manual of Mental Disorders fifth edition [26].Table 1 reports all inclusion and exclusion criteria, and their rationale. Of note, comorbidity with additional anxiety disorders and depressive disorders is permitted, but the presence of psychotic disorders, obsessive compulsive disorder, eating disorders, bipolar disorder, developmental or organic mentor disorders, current post-traumatic stress disorder or substance use disorder are excluded to assure the main focus of treatment would be the primary anxiety disorder in a practice setting.

Journal Pre-proof

Further, to minimize confounders and focus on individuals for whom both treatments would be a potentially reasonable option in practice, participants are required to have limited prior experience with meditation (i.e., cannot have completed an MBSR course or equivalent meditation training within the last year, or have an ongoing daily meditation practice), and cannot be taking antidepressants, mood

of

stabilizers, barbiturates, or antipsychotic medications.

-p

ro

2.2. Recruitment and screening procedures

Participant recruitment will occur across the three study sites: Georgetown University Medical Center,

re

(GUMC) in Washington DC, New York University Langone (NYU) in New York City, NY, and Massachusetts

lP

General Hospital (MGH) in Boston, MA. Recruitment strategies include advertisements in print media, social media postings, flyers, postings at other primary care and psychiatric facilities and programs, and

na

clinical referrals. Individuals who contact study personnel will undergo an initial phone screen to

ur

determine potential eligibility and interest in research participation. Participants must be willing to be

Jo

randomized to and participate in either an MBSR class or medication, and to complete study assessments. Interested patients who satisfy brief phone pre-screening eligibility assessments will be scheduled to meet with a trained study clinician evaluator to obtain written informed consent, and subsequently complete a full evaluation to determine their psychiatric diagnosis and eligibility.

Table 1. Inclusion and Exclusion Criteria Inclusion Criteria

Rationale

Man or woman between ages 18 and 75 years old

Higher Risk of ECG QT interval prolongation with advanced age

Journal Pre-proof Have a primary anxiety disorder, including: social anxiety disorder, generalized anxiety disorders, panic disorder, or agoraphobia

Target population with clinically significant pretreatment severity

Understands study procedures and is willing to participate in all study visits, and treatment as assigned

Treatment confounder

Must be able to give informed consent to the study procedures

Treatment confounder

Rationale

of

Exclusion Criteria

Treatment confound

Inability to understand study procedures or informed consent process, or significant personality dysfunction likely to interfere with study participation (assessed during the clinical interview)

Treatment confound, subject safety

lP

re

-p

ro

Other axis I psychiatric disorders (with the exception of depression) such as lifetime bipolar disorder, psychotic disorders, obsessive compulsive disorder, as well as current eating disorders, post-traumatic stress disorder, and substance use disorders (past 6 months).

na

Concurrent psychotherapy initiated within 1 month of screen interview, Treatment confound or ongoing psychotherapy of any duration directed specifically toward the treatment of anxiety (such as CBT).

ur

A serious medical condition that may result in surgery or hospitalization

Jo

A history of head trauma causing prolonged loss of consciousness, or ongoing cognitive impairment

Treatment confound, subject safety Treatment confound, subject safety

Subjects taking barbiturates, SSRIs, antipsychotics, or sedative medications. Sleep medications (other than anti-depressants) and benzodiazepines will be allowed, if has been taken at stable dose 4 weeks prior to baseline and the patient plans to continue at the same dose through the trial. Trazadone (for sleep) above 100mg will be disallowed.

Treatment confound, subject safety

Planning on becoming pregnant in next 6 months. Pregnancy as assessed by urine test at screen

Human subject safety

Individuals reporting significant active suicidal ideation or suicidal behaviors within the past year

Human subject safety

Individuals with a medical condition (i.e., epilepsy) that may be exacerbated by study treatment, as determined by a study physician or nurse practitioner based on history, physical, and/or labs

Human subject safety

Journal Pre-proof Subjects who will be non-compliant with the study procedures. This may include planned travel out of town (interfering with participation).

Treatment confound

Individuals who have completed a course of MBSR an equivalent meditation training in the past year, or have an ongoing daily meditation practice.

Treatment confound

2.3. Study Design This study aims to assess the comparative effectiveness of MBSR compared to escitalopram for anxiety

of

disorders (i.e., a primary diagnosis of generalized anxiety disorder, panic disorder, agoraphobia, or social

ro

anxiety disorder), by recruiting and randomizing treatment seeking adults to eight weeks of (1) MBS R

-p

delivered in group format consistent with standard protocols (see Treatment Interventions below) or (2)

re

flexible-dose escitalopram. This two-arm, three-site randomized controlled trial uses a non-inferiority study design which builds on previously published data on the efficacy of escitalopram for anxiety

lP

disorder treatment compared to pill placebo in randomized controlled trials [27-29]. Based on our

na

power calculations (see Analysis plan), we will randomize 368 participants across the three sites to either MBSR or escitalopram, anticipating that 276 will complete the protocol (i.e., 25% dropout). In

ur

addition, treatment satisfaction including dropout, and intent-to-treatment analyses will also be

Jo

important outcomes to guide conclusions about patient preferences and treatment responses. Patients who do not wish to stay in treatment (escitalopram or MBSR) will be allowed to discontinue treatment but will be requested to continue data collection visits for the rest of the study all the way to the last study visit at Week 24 so that we can capture their data for the ITT analysis.

2.3.1. Assessment instruments and procedures Doctoral or Masters-level independent clinical evaluators (IE) blinded to treatment allocation will assess participants’ anxiety symptom severity throughout the study: at pre -treatment (baseline week 0 visit), mid-treatment (week 4), post treatment (week 8), and at follow-ups (weeks 12 and 24). IEs will use

Journal Pre-proof standard clinician-rated assessments to rate anxiety symptoms and severity (see below). The IEs will be trained to do structured clinical interviews and will receive certification for this study under the direction of an IE trainer and supervisor. They will participate in a monthly cross-site teleconference to discuss procedural questions that arise and to conduct checks on IE assessments for consistency an d reliability. Inter-rater reliability ratings will be used to calculate kappa coefficients and to facilitate supervision, during which the IE trainer will discuss potential disagreements and provide instruction to

ro

of

further enhance inter-rater reliability. Table 2 reports the schedule of these assessments.

-p

Primary outcome measure

re

The primary outcome is the Clinician Global Impression-Severity Scale (CGI-S) assessed by IEs blind to

lP

treatment assignment [11, 30-33]. The CGI-S is widely used, has good psychometric properties, is

Jo

ur

Secondary outcomes

na

treatment sensitive, and highly correlated with anxiety and depression scales across disorders.

Independent-Evaluator Rated Outcomes

The Clinician Global Impression-Improvement Scale (CGI-I) [30-32] will also be assessed by an independent evaluator who will also assess disorder-specific anxiety symptoms using standard clinical ratings. The Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) is designed to assist clinicians in evaluating anxiety symptoms through the Hamilton Anxiety Scale (HAM-A). The 14-item HAM-A [34] was developed to assess general anxiety symptoms in a clinical population and has proven sensitive to change with treatment. The SIGH-A provides specific and detailed rating guidelines for the

Journal Pre-proof purposes of administering and scoring the HAM-A and has demonstrated high inter-rater and test-retest reliability [35].

The Panic Disorder Severity Scale (PDSS) is a semi-structured interview of panic symptom severity. It contains 7 items assessing multiple dimensions of PD severity, including frequency of panic attacks, distress during panic attacks, anticipatory anxiety, agoraphobic fear and avoidance, interoceptive fear

of

and avoidance, impairment of work and social functioning. The PDSS is a widely applied measure of the

-p

ro

severity of panic disorder symptoms [36].

The Liebowitz Social Anxiety Scale (LSAS) is a reliable and validated measure of social anxiety, that

re

assesses both fear and anxiety about common social situations, as well as avoidance components of

na

ur

Patient-Reported Outcomes

lP

social anxiety [37].

Jo

Overall Anxiety Severity and Impairment Scale (OASIS) is the primary patient-reported measure of anxiety symptoms. The OASIS is a 5-item, self-report measure used to assess overall anxiety levels across diagnostic groups. Items are rated on likert-type scale ranging 0-4, with higher values indicating greater clinical anxiety symptom severity. The OASIS has demonstrated good validity and reliability transdiagnostically in psychiatric samples of individuals with anxiety disorders, including patients with primary GAD, SAD, or PD [38-40]. This measure has been utilized in several trials investigating treatment effectiveness across GAD, SAD, and PD patient populations [41, 42].

Journal Pre-proof The Penn State Worry Questionnaire (PSWQ) Is a validated, widely-use patient-rated instrument of worry and anxiety [43]. The 24-item Pittsburgh Sleep Quality Index (PSQI) is a patient administered scale with demonstrated validity and reliability assessing subjective sleep quality [44]. The PROMISSleep is the PROMIS-Sleep Disturbance 8-item with five additional items from the item bank directly related to sleep disturbance due to anxiety and worry [45].

-p

ro

[46] and the Reactions to Treatment Questionnaire (RTQ) [47].

of

To assess satisfaction/acceptability of treatment, we will use the Client Satisfaction Questionnaire (CSQ)

The 21-item self-report Beck Anxiety Inventory (BAI) is designed to measure severity of anxiety

re

symptoms in psychiatric populations, and has high internal consistency, established validity, and test -

lP

retest reliability [48]. The BAI has both a cognitive and somatic subscale and has been used for over 20

na

years.

ur

The PROMIS - Emotional Distress scales (ED) [49] will be used to assess emotional distress in the past 7

Jo

days, including depressive symptoms, anxiety symptoms, and anger. We will also use the Quick Inventory of Depressive Symptomatology, Self-Report, or QIDS-SR [50] to measure depression severity.

To assess quality of life, we will use the PROMIS - Satisfaction with Participation in Social Roles - Short Form (SPSR) [51] that assess contentment with social roles, such as work and family responsibilities, within the past 7 days, and the PROMIS - Ability to Participate in Social Roles and Activities - Short Form 4A (APSRA) [51] that assess participants’ perceived ability to perform their usual social roles and activities.

Journal Pre-proof The Health Performance Questionnaire (HPQ) is a self-report survey measure of job performance [52]. The HPQ quantifies measures such as sickness absence and work performance. The HPQ is a valid and reliable tool for estimating the indirect workplace costs of illness [53]. It is also sensitive to changes [53] and when used longitudinally, the HPQ can reveal the cost-effectiveness of treatment.

The remainder of the measures in table 2 will be examined in secondary and exploratory moderator and

of

mediator analyses. These include the Difficulties in Emotion Regulation scale, short form (DERS -SF)[54],

re

Measures Related to Study Safety and Integrity

-p

ro

the Childhood Trauma Questionnaire [55], and the Life Events Checklist [56].

lP

Adherence for the MBSR arm will be measured by teacher tracking of class participation and a self report treatment racking log in which participants will report the number of minutes that they spend

na

meditating each day over the past week. At each treatment visit, we will collect data regarding if

ur

participant took their study medication as recommended from self-report and pill count. For the MBSR

Jo

group, high adherence will be defined as those who attended 6 out of the 9 required sessions (8 weekly classes plus the retreat=9). For the medication group, high adherence will be defined as those who took the 80% or more of the medication doses [57].

The Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER) is a 3-item, validated measure to assess the frequency, intensity, and interference of side effects due to study treatment. The Adverse Events Form is a form for the study clinician to fill out while interviewing patient which lists all adverse events and side effects due to study treatment for both groups. The Concomitant Treatment Form is a

Journal Pre-proof clinician completed tracking log for monitoring the presence, onset or offset of co-occurring treatments with the patient.

The Clinician Suicide Assessment Form, derived from the Columbia-Suicide Severity Rating Scale (C-

NP or RA

Vital Signs CGI-S

Primary Outcome s Secondar CGI-I y Outcome

-p

Urine Pregnancy & Drug Test Medical Review (history) Medical Review (bloodwork & EKG) MINI

W W k1 k2

Wk 4 (Mi d TX)

Wk W 8 k 6 (Pos t TX)

re

Clinician/M X D

Baselin e

lP

Informed Consent

X

na

ur

MD or NP

Jo

Diagnosi s& Screenin g

Mo. -1 (Scree n)

ro

Table 2: Table of Assessments Form Administer Type Measure ed by

of

SSRS), is clinician rated assessment of the severity of a patient’s suicidal ideation [58].

MD or NP

X

X

Clinician/M X D RA X IE

X

X X

X X

Wk 12 (follo w up)

Wk 24 (follo w up)

Journal Pre-proof s X X X X X X X

Self

X

Self Self

X X

Self Self Self Self Self Self Self Self

X X X X

CSQ Adverse Events Medication Tracking Form Treatment Tracking Concomita nt Medication Form Clinician Suicide Assessmen

Self MD or NP

Safety

X X X X X X X

X X X X

X X X X

X

X

X

X X

X X

X X

X X

X X

X X

X X

X X X

X

X

X X

X X

X

X

X X

X X

X X

X

X

X X

X

X

X

X

X

X

X

X

X

X X X X X X X

X

X

lP

re

-p

ro

of

IE IE IE Self Self Self Self

X

ur

na

X X

Jo

TX Details

LSAS SIGH-A PDSS OASIS BAI PSWQ PROMIS SF v1.0 EDAnxiety 8a PROMIS SF v1.0 EDDepression 8b PSQI PROMIS Sleep SPSR APSRA HPQ DERS CTQ LEC QIDS-SR RTQ

RA

X

Self

X

X

MD or NP

X

X

X

X

X

X

X

X

X

MD or NP

X

X

X

X

X

X

X

X

X

Journal Pre-proof t Checklist Note: IE = independent evaluator; self = self-report; MD = doctor of medicine; NP = nurse practitioner; RA = research assistant; CGI–S/CGI–I = Clinical Global Impressions Scale-Severity/Improvement; BAI = Beck Anxiety Inventory; PSWQ = Penn State Worry Questionnaire; OASIS = Overall Anxiety Severity and Impairment Scale; RTQ = Reaction to Treatment Questionnaire; CSQ = Client Satisfaction Questionnaire; PSQI = Pittsburgh Sleep Quality Index; HPQ = Absenteeism and Presenteeism Questions; MINI = Mini international Neuropsychiatric Interview; PDSS = Panic Disorder Severity Scale; LSAS = Leibowitz Social Anxiety Scale; SPSR = Satisfaction with Social Role Participation; APSRA = Ability to Participate in Social Roles and Activities; DERS = Difficulties In Emotion Regulation Scale; CTQ = Childhood Trauma Questionnaire; LEC = Life Events Checklist

of

2.4 Treatment Interventions 2.4.1. Escitalopram (ESC)

ro

During the 8 weeks of randomized treatment with ESC, subjects will be interviewed at baseline, post -

-p

baseline medication pick-up visit, weeks 1, 2, 4, 6, and 8-week endpoint, and at 12 week follow-up, (9

re

visits total) by a study physician or nurse practitioner. The medication will be provided to the

lP

participants by a study physician who will review and confirm dosing instructions for the participant to self-administer for the period between baseline to week 12. ESC will be initiated at 10 mg/day; at week

na

2, ESC will be increased to 20mg/day if well tolerated (or delayed if not). Medication adherence will be assessed by pill count and a standardized adherence measurement [59]. Side effects will be assessed at

ur

each visit (see above). Participants will be instructed to contact study staff immediately if any significant

Jo

side effects, symptomatic worsening, or suicidal ideation develops between visits. After week 8, if the patient desires to stay on the medication, s/he will be provided with another four-week supply by the study MD or NP, who will simultaneously work with the participants on a plan for the transition to care after the study so that the patient can continue treatment, if desired. If the patient wants to discontinue the study medication at week 8 or week 12, s/he will be assisted in tapering off the medication.

2.4.2. Mindfulness-Based Stress Reduction (MBSR)

Journal Pre-proof MBSR is an 8-week group-based course developed by Jon Kabat-Zinn (1990) and colleagues at the University of Massachusetts’ Center for Mindfulness [60]. Weekly 2.5 hour long classes are given once a week, as well as one day-long weekend class during the 6th week. The classes instruct participants in the theory and practice of several forms of mindfulness meditation: a body scan (bringing awareness through the body systematically); breathing awareness (attention focused on the breath and other physical sensations); and mindfulness stretching exercises designed to bring awareness of the body and

of

current experience of movement. Didactic teaching of the theory of mindfulness and experiential

ro

practice are both utilized during weekly classes and at-home audiorecorded-guided practice sessions.

re

continue to have access to the audiorecordings.

-p

Participants are encouraged to continue practicing their meditation skills after the course ends, and

lP

2.5. Safety Protocol

To optimize safety, study exclusions include a history of head trauma causing prolonged loss of

na

consciousness, cognitive impairment, or a medical condition that may be exacerbated by the study

ur

treatment, as determined by a study physician or nurse practitioner based on history, physical, and/or

Jo

labs. For safety, all women who are pregnant or planning on becoming pregnant within the next 6 months are excluded. Adverse events are assessed at each safety visit by inquiring whether any major change in mental or physical health occurred since the previ ous visit. Similarly, the suicide risk assessment is administered to detect emerging suicidality. Any patient who scores a 2 or 3 on the suicide assessment (non-specific thoughts of ending his/her life; thoughts but no specific plans or details) will be reassessed weekly. Any patient who scores a 4 or 5 (active suicidal thoughts without plan; plan full or partially worked out) will be referred as needed to the most appropriate level of medical care based on clinician judgment. The CGI-I is also administered at major assessment points to

Journal Pre-proof detect emerging worsening. If the CGI-I is 5 (minimally worse) or higher, weekly safety monitoring with a study clinician will occur until the CGI-I is less than 5 (or until study endpoint).

2.6. Fidelity monitoring MBSR instructors will have completed formal training and been deemed qualified to teach by the University of Massachusetts Center for Mindfulness (or at an equivalent training center if applicable).

of

The study’s MBSR expert investigator (MAD) will review all potential MBSR teachers’ training and

ro

experience to confirm their qualifications for teaching participants in the study. Treatment integrity will

-p

be further insured through adherence monitoring by the study overseeing MBSR expert, who will review the initial 5th session of each MBSR instructor’s class, using audio-recorded sessions of MBSR and

re

standardized adherence forms; feedback instructors will be provided with changes made to the

lP

instructors if deemed necessary.

na

2.7 Independent Evaluators Training and Inter-Rater Reliability

ur

All clinician rated outcome measures will be assessed by blinded independent evaluators ( IEs). All IEs will

Jo

be required to complete a rating training, be officially certified, and be approved by both their site PI and the cross-site IE supervisor, prior to completing any study assessments. Five percent of assessments will be randomly selected, rated, and used to calculate study interrater reliability ( IRR)[61-63]. Each month, all IEs will co-rate randomly selected audiotaped IE assessments (SIGH-A, CGI-S, CGI-I).

2.8. Data Analytic Strategy A randomization scheme stratified study site and anxiety severity was generated for this study on April 25, 2018 by the study statistician using an online [64] randomizer algorithm, and programmed in MedStar Health Research Institute’s RedCap database [65, 66]. All investigators involved in decisions

Journal Pre-proof about entry of subjects are blind to the randomization scheme. For this stratification, low anxiety severity is defined as CGI-S score ≤4, and high anxiety severity as CGI-S score >4. After the patient completes the baseline measures, an unblinded member of the study team (who does not perform any study assessments) will obtain the treatment allocation of each new participant from the study’s database in RedCap.

ro

of

Basic Statistical Analyses:

-p

Descriptive statistics will present demographic and clinical characteristics of the study participants using means, standard deviations, median and range for continuous variables and frequencies and

re

percentages for categorical variables. Potential differences between the groups at baseline will be

lP

examined with two-sample t-tests, nonparametric rank tests, chi-square and Fisher’s exact test as

na

appropriate.

Jo

ur

Sample Size and Non-inferiority Margin

Sample size calculations were conducted in Power Analysis and Sample Size Software (PASS) based on a non-inferiority hypothesis for two unpaired means (PASS 16 Power Analysis and Sample Size Software, 2018, NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass). A recent review of eight non -inferiority studies on behavioral treatments [67] found that the effect size used in the non-inferiority margin calculations ranged between d=0.26 and d=0.6. The method from one included CBT trial for all anxiety disorders [68] was particularly relevant to the current trial, and thus was used to determine the noninferiority margin for our sample size calculations. Norton and Barrera [68] proposed that the noninferiority margin be computed by multiplying the standard deviation of the outcome measure by the

Journal Pre-proof meta-analytically derived effect size; their approach was derived from a standard methodology recommended for rigorous equivalence designs [59]. Following this formulae, we computed a noninferiority margin of 0.66 (SD of 1.1 points for CGI-S change scores multiplied by a moderate effect size of 0.60) based on other escitalopram trials across anxiety disorders [28, 69]. However, to be more conservative, a non-inferiority margin of 0.33 (0.3*1.1) was used in our sample size calculations. This margin represents a difference of 1/3 of a point on the CGI-S score. We also defined a largest-clinically-

of

acceptable non-inferiority margin following the literature by determining the halfway point between

ro

these two numbers (0.66 and 0.33) to get 0.495, (0.45*1.1) such that a difference of 0.495 or smaller

-p

will still allow us to declare MBSR to be non-inferior to escitalopram treatment. Further support for the appropriateness of this margin comes from the literature where a change of 1.0 unit, substantially

re

higher than a margin of 0.495, is considered the Minimal Clinically Important Change (MCID) score for

lP

the CGI-S and has been used to anchor definitions of clinically significant change across other measures [70, 71]. As our primary analysis, we will analyze the per-protocol (completer) dataset, and the intent-

na

to-treat (ITT) primary dataset as secondary, as typically done in non-inferiority trials due to the

ur

theoretically increased chance of evidence in favor of non-inferiority in ITT analyses [72]. For the

Jo

analyses of the secondary outcomes, we will explore the missingness patterns in the data. If missingness is at random or completely at random, we will employ multiple imputation models for the analyses of the secondary outcomes. If diagnostic analyses suggest missingness may not be at random, we w ill conduct sensitivity analyses using maximum likelihood models to evaluate the effect of missingness on the results. Changes in the secondary outcome measures will be compared post-treatment and at follow-up using traditional hypothesis testing.

Multivariate Analyses

Journal Pre-proof We will conduct secondary/advanced analyses by specifying multivariate and longitudinal regression models of the primary and secondary outcome measures, in order to estimate treatment differences adjusted by potential confounders, and to explore individual and group trajectories using available repeated measures data. Final analyses will include multi-level linear mixed-effect models and generalized linear and latent mixed models (GLLAMM) of the primary and secondary outcome measures by combining the data across all time points (depending on the measurement scale of the dependent

of

variables). We will include covariates for variables such as age, gender, race/ethnicity, education,

ro

income, diagnosis and severity in these models as potential confounders or moderators. The statistical

-p

evaluation of the coefficient estimate for the MBSR intervention indicator (average difference between the groups across all time points) will be based on both the confidence interval and p -value approaches

re

described earlier (see Outcome Assessment) to assess the non-inferiority hypothesis in the context of

lP

generalized linear mixed effect models. The mixed models based on repeated measures data will also allow us to conduct exploratory subgroup analyses to test that the difference in the response rates

na

between the MBSR and the drug group is not statistically different by: a. gender (men vs. women), b.

ur

between different diagnosis groups (GAD, SAD, PD, Agoraphobia) and c. symptom severity (low vs high),

3. Discussion

Jo

as defined by the CGI-S score.

This study will examine the comparative effectiveness of MBSR with the antidepressant, escitalopram for patients who meet DSM-5 criteria on structured clinical interview for a primary anxiety disorder. The non-inferiority design will allow us to determine whether this relatively new treatment, MBSR, is clinically equivalent to a standard first line treatment, an antidepressant. Although mindfulness meditation has exploded in popularity, there is no evidence yet available to help providers and patients understand how its effect compares to standard treatments for anxiety such as pharmacotherapy with

Journal Pre-proof an SSRI. A non-inferiority design is the best way to answer the question whether two active treatments are comparable to each other; specifically, whether MBSR is equivalent (not inferior) to the drug escitalopram will be examined. This design also allows us to directly compare treatment-associated side effects, quality of life, sleep quality, and other variables.

Meditation training has seen an exponential growth in popularity in the general public, as illustrated by

of

results from the NIH National Health Interview Survey finding that 18 million adults in the US have now

ro

tried meditation [73]. However, research on mindfulness meditation has been criticized, especially

-p

concerning study methodology, external validity and comparison with known treatments. For example, a large review and meta-analysis prepared for the Agency for Healthcare Research and Quality (AHRQ)

re

stated that, “Firm conclusions on the effects of meditation practices in healthcare cannot be drawn

lP

based on the available evidence…special attention should be paid to developing studies that provide a more accurate assessment of the efficacy and effectiveness of meditation practices, both against

na

standard therapies and against each other” [74]. If mindfulness meditation was just as effective and

ur

well-tolerated as SSRI medication, this would support insurance reimbursement and wider

Jo

implementation of mindfulness meditation treatments across healthcare domains.

Although there is a clear need to compare Mindfulness-Based Interventions to standard therapies such as SSRI antidepressants, this type of study design also has some inherent challenges. For example, in order to participate, study participants must be willing to be randomized to one of two very different treatments. Many patients have a strong personal or philosophical partiality for either mindfulness training or drug treatment. A strong patient preference combined with a lack of a preference match upon randomization may result in patient choosing to withdraw from the study, whether they inform the investigators of this reason or not. Therefore, we will strive to find and enroll patients who are open-

Journal Pre-proof minded to both treatments and train all study staff to assure potential participants understand fully the nature of the study design and are encouraged to adhere to the assigned treatment long enough to determine if it is tolerable and effective for them or not.

A second challenge is that the format and time commitment of the two treatments are quite different; much more time is spent doing treatment-related activities in the MBSR class than in the drug treatment

of

group. This difference in time spent could potentially lead to an expectancy bias, as patients in one

ro

group expend more effort and have more time with providers, and therefore may have a more positiv e

-p

expectation, than the other. Alternately, if scheduling difficulties emerge for patients over the treatment course, group MBSR classes delivered on a fixed schedule with homework may be less

re

accommodating than continuing medication with a prescriber, making adherence to a medication

lP

treatment easier. Yet, there is no way to balance the contact time spent with providers, or other inherent treatment delivery differences without creating contrived interventions which deviate wildly

na

from what is actually available. Therefore, we are using a comparative effectiveness approach, and

ur

utilize treatment formats for both interventions as they are usually delivered in general practice. This

Jo

will allow conclusions about the treatment effectiveness that includes the se aspects inherent in their delivery (e.g., group vs individual format, time commitment, flexibility for scheduling etc).

Our rigorous study approach was designed to improve on study methodology of Mindfulness -based Interventions, given complaints about the quality of some prior research. Several features are in place to improve rigor and minimize bias. First, this is a randomized, well-powered study with a goal of 368 enrolled to assure confidence in study conclusions. Second, although we cannot blin d participants to the treatment they are receiving, to minimize bias we utilize blinded clinician independent evaluators who are uniformly trained to do standardized clinical assessments of anxiety symptoms, and undergo

Journal Pre-proof regular cross-site rating supervision and adherence training to enhance reliability and minimize site differences. Third, we utilize the same instruments for clinical symptoms that are considered standard by the Federal Drug Administration when evaluating drug trials for anxiety disorders, assuring scales are all well validated and allow comparison with existing anxiety disorder treatment literature. Finally, we actively assess adverse events (side effects) using the standardized approach for drug trials for both arms, given the complaints that meditation research often fails to assess adverse events adequately

ro

of

[75].

-p

This study will also enable secondary examination of several different constructs related to anxiety disorders, in addition to anxiety symptom frequency and intensity, to better understand the

re

comparability of a range of effects of these two very different treatments (see Table 2). For example, a

lP

well validated self-report measure of sleep quality, a common problem in anxiety disorders, is assessed. In addition, functional measures critical to patients such as work performance will be measured, as

na

anxiety disorders have been associated with reduced labor force participation as well as impaired work

ur

performance; in the long term, anxiety is also associated with degraded employment trajectories [76].

Jo

Anxiety disorders have also been shown to be predictive of absenteeism, a common measure of missed work relative to work expectations [77]. We will also be able to examine whether there are subgroups for which one treatment works better than another, and to detect predictors of tre atment success.

In summary, this study was funded by PCORI and designed to rigorously answer questions important to the treatment of patients with anxiety disorders. Specifically, this study will provide important information about how MBSR compares to a first-line standard treatment with an antidepressant. As of now, there is no information to help clinicians advise patients with anxiety disorders on whether MBSR or other mindfulness-based interventions are treatments that are as effective, or not inferi or to,

Journal Pre-proof medication treatments, or how MBSR compares to medication treatment on other variables such as tolerability and co-occurring symptoms. If this study finds that MBSR is not inferior to escitalopram, clinicians and patients can feel more confident about making this treatment choice, and healthcare insurance companies could consider including MBSR as a reasonable, covered first line treatment strategy for anxiety disorders.

of

Funding:

ro

This work was supported by the Patient-Centered Outcomes Research Institute [PCORI/CER-2017C1-

-p

6522]. The statements in this work are solely the responsibility of the authors and do not necessarily

lP

Governors or Methodology Committee.

re

represent the views of the Patient-Centered Outcomes Research Institute (PCORI), its Board of

na

References

ur

[1] Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 617-627.

Jo

[2] National Comorbidity Survey. In:

[3] Ormel J, VonKorff M, Ustun TB, Pini S, Korten A, Oldehinkel T Common mental disorders and disability across cultures. Results from the WHO Collaborative Study on Psychological Problems in General Health Care. JAMA 1994; 272: 1741-1748. [4] Nepon J, Belik S, Bolton J, Sareen J The relationship between anxiety disorders and suicide attempts: findings from the National Epidemiologic Survey on Alcohol and Related Conditions. Depress Anxiety 2010; 27: 791-798. [5] Bandelow B, Reitt M, Röver C, Michaelis S, Görlich Y, Wedekind D Efficacy of treatments for anxiety disorders: a meta-analysis. Int Clin Psychopharmacol 2015; 30: 183-192. [6] Farach FJ, Pruitt LD, Jun JJ, Jerud AB, Zoellner LA, Roy-Byrne P Pharmacological treatment of anxiety disorders: current treatments and future directions. J Anxiety Disord 2012; 26: 833-843.

Journal Pre-proof [7] Locke AB, Kirst N, Shultz CG Diagnosis and management of generalized anxiety disorder and panic disorder in adults. Am Fam Physician 2015; 91: 617-624. [8] Pollack MH, Otto MW, Roy-Byrne P, Coplan JD, Rothbaum BO, Simon NM, Gorman JM Novel treatment approaches for refractory anxiety disorders. Depress Anxiety 2008; 25: 467-476. [9] Givens JL, Datto CJ, Ruckdeschel K, Knott K, Zubritsky C, Oslin DW, Nyshadham S, Vanguri P, Barg FK Older patients' aversion to antidepressants. A qualitative study. J Gen Intern Med 2006; 21: 146-151. [10] Mitchell AJ, Selmes T Why don't patients take their medicine? Reasons and solutions in psychiatry. Advances in Psychiatric Treatment 2007; 13: 336-346.

of

[11] Priest RG, Vize C, Roberts A, Roberts M, Tylee A Lay people's attitudes to treatment of depression: results of opinion poll for Defeat Depression Campaign just before its launch. BMJ 1996; 313: 858-859.

-p

ro

[12] Mullins CD, Shaya FT, Meng F, Wang J, Bron MS Comparison of first refill rates among users of sertraline, paroxetine, and citalopram. Clin Ther 2006; 28: 29-305; discussion 296.

re

[13] Shafran R, Clark DM, Fairburn CG, Arntz A, Barlow DH, Ehlers A, Freeston M, Garety PA, Hollon SD, Ost LG, Salkovskis PM, Williams JMG, Wilson GT Mind the gap: Improving the dissemination of CBT. Behav Res Ther 2009; 47: 902-909.

lP

[14] Issakidis C, Andrews G Pretreatment attrition and dropout in an outpatient clinic for anxiety disorders. Acta Psychiatr Scand 2004; 109: 426-433.

na

[15] Corrigan PW, Druss BG, Perlick DA The Impact of Mental Illness Stigma on Seeking and Participating in Mental Health Care. Psychol Sci Public Interest 2014; 15: 37-70.

Jo

ur

[16] Mojtabai R, Olfson M, Sampson NA, Jin R, Druss B, Wang PS, Well s KB, Pincus HA, Kessler RC Barriers to mental health treatment: results from the National Comorbidity Survey Replication. Psychol Med 2011; 41: 1751-1761. [17] Stringer KL, Baker EH Stigma as a Barrier to Substance Abuse Treatment Among Those With Unmet Need: An Analysis of Parenthood and Marital Status. J Fam Issues 2018; 39: 3-27. [18] Goyal M, Singh S, Sibinga EMS, Gould NF, Rowland-Seymour A, Sharma R, Berger Z, Sleicher D, Maron DD, Shihab HM, Ranasinghe PD, Linn S, Saha S, Bass EB, Haythornthwaite JA Meditation programs for psychological stress and well-being: a systematic review and meta-analysis. JAMA Intern Med 2014; 174: 357-368. [19] Kang Y, Gruber J, Gray JR Mindfulness and De-Automatization. Emotion Review 2013; 5: 192-201. [20] John Kabat-Zinn (1990) Full Catastrophe Living: Using the Wisdom of Your Body and Mind to Face Stress, Pain, and Illness. Bantam Dell

Journal Pre-proof [21] Kabat-Zinn J, Massion AO, Kristeller J, Peterson LG, Fletcher KE, Pbert L, Lenderking WR, Santorelli SF Effectiveness of a meditation-based stress reduction program in the treatment of anxiety disorders. Am J Psychiatry 1992; 149: 936-943. [22] Kabat‐Zinn J Mindfulness‐Based Interventions in Context: Past, Present, and Future. Clinical Psychology: Science and Practice 2003; 10: 144-156. [23] Vøllestad J, Sivertsen B, Nielsen GH Mindfulness-based stress reduction for patients with anxiety disorders: evaluation in a randomized controlled trial. Behav Res Ther 2011; 49: 281-288.

of

[24] Evans S, Ferrando S, Findler M, Stowell C, Smart C, Haglin D Mindfulness-based cognitive therapy for generalized anxiety disorder. J Anxiety Disord 2008; 22: 716-721.

ro

[25] Hoge EA, Bui E, Marques L, Metcalf CA, Morris LK, Robinaugh DJ, Worthington JJ, Pollack MH, Simon NM Randomized controlled trial of mindfulness meditation for generalized anxiety disorder: effects on anxiety and stress reactivity. J Clin Psychiatry 2013; 74: 786-792.

re

-p

[26] American Psychiatric Association., American Psychiatric Association.,DSM-5 Task Force., (2013) Diagnostic and statistical manual of mental disorders : DSM-5. American Psychiatric Association, Arlington, VA

lP

[27] Stahl SM, Gergel I, Li D Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2003; 64: 1322-1327.

na

[28] Davidson JRT, Bose A, Korotzer A, Zheng H Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, flexible-dose study. Depress Anxiety 2004; 19: 234-240.

ur

[29] Stein DJ, Andersen EW, Lader M Escitalopram versus paroxetine for social anxiety disorder: an analysis of efficacy for different symptom dimensions. Eur Neuropsychopharmacol 2006; 16: 33-38.

Jo

[30] Worthington JJ, Kinrys G, Wygant LE, Pollack MH Aripiprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients. Int Clin Psychopharmacol 2005; 20: 9-11. [31] Varia I, Rauscher F Treatment of generalized anxiety disorder with citalopram. Int Clin Psychopharmacol 2002; 17: 103-107. [32] Guy W .ECDEU assessment manual for psychopharmacology1976; [33] Zaider TI, Heimberg RG, Fresco DM, Schneier FR, Liebowitz MR Evaluation of the clinical global impression scale among individuals with social anxiety disorder. Psychol Med 2003; 33: 611-622. [34] Hamilton M The assessment of anxiety states by rating. Br J Med Psychol 1959; 32: 50-55. [35] Shear MK, Vander Bilt J, Rucci P, Endicott J, Lydiard B, Otto MW, Pollack MH, Chandler L, Williams J, Ali A, Frank DM Reliability and validity of a structured interview guide for the Hami lton Anxiety Rating Scale (SIGH-A). Depress Anxiety 2001; 13: 166-178.

Journal Pre-proof [36] Shear MK, Brown TA, Barlow DH, Money R, Sholomskas DE, Woods SW, Gorman JM, Papp LA Multicenter collaborative panic disorder severity scale. Am J Psychiatry 1997; 154: 1571-1575. [37] Heimberg RG, Horner KJ, Juster HR, Safren SA, Brown EJ, Schneier FR, Liebowitz MR Psychometric properties of the Liebowitz Social Anxiety Scale. Psychol Med 1999; 29: 199-212. [38] Bragdon LB, Diefenbach GJ, Hannan S, Tolin DF Psychometric properties of the Overall Anxiety Severity and Impairment Scale (OASIS) among psychiatric outpatients. J Affect Disord 2016; 201: 112115.

of

[39] Moore SA, Welch SS, Michonski J, Poquiz J, Osborne TL, Sayrs J, Spanos A Psychometric evaluation of the Overall Anxiety Severity And Impairment Scale (OASIS) in individuals seeking outpatient specialty treatment for anxiety-related disorders. J Affect Disord 2015; 175: 463-470.

ro

[40] Norman SB, Cissell SH, Means-Christensen A, Stein MB Development and validation of an Overall Anxiety Severity And Impairment Scale (OASIS). Depress Anxiety 2006; 23: 245-249.

re

-p

[41] Muntingh A, van dF, van Marwijk H, Spinhoven P, Assendelft W, de Waal M, Adèr H, van Balkom A Effectiveness of collaborative stepped care for anxiety disorders in primary care: a pragmatic cluster randomised controlled trial. Psychother Psychosom 2014; 83: 37-44.

lP

[42] Roy-Byrne P, Craske MG, Sullivan G, Rose RD, Edlund MJ, Lang AJ, Bystritsky A, Welch SS, Chavira DA, Golinelli D, Campbell-Sills L, Sherbourne CD, Stein MB Delivery of evidence-based treatment for multiple anxiety disorders in primary care: a randomized controlled trial. JAMA 2010; 303: 1921-1928.

na

[43] Meyer TJ, Miller ML, Metzger RL, Borkovec TD Development and validation of the Penn State Worry Questionnaire. Behav Res Ther 1990; 28: 487-495.

ur

[44] Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989; 28: 193-213.

Jo

[45] Yu L, Buysse DJ, Germain A, Moul DE, Stover A, Dodds NE, Johnston KL, Pilkonis PA Development of short forms from the PROMIS sleep disturbance and Sleep-Related Impairment item banks. Behav Sleep Med 2011; 10: 6-24. [46] Attkisson CC, Zwick R The client satisfaction questionnaire. Psychometric properties and correlations with service utilization and psychotherapy outcome. Eval Program Plann 1982; 5: 233-237. [47] Holt C, H. The Reaction to Treatment Questionnaire: Measuring treatment credibility and outcome expectancies. The Behavior Therapist 1990;13(21-214): p. 222. [48] Beck AT, Epstein N, Brown G, Steer RA An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988; 56: 893-897. [49] Pilkonis PA, Choi SW, Reise SP, Stover AM, Riley WT, Cella D Item banks for measuring emotional distress from the Patient-Reported Outcomes Measurement Information System (PROMIS®): depression, anxiety, and anger. Assessment 2011; 18: 263-283.

Journal Pre-proof [50] Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz JC, Ninan PT, Kornstein S, Manber R, Thase ME, Kocsis JH, Keller MB The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry 2003; 54: 573-583. [51] Hahn EA, Devellis RF, Bode RK, Garcia SF, Castel LD, Eisen SV, Bosworth HB, Heinemann AW, Rothrock N, Cella D Measuring social health in the patient-reported outcomes measurement information system (PROMIS): item bank development and testing. Qual Life Res 2010; 19: 1035-1044.

of

[52] Kessler RC, Barber C, Beck A, Berglund P, Cleary PD, McKenas D, Pronk N, Simon G, Stang P, Ustun TB, Wang P The World Health Organization Health and Work Performance Questionnaire (HPQ). J Occup Environ Med 2003; 45: 156-174.

ro

[53] Kessler RC, Ames M, Hymel PA, Loeppke R, McKenas DK, Richling DE, Stang PE, Ustun TB Using the World Health Organization Health and Work Performance Questionnaire (HPQ) to evaluate the indirect workplace costs of illness. J Occup Environ Med 2004; 46: 23.

re

-p

[54] Kaufman EA, Xia M, Fosco G, Yaptangco M, Skidmore CR, Crowell SE The Difficulties in Emotion Regulation Scale Short Form (DERS-SF): Validation and replication in adolescent and adult samples. Journal of Psychopathology and Behavioral Assessment 2016; 38: 443-455.

lP

[55] Bernstein DP, Ahluvalia T, Pogge D, Handelsman L Validity of the Childhood Trauma Questionnaire in an adolescent psychiatric population. J Am Acad Child Adolesc Psychiatry 1997; 36: 340-348.

na

[56] Gray MJ, Litz BT, Hsu JL, Lombardo TW Psychometric properties of the life events checklist. Assessment 2004; 11: 330-341.

ur

[57] Haynes RB, Taylor DW, Sackett DL, Gibson ES, Bernholz CD, Mukherjee J Can simple clinical measurements detect patient noncompliance?. Hypertension 1980; 2: 757-764.

Jo

[58] Shear MK, Reynolds CF, Simon NM, Zisook S, Wang Y, Mauro C, Duan N, Lebowitz B, Skritskaya N Optimizing Treatment of Complicated Grief: A Randomized Clinical Trial. JAMA Psychiatry 2016; 73: 685694. [59] Jones B, Jarvis P, Lewis JA, Ebbutt AF Trials to assess equivalence: the importance of rigorous methods. BMJ 1996; 313: 36-39. [60] Authorized!Curriculum!Guide! .Mindfulness-Based!Stress!Reduction!(MBSR)! [61] Muller S, Stice E Moderators of the intervention effects for a dissonance-based eating disorder prevention program; results from an amalgam of three randomized trials. Behav Res Ther 2013; 51: 128133. [62] Rohde P, Beevers CG, Stice E, O'Neil K Major and minor depression in female adolescents: onset, course, symptom presentation, and demographic associations. J Clin Psychol 2009; 65: 1339-1349.

Journal Pre-proof [63] Bryant RA, Brooks R, Silove D, Creamer M, O'Donnell M, McFarlane AC Peritraumatic dissociation mediates the relationship between acute panic and chronic posttraumatic stress disorder. Behav Res Ther 2011; 49: 346-351. [64] Create a blocked randomisation list(2019) . In: . https://www.sealedenvelope.com/simplerandomiser/v1/lists https://www.sealedenvelope.com/simple-randomiser/v1/lists https://www.sealedenvelope.com/simple-randomiser/v1/lists. Accessed 30 2019 [65] 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. J Biomed Inform 2009; 42: 377-381.

ro

of

[66] Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O'Neal L, McLeod L, Delacqua G, Delacqua F, Kirby J, Duda SN The REDCap consortium: Building an international community of software platform partners. J Biomed Inform 2019; 95: 103208.

-p

[67] Steinert C, Munder T, Rabung S, Hoyer J, Leichsenring F Psychodynamic Therapy: As Efficacious as Other Empirically Supported Treatments? A Meta-Analysis Testing Equivalence of Outcomes. Am J Psychiatry 2017; 174: 943-953.

lP

re

[68] Norton PJ, Barrera TL Transdiagnostic versus diagnosis-specific cbt for anxiety disorders: a preliminary randomized controlled noninferiority trial. Depress Anxiety 2012; 29: 874-882.

na

[69] Bandelow B, Baldwin DS, Dolberg OT, Andersen HF, Stein DJ What is the threshold for symptomatic response and remission for major depressive disorder, panic disorder, social anxiety disorder, and generalized anxiety disorder?. J Clin Psychiatry 2006; 67: 1428-1434.

ur

[70] Hermes EDA, Sokoloff D, Stroup TS, Rosenheck RA Minimum clinically important difference in the Positive and Negative Syndrome Scale with data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). J Clin Psychiatry 2012; 73: 526-532.

Jo

[71] Falissard B, Sapin C, Loze J, Landsberg W, Hansen K Defining the minimal clinically important difference (MCID) of the Heinrichs-carpenter quality of life scale (QLS). Int J Methods Psychiatr Res 2016; 25: 101-111. [72] Rothmann MD, W. Design and analysis of non-inferiority trials. Chapman & Hall/CRC 2012; [73] Clarke P, Macleod C, Shirazee N Prepared for the worst: readiness to acquire threat bias and susceptibility to elevate trait anxiety. Emotion 2008; 8: 47-57. [74] Ospina MB, Bond K, Karkhaneh M, Tjosvold L, Vandermeer B, Liang Y, Bialy L, Hooton N, Buscemi N, Dryden DM, Klassen TP Meditation practices for health: state of the research. Evid Rep Technol Assess (Full Rep) 2007; (155): 1-263. [75] Van Dam NT, van Vugt MK, Vago DR, Schmalzl L, Saron CD, Olendzki A, Meissner T, Lazar SW, Kerr CE, Gorchov J, Fox KCR, Field BA, Britton WB, Brefczynski-Lewis J, Meyer DE Mind the Hype: A Critical

Journal Pre-proof Evaluation and Prescriptive Agenda for Research on Mindfulness and Meditation. Perspect Psychol Sci 2018; 13: 36-61. [76] Waghorn G, Chant D, White P, Whiteford H Disability, employment and work performance among people with ICD-10 anxiety disorders. Aust N Z J Psychiatry 2005; 39: 55-66.

Jo

ur

na

lP

re

-p

ro

of

[77] Bailey SK, Haggarty J, Kelly S Global absenteeism and presenteeism in mental health patients referred through primary care. Work 2015; 53: 399-408.