Japan Unified Protocol Clinical Trial for Depressive and Anxiety Disorders (JUNP study): study protocol for a randomized controlled trial
Ito et al. BMC Psychiatry
Japan Unified Protocol Clinical Trial for Depressive and Anxiety Disorders (JUNP study): study protocol for a randomized controlled trial
Masaya Ito 0
Masaru Horikoshi 0
Noriko Kato 0
Yuki Oe 0
Mitsuhiro Miyamae 0
0 National Center for Cognitive Behavior Therapy and Research, National Center of Neurology and Psychiatry , Ogawa Higashi 4-1-1, Kodaira, Tokyo 187-8511 , Japan
Background: The unified protocol for the transdiagnostic treatment of emotional disorders is a promising treatment approach that could be applicable to a broad range of mental disorders, including depressive, anxiety, trauma-related, and obsessive-compulsive disorders. However, no randomized controlled trial has been conducted to verify the efficacy of the unified protocol on the heterogeneous clinical population with depressive and anxiety disorders. Methods/design: The trial was designed as a single-center, assessor-blinded, randomized, 20-week, parallel-group superiority study in order to compare the efficacy of the combination of unified protocol and treatment-as-usual versus waiting-list with treatment-as-usual for patients with depressive and/or anxiety disorders. The primary outcome was depression at 21 weeks, assessed by the 17-item version of the GRID-Hamilton Rating Scale for Depression. Estimated minimum sample size was 27 participants in each group. We will also examine the treatment mechanisms, treatment processes, and neuropsychological correlates. Discussion: The results of this study will clarify the efficacy of the unified protocol for depressive and anxiety disorders, and the treatment mechanism, process, and neurological correlates for the effectiveness of the unified protocol. If its efficacy can be confirmed, the unified protocol may be of high clinical value for Japan, a country in which cognitive behavioral treatment has not yet been widely adopted. Trial Registration: ClinicalTrials.gov NCT02003261 (registered on December 2, 2013)
Anxiety disorder; Depressive disorder; Emotion; Transdiagnostic; Unified protocol; Randomized controlled trial
Transdiagnostic treatment for emotional disorders
Emotion is one of the biggest sources of human distress.
Symptoms of emotional difficulties, in particular
depression and anxiety, are among the most common
symptoms observed in psychiatric and clinical-psychological
settings. Lifetime prevalence of depressive and anxiety
disorders is estimated at 6.3 and 6.7 % in Japan [
16.6 and 28.8 % each in the U.S. [
]. Depressive and
anxiety disorders were respectively ranked as the
secondand ninth-largest causes of global years lived with
disability in 2013 [
], and depressive disorders in
particular are predicted to become the first cause of disease
burden by 2030 [
]. The economic burden of depressive
disorder has been enormous ($11–18 billion in Japan
and $173–211 billion in the U.S. in 2010) [
Similarly, the economic burden of anxiety disorders was
reported as $20.5 billion in Japan and $42.3 billion in the
U.S. in 1990 [
]; and it should be noted that this figure
for anxiety disorders in the U.S. could be greatly
underestimated, because it did not consider long-term
opportunity cost or the cost associated with comorbidity, which
could bring total costs to the U.S. economy as a result of
anxiety disorder to an estimated $100 billion .
Depressive and anxiety disorders, which are commonly
comorbid, are both conceptualized as disorders of
]. Accumulated findings show shared
psychopathology, etiology, neurobiological characteristics, and
similar cognitive-affective, interpersonal, and
behavioralmaintenance factors commonly observed among
depression, anxiety, and trauma-related, obsessive-compulsive,
and other emotion-related disorders [
findings leads to the idea of transdiagnostic conceptualization
of these disorders [
]; the term often used is
“emotional disorders” [
]. This broad category includes,
at minimum, the Diagnostic and Statistical Manual
of Mental Disorders 5th edition (DSM-5) categories
of depressive disorders, anxiety disorders,
traumarelated disorders, and obsessive-compulsive disorders
Cognitive behavioral therapy (CBT) has been shown
to be an efficacious treatment for emotional disorders
], and is recommended by treatment guidelines
as a high-intensity treatments for depressive and anxiety
]. Most CBT protocols have been
developed to treat one specific disorder. Recently, however, the
accumulated evidence of shared psychopathology has
influenced not only the conceptualization of emotional
disorders, but also their treatment. Transdiagnostic
psychological treatment has been developed to treat
depression, anxiety, and trauma-related, obsessive-compulsive,
and other emotion-related disorders by targeting their
shared psychopathology [
11, 29, 30
transdiagnostic approach has several potential strengths over the
disorder-specific treatment: applicability to diverse
disorders with comorbidity, simplification of treatment
models for diverse emotional disorders, and ease of
learning for novice therapists [
Though the transdiagnostic approach for emotional
disorders has been proposed only relatively recently,
uncontrolled/nonrandomized and randomized controlled
trials (RCTs) have already been mounted to investigate
its efficacy and feasibility. Transdiagnostic psychological
treatments vary in format (individual, group, internet),
theoretical orientation (transdiagnostic cognitive behavior
therapy, transdiagnostic mindfulness- and
acceptancebased treatments), strictness or flexibility of the
application of the protocol to individual patients, and range of
disorders covered (anxiety disorders only, both anxiety
and depressive disorders). The latest meta-analysis has
identified 47 clinical trials (31 RCTs) on the
transdiagnostic approach, with a total of 3705 participants. That study
reported the cumulative effect sizes of transdiagnostic
CBT on self-report measures among patients with
diagnosis of depressive and/or anxiety disorders, in
comparison to control groups (waiting-list, supportive
counseling, psychoeducation, treatment-as-usual, etc.):
medium for anxiety (n = 24, g = .65, 95 % CI .51–.79),
large for depression (n = 22, g = .80, 95 % CI .62–.98),
and medium for quality of life (n = 13, g = .46, 95 % CI
Despite the promise of transdiagnostic treatment,
there are several limitations to it in its current state.
First, the evidence of its efficacy is still inconclusive,
because most existing trials have had a high risk of bias
and because there is significant heterogeneity between
the trials [
]. Newby et al. reported that only seven
out of 31 RCTs were rated low risk for bias in all of five
criteria (namely, random sequence, concealment,
blinding of assessors, incomplete outcome data, selective
reporting); and clinical trials for transdiagnostic
treatment on anxiety and depression in comparison to
control group(s) have been shown to have moderate
heterogeneity (I2 = 51–83 %) [
]. More importantly,
the latest meta-analysis did not examine the results for
clinician-rated measures, because only 13 out of 31
RCTs reported an independent assessor rating for a
structured clinical interview, and the interviews used
varied from trial to trial. Second, no RCT for
transdiagnostic CBT has been conducted in non-Western
countries, which means that transdiagnostic treatment
cannot yet be regarded as a transcultural treatment [
Third, only eight out of 31 RCTs have included both
depressive and anxiety disorders, which are the putative
populations for transdiagnostic treatment, which means
that, many trials included a sub-category of anxiety
disorders only. It is necessary to include transdiagnostic
clinical populations in clinical trials to examine the
external validity (i.e., generalizability) of the findings.
Fourth, few studies have examined the putative
treatment mechanism that rationalizes the treatment as
transdiagnostic (e.g., neuroticism, emotion regulation)
]. Fifth, no study has examined the
neuropsychological underpinnings of transdiagnostic treatment.
Unified protocol for the transdiagnostic treatment of emotional disorders (UP)
The UP is one of the most empirically well-supported
transdiagnostic psychological treatments [
was developed based on the recognition of diagnostic
overlap across emotional disorders (i.e., comorbidity),
non-specificity of treatment response to comorbid
symptoms by diagnosis-specific treatments, latent structure of
emotional disorders (e.g., negative affectivity), etiology,
and commonality of findings of affective neuroscience on
emotional disorders (e.g., reductions in connectivity
between the amygdala and ventromedial prefrontal cortex)
]. Evidence relating to individual UP has been
reported in various forms: theoretical paper [
report , pilot clinical trial [
], and RCT with
]. Moreover, the feasibility of UP has been extended
to individual and group formats for depressive and anxiety
], individual format for bipolar disorder [
borderline personality disorder [
], and emotional
disorders in adolescents [
The existing evidence, however, should be regarded as
preliminary at best [
]. Findings by RCT to date are
limited to one trial each for individual- and
groupformat UP, with small sample sizes [
there is clear lack of evidence regarding UP efficacy for
depressive disorders and for Asian populations. Previous
pilot studies for individual UP have examined only three
patients with the principal diagnosis of major depressive
], and there is no RCT of UP efficacy for
depressive disorders. Comparative clinical trials have
been limited to one in the U.S. and one in Brazil .
Thus, we aimed to examine the efficacy of UP for
Japanese patients with either or both depressive and
anxiety disorders. Though such a broad category of
participants constitutes a heterogeneous clinical population
in terms of the standard diagnostic criteria (i.e., DSM-5
or International Classification of Diseases 10th revision;
ICD-10) and leads to some methodological challenges
unique to transdiagnostic treatment [
nevertheless selected this population because the unified protocol
was originally developed to treat heterogeneous clinical
Primary hypothesis and objectives
We hypothesize that the addition of the unified protocol
to patients’ usual treatment by psychiatrists would be
more efficacious in comparison to waiting-list for UP
with usual treatment for the reduction of emotional
symptoms among patients with depressive and anxiety
disorders in a Japanese outpatient clinical setting.
Treatment mechanism and process for enhancing the effectiveness of implementation of unified protocol
Though this clinical trial is mounted primarily to test
the efficacy of the unified protocol on the primary
outcome (i.e., emotional symptoms), it is also important to
examine the treatment mechanism, process, and
neurological correlates [
]. Furthermore, because the UP
was developed based on the findings on the shared
underlying process of psychopathology across a wide
range of emotional disorders (depressive, anxiety,
traumarelated, and obsessive-compulsive disorders), it is
important to examine how this shared process actually relates to
the outcome of the treatment. These examinations are
expected to not only allow theoretical refinement of UP, but
also sharpen its clinical implementation. We focus on four
different variables to examine the treatment mechanism;
neuroticism, emotion regulation, emotion exposure, and
anxiety sensitivity. These variables are considered to be
transdiagnostic mediators/moderators of the treatment.
Neuroticism here refers to the shared aspects of
temperament commonly observed between depressive and anxiety
]. Deficits of emotion regulation are also
a putative transdiagnostic treatment mechanism of CBT
19, 34, 46
]: through UP, patients will learn to engage
adaptive emotion regulation and disengage maladaptive
emotion regulation. The core module of the unified
protocol is emotion exposure [
]; theoretically, the
other modules will be expected to function to maximize
the therapeutic effect of emotion exposure [
hence the patient’s ability to expose themselves to their
own emotion should be one of the key focuses in terms
of treatment mechanisms [
]. Finally, anxiety
sensitivity is regarded as the transdiagnostic process
affecting the (non) maintenance of emotional disorders .
The effects of psychotherapy depend on its process:
who delivers the protocol, how it is delivered, the degree
to which the patient understands the concept or
practices the skill, etc. [
47, 50, 51
]. Past studies suggest that
strict adherence to CBT protocols does not linearly
predict the treatment outcome [
]. Hence, it is not
enough to monitor adherence to the treatment protocol;
one must also assess various aspects of the
implementation or processes of the psychotherapy. In this clinical
trial, we will collect some of the most important process
measures regarding the implementation of the unified
protocol. These include treatment expectancy [
therapeutic relationship [
], homework compliance
], and patient comprehension of treatment
rationale. Examination of the relationships between these
process measures and treatment outcome is expected to
inform and help optimize the implementation of UP for
patients with emotional disorders.
Neurological correlates regarding the unified protocol
To the best of our knowledge, no study has yet examined
neurological change after the intervention of
transdiagnostic treatment; nevertheless, the existence of transdiagnostic
neurological commonalities across emotional disorders has
been suggested. Some researchers have developed the
transdiagnostic neural model [
] to reflect this. Recent
studies have been focused more on the similarity of neural
systems between depression and anxiety disorders, in
addition to the differences ; this focus is consistent with
the view taken by the Research Domain Criteria project of
the U.S. National Institute of Mental Health [
]. In fact,
neurobiological studies have shown some similarity in
changes from before to after CBT across emotional
]. Considering that UP is a transdiagnostic
treatment partly based on findings from the field of affective
], transdiagnostic change at the
neurological level is indeed expected across emotional disorders.
Moreover, recent investigation of the domain of
neuropsychological perspective has predicted treatment efficacy
using neurological measures; for example, Ball et al. [
showed that the random forest model using pre-treatment
neuroimaging data predicted treatment response of
generalized anxiety disorder and panic disorder patients with
good test characteristics. Hence, we will correct these
neuropsychological data as an ancillary study.
Trial design, randomization, and ethical aspects
This study is a single-center, assessor-blinded,
randomized, parallel-group superiority design with a target
sample of 54 patients with depressive or anxiety disorders.
Participant flow is depicted in Fig. 1. We will employ
central randomization using Allocation and Registration
Control System (ARCS) computer software, set up and
managed independently of the study by the Project
Management Office at the Keio Center for Clinical
Research. A random sequence will be generated using
minimization, with a ratio of 1:1 to balance stratified
factors (depressive vs. anxiety disorder). Allocation will
be implemented by the primary investigator or research
coordinator via internet using a laptop in front of the
eligible participant. This protocol has been reviewed
and approved by the institutional review board of the
(Japanese) National Center of Neurology and Psychiatry
(accepted on October 18, 2013; A2013-092). All
participants will give written informed consent to participation
in the study. This trial is registered within ClinicalTrials.
gov, number NCT02003261.
This single-site study has been conducted at the
National Center of Neurology and Psychiatry (NCNP)
Hospital in Tokyo; this is the national hospital
specializing in the research and treatment of psychiatric,
neurological, muscular, and developmental diseases in Japan.
The hospital provides mainly secondary or tertiary
inpatient and outpatient psychiatric treatments to
socioeconomically diverse Japanese populations. Most new
patients are referred to the NCNP Hospital because of
non-response on their part to their usual care in their
local clinic or hospital. Participants eligible for our pilot
study had a long history from the first onset of the
disorder (Mean months = 93.64, SD = 80.7) [
Treatment for depressive and anxiety disorders, usually
provided in the NCNP Hospital outpatient department, had
largely consisted of pharmacotherapy, supportive
therapy, or active monitoring. Totals of 1017 and 2138 CBT
sessions were respectively conducted in fiscal 2013 and
2014 at the hospital. In the Japanese medical setting, all
patients basically continue their usual treatment with
their treating psychiatrists when receiving any
psychosocial treatments at the same medical institute. In the
other words, the psychologist is not able to conduct any
intervention with patients without the permission or
direction of the treating psychiatrist. Along with the need
for medical monitoring and clinical management, this is
why all participants in both intervention and control
groups need to continue treatment-as-usual (TAU) even
if they are not pharmacologically prescribed. Japan’s
universal health insurance system allows every Japanese
resident to have access to any medical services at any
medical institution nationwide without a gatekeeper and
helps them pay incurred medical costs.
Participants need to fulfill all of the following inclusion
criteria and to not meet any of the following exclusion
criteria. We used DSM-IV criteria because the Japanese
version of the DSM-5 had not yet been finalized and
there was no structured method for diagnosing DSM-5
criteria (e.g., SCID-5) at the start of this trial.
1. No alcohol or substance use disorder in 6 months
prior to the baseline assessed by SCID-IV-TR.
2. No current manic episode or current schizophrenia
or other psychotic disorder at baseline assessed by
3. No serious suicidal ideation at baseline (GRID-HAMD
Item 3 symptom intensity is less than moderate).
4. No life-threatening, severe, or unstable physical
disorders or major cognitive deficits at baseline.
5. No evidence of inability to participate in half or
more of the intervention phase.
6. No structured psychotherapy at baseline.
7. Other relevant reason as determined by the
We compare the UP with TAU intervention group with
the waiting-list with TAU control group.
UP is an transdiagnostic cognitive behavior therapy for
emotional disorders [
]. Complete implementation
usually takes 12–18 weekly sessions of 50–60 min each.
Patient use the treatment workbook throughout the
], and practice newly learned
cognitivebehavioral skills in between sessions. In this study,
patients will receive approximately 16 face-to-face,
individual sessions (range: 9–20) within 20 weeks. The
therapist can shorten or lengthen needed sessions or intervals
(weekly or biweekly) in accordance with the patient’s level
of understanding or acquisition of the skills. Up to five
additional sessions during the follow-up period for the
intervention group will be allowed if the therapist and
patient deem it necessary and if the patient has not
completed all modules.
The unified protocol consists of one introductory
session and eight modules for learning transdiagnostic
cognitive behavioral skills: motivation enhancement,
psychoeducation of emotion, emotion awareness training,
cognitive reappraisal, emotion avoidance and
emotiondriven behavior, tolerance training for physical sensations,
emotion exposure, and relapse prevention (Table 1).
Details of this intervention are described in the therapist’s
guide to UP [
]. To be eligible for this clinical trial, a
therapist needs to be qualified as a clinical psychologist by
the Foundation of the Japanese Certification Board for
Clinical Psychologists or possess a Japanese physician’s
license, to have received adequate training using the
therapist’s guide for UP and the CBT treatment manual
published by the Japanese Ministry of Health, Labour and
Welfare (at least 10 h of workshops), and to sit in on or
listen to the full treatment course of at least two UP cases.
At the beginning of this trial, four therapists (two females;
clinical practice after certification of 4–6 years; experience
of UP cases, 3–8 cases) were registered as staff therapists.
Treatment adherence will be monitored by weekly
group supervision and assessed using the Treatment
Adherence Scale for UP. Two clinical psychologists
(MH, MI), who translated the UP workbook and
therapist guide, will supervise the study therapist. MH has
clinical experience of more than 20 years. (MI will also
serve as a staff therapist.) The Treatment Adherence
Scale was developed by the developer of the unified
protocol, and consists of 74 adherence items (12 for
initial session, four for motivation enhancement, nine for
psychoeducation, eight for emotion awareness training,
eight for cognitive reappraisal, 11 for emotion avoidance
and emotion-driven behavior, seven for tolerance of
physical sensations, eight for emotion exposure, seven
for relapse prevention). Items are rated according to
whether the intervention has been implemented or not
(Yes or No). To assess treatment adherence, we
randomly select one-fourth of each participant’s sessions.
The simple random sampling procedure was conducted
using the True Randomization process (www.random.org)
before the beginning of this clinical trial. The evaluation
was conducted by a therapist who did not serve as a staff
therapist for this study.
Though treatments for depressive and anxiety disorders
in Japanese medical settings have not been systematically
investigated, the majority seem to involve
pharmacotherapy, unsystematic supportive therapy, or clinical
monitoring by psychiatrists. The Japanese Society of Mood
Disorders has published treatment guidelines for Major
Depressive Disorders (MDDs) that recommend
pharmacotherapy for moderate or severe MDD patients and
pharmacotherapy and psychotherapy for mild MDD
]. However, there are no such treatment
guidelines for anxiety disorders specific to Japanese
clinicians. One study showed that Japanese psychiatrists tend
to choose pharmacotherapy for the first and second
instance of treatment of MDD [
], and the results of our
pilot study showed that almost all participants had
received pharmacotherapy [
]. Based on the knowledge,
we expected TAU for depressive and anxiety symptoms
to be mostly pharmacotherapy. For this clinical trial, we
defined TAU as any pharmacological or (non-systematic)
psychological intervention except for systematic
psychotherapy (e.g., any other type of cognitive behavioral
therapy) and electroconvulsive therapy. We considered that the
clinical success of participant’s treatment should be
prioritized over our research purpose. Hence, we will not restrict
any usual treatment by treating psychiatrists, including
change of dose or type of drug. If treating psychiatrists start
other systematic psychotherapy (e.g., another type of
cognitive behavioral therapy) or electroconvulsive therapy, the
patient will be excluded from the intervention in this study.
Content of TAU will be documented in case report form.
We set the assessment period at 43 weeks in order to
exploratorily examine the trajectory after treatment for
the intervention group. Participants assigned to the
control group will receive the unified protocol in addition to
TAU during the follow-up period (21–43 weeks). Data
including the 43-week assessment will be used to
exploratorily examine the persistence of the effect for the
intervention group as well as the immediate treatment
effect for the control group. There will be no treatment
restrictions on the intervention group in the follow-up
Any participant in the intervention group who meets
any of the discontinuation criteria will have their
intervention (UP) stopped. Where possible, subsequent
assessment will be conducted.
1. Participant request for discontinuation or participant
withdrawal of consent.
2. Inability to contact the participant for a month.
3. Difficulty continuing the intervention because of a
severe adverse event.
4. Difficulty continuing the intervention because of the
exacerbation of comorbid symptoms.
5. Participant proves after assignment not to fulfill the
6. The whole clinical trial is stopped.
7. Any other reason that the primary investigator,
therapist, and supervisor agree to warrants
We will assess several measures of outcome, treatment
mechanism, process, and neurological correlates. Most
assessments will be conducted at baseline (0 weeks),
10 weeks (mid assessment), 21 weeks (post assessment),
and 43 weeks (follow-up assessment). Table 2 shows the
list and schedule of assessments.
The primary outcome is change of depressive symptoms
over the intervention period as assessed by the 17-item
version of the semi-structured interview included in the
GRID–Hamilton Depression Rating Scale (GRID-HAMD)
]. GRID-HAMD employs a “grid” scoring system
using the dimensions of symptom intensity and symptom
frequency; higher scores indicate severer depressive
symptoms (range: 0–52). This interview instrument has been
reported to have excellent interrater reliability among
Japanese clinicians (intraclass correlation coefficient; ICC
= 0.95–0.99) [
], a finding borne out by our pilot study
(ICC = .974, 95%CI = .966–.980) [
]. Internal consistency
Eysenck Personality Questionnaire Revised-Short version, Neuroticism subscale P
IE assessment of independent evaluator, P patient self-report, T therapist self-report
was reported to be 0.78 [
]. The interview instrument’s
concurrent validity was demonstrated by high correlation
between item and total score per the structured interview
guide for HAMD [
]. We decided to use GRID-HAMD
to assess “emotional symptoms” because it assesses not
only depressive symptoms (depressed mood, guilt, suicide,
insomnia early, insomnia middle, insomnia late, work and
activities, psychomotor retardation, psychomotor
agitation, loss of appetite, loss of sexual interest, loss of weight,
and loss of insight) but also anxiety symptoms (psychic
and somatic anxiety, general somatic symptoms, and
hypochondriasis). Moreover, the GRID-HAMD is an
appropriate choice for our study because it is one of the
few depression rating measures that has been validated in
Japanese and utilized in many clinical trials in Japan
], making implementation of assessment more
straightforward. In our pilot study, we used GRID-HAMD
and the Structured Interviews Guide for Hamilton Rating
Scale for Anxiety (SIGH-A) as outcome measures. The
result showed the GRID-HAMD showed higher treatment
responsiveness than SIGH-A .
Secondary outcomes for treatment efficacy are severity of
anxiety assessed by SIGH-A, overall severity and
improvement rated by Clinical Global Impression, responder
status defined by 50 % or more baseline reduction in score
on GRID-HAMD, remission of symptom defined as less
than 8 on GRID-HAMD [
], and absence of met
psychiatric diagnoses as assessed by SCID-IV-TR at baseline.
These secondary measures are assessed at post-treatment
A semi-structured interview, SIGH-A includes 14 items
for anxiety symptoms [
]. Each anxiety-related item
is rated from 0 to 4 on the basis of frequency, degree of
distress, and symptom-related functional impairment
during the previous week. Higher scores indicate more severe
symptoms of anxiety (range: 0–56). Test–retest reliability
and interrater reliability were respectively reported as 0.89
(95 % CI 0.83–0.93) and 0.99 (95 % CI 0.98–0.99).
Concurrent and construct validity were demonstrated by high
correlation with the traditional-format Hamilton Anxiety
Rating Scale (r = 0.75–0.77) and equivalent correlations
with self-report measures in the traditional format .
Clinical Global Impression (CGI)
CGI is an overall clinician rating of the severity of
psychopathology (CGI-Severity; CGI-S) and improvement
of it (CGI-Improvement, CGI-I) [
]. These are rated
from 0 to 7 based on the assessor’s overall evaluation,
which incorporates all available information about a
patient’s history, psychosocial circumstances, symptoms,
behavior, and the impact of symptoms on the patient’s
ability to function [
]. In this study, essentially, the
independent evaluator assesses the same patient at
baseline, mid, post, and follow-up (0, 10, 21, and 43 weeks).
Hence, the evaluator’s overall impression of longitudinal
change will be reflected in the CGI-I rating.
Global Assessment of Functioning (GAF)
The GAF is a single measure for evaluating degree of
global functioning, which is used for Axis V evaluation
in DSM-IV [
]. A score is assigned from 0–100, based
on symptom severity and the effects on social,
occupational, and/or educational functioning.
Structural clinical interview for DSM-IV-TR axis I disorders (SCID-IV-TR)
SCID-IV-TR is a semi-structured interview used to asses
the diagnostic status of DSM-IV-TR Axis I disorders
]. We will administer modules A (Mood Episodes), B
(Psychotic Symptoms), D (Mood Disorders), E (Substance
Use Disorders), and F (Anxiety Disorders) at baseline to
evaluate patients according to the inclusion and exclusion
criteria. At post-intervention and follow-up, the
independent evaluator administers part of each module to examine
the presence or absence of the diagnoses met at baseline
assessment. The Japanese version of SCID-IV-TR has been
utilized in many clinical trials since its publication.
Overall Anxiety Severity and Impairment Scale (OASIS)
OASIS assesses the symptom of global anxiety by severity
and impairment, using a (five-point) Likert scale [
Items cover anxiety frequency, severity, and influence on
symptoms. OASIS’s reliability and validity have been
reported among U.S. and Japanese clinical and
nonclinical populations [
Overall Depression Severity and Impairment Scale (ODSIS)
ODSIS assesses the symptom of depression in terms of
severity and impairment [
], on a (five-point) Likert
scale. Similarly to OASIS, this scale assesses depression
frequency, severity, and related impairment. Two
studies suggest its reliability and validity among U.S. and
Japanese clinical and non-clinical populations,
In accordance with the diagnosis by SCID-IV-TR at
baseline, each patient conducted the self-report
measures to assess symptoms of met diagnoses. We used the
Beck Depression Inventory-II (BDI-II) for Depressive
], Panic Disorder Severity Scale (PDSS)
for Panic Disorder with or without Agoraphobia ,
Liebowitz Social Anxiety Scale (LSAS) for Social Anxiety
], Penn State Worry Questionnaire (PSWQ)
for Generalized Anxiety Disorder [
Obsessive Compulsive Scale (Y-BOCS) for Obsessive
Compulsive Disorder [
], Impact of Event Scale-Revised
(IES-R) for Posttraumatic Stress Disorder [
Fear Questionnaire (FQ) for Agoraphobia without
history of Panic Disorder . All scales except for FQ have
had their reliability and validity tested.
Euro Qol (EQ-5D-3L)
Patient quality of life is assessed by Euro Qol
]. This scale consists of five items in the
domain of quality of life (mobility, self-care, usual
activities, pain/discomfort, and anxiety/depression) and one
visual analogue scale regarding overall health status,
ranging from 0 (worst imaginable health state) to 100 (best
imaginable health state). Quality-adjusted life years will
be calculated using the Japanese EQ-5D tariff .
Sheehan Disability Scale (SDS)
SDS is used to assess overall functional impairment
]. This scale consists of three domains of
function (work/school, social life, and family life/home
responsibilities). These items are rated on a 10-point
visual analogue scale (from “not at all” to “extremely”).
Its reliability and validity for a Japanese population has
been reported .
Sense of Authenticity Scale (SOA)
SOA assess one’s sense that one is being true to oneself.
It comprises seven items to be answered on a
(fivepoint) Likert scale (1: Strongly disagree–5: Strongly
agree). This scale was originally developed among a
Japanese population [
]. Research in personality, social
psychology, and positive psychology has suggested that
authenticity can be conceptualized as a healthy type of
] and can serve as an indicator of
positive functioning . Its reliability and validity has
been repeatedly reported among Japanese population
Neuroticism subscale of the Eysenck Personality
Questionnaire Revised–Short-Form (EPQR-S)
Neuroticism is the tendency to experience negative affect
frequently and intensely, which is a putative transdiagnostic
factor for persistence of emotional disorders. This scale
assesses this personality tendency using 12 dichotomous
items. Its reliability and validity has been shown in the
U.S. and in Japanese [
Anxiety Sensitivity Index-3 (ASI-3) ASI-3 is a
selfreport questionnaire for assessing beliefs about the
feared consequences of symptoms associated with
harmful physical, cognitive, or social concerns [
questionnaire consists of 18 items evaluated on a
fourpoint Likert-type scale (0: very little; 4: very much). The
measure possesses excellent psychometric properties,
performing well on various indices of reliability and
Emotion Regulation Skills Questionnaire (ERSQ)
ERSQ assesses how the respondent has dealt with
negative emotions in the previous week [
]. This 27-item
questionnaire has nine subscales: awareness, clarity,
sensation, understanding, compassionate self-support,
modification, acceptance, tolerance, and readiness to confront.
Each subscale comprises three items, measured on a
(fivepoint) Likert scale (0: not at all; 4: almost always). The
scale demonstrates sufficient reliability and validity [
Emotion Exposure Questionnaire (EEQ) EEQ was
originally developed to assess overall patient tendency to
expose themselves to their own emotions, which is
understood to be a hallmark of the treatment
mechanism of the unified protocol. The items represent
willingness or ability to expose oneself to emotions (e.g., “Even
if it is distressing, I try to feel the emotion fully”). This
questionnaire consists of thirty items evaluated on a
(five-point) Likert-type scale.
Treatment Rationale of Unified Protocol (TRUP)
TRUP was originally developed to assess comprehension
of treatment rationale for the unified protocol. It consists
of 12 statements to be answered yes or no. We developed
two items for each treatment module (psychoeducation of
emotion, emotional awareness, cognitive reappraisal,
emotion avoidance and emotion-driven behavior, tolerance of
physical sensation, and emotion exposure). A sample item
regarding psychoeducation of emotion is “It is better to
suppress emotion and feelings and try not to feel it.”
Session Rating Scale (SRS) SRS is used to assess the
therapeutic alliance [
]. It consists of four
visualanalogue items (bond, consensus of task, consensus of
goal, and overall evaluation). These item are consistent
with the conceptualization of the “working alliance” and
have good psychometric properties in terms of reliability
and validity [
Credibility/Expectancy Questionnaire (CEQ) CEQ
assesses the patient’s perception of the credibility of
treatment and expectancy regarding treatment. It measures
cognitive and emotional aspects of credibility and
expectancy, using six items. Because there was no Japanese
version of this questionnaire, we translated it using a
rigorous back-translation procedure, with the permission
and support of the original developer of this
Homework Compliance Scale (HCS) HCS is a single
measure for the therapist to assess the patient’s degree
of completion of their homework [
]. Therapists who
conduct the unified protocol assess patient homework
compliance at the end of every session, using 0–6
anchors. We translated this measure using a
backtranslation procedure, with permission and support from
one of the original authors of the scale.
Adverse events, treatment, and assessment integrity
We defined adverse events to include any undesirable
physical or psychological event during the research
period, irrespective of its relation with the intervention.
Using the forms described above, therapists or
independent evaluators solicit patients at each visit for
assessment of occurrence or worsening of the following
symptoms: dry mouth, astriction, dysuria, accommodation
disorder, orthostatic hypotension (dizziness,
lightheadedness), sleepiness, malaise, insomnia, anxiety/irritation,
asitia, weight gain or loss, loss of sexual interest, suicidality,
suicidal attempt, and other symptoms. We assessed the
severity of the adverse event using criteria from the
Japanese version of the Common Terminology Criteria
for Adverse Events (CTCAE v4.0) [
]. This rating
system uses a (five-point) Likert-type scale (1: Grade 1,
Mild; 2: Grade 2, Moderate; 3: Grade 3, Severe or
medically significant but not immediately life-threatening;
4: Grade 4, Life-threatening consequences; 5: Grade 5,
Death). A “severe” adverse event is defined as one with
a 3 or higher severity rating.
Data are acquired using a 3-tesla Siemens Verio magnetic
resonance imaging (MRI) scanner (Erlangen, Germany)
with a standard Siemens 32-channel phased array head
coil. The MRI protocol includes acquisition of (1)
restingstate functional MRI (7 min), (2) T1-weighted imaging
(4 min), (3) fluid attenuated IR (FLAIR) (4 min), (4)
diffusion weighted imaging (DWI) (8 min), for a total of under
23 min of scanning. Resting-state fMRI will be conducted
to measure functional region connectivity, and DWI to
measure anatomical region connectivity. T1-weighted
images and FRAIR images will be used for the volumetric
analysis. Participants who meet any exclusion criteria for
MRI (e.g., currently pregnant; currently breastfeeding;
wearing pacemaker, aneurysm clips, or other implants)
will be excluded from the MRI scan.
Procedure for assessment; blinding
Independent evaluators not involved with the
intervention for or coordination of this clinical trial will conduct
the SCID-IV-TR, GRID-HAMD, SIGH-A, and rate CGI
and GAF. These independent evaluators are prohibited
from accessing any information that could confer
participant assignment. Independent evaluators need to be
trained at least 20 h to be eligible to serve. For the
primary outcome of GRID-HAMD, the evaluators trained
by attending workshops, watching a training DVD,
roleplay with a mock patient, direct observation of
evaluation, and conducting GRID-HAMD with patients. All
evaluator assessments will be recorded and used for
other evaluator ratings to examine the reliability of the
assessment. We will choose one-fifth of the assessments
using the same random sampling technique as for
treatment adherence, and examine assessment integrity on
The independent evaluators will respond to the
modified version of the Independent Evaluator Knowledge of
Treatment scale at mid (10 weeks), post (21 weeks) and
follow-up assessment (43 weeks). This three-item scale
for assessing the evaluator’s knowledge of patient
assignment has been used in clinical trials of cognitive
behavior therapy for panic disorder as well as the unified
protocol for emotional disorders [
]. The independent
evaluators give their conjectures, rate their confidence in
their answer, and provide any relevant information that
led to the conjecture.
Data management and monitoring
Acquired data will be entered immediately into a
database constructed using Microsoft Access. Each entry
form will be restricted to the possible range of items.
Data entry and verification will be conducted
independently by study assistants. Central and onsite monitoring
will be conducted periodically by a data manager at
NCNP throughout the course of the trial.
Sample size calculation
Because this clinical trial is intended to examine the
efficacy of a novel treatment (the unified protocol) that
targets clinical populations that are heterogeneous in terms
of a traditional diagnostic perspective, we had to collect
information on the treatment effect size from various
sources in order to estimate the sample size. Estimation
was based on information from previous findings on
efficacy of transdiagnostic and disorder-specific CBT for
depressive and anxiety disorders, results of our pilot
study, and previous randomized controlled trials of the
unified protocol among U.S. participants [
Meta-analysis of the RCT to examine the effect of
CBT in comparison to waiting-list on major depressive
disorder reported a standardized mean difference (SMD)
of 0.82–0.85 [
]. For anxiety disorders by
DSMIV criteria, separate meta-analysis of RCT comparing
CBT with waiting-list or seemingly equivalent condition
(e.g., no treatment, or placebo attention control) showed
an effect size of 0.82 for generalized anxiety disorder
(n = 4) , 0.91 for panic disorder with/without
agoraphobia (n = 7) [
], 0.93 for social anxiety
disorder (n = 7) [
], and 1.36–1.70 for posttraumatic
stress disorder (n = 21) [
]. Finally, other
metaanalysis reported a large effect size of CBT against
waiting-list or active placebo control for emotional
disorders (SMD = 0.63–1.09) [
There are few previous findings on the efficacy of the
unified protocol. In the pilot randomized controlled trial
comparing with waiting-list, an SMD of 0.52–1.11 for
depression measures and 1.10 for anxiety measures was
observed among patients with anxiety disorders [
Our pilot clinical trial of the unified protocol among
Japanese patients with depressive and anxiety disorders
demonstrated a within SMD of 1.70 (95 % CI = 0.81–
2.67) for GRID-HAMD, 1.14 (95 % CI = 0.40–1.89) for
ODSIS, 0.76 (95 % CI = −0.05–1.57) for BDI-II, 1.29
(95 % CI = 0.56–2.06) for SIGH-A, and 1.71 (95 % CI =
0.91–2.50) for OASIS [
Summarizing these findings, we assumed a large effect
size of 0.85 for UP with TAU against waiting-list with
TAU for the reduction of primary outcome assessed by
GRID-HAMD. Using G*Power, in order to detect the
difference between groups with a statistical power of
80 % for a two-tailed test, the needed sample size was
calculated to be 23 for each group. In consideration of
reported dropout rates of 11.76–15.39 % in previous
], we assumed a dropout rate of 15 % and
a need to have at least 27 participants in each group to
test the primary hypothesis of this study (difference of
GRID-HAMD scores between intervention and control
groups over the 21-week period). We will continue
recruiting patients for ancillary study of neuroimaging,
treatment process, and mechanism.
Two separate meta-analyses reported the effect size of
transdiagnostic cognitive-behavioral treatment after we
had finished designing this clinical trial and had started
the actual trial [
]. These latest analyses showed the
effects of transdiagnostic treatments (including
individual, group, and internet format) with control group
(waiting-list, supportive counseling, psychoeducation,
TAU, online support, or discussion forum) on the
selfreport measure of anxiety (SMD = .65, 95 % CI = .34–.57,
n = 24) and depression (SMD = .80, 95 % CI = .62–.98,
n = 22). Reinholt and Krogh  reported pooled SMD
for four RCTs testing the efficacy of transdiagnostic
individual or group treatment in comparison to
waitinglist controls as −1.00 (95 % CI −1.74–-0.26). Taking into
account this information, our estimation might have been
a bit optimistic, suggesting the risk that our method is
underpowered to test our primary hypothesis.
All analyses for testing efficacy of treatment on primary
and secondary measures will be analyzed on the basis of
the intent-to-treat principle, using a linear mixed model
(LMM). The LMM approach was selected because of its
strength in dealing with missing data and its ability to
incorporate random effects (i.e., of the participants) into
the analyses. For the primary outcome, the dependent
variable is the GRID-HAMD score, and the independent
variables are assignment (i.e., intervention vs. control
group), time (i.e., 0, 10, and 21 weeks), and interaction
of the assignment and time, as a fixed-effect variable,
and participants, as random-effects variable. We will
construct a conditional growth model [
] using a
restricted maximum likelihood estimation method to
compare changes in depression severity between groups
from baseline to 21 weeks. The assessment period is
measurement time for the growth model (weeks 0, 10,
and 21), which will be coded as an ordinal scale (0, 1, 2).
We assume an unstructured error covariance for this
model. If the analysis will not converge, we will use
other covariance structures. The covariance structure
that will show convergence of the analysis and best fit to
the data, evaluated by Akaike’s information criterion, will
be used as the primary analysis.
To test robustness, we will conduct the same LMM,
including a stratified variable (depressive vs. anxiety
disorder) as covariate and other sensitive analyses taking into
account the following aspects: ITT vs. per-protocol, and
multiple imputation methods for missing data [
Secondary outcomes will be analyzed in the same way as
primary outcomes. For all analyses, P < .05 will be
considered statistically significant. The other statistical analyses
will be conducted to examine treatment mechanism,
process, and neurological implications in relation to
This study will be announced to the psychiatrists at the
National Center of Neurology and Psychiatry (NCNP)
Hospital. When a patient requests cognitive behavioral
treatment and their primary psychiatrist deems it
feasible for that patient, the psychiatrist refers the patient to
the hospital’s department of clinical psychology. After
the intake session for CBT, the team in that department,
consisting of psychiatrists and clinical psychologists,
holds a conference to determine the most appropriate
CBT program for that patient. Patients with depressive
and anxiety disorders who seem suited to this study will
be referred to this clinical trial.
Completion of this clinical trial will add to the evidence
of efficacy for transdiagnostic psychological treatment of
emotional disorders, which is not conclusive at this time
]. This trial has importance especially with regard
to the question of the efficacy of UP for depressive
disorders and in an Asian population. UP is considered to be
promising as a treatment for depressive disorders
because of the enormous efficacy shown in existing
findings for treatment of this disorder by diagnosis-specific
18, 113, 123
]. There seems to be no reason to
expect weaker efficacy with UP, and there is some reason
to expect enhanced efficacy of UP on depressive
disorders. That is, one of the core modules of UP is emotion
exposure, and the rationale of “avoiding avoidance” was
originally considered important for treatment of anxiety
disorders; however, recent advances in the
understanding of behavioral activation lead us to regard avoidance
as a key maintenance factor for depression. Further,
positive as well as negative emotion regulation has been
found to be an important treatment target . The
UP has been modified to incorporate these findings in
order to enhance its efficacy [
Transdiagnostic treatments have several strengths,
including versatility to treat a broad range of emotional
disorders, and the relative parsimony of learning core
principles of cognitive behavioral therapy. These strengths
are especially important to clinical practice in Japan,
which has many barriers that hinder patients from
receiving evidence-based treatments and where there are severe
problems for the dissemination of CBT [
]. Only three
randomized controlled clinical trials have been conducted
to assess the efficacy of CBT in medical settings in Japan
(one trial each for obsessive–compulsive disorder,
insomnia, and hypochondria). If its efficacy is confirmed by the
present study, this versatile treatment will contribute to
the more rapid adoption of evidence-based treatment to
those who need it for emotional difficulties in Japan.
In addition to the results for the primary hypothesis,
secondary analyses of treatment mechanism, process,
and neurological correlates will inform better
implementation of the unified protocol, and, possibly, other
Current study status
The JUNP study began recruiting participants in December
2013. Forty-four participants have been enrolled at the
time of submission of this protocol.
JUNP: Japan unified protocol clinical trial for depressive and anxiety disorders;
DSM: diagnostic and statistical manual for mental disorders; UP: unified
protocol for transdiagnostic treatment of emotional disorders; CBT: cognitive
behavioral therapy; RCT: randomized controlled trial; ICD: international
classification of diseases; NCNP: national center of neurology and psychiatry
(Japan); TAU: treatment-as-usual; SCID-IV-TR: structural clinical interview for
DSM-IV-TR axis I disorders; GRID-HAMD: GRID-Hamilton rating scale for
depression; MDD: major depressive disorders; ADIS-IV: anxiety disorder interview
schedule for DSM-IV; SIGH-A: structured interviews guide for Hamilton rating
scale for anxiety; CGI: clinical global impression; GAF: global assessment of
functioning; OASIS: overall anxiety severity and impairment scale; ODSIS: overall
depression severity and impairment scale; BDI-II: Beck depression inventory-II;
PDSS: panic disorder severity scale; LSAS: Liebowitz social anxiety scale;
PSWQ: Penn State worry questionnaire; Y-BOCS: Yale–Brown obsessive
compulsive scale; IES-R: impact of event scale-revised; FQ: fear questionnaire;
EQ-5D: euro Qol; SDS: Sheehan disability scale; SOA: sense of authenticity scale;
EPRQ-S: Eysenck personality questionnaire revised–short-form; ASI-3: anxiety
sensitivity index-3; ERSQ: emotion regulation skills questionnaire; EEQ: emotion
exposure questionnaire; TRUP: treatment rationale of unified protocol;
SRS: session rating scale; CEQ: credibility/expectancy questionnaire;
HCS: homework compliance scale; CTCAE: common terminology criteria for
adverse events; MRI: magnetic resonance imaging; LMM: linear mixed model;
ARCS: allocation and registration control system.
All authors declare no competing interest.
All authors contributed to the conception and conduct of this clinical trial.
MI is the primary investigator of this trial. MI, YO, and MH designed the
overall framework of the trial. YO is responsible for statistics design to test
efficacy. MI and NK, in particular, conceived the treatment implementation
and coordinated the research. MI, YO, and AN, in particular, conceived the
assessment procedure and trained independent evaluators. MM and MI
designed the ancillary study for neurological correlates. NH and AK will
monitor adverse events and take necessary medical action if they occur. AN,
YO, MH, NH, and AK arranged the infrastructure essential to execute the trial.
MI drafted the manuscript, and all co-authors read it and provided critical
comments. All authors approved the final manuscript.
This study was supported by a National Center of Neurology and Psychiatry
(NCNP) Intramural Research Grant (24–4) for Neurological and Psychiatric
Disorders, and a Grant-in-Aid for Young Scientists (A) (25705018) awarded to
MI from the Japan Society for the Promotion of Science. These funders had
no role in designing or executing the study. The authors express their
appreciation to Hiroko Fujisato, Ph.D., and Shun Nakajima, Ph.D., for their
suggestions that improved the implementation of the unified protocol; Yoshiya
Moriguchi, MD, Ph.D., and Takashi Hanakawa, MD, Ph.D., for designing and
conducting the ancillary study of neurological correlates; David Barlow, Ph.D.,
Todd Farchione, Ph.D., Kristen Ellard, Ph.D., James Boswell, Ph.D., and Matthew
Gallagher, Ph.D. for assistance with translating the treatment materials and
providing useful comments on conducting the clinical trial; Toshiaki Furukawa,
M.D., Ph.D., and Junichiro Kanazawa, Ph.D., for their help with translating the
treatment materials; En Kimura, M.D., and the staff of the cluster ward at the
NCNP Hospital for organizing therapy rooms; Yutaka Matsuoka, M.D., Ph.D., for
his continuing help in the process of preparing and conducting this study;
Kyoko Akutsu for constructing the database and doing data entry; Yukiko
Hanada, M.A., and Ayaka Toyota, M.A., for data entry, data verification, and
assistance in coordinating the trial; Keiko Yamaguchi, Ph.D., for assistance
in assessment; and Fumi Imamura, Ph.D., for assistance in recruiting the
1National Center for Cognitive Behavior Therapy and Research, National
Center of Neurology and Psychiatry, Ogawa Higashi 4-1-1, Kodaira, Tokyo
187-8511, Japan. 2Institute for Health Economics and Policy, Association for
Health Economics Research and Social Insurance and Welfare, Tokyo, Japan.
3National Center of Neurology and Psychiatry, Tokyo, Japan. 4Center for
Clinical Research, Keio University School of Medicine, Tokyo, Japan. 5Center
for the Development of Cognitive Behavior Therapy Training, Tokyo, Japan.
1. Kawakami N. Epidemiological survey for mental health . Tokyo: Ministry of Health Labour and Welfare of Japan; 2006 .
2. Kessler RC , Berglund P , Demler O , Jin R , Merikangas KR , Walters EE . Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication . Arch Gen Psychiatry . 2005 ; 62 ( 6 ): 593 - 602 .
3. Vos T , Barber RM , Bell B , Bertozzi-Villa A , Biryukov S , Bolliger I , et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013, a systematic analysis for the Global Burden of Disease Study 2013 . Lancet. 2013 ; 386 ( 9995 ): 743 - 800 .
4. World Health Organization. The global burden of disease: 2004 update. Geneva: WHO Press; 2008 .
5. Greenberg PE , Fournier AA , Sisitsky T , Pike CT , Kessler RC . The economic burden of adults with major depressive disorder in the United States (2005 and 2010) . J Clin Psychiatry . 2015 ; 76 ( 2 ): 155 - 62 .
6. Okumura Y , Higuchi T. Cost of depression among adults in Japan . Prim Care Companion CNS Disord . 2011 ; 13 ( 3 ):PCC. 10m01082 .
7. Sado M , Yamauchi K , Kawakami N , Ono Y , Furukawa TA , Tsuchiya M , et al. Cost of depression among adults in Japan in 2005 . Psychiatry Clin Neurosci . 2011 ; 65 ( 5 ): 442 - 50 .
8. Greenberg PE , Sisitsky T , Kessler RC , Finkelstein SN , Berndt ER , Davidson JR , et al. The economic burden of anxiety disorders in the 1990s . J Clin Psychiatry . 1999 ; 60 ( 7 ): 427 - 35 .
9. Sado M , Takechi S , Inagaki A , Fujisawa D , Koreki A , Mimura M , et al. Cost of anxiety disorders in Japan in 2008: a prevalence-based approach . BMC Psychiatry . 2013 ; 13 : 338 - 40 .
10. Kessler RC , Greenberg PE . The economic burden of anxiety and stress disorders . Neuropsychopharmacology . 2002 ; 67 : 982 - 92 .
11. Barlow DH , Allen LB , Choate ML . Toward a unified treatment for emotional disorders . Behav Ther . 2004 ; 35 ( 2 ): 205 - 30 .
12. Norton PJ , Paulus DJ . Toward a unified treatment for emotional disorders: update on the science and practice . Behavior Therapy . 2015 . ISSN 0005- 7894 . http://dx.doi.org/10.1016/j.beth. 2015 .
13. Wilamowska ZA , Thompson-Hollands J , Fairholme CP , Ellard KK , Farchione TJ , Barlow DH , et al. Conceptual background, development, and preliminary data from the unified protocol for transdiagnostic treatment of emotional disorders . Depress Anxiety . 2010 ; 27 ( 10 ): 882 - 90 .
14. Watkins E. An alternative transdiagnostic mechanistic approach to affective disorders illustrated with research from clinical psychology . Emotion Review . 2015 ; 7 ( 3 ): 250 - 255 .
15. Rosellini A , Boettcher H , Brown T , Barlow DH . A transdiagnostic temperament-phenotype profile approach to emotional disorder classification: an update . Psychopathol Rev . 2015 ; 2 ( 1 ): 110 - 28 .
16. Krueger RF , Eaton NR . Transdiagnostic factors of mental disorders . World Psychiatry . 2015 ; 14 ( 1 ): 27 - 9 .
17. American Psychiatric Association. Diagnostic and statistical manual-5 . Washington: American Psychiatric Association; 2013 .
18. Butler AC , Chapman JE , Forman EM , Beck AT . The empirical status of cognitive-behavioral therapy: a review of meta-analyses . Clin Psychol Rev . 2006 ; 26 ( 1 ): 17 - 31 .
19. Hofmann SG , Asnaani A , Vonk IJ , Sawyer AT , Fang A . The efficacy of cognitive behavioral therapy: a review of meta-analyses . Cogn Ther Res . 2012 ; 36 ( 5 ): 427 - 40 .
20. National Collaborating Centre for Mental Health. Depression: the treatment and management of depression in adults . Updated ed. Leicester: British Psychological Society/London: Royal College of Psychiatrists; 2010 .
21. McIntosh A , Cohen A , Turnbull N , Esmonde L , Dennis P , Eatock J , et al. Clinical guidelines and evidence review for panic disorder and generalised anxiety disorder . Sheffield: University of Sheffield/London: National Collaborating Centre for Primary Care; 2004 .
22. National Collaborating Centre for Mental Health. Common mental health disorders: identification and pathways to care . Leicester: British Psychological Society/London: Royal College of Psychiatrists; 2011 .
23. National Collaborating Centre for Mental Health . Social anxiety disorder: recognition, assessment and treatment . Leicester: British Psychological Society/London: Royal College of Psychiatrists; 2013 .
24. National Collaborating Centre for Mental Health and Clinical Excellence. Post-traumatic stress disorder: the management of PTSD in adults and children in primary and secondary care . Leicester: British Psychological Society/London: Royal College of Psychiatrists; 2005 .
25. Gelenberg AJ , Freeman MP , Markowitz JC , Rosenbaum JF , Thase ME , Trivedi MH , et al. Practice guideline for the treatment of patients with major depressive disorder . 3rd ed. Am J Psych . 2010 ; 167 ( 10 ): 1 - 152 .
26. Koran LM , Simpson HB . Guideline watch (March 2013 ) : practice guideline for the treatment of patients with obsessive-compulsive disorder . Arlington: American Psychiatric Association; 2013 .
27. Stein MB , Goin MK , Roy-Byrne P , Sareen J , Simon N , Campbell-Sills L . Practice guideline for the treatment of patients with panic disorder . 2nd ed. Arlington: American Psychiatric Association; 2010 .
28. Jonas DE , Cusack K , Forneris CA , Wilkins TM , Sonis J , Middleton JC , et al. AHRQ comparative effectiveness reviews: psychological and pharmacological treatments for adults with posttraumatic stress disorder (PTSD). Rockville: Agency for Healthcare Research and Quality (US); 2013 .
29. Mansell W , Harvey A , Watkins E , Shafran R . Conceptual foundations of the transdiagnostic approach to CBT . J Cogn Psychother. 2009 ; 23 ( 1 ): 6 - 19 .
30. McManus F , Shafran R , Cooper Z. What does a transdiagnostic approach have to offer the treatment of anxiety disorders? Br J Clin Psychol . 2010 ; 49 (Pt 4): 491 - 505 .
31. Clark DA . Cognitive behavioral therapy for anxiety and depression: possibilities and limitations of a transdiagnostic perspective . Cognitive Behaviour Therapy . 2009 ; 38 ( Suppl 1 ): 29 - 34 .
32. Newby JM , McKinnon A , Kuyken W , Gilbody S , Dalgleish T. Systematic review and meta-analysis of transdiagnostic psychological treatments for anxiety and depressive disorders in adulthood . Clin Psychol Rev . 2015 ; 40 : 91 - 110 .
33. Reinholt N , Krogh J . Efficacy of rransdiagnostic cognitive behaviour therapy for anxiety disorders: a systematic review and meta-analysis of published outcome studies . Cogn Behav Ther . 2014 ; 43 ( 3 ): 171 - 84 .
34. Fairholme CP , Boisseau CL , Ellard KK , Ehrenreich J , Barlow DH . Emotions, emotion regulation, and psychological treatment: a unified perspective . In: Emotion regulation and psychopathology: a transdiagnostic approach to etiology and treatment . New York: Guilford Press; 2010 . p. 283 - 309 .
35. Barlow DH , Farchione TJ , Fairholme CP , Ellard KK , Boisseau CL , Allen LB , et al. Unified protocol for transdiagnostic treatment of emotional disorders: therapist guide . New York: Oxford University Press; 2011 .
36. Boswell JF , Anderson LM , Barlow DH . An idiographic analysis of change processes in the unified transdiagnostic treatment of depression . J Consult Clin Psychol . 2014 ; 82 ( 6 ): 1060 - 71 .
37. Ellard KK , Fairholme CP , Boisseau CL , Farchione TJ , Barlow DH . Unified protocol for the transdiagnostic treatment of emotional disorders: protocol development and initial outcome data . Cogn Behav Pract . 2010 ; 17 ( 1 ): 88 - 101 .
38. Farchione TJ , Fairholme CP , Ellard KK , Boisseau CL , Thompson-Hollands J , Carl JR , et al. Unified protocol for transdiagnostic treatment of emotional disorders: a randomized controlled trial . Behav Ther . 2012 ; 43 ( 3 ): 666 - 78 .
39. de Ornelas Maia ACC , Nardi AE , Cardoso A . The utilization of unified protocols in behavioral cognitive therapy in transdiagnostic group subjects: a clinical trial . J Affect Disord . 2015 ; 172 : 179 - 83 .
40. Ellard KK , Deckersbach T , Sylvia LG , Nierenberg AA , Barlow DH . Transdiagnostic treatment of bipolar disorder and comorbid anxiety with the unified protocol: a clinical replication series . Behav Modif . 2012 ; 36 ( 4 ): 482 - 508 .
41. Sauer-Zavala S , Bentley KH , Wilner JG . Transdiagnostic treatment of borderline personality disorder and comorbid disorders: a clinical replication series . J Personal Disord . 2015 ; 24 : 1 - 17 .
42. Ehrenreich JT , Goldstein CM , Wright LR , Barlow DH . Development of a unified protocol for the treatment of emotional disorders in youth . Child Fam Behav Ther . 2009 ; 31 ( 1 ): 20 - 37 .
43. Gros DF . Design challenges in transdiagnostic psychotherapy research: comparing Transdiagnostic Behavior Therapy (TBT) to existing evidencebased psychotherapy in veterans with affective disorders . Contemp Clin Trials . 2015 ; 43 : 114 - 9 .
44. Barlow DH , Sauer-Zavala S , Carl JR , Bulis JR , Ellard KK . The nature, diagnosis, and treatment of neuroticism: Back to the future . Clin Psychol Sci . 2014 ; 2 ( 3 ): 344 - 65 .
45. Sauer-Zavala S , Boswell JF , Gallagher MW , Bentley KH , Ametaj A , Barlow DH . The role of negative affectivity and negative reactivity to emotions in predicting outcomes in the unified protocol for the transdiagnostic treatment of emotional disorders . Behav Res Ther . 2012 ; 50 ( 9 ): 551 - 7 .
46. Berking M , Wupperman P , Reichardt A , Pejic T , Dippel A , Znoj H . Emotionregulation skills as a treatment target in psychotherapy . Behav Res Ther . 2008 ; 46 ( 11 ): 1230 - 7 .
47. Glenn D , Golinelli D , Rose RD , Roy-Byrne P , Stein MB , Sullivan G , et al. Who gets the most out of cognitive behavioral therapy for anxiety disorders? The role of treatment dose and patient engagement . J Consult Clin Psychol . 2013 ; 81 ( 4 ): 639 - 49 .
48. Cammin-Nowak S , Helbig-Lang S , Lang T , Gloster AT , Fehm L , Gerlach AL , et al. Specificity of homework compliance effects on treatment outcome in CBT: evidence from a controlled trial on panic disorder and agoraphobia . J Clin Psychol . 2013 ; 69 ( 6 ): 616 - 29 .
49. Boswell JF , Farchione TJ , Sauer-Zavala S , Murray HW , Fortune MR , Barlow DH . Anxiety sensitivity and interoceptive exposure: a transdiagnostic construct and change strategy . Behav Ther . 2013 ; 44 ( 3 ): 417 - 31 .
50. McHugh RK , Murray HW , Barlow DH . Balancing fidelity and adaptation in the dissemination of empirically-supported treatments: the promise of transdiagnostic interventions . Behav Res Ther . 2009 ; 47 ( 11 ): 946 - 53 .
51. Holdsworth E , Bowen E , Brown S , Howat D. Client engagement in psychotherapeutic treatment and associations with client characteristics, therapist characteristics, and treatment factors . Clin Psychol Rev . 2014 ; 34 ( 5 ): 428 - 50 .
52. Webb CA , Derubeis RJ , Barber JP . Therapist adherence/competence and treatment outcome: A meta-analytic review . J Consult Clin Psychol . 2010 ; 78 ( 2 ): 200 - 11 .
53. Hogue A , Henderson CE , Dauber S , Barajas PC , Fried A , Liddle HA . Treatment adherence, competence, and outcome in individual and family therapy for adolescent behavior problems . J Consult Clin Psychol . 2008 ; 76 ( 4 ): 544 - 55 .
54. Devilly GJ , Borkovec TD . Psychometric properties of the credibility/ expectancy questionnaire . J Behav Ther Exp Psychiatry . 2000 ; 31 ( 2 ): 73 - 86 .
55. Webb CA , Kertz SJ , Bigda-Peyton JS , Björgvinsson T. The role of pretreatment outcome expectancies and cognitive-behavioral skills in symptom improvement in an acute psychiatric setting . J Affect Disord . 2013 ; 149 ( 1-3 ): 375 - 82 .
56. Keijsers GP , Schaap CP , Hoogduin CA. The impact of interpersonal patient and therapist behavior on outcome in cognitive-behavior therapy: a review of empirical studies . Behav Modif . 2000 ; 24 ( 2 ): 264 - 97 .
57. Flückiger C , Del Re AC , Wampold BE , Symonds D , Horvath AO . How central is the alliance in psychotherapy? A multilevel longitudinal meta-analysis . J Couns Psychol . 2012 ; 59 ( 1 ): 10 - 7 .
58. Horvath AO , Del Re AC , Flückiger C , Symonds D. Alliance in individual psychotherapy . Psychotherapy . 2011 ; 48 ( 1 ): 9 - 16 .
59. Conklin LR , Strunk DR . A session-to-session examination of homework engagement in cognitive therapy for depression: Do patients experience immediate benefits? Behav Res Ther . 2015 ; 72 : 56 - 62 .
60. Mausbach BT , Moore R , Roesch S , Cardenas V , Patterson TL . The relationship between homework compliance and therapy outcomes: an updated metaanalysis . Cogn Ther Res . 2010 ; 34 ( 5 ): 429 - 38 .
61. Kazantzis N , Whittington C , Dattilio F. Meta-analysis of homework effects in cognitive and behavioral therapy: a replication and extension . Clin Psychol Sci Pract . 2010 ; 17 ( 2 ): 144 - 56 .
62. Hofmann SG , Ellard KK , Siegle GJ . Neurobiological correlates of cognitions in fear and anxiety: a cognitive-neurobiological information-processing model . Cogn Emot . 2012 ; 26 ( 2 ): 282 - 99 .
63. Sharp PB , Miller GA , Heller W. Transdiagnostic dimensions of anxiety: neural mechanisms, executive functions, and new directions . Int J Psychophysiol . 2015 ; 98 : 365 - 77 .
64. Fonzo GA , Ramsawh HJ , Flagan TM , Sullivan SG , Simmons AN , Paulus MP , et al. Common and disorder-specific neural responses to emotional faces in generalised anxiety, social anxiety and panic disorders . Br J Psychiatry . 2015 ; 206 ( 3 ): 206 - 15 .
65. Insel T , Cuthbert B , Garvey M , Heinseen R , Pine DS , Quinn K , et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders . Am J Psychiatry . 2010 ; 167 ( 7 ): 748 - 51 .
66. Porto PR , Oliveira L , Mari J , Volchan E , Figueira I , Ventura P . Does cognitive behavioral therapy change the brain? A systematic review of neuroimaging in anxiety disorders . J Neuropsychiatry Clin Neurosci . 2009 ; 21 ( 2 ): 114 - 25 .
67. Ball TM , Stein MB , Ramsawh HJ , Campbell-Sills L , Paulus MP . Single-subject anxiety treatment outcome prediction using functional neuroimaging . Neuropsychopharmacology . 2014 ; 39 ( 5 ): 1254 - 61 .
68. Ito M , Horikoshi M , Kato N , Oe Y , Fujisato H , Nakajima S , et al. Transdiagnostic and transcultural: pilot study of unified protocol for depressive and anxiety disorders in Japan. Behavior Therapy . in press.
69. Barlow DH , Ellard KK , Fairholme CP , Farchione TJ , Boisseau CL , Allen LB , et al. Unified protocol for transdiagnostic treatment of emotional disorders: client workbook . New York: Oxford University Press; 2011 .
70. Japan Society for Mood Disorders. [Japan Society for Mood Disorders treatment guideline II: Major depressive disorder 2013 ver. 1 .1]. Tokyo: Japan Society for Mood Disorders; 2013 .
71. Nakagawa A , Williams A , Sado M , Oguchi Y , Mischoulon D , Smith F , et al. Comparison of treatment selections by Japanese and US psychiatrists for major depressive disorder: a case vignette study . Psychiatry Clin Neurosci . 2015 ; 69 : 553 - 62 .
72. Hamilton M. A rating scale for depression . J Neurol Neurosurg Psychiatry . 1960 ; 23 : 56 - 62 .
73. Tabuse H , Kalali A , Azuma H , Ozaki N , Iwata N , Naitoh H , et al. The new GRID Hamilton Rating Scale for Depression demonstrates excellent inter-rater reliability for inexperienced and experienced raters before and after training . Psychiatry Res . 2007 ; 153 ( 1 ): 61 - 7 .
74. Williams JB , Kobak KA , Bech P , Evans K , Lipsitz J , Olin J , et al. The GRIDHAMD: standardization of the Hamilton Depression Rating Scale . Int Clin Psychopharmacol . 2008 ; 23 ( 3 ): 120 - 9 .
75. Watanabe N , Furukawa TA , Shimodera S , Morokuma I , Katsuki F , Fujita H , et al. Brief behavioral therapy for refractory insomnia in residual depression: an assessor-blind, randomized controlled trial . J Clin Psychiatry . 2011 ; 72 ( 12 ): 1651 - 8 .
76. Nakagawa A , Sado M , Mitsuda D , Fujisawa D , Kikuchi T , Abe T , et al. Effectiveness of cognitive behavioural therapy augmentation in major depression treatment (ECAM study): study protocol for a randomised clinical trial . BMJ Open . 2014 ; 4 ( 10 ): e006359 .
77. Frank E , Prien RF , Jarrett RB , Keller MB , Kupfer DJ , Lavori PW , et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder: remission, recovery, relapse, and recurrence . Arch Gen Psychiatry . 1991 ; 48 ( 9 ): 851 - 5 .
78. Shear MK , Vander Bilt J , Rucci P , Endicott J , Lydiard B , Otto MW , et al. Reliability and validity of a structured interview guide for the Hamilton Anxiety Rating Scale (SIGH-A) . Depress Anxiety . 2001 ; 13 ( 4 ): 166 - 78 .
79. Inada T , Ozaki N. SIGH-A Japanese Version . Tokyo: The Japanese Society of Psychiatric Rating Scales; 2004 .
80. Guy W. ECDEU assessment manual for psychopharmacology . Rockville: National Institute of Mental Health; 1976 .
81. Busner J , Targum SD . The Clinical Global Impressions Scale: applying a research tool in clinical practice . Psychiatry . 2007 ; 4 ( 7 ): 28 - 37 .
82. American Psychiatric Association. Diagnostic and statistical manual-IV-text revision (DSM-IV-TR) . Washington: American Psychiatric Association; 2000 .
83. First MB , Spitzer RL , Gibbon M , Williams JBW , Benjamin LS . Structured Clinical Interview for DSM-IV® Axis I Disorders (SCID-I), Clinician Version, administration booklet . Arlington: American Psychiatric Publishing; 1997 .
84. Norman SB , Cissell SH , Means-Christensen AJ , Stein MB . Development and validation of an Overall Anxiety Severity and Impairment Scale (OASIS) . Depress Anxiety . 2006 ; 23 ( 4 ): 245 - 9 .
85. Ito M , Oe Y , Kato N , Nakajima S , Fujisato H , Miyamae M , et al. Validity and clinical interpretability of Overall Anxiety Severity and Impairment Scale (OASIS) . J Affect Disord . 2015 ; 170 : 217 - 24 .
86. Bentley KH , Gallagher MW , Carl JR , Barlow DH . Development and validation of the overall depression severity and impairment scale . Psychol Assess . 2014 ; 26 : 815 - 30 .
87. Ito M , Bentley KH , Oe Y , Nakajima S , Fujisato H , Kato N , et al. Assessing depression related severity and functional impairment: the overall depression severity and impairment scale (ODSIS) . PLoS ONE . 2015 ; 10 ( 4 ): e0122969 .
88. Beck A , Steer R , Brown G. BDI-II: Beck Depression Inventory , Second Edition, manual. San Antonio: The Psychological Corporation; 1996 .
89. Kojima M , Furukawa TA , Takahashi H , Kawai M , Nagaya T , Tokudome S , et al. Cross-cultural validation of the Beck Depression Inventory-II in Japan . Psychiatry Res . 2002 ; 110 ( 3 ): 291 - 9 .
90. Shear MK , Rucci P , Williams J , Frank E , Grochocinski V , Vander Bilt J , et al. Reliability and validity of the Panic Disorder Severity Scale: replication and extension . J Psychiatr Res . 2001 ; 35 ( 5 ): 293 - 6 .
91. Liebowitz MR . Social phobia . Mod Probl Pharmacopsychiatry . 1987 ; 22 : 141 - 73 .
92. Meyer TJ , Miller ML , Metzger RL , Borkovec TD . Development and validation of the Penn State Worry Questionnaire . Behav Res Ther . 1990 ; 28 ( 6 ): 487 - 95 .
93. Goodman WK , Price LH , Rasmussen SA , Mazure C. The Yale-Brown Obsessive-Compulsive Scale . I: Development, use, and reliability . Arch Gen Psychiatry . 1989 ; 46 ( 11 ): 1006 - 11 .
94. Weiss DS , Marmar CR . The impact of event scale-revised . Assessing Psychological Trauma and PTSD . 1997 ; 2 : 168 - 89 .
95. Asukai N , Kato H , Kawamura N , Kim Y , Yamamoto K , Kishimoto J , et al. Reliabiligy and validity of the Japanese-language version of the Impact of Event Scale-Revised (Ies-RJ): four studies of different traumatic events . J Nerv Ment Dis . 2002 ; 190 ( 3 ): 175 - 82 .
96. Marks IM , Mathews AM . Brief standard self-rating for phobic patients . Behav Res Ther . 1979 ; 17 ( 3 ): 263 - 7 .
97. Rabin R , Charro F. EQ-SD: a measure of health status from the EuroQol Group . Ann Med . 2001 ; 33 ( 5 ): 337 - 43 .
98. Ikeda S , Shiroiwa T , Igarashi A , Noto S , Fukuda T , Saito S , et al. Developing a Japanese version of the EQ-5D-5 L value set . J Natl Inst Public Health . 2015 ; 64 : 47 - 55 .
99. Sheehan DV , Harnett-Sheehan K , Raj BA . The measurement of disability . Int Clin Psychopharmacol . 1996 ; 11 Suppl 3 : 89 - 95 .
100. Yoshida T , Ohtsubo T , Tsuchida H , Wada Y , Ueshima K , Hukkyo K. Development of Sheehan Disability Scale (SDISS) and its reliability and validity . Jpn JClin Psychopharmacol . 2004 ; 7 : 1645 - 53 .
101. Ito M , Kodama M. Sense of authenticity, self-esteem, and subjective and psychological well-being . Jpn J Educ Psychol . 2005 ; 53 ( 1 ): 74 - 85 .
102. Kernis MH , Goldman BM . A multicomponent conceptualization of authenticity: theory and research . Adv Exp Soc Psychol . 2006 ; 38 : 283 - 357 .
103. Joseph S , Wood A . Assessment of positive functioning in clinical psychology: Theoretical and practical issues . Clin Psych Rev . 2010 ; 30 ( 7 ): 830 - 8 .
104. Ito M , Horikoshi M , Kodama M. A cross-sectional survey of age and sense of authenticity among Japanese . Psychol Rep . 2009 ; 105 ( 2 ): 575 - 81 .
105. Eysenck SB , Eysenck HJ , Barrett P. A revised version of the psychoticism scale . Personal Individ Differ . 1985 ; 6 ( 1 ): 21 - 9 .
106. Hosokawa T , Ohyama M. Reliability and validity of a Japanese version of the short-form Eysenck Personality Questionnaire-Revised . Psychol Rep . 1993 ; 72 ( 3 ): 823 - 32 .
107. Taylor S , Zvolensky MJ , Cox BJ , Deacon B , Heimberg RG , Ledley DR , et al. Robust dimensions of anxiety sensitivity: development and initial validation of the Anxiety Sensitivity Index-3 . Psychol Assess . 2007 ; 19 ( 2 ): 176 - 88 .
108. Berking M , Znoj H . Entwicklung und Validierung eines Fragebogens zur standardisierten Selbsteinschätzung emotionaler Kompetenzen (SEK- 27 ). Z Psychiatr Psychol Psychother . 2008 ; 56 ( 2 ): 141 - 53 .
109. Duncan BL , Miller S , Sparks JA , Reynolds LR , Brown J , Johnson LD , et al. The Session Rating Scale: preliminary psychometric properties of a “working” alliance measure . J Brief Ther . 2003 ; 3 ( 1 ): 3 - 12 .
110. Primakoff L , Epstein N , Covi L . Homework compliance: an uncontrolled variable in cognitive therapy outcome research . Behav Ther . 1986 ; 17 ( 4 ): 433 - 46 .
111. US Department of Health and Human Services/National Insititutes of Health/National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 4 .0. Washington: U.S. Department of Health and Human Services/National Insititutes of Health/National Cancer Institute; 2009 .
112. Roll D , Ray SE , Marcus SM , Passarelli V , Money R , Barlow DH , et al. Independent evaluator knowledge of treatment in a multicenter comparative treatment study of panic disorder . Neuropsychopharmacology . 2004 ; 29 ( 3 ): 612 - 8 .
113. Barth J , Munder T , Gerger H , Nüesch E , Trelle S , Znoj H , et al. Comparative efficacy of seven psychotherapeutic interventions for patients with depression: a network meta-analysis . PLoS Med . 2013 ; 10 ( 5 ): e1001454 .
114. Gloaguen V , Cottraux J , Cucherat M , Blackburn IM . A meta-analysis of the effects of cognitive therapy in depressed patients . J Affect Disord . 1998 ; 49 ( 1 ): 59 - 72 .
115. Gould RA , Otto MW , Pollack MH , Yap L . Cognitive behavioral and pharmacological treatment of generalized anxiety disorder: A preliminary meta-analysis . Behav Ther . 1997 ; 28 ( 2 ): 285 - 305 .
116. Gould RA , Ott MW , Pollack MH . A meta-analysis of treatment outcome for panic disorder . Clin Psychol Rev . 1995 ; 15 ( 8 ): 819 - 44 .
117. Gould RA , Buckminster S , Pollack MH , Otto MW , Yap L . Cognitive-behavioral and pharmacological treatment for social phobia: A meta-analysis . Clin Psychol Sci Pract . 1997 ; 4 ( 4 ): 291 - 306 .
118. National Collaborating Center for Mental Health. Post-Traumatic Stress Disorder: the management of PTSD in adults and children in primary and secondary care . Leicester: British Psychological Society/London: Royal College of Psychiatrists; 2005 .
119. Haby MM , Donnelly M , Corry J , Vos T. Cognitive behavioural therapy for depression, panic disorder and generalized anxiety disorder: a metaregression of factors that may predict outcome . Aust N Z J Psychiatry . 2006 ; 40 ( 1 ): 9 - 19 .
120. National Collaborating Centre for Mental Health and Clinical Excellence. Generalised anxiety disorder in adults: Management in Primary, Secondary and Community Care . Leicester: British Psychological Society/London: Royal College of Psychiatrists; 2011 .
121. Singer JD , Willett JB . Applied longitudinal data analysis: modeling change and event occurrence . New York: Oxford University Press; 2003 .
122. Thabane L , Mbuagbaw L , Zhang S , Samaan Z , Marcucci M , Ye C , et al. A tutorial on sensitivity analyses in clinical trials: the what, why, when and how . BMC Med Res Methodol . 2013 ; 13 ( 1 ): 92 .
123. Cuijpers P , van Straten A , Bohlmeijer E , Hollon SD , Andersson G. The effects of psychotherapy for adult depression are overestimated: a meta-analysis of study quality and effect size . Psychol Med . 2010 ; 40 ( 2 ): 211 - 23 .
124. Carl JR , Soskin DP , Kerns C , Barlow DH . Positive emotion regulation in emotional disorders: a theoretical review . Clin Psychol Rev . 2013 ; 33 ( 3 ): 343 - 60 .
125. Ono Y , Furukawa TA , Shimizu E , Okamoto Y , Nakagawa A , Fujisawa D. Current status of research on cognitive therapy/cognitive behavior therapy in Japan . Psychiatry Clin Neurosci . 2011 ; 65 ( 2 ): 121 - 9 .