Adding smartphone-based cognitive-behavior
therapy to pharmacotherapy for major depression(FLATT project): study protocol for a randomized
controlled trial
Watanabe et al.
Watanabe et al. Trials (2015) 16:293
DOI 10.1186/s13063-015-0805-z

Watanabe et al. Trials (2015) 16:293
DOI 10.1186/s13063-015-0805-z

TRIALSSTUDY PROTOCOLOpen Access

Adding smartphone-based cognitivebehavior therapy to pharmacotherapy for
major depression (FLATT project): study
protocol for a randomized controlled trial
Norio Watanabe1*†, Masaru Horikoshi2, Mitsuhiko Yamada3, Shinji Shimodera4, Tatsuo Akechi5, Kazuhira Miki6,
Masatoshi Inagaki7, Naohiro Yonemoto3, Hissei Imai8, Aran Tajika9, Yusuke Ogawa9, Nozomi Takeshima9,
Yu Hayasaka9, Toshi A. Furukawa9*† and On behalf of steering committee of the Fun to Learn to Act and Thinkthrough Technology (FLATT) project

Abstract
Background: Major depression is one of the most debilitating diseases in terms of quality of life. Less than half ofpatients suffering from depression can achieve remission after adequate antidepressant treatment. Another promisingtreatment option is cognitive-behavior therapy (CBT). However, the need for experienced therapists and substantive
dedicated time prevent CBT from being widely disseminated.
In the present study, we aim to examine the effectiveness of switching antidepressants and starting asmartphone-based CBT program at the same time, in comparison to switching antidepressants only, among
patients still suffering from depression after adequate antidepressant treatment.
Methods/design: A multi-center randomized trial is currently being conducted since September 2014. The
smartphone-based CBT program, named the “Kokoro-App,” for major depression has been developed and its feasibility
has been confirmed in a previous open study. The program consists of an introduction, 6 sessions and an epilogue,
and is expected to be completed within 9 weeks by patients. In the present trial, 164 patients with DSM-5 major
depressive disorder and still suffering from depressive symptoms after adequate antidepressant treatment for morethan 4 weeks will be allocated to the Kokoro-App plus switching antidepressant group or the switching antidepressantalone group. The participants allocated to the latter group will receive full components of the Kokoro-App after
9 weeks.
The primary outcome is the change in the total score on the Patient Health Questionnaire through the 9 weeksof the program, as assessed at week 0, 1, 5 and 9 via telephone by blinded raters. The secondary outcomes
include the change in the total score of the Beck Depression Inventory-II, change in side effects as assessed by
the Frequency, Intensity and Burden of Side Effects Rating, and treatment satisfaction.
(Continued on next page)* Correspondence: noriowncu@gmail.com; furukawa@kuhp.kyoto-u.ac.jp†
Equal contributors
1
Department of Clinical Epidemiology, Translational Medical Center, National
Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo
187-8551, Japan
9
Departments of Health Promotion and Human Behavior, Kyoto University
Graduate School of Medicine/School of Public Health, Yoshida Konoe-cho,
Sakyo-ku, Kyoto 606-8501, Japan
Full list of author information is available at the end of the article© 2015 Watanabe et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution
License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://
creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Watanabe et al. Trials (2015) 16:293

Page 2 of 13(Continued from previous page)

Discussion: An effective and reachable intervention may not only lead to healthier mental status among depressed
patients, but also to reduced social burden from this illness. This paper outlines the background and methods of a trialthat evaluates the possible additive value of a smartphone-based CBT program for treatment-resistant depression.
Trial registration: UMIN-CTR: UMIN000013693 (registered on 1 June 2014)
Keywords: Behavior therapy, Cognitive therapy, Computer-assisted therapy, Depression, Randomized controlled trials

Background
Major depression is the second leading cause of deterioration of quality of life in humankind [1]. The economic
loss due to depression is estimated at approximately 2
trillion yen per year in Japan [2]. Approximately 30,000
people a year die due to suicide in Japan. Half of thesesuicide victims are estimated to suffer from depression
immediately before committing suicide [3].
The first-line treatment for depression in clinical settings
is pharmacotherapy, especially antidepressant treatment;
however, less than 50 % of patients receiving acute-phase
antidepressant treatment for 2 to 4 months can achieve remission [4]. Other effective treatment options for depression include cognitive-behavior therapy (CBT); this has
been shown to be as efficacious as pharmacotherapy [5]and to be more efficacious when combined with pharmacotherapy than pharmacotherapy alone [6]. CBT can,therefore, be a viable treatment option not only for patients
preferring CBT to pharmacotherapy but also for patientsstill suffering from depression after an adequate trial ofantidepressant treatment.
However, patients willing to receive CBT can rarely doso even in developed countries, because a typical courseof CBT consists of sixteen 1-hour face-to-face sessions led
by an experienced therapist. On the other hand, CBT delivered via the Internet or computers has been recently
provided in Western countries, including Australia, theUnited Kingdom, the Netherlands and Sweden. The efficacy of computer-based or Internet-based CBT has been
examined in previous systematic reviews. A systematic review and meta-analysis, combining results from 6 randomized controlled trials (RCTs) with 645 participants,
estimated an effect size of computer-based CBT to be 0.78
(95 % confidence interval (CI): 0.59 to 0.63) in comparison
with treatment as usual (TAU) or waiting-list controls [7].
Another systematic review combining results from 16
RCTs with 2807 participants showed that computer-based
CBT led to a greater proportion of dropouts but to better
efficacy at an effect size of 0.48 (0.33 to 0.63) in the shortterm follow up than those in control conditions, whilst toneither superiority nor inferiority in the long term [8].
In the wake of recent developments in information andcommunication technology (ICT), CBT delivered via
smartphones can be a better treatment option for depression than a computer-based one in terms of accessibility

and portability. A clinical trial involving 52 participants inthe community has shown that smartphone-based CBT
was not inferior to computer-based CBT at 3-month follow up [9].
Given the vast number of patients with depression andthe still very limited accessibility of effective CBT for
them, it will be very meaningful and helpful to develop a
CBT program taking advantage of this rapidly evolving
ICT. In the present study, we aim to examine the effectiveness of adding a smartphone-based CBT program toswitching antidepressants in comparison to that ofswitching antidepressants alone, for patients still suffering from depression after adequate antidepressant treatment. Among antidepressants, a systematic review andmultiple-treatment meta-analysis evaluating the comparative efficacy of 12 newer antidepressants has suggested that escitalopram and sertraline are the mostfavorable in terms of efficacy and acceptability [10]. We
aim to examine the effectiveness of switching from theprevious antidepressant to escitalopram or sertraline andstarting a smartphone-based CBT program at the sametime, in comparison to switching to escitalopram or
sertraline only, among patients still suffering from depression after adequate antidepressant treatment. We
hypothesized that adding a smartphone-based CBTprogram to switching antidepressants could lead to greater
improvement in depression symptoms among patientswith treatment-refractory depression than switching antidepressants alone.

Methods/design
Trial design

A multi-center, parallel-arm, rater-blinded RCT has beenplanned. Participants who still suffer from full or residual
major depressive disorder after adequate antidepressanttreatment will be randomly allocated to either of the twointervention arms: 1) switching antidepressants to escitalopram or sertraline plus smartphone-based CBT programthe “Kokoro-App” (“kokoro” means “mind” or “heart” inJapanese) consisting of 8 sections, or 2) switching antidepressants to escitalopram or sertraline only for 8 weeks
after 1 week of introductory lead-in. The primary outcome
is the slope of the Patient Health Questionnaire-9 (PHQ-9)
through 0 to 9 weeks. The secondary outcomes include theslope of the Beck Depression Inventory (BDI-II) through 0

Watanabe et al. Trials (2015) 16:293

to 9 weeks; treatment satisfaction at 9 weeks; continuationof antidepressant pharmacotherapy up to 9 weeks; and theslope of the Frequency, Intensity and Burden of Side Effects
Rating (FIBSER) through 0 to 9 weeks.
Interventions
Smartphone-based CBT program: “Kokoro-App”

The smartphone-based CBT program the “Kokoro-App”
for iPhones and iPads (Apple Inc., Cupertino, CA, USA)has been developed, based on an empirically supported
CBT manual [11–13], and pilot tested for feasibility andacceptability. It consists of eight sections, including one
introductory section, two sessions on self-monitoring,two sessions on behavioral activation, two sessions on
cognitive restructuring, and one epilogue.
The Kokoro-App can be completed within 7 weeks at
the fastest. The main program consists of dialogues between characters who explain the principles and skills of
CBT (Fig. 1). Homework needs to be completed by theparticipant between sessions. The participant can proceed
to the next session 1 week after they start the previous
one and after they finish the homework. One session
needs approximately 30 minutes to complete. The central
trial office sends an Email to each participant to encourage
him/her to complete the session and the homework once
every week during the program.

Fig. 1 Screen shots from the Kokoro-App on an iPhone

Page 3 of 13

The participants and their attending physicians cancheck the entries made by the participants into the program by looking at the website (Kokoro-App Web). They
can thus discuss the contents uploaded to the KokoroApp Web during their consultations.
Security of the data exchanged through the Internet
has been certificated by Secure Sockets Layer (SSL). An
identification number and a password are required toenter the program or website when: 1) a participant logs
in to the program at week 0; 2) a participant logs in to
the Kokoro-App Web; and 3) the attending physician
logs in to the Kokoro-App Web.

Antidepressant pharmacotherapy

In the present study, antidepressants that the participants
had been taking before entry to the study will be switchedto escitalopram or sertraline. A systematic review and amultiple-treatment meta-analysis have suggested that escitalopram and sertraline are the most favorable in terms of
the efficacy and acceptability among 12 newer antidepressants [10]. The attending physician will start escitalopram
or sertraline at entry (week 0) and aim to stop antidepressants other than these two by week 5 and to prescribe either 5–10 mg/day of escitalopram or 25–100 mg/day ofsertraline at week 5.

Watanabe et al. Trials (2015) 16:293

Concomitant interventions

From week 0 through week 9, mood stabilizers (e.g.,lithium, valproic acid, carbamazepine and lamotrigine), antipsychotics, electroconvulsive therapy, repetitive transcranial magnetic stimulation, individual
CBT, and individual interpersonal therapy will not beallowed. Two antidepressant drugs may be prescribeduntil week 5 while the drug previously prescribed
before entry is tapered and discontinued. After week
5, either escitalopram or sertraline should be prescribed as antidepressant monotherapy.
Any psychotherapy that is not specifically designed
for depression, anxiolytics and hypnotics can be prescribed, and dosage of these can be changed between
week 0 and week 9. Group psychotherapy during thisperiod is allowed, but may not be changed or started.
The period after the assessment at week 9 is a followup phase, and any treatment is allowed at the attending
physician’s discretion as TAU.

Page 4 of 13

Concomitant use of anxiolytics or hypnotics isallowed;6) Willing to do the Kokoro-App program, and being
judged suitable for the program by the attending
physician;7) Being used to smartphones, which is confirmed by
the following conditions: a) the patient uses an
iPhone, iPad (Apple Inc., Cupertino, CA, USA),
Android smartphone or an equivalent in daily life; b)
has an Email address for daily use; and c) has amobile phone number for daily use;
8) Being an outpatient at entry, and having no plan tobe hospitalized more than 1 week for any reason
within 4 months;9) Having no plan to transfer to a different hospital
within 4 months;
10) Being able to respond to assessments about
symptoms and side effects via telephone; and
11) Being able to understand and sign a written
informed consent.

Participants

The inclusion criteria for the participants are:1) Men or women aged between 25 and 59 years uponentry into the study. We will limit participants to
those aged 25 or older because patients younger
than this age have been reported to be susceptible toincreased suicidality after taking antidepressants incomparison with those taking placebo [14];2) Primary diagnosis as major depressive disorderwithout psychotic features, according to the
Diagnostic and Statistical Manual of Mental
Disorders, version 5 (DSM-5). This is confirmed by thetreating psychiatrist through the semi-structured
interview using the Primary Care Evaluation of Mental
Disorders (PRIME-MD) [15]. It is not necessary thatthe patient satisfies the full criteria for a current major
depressive episode upon entry. As long as the patientdoes not experience remission lasting for 2 months or
more, the patient is considered to be in the same
major depressive episode. Comorbid secondary
diagnosis of anxiety disorders is allowed;
3) Not having taken either escitalopram or sertraline
for the current episode;4) Being antidepressant-resistant, defined as scoring 10
or more on the BDI-II at entry after taking one ormore kinds of antidepressants at an adequate dosage
for 4 or more weeks (corresponding to Stage I, II or
III according to the criteria by Thase and Rush [16]),and it is judged by the attending physician that thepatients should be switched to escitalopram or
sertraline;
5) Taking only one kind of antidepressant at entry, andnot taking any antipsychotics or mood stabilizers.

The exclusion criteria include:
1) Having taken any of the following interventions forthe current episode: a) monoamine oxidase inhibitors(corresponding to Stage IV according to the criteria ofThase and Rush [16]); b) electroconvulsive therapy or
repetitive transcranial magnetic stimulation(corresponding to Stage V [16]); c) both escitalopram
and sertraline; or d) face-to-face individual CBT or
face-to-face interpersonal psychotherapy;2) Any of the following comorbid illnesses: a) pasthistory of schizophrenia, schizoaffective disorder, or
bipolar and related disorders according to DSM-5;or b) current diagnosis of neurocognitive disorders,feeding and eating disorders, substance-related andaddictive disorders or borderline personality
disorder;3) Imminent risk of suicide as judged by the treating
physician;4) Physical illnesses possibly interfering withpharmacotherapy by escitalopram or sertraline,
including: a) a possible prolonged QT syndrome, as
judged through an interview with the attending
physician; b) prolonged heart-rate corrected QTinterval (QTc) in the electrocardiogram within
1 month (male: QTc > 450 ms, female: QTc >470 ms [17]); c) taking medication known to prolong
the QT interval and being judged unsuitable to takeescitalopram or sertraline by the attending physician;d) severe or extremely unstable cardiovasculardisease, such as current or past severe bradycardia,
congestive heart failure or hypokalemia; e) severe or
extremely unstable hepatic, renal, respiratory, blood,Watanabe et al. Trials (2015) 16:293

or endocrine function, or central nervous systemdisease or head injury; f ) terminal stage of physicalillnesses; g) currently taking pimozide; or h) historyof hypersensitivity or allergy to escitalopram or
sertraline;
5) Being currently pregnant or breastfeeding;6) Currently participating in another clinicalintervention study;7) Family members living with the researchers of thepresent study; or
8) Being unable to understand the written Japanese
language.
Trial sites

A participating trial site must fulfill the following eligibility
criteria:1) Have a department of psychiatry or of
psychosomatic medicine;2) The principal trial physician and all the participating
trial physicians at the site have understood the study
protocol; and
3) The site is within mobile phone range.
On the other hand, a trial site will be ineligible if it satisfies one or more of the following conditions:1) The principal trial physician withdraws consent forparticipating in the study;2) No participant is registered for 6 months; or3) The steering committee of the present trial judges
the site to be inappropriate to recruit participants.
Initial trial sites include Nagoya City University Hospitalin Aichi, Waseda Clinic in Gifu, Kochi University Hospitaland Atago Hospital in Kochi, Japan.
Assessment measures
Screening tools

Primary Care Evaluation of Mental Disorders (PRIMEMD) Major depressive disorder, according to DSM-5,
will be diagnosed through semi-structured interview
using PRIME-MD [18] by the attending physicians atbaseline.
The Beck Depression Inventory-II (BDI-II) The BDI-II
is a 21-item self-report instrument to measure the severityof depression. Its first version was developed in 1961 [19]and a major revision was undertaken in 1996 to make thescale more congruent with the modern diagnostic criteria
for major depression [20]. Good reliability and validity havebeen reported for the Japanese version [21].
The time frame for evaluation is set to the past 2 weeks
including the day of assessment. The BDI-II will be used

Page 5 of 13

for a screening tool at week 0 and participants with a total
score of 10 or more will be included in the present study.
Electrocardiogram The QTc will be checked using anelectrocardiogram within 1 month before week 0. The
QTc will be deemed prolonged if > 450 ms for males
and > 470 ms for females, respectively, and will bechecked again at week 1.
Primary outcome measure

Patient Health Questionnaire-9 (PHQ-9) The PHQ-9
consists of the 9 diagnostic criteria items of theDSM-4 [15]. Each item is rated between 0 = “Not atall” through 3 = “Nearly every day,” making the total
score range between 0 and 27. Excellent test-retest reliability and internal consistency reliability have beenreported [15, 22]. Good construct validity has been
demonstrated through associations with various severity indices [23]. The sensitivity to change is as goodas or better than extant scales [24].
Secondary outcome measures

Patients’ satisfaction with treatment The following 2
questions will be graded on a scale of 100 by patients: 1)“To what extent has the treatment met your needs forthese two months? Please answer on a scale of 1 to 100,
presuming 60 as a passing mark”; and 2) “To what extent have you been satisfied with the treatment for these
2 months? Please answer on a scale of 1 to 100, presuming 60 as a passing mark.”
Continuation of protocol treatment up to week 9 In
order to evaluate whether the Kokoro-App may have interfered with pharmacotherapy as defined in the protocol, continuation rates of protocol pharmacotherapy atweek 9 will be compared between the intervention andcontrol groups. Discontinuation of pharmacotherapy isdefined as not taking a prescribed antidepressant for
more than 1 week due to any reason as judged by the attending physician.
Frequency, Intensity, and Burden of Side Effects Rating(FIBSER) FIBSER was originally used in STAR*D as a
global rating scale for side effects. The FIBSER consistsof 3 domains evaluating the frequency, intensity and severity of side effects, each of which has a score from 0 to
6. The reliability and validity of the FIBSER have been
confirmed [25].
K6 K6 is a very short (6-item) self-report questionnaire toscreen for common mental disorders and to evaluate theseverity of general psychological distress [26]. Good validity and reliability have been confirmed [27], and its area
under the curve compared to “gold-standard” diagnoses ofWatanabe et al. Trials (2015) 16:293

depressive and anxiety disorders was 0.94 [28]. The Japanese version has been validated [28].
Procedures
Screening

Physicians (psychiatrists) in the recruiting sites will identify patients possibly eligible for the study by checking
diagnosis of major depressive disorder according to DSM5 by means of the PRIME-MD. They will also confirm

Page 6 of 13

absence of a history of heart disease or current prolonged
QTc by electrocardiogram within 1 month before entry,
and check the other eligibility criteria (Fig. 2, Table 1).
Informed consent, installing the Kokoro-App and medication
at week 0

A clinical research coordinator at a recruiting clinic (site
CRC) will seek written informed consent from the candidate participant at the clinic at week 0. Participants

Fig. 2 Flowchart of the trial. Abbreviations: BDI-II, Beck Depression Inventory-II; CRC, clinical research coordinator; FIBSER, Frequency, Intensity, and
Burden of Side Effects Rating; PHQ-9, Patient Health Questionnaire-9; PRIME-MD, Primary Care Evaluation of Mental Disorders; TAU, treatment as usual

Watanabe et al. Trials (2015) 16:293

Page 7 of 13

Table 1 Schedule for the assessments
Item

Week 0PRIME-MD√

Basic characteristicsa√

Electrocardiogram√

Informed consent√

BDI-II√

PHQ-9
FIBSER

Week 1

Week 5

Week 9Week 17

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

Blindness
Treatment satisfaction√

Allocation

Participant

K6

√

√

√

√

(Only those
allocated to
Kokoro-App)(Only those
allocated to
Kokoro-App)(Only those
allocated to
Kokoro-App)

BDI-II Beck Depression Inventory-II, CRC clinical research coordinator, FIBSER Frequency, Intensity, and Burden of Side Effects Rating, K6 6-item self-report questionnaire
to evaluate the severity of general psychological distress, PHQ-9 Patient Health Questionnaire-9, PRIME-MD Primary Care Evaluation of Mental Disordersa
Basic characteristics include sex, age, education, work status, marital status, age at first depressive episode, number of episodes, duration of the current
depressive episode, information about treatment for current episode, and current history of physical illnesses

will be informed that they can withdraw their consent at
any time without stating the reason and that their withdrawal will not affect the medical services they receive.
The written informed consent will be obtained alongwith the mobile phone number of the participant, withwhich the central trial office can contact him or her toassess the outcomes.
Immediately after consent, all participants will install
the Kokoro-App onto his or her smartphone with an assistance of the site CRC. After successful installation, theserver will provide a password specific to each participant
via an Email to the participant. The participant will be able
to proceed to the introductory section of the Kokoro-Appby entering the password. In the introduction, the participant will practice entering some sentences into the smartphone and fill in a self-report measure of psychologicaldistress (K6). All participants will receive an interview

using the PHQ-9 and the FIBSER at the clinic via telephone from the central trial office.
The attending physician of the participant will startswitching the previous antidepressant at week 0 to either
5–10 mg/day of escitalopram or 25–100 mg/day of sertraline. The patient will take escitalopram if he or she
has taken sertraline for the current episode, and viceversa. If the patient has taken neither escitalopram nor
sertraline for the current episode, one of these two will
be selected by the attending physician. The maximum
dosage of escitalopram was set at 10 mg/day because: 1)
the efficacy of 20 mg/day of escitalopram has not been
proved to be superior to that of 10 mg/day [29, 30]; 2)
the tolerability of the former has been proved to be inferior to that of the latter in terms of dropout rates due
to side effects [31]; and 3) a dose response has been reported between dosage of escitalopram and prolonged

Watanabe et al. Trials (2015) 16:293

QT interval [32]. Anxiolytics and hypnotics can be used,
started, increased/decreased and discontinued during
the study.
Randomization and medication at week 1

An appointment at week 1 will be scheduled within 3
to 14 days from the entry. At week 1, the participant
will receive an electrocardiogram and an interview,using the PHQ-9 and the FIBSER, via telephone fromthe central trial office. Based on these results, the participant will be classified into either of the following
two groups: A) primary comparison set: those who have
not responded or only partially responded to escitalopram or sertraline (defined by the total score of the
PHQ-9 of 5 or more at week 1), are tolerant to escitalopram or sertraline (defined by item 1 of the FIBSER of
3 or more and items 3 and 4 of 3 or less at week 1,
which means that the participant has been able to takethe antidepressant for 3 days or more and the intensity
and the interference with daily functions due to side effects of the medication is mild or less), and have noproblems in using the smartphones and the KokoroApp; B) secondary comparison set: those who have notsatisfied any of the above criteria.
Within each group, the participants will be randomly
allocated to either the combined smartphone-based
CBT and antidepressant switch group (intervention
group) or the antidepressant switch alone group (control group) at 1:1 ratio with a minimization method
using the electronic data-capturing web program (EDC)
at the central trial office. Random allocation will, therefore, be concealed. Clinics, number of antidepressantspreviously prescribed for the index episode (3 or moreversus 2 or less), and a total score of the PHQ-9 (10 ormore versus 9 or less) at week 1 will be used as stratification variables.
If the participant is allocated to the intervention
group, he or she will be provided with a password toproceed to Session 1 of the Kokoro-App. If the participant is allocated to the control group, he or she will be
informed that the Kokoro-App can be resumed if theparticipant is willing to do so after week 9.
With regard to antidepressants, if the participant is intolerant of escitalopram or sertraline prescribed at week 0(defined by scores of 4 or more on either item 3 or 4 of
FIBSER), the physician will suggest stopping the antidepressant and starting previous or new antidepressantsother than escitalopram and sertraline.
Trial period: from week 1 through week 9

For all the participants, an appointment with the attending physician will be scheduled at least every
4 weeks. Visits must take place at weeks 5 and 9. The
previous antidepressant must be tapered off by week 5,

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and either escitalopram or sertraline (or another antidepressant if the participant is intolerant of these two)must be prescribed as monotherapy at week 5. Only
anxiolytics and hypnotics are allowed as psychotropic
drugs other than antidepressants.
For the participants allocated to the intervention group,
the physician can check the patient’s progress of the
Kokoro-App through the Kokoro-App Web, and discuss
it with the participant during consultations. If the participants allocated to the control group express interest in
CBT by week 9, the physician is allowed to suggest selfhelp books about CBT but not to provide any specific
CBT sessions.
At weeks 5 and 9, the participant will receive an interview, using the PHQ-9 and the FIBSER, via telephone at
the clinic from the central trial office. Depression severity
will also be assessed with the BDI-II. At week 9, an interview using a scale on treatment satisfaction will also be
administered via telephone.
Follow-up period: from week 9 through week 17

After assessments at week 9, no restrictions will be
posed in terms of medications, frequency of appointments, or CBT. The participants allocated to thecontrol group can resume the Kokoro-App if theywish to. At week 17, all the participants will receive
an assessment of the PHQ-9, the FIBSER and thescale on treatment satisfaction via telephone from thecentral trial office as well as to fill in a self-rating
scale of the BDI-II.
Stopping rules for participants

Dropouts from the trial The participants will be excluded from the intention-to-treat (ITT) cohort of thetrial, if it was not possible to randomize them at week 1
or if their primary diagnosis was changed before week 1.
Deviation from protocol treatment The following cases
will be considered deviation from the trial protocol; however, the participant will not be considered to have
dropped out of the trial at this stage and will receive theprotocol assessments:
1) When prohibited concurrent treatments orprescription of the intervention antidepressant above
the maximum dosage defined in the protocol (10 mg/
day for escitalopram, and 100 mg/day for sertraline)
took place between week 0 and week 9;2) When changes in treatment that are allowed to beco-administered but not to be changed between week
0 and week 9 took place;3) If the participant cannot take any pills of sertraline or
escitalopram due to side effects between week 1 andweek 9;Watanabe et al. Trials (2015) 16:293

4) If the participant develops a manic/hypomanic/
mixed episode, or is diagnosed with schizophrenia ordementia between week 1 and week 9.
Discontinuation of protocol treatment If the participant meets any of the following conditions, the trial
physician can stop the antidepressant or the KokoroApp. The participant, however, will not be considered tohave dropped out of the trial at this stage and will receive the protocol assessments:
1) The participant wishes to stop the protocoltreatment;
2) The trial physician judges that it is difficult tocontinue the protocol treatment because of serious
side effects;
3) The trial physician judges that the risk outweighs
the benefit in continuing the protocol treatment
even when no serious side effect is reported;
4) The participant becomes pregnant and the trial
physician judges that the risk outweighs the benefit
in continuing the protocol treatment;
5) The trial physician judges that it is inappropriate tocontinue the protocol treatment for some otherreason.
Stopping assessment If the participant withdraws consent for assessments, he/she will not be followed up.
Blindness and reliability of assessment from the central trial
officeThe primary outcome (PHQ-9) and information aboutside effects (FIBSER) at weeks 0, 5, 9, and 17 and treatment satisfaction judged by participants at weeks 9 and17 will be collected via telephone by central CRCs, who
are kept blind to groups to which the participant has
been allocated.
At week 5, 9 and 17 assessments, the blindness of thecentral CRCs as to the participant’s treatment will beassessed by having the CRCs guess the allocated treatment by selecting one from the following: 1) I strongly
believe that the patient is allocated to the combinationgroup; 2) I guess that the patient is allocated to the combination group but am not confident; 3) I cannot tell; 4)
I guess that the patient is allocated to the antidepressantalone group but am not confident; and 5) I strongly believe that the patient is allocated to the antidepressantalone group.
The inter-rater reliability of the central CRCs will
be examined by comparing the assessors’ ratings ofaudio recordings of the PHQ-9 and FIBSER, recordedin our previous study [11], with the original ratings.
In addition, five recordings in the present study will
be assessed again by another rater blinded to the

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original rating in order to evaluate the inter-rater reliability in the present study.

Reporting of adverse events and protection ofparticipants
Definition of adverse events

An adverse event is defined as any unwanted or unintended sign (including laboratory exams), symptom ordisease seen in participants of the trial. According to the“Ethical Guidelines for Clinical Studies: Questions andAnswers,” which is published by the Japanese Ministry of
Health, Labor and Welfare, severe adverse events are defined as events leading to any one the following: a)death; b) threatened death; c) admission or prolongationof admission for treatment; d) enduring and severe impairment and dysfunction; or e) congenital anomaly.
When a serious adverse event occurs, the trial physician
must notify the principal investigator within 48 hours,
regardless of the causal relationship with the trial intervention. The principal investigator shall report to theinstitutional review board in Kyoto University Graduate
School of Medicine within 72 hours, and notify all the coprincipal investigators. The principal investigator mustalso notify all the collaborators at all the recruiting sites.
The collaborators will take the necessary measures according to the information from the principal investigator.
If it concerns an unforeseen serious adverse event, theprincipal investigator shall report it to the Ministry of
Health, Labor and Welfare.
Foreseeable adverse events

Escitalopram Frequent side effects include: nausea(23.8 %), somnolence (23.5 %), headache (10.2 %), drymouth (9.6 %), dizziness (8.7 %), fatigue (7.1 %), diarrhea(6.2 %), etc.
Serious side effects include: convulsion (unknown frequency), the syndrome of inappropriate anti-diuretic
hormone secretion (SIADH) (unknown frequency), serotonin syndrome (unknown frequency), prolonged QT(unknown frequency), and ventricular tachycardia (unknown frequency).
Sertraline Frequent side effects include: nausea (18.9 %),somnolence (15.2 %), dry mouth (9.3 %), headache (7.8 %),diarrhea (6.4 %), dizziness (5.0 %), etc.
Serious side effects include: serotonin syndrome (unknown frequency), malignant syndrome (unknown frequency), convulsion (unknown frequency), coma (unknown
frequency), liver dysfunction (unknown frequency), SIADH(unknown frequency), Lyell syndrome and toxic epidermal
necrolysis (unknown frequency), and anaphylactoid symptoms (unknown frequency).

Watanabe et al. Trials (2015) 16:293

Kokoro-App No specific adverse events are presumed inparticipants who use the Kokoro-App. However, using the
Kokoro-App might lead to psychological distress in someparticipants depending on their psychological state.
Compensation insurance

Because all the protocol antidepressant interventions areadministered within the approved regulations in Japan,
any health hazards shall be covered by the National
Health Insurance. However, because the trial involves
random allocation, we have contracted a private healthinsurance (Tokio Marine and Nichido Fire InsuranceCo., Ltd.) to compensate for health hazards that havearisen due to this trial.
Data monitoring

The trial will be supervised by the Data and Safety
Monitoring Board (DSMB). The board consists of three
independent experts in psychiatry and clinical trial
methodology. The members of the committee are independent from the present study: Dr Teruhiko Higuchi(Chair of the DSMB, Psychiatrist, National Center for
Neurology and Psychiatry), Professor Yoshio Hirayasu(Psychiatrist, Yokohama City University) and Dr Akiko
Kada (Biostatistician, National Hospital Organization
Nagoya Medical Center). The purpose of DSMB is tocheck the data monitoring reports prepared by the data
center and make recommendations to the principal investigator, where necessary.

Page 10 of 13

statistician. The analyses will be conducted according to
the plan.
Primary analyses

The primary outcome will be analyzed using a mixed
model with repeated measures to examine treatment effect parameters of all the eligible subjects in the primarycomparison set according the ITT principle. Allocationgroup (intervention) and stratification variables used in
randomization will be incorporated into the model. A
regression coefficient (beta), its 95 % CIs, and a 2-side P
value will be calculated. The statistical significance is set
at 0.05 (2-sided). If the changes are not linear, an appropriate model will be applied.
Secondary analyses

We will perform secondary analyses to supplement our
primary analysis and to obtain finer understanding of
our clinical questions. The secondary analyses will use
models similar to those of the primary analysis, will
analyze data from both the primary and secondary comparison sets as well as from the per protocol set, and will
also examine data for the secondary outcome measures.
These analyses will be conducted for exploratory purposes. We will not use adjustment for multiple tests. We
will report the effect sizes and their 95 % CIs. The
methods for these secondary analyses will be stated indetail in the Statistical Analysis Plan.

Ethical issues

Interim analyses

The present study is subject to the ethical guidelines
for clinical studies published by the Japanese Ministryof Health, Labor and Welfare, as well as the ethicalprinciples established for research on human beings
as stipulated in the Declaration of Helsinki and further amendments thereto.
The protocol has been approved by the institutional
review boards of Kyoto University Medical School on 12
June 2014 (ID: C842), of Nagoya City University on 11
August 2014 (ID: 45-14-0009) and of Kochi Medical
School on 10 September 2014 (ID: ERB-100826). If important protocol modifications such as changes to eligibility criteria, outcomes, or analyses are needed, theinvestigators will discuss them and report to the review
boards for approval.
Written informed consent will be obtained from allparticipants included in this study. Data of each participant will be handled with sequentially allocated numbers
to maintain participant confidentiality.

We will not perform interim analyses.

Data analysis

Details of the planned analyses for the trial will be givenin the Statistical Analysis Plan, to be drafted by the trial

Sample size

Sample size was based on a power analysis with 0.8
power to detect an effect size of 0.5 between the groups
at P = 0.05 (2-sided). It was calculated that 63 patientswould be required for each of the two arms for the primary comparison set. Assuming that 30 % of the initial
entries would drop out or otherwise be classified into
the secondary comparison set at week 1, 164 participants
would need to be recruited into the trial.
The effect size of the Kokoro-App was estimated at
0.5 because we anticipated a medium effect size [33]compared with the wait-list control group. In fact, an effect size of 0.69 was observed when we conducted aclinical trial of a 1-to-1 telephone-based CBT program,which formed the prototype of the Kokoro-App, in comparison with a wait-list control [11]. Systematic reviewsof clinical trials on the efficacy of computer or Internetbased CBT showed 0.49 [8] and 0.78 [7] in the acutephase treatment. We therefore calculate that we could
anticipate an effect size of approximately 0.5 for the
Kokoro-App.

Watanabe et al. Trials (2015) 16:293

The primary outcome of the present trial is the change
in the PHQ-9 through weeks 0, 1, 5 and 9. Taking accountof the sample size calculation for repeated measures [34],a sample size per group will not exceed 63 even when we
consider associations of 4 time points. However, this is derived from presumption that the treatment effect is stablebetween any two time points. If there is a large difference
between time points, statistical power would decrease. If
this does occur, we will recalculate and examine theachieved statistical power post hoc.
Funding

This study is funded by the Pragmatic Psychopharmacotherapy Research Project initiated by the JapanFoundation for Neuroscience and Mental Health. The
Project has received donations from Asahi Kasei
Pharma Corp., Eli Lilly Japan KK, GlaxoSmithKline
KK, Ltd., Janssen Pharmaceuticals KK, Meiji Seika
Pharma Co., Mitsubishi Tanabe Pharma Corporation,
MSD KK, Mochida Pharmaceutical Co., Ltd., Otsuka
Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co.,
Ltd., Pfizer Japan Inc., Ltd. and Shionogi & Co. The
up-to-date information will be uploaded on the trial
website (http://ebmh.med.kyoto-u.ac.jp/flatt/) and will
be provided in the informed consent document forthe participant.
Publication policy

The results from the study will be submitted to peerreviewed journals. The collaborating researchers havethe right to be named as the first author of these papers
in the order of their number of recruitment. TAF will be
the corresponding author for all the papers.
Trial principal physicians, trial participating physiciansand other members of the Steering Committee, if they
do not appear as co-author, will be listed at the end of
the article. Such authors may be counted as co-authors
in some journals but not in others.
Study period

The study period of this trial will be between September
2014 and March 2017, with the participant entry period
between June 2014 and October 2016.

Discussion
To our knowledge, the present study represents thefirst trial investigating the efficacy of smartphone-based
CBT in clinical settings, especially for patients still suffering from depression after an adequate trial of antidepressant treatment. Considering the high dropout
rate of computer-based CBT [8], smartphone-based CBT
may offer a more accessible option because patients
can access it anywhere and anytime they have a chance
and are willing to do so. Only fewer than 50 % ofPage 11 of 13

patients receiving acute-phase antidepressant treatment
can achieve remission [4], so that easily accessible CBTmay offer some additional benefits in the treatment ofdepression. The present study focuses on patients withantidepressant-resistant depression, so that targeted
population may be those in most need. If the efficacy ofa smartphone-based CBT program in this population is
confirmed, applicability of the program in real clinicalsettings is quite promising.
The present study is, however, not without some methodological limitations. First of all, not all patients who areinterested in and willing to do the Kokoro-App have asmartphone. This may undermine the applicability of theresults from this trial to all patients with antidepressantresistant depression. Especially, the results might not beapplicable to patients in developing countries and to patients with poor ICT literacy.
Second, we selected a wait-list control as the comparator due to the feasibility and ethical considerations, but
the nocebo effects of the latter condition can play animportant role in the estimation of the efficacy of thesmartphone-based CBT. In a network meta-analysis of
CBTs, waiting-list controls and no treatment controls, theodds ratio of response for no treatment over waiting-list
was statistically significant at 2.9 (95 % CI: 1.3 to 5.7) [35].
However, in the present trial we planned to switch a previous antidepressant treatment to a newer drug for each patient (e.g., sertraline or escitalopram) for all participants atentry to the study, thus raising expectation across theintervention and control arms. This might lead to decreasing nocebo effects of the waiting-list control.
Third, one may consider that results from the primarycomparison set are those of an efficacy trial not of an effectiveness trial, because we would only include patients
who are able to tolerate the trial antidepressant for
1 week and are accustomed to using a smartphone. Thisdecision was made a priori because the trial is the firstone of this kind. However, we will include patients who
had failed to meet these conditions in our secondary
comparison set, and results from these analyses can beutilized in future effectiveness trials.
Fourth, although the effect size of 0.5 used for calculation of sample sizes was estimated from results of theprevious studies on the efficacy of computer or Internetbased CBT [7, 8], one may think that the effect size is
too optimistic because the present study focuses on patients with treatment-refractory depression. In addition,a majority of the control conditions used in trials included in previous systematic reviews [7, 8] were
waiting-list, which might have led to plausibly large effect sizes. However, our previous clinical trial comparing the efficacy of a telephone-based CBT program
added to the employee assistance program with that of
the latter alone showed an effect size of 0.69 [11]. The

Watanabe et al. Trials (2015) 16:293

smartphone-based CBT program in the present study
was based on this telephone-based program, and we
considered that the estimated effect size of 0.5 in thepresent study was reasonable.

Trial status
The randomized trial, which commenced in September
2014, is currently in the phase of participant enrollment
and follow up.
Abbreviations
BDI-II: Beck Depression Inventory-II; CI: Confidence interval; CRC: Clinicalresearch coordinator; CBT: Cognitive-behavior therapy; DSM: Diagnostic andStatistical Manual of Mental Disorders; DSMB: Data and Safety Monitoring
Board; EDC: Electronic data capturing; FIBSER: Frequency, Intensity, and
Burden of Side Effects Rating; ICT: Information and communication
technology; ITT: Intention-to-treat; PHQ-9: Patient Health Questionnaire-9;
PRIME-MD: Primary Care Evaluation of Mental Disorders; QTc: Heart-ratecorrected QT interval; RCT: Randomized controlled trial; SIADH: Syndrome of
inappropriate anti-diuretic hormone secretion; SSL: Secure Sockets Layer;
TAU: Treatment as usual.
Competing interests
The authors have no conflicts of interests to declare that may be affected by
the publication of the manuscript.
NW has research funds from the Japanese Ministry of Health, Labor andWelfare and the Japanese Ministry of Education, Science, and Technology.
He has also received royalties from Sogensha and Paquet, and speaking feesand research funds from Asahi Kasei, Dai-Nippon Sumitomo, Eli Lilly, Glaxo
SmithKline, Janssen, Meiji, MSD, Otsuka and Pfizer.
MH has research funds from the Japanese Ministry of Health, Labor andWelfare and the Japanese Ministry of Education, Science, and Technology.
He has received royalties from Igaku Shoin, Shogakukan Shueisha
Production, Shindan to Chiryosha, Sogensha, Kangokyokai Shuppan, Kitaoji
Shobo and Kongo Shuppan.
MY has research funds from the Japanese Ministry of Health, Labor andWelfare and the Japanese Ministry of Education, Science, and Technology.
He has received honoraria for lectures from Meiji Seika Pharma, MSD, Asahi
Kasei Pharma, and has contracted research with Nippon Chemiphar. He hasreceived royalties from Igaku Shoin, Seishin Shobou, Koubundou, Sentan
Igakusha.
SS has received speaking fees and/or research funds from Astellas,
Dainippon-Sumitomo, GlaxoSmithKline, Janssen, Lilly, MSD, Otsuka, Pfizer,
Shering-Plough, Shionogi and Yoshitomi.
TA has received speaking fees and/or research funds from Astellas,
Astra-Zeneca, GlaxoSmithKline, Meiji, MSD, Otsuka, Pfizer, Lilly, Mochida,
Tanabe, Yoshitomi , and Shionogi. He has received royalties from
Igaku-Shoin, Nanzando, Dainippon-Sumitomo, Takeda, Chugai-igakusya,
Kyorin medical supply and NHK enterprise.
KM has received speaking fees from Astellas, Dainippon-Sumitomo,
GlaxoSmithKline, Janssen, Lilly, Meiji, Otsuka, Pfizer and Shering-Plough.
MI has received grants from the Ministry of Health, Labor and Welfare,personal fees from Pfizer Japan Inc., personal fees from MochidaPharmaceutical Co., Ltd., personal fees from Shionogi & Co., Ltd., personal
fees from Nippon Hyoron Sha Co., Ltd., personal fees from Nanzando Co.,
Ltd., personal fees from Seiwa Shoten Co., Ltd., personal fees from
Igaku-shoin Ltd., and personal fees from Technomics, Inc., outside thesubmitted work.
NY has research funds from the Japanese Society of Clinical Pharmacology
and Therapeutics, the Japanese Ministry of Health, Labor and Welfare and
the Japanese Ministry of Education, Science, and Technology. He also
received royalties from Seiwa-Shoten, Herusu-Shupan and Arc Media.
HI has no conflicts of interest to declare.
AT has received honoraria for speaking at a meeting sponsored by Eli Lilly
and Tanabe-Mitsubishi.
YO has received research funds from the Japan Society for the Promotion of
Science and speaking fees from Eli Lilly.
NT has no conflicts of interest to declare.
YH has no conflicts of interest to declare.

Page 12 of 13

TAF has received lecture fees from Eli Lilly, Meiji, Mochida, MSD, Otsuka,
Pfizer and Tanabe-Mitsubishi, and consultancy fees from Sekisui Chemicals
and Takeda Science Foundation. He has received royalties from Igaku-Shoin,
Seiwa-Shoten and Nihon Bunka Kagaku-sha publishers. He has received grantor research support from the Japanese Ministry of Education, Science, andTechnology, the Japanese Ministry of Health, Labor and Welfare, the JapanFoundation for Neuroscience and Mental Health, Mochida andTanabe-Mitsubishi. He is a diplomate of the Academy of Cognitive Therapy.
Authors’ contributions
All authors contributed to the manuscript as follows: NW designed thestudy, interpreted the data, and drafted the manuscript. MH designed thestudy and interpreted the data. MY obtained funding, designed the study,
and interpreted the data. SS designed the study, acquired data, andinterpreted the data. TA designed the study, acquired data, and interpreted
the data. KM designed the study, acquired data, and interpreted the data. MI
designed the study, and interpreted the data. NY designed the study, andconducted statistical analysis. HI acquired data, and developed administrativeor technical materials. AT acquired data, and developed administrative or
technical materials. YO acquired data, and developed administrative or
technical materials. NT acquired data. YH acquired data. TAF obtained
funding, conceived of and designed the study, acquired data, interpreted
the data, developed administrative or technical materials and drafted themanuscript. He has also full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data
analysis. All authors have revised the important intellectual content criticallyand have read and approved the final manuscript.
Acknowledgments
This study has been supported by a Grant-in-Aid from the Ministry of Health,
Labor and Welfare Japan (H22-Seishin-Ippan-008) between 2010 and 2011,and by a grant for “Research Project for Pragmatic PsychopharmacologicalTreatment” by the Japan Foundation for Neuroscience and Mental Healthsince 2012. The Project has received donations from Asahi Kasei Pharma
Corp., Eli Lilly Japan KK, GlaxoSmithKline KK, Ltd., Janssen Pharmaceuticals KK,
Meiji Seika Pharma Co., Mitsubishi Tanabe Pharma Corporation, MSD KK,
Mochida Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Taisho
Pharmaceutical Co., Ltd., Pfizer Japan Inc., Ltd. and Shionogi & Co.
Institution at which the work was performed:
National Center of Neurology and Psychiatry, Japan;
Kyoto University Graduate School of Medicine/School of Public Health,Japan.
Author details
1
Department of Clinical Epidemiology, Translational Medical Center, National
Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo
187-8551, Japan. 2National Center for Cognitive Behavior Therapy andResearch, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi,
Kodaira, Tokyo 187-8551, Japan. 3Department of Neuropsychopharmacology,
National Institute of Mental Health, National Center of Neurology andPsychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8551, Japan.
4
Department of Neuropsychiatry, Kochi Medical School, Kochi University,
Kohasu, Okoh-cho, Nankokushi, Kochi 783-8505, Japan. 5Department of
Psychiatry and Cognitive-Behavioral Medicine, Nagoya City University
Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya
467-8601, Japan. 6Miki Clinic, 1-1-3 Hiranuma, Nishi-ku, Yokohama 220-0023,
Japan. 7Department of Neuropsychiatry, Okayama University Hospital, 2-5-1
Shikata-cho Kita-ku, Okayama 700-8558, Japan. 8Department of Field
Medicine, Kyoto University Graduate School of Medicine, 46
Shimoadachi-cho, Yoshida Sakyo-ku, Kyoto 606-8501, Japan. 9Departments ofHealth Promotion and Human Behavior, Kyoto University Graduate School of
Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto
606-8501, Japan.
Received: 9 February 2015 Accepted: 10 June 2015

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