JOURNAL OF MEDICAL INTERNET RESEARCH

Mantani et al

Original Paper

Smartphone Cognitive Behavioral Therapy as an Adjunct toPharmacotherapy for Refractory Depression: Randomized
Controlled Trial
Akio Mantani1, MD, PhD; Tadashi Kato2, MD; Toshi A Furukawa3, MD, PhD‡; Masaru Horikoshi4, PhD; Hissei
Imai3, MD, PhD; Takahiro Hiroe5, MD, PhD; Bun Chino6, MD, PhD; Tadashi Funayama7, MD, PhD; Naohiro
Yonemoto8, MPH; Qi Zhou9, PhD; Nao Kawanishi10, PhD
1

Mantani Mental Clinic, Hiroshima, Japan

2

Aratama Kokorono Clinic, Nagoya, Japan3

Department of Health Promotion and Human Behavior, School of Public Health, Graduate School of Medicine, Kyoto University, Kyoto, Japan

4

National Center of Neurology and Psychiatry, Kodaira, Japan

5

Waseda Clinic, Kani, Japan

6

Ginza Taimei Clinic, Tokyo, Japan

7

Funayama Mental Clinic, Nagoya, Japan

8

Department of Biostatistics, School of Public Health, Graduate School of Medicine, Kyoto University, Kyoto, Japan

9

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada

10

Advanced Telecommunications Research Institute International, Kyoto, Japan‡the FLATT Investigators

Corresponding Author:
Toshi A Furukawa, MD, PhD
Department of Health Promotion and Human Behavior
School of Public Health, Graduate School of Medicine
Kyoto University
Yoshida Konoe-cho
Sakyo-ku
Kyoto, 6068501
Japan
Phone: 81 757538941
Fax: 81 757534643
Email: furukawa@kuhp.kyoto-u.ac.jp

Abstract
Background: In the treatment of major depression, antidepressants are effective but not curative. Cognitive behavioral therapy(CBT) is also effective, alone or in combination with pharmacotherapy, but accessibility is a problem.
Objective: The aim is to evaluate the effectiveness of a smartphone CBT app as adjunctive therapy among patients withantidepressant-resistant major depression.
Methods: A multisite, assessor-masked, parallel-group randomized controlled trial was conducted in 20 psychiatric clinics andhospitals in Japan. Participants were eligible if they had a primary diagnosis of major depression and were antidepressant-refractory
after taking one or more antidepressants at an adequate dosage for four or more weeks. After a 1-week run-in in which participants
started the medication switch and had access to the welcome session of the app, patients were randomized to medication switch
alone or to medication switch plus smartphone CBT app via the centralized Web system. The smartphone app, called Kokoro-app(“kokoro” means “mind” in Japanese), included sessions on self-monitoring, behavioral activation, and cognitive restructuring
presented by cartoon characters. The primary outcome was depression severity as assessed by masked telephone assessors with
the Patient Health Questionnaire-9 (PHQ-9) at week 9. The secondary outcomes included the Beck Depression Inventory-II(BDI-II) and Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER).
Results: In the total sample (N=164), 81 participants were allocated to the smartphone CBT in addition to medication change
and 83 to medication change alone. In the former group, all but one participant (80/81, 99%) completed at least half, and 71 (88%)
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Mantani et alcompleted at least six of eight sessions. In the intention-to-treat analysis, patients allocated the CBT app scored 2.48 points (95%
CI 1.23-3.72, P<.001; standardized mean difference 0.40) lower on PHQ-9 than the control at week 9. The former group alsoscored 4.1 points (95% CI 1.5-6.6, P=.002) lower on BDI-II and 0.76 points (95% CI –0.05 to 1.58, P=.07) lower on FIBSER.
In the per-protocol sample (comfortable with the smartphone app, still symptomatic, and adherent to medication with mild or lessside effects after run-in), the intervention group (n=60) scored 1.72 points (95% CI 0.25-3.18, P=.02) lower on PHQ-9, 3.2 points(95% CI –0.01 to 6.3, P=.05) lower on BDI-II, and 0.75 points (95% CI 0.03-1.47, P=.04) lower on FIBSER than the control(n=57). The treatment benefits were maintained up to week 17.
Conclusions: This is the first study to demonstrate the effectiveness of a smartphone CBT in the treatment of clinically diagnosed
depression. Given the merits of the mobile mental health intervention, including accessibility, affordability, quality control, andeffectiveness, it is clinically worthwhile to consider adjunctive use of a smartphone CBT app when treating patients withantidepressant-resistant depression. Research into its effectiveness in wider clinical contexts is warranted.
Trial Registration: Japanese Clinical Trials Registry UMIN CTR 000013693; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/
ctr_view.cgi?recptno=R000015984 (Archived by WebCite at http://www.webcitation.org/6u6pxVwik)(J Med Internet Res 2017;19(11):e373) doi:10.2196/jmir.8602
KEYWORDS
major depressive disorder; pharmacotherapy-resistant depression; mobile phone app; cognitive behavioral therapy; eHealth

Introduction
Major depression is highly prevalent, debilitating, and costly[1-3]. It is predicted to be the leading cause of premature
mortality and disability in high-income countries by 2030, andthe third-leading cause in low- and middle-income countries[4]. Resources for and access to care by those who suffer remain
constrained in high-income countries, and severely so in lowto middle-income ones [5,6].
Although antidepressant pharmacotherapy represents themainstay of treatment of major depression [7], after several
weeks of treatment only 50% show reduction by half or morein their depression severity and only 30% return to a euthymic
state [8]. No standard approach in the management oftreatment-refractory
depression
exists.
Guideline
recommendations include increasing the dose, switching toanother antidepressant, or augmenting treatment with anotherpharmacological or psychological therapy [9,10].
Cognitive behavioral therapy (CBT) has proved an effective
treatment of major depression either alone [11] or in
combination with pharmacotherapy [12,13]. A standard courseof CBT, however, requires 10 to 20 sessions, each lasting 45 to
60 minutes, with an adequately qualified professional. Therefore,
its availability is limited everywhere in the world [14,15].
Telephone or videoconference CBT eliminates the burden of
in-person visits, but requires approximately equal therapist timeand equal competence.
Guided self-help CBT requires minimal to no clinician time andhas proved of comparable effectiveness to its face-to-faceversions [16]. Information and communication technologies(ICT) for self-help CBT, including computerized stand-alone
software and Internet-based webpages, have shown promising
results in initial trials [17]. However, one recent pragmatic trial
using two widely known online Web-based CBT packages failed
to demonstrate added value over usual care in primary carelikely because adherence to the program was very low [18].

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The dominant modality of ICT is evolving rapidly and thesmartphone is now transforming people’s lives across the world.
In comparison with stand-alone or Internet-connected computers,
the smartphone enhances portability and immediacy, making
CBT fully accessible and therefore promising new dimensionsof guided self-help. Mobile health apps are currently
proliferating in the electronic world, with more than 165,000
health apps available online [19-21]. However, few apps havedemonstrated quality [22,23] and no randomized controlled trial(RCT) has yet proved the benefits of a smartphone app incomparison with a control condition in the treatment of clinicallydiagnosed major depressive disorder. Several trials haveexamined the use of smartphone to monitor symptoms [24-26]
or smartphone apps applying the CBT principles, but only
among participants recruited from the general population who
had reported elevated levels of depressive symptoms on
self-reports [27-33]. A few have examined participants withdiagnosed major depression, but only against active controls.
One pilot RCT compared the original Web-based CBT against
its smartphone version in 35 participants with depression
confirmed through telephone diagnostic interview [34]. Anothergroup of researchers developed a smartphone app for behavioral
activation and tested it against its face-to-face full version [35]or against a mindfulness-based program [36] among 93 and 81
patients, respectively, who were recruited throughadvertisements in mass media but whose diagnosis of major
depression was confirmed through telephone interview. In thesestudies, results did not differ significantly between theintervention and control groups.
Whether smartphone-based CBT can have any demonstrable
value in the treatment of clinically diagnosed major depression
is a pressing issue for patients, clinicians, and policy makers
around the world [22,23]. We have developed and pilot-tested
a smartphone app, called Kokoro-app (kokoro means “mind”
in Japanese), that is based on a CBT manual with demonstrated
effectiveness in remote telephone or group formats in several
RCTs either alone [37,38] or in combination withantidepressants [39]. This study represents the first RCT toexamine adjunctive smartphone-based CBT to medication
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change among patients with major depression unresponsive toprior antidepressant treatments.

Methods
DesignThe study was a multisite, assessor-masked, parallel-group RCT
with a 1:1 allocation ratio.

Participants
A detailed description of the study protocol has been reported
elsewhere [40] and is attached as Multimedia Appendix 1. The
study, which was approved by the ethics committees of theparticipating centers and registered in the Japanese clinical trials
registry (UMIN CTR 000013693), took place in 20 psychiatricclinics and hospitals across Japan between September 2014 andOctober 2016. Multimedia Appendix 2 provides the complete
list of trial sites and investigators.
Eligible participants (1) were aged between 25 and 59 years,(2) had a primary diagnosis of major depressive disorder without
psychotic features according to the Diagnostic and Statistical
Manual of Mental Disorders (Fifth Edition) [41] as ascertainedby using the Primary Care Evaluation of Mental Disorders
procedure [42], (3) were antidepressant-resistant, defined as
scoring 10 or more on the Beck Depression Inventory-II (BDI-II)[37,43] after taking one or more antidepressants at an adequate
dosage for four or more weeks (stage I, II, or III according to
the criteria by Thase and Rush [44]), (4) had not been prescribed
escitalopram or sertraline, or received CBT or interpersonal
therapy for the index episode.
The study psychiatrists introduced the trial to the potentiallyeligible patients from among the patients they were seeing andinvited them to participate voluntarily. After full disclosure of
the trial contents and procedures, all participants provided
written informed consent. No advertisement through the media
was used.

Randomization
On entry, all participants started switching their antidepressant,had the Kokoro-app installed onto their iPhone, and had accessto the welcome session, which mainly aimed at, after a brief
description of CBT, training the participants in the use of thesmartphone and its speech recognition. (When the participants
did not own an iPhone, we lent one to them for the duration of
the trial.) After this 1-week run-in, they had a telephoneinterview with the Patient Health Questionnaire-9 (PHQ-9) andthe Frequency, Intensity, and Burden of Side Effects Ratings(FIBSER) and were classified into one of two samples. The
per-protocol sample comprised those who had not or only
partially responded since week 0 (PHQ-9 scores ≥5 [45] at week1), who tolerated and adhered to the new antidepressant, andhad no problem using the smartphone and Kokoro-app. The
auxiliary sample included all others. The total sample (theper-protocol sample plus the auxiliary sample) would answer
the real-world question of the value of smartphone CBT among
the patients for whom the clinicians would initially consider
prescribing the smartphone CBT, including those who would

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Mantani et al
not tolerate the new medication or who may have some difficultyusing the smartphone app, whereas the per-protocol sample
would answer the question of the value of smartphone CBTunder the narrower circumstances (ie, among patients who wereable to follow the protocol and for whom the app would be
expected to demonstrate its full effects).
After stratification by group, the participants were randomized
1:1 to the combined antidepressant switch plus smartphone CBTarm (intervention arm) or the antidepressant switch alone arm(control arm) using an automated Web program implementing
the method of minimization. Therefore, the randomization wasconcealed. Clinics, number of antidepressants previouslyprescribed for the index episode (≥3 vs <3), and a total scoreof the PHQ-9 at week 1 (≥10 vs <10) were used as minimization
variables.
During the telephone interview for the PHQ-9, if participants
reported suicidal ideation for more than half the days or nearly
every day of the previous 2 weeks, the interviewer immediately
notified the staff in the central office, who then notified the
responsible psychiatrist.

Interventions
The intervention group received both the antidepressant switch
and the smartphone CBT, whereas the control group received
only the antidepressant switch during the intervention period
up to week 9. Details of each intervention are described
subsequently.

Antidepressant Switch
All study participants started switching their antidepressanteither to escitalopram (5-10 mg/day) or to sertraline (25-100
mg/day) at week 0. The previous antidepressant was tapered
off by week 5. We limited choice of antidepressants toescitalopram and sertraline, which showed a favorable profilein efficacy and acceptability in a previous systematic review[46], to ensure balance in antidepressant treatments during thetrial. If the participants did not tolerate escitalopram or sertraline,
the physician could revert to the previous antidepressant or starta new one. Only anxiolytics and hypnotics were allowed as
coprescribed psychotropics. The frequency of visit was set atleast once in four weeks, with additional visits as judged
necessary by the study physician.

Smartphone Cognitive Behavioral Therapy
Kokoro-app is a self-help smartphone app consisting of eight
sessions, including one welcome session, two sessions on
self-monitoring, two sessions on behavioral activation, twosessions on cognitive restructuring, and an epilog focusing on
relapse prevention. In each session, explanation of the principles
and skills of CBT is provided in the format of instant messenger
exchanges among cartoon characters (Figure 1). In the
self-monitoring sessions, patients learn how to monitor theirreactions to situations in terms of feelings, thoughts, bodyreactions, and behaviors and describe them in “mind maps.” In
the behavioral activation sessions, patients learn to engage in“personal experiments” of small pleasurable actions according
to the principle “When your body moves, so does your mind.”

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Figure 1. Screenshots from Kokoro-app.

To help patients broaden their thoughts, the cognitive
restructuring sessions provide four tools, each of which guides
the patients to alternative thoughts through interaction with thecharacters. Each session is supposed to take 1 week: participants
can proceed to the next session only after 1 week and only after
they have completed one homework from that session. See
Multimedia Appendix 3 for more details. One session requires
approximately 20 minutes to complete.
The progress of each participant on Kokoro-app could bemonitored at “Kokoro-Web.” Participants and their treating
psychiatrists could access their records using a unique
identification number and password. Secure Sockets Layercertified security of the data exchanged through the Internet.
Every week, the central office sent an email to participants tocongratulate them on their progress. The message was templated
but individually modified based on the progress of participants
and the comments they uploaded at the end of each session.
Writing one such email took 3 to 10 minutes.
All study participants had access to the welcome session at week
0. After randomization at week 1, the intervention group
received another password and continued with further sessions.
The control group continued with the medication change only.
Face-to-face CBT or interpersonal therapy were prohibited for
either group.

Follow-Up Period After 9 Weeks
After assessments at week 9, there were no further restrictions
in medications or psychotherapies. The participants in thecontrol arm received a password to begin the Kokoro-app;follow-up assessments took place at week 17.

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Outcomes
The masked assessors interviewed the participants by telephonewith PHQ-9 and FIBSER at weeks 0, 1, 5, 9, and 17.
The primary outcome was the PHQ-9 at week 9. It consists of
the nine diagnostic criteria items of major depression [47]. Each
item is rated between 0=“not at all” through 3=“nearly everyday.” The total score ranges between 0 and 27. The instrument
has excellent reliability, validity, and responsiveness [48].
Remission was defined as scoring four or less on PHQ-9, andresponse as 50% or greater reduction from baseline.
Secondary outcomes included the FIBSER, which assesses thefrequency, intensity, and burden of side effects, each on a
7-point scale, with a total score between 3 and 27, [49] and the
BDI-II [43], a self-report measure of depression severity thatasks about 21 symptoms of depression, each on a scale between
0 and 3, with the total score between 0 and 63.
The study participants and the psychiatrists in charge of
medication change were aware of the treatment allocation. The
outcome assessors conducting telephone interviews were
unaware of allocation. The success of this masking wasevaluated by calculating the Bang Index [50] of assessors’
treatment guesses after each telephone assessment. The Bang
Index is scaled to an interval of –1 to 1, 1 being complete lackof blinding, 0 being consistent with perfect random guessing,and –1 indicating opposite guessing.

Sample Size
The study was powered to detect a moderate effect size of 0.5
in terms of standardized mean difference between the twotreatments for the primary outcome at week 9, with 80% power
at two-sided alpha level of .05. Assuming that 30% would leave

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the study or be classified into the auxiliary group at week 1, therequired total sample size was 164 participants.

Statistical Analysis
All analyses were undertaken according to the intention-to-treat
principle, including all the randomized participants for the total
sample as well as for the per-protocol sample.
For each continuous outcome up to week 9, we used a linear
mixed model including sites and patients as random effects andtime (5 and 9 weeks), treatment, and time*treatment interaction,
adjusting for its baseline score and the stratification variables,
as fixed effects. The primary endpoint was the estimate of theleast squares mean difference along with the 95% confidence
interval (95% CI) at week 9. For the continuous outcome atweek 17 follow-up, we used the similar linear mixed model but
without the time*treatment interaction because this was a
one-time comparison after all the participants received thesmartphone CBT both in the intervention and the control groups.
For the dichotomous outcomes, we used a generalized linear
mixed model with the same random effects and the fixed effects.
We chose odds ratios as the measure of effect. We used SAS
version 9.4 (SAS Institute Inc, Cary, NC, USA). Multimedia
Appendix 1 provides the statistical analysis plan.

Blinded Interpretation of the Results
The statistician (QZ), blinded to allocation, conducted thestatistical analyses. The writing committee reviewed a statisticalreport in which the two treatment arms were designated A andB, and developed interpretation of the results and associated

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Mantani et alconclusions under two different scenarios, one assuming A to
be the smartphone CBT plus medication change arm and B tobe the medication change alone arm, and another alternative
scenario. The code was broken only after the writing committee
signed off on the agreed-on interpretations (see Multimedia
Appendix 4).

Results
Participant Characteristics
Figure 2 shows the flow of participants through the study.
Between September 2, 2015, and July 1, 2016, 323 patientswere assessed for eligibility; 166 patients provided informed
consent and started medication change. Two withdrew consent
before randomization at week 1. Therefore, we recruited 164
patients, of whom 117 found no difficulty with the smartphone,were adherent to the protocol treatment, remained at least
moderately symptomatic, and constituted the per-protocol
sample; 60 were allocated to the smartphone CBT and 57 to
medication change alone. Of the remaining 47 participants inthe auxiliary group, 21 were allocated to the intervention groupand 26 to control. Primary outcome data at 9 weeks wereobtained from all but one randomized participant (163/164,
99.4%).
Table 1 shows that the baseline demographic and clinicalcharacteristics of the treatment groups were well balanced.
Typically, patients were in their thirties to forties, had threeprevious episodes, were in the current episode for nearly 2 years,
and were severely to moderately depressed.

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Figure 2. Assessment, randomization, and follow-up of study participants. CBT: cognitive behavioral therapy; PHQ-9: Patient Health Questionnaire
9; TAU: treatment as usual.

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Table 1. Baseline characteristics of the intention-to-treat samples.
Characteristics

Total sample (N=164)

Per-protocol sample (n=117)

Smartphone CBT +medication change(n=81)

Medication change
alone (n=83)

Smartphone CBT +medication change(n=60)

Medication change
alone (n=57)

Age (years), mean (SD)40.2 (8.8)

41.6 (8.9)

40.1 (9.0)

41.2 (8.6)

Sex (female), n (%)

46 (57)41 (50)35 (58)31 (54)

Education (years), mean (SD)14.6 (2.5)

14.9 (2.7)

14.8 (2.5)

15.1 (2.9)

Employed full-time

34 (42)29 (35)27 (45)21 (37)

Employed part-mime

7 (9)

5 (6)

5 (8)

5 (9)

On medical leave

21 (26)30 (36)14 (23)21 (37)

Housewife

6 (7)

5 (6)

5 (8)

3 (5)

Student

0

2 (21)0

1 (2)Retired

0

0

0

0

Not employed13 (16)12 (15)9 (15)

6 (11)

34 (42)31 (38)24 (40)22 (39)Single, divorced, separated or widowed 13 (16)7 (8)12 (20)5 (9)Married34 (42)45 (54)24 (40)30 (53)Age of onset at first episode (years)

31.8 (10.8)

34.6 (10.0)

32.2 (11.0)

34.0 (10.2)

Number of previous depressive episodes

3.4 (4.9)

3.0 (4.5)

3.5 (4.7)

2.8 (4.6)

Length of current episode (months)

24.2 (46.3)

23.0 (46.5)

27.0 (52.6)

22.3 (42.5)

Week 013.5 (5.5)

12.9 (5.3)

14.0 (5.2)

13.8 (5.1)

Week 1

12.6 (6.2)

11.9 (5.9)

13.4 (5.6)

12.6 (5.5)

Week 028.2 (11.2)

26.2 (11.0)

29.4 (10.6)

27.4 (10.7)

Week 1

26.2 (11.7)

24.7 (12.2)

28.1 (11.0)

26.2 (11.6)

Week 04.8 (4.5)

5.2 (3.1)

4.4 (2.8)

5.4 (2.9)

Week 1

6.4 (4.5)

6.8 (4.4)

5.0 (3.0)

5.2 (2.5)

Demographic characteristics

Employment status, n (%)

Marital status, n (%)
Single, never marriedBaseline clinical characteristics, mean (SD)

PHQ-9 aBDI-II a

FIBSER aa

BDI-II: Beck Depression Inventory-II; FIBSER: Frequency, Intensity, and Burden of Side Effects Ratings; PHQ-9: Patient Health Questionnaire 9.

Treatments Received
In the total sample, 16 of 81 participants (20%) stopped theprotocol antidepressant treatment by escitalopram or sertraline
in the intervention arm, as did 14 of 83 (17%) in the medication
only arm (Table 2). Some received augmentation drugs, suchas antipsychotics or lithium, which were not allowed in the
protocol for the antidepressant switch (n=15 in the total sample),a few had deterioration or side effects and could not continue
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did not want to continue with the protocol medication (n=2).
The medication dosages were comparable between the arms.
For the smartphone CBT, all but one participant (80/81, 99%)
completed at least half the sessions of the program, and 71 of
81 (88%) completed at least six of eight sessions. It took thepatients, on average, 10.8 (SD 4.2) days to complete one session.
The patients filled in a mean 11.2 (SD 11.4) “mind maps” forself-monitoring, conducted a mean 14.4 (SD 17.1) behavioral
activation “personal experiments,” and generated a mean 6.1(SD 6.0) alternative thoughts for cognitive restructuring (Table
2).
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Table 2. Treatment received in the intention-to-treat samples.
Therapy

Total sample (N=164)
Smartphone CBT +medication change(n=81)

Per-protocol sample (n=117)
Medication change
alone (n=83)

Smartphone CBT +medication change(n=60)

Medication change
alone (n=57)

14 (17)10 (17)8 (14)

Pharmacotherapy
Discontinuation of protocol antidepressant 16 (20)treatment by escitalopram or sertraline by
week 9, n (%)
Discontinuation reason, n
Prescription of prohibited drugs

6

9

4

5

Amelioration

1

1

—

1

Deterioration

1

—

1

—

Side effects

3

1

1

—

Other

5

3

4

2

Discontinuation of any antidepressant ther- 5 (6)apy by week 9, n (%)

2 (2)

2 (3)

2 (4)

Escitalopram dosage at week 9 (mg/day),mean (SD)

10.0 (3.2), n=49

9.7 (3.1), n=38

10.1 (2.9), n=34

83.6 (23.4), n=29

81.6 (26.1), n=19

83.0 (24.9), n=22

9.5 (3.0), n=48

Sertraline dosage at week 9 (mg/day), mean 79.0 (26.7), n=25
(SD)
Smartphone CBT—Sessions completed, n
0

1

—

3

1

1

4

4

3

5

4

2

6

11

8

7

17

13

8

43

33

Time per session (days), mean (SD)

10.8 (4.2)—

10.7 (4.0)—

Number of mind maps for self-monitoring, 11.2 (11.4)
mean (SD)—

10.8 (10.3)—

Number of behavioral activation tasks,
mean (SD)—14.6 (17.8)——

6.5 (6.0)—

14.4 (17.1)

Number of alternative thoughts, mean (SD) 6.1 (6.0)

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Table 3. Outcomes at weeks 9 and 17 for the total sample (N=164).
Outcomesa

P value

Smartphone CBT + medication change

Medication change alone

Adjusted difference/OR(n=81), mean/% (95% CI)(n=83), mean/% (95% CI)(95% CI)b

PHQ-9

7.94 (6.98, 8.89)

10.41 (9.45, 11.33)–2.48 (–3.72, –1.23)<.001

Remission

30.5% (19.7%, 43.9%)

17.8% (10.3%, 29.0%)

2.02 (0.93, 4.42).08

Response

42.3% (29.4%, 56.4%)

21.2% (12.7%, 33.2%)

2.73 (1.35, 5.53).005

BDI-II

19.3 (17.0, 21.5)

23.3 (21.6, 25.5)–4.1 (–6.6, –1.5).002

FIBSER

4.38 (3.72, 5.03)

5.14 (4.52, 5.76)–0.76 (–1.58, 0.05)

.07

PHQ-9

7.95 (6.73, 9.17)

8.76 (7.58, 9.95)–0.81 (–2.24, 0.62).26

BDI-II

17.2 (14.4, 20.0)

19.1 (16.4, 21.8)–1.9 (–4.9, 1.2)

.22

FIBSER

4.62 (3.83, 5.42)

5.10 (4.32, 5.89)–0.48 (–1.34, 0.37).27

End of randomized trial (week 9)

Follow-up (week 17)a

BDI-II: Beck Depression Inventory-II, FIBSER: Frequency, Intensity, and Burden of Side Effects Ratings, PHQ-9: Patient Health Questionnaire 9.

b

For each continuous outcome up to week 9, we used a linear mixed model including sites and patients as random effects and time (5 and 9 weeks),
treatment, and time*treatment interaction, adjusting for its baseline score and the stratification variables, as fixed effects. For the continuous outcome
at week 17 follow-up, we used the similar linear mixed model but without time*treatment interaction. For the dichotomous outcomes, the generalized
linear mixed model was used along with the same random effects and the fixed effects. The summary effect measures are adjusted score differences for
PHQ-9, BDI-II, and FIBSER, and are odds ratios for remission and response.

Outcomes for the Total Sample
In the intention-to-treat analysis of the total sample, patients
who were allocated the CBT app (n=81) scored 2.48 points(95% CI 1.23-3.72, P<.001; standardized mean difference[SMD] 0.40) lower on PHQ-9 than those who were not (n=83)
at week 9 (Table 3, Figure 3). The former group also scored 4.1
points (95% CI 1.5-6.6, P=.002) lower on BDI-II. Significantly
more participants showed response (OR 2.73, 95% CI 1.35-5.53,
P=.005). However, the increase in remission did not reachstatistical significance (OR 2.02, 95% CI 0.93-4.42, P=.08).
With regard to the harm outcomes, patients using the smartphone
CBT reported somewhat less overall burden of side effects, but
the difference was not statistically significant (FIBSER meandifference=–0.76, 95% CI –1.58 to 0.05, P=.07). There was one
report of suicidality (self-injurious behavior without suicidal
intent) in the combined treatment arm and one report of a serious
adverse event in the control arm (brief hospital admission for
examination of preexisting spinal canal stenosis).

Outcomes for the Per-Protocol Sample
In the per-protocol sample, who were comfortable with thesmartphone app, were still symptomatic, and were adherent tomedication with mild or less side effects after the run-in, thepatients who received smartphone CBT in addition to medication
change (n=60) scored mean 1.72 (95% CI 0.25-3.18, P=.02;
SMD 0.28) points lower on PHQ-9 than those undergoing
medication change alone (n=57) at week 9. The combined
treatment arm was superior to the control arm in terms of BDI-II

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RenderX(difference=–3.2, 95% CI –6.3 to 0.0, P=.05, not statisticallysignificant), but not in terms of remission (OR 1.99, 95% CI
0.74-5.38, P=.17) or response (OR 2.11, 95% CI 0.92-4.85,
P=.08).
In terms of the harm outcome, the combination treatment arm
reported significantly less overall burden of side effects(FIBSER mean difference=–0.75, 95% CI –1.47 to –0.03, P=.04)(Table 4, Figure 3).

Follow-Up at Week 17
The participants who had access to the smartphone app in thefirst 9 weeks maintained their gains for a further 8 weeks. At
week 17, when the participants in the control arm also had accessto the smartphone app, the results were comparable between
the two groups in terms of PHQ-9, BDI-II, and FIBSER, bothfor the total sample and for the per-protocol sample (Tables 3
and 4).

Masking
The Bang Index of the treatment guesses by the masked
assessors at weeks 5, 9, and 17 was 0.10 (95% CI –0.13 to 0.33),
0.29 (95% CI 0.06-0.51), and 0.30 (95% CI 0.08-0.52) for theintervention arm and –0.21 (95% CI –0.45 to 0.03), –0.18 (95%
CI –0.41 to 0.06), and –0.30 (95% CI –0.53 to –0.07) for thecontrol arm, respectively. The observed patterns indicate thatthe raters guessed the treatment allocation haphazardly orguessed it to be the smartphone CBT arm more often regardlessof the actual allocation, resulting in ideally unbiased assessmentof outcomes in the trial [51].

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Mantani et al

Figure 3. Trajectory of the Patient Health Questionnaire-9 (PHQ-9), Beck Depression Inventory-II (BDI-II), and Frequency, Intensity, and Burden ofSide Effects Ratings (FIBSER) scores for the intervention (blue line) and control (red line) groups in the total (N=164) and per-protocol (n=117) samples.
Error bars show standard errors for model-based least squares means.

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Mantani et al

Table 4. Outcomes at weeks 9 and 17 for the per-protocol sample (n=117).
Outcomesa

P value

Smartphone CBT + medication change

Medication change alone

Adjusted difference/OR(n=60), mean/% (95% CI)(n=57), mean/% (95% CI)(95% CI)b

PHQ-98.92 (7.81, 10.03)

10.64 (9.52, 11.76)–1.72 (–3.18, –0.25)c.02

Remission

18.2% (8.5%, 34.8%)

10.0% (4.0%, 23.2%)

1.99 (0.74, 5.38).17

Response

31.6% (18.7%, 48.3%)

18.0% (9.2%, 32.3%)

2.11 (0.92, 4.85).08

BDI-II

21.0 (18.6, 23.5)

24.2 (21.7, 26.8)–3.2 (–6.3, 0.0).05

FIBSER

4.11 (3.44, 4.78)

4.86 (4.18, 5.53)–0.75 (–1.47, –0.03)

.04

PHQ-9

8.92 (7.40, 10.44)

8.85 (7.31, 10.39)

0.07 (–1.68, 1.82).94

BDI-II

19.4 (15.9, 22.9)

20.0 (16.5, 23.6)–0.6 (–4.4, 3.1)

.75

FIBSER

4.14 (3.40, 4.88)

4.46 (3.71, 5.21)–0.32 (–1.28, 0.63).50

End of randomized trial (week 9)

Follow-up (week 17)a

BDI-II: Beck Depression Inventory-II; FIBSER: Frequency, Intensity, and Burden of Side Effects Ratings; PHQ-9: Patient Health Questionnaire 9.

b

For each continuous outcome up to week 9, we used a linear mixed model including sites and patients as random effects and time (5 and 9 weeks),
treatment, and time*treatment interaction, adjusting for its baseline score and the stratification variables, as fixed effects. For the continuous outcome
at week 17 follow-up, we used the similar linear mixed model but without time*treatment interaction. For the dichotomous outcomes, the generalized
linear mixed model was used along with the same random effects and the fixed effects. The summary effect measures are adjusted score differences for
PHQ-9, BDI-II, and FIBSER, and are odds ratios for remission and response.
cPrimary endpoint per protocol.

Discussion
In patients with major depression who had not responded to one
or more antidepressants, adding smartphone CBT to medication
change was more effective than treatment by medication change
alone. The smartphone CBT also decreased the overall side
effect burden of the pharmacotherapy.
The magnitude of benefit of the adjunctive mobile CBT wasapproximately 2 points on the PHQ-9 and 3 to 4 points on the
BDI-II. Using the observed standard deviation at week 9, thesedifferences translate into standardized mean differences of 0.28
to 0.40 and are comparable to that of 0.31 for antidepressants
over placebo reported in a comprehensive systematic review ofphase II or III RCTs [52]. The remission and response rates
almost doubled, corresponding with numbers needed to treat
between 5 and 12.
Although several smartphone CBT apps have been experimented
among general population participants with elevatedself-reported symptoms [27-33], Kokoro-app is the firstsmartphone CBT app to prove to be effective in a RCT incomparison with an alternative treatment for patients sufferingfrom clinically diagnosed major depression. Advantages ofsmartphone CBT include high accessibility, efficiency, andaffordability. Further, it is less susceptible to quality control
problems that may plague face-to-face therapies [53].
Unexpectedly, Kokoro-app also reduced the global burden ofside effects due to pharmacotherapy. We speculate that thesmartphone CBT, through which the patient actively searches
for ways to overcome their depression, may increase their senseof self-control and decrease the subjective burden of side effects
in comparison with standard pharmacotherapy.

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All benefits were larger in the total sample than in the
per-protocol comparison, where we had anticipated a larger
effect at the protocol stage. Participants were not included in
the per-protocol sample mainly because they suffered from side
effects from the medication change (31 of 47, see Figure 1).
The CBT app may be particularly beneficial to those patients
who experience significant side effects with medication.
Strengths of this study include the concealed randomization,
the successful masking of the outcome assessors, the close to100% follow-up, the stratified randomization that allowed
assessment of intervention impact in two key samples, andcorroboration of the secondary outcomes including patients’
self-reports. We followed the participants for 8 weeks after theend of the randomized comparison: the participants in the active
intervention arm maintained the benefits, and the participantsin the control arm who had access to Kokoro-app improved.
Finally, the uptake of the CBT sessions via smartphone wassatisfactory, with close to 90% of the participants finishing atleast six of eight program sessions and actively engaging in
homework tasks.
This study is not without limitations. First, it is possible thatparticipants in the control condition, who were not allowed
access to CBT sessions at the beginning but only after thewaiting period, may have suffered “disappointment effect”
through the intervention period. We tried to mitigate thislimitation that may be common to many waiting list-controlled
trials by not making our control condition a simple waiting list
control in which the participants are not allowed to change theirtreatment [54], but an active medication change, which is oneoftherecommended
treatment
optionsfor
antidepressant-refractory patients. Nonetheless, the possibilityof some contribution of disappointment effect among the control
group cannot be negated. Secondly, it was impossible to mask
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JOURNAL OF MEDICAL INTERNET RESEARCH
the participants and the clinicians administering drug treatment
to the treatment allocation. However, we employed the remotetelephone assessors to conduct assessments of the primary
outcome, which resulted in successful masking. Lastly, it must
be pointed out that in this refractory population, although thesmartphone CBT in conjunction with medication switch
substantively decreased depression severity, approximately 70%
to 80% were still not remitted after 2 months of the combined
treatment; additional face-to-face standard CBT may be helpful
for these remaining patients.
These findings have demonstrated the effectiveness of
smartphone CBT as an adjunctive intervention for
antidepressant-resistant major depression. Given the merits ofMantani et al
the mobile mental health intervention, including accessibility,
affordability, quality control, and effectiveness, patients andclinicians may wish to use smartphone CBT as an adjunctive
intervention when their depression does not respond adequately
to antidepressant treatment alone. Further research of its
effectiveness in wider clinical contexts, including its use as astand-alone treatment in major depression and its role in relapse
prevention, and in public health contexts such as its use forsubthreshold depressive states or its utility in low- andmiddle-income countries is warranted. Elucidation of theeffective components of the smartphone CBT package and theirappropriate dosages and their integration within the existing
health care systems also constitute areas needing further
research.

Acknowledgments
The study was funded by the Ministry of Health, Labor and Welfare, Japan (H-22-Seishin-Ippan-008) from April 2013 throughMarch 2014, and thereafter by the Japan Foundation for Neuroscience and Mental Health (JFNMH). The JFNMH received
donations from Asahi Kasei, Eli Lilly, GSK, Janssen, MSD, Meiji Seika, Mochida, Otsuka, Pfizer, Shionogi, Taisho, andMitsubishi-Tanabe. The funders had no role in the design and conduct of the study; collection, management, analysis, andinterpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Authors' Contributions
TAF and QZ had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy ofthe data analysis. Study concept and design: TAF, MH, and NY. Acquisition, analysis, or interpretation of data: AM, TK, TAF,
MH, HI, TH, BC, TF, NY, QZ, and NK. Drafting of the manuscript: TAF. Critical revision of the manuscript for important
intellectual content: AM, TK, TAF, MH, HI, TH, BC, TF, NY, QZ, and NK. Statistical analysis: QZ and TAF. Obtained funding:
TAF. Administrative, technical, or material support: HI, NY, and NK. Study supervision: TAF and MH.

Conflicts of Interest
AM has received lecture fees from Mochida, Eli Lilly, and Meiji. TK has received lecture fees from Eli Lilly and Mitsubishi-Tanabe,
and has contracted research with GlaxoSmithKline, MSD, and Mitsubishi-Tanabe. TAF has received lecture fees from Eli Lilly,
Janssen, Meiji, MSD, Otsuka, Pfizer, and Mitsubishi-Tanabe, and consultancy fees from Takeda Science Foundation. He hasreceived research support from Mochida and Mitsubishi-Tanabe. TH has received lecture fees from Otsuka and MSD. BC has
received lecture fees from Eli Lilly, Meiji, and Mitsubishi-Tanabe. TF has received lecture fees from Eli Lilly, Meiji, MSD,
Otsuka, Pfizer, and Mitsubishi-Tanabe. TAF and MH developed the Kokoro-app. All the other authors declare that they have nocompeting interests.

Multimedia Appendix 1
Original study protocol (August 2014) and statistical analysis plan (July 2016).
[PDF File (Adobe PDF File), 275KB - jmir_v19i11e373_app1.pdf ]Multimedia Appendix 2
FLATT investigators and committee members.
[PDF File (Adobe PDF File), 77KB - jmir_v19i11e373_app2.pdf ]Multimedia Appendix 3
Contents of Kokoro-app.
[PDF File (Adobe PDF File), 824KB - jmir_v19i11e373_app3.pdf ]Multimedia Appendix 4
Blinded data analyses statement of interpretation.

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Mantani et al[PDF File (Adobe PDF File), 128KB - jmir_v19i11e373_app4.pdf ]Multimedia Appendix 5
CONSORT‐EHEALTH checklist (V.1.6.1).
[PDF File (Adobe PDF File), 8MB - jmir_v19i11e373_app5.pdf ]References
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Abbreviations
BDI-II: Beck Depression Inventory-II
CBT: cognitive behavioral therapy
FIBSER: Frequency, Intensity, and Burden of Side Effects Ratings
PHQ-9: Patient Health Questionnaire 9
RCT: randomized controlled trial

Edited by G ; submitted 29.07.17; peer-reviewed by K Hallgren, S Moritz; comments to author 24.08.17; revised version received
02.09.17; accepted 23.09.17; published 03.11.17
Please cite as:
Mantani A, Kato T, Furukawa TA, Horikoshi M, Imai H, Hiroe T, Chino B, Funayama T, Yonemoto N, Zhou Q, Kawanishi N
Smartphone Cognitive Behavioral Therapy as an Adjunct to Pharmacotherapy for Refractory Depression: Randomized Controlled
Trial
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