Furukawa et al. Trials 2011, 12:116
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STUDY PROTOCOL

TRIALS
Open Access

Strategic use of new generation antidepressantsfor depression: SUN(^_^)D study protocol
Toshi A Furukawa1*, Tatsuo Akechi2, Shinji Shimodera3, Mitsuhiko Yamada4,5, Kazuhira Miki6, Norio Watanabe2,
Masatoshi Inagaki4,7 and Naohiro Yonemoto5

Abstract
Background: After more than half a century of modern psychopharmacology, with billions of dollars spent on
antidepressants annually world-wide, we lack good evidence to guide our everyday decisions in conducting
antidepressant treatment of patients with major depression. First we did not know which antidepressant to use as
first line treatment. Second we do not know which dosage we should be aiming at with that antidepressant.
Because more than half of the patients with major depression starting treatment do not remit after adequate trial
with the first agent, they will need a second line treatment. Dose escalation, augmentation and switching are thethree often recommended second line strategies but we do not know which is better than the others. Moreover,
we do not know when to start considering this second line treatment.
The recently published multiple-treatments meta-analysis of 12 new generation antidepressants has provided somepartial answers to the first question. Starting with these findings, this proposed trial aims to establish the optimum
1st line and 2nd line antidepressant treatment strategy among adult patients with a non-psychotic unipolar major
depressive episode.
Methods: SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded,parallel-group, multi-centre randomised controlled trial. Step I is a cluster-randomised trial comparing titration up to theminimum vs maximum of the recommended dose range among patients starting with sertraline. The primary outcome
is the change in the Patient Health Questionnaire (PHQ)-9 scores administered by a blinded rater via telephone at week
1 through 3. Step II is an individually randomised trial comparing staying on sertraline, augmentation of sertraline withmirtazapine, and switching to mirtazapine among patients who have not remitted on the first line treatment by week 3.
The primary outcome is the change in the PHQ-9 scores at week 4 through 9. Step III represents a continuation phase
to Steps I and II and aims to establish longer-term effectiveness and acceptability of the above-examined treatment
strategies up to week 25. The trial is supported by the Grant-in-Aid by the Ministry of Health, Labour and Welfare, Japan.
Discussion: SUN(^_^)D promises to be a pragmatic large trial to answer important clinical questions that every clinician
treating patients with major depression faces in his/her daily practices concerning its first- and second-line treatments.
Trial registration: ClinicalTrials.gov: NCT01109693

Background
Depression is costly

Major depression is the 1 st leading cause of disability
adjusted life years (DALY) lost excluding death, and the
3rd leading cause of DALY including death in the world
according to the most recent WHO estimates [1].
* Correspondence: furukawa@kuhp.kyoto-u.ac.jp
1
Department 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

Moreover, this burden is expected to rise in the next 20
years. According to the same estimates, major depression is currently the 1st leading cause of DALY excluding death and the 2nd leading cause of DALY including
death after cerebrovascular disease in Japan, comprising
approximately 6% of all DALY lost among its people.
Major depression is indeed one of the most prevalentmental disorders in the United States and Europe, with
16.2% and 6.6% lifetime prevalence for American
women and men [2] and with 16.5% and 8.9% for European women and men [3]. In Japan, while the point© 2011 Furukawa et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

Furukawa et al. Trials 2011, 12:116
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estimates are lower than in US or Europe, it is still themost prevalent mental disorder for its people, affecting
one in 12 women (8.5%) and one in 29 men (3.5%) atleast once in their lifetime [4].
Both pharmacotherapy and psychotherapy have beenfound to be equally effective in treating major depression [5] but the former remains the mainstay in everyday clinical practices due to its greater availability,
tighter quality control and cheaper costs. Effective antidepressive agents include heterocyclic antidepressants(HCA), monoamine oxidase inhibitors (MAOI), selective
serotonin reuptake inhibitors (SSRI), serotonin and noradrenaline reuptake inhibitors (SNRI), noradrenalinergicand specific serotonergic antidepressant (NaSSA) andothers (such as bupropion). The dramatic rise in the
consumption of antidepressants in developed countries
in the past two decades has been mainly due to increasein use of SSRI, SNRI and other new generation antidepressants, which now are the most commonly prescribed antidepressants in the world [6]. In Japan themarket for antidepressants had been hovering around 15
billion yen (166 million US dollars) per year up to 1999
but has been expanding by some 20% annually, reaching
120 billion yen (1.3 billion US dollars) in 2009, in which
new generation antidepressants holds 89% share.
Evidence on 1st line choice of antidepressants

There is no question that we need a specific, detailed
and appropriate guidelines in the treatment of major
depression. However, all the guidelines up to 2008,
including the one by the American Psychiatric Association [7], the one by the Canadian Psychiatric Association[8], the one by the National Institute of Clinical Excellence in the United Kingdom [9] and the Japanese one[10], recommend that the choice of antidepressants bemade “on the basis of adverse effect profiles, cost, andpatient preferences” [11] because there are differences inside effect profiles but not in effectiveness among various antidepressants [12].
However, in 2009, the research group from Japan, Italy
and UK published the results of a systematic review of
117 RCTs (25928 subjects) of 12 new generation antidepressants in the acute phase treatment of major depression [13]. The Meta-analyses of New Generation
Antidepressants (MANGA) study is based on the mostcomprehensive dataset of RCTs involving new generation antidepressants from the Cochrane Collaboration
Depression, Anxiety and Neurosis Group and makes useof a new meta-analytic method called multiple-treatments meta-analysis (MTM; also sometimes referred toas network meta-analysis), which integrates data fromdirect (when treatments are compared within a randomised trial) and indirect comparisons (when treatments
are compared between trials by combining results on

Page 2 of 20

how effective they are compared with a common comparator treatment). MTM thus allows a more precise
estimate of comparative effectiveness with narrower
confidence intervals than the traditional meta-analyses
because it makes use of all direct and indirect comparisons. MTM also minimizes the influence of publication
bias because a possible publication bias favoring a particular antidepressant can be counterbalanced by othersimilar biases favoring other antidepressants when all
direct and indirect comparisons are combined through
MTM.
The MANGA Study observed many statistically significant and clinical meaningful differences among the 12
new generation antidepressants. In terms of efficacy,
mirtazapine, escitalopram, venlafaxine and sertraline
were among the top four drugs; in terms of acceptability, escitaloporam, sertraline, bupropion and citalopram
were superior to the others. The authors concluded that
sertraline might be the best choice when starting treatment for moderate to severe major depression in adults
because it has the most favorable balance between benefits, acceptability, and acquisition cost.
Evidence on 2nd line choice of antidepressants

Treatment of major depression is not easy because only
some 50% respond, i.e. achieve depression severity lessthan half that at baseline, or only some 30% achieveremission, i.e. return to an euthymic state, after treatment with an adequate dose of antidepressant given for
an adequate duration [14]. When patients show no to
only partial response to the 1st line treatment, 2nd line
treatments must be initiated. Guidelines recommendations for the 2nd line treatment include dose escalation,
switching to a different antidepressant possibly from adifferent class and augmentation [9,15]. Unfortunately,
however, when many RCTs are planned and executedwith the purpose of drug approval by the regulatory
agency and as part of initial marketing strategy, evidence
on the 2nd line treatment is much scanter than that on
the 1st line.
First, with regard to dose escalation strategy, threesystematic reviews have been published and all concluded that there is no evidence to suggest that dose
escalation increases efficacy in comparison with continuing on the same dosage after failure to respond to
the 1st line antidepressant [16-18]. Next, with regard to
switching, we find two systematic reviews in the literature [19,20] both of which was able to identify only
one RCT that directly compared continuing on thesame drug and switching to another. In this trial, 104patients not responding to 6 weeks of fluoxetine
20 mg/d were randomly assigned to further 6 weeks offluoxetine and switching to mianserin 60 mg/d;
the remission rate was 18% and 36%, respectively (p =Furukawa et al. Trials 2011, 12:116
http://www.trialsjournal.com/content/12/1/1160.10) [21]. When different switching options are compared, switching to venlafaxine after failure to respondon an SSRI may be marginally better than switching toanother SSRI but there was no strong evidence torecommend other classes of antidepressants [20].
Lastly, many RCTs and systematic reviews have been
published on various augmentation strategies. The
ones with most randomized evidence include lithium
augmentation [22], thyroid hormone augmentation[23] and augmentation with atypical antipsychotics[24]. Other options include augmentation with mirtazapine/mianserin [21,25,26] and augmentation withpindolol [27].
Even less evidence can be found comparing these different 2nd line strategies against each other than comparing each strategy with staying on the former
treatment. For example, the Sequenced Treatment
Alternatives to Relieve Depression (STAR*D), which was
funded by the NIMH and cost approximately 3 million
dollars, examined five switching strategies and four augmentation strategies among the patients who had notachieved remission to the 1 st line SSRI treatment but
was unable to compare switching versus augmentation
as few patients agreed to this randomization [28,29].
How to establish the optimum treatment strategy withnew generation antidepressantsReview of the literature has revealed that there areindeed many urgent and critical clinical questions thatmust be answered before clinicians can confidently andcompetently administer pharmacotherapy for major
depression. Urgent because every practitioner encounters these clinical questions almost on a daily basis. Critical because answers to these clinical questions canmaterially affect the patients’ lives. Bandolier (http://
www.medicine.ox.ac.uk/bandolier/index.html), an independent evidence review journal in UK, concluded its
review on the MANGA Study by saying, “What themeta-analysis provides is the raw material for the next
step, namely creating and testing a care pathway or
pathways for depression that provides good results forthe largest number of sufferers in the shortest time andat the lowest cost.” (http://www.medicine.ox.ac.uk/bandolier/booth/mental/cipriani.html). This proposed study
precisely aims to create and test this optimum carepathway for depression.
1st line treatment

According to the results of the MANGA Study, it iswise to use sertraline as 1 st line treatment of major
depression in Japan because it represents the best balance in effectiveness and acceptability. However, practitioners immediately face an important clinical decision
question at this stage, namely the problem of initial dosing strategy. The standard dosage range for sertraline isPage 3 of 20

50-100 mg/d but should clinicians aim at achieving 50
mg/d or 100 mg/d in the initial dosing strategy? Papakostas et al [30] published a systematic review of fixeddose trials comparing different starting doses of SSRIs.
In comparison with starting with the minimum of thestandard dose range, starting with the maximum of thestandard range may be more effective (RR = 1.12, 95%
CI: 0.99 to 1.27) but less acceptable (0.74, 0.54 to 1.00).
The response rate may increase from 51% to 54%, at theexpense of the dropout rate also rising from 10% to
17%. It must be noted that they compared different
starting doses, i.e. they administered the minimum or
maximum of the standard dose range from the very
beginning, and the dropouts are accounted for by lastobservation-carried forward which is bound to affectand bias the results in an unknown way.
Can the initial dosing strategy to gradually increase
the dosage up to the maximum of the standard range,
recommended by many guidelines [8,10,31], be more
effective and at least not any more unacceptable than
the strategy to aim at the minimum of the standard
range? No one knows the answer. It is truly unacceptable that a clinical question as urgent as this, because
every single patient with major depression starting treatment with antidepressant faces this decision point, is
not yet answered. We therefore planned an RCT toanswer this question.
2nd line treatment

Even if we optimize the 1st line antidepressant treatment
strategy, more than half the patients cannot achieveremission [32]. What should we do as the 2nd line treatment, and when should we make this decision?
No systematic review has found evidence for dose
escalation and the present study will therefore notexamine this option. There are many RCTs examining
various augmentation strategies but only mirtazapine ormianserin augmentation is allowable according to thecurrent Japanese regulations. As reviewed, we do not yet
know which of augmentation or switching is superior interms effectiveness and acceptability. Furthermore, we
do not yet know when we should make this clinicaldecision to consider the 2nd line treatment. Since eachclinical research can answer only a limited number ofwell formulated clinical questions, this study will focus
on switching to mirtazapine, which was the most effective antidepressant according to the MANGA study, andcompare it to mirtazapine augmentation of SSRI, forwhich a number of RCTs provide some support.
Switching to mirtazapine is a plausible option as the
2 nd line treatment for the following reasons. (i)MANGA study showed mirtazapine may be the mosteffective new generation antidepressant. Due to its lessfavorable acceptability profile, it was not recommended
as the 1st line treatment but, when the latter fails, it isFurukawa et al. Trials 2011, 12:116
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only logical to consider the more effective antidepressant. (ii) Switching is arguably to be preferred over augmentation because combining two drugs may lead tomore known and unknown side effects than staying on
the same drug.
Mirtazapine augmentation of SSRI is another option
as the 2nd line treatment for the following reasons. (i)A number of RCTs have provided some evidence tosuggest its effectiveness. One small RCT randomly
assigned 26 patients who had not responded to SSRI,
bupropion or venlafaxine to augmentation either withmirtazapine 15-30 mg/d or with placebo. The remission rates were 46% versus 13% (p = 0.068) [26].
Another RCT administered fluoxetine plus mirtazapine
or fluoxetine alone from the beginning of the acutephase treatment and the remission rates were 25% vs
52% (p = 0.052) [33]. (ii) It makes sense pharmacologically to combine sertraline, which is an SSRI (specificserotonin reuptake inhibitor), with mirtazapine,which is a NaSSA (noradrenergic specific serotonergic
antidepressant). Mirtazapine increases noradrenaline
and serotonin release through antagonism of central
a2-adrenergic autoreceptors and heteroreceptors. Mirtazapine also exhibits antagonism to both 5-HT 2A , 5HT 2C and 5-HT 3 receptors, which results in a netincrease in 5-HT1-mediated neurotransmission which
is believed to be the primary mediator of efficacy ofmost antidepressant drugs. Antagonsim of the 5-HT2A
receptors has beneficial effects on sexual dysfunction
and insomnia, that of the 5-HT2B receptors on anxiety,and that of 5-HT3 on gastrointestinal symptoms, all ofwhich constitute major side effects of SSRIs. (iii) Mirtazapine does not inhibit any liver enzymes and posesvery low risk of interaction with other drugs. Sertraline
exerts mild inhibition against CYP2D6 and 3A4 but isgenerally believed to be a safer drug when administered concomitantly with other drugs than many other
SSRIs.
Another very important clinical question to beanswered with regard to the 2nd line treatment is whento consider it. As far as practitioners are concerned, thisrepresents just as urgent a clinical question as that of
initial titration strategy but, to the best of the authors’knowledge, no RCT has explicitly examined this issue
and the guidelines are ambiguous and self-contradictory.
For example, the guideline by the American College ofPhysicians [11] recommends that clinicians modify treatment if the patient does not have an adequate responseto pharmacotherapy within 6 to 8 weeks of the initiationof therapy but this time frame appears to be based on
the average length of clinical trials conducted mainly for
drug approval. The NICE guidelines are self-contradictory as it recommends 3-4 weeks at one place and 6-8

Page 4 of 20

weeks at another before considering the 2nd line treatment alternatives [9]. We therefore decided to randomize the patients with regard to the 2nd line treatment
as early as 3 weeks and aimed to examine if considering
the 2 nd line treatment at this early stage may or may
not be beneficial in comparison with continuing the 1stline treatment for 6 more weeks.
Continuation treatment

The last but not least factor to be considered in constructing the optimum treatment strategy for the 1st and2nd line treatments is the continuation treatment following the acute phase treatment. A systematic review has
unambiguously demonstrated that discontinuing antidepressants at the end of acute phase treatment can double the relapse/recurrence rates [34], and all theguidelines recommend continuation treatment of atleast several months following acute phase treatment.
However, in reality, many patients do not stay on thecontinuation phase [35]. It therefore follows that
another very important factor in deciding the 1st and2nd line treatment strategies is how easy and acceptable
it is for patients to continue into the continuation treatment after acute phase treatment, in addition to theireffectiveness and acceptability during the acute phasetreatment.
Aims

The current randomized trial aims to elucidate “pathways for depression that provides good results for thelargest number of sufferers in the shortest time and at
the lowest cost” (Bandolier 2009). More specifically, theobjectives of this trial are to examine the following
treatment options among patients with an untreated,
non-psychotic unipolar major depressive episode:(1) When the 1st line treatment is started with sertraline, which is better as an initial prescription strategy up
to 3 weeks in terms of effectiveness and safety (i.e. side
effects and treatment continuation), to titrate to thelowest dosage of the effective range or to its highest
dosage?
(2) When the patients do not remit on the 1 st line
treatment at 3 weeks, which is better as acute phasetreatment up to 9 weeks in terms of effectiveness andsafety, to continue sertraline, to augment sertraline withmrtazapine or to switch to mirtazapine?
(3) Which of the above strategies of 1st and 2nd line
treatments is better as acute phase and continuation
treatments up to 25 weeks in terms of effectiveness andsafety?

Methods
This is an assessor-blinded, parallel-group, multi-centre
randomized controlled trial.

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ParticipantsParticipants will be recruited from among those visiting
the clinical trial sites according to the following eligibility criteria.
Inclusion criteria

1) The participant fulfills criteria for non-psychotic
unipolar major depressive episode (DSM-IV) within
one month before starting sertraline
2) Age between 25 and 75 on the day when sertraline is started
3) The major depressive episode is the focus of thetreatment and the treating physician has judged sertraline to be its appropriate 1st line drug4) Tolerability to sertaline has been ascertained after
3-16 days of treatment with sertraline 25 mg/d
5) The participant is able to understand and sign
written informed consent
6) The participant is available on the phone forassessment of symptoms and side effects
Exclusion criteria

1) Having taken antidepressants, mood stabilizers(lithium, valproate, carbamazepine), antipsychotics,
psychostimulants (methylphenidate, pemoline,
atmoxetine), electroconvulsive therapy, or depression-specific psychotherapies (cognitive-behavior
therapy, interpersonal therapy) within one month
before starting sertraline
2) History of schizophrenia, schizoaffective disorder
or bipolar disorder (DSM-IV) as judged by treating
physician3) Current dementia, borderline personality disorder,
eating disorder or substance dependence (DSM-IV)
as judged by treating physician
4) Physical diseases which may contraindicate treatment with sertraline or mirtazaapine
5) Allergy to sertraline or mirtazapine
6) Terminal physical diseases
7) Women who are pregnant or breastfeeding (ifthere is a possibility of getting pregnant within 6months of trial entry, participation is allowed only
after providing signed consent to avoid pregnancy
during the trial period)8) Imminent high risk of suicide as judged by treating physician
9) Needing non-voluntary hospitalization
10) High probability of changing hospital due torelocation etc within 6 months of trial entry11) Cohabiting family members of research staff
members of the trial
12) Inability to understand written JapanesePage 5 of 20

in comparison with placebo for people under age 25
but decreases suicidality for people aged 25 or older[36].
2) Both males and females are accepted.
3) There is no eligibility criteria for severity ofdepression as long as the participant meets the diagnostic criteria for major depression. Both outpatientsand inpatients are accepted.
4) Patients having taken benzodiazepine anxiolytics,
tandospirone, hydroxyzine, hypnotic medications,traditional Kampo medications within one month
before starting sertraline are not excluded.
5) Patients having received psychotherapies otherthan depression-specific ones (cognitive-behavior
therapy and interpersonal therapy) are not excluded.
6) Patients with physical diseases that the treating
physician judged would not interfere with treatment
with sertraline or mirtazapine are not excluded.
7) The participant will continue the trial even if his/her diagnosis is changed after trial entry.
Trial Site Recruitment
Eligibility criteria for a trial site

A participating trial site must fulfill the following eligibility criteria.
1) It must have a department of psychiatry or of psychosomatic medicine.
2) The principal trial physician and all the participating trial physicians at the site must have understoodthe study protocol (e.g. cluster randomization to 50
mg/d or 100 mg/d of sertraline at Step I) and haveagreed to collaborate.
Nb
A site-visiting CRC will be dispatched to a trial sitewhich1) Is located within one hour at most approximatelyfrom the regional centre
2) Has more than 100 first-visit patients with major
depression per annum
3) Has a separate room that the CRC can use for
informed consent and that the central assessor canuse for telephone assessment.
Such trial sites will open, if possible, “a trial clinic” ona certain day of the week to facilitate patients’participation.
Procedure for a trial site to participate

Nb1) A comprehensive systematic review and meta-analysis has shown that antidepressants increase suicidality

Each regional centre will recruit collaborating trial sites(psychiatric private practice, department of psychiatry ofa general hospital, psychiatric hospital) in units of 4-5.

Furukawa et al. Trials 2011, 12:116
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Page 6 of 20

Exposure1: Strategy to titrate sertraline up to the maximum of the effective range, i.e. 25 mg/d -> 50 mg/d ->100 mg/d
Exposure2: Strategy to titrate sertraline upt to theminimum of the effective range, i.e. 25 mg/d -> 50 mg/
d -> 50 mg/d
Outcomes: The primary outcome is the change
inPHQ9 scores at week 1 through week 3
The secondary outcomes include:

If the trial site has its own Institutional Review Board,the principal trial physician will seek approval from his/her own IRB and then fax the document of approval to
the national centre office. The national central officewill examine the document(s) and return the review
results to the trial site principal physician by email.
If the trial site does not have its own IRB, the principal trial physician will send a proxy form to the IRB at
its regional centre and seek approval there.
Before the trial site starts recruiting the participants, all
the principal trial physician and the participating trial physicians must attend the start-up meeting held either at thetrial site or at the national centre. The co-PI and CRC at theregional centre will visit each trial site in order to make surethat the site has finished the preparation and to rehearse the
EDC system and blinded central telephone assessment.

1) Change in BDI2 scores at week 1 through week 32) Proportion of remission (4 or less on PHQ9) atweek 3
3) Proportion of response (50% or greater reduction
on PHQ9) at week 34) Proportion of successful continuation of the allocated treatment up to week 35) Change in FIBSER at week 1 through week 36) Change inPHQ9 at week1 through week 97) Change in BDI2 at week 1 through week 98) Proportion of remission (4 or less on PHQ9) atweek 9
9) Proportion of response (50% or greater reduction
on PHQ9) at week 910) Proportion of successful continuation of the allocated treatment up to week 911) Change in FIBSER at week 1 through week 9

Procedures

The overall procedure of the trial is shown in Figures 1
and 2.
Formulation of clinical questions

Clinical questions to be answered at each step can beformulated as follows.
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Furukawa et al. Trials 2011, 12:116
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Page 7 of 20

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12) Suicidality as assessed with C-CASA between
week 1 and week 913) Manic/hypomanic/mixed episode between week
1 and week 914) Serious adverse events between week 1 andweek 9
Step II Patients: Patients whose major depressive episode did not remit (5 or more on PHQ9) at week 3 tothe 1st line treatment with sertraline
Exposure1: Continue sertraline 50 mg/d or 100 mg/dfor 6 more weeks
Exposure2: Augment sertraline with mirtazapine 15-45
mg/dExposure3: Switch to mirtazapine 15-45 mg/d
Outcome: The primary outcome is the change in
PHQ9 at week4 through week 9

The secondary outcomes include:
1) Change in BDI2 at week 4 through week 92) Proportion of remission (4 or less on PHQ9) atweek 93) Proportion of response (50% or greater reduction
on PHQ9) at week 94) Proportion of successful continuation of the allocated treatment up to week 95) Change in FIBSER at week 4 through week 96) Suicidality as assessed with C-CASA between
week 3 and week 97) Manic/hypomanic/mixed episode between week 3
and week 98) Serious adverse events between week 3 andweek 9Furukawa et al. Trials 2011, 12:116
http://www.trialsjournal.com/content/12/1/116

Step IIIa [exploratory analysis of continuation treatment for Step I] Patients: Patients with non-psychotic
unipolar major depressive episode who had not received
treatment for the index episode before starting sertraline
and who tolerate sertraline 25 mg/d
Exposure1: Strategy to titrate sertraline up to the maximum of the effective range, i.e. 25 mg/d -> 50 mg/d ->100 mg/d by week 3, then allocated to continue sertraline between week 3 and week 9, then treated at the discretion of the trial physician
Exposure2: Strategy to titrate sertraline up to theminimum of the effective range, i.e. 25 mg/d -> 50 mg/
d -> 50 mg/d by week 3, then allocated to continue sertraline between week 3 and week 9, then treated at thediscretion of the trial physician
Outcome: The primary outcome is the proportion ofpatients who continue the allocated treatment up to
week 25 and are in remission (4 or less on PHQ9) atweek 25
The secondary outcomes include:
1) Proportion of patients who continue the allocatedtreatment up to week 25 and are showing response(50% or greater reduction on PHQ9) at week 252) Rate of continuation of allocated treatments up to
week 253) Change in PHQ9 at week 1 through week 25
4) Change in BDI2 at week 1 through week 255) Suicidality as assessed with C-CASA between
week 1 and week 25
6) Manic/hypomanic/mixed episode between week 1
and week 257) Serious adverse events between week 1 andweek 25
Step IIIb [exploratory analysis of continuation treatment for Step II] Patients: Patients whose major depressive episode did not remit (5 or more on PHQ9) atweek 3 to the 1st line treatment with sertraline
Exposure1: Continue sertraline 50 mg/d or 100 mg/dfor 6 more weeks, then treated at the discretion of thetrial physician
Exposure2: Augment sertraline with mirtazapine 15-45
mg/d up to week 9, then treated at the discretion of thetrial physician
Exposure3: Switch to mirtazapine 15-45 mg/d up to
week 9, then treated at the discretion of the trial
physician
Outcome: The primary outcome is the proportion ofpatients who continue the allocated treatment up to
week 25 and are in remission (4 or less on PHQ9) atweek 25
The secondary outcomes include:

Page 8 of 20

1) Proportion of patients who continue the allocatedtreatment up to week 25 and are showing response(50% or greater reduction on PHQ9) at week 252) Rate of continuation of allocated treatments up to
week 253) Change in PHQ9 at week 4 through week 25
4) Change in BDI2 at week 4 through week 255) Suicidality as assessed with C-CASA between
week 3 and week 25
6) Manic/hypomanic/mixed episode between week 3
and week 257) Serious adverse events between week 3 andweek 25
Pilot study

In order to test the feasibility of the study, a pilot study
will be run according to this same protocol between
December 2010 and October 2011. The pilot study will
be a multi-centre study involving:• Nagoya City University Hospital and its affiliatedprivate practices and departments of psychiatry in a
general hospital• Kochi Medical School Hospital and its affiliatedprivate practices, departments of psychiatry in a general hospital and psychiatric hospitals• Private practices in Yokohama
The Nagoya site will test recruitment using site CRCs,
the Kochi site will test recruitment using site CRCs anddirect recruitment by trial physicians, and the Yokohama site will test recruitment using site CRCs dispatched from a commercial site management
organization. Feasibility and efficiency of these different
recruitment methods will be examined.
The pilot study will use data of the 1st 200 patients up
to week 25. The pilot study will be reviewed by DSMB
who will advise the Steering Committee on the feasibility and safety of the study and on appropriateness ofcontinuing the study. The final decision about whether
to continue the study will be made by the Steering
Committee. Before continuing the study, the protocol
may be amended if necessary and additional trial sites
will be recruited.
Step I

Ascertaining eligibility criteria The trial physician and/or site CRC will seek informed consent from a participant at week 1, i.e. 3-16 days after starting sertraline 25
mg/d. The “3-16 days” time frame was chosen to allow
two possible visit days to accommodate the participant’sschedule at a site where the site CRC makes his/her visits every week. After obtaining the written informed
consent, the trial physician or the site CRC makes aFurukawa et al. Trials 2011, 12:116
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face-to-face interview or the central CRC or the central
rater will make a telephone interview to assess
1) PHQ9 at week 12) FIBSER at week 1
These week 1 assessment results will be entered into
the EDC along with the complete data on the “Eligibility
Form.”
Allocation to treatments Eligible participants will beallocated 1:1 to the sertraline 50 mg/d arm and to thesertraline 100 mg/d arm. We will employ cluster randomization by trial site. This cluster randomization will bemade by the EDC system. The allocation will use theminimization method adjusting for the number of probable entries as judged by the principal investigator andco-principal investigators (40 or more participants per
year vs less than 40 participants per year).
We employ cluster randomization for Step I for thefollowing reasons.
1) The comparison for Step I is between physician’s
choice of a strategy to titrate sertraline used as the
1st line antidepressant up to the minimum effective
range or up to the maximum effective range. It istherefore logical to randomize by physician.
2) In reality, because this is an open trial in which
the trial physician gradually titrates the dosage taking into account the side effects, having one patientin the sertraline 100 mg/d arm and another in thesertraline 50 mg/d arm may at the same time createcontamination in the doctor’s decisions. That is, if
we randomized by patient, the doctor might tend to
stick to his/her personally preferred titration schedule regardless of the individual patient’s assignmentand reported side effects.
3) Likewise, having different doctors with different
titration policies within the same trial site mightcause unnecessary confusion among the physicians
and co-medical staff at the site.
4) Asking the participant to undergo individual randomization twice might increase the barrier toparticipation.
5) A number of previous studies have repeatedly
reported negligible to very small intra-cluster correlation coefficients [37,38].
Treatments The trial physician will prescribe according
to either of the following schedule, depending on his/her own allocated treatment strategy.
1) In the 100 mg/d arm, prescribe 50-75 mg/d (onceafter dinner or before bedtime) for one week atweek 1, then prescribe 100 mg/d (once or divided
twice per day) for one week at week 2

Page 9 of 20

2) In the 50 mg/d arm, prescribe 50 mg/d (onceafter dinner or before bedtime) for one week atweek 1, then prescribe the same regimen for one
week at week 2
Outcome assessments The trial physician or the site
CRC will ask the participant to fill in BDI2 upon week 2
and week 3 visits. The CRC or the physician will enter
the data into EDC.
At week 3, the central rater will administer
1) PHQ9 at week 32) FIBSER at week 3
by telephone. The central CRC will obtain thepatient’s name and phone number and will keep therater blind to the name of the clinic and the treatment
the participant is receiving. This telephone assessment
will normally be conducted in a separate room after thepatient arrives at the clinic and before the consultation
with the trial physician, so that imminent suicidality
may be handled promptly and appropriately according
to the “Suicidality Management Manual.” If the patient
has dropped from the treatment, the telephone call will
be made to the mobile phone which he/she has previously registered upon entry into the trial. If strong suicidal wishes are expressed, the central rater will follow
the “Suicidality Management Manual.”
Step II

Ascertaining eligibility criteria If the patient scores 5
or more on PHQ9 at week 3, as assessed by the central
rater, he/she will be randomized for Step II according to
the following procedures.
If the patient scores 4 or less on PHQ9 at week 3, he/she will continue on the same regimen, and receive theassessments at week 9 and week 25 as planned.
Allocation to treatments The patients scoring 5 ormore on PHQ9 at week 3 will be allocated 1:1:1 to thecontinue-sertraline arm, the mirtazapine augmentation
arm, and the mirtazapine switch arm. This randomization will use the minimization method adjusting for (i)site, (ii) whether 50% or greater reduction on PHQ9 isachieved or not, and (iii) whether “moderate” or greater
impairment due to side effects is reported on item 4 of
FIBSER.
The central CRC will enter the necessary data from
PHQ9 and FIBSER into EDC. The EDC program willthen output “The patient is making steady recovery.
Please continue with the same regimen” if the PHQ9score is 4 or less, and any one of “Augment with mirtazapine. Please add mirtazapine 15 mg/d,” “Switch tomirtazapine. Decrease sertraline to half the current doseand add mirtazapine 15 mg/d,” or “Continue with sertraline” if thePHQ9 score is 5 or more according to theabove randomization. The central CRC will fax theFurukawa et al. Trials 2011, 12:116
http://www.trialsjournal.com/content/12/1/116

output to the trial physician and the site CRC, so thatthe physician need not start up the computer everytime.
If the EDC server is down and/or the trial site cannot
use the EDC system for various reasons, the randomisation can be done by calling up the central CRC or thedata centre.
Treatments The details of the three intervention arms
are as follows.
1) Continue sertraline as specified by Step I cluster
randomization. Between week 4 and week 9, sertraline must be kept within the maximum as specified
by Step I cluster randomization. If the dosage has
not reached this maximum (e.g. 100 mg/d) at week
3, it can be increased to this maximum (in this case,
100 mg/d) between week 3 and week 9.
2) Continue sertraline as specified by Step I cluster
randomization and add mirtazapine 15 mg/d at bedtime to augment sertraline. After week 4, mirtazapine can be given in 7.5-45 mg/d at bedtime.
Between week 4 and week 9, sertraline must be kept
within the maximum as specified by Step I cluster
randomization. If the sertraline dosage has notreached this maximum (e.g. 100 mg/d) at week 3, it
can be increased to this maximum (in this case, 100mg/d) between week 3 and week 9. Mirtazapine
should usually be started at 15 mg/d but can behalved by the treating psychiatrist taking into
account age etc of the patient.
3) Decrease sertraline to half the current dose andadd mirtazapine 7.5-15 mg/d at bedtime in order toswitch to mirtazapine. Sertraline must be halved at
week 3 and stopped by week 4 or week 5 (sertraline
should no longer be prescribed at week 7 at the latest), so that the patient will receive mirtazapine 7.545 mg/d only between week 7 and week 9.
Outcome assessments The trial physician or the site
CRC will continue to ask the participant to fill in BDI2
at every visit between week 4 and week 9. The CRC or
the physician will enter the data into EDC.
At week 9, the central rater will administer
1) PHQ9 at week 92) FIBSER at week 9
by telephone. The central CRC will obtain thepatient’s name and phone number and will keep therater blind to the name of the clinic and the treatment
the participant is receiving. This telephone assessment
will normally be conducted in a separate room after thepatient arrives at the clinic and before the consultation
with the trial physician, so that imminent suicidality
may be handled promptly and appropriately according

Page 10 of 20

to the “Suicidality Management Manual.” If the patient
has dropped from the treatment, the telephone call will
be made to the mobile phone which he/she has previously registered upon entry into the trial. If strong suicidal wishes are expressed, the central rater will follow
the “Suicidality Management Manual.”
Step III

Ascertaining eligibility criteria All the participants
who have entered the trial are eligible.
Treatments All the available treatment guidelines fordepression recommends that the acute phase treatment,
if successful, be continued at least several months. All
the treatments between week 9 and week 25 are at thetreating physician’s discretion. He/she may continue
with the same regimen or completely change the regimen. Electroconvulsive therapy and depression-specificpsychotherapies can also be administered.
Outcome assessments The trial physician or the site
CRC will continue to ask the participant to fill in BDI2
at every visit between week 10 and week 25. The physician or the CRC will enter the data into EDC.
At week 25, i.e. approximately 6 months after trial
entry and 4 months after week 9 assessments, the central rater will administer
1) PHQ9 at week 252) FIBSER at week 25
3) History of prescription up to week 25, especially
how long the treatment assigned at week 3 wasadhered toby telephone. The central CRC will obtain thepatient’s name and phone number and will keep thecentral rater blind to the name of the clinic and thetreatment the participant is receiving. This telephoneassessment will normally be conducted in a separate
room after the patient arrives at the clinic and before
the consultation with the trial physician, so that imminent suicidality may be handled promptly and appropriately according to the “Suicidality Management
Manual.” If the patient has dropped from the treatment,
the telephone call will be made to the mobile phonewhich he/she has previously registered upon entry into
the trial. If strong suicidal wishes are expressed, the central rater will follow the “Suicidality Management
Manual.”Concurrent Treatments
Permitted concurrent treatments

The following medications are allowed throughout thetrial at the discretion of the trial physician.
1) Benzodiazepine anxiolytics and hypnotics
2) Tandospirone, hydroxyzineFurukawa et al. Trials 2011, 12:116
http://www.trialsjournal.com/content/12/1/116

3) Gastrointestinal and digestive drugs (except for
sulpiride)4) Medications for concurrent physical diseases
5) Non-specific psychotherapies (psychotherapies
other than depression-specific CBT and IPT), exercise therapy, music therapy, family psychoeducation
Prohibited concurrent treatments

Through Step I and Step II, the following treatments areprohibited in principle. However, the patient’s safety
should be the utmost concern and takes priority overeverything else, all appropriate care should be given
depending on the patient’s condition.
1) Antidepressants other than sertraline or
mirtazapine
2) Antipsychotics
3) Mood stabilizers (lithium, valproate,carbamazepine)4) Depression-specific psychotherapies (CBT, IPT)
5) Electroconvulsive therapy
There is no prohibited treatments for Step III.
Stopping Rules For Participants & Trial Sites
Deviation from protocol treatment

Page 11 of 20

be considered to have dropped out of the study at thisstage 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 emergence of serious adverse events (SAE) as defined
below.
3) The trial physician judges that the risk outweighs
benefit in continuing the protocol treatment evenwhen no SAE is reported.
4) The participant becomes pregnant and the trial
physician judges that the risk outweighs benefit incontinuing the protocol treatment.
5) The trial physician judges that it is inappropriate
to continue the protocol treatment for any otherreason.
Stopping assessment

If the participant meets any one of the following conditions, he/she will never be contacted for assessments.
1) The participant withdraws consent to receiving protocol assessments, regardless of whether he/she is continuing the protocol treatment.
Dropping trial sites

The following cases will be considered deviation fromthe trial protocol. The participant, however, will not be
considered to have dropped out of the study at thisstage and will receive the protocol assessments.

If the trial site meets any of the following conditions, itwill be judged “dropout” and will no longer be able torecruit patients. However, the patients who have alreadyentered the study will be followed-up.

1) Prohibited concurrent treatments were administered in Step I or II
2) The participant was not randomised within the
pre-specified time frame for week 3.
3) The participant cannot take any sertraline in StepI.
4) The participant switches to manic/hypomanic/
mixed in Step I.
5) The participant turns out to suffer from bipolar
disorder, schizophrenia or dementia in Step II.

1) The principal trial physician withdraws his
consent.
2) No study entry was made within 6 months.
3) The Steering Committee judges that it is inappropriate to continue recruitment at this site.

The treating physician is to judge whether 1) through5) has occurred. If so judged, the physician should
immediately notify the site CRC, who will notify thecentral office.
If 1) through 4) occurs in Step I, the randomization
for step II will not be made but assessment willcontinue.
If 1) or 5) occurs in Step II, the patient will be analysed as randomized.
Stopping intervention

If the participant meets any one of the following conditions, the trial physician will stop the protocol treatment
at his/her discretion. The participant, however, will not

Assessments
Measures

Patient Health Questionnaire-9 (PHQ9) The Patient
Health Questionnaire was developed in 1999 as a selfreport version of the Primary Care Evaluation of Mental
Disorders (PRIME-MD) which aims at criteria-based
diagnosis of several mental disorders commonly seen in
primary care [39]. The depression module of the PHQ
is called PHQ9 and consists of the nine diagnostic criteria items of the DSM-IV. Each item is rated between 0= “Not at all” through 3 = “Nearly every day,” making
the total score range between 0-27. Excellent test-retest
reliability (ICC = 0.92) [40] and internal consistency
reliability (Cronbach’s alpha = 0.89) [39] have beenreported. Good construct validity has been demonstrated through associations with various severity indices[41]. The sensitivity to change is as good as or better
than extant scales [42].

Furukawa et al. Trials 2011, 12:116
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Kroenke and his colleagues have provided the following rules of thumb for interpreting the continuous
PHQ9 scores [41].
0-4 no depression
5-9 mild depression
10-14 moderate depression
15-19 moderately severe depression
20- severe depression
The minimal clinically important difference, i.e. thesmallest difference in score that is considered to be aclinically important intra-individual change, was established to be 5 [42].
The PHQ9 should require less than one minute to fillin for the patient and less than one minute to administer for the clinician [41]. The Japanese version has been
established by Muramatsu through backtranslation [43].
In this trial, PHQ9 will be administered 5 times atweek1, week 3, week 9 and week 25. The central rater
will receive training in administering PHQ9 throughsimulated interviews and will have demonstrated satisfactory reliability. The blindness of the central rater asto the participant’s treatment will be assessed by asking
the central rater to guess the allocated treatment atweek 3, 9 and 25 assessments.
Beck Depression Inventory-II (BDI2) BDI2 is a 21-item
self-report instrument to measure the severity of depression in adolescents and adults. Its first version wasdeveloped in 1961 and slightly amended in 1979 but in1996 a major revision was undertaken to make the scale
more congruent with the modern diagnostic criteria for
major depression. In its 40 years of usage, the BDI has
become one of the most widely used instruments for
detecting possible depression in normal populations andfor assessing severity of depression in diagnosed patients[44].
The time frame for evaluation is set to the past 2
weeks including the day of assessment. Each item inthe BDI2 has a series of four statements, which
describe symptom severity along an ordinal continuum
from absent or mild (a score of 0) to severe (a score of3). The total score therefore ranges from 0 through63.
Good reliability and validity have been reported forthe original [45] as well as the Japanese version [46].
The original authors proposed the following rules of
thumb for interpreting the BDI2 scores [45]0-13 Minimal
14-19 Mild
20-28 Moderate
29-63 Severe

Page 12 of 20

Two subsequent studies from the US and from Japanbasically confirmed these interpretations [46,47].
A rough guide for interpreting the changes in BDI2
scores may be [46]0-9 no or slight change, with 5 indicating a minimally important clinical difference
10-19 moderate change>= 20 large change.
Most patients are comfortable with this 21-item questionnaire and can complete them within 5-10 minutes.
In this trial, BDI2 will be filled in by the patient at
each visit.
Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) FIBSER was originally used in STAR*D asa global rating scale for side effects. This is an observerrated scale and the Japanese translation has not gone
through backtranslation.
Continuation of protocol treatment Continuation of
protocol treatment without stopping intervention or
stopping assessment as defined above is called “treatment continuation.” In Step III, concurrent treatments
prohibited in Steps I and II can be used and this will
not constitute “treatment continuation.”
Timing of assessments

Assessments at week 3, 9 and 25 may be made within
the following time frames after week 1.
1) ±4 days for assessments at week 1 through 92) ±14 days for assessments after week 9
Assessment for week 3 must be made between -4 days
to +14 days of the planned date, and that for week 9must also be made between -4 days to +14 days of theplanned date.
Data monitoring and site audit

Data monitoring The data centre will provide the following data monitoring report to the Steering Committee and the DSMB every six months. The chair of the
DSMB will assess the data monitoring report, and if he/she finds an ethical problem in the continuation of thetrial from the viewpoints of safety or effectiveness, he/she will convene the DSMB and advise the principal
investigator to change or stop the study.
The data monitoring report will include:
1) Progress of the trial regarding trial entry and follow-up
2) Implementation of assessments (allocation will bemasked)3) Incidence of serious adverse events (allocation will
be masked)

Furukawa et al. Trials 2011, 12:116
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4) Any other problems.
Site audit Each site will be surveyed within 6 months
after the study commencement. The site audit teamnominated by the Steering Committee will survey thesites according to the Site Audit Manual. The audit
team will report the results to the Steering Committee,
which will review them.
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, regardless of thecausal relationship with the study intervention.
Reportings according to Pharmaceutical Affairs Act (1950
Law 145)

All the protocol interventions in the current trial arewithin the approved dosage and administration in Japanand will therefore have to follow the Japanese Pharmaceutical Affairs Act.
Adverse events will be assessed according to the“Adverse Events Manual” which follows the Japanese
Ministry of Health, Labour and Welfare’s “Manual for
rating the severity of side effects by pharmaceutical products,” with an amendment to allow more detailed
assessment of suicidality according to Columbia Classification Algorithm for Suicide Assessment (C-CASA)[48].
Adverse events will be classified into:
Grade 1: minor side effects
Grade 2: neither major nor minor side effects
Grade 3: major side effects, i.e. side effects that may
lead to death or to enduring severe impairment
depending on the patient’s conditions andcircumstances
All grade 3, and unforeseeable grade 2 adverse events
shall be reported to the relevant section of the Ministry of Health, Labour and Welfare as well as to thenational centre office. Foreseeable adverse events are
judged according to the package inserts of respective
drugs. Any grade 3 adverse events that occurred within
30 days of the completion of the protocol treatment
shall be reported to the Ministry and the national centre office. The reporting shall be done using theattached “Reporting form on safety of pharmaceuticalproducts.”
The principal investigator, upon receiving the report,
will consult with the trial physician to discuss the courseof actions to be taken with regard to the patient inquestion and also with regard to the study.

Page 13 of 20

Reportings according to the Ethics Guideline for ClinicalResearch (Ministry of Health, Labour and Welfare, revised in
2008)

When a serious adverse event occurs, the trial physician
must take all the necessary and appropriate measures toensure safety of the participant. He/she must also notify
the principal investigator immediately. The principal
investigator must notify co-principal investigators at all
the regional centres within 24 hours, and report to thehead of the clinical research institution (In the pilot
study, Director of Nagoya City University Hospital or
Director of Kochi Medical School Hospital) through theco-principal investigators. The principal investigatormust also notify all the collaborators. The head of theclinical research institution must report to its own IRB
and, if it concerns an unforeseeable serious adverse
event, must report to the Ministry of Health, Labourand Welfare.
“A serious adverse event” is defined here as “anadverse event that may lead to death or to enduring
severe impairment depending on the patient’s conditions
and circumstances” and will include:
1. Death
1.1. All deaths regardless of causal relationshipwith the protocol treatment, if it is a death during the protocol treatment
1.2. Deaths whose causal relationship with theprotocol treatment cannot be denied, if it is adeath within 30 days after completion of the protocol treatment.
2. Life-threatening event
3. Event leading to enduring and severe impairment
and dysfunction
When treatment is required, the trial physician will
provide and/or arrange appropriate treatments including
hospital admission.
Foreseeable adverse events according to the package
inserts

Sertraline Frequent side effects
Nausea (18.9%), somnolence (15.2%), dry mouth(9.3%), headache (7.8%), diarrhea (6.4%), dizziness (5.0%)
etc.
Serious side effects
Serotonin syndrome (unknown frequency), malignant
syndrome (unknown frequency), convulsion (unknown
frequency), coma (unknown frequency), liver dysfunction (unknown frequency), SIADH (unknown frequency), Lyell syndrome & toxic epidermal necrolysis(unknown frequency), anaphylactoid symptoms(unknown frequency)
Mirtazapine Frequent side effects

Furukawa et al. Trials 2011, 12:116
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Somnolence (50.0%), dry mouth (20.6%), fatigue(15.2%), constipation (12.7%), increased AST/ALT(12.4%)
Serious side effects
Serotonin syndrome (unknown frequency), agranulocytosis/neutropenia (unknown frequency), convulsion(unknown frequency), liver dysfunction/jaundice(unknown frequency), SIADH (unknown frequency)
Stopping Rule For Study

The study will be discontinued by the Steering Committee (or the principal investigator in the case of an emergency) upon advice from the DSMB if any of thefollowing conditions is met.
1) The causal relationship between any of the protocol treatments and serious adverse events including
death is established by this study or by any otherstudy.
2) Provision of study drugs becomes impossible forany reason.

Data Management And Publication Policy
Data Management

The data management will be done by the data centre.
The electronic data is anonymized in a linkable record,
and the participants’ names and ID numbers will berecorded only on non-electronic media (e.g. paper notebook) and kept at each trial site.
The central CRC will check the progress of all theentered participants every day by use of the EDC andwill contact the site CRC or the trial physician should
any doubt arise.
The data centre will perform similar checks and willcontact the central CRC should any doubt arise.
Publication Policy

The protocol will be published, with TAF as first author.
The main papers stemming from Steps I, II and III,
especially the one from Step II, will be submitted to ahigh impact journal. The collaborating researcher has
the right to be the first author of these papers in orderof their number of recruitment. TAF will remain thecorresponding author for all the papers. All the trial
principal physicians and the trial participating physicians
who have entered more than 10 patients will appear as
co-author of at least one paper.
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.
The results shall be reflected in treatment guidelines
and systematic reviews.

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Study Period

The study period of this trial will be between December
2010 and March 2014, with the patient entry period
between December 2010 and September 2013.
The study period of the pilot study will be between
December 2010 and March 2012, with the patient entry
period between December 2010 and October 2011.
Statistical Analyses
Sample size calculation

Sample size for Step I Assuming an intra-cluster correlation coefficient to be 0.05 [37,38], with alpha error at
0.05 and statistical power at 0.80, to detect a mean difference of 1 point on PHQ9 (SD = 5), i.e. to detect aneffect size of 0.2, we need 66 patients at each of 30 sites.
The total sample size is therefore 1980.
Sample size for Step II The clinical question for Step II
is the main hypothesis of this trial. Previous studies
using PHQ9 in the acute phase treatment of major
depression have shown that, on average, the PHQ9scores will drop from 15 (SD = 5) at baseline to 10 (SD= 6) at end of treatment, with a mean change of 5 (SD= 5) [49-51]. We expect a difference of 20% (1 point) in
the PHQ9 change scores among the intervention arms
and consider this to be a clinically meaningful differencein effect. With alpha error set at 0.05 and statisticalpower at 0.80, in order to detect a between-group difference of 1 point (SD = 5) in the reduction of PHQ9scores from baseline, we need 522 per group and 1566
in toto at Step II. Assuming a dropout rate of 20% anda remission rate of 10% at week 3, we need 2175 participants for Step I.
One point difference in the mean change score on
PHQ9 corresponds with an effect size of 0.2. This is asmall effect according to Cohen’s rough rule of thumbfor effect size interpretation [52]. However, because thepresent trial represents comparison among active treatments and because the true effect size of antidepressants
over placebo appears to be around 0.3 [53] and theaverage effect size of all the health interventions examined in the Cochrane Library appears to be between 0.3
and 0.4 [54], we consider this to be a clinically meaningful difference in effectiveness worth detecting in a large
clinical trial. As a matter of fact, an effect size of 0.2 willbe translated into an NNT of 10 if the control event
rate is around 50% (e.g. response as defined usually by
50% or greater reduction in depression severity frombaseline) and 20 if the control event rate is around 20%(e.g. remission of depression) [55]. They therefore represent clinically meaningful difference in effect.
The sample size will be revisited after completion of
the pilot study.
Sample size for Step III Step III represents continuation treatment for Steps I and II, and will therefore beFurukawa et al. Trials 2011, 12:116
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examined as exploratory studies. We therefore will not
calculate sample size necessary to detect a significant
difference. However, we will calculate the obtained statistical power post-hoc.
Sample size for pilot study The pilot study is a feasibility study and needs no sample size calculation. The target sample size is 200. We will perform no statisticalanalyses looking at the comparison arms at the end of
the pilot study, whose participants will therefore be
included in the main study unless there is a majorchange in the study protocol.

Page 15 of 20

However, we will examine the following aspects inorder to ascertain the feasibility of the study without
revealing the treatment allocation.
1) Number of entered subjects per trial site to calculate the number of trial sites and the time necessary
to complete the intended study2) The intra-cluster correlation coefficient will becalculated in order to make sure that it is not very
different from the one assumed in this protocol. We
will re-calculate the sample size if necessary.

Statistical analyses

Primary analyses For Step I, we will compare the sertraline 50 mg/d arm and the sertraline 100 mg/d arm
at an individual level. We will test whether the changes
in PHQ9 scores at week 1 through week 3 are statistically significantly different between the two arms.
Because Step I employs cluster randomization, we will
have to take into consideration intra-class correlation
coefficients.
For Step II, we will test whether the changes in PHQ9scores at week 4 through week 9 are statistically significantly different among the sertraline continuation arm,
the mirtazapine augmentation arm and the mirtazapine
switch arm. The null hypothesis that the changes are
not different among the treatment arms will be tested
by examining treatment effect parameters in therepeated measures analyses of all the eligible subjects in
the ITT analysis. We will use random effects model taking into consideration the Step I randomization andStep II randomization factors. We will examine interaction effect of Step I cluster randomisation. The test will
be double-sided. The alpha error is set at 0.05 and statistical power at 0.80. We will impute the missing dataand carry out sensitivity analyses as necessary.
Secondary analyses We will perform secondary analyses
to supplement our primary analyses and to obtain moreelaborate understanding of our clinical questions. The
secondary analyses will use models similar to those of
the primary analyses. We will calculate relative risks andtheir 95% confidence intervals for differences in proportions. We will calculate hazard ratios and their 95% confidence intervals for differences in treatment
continuation.
Details of the statistical analyses will be laid down in
the “Statistical Analysis Protocol”, which will be prepared by the statistician in the Steering Committee by
the time the analyses will be undertaken.
Interim analyses We will not perform interim analyses
to examine the study hypotheses for two reasons. First,
we are not expecting a huge effect size for the planned
comparisons and second, it is theoretically likely thattrials stopped early for benefit may overestimate thetrue effect size.

The analyses for the pilot study will be given in detailin the “Statistical Analysis Plan.”
Ethical Aspects
Adherence to the study protocol and study manual

All the researchers participating in this trial will place
the participants’ safety and human rights above everything else and will adhere by the study protocol and thestudy manual so long as they do not undermine theirsafety and human rights.
Regulations to be adhered to

All the researchers participating in this trial will abideby the Declaration of Helsinki and its amendments aswell as the Ethics Guideline for Clinical Research (2008
revision, Ministry of Health, Labour and Welfare).
Procedures for informed consent

Before entry into the trial, the trial physician must
explain the following items using the written materials
and make sure that the participant has understood thecontents of the trial well. Written informed consent will
only then be obtained from the participant.
1) About clinical trials2) Objectives of the trial
3) Name and position of the principal trial physician
and names of the participating trial physicians4) Procedures and duration of the trial and what
happens after the trial is over5) Advantages to be expected and disadvantages tobe anticipated
6) Other available treatment options
7) The participant can withdraw consent and stop
participating in the trial at any time8) There is no disadvantage if the subject does notparticipate in the trial or stops participating in thetrial.
9) Medical records that are related to this trial will
be seen by study personnel of this trial
10) Privacy will be maintained and protected11) Contact address and method when the participant wants more information about the clinical trial
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12) Compensation insurance for any health hazards
13) Fundings for this trial
14) Others
Protection of privacy

All the researchers and outsourcers of this trial muststrictly protect personal information of the participantsin adherence with the Ethics Guideline for ClinicalResearch and the Private Information Protection Law.
Each trial site, each regional centre and the national
centre will collect information in anonymized and linkable format. The data centre will not deal with personal
information of the participants. The linking information
for the participants is strictly managed at each trial siteor at the national centre without being computerized, i.
e. in paper format.
At week 3, week 9 and week 25, the central rater willadminister PHQ9 and FIBSER by telephone while being
blind to the participant’s allocated treatment. The central CRC will arrange this blinded telephone call by
obtaining the participant’s name and telephone number
from each clinic every time. The central CRC will notkeep this privacy information at the national centre
office.
Approval by the IRB

This study has been approved by the Ethics Committeeof Kyoto University Graduate School of Medicine, theInstitutional Review Boards (IRBs) of Nagoya City University Hospital and of Kochi Medical School Hospital.
Each trial site will seek approval of the same protocol
if it has its own IRB. If there is no IRB, the trial site willcommission its approval to the IRB at Nagoya City University Hospital or at Kochi Medical School Hospital.

Page 16 of 20

Study Organization
Steering Committee

The Steering Committee will hold online meetings every
two weeks and offline meetings every two months.
Principal investigator:
Toshiaki A. Furukawa, MD, PhD (Kyoto University
Graduate School of Medicine/School of Public Health,
Department of Health Promotion and Human Beahvior)
Co-principal investigators:
Tatsuo Akechi, MD, PhD, Norio Watanabe, MD, PhD(Nagoya City University Graduate School of Medical
Sciences, Department of Psychiatry and Cognitive-Behavioral Medicine)
Shinji Shimodera, MD, PhD (Kochi University Department of Neuropsychiatry)
Mitsuhiko Yamada, MD, PhD, Masatoshi Inagaki, MD,
PhD (National Center for Neurology and Psychiatry,
Institute of Mental Health)
Trial statistician:Naohiro Yonemoto, MPH (National Center for Neurology and Psychiatry, Translational Medical Centre)
Data and Safety Monitoring Board: DSMBDSMB will consist of three professionals in clinical trials
and in psychiatry, who are not involved in this trial: Dr
Teruhiko Higuchi (Psychiatrist, National Centre for
Neurology and Psychiatry), Professor Yoshio Hirayasu(Psychiatrist, Yokohama City University) and Akiko
Kada (Biostatistician, National Cerebral and Cardiovascular Center). The purpose of DSMB is to check thedata monitoring reports prepared by the data centre andmake recommendations, where necessary, to the principal investigator.
Research organization

Compensation Insurance

All the protocol interventions in the current trial arewithin the approved dosage and administration in
Japan. However, because the trial involves random
allocation, we will contract a private health insurance
to compensate for health hazards that have arisen due
to this trial. The contract will be between Kyoto University and Tokio Marine and Nichido Fire Insurance
Company. This insurance will cover only death orgrade 1 impairment or grade 2 impairment whose causal relationship with the trial cannot be negated.
Grades 3-14 impairments will not be covered by thisinsurance but will be covered by the National Health
Insurance, which therefore can incur some copayment.
Because all the protocol interventions are within theapproved dosage and administration, any healthhazards may be object of the National Rescue Scheme
for Side Effects. If there is any negligence on the partof the physician, it may be covered with the doctors’
liability insurance.

Figure 3 shows the organizational structure for the pilot
study.
Data centre

The data centre will be in charge of collecting andmanaging information independently from the researchers. The data centre will handle site registration, participant registration and allocation, monitor data entry,
manage quality assurance of data, manage quality control of data, prepare monitoring reports, and prepare
datasets for statistical analyses.
The data centre will make monitoring reports on the
progress of recruitment, progress of data collection andadverse events to the Steering Committee and DSMB.
The data centre will be entrusted a contract researchorganization to be chosen by public tender bidding.
National centre and Regional centres

The national centre office will be located within Department of Health Promotion and Behavioral Medicine,
Kyoto University School of Public Health. It will have acentral rater, a CRC and a secretary.

Furukawa et al. Trials 2011, 12:116
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Page 17 of 20

Steering Committee㻌

DSMB㻌
PI, co-PI, Biostatistician㻌3 external reviewers㻌
2 meetings/year㻌

National Center& Regional Centers
Central CRCs at Kyoto U㻌
Telephone assessment by
central raters㻌

Data Center㻌

Site CRCs at Nagoya City U㻌
Site CRCs at Kochi U㻌

EDC by Contract Research
Organization㻌

Site Management
Organization at Yokohama
Informed consent and data entry bysite CRCs㻌

Figure 3 Organizational structure for the pilot study

There will be regional centres at Nagoya City University and Kochi University. There will be site CRCs whowill make weekly visits to participating trial sites toassist informed consent procedures and to monitor andenter clinical data.

Discussion
The SUN(^_^)D is an assessor-blinded, parallel-group,
mutli-centre randomised controlled trial sequentiallycomparing active treatment options and combinations
currently approved for treatment of depression in Japan.
The prominent characteristics of the SUN(^_^) D
include the following.
First, the treatment arms in this trial are based on true
clinical uncertainty, because all of them are treatment
options currently approved by the regulatory bodies inJapan. In other words, they represent treatment alternatives from which both clinicians and their patients havedifficulties choosing at the present moment.
Second, the clinical questions to be examined in thistrial pertain to urgent and critical decision points forwhich the world psychiatric and psychopharmacologicalresearch community has hitherto failed to provide guidance or answer to.
Third, the trial will take place mostly in front-line psychiatric facilities such as private practices and departments of psychiatry of general hospitals from all overJapan, where many if not most of the patients with major
depression receive their initial treatment. Because Japan
does not have the primary care system as represented by
the general practitioners in UK, these are the primarycare mental health services in Japan and the current trialis thus expected to have maximum external validity withrespect to initial treatment of major depression in Japan.
Fourth, several important measures are built in toensure good internal validity for this pragmatic trial,
such as central randomization, blind assessment ofsymptoms and side effects via telephone and adherence
to true intention-to-treat principle through differentiation of discontinuation of protocol treatments and withdrawal from study. Whether we can achieve the lastpoint will depend on whether we can follow up andassess all the patients even when they stop or deviate
from the assigned treatments.

Furukawa et al. Trials 2011, 12:116
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As discussed in the Introduction, major depression
represents the greatest non-fatal burden of disease forthe humankind, with commensurate rise in spending on
the antidepressants world-wide. We maintain that thismust be accompanied by commensurate increase in evidence base to guide their wise clinical administration.
For example, the total annual sales of antidepressantsamount to 120 billion yen (1.3 billion US dollars), andwe would like to advocate that at least 0.1% of this sum
be spent on public-domain pragmatic research of theiruse for mood and anxiety disorders. Many urgent andcritical clinical questions can be answered with thisresearch funds only if the research can be simple andpragmatic enough. We hope that SUN(^_^)D can be atemplate for such future clinical trials, and that it ultimately can provide good evidence to improve the treatment guidelines for depression in the world.
List of abbreviations
5-HT: 5-hydroxytryptamine; BDI2: Beck Depression Inventory-II; C-CASA:
Columbia Classification Algorithm of Suicide Assessment; CRC: ClinicalResearch Coordinator; CRO: Contract Research Organization; CYP:
Cytochrome pigment; DALY: Disability-Adjusted Life Years; DSMB: Data Safety
Monitoring Board; EDC: Electronic Data Capturing; FIBSER: Frequency,
Intensity, and Burden of Side Effects Rating; MANGA: Meta-Analyses of New
Generation Antidepressants; MAO: Monoamine oxidase; NICE: National
Institute of Clinical Excellence; NaSSA: Noradrenergic and Specific
Serotonergic Antidepressant; NNT: Number needed to treat; PHQ9: Personal
Health Questionnaire-9; RCT: Randomized controlled trial; SMO: Site
Management Organization; SNRI: Serotonin & Noradrenalin Reuptake
Inhibitor; SSRI: Selective Serotonin Reuptake Inhibitor; STAR*D: Sequenced
Treatment Alternatives to Relieve Depression; SUN ☺ D: Strategic Use of New
generation antidepressants for Depression.
Acknowledgements
This study is supported by the Grant-in-Aid by the Ministry of Health, Labourand Welfare (H22-Seishin-Ippan-008).
Author details
1
Department 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. 2Department of Psychiatry and CognitiveBehavioral Medicine, Nagoya City University Graduate School of Medical
Sciences, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 Japan. 3Department of
Neuropsychiatry, Kochi Medical School, Kohasu, Okoh-cho, Nankokushi, Kochi
783-8505 Japan. 4Department of Neuropsychopharmacology, National
Institute of Mental Health, National Center of Neurology and Psychiatry, 4-11 Ogawa-Higashi, Kodaira, Tokyo 187-8553 Japan. 5Department of
Epidemiology and Biostatistics, Translational Medical Center, National Centerof Mental Health, National Centre of Neurology and Psychiatry, 4-1-1 OgawaHigashi, Kodaira, Tokyo 187-8502 Japan. 6Miki Clinic, 1-1-3 Hiranuma, Nishiku, Yokohama 220-0023 Japan. 7Center for Suicide Prevention, National
Institute of Mental Health, National Center of Neurology and Psychiatry, 4-11 Ogawa-Higashi, Kodaira, Tokyo 187-8553 Japan.
Authors’ contributions
TAF conceived the study, TAF, MY, MI and NY prepared the original
manuscript. TAF, TA, SS, MY, KM, NW, MI and NY participated in therefinement of the protocol. NY is the trial statistician. All authors criticallyreviewed and approved the final version of the manuscript.
Competing interests
TAF has received honoraria for speaking at CME meetings sponsored byAstellas, Dai-Nippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Kyorin,
MSD, Meiji, Otsuka, Pfizer, Shionogi and Yoshitomi. He is on advisory board

Page 18 of 20

for Sekisui Chemicals and Takeda Science Foundation. He has received
royalties from Igaku-Shoin, Seiwa-Shoten, Nihon Bunka Kagaku-sha andAmerican Psychiatric Publication. TA has received speaking fees and/or
research funds from Astellas, Astra-Zeneca, Bristol-Meyers-Squib, DaiichiSankyo, Dainippon-Sumitomo, Eisai, GlaxoSmithKline, Janssen, Kyowa-HakkoKirin, Lilly, Meiji, Otsuka, Pfizer, Sanofi-Aventis, Shionogi and Yakult. NW has
received speaking fees and/or research funds from Dainippon-Sumitomo,
GlaxoSmithKline, Lilly, Otsuka, Pfizer, Asahi-Kasei and Shering-Plough. SS has
received speaking fees and/or research funds from Astellas, DainipponSumitomo, GlaxoSmithKline, Janssen, Lilly, Otsuka, Pfizer, Shering-Plough,Shionogi and Yoshitomi. MY and NY have no conflicts of interest to declare.
NY received royalties from Seiwa-Shoten. MI has received a speaking fee
from Lilly. KM has received speaking fees from Astellas, DainipponSumitomo, GlaxoSmithKline, Janssen, Lilly, Meiji, Otsuka, Pfizer and SheringPlough.
Received: 9 April 2011 Accepted: 11 May 2011 Published: 11 May 2011
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doi:10.1186/1745-6215-12-116
Cite this article as: Furukawa et al.: Strategic use of new generation
antidepressants for depression: SUN(^_^)D study protocol. Trials 201112:116.

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