Kato et al. BMC Medicine (2018) 16:103
https://doi.org/10.1186/s12916-018-1096-5

RESEARCH ARTICLE

Open Access

Optimising first- and second-line treatment
strategies for untreated major depressive
disorder — the SUN☺D study: a pragmatic,
multi-centre, assessor-blinded randomised
controlled trial
Tadashi Kato1, Toshi A. Furukawa2*, Akio Mantani3, Ken’ichi Kurata4, Hajime Kubouchi5, Susumu Hirota6,
Hirotoshi Sato7, Kazuyuki Sugishita8, Bun Chino9, Kahori Itoh10, Yoshio Ikeda11, Yoshihiro Shinagawa12,
Masaki Kondo13, Yasumasa Okamoto14, Hirokazu Fujita15, Motomu Suga16, Shingo Yasumoto17, Naohisa Tsujino18,
Takeshi Inoue19, Noboru Fujise20, Tatsuo Akechi13, Mitsuhiko Yamada21, Shinji Shimodera15, Norio Watanabe2,
Masatoshi Inagaki22, Kazuhira Miki23, Yusuke Ogawa2, Nozomi Takeshima2, Yu Hayasaka2, Aran Tajika2,
Kiyomi Shinohara2, Naohiro Yonemoto24, Shiro Tanaka25, Qi Zhou26, Gordon H. Guyatt26 and for the SUN☺D
Investigators

Abstract
Background: For patients starting treatment for depression, current guidelines recommend titrating the antidepressantdosage to the maximum of the licenced range if tolerated. When patients do not achieve remission within several weeks,
recommendations include adding or switching to another antidepressant. However, the relative merits of these guideline
strategies remain unestablished.
Methods: This multi-centre, open-label, assessor-blinded, pragmatic trial involved two steps. Step 1 used open-cluster
randomisation, allocating clinics into those titrating sertraline up to 50 mg/day or 100 mg/day by week 3. Step 2 used
central randomisation to allocate patients who did not remit after 3 weeks of treatment to continue sertraline, to add
mirtazapine or to switch to mirtazapine. The primary outcome was depression severity measured with the Patient Health
Questionnaire-9 (PHQ-9) (scores between 0 and 27; higher scores, greater depression) at week 9. We applied mixedmodel repeated-measures analysis adjusted for key baseline covariates.
Results: Between December 2010 and March 2015, we recruited 2011 participants with hitherto untreated major
depression at 48 clinics in Japan. In step 1, 970 participants were allocated to the 50 mg/day and 1041 to the 100 mg/day
arms; 1927 (95.8%) provided primary outcomes. There was no statistically significant difference in the adjusted PHQ-9
score at week 9 between the 50 mg/day arm and the 100 mg/day arm (0.25 point, 95% confidence interval (CI), − 0.58
to 1.07, P = 0.55). Other outcomes proved similar in the two groups.
In step 2, 1646 participants not remitted by week 3 were randomised to continue sertraline (n = 551), to add mirtazapine(n = 537) or to switch to mirtazapine (n = 558): 1613 (98.0%) provided primary outcomes. At week 9, adding mirtazapine(Continued on next page)* Correspondence: furukawa@kuhp.kyoto-u.ac.jp
2
Department of Health Promotion of 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© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Kato et al. BMC Medicine (2018) 16:103

Page 2 of 16(Continued from previous page)achieved a reduction in PHQ-9 scores of 0.99 point (0.43 to 1.55, P = 0.0012); switching achieved a reduction of 1.01 points(0.46 to 1.56, P = 0.0012), both relative to continuing sertraline. Combination increased the percentage ofremission by 12.4% (6.1 to 19.0%) and switching by 8.4% (2.5 to 14.8%). There were no differences in adverse effects.
Conclusions: In patients with new onset depression, we found no advantage of titrating sertraline to 100 mg vs
50 mg. Patients unremitted by week 3 gained a small benefit in reduction of depressive symptoms at week 9 byswitching sertraline to mirtazapine or by adding mirtazapine.
Trial registration: ClinicalTrials.gov, NCT01109693. Registered on 23 April 2010.
Keywords: Major depressive disorder, Antidepressive agents: first-line treatment, Second-line treatment, Randomised
controlled trial

Background
Every year, an estimated five million people inhigh-income countries alone start new antidepressantsto treat their depression [1–3]. In the USA, the annual
prevalence of prescribed antidepressant use exceeds 10%of the population, almost double that of 10 years before[2]. Antidepressant use is similarly high and increasingin European countries, ranging between 4 and 9% [1],with a 1-year incidence of new antidepressant prescription of approximately 1% [3]. Clinicians need specific,
detailed and appropriate guidelines to guide their antidepressant pharmacotherapy.
To initiate antidepressant treatment, modern guidelines recommend new generation antidepressants and inparticular selective serotonin reuptake inhibitors (SSRIs)[4]. A network meta-analysis of 12 new generation antidepressants suggested that the SSRI sertraline, becauseof its favourable balance of benefits, acceptability andcost, may be the best choice when starting treatment for
major depression [5]. Sertraline has been the mostwidely prescribed antidepressant in the USA [6] andelsewhere [7].
Once they choose a first-line antidepressant, practitioners must optimise its dosage, considering the wide
approved dose range for most drugs. Many guidelines
only list such ranges and do not specify where within
this range the initial treatment should aim [4, 8, 9]. The
American Psychiatric Association guideline is more
specific and recommends that the initial doses be incrementally raised and maximised, side effects permitting([10], p. 43). However, systematic reviews of randomised
controlled trials (RCTs) have provided conflicting results
regarding the benefits and harms of lower vs higher
doses of various antidepressants within their therapeutic
ranges. One review synthesised results from 33 RCTs
comparing two or more doses of the same antidepressants and found that a dose level of 100–200 mg imipramine equivalents (or 20–40 mg fluoxetine equivalents)
showed the highest response rate, while lower doses
showed a reduction in efficacy and higher doses were
not accompanied by increased efficacy. Adverse events

increased monotonically with dose [11]. However, thisstudy included both old and new generation antidepressants. The dose-response curves may be different fordifferent classes of antidepressants. More recent reviews
focussing on a single agent [12] or several agents [13]suggested that there was no dose-response relationshipwithin the approved dose ranges for SSRIs.
Clinicians face another challenge because, after several
weeks of the first-line treatment, only 50% of patients respond (i.e. achieve depression severity less than half thatat pre-treatment), and only 30% remit (i.e. return to aeuthymic state). Patients’ failure to respond or remit
requires consideration of alternative treatments.
Guideline recommendations for second-line treatment
include dose escalation, switching to a different antidepressant or adding a different drug [4, 10]. The last
strategy may be divided into ‘augmentation’ when a
non-antidepressant drug is added to an antidepressantand ‘combination’ when two antidepressants are used together [4]. Systematic reviews of RCTs agree that dose
escalation confers no benefit beyond continuing theinitial drug dose [14–17]; consistent with these results,
the German National Guideline clearly states that dose
escalation for SSRI does not work [8]. Two previous
systematic reviews have found some support for theswitching strategy [18], especially to an antidepressantfrom a different class [19]. However, a recent more
rigorous meta-analysis found no high-level evidence thatswitching the antidepressant is effective when comparedto simply continuing the initial antidepressant [20].
There are also reviews that support various augmentation strategies [21] and combination strategies [22].
However, most of the RCTs addressing patients who failto respond to initial pharmacotherapy for depression
compared new strategies against continuing preceding
treatment; far less evidence exists comparing alternative
second-line strategies against one another. For example,
only two reports have directly compared switching vscombination strategies among patients who failed
first-line treatment: one study compared combination vsswitching vs continuing the prior treatment [23], while

Kato et al. BMC Medicine (2018) 16:103

another compared dose escalation vs combination vscontinuing the prior treatment [24]. Unfortunately, neither study was sufficiently powered (only 32–38 patientsin each arm in the first study and 98–99 patients in thesecond study) to reach meaningful conclusions. The
STAR*D trial randomised 1439 patients with major depression who had not remitted on citalopram to various
switching strategies or augmentation/combination strategies. However, they used an equipoise-stratified design
which gave patients choices in their treatment regimen:
only 105 patients consented to randomisation to any ofthe drug switching or augmentation strategies, and consequently the analyses had to be conducted separately
among the switching strategies or among the augmentation/combination strategies [25, 26]. A recently published study compared switching to bupropion against
combining with bupropion or augmenting with an antipsychotic aripiprazole among 1522 patients withantidepressant-refractory major depression and foundthat aripiprazole augmentation significantly increased
response over bupropion combination or switching[27]. Most patients in this trial were, however, chronically depressed and highly refractory (the mean duration of index episode was more than 85 months andthe mean number of previous medication courses was2.4). The trial does not, therefore, address the initial
treatment of a new depressive episode.
Even less is known about when to institute second-line
treatment. The American Psychiatric Association
practice guideline recommends 4–8 weeks [10], theAmerican College of Physicians 6–8 weeks [28] andthe National Institute for Clinical Excellence (NICE)
guideline 3–4 weeks at one place but 6–8 weeks at
another [4].
Thus, in trying to optimise antidepressant pharmacotherapy for patients with major depression, clinicians faceconflicting guidelines informed by low quality evidence.
We therefore conducted a pragmatic RCT — an RCT thatmimics the practice environment and thus maximises applicability — to examine the following two questions concerning the first- and second-line treatments for ahitherto untreated episode of major depression:
1. What is the relative effectiveness and safety of
initially titrating to the lowest vs the highest
value of the therapeutic dose range of anantidepressant? On the basis of the results ofprior evidence [5] and existing practices [6, 7],
we chose sertraline as the drug to be tested.
Since the available evidence suggests that there
may be differences between different classes ofantidepressants with respect to dose-response
relationship [15], the first hypothesis pertains tothe choice of the initial target dose of an SSRI,

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and of sertraline in particular, within its therapeutic
range.
2. When patients do not remit on first-line treatment,
what is the relative effectiveness and safety ofcontinuing initial treatment, combining withmirtazapine or switching to mirtazapine? We set 3
weeks as this decision point as the earliest time
point in guideline recommendations [4]. Our choiceof mirtazapine is consistent with a systematic
review reporting that combination of a reuptake
inhibitor antidepressant such as an SSRI and a
blocker of presynaptic alpha-2 autoreceptor(mirtazapine, mianserin, trazodone) was superior
to other combinations [22]. In addition, mirtazapine
poses a very low risk of drug interaction. Finally, inthe recently updated network meta-analysis of 21
antidepressants, mirtazapine was the second mostpotent antidepressant after amitriptyline [29]; itsless favourable acceptability profile renders it lesssuitable as first-line treatment, but when first-line
treatment fails, mirtazapine represents a potentiallyappropriate second choice.

Methods
Study design and participants

The Strategic Use of New generation antidepressants for
Depression (SUN☺D) is a multi-centre, open-label,assessor-blinded, pragmatic RCT that involved two randomisation steps to examine the first- and second-line
treatment strategies for untreated unipolar major depressive episodes.
The study was conducted in the departments of psychiatry at 48 clinics and hospitals across Japan between
December 2010 and September 2015. We recruited adultmen and women between 25 and 75 years who had a
primary diagnosis of a non-psychotic unipolar major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)[30] within the past month as ascertained by the study
psychiatrists administering the semi-structured interview
using the major depression section of the Primary Care
Evaluation of Mental Disorders (PRIME-MD) [31]. All
recruited persons were also not allowed to be taking any
antidepressant, antipsychotic or mood stabiliser. Other
exclusion criteria included history of schizophrenia, schizoaffective disorder, bipolar disorder; current dementia,
borderline personality disorder, eating disorder or substance dependence; and imminent high risk of suicide,
as judged by the study psychiatrist. No severity threshold
was required so long as the participant satisfied the diagnostic criteria for major depressive disorder in the pastmonth. The protocol provides additional details of theeligibility criteria [32]. When the study psychiatrist decided that sertraline was indicated, the patient beganKato et al. BMC Medicine (2018) 16:103

taking 25 mg/day of sertraline; only those who tolerated
sertraline for 3–16 days were eligible.
An institutional review board at each participating site
approved the study. An independent data monitoring
committee oversaw the trial. All participants provided
written informed consent. The study protocol, its
amendment and the statistical analysis plan have been
published elsewhere [32, 33].
Randomisation and masking

Figure 1 presents the study flow. In step 1, using theminimisation method adjusting for expected recruitment, study sites were randomised to titrate sertraline
up to the minimum or the maximum of the licenced

Fig. 1 Trial profile. ® randomised, EDC electronic data capture system

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dosage in Japan (50 mg/day or 100 mg/day) by week 3.
The unit of randomisation was therefore by site. The
cluster randomisation design was chosen to avoid any
confusion and possible protocol violation that might
have arisen had we asked study physicians, who often
had their own preference for either the minimum or the
maximum target doses, to use different titrating strategies for different patients. Further, we were concernedthat requiring patients to undergo two individual randomisations within 3 weeks might decrease the feasibilityof this large pragmatic trial.
In step 2, participants who had not reached remission,
defined as scoring 4 or less on the Patient Health Questionnaire (PHQ-9) [34] at week 3, were randomised 1:1:1

Kato et al. BMC Medicine (2018) 16:103

through the web-based central computer system to continue with sertraline, to combine sertraline with mirtazapine or to switch to mirtazapine. The step 2
randomisation used the minimisation method adjustingfor site; whether 50% or greater reduction on PHQ-9
had been achieved; and whether patients reported moderate or greater impairment due to side effects.
Physicians and patients were aware of their treatments.
Outcome assessors were blinded throughout. The statisticians conducting the analyses and the writing committee were masked to treatment allocation until they
signed the agreed-upon interpretations of the results.
Procedures

In step 1, participants in the minimum dosage arm received 50 mg/day of sertraline at week 1 to be continued
through week 3, and those in the maximum dosage arm
received 50–75 mg/day at week 1 and 100 mg/day atweek 2 to be continued through week 3. When these target dosages were not tolerated, lower dosages were
accepted.
In step 2, in the continuing sertraline arm, sertraline
was administered as 50 or 100 mg/day according to theinitial randomisation. In the combination arm, sertraline
was continued and mirtazapine was added between 7.5
and 45 mg/day at the discretion of the study psychiatrist.
In the mirtazapine switch arm, mirtazapine between
7.5 mg and 45 mg/day was administered; sertraline wastapered and discontinued by week 7.
Co-administration of benzodiazepines, but not of
another antidepressant, antipsychotic or mood stabiliser
was allowed up to week 9. Neither was any
depression-specific psychotherapy such as cognitive behavioural therapy (CBT) or interpersonal psychotherapy(IPT) allowed. Those who withdrew consent to the study
treatments by week 9 but still participated in follow-up
evaluations received treatment as negotiated with their
physician. Between weeks 9 and 25, there were no restrictions on treatments, and the continuation therapy
was at the physician’s discretion.
Outcomes

For both the step 1 and step 2 randomisations, the primary outcome was depression severity as measured bymasked assessors conducting semi-structured interviews
using the PHQ-9 at week 9. The PHQ-9 consists of thenine diagnostic criteria items of major depression fromthe DSM-IV [35]. Each item is rated between 0 = ’Not atall’ through 3 = ’Nearly every day’, making the total score
range 0–27, with higher ratings indicating increased depression severity. The instrument has demonstrated excellent reliability, validity and responsiveness [34].
Secondary outcomes included the Frequency, Intensity
and Burden of Side Effects Rating (FIBSER) and thePage 5 of 16

Beck Depression Inventory 2nd edition (BDI-II). The
FIBSER collects information regarding the frequency, intensity and burden of side effects, each on a 7-point
scale with higher ratings indicating greater severity, andprovides a total score between 3 and 21 [25]. The BDI-II
is a self-report measure of depression severity addressing
21 symptoms of depression, each on a scale between 0
and 3, with the total score ranging between 0 and 63;
higher scores indicate more severe depression [36]. In
addition, the study psychiatrist recorded any incident ofsuicidality according to the Columbia Classification Algorithm of Suicide Assessment (C-CASA) [37] or ofmanic/hypomanic/mixed episodes at weeks 9 and 25,
and reported any serious adverse events throughout the
study. Response was defined as 50% or greater reduction
from week 1 on PHQ-9, and remission as scoring 4 orless on PHQ-9 [34].
The PHQ-9 and the FIBSER were administered by
telephone assessors [38], trained at and operating fromthe central office and blind to the treatment assignment
and the timing of the assessment, at weeks 1, 3, 9 and
25. We had previously established the high inter-rater
reliability of our telephone assessors [39]. The BDI-II
was filled in by the participants at weeks 0, 1 and thenevery 2 weeks up to week 9, and every 4 weeks up to
week 25.
Sample size

For step 1, we calculated that we would need 66 participants at each of 30 sites in order to ensure adequate
power (beta level of 0.20) at a two-sided alpha level of
0.05 to detect a mean difference of 1 point on PHQ-9
with an estimated standard deviation (SD) of 5 or a standardised mean difference of 0.20 between the two arms,
for the null hypothesis of no difference and an intracluster correlation coefficient of 0.05 [40]. We reasoned thatan effect size of 0.20, corresponding with a small effectaccording to Cohen [41], would represent an importantdifference between active treatments. The required total
sample size for step 1 was 1980.
For step 2, we calculated that 522 participants pergroup would ensure adequate power (beta level of 0.20)
at a two-sided alpha level of 0.05 to detect a standardised mean difference of 0.20 among any two of thethree treatment groups. Assuming a dropout rate of 10%
and a remission rate of 10% at week 3, we needed 1934
participants entering step 1.
Statistical analysis

In order to examine the optimum initial target dose ofsertraline, we analysed results from all those who werecluster-randomised at week 1 to titrate sertraline up to
50 mg/day or 100 mg/day and, had they followed theprotocol, would have stayed on that sertraline dose up

Kato et al. BMC Medicine (2018) 16:103

to week 9 — that is, those who had remitted and continued on sertraline; those who had not remitted and wererandomised at week 3 to continue sertraline; and those
who declined the second randomisation. We used aweighted mixed-model repeated-measures analysis tocompare model-adjusted least squares means: the primary outcome was the PHQ-9 at week 9 as pre-specified
in the study protocol. The model included random effects for subjects and sites and fixed effects of treatment,
visit (as categorical) and treatment-by-visit interaction,
adjusted for age, sex, education, marital status, numberof previous depressive episodes and baseline scores atweeks 0 and 1. At the first blinded interpretation committee meeting, the statistician reported an imbalance inthe baseline demographic and clinical variables. The
writing committee therefore agreed, at that meeting,without knowledge of the identity of the arms and basedon their prior knowledge regarding variables that may be
associated with depression severity, on the following
variables to be entered in the primary analysis as possible confounders: age, sex, education, marital status,
number of previous depressive episodes and baseline
PHQ-9 scores at weeks 0 and 1. Each observation was
weighted by inverse probability of censoring (IPCW) toaccount for missing outcomes due to being allocated tothe combination or switching arms at step 2 randomisation. The weight for IPCW was calculated by a logistic
regression that included age, sex, education, marriage,
number of episodes, PHQ-9 scores at weeks 0 and 1 andwhether the participant was allocated to continue sertraline or otherwise at week 3 as predictors of missingness.
We applied the same modelling approach to thecontinuous secondary outcomes. We used weighted generalised linear mixed models with the logit link and binomial distributions to account for clustering effects forthe dichotomous secondary outcomes. For the time todiscontinuation of the allocated or any treatment, weapplied Cox regression with the same covariates andcalculated the hazard ratio (HR) and its 95% confidence interval (CI). For step 1 analyses, we examined
two subgroup hypotheses, pre-specified in the statistical analysis plan [33]: (1) whether the PHQ-9 score
at week 1 was less than or greater than 15 and (2)whether the patient had shown improvement fromweek 0 to week 1 at or above the median of the sample. We also conducted four sensitivity analyses
employing mixed models with different assumptions,described in the statistical analysis plan [33].
To compare the second-line strategies, we used themixed-model repeated-measures analysis comparing
model-adjusted least squares means of the PHQ-9 atweek 9 among the three treatment arms. This model included the following: fixed effects of PHQ-9 at week 3,
treatment, visit (as categorical), treatment-by-visit

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interaction, minimisation variables for step 2 randomisation. The model included individuals and sites as random effects. We applied the same modelling approachto the continuous secondary outcomes and the logistic
regression model for the dichotomous secondary outcomes. In order to facilitate the clinical interpretation of
the obtained odds ratio (OR), we calculated the risk difference (RD) and its CI by applying the model-adjusted
OR and its CI to the event rate in the sertraline continuation arm. For the time to discontinuation, we applied
Cox regression with the same covariates. We applied the
Hochberg procedure for adjusting the multiple comparisons involved with three treatment arms in the primarycomparison and reported adjusted P values. For step 2
analyses, we examined three pre-specified hypotheses regarding possible effect modifiers [33]: (1) whether
patients had achieved a 50% or greater reduction on
PHQ-9 from week 1 to week 3, (2) whether FIBSER results indicated ’moderate’ or greater impairment due toside effects or (iii) whether step 1 was high or low dose.
All efficacy and safety analyses followed theintention-to-treat principle, and all patents were analysed in the groups to which they were randomised.
Blinded interpretation of the results

The writing committee reviewed a statistical report inwhich the treatments were masked, and developed interpretation of the results and associated conclusions underalternative scenarios for all possible permutations oftreatments [42]. The treatments were revealed only after
the writing committee signed off on the agreed-upon interpretations (See Additional file 1).
Role of the funding source

The funders of the study had no role in study design,
data collection, data analysis, data interpretation or inwriting of the report. The corresponding author had fullaccess to all the data in the study and had final responsibility for the decision to submit for publication.
Changes from the original protocol

No major change was made since the original protocol
and statistical analysis plan [32, 33]. Our publishedprotocol [32] lists the several minor changes in thedetails since the original protocol.

Results
Figure 1 shows the screening, randomisation andfollow-up of the study participants. Between December
2010 and March 2015, 56,261 first-visit patients to theparticipating 48 clinics and hospitals in Japan underwent
eligibility assessment, of whom 7895 suffered from untreated unipolar major depressive episodes. Of these,
2011 patients satisfied eligibility criteria and were clusterKato et al. BMC Medicine (2018) 16:103

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randomised to titrate sertraline up to the minimum or
maximum of the licenced dosage within 3 weeks: 970 in
22 clinics and hospitals to the 50 mg/day arm and 1041
in 26 clinics and hospitals to the 100 mg/day arm. The
participants’ characteristics differed between the twoarms, especially with regard to sex and PHQ-9 scores atweeks 0 and 1 (Table 1). Of those randomised at week 1,
1927 (95.8%) and 1910 (95.0%) were successfully
followed up at week 9 and week 25, respectively.
Of these, 1647 had not remitted by week 3 and wereindividually randomised to continue sertraline (n = 551),
Table 1 Baseline characteristics of the participants at step 1
randomisation
Titrate sertraline up
to 50 mg/day by
week 3 (n = 970)

Titrate sertraline up
to 100 mg/day by
week 3 (n = 1041)

Age, year mean (SD)43.3 (12.2)

41.8 (12.3)

Female sex, n (%)

572 (59.0)

506 (48.6)

Education year, mean (SD)

13.8 (2.2)

14.1 (2.5)

Employed full-time

398 (41.1)

374 (36.0)

Employed part-time

103 (10.6)

76 (7.3)

On medical leave

206 (21.3)

328 (31.6)

Housewife

114 (11.8)

116 (11.9)

Demographic characteristics

Job status, n (%)

Student

5 (0.5)14 (1.4)

Retired18 (1.9)

5 (0.5)Not employed

124 (12.8)

125 (12.0)

Missing2

3Single, never married262 (27.1)

355 (34.1)

Single, divorced or
separated

148 (15.3)

124 (11.9)

Marital status, n (%)

Single, widowed

29 (3.0)25 (2.4)

Married528 (54.6)

537 (51.6)

Missing

30

Age of onset at first
episode, years, mean (SD)38.6 (13.3)

37.1 (13.5)

Number of previous
depressive episodes,
mean (SD)

2.3 (4.2)

2.2 (3.1)

Length of current episode,months, mean (SD)

6.6 (17.2)

5.3 (10.0)

Inpatient status at timeof entry, n (%)

2 (0.2)3 (0.3)

PHQ-9 at week 0

18.1 (4.1)

18.8 (3.7)

PHQ-9 at week 1

14.7 (5.5)

15.9 (4.9)

BDI-II at week 1

26.2 (10.9)

28.7 (10.6)

Clinical characteristics

BDI-II Beck Depression Inventory 2nd edition, PHQ-9 Patient
Health Questionnaire-9

combine sertraline with mirtazapine (n = 538) or switch
to mirtazapine (n = 558). Participants’ characteristics
proved similar across the three arms (Table 2). Of thoserandomised at week 3, 1613 (98.0%) and 1597 (97.0%)
were successfully followed up at week 9 and week 25,
respectively.
With regard to step 1 treatments, in the 50 mg/day
arm, 91.7% (889/970) had been prescribed 50 mg/day,
0.1% (1/970) 37.5 mg/day, 1.3% (13/970) 25 mg/day and0.1% (1/970) 75 mg/day by week 3; in the 100 mg/day
arm, 82.0% (854/1041) had reached 100 mg/day, 5.3%
(55/1041) 75 mg/day, 6.7% (70/1041) 50 mg/day and0.9% (9/1041) 25 mg/day. In the 50 mg/day arm 6.8%
(66/970) had stopped treatment as had 5.1% (53/1041)
in the 100 mg/day arm. For step 2 randomised allocations at week 3, 99.5% (548/551), 96.1% (516/537) and
96.8% (540/558) of the randomised participants started
their allocated treatment for the continuation, combination and switch arms, respectively; of the last group,
72.9% (407/558), 83.9% (468/558) and 87.8% (490/558)
were successfully tapered off sertraline by weeks 5, 6 and7, respectively.
In the following analyses, we ascertained the assumptions of normality and the homoscedasticity of the error
in both the steps 1 and 2 mixed-effects models. We also
ascertained the proportional hazards assumption by visual inspection of the log cumulative hazard curves andby testing the treatment*time interaction in Cox regression models.
Step 1: 50 mg/day vs 100 mg/day as initial target dose ofsertraline

According to the adjusted and weighted mixed-model
repeated-measures analyses, there was no statisticallysignificant difference (0.25 point, 95% CI − 0.58 to 1.07,
P = 0.55) between the 100 mg/day arm and the 50 mg/
day arm in the PHQ-9 score at week 9 (Table 3). There
were no statistically significant differences in the secondary efficacy outcomes at week 9. Neither were there any
statistically significant differences in the global burden ofside effects between the 50 mg/day and 100 mg/dayarms.
At week 25, the 100 mg/day arm scored lower (− 2.28,
95% CI − 3.91 to − 0.66, P = 0.0059) on self-rated BDI-II
than the 50 mg/day arm (Table 4). The two arms did not
differ, however, in the other efficacy outcomes of
PHQ-9, the proportion of remission or in the global burden of side effects.
The incidence of suicidality, manic switches or serious
adverse events was very small, and there were no statistically significant differences between the two arms
through 25 weeks (Additional file 2: Tables S1, S2).
Results were similar regardless of baseline depression
severity or initial response (Additional file 2: Table S3).

Kato et al. BMC Medicine (2018) 16:103

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Table 2 Baseline characteristics of the participants at step 2 randomisation
Continue with sertraline(n = 551)

Combine sertraline withmirtazapine (n = 537)

Switch to mirtazapine(n = 558)

Age, year mean (SD)41.5 (11.6)

42.0 (11.7)

41.4 (11.4)

Female sex, n (%)

289 (52.5)

284 (52.9)

281 (50.4)

Education year, mean (SD)14.1 (2.4)

13.8 (2.2)

14.1 (2.3)

Demographic characteristics

Job status, n (%)
Employed full-time

213 (38.7)

218 (40.8)215 (38.7)

Employed part-time

52 (9.4)

52 (9.7)

40 (7.2)

On medical leave

146 (26.5)

143 (26.7)

163 (29.3)

Housewife

47 (8.5)

62 (11.6)

53 (9.5)

Student

3 (0.5)3 (0.6)8 (1.4)Retired6 (1.1)5 (0.9)4 (0.7)Not employed84 (15.3)

52 (9.7)

73 (13.1)

Missing022

188 (34.2)

144 (26.9)

188 (33.7)

Marital status, n (%)
Single, never marriedSingle, divorced or separated

75 (13.6)

182 (15.3)

80 (14.3)

Single, widowed

10 (1.8)

17 (3.2)

9 (1.6)

Married277 (50.4)

292 (54.6)

281 (50.4)

Missing120

Age of onset at first episode, years, mean (SD)37.0 (12.9)

37.0 (12.8)

36.4 (12.4)

Number of previous depressive episodes, mean (SD), range

2.4 (3.4), 1–30

2.1 (3.2), 1–50

2.4 (4.2), 1–50

Length of current episode, months, mean (SD), range

5.7 (10.6), 0.5–139

6.7 (16.9), 0.5–240

6.5 (16.3), 0.5–276

Inpatient status at baseline, n (%)

1 (0.2)1 (0.2)2 (0.4)

PHQ-9 at week 3, mean (SD)12.8 (5.2)

12.6 (5.1)

12.8 (5.2)

Clinical characteristics

BDI-II at week 3, mean (SD)24.5 (10.7)

24.1 (10.7)

24.4 (10.9)

Sertraline at week 3, mean (SD), mg/day

72.2 (26.6)

71.4 (27.6)

72.6 (28.3)

BDI-II Beck Depression Inventory 2nd edition, PHQ-9 Patient Health Questionnaire-9

All sensitivity analyses differed little from the primaryfindings (Additional file 2: Table S4).
Step 2: Continue sertraline vs combine with mirtazapine
vs switch to mirtazapine at week 3

The adjusted mixed-model repeated-measures analysis
revealed that the mirtazapine combination arm and themirtazapine switch arm were both superior to the sertraline continuation arm; the combination arm by − 0.99
points (95% CI − 1.55 to − 0.43, P = 0.0012) and theswitch arm by − 1.01 points (95% CI − 1.56 to − 0.46, P =0.0012) on PHQ-9 after Hochberg adjustment for multiple
comparison. Results were very similar between the
combination and switch arms (0.02, 95% CI − 0.54 to
0.57, P = 0.95); see Table 5. Self-rated BDI-II scoresand the dichotomised response and remission rates
were consistent with the primary analysis. RDs for response and remission, respectively, were 9.1% (95% CI

2.8–15.4%) and 12.4% (6.1–19.0%) for the combination
strategy, and 8.2% (1.7–14.3%) and 8.4% (2.5–14.8%) for
the switching strategy, over the continuation strategy.
They corresponded with numbers needed to treat (NNTs)of 11.0 (6.5–35.7) and 8.1 (5.3–16.4) for the combinationand 12.2 (7.0–59) and 11.9 (6.8–40) for the switchingstrategies.
The proportion of continuation of the allocated treatment was significantly lower in the combination arm(RD 8.5%, 95% CI 2.9–14.9%) and the switching arm(6.4%, 95% CI 1.3–12.5%) than the continuation arm.
The overall burden of side effects as measured with FIBSER did not, however, differ among the three strategies(Table 5). Neither were there any material differences regarding incidence of suicidality, manic switches or serious adverse events (Additional file 2: Table S5).
At week 25, the treatment arms did not differ in anyof the efficacy (PHQ-9, BDI-II, remission), acceptability

Kato et al. BMC Medicine (2018) 16:103

Page 9 of 16

Table 3 Primary and secondary outcomes at week 9 for step 1 randomisation
Titrate sertraline up to
50 mg/day by week 3

Titrate sertraline up to
100 mg/day by week 3

100 mg/day vs
50 mg/dayLeast squares mean (95% CI)

Least squares mean (95% CI)

Adjusteda difference(95% CI) P value

PHQ-9

7.90 (7.14 to 8.66)

8.15 (7.78 to 8.52)

0.25 (−0.58 to 1.07)
P = 0.55

BDI-II

16.55 (15.43 to 17.67)

16.00 (14.88 to 17.13)−0.55 (−2.09 to 1.00)
P = 0.49

FIBSER

5.03 (4.81 to 5.26)

5.28 (4.96 to 5.61)

0.25 (− 0.15 to 0.65),
P = 0.22

Raw numbers

Raw numbers

Adjustedb OR(95% CI)P value

Proportion of response

216/424 (111 of 251 who wereunremitted and allocated tocontinue sertraline, 91 of 129
who remitted and continued
on sertraline and 14 out of 44
who withdrew from protocol)

229/425 (122 of 286 who were unremitted
and allocated to continue sertraline, 84 of
99 who remitted and continued on sertraline
and 23 out of 40 who withdrew from protocol)

1.23 (0.90 to 1.67),
P = 0.19

Proportion of remission

185/424 (64 of 251 who wereunremitted and allocated tocontinue sertraline, 110 of 129
who remitted and continued
on sertraline and 11 out of 44
who withdrew from protocol)

170/426 (68 of 286 who were unremitted
and allocated to continue sertraline, 86 of
99 who remitted and continued on sertraline
and 16 out of 41 who withdrew from protocol)

1.09 (0.75 to 1.58),
P = 0.64

Proportion of continuation of theallocated treatment up to week 9302/460 (204 of 261 who wereunremitted and allocated tocontinue sertraline, 96 of 129
who remitted and continued
on sertraline and 2 out of 70
who withdrew from protocol)

330/455 (248 of 290 who were unremitted
and allocated to continue sertraline, 80 of 101
who remitted and continued on sertraline
and 2 out of 64 who withdrew from protocol)

1.17 (0.70 to 1.98)
P = 0.53

Mean (SD)

Mean (SD)45.5 (19.8), n = 384

85.3 (32.1), n = 391

Sertraline prescribed at week
9 (mg/day)a
The linear mixed-effects repeated-measures model included fixed effects of treatment, visit (as categorical) and treatment-by-visit interaction, and random effects
for subjects and sites, adjusted for age, sex, education, marital status, number of previous depressive episodes, baseline scores at weeks 0 and 1, and wasweighted by inverse probability of censoring (IPCW) to account for missing outcomes due to being allocated to the combination or switching arms at step
2 randomisationb
We used weighted generalised linear mixed models with the logit link and binomial distributions to account for clustering effects for the dichotomous secondary
outcomes, adjusted for age, sex, education, marital status, number of previous depressive episodes, baseline scores at weeks 0 and 1
BDI-II Beck Depression Inventory 2nd edition, FIBSER Frequency, Intensity and Burden of Side Effects Rating, PHQ-9 Patient Health Questionnaire-9(time to discontinuation of the allocated treatment or of
any treatment) or harm outcomes (Table 6, Additional file 2:
Table S6).
There was no evidence of effect modification in any of
the three pre-planned subgroup analyses (Additional file 2:
Table S7).

Discussion
The SUN☺D trial involved two randomisations to
examine the first- and second-line antidepressant pharmacotherapies for the acute phase treatment of hitherto
untreated major depressive disorder.
The step 1 randomisation examined the impact of titrating to the minimum or maximum of the licenced
dose of sertraline by week 3. In patients starting treatment for major depressive disorder, there were no important differences in effectiveness or adverse effects

between these two starting sertraline doses. The resultsof the primary outcome at week 9 (0.25 point differencein adjusted PHQ-9 score, 95% CI − 0.58 to 1.07, P =0.55) excluded an important difference in favour of thehigher dose. Neither were there any important differences between the minimum vs the maximum target
doses in side effects, burden or treatment acceptability
up to either week 9 or week 25.
When patients do not remit after 3 weeks of sertraline
treatment, however, adding mirtazapine or switching sertraline to mirtazapine resulted in approximately aone-point benefit in PHQ-9 at week 9, a standardisedmean difference of around 0.16. This difference corresponded to RDs in response of 9.1% (95% CI 2.8–15.4%)
for the combination and 8.2% (1.7–14.3%) for theswitching strategy and, in remission, of 12.4% (6.1–
19.0%) for the combination and 8.4% (2.5–14.8%) for theKato et al. BMC Medicine (2018) 16:103

Page 10 of 16

Table 4 Secondary outcomes at week 25 for step 1 randomisation
Titrate sertraline up to
50 mg/day by week 3

Titrate sertraline up to
100 mg/day by week 3

100 mg/day vs
50 mg/dayLeast squares mean (95%CI)

Least squares mean (95% CI)

Adjusteda difference (95% CI)
P value

PHQ-9

6.00 (5.33 to 6.67)

5.52 (4.89 to 6.16)−0.47 (− 1.39 to 0.44)
P = 0.31

BDI-II

13.29 (12.11 to 14.46)

11.00 (9.82 to 12.19)−2.28 (− 3.91 to − 0.66)
P = 0.006

FIBSER

4.14 (3.86 to 4.42)

4.28 (4.04 to 4.51)

0.14 (−0.20 to 0.48)
P = 0.43

Raw numbers (%)

Raw numbers (%)

Adjustedb OR(95%CI)
P value

240/427 (117 of 252 who wereunremitted and allocated tocontinue sertraline, 110 of
127 who remitted andcontinued on sertraline and
13 out of 48 who withdrew
from protocol)

226/423 (128 of 286 who wereunremitted and allocated tocontinue sertraline, 84 of 97
who remitted and continued
on sertraline and 14 out of 40
who withdrew from protocol)

0.99 (0.66 to 1.47),
P = 0.94

Mean (SE)Mean (SE)HR (95% CI)
P valueTime to discontinuation of
allocated treatment by week 25

14.68 (0.40)

13.82 (0.37)

0.88 (0.52 to 1.48)
P = 0.63

Time to discontinuation of
any treatment by week 25

17.55 (0.38)

15.55 (0.28)

1.37 (0.80 to 2.35)
P = 0.25

Mean (SD)

Mean (SD)40.7 (29.1), n = 341

57.0 (45.0), n = 321

Proportion of remission

Sertraline prescribed at week 25 (mg/day)a

The linear mixed-effects repeated-measures model included fixed effects of treatment, visit (as categorical) and treatment-by-visit interaction, and random effects
for subjects and sites, adjusted for age, sex, education, marital status, number of previous depressive episodes, baseline scores at weeks 0 and 1, and wasweighted by inverse probability of censoring (IPCW) to account for missing outcomes due to being allocated to the combination or switching arms at step
2 randomisationb
We used weighted generalised linear mixed models with the logit link and binomial distributions to account for clustering effects for the dichotomous secondary
outcomes, adjusted for age, sex, education, marital status, number of previous depressive episodes, baseline scores at weeks 0 and 1
BDI-II Beck Depression Inventory 2nd edition, FIBSER Frequency, Intensity and Burden of Side Effects Rating, PHQ-9 Patient Health Questionnaire-9, SE Standard error

switching strategy. These values are slightly below or
above the usually accepted clinically significant
threshold of 10% RD, but they may be important topatients when one considers that they are differences
between alternative active treatments and that RDs
for antidepressants over placebo are approximately
20% only [29, 43]. In addition, these results were consistent with patients’ self-reports by BDI-II. The benefits of combination and switching did not, however,
persist after continuation treatment at the treating
physician’s discretion at week 25.
Combination or switching strategies resulted in 6–8%
fewer patients continuing the allocated treatments up to
week 9 than continuing on sertraline. However, given
the greater improvement in depressive symptoms withthe strategies that included mirtazapine; similar global
ratings of side effects among the treatment arms at
weeks 9 and 25; and similar time to discontinuation of
allocated treatment or any treatment when considered
up to 25 weeks; this finding does not raise concern regarding the use of combination and switching strategies.

The most recent comprehensive network meta-analysis of antidepressants found that mirtazapine may havea greater response rate than sertraline (OR = 1.15, 95%
CI 0.93–1.43) when used as first-line monotherapy [29].
The current study findings are compatible with this network meta-analysis, and this superior efficacy of mirtazapine may be responsible for some of the benefits ofswitching or combination strategies over sertraline continuation found in the current study.
Some guidelines recommend dose increase within theapproved range after non-response to a lower dose ([4],p. 356, [10], p.53). Two previous studies have tested thisstrategy for sertraline and found that there was no additional benefit: one study compared 50 mg vs 150 mg ofsertraline for 5 weeks after an initial 3 weeks on 50 mg
and reported no difference [44]. Another study compared 100 mg vs 200 mg of sertraline for 5 weeks after
an initial 6 weeks in which patients received up to
100 mg and reported that the increase to 200 mg resulted in a lower response rate [24]. Although thecurrent study did not specifically address this strategy,

5.43 (5.14 to 5.72)
Raw numbers (%)

5.34 (5.05 to 5.63)

Raw numbers (%)

FIBSER

400/537 (74.5%)

452/551 (82.0%)

Proportion of continuationof the allocated treatment
up to week 918.4 (13.0), n = 524

15.1 (11.8), n = 501

0.6 (3.9), n = 520

Mirtazapine prescribedat week 9 (mg/day)

0.61 (0.45 to 0.83)
P = 0.0014

1.80 (1.36 to 2.38)
P < 0.0001

0.68 (0.50 to 0.92)
P = 0.0131

1.51 (1.14 to 1.99)
P = 0.0037

1.39 (1.08 to 1.78)
P = 0.0109

Adjustedc OR(95% CI)P value

Adjustedc OR(95% CI)P value
1.41 (1.11 to 1.85)
P = 0.0055

0.25 (−0.16 to 0.66)
P = 0.22− 1.62 (− 2.63 to − 0.61)
P = 0.0017−2.10 (−3.12 to − 1.07)
P < 0.0001
0.09 (−0.32 to 0.50)
P = 0.66

0.02 (− 0.54 to 0.58)
P = 0.94
P = 0.94b−1.01 (− 1.56 to − 0.46)
P = 0.0004
P = 0.0012b−0.99(−1.55 to − 0.43)
P = 0.0006
P = 0.0012b0.90 (0.67 to 1.19)
P = 0.46

1.19 (0.92 to 1.55)
P = 0.19

1.03 (0.81 to 1.33)
P = 0.79

Adjustedc OR(95% CI)P value− 0.16 (− 0.57 to 0.25)
P = 0.44−0.47 (− 1.49 to 0.55)
P = 0.36

Adjusteda difference(95% CI)P value

Combine vs switch

Adjusted difference(95% CI)P valuea

Switch vs continue

Adjusted difference(95% CI)P valueaCombine vs continueaThe linear mixed-effects repeated-measures model included fixed effects of PHQ-9 at week 3, treatment, visit (as categorical), treatment-by-visit interaction and minimisation variables for step 2 randomisation (step 1
treatment, 50% or greater reduction on PHQ-9 by week 3, moderate or greater impairment on FIBSER at week 3) and random effects for individuals and sitesb
Hochberg method was used for adjustment of multiplicity for the primary outcome (italicised P values for PHQ-9) but not for secondary outcomes, as postulated in the statistical analysis plan [33]c
We used the logistic regression model adjusted for sites, step 1 treatment, 50% or greater reduction on PHQ-9 by week 3 and moderate or greater impairment on FIBSER at week 3
BDI-II Beck Depression Inventory 2nd edition, FIBSER Frequency, Intensity and Burden of Side Effects Rating, PHQ-9 Patient Health Questionnaire-9

6.5 (19.0), n = 524

71.1 (29.1), n = 502

71.7 (30.0), n = 520

Mean (SD)

Mean (SD)

Mean (SD)427/558 (76.5%)

174/550 (31.6%)

275/550 (50.0%)

Raw numbers (%)

5.59 (5.30 to 5.88)

17.06 (16.25 to 17.86)

8.25 (7.79 to 8.71)

Least squares
mean (95% CI)

Switch to mirtazapine

Sertraline prescribed at
week 9 (mg/day)

188/527 (35.7%)

132/537 (24.6%)

Proportion of remission

273/527 (51.8%)

233/537 (43.4%)

Proportion of response

16.59 (15.77 to 17.40)

18.68 (17.87 to 19.49)

BDI-II

8.27 (7.80 to 8.74)

9.26 (8.79 to 9.72)

Least squares
mean (95% CI)

Least squares
mean (95% CI)

PHQ-9

Combine with mirtazapine

Continue sertraline

Table 5 Primary and secondary outcomes at week 9 for step 2 randomisation

Kato et al. BMC Medicine (2018) 16:103
Page 11 of 16

Raw numbers (%)

Raw numbers (%)

51.2 (38.3), n = 440
12.3 (13.0), n = 440

51.6 (38.5), n = 448

3.9 (10.6), n = 448

Mirtazapine prescribed at
week 52 (mg/day)Switch to mirtazapine

14.6 (13.8), n = 456

10.3 (24.7), n = 457

Mean (SD)20.22 (0.23)

15.56 (0.31)

Mean (SE)262/540 (48.5%)

Raw numbers (%)

4.48 (4.24 to 4.72)

13.72 (12.78 to 14.67)

6.61 (6.12 to 7.10)

Least squares mean (95% CI)

0.89(0.69 to 1.14)
P = 0.35

1.07(0.92 to 1.25)
P = 0.40

HR (95% CI)
P value

1.24 (0.96 to 1.49)
P = 0.10

1.08(0.85 to 1.38)
P = 0.51

1.04(0.89 to 1.21)
P = 0.64

HR (95% CI)
P value

1.16 (0.90 to 1.48),
P = 0.25

Adjustedb OR(95% CI)P value

Adjustedb OR(95% CI)P value−0.37 (− 1.59 to 0.86)
P = 0.56−0.64 (− 1.88 to 0.60)
P = 0.31

0.14 (−0.21 to 0.48)
P = 0.44

0.03 (− 0.56 to 0.63)
P = 0.91−0.20 (− 0.80 to 0.40)
P = 0.51

0.12 (−0.23 to 0.47)
P = 0.51

Switch vs continue
Adjusteda difference(95% CI)P value

Combine vs continue
Adjusteda difference(95% CI)P value

Combine vs switch

0.82(0.64 to 1.05)
P = 0.11

1.03(0.88 to 1.20)
P = 0.70

HR (95% CI)
P value

1.07 (0.80 to 1.37)
P = 0.60

Adjustedb OR(95% CI)P value− 0.02 (− 0.36 to 0.33)
P = 0.92−0.27 (− 1.51 to 0.96)
P = 0.66−0.24 (− 0.84 to 0.37)
P = 0.44

Adjusteda difference(95% CI)P valuea
The linear mixed-effects repeated-measures model included fixed effects of PHQ-9 at week 3, treatment, visit (as categorical), treatment-by-visit interaction, and minimisation variables for step 2 randomisation (step 1
treatment, 50% or greater reduction on PHQ-9 by week 3, moderate or greater impairment on FIBSER at week 3), and random effects for individuals and sitesb
We used the logistic regression model adjusted for sites, step 1 treatment, 50% or greater reduction on PHQ-9 by week 3 and moderate or greater impairment on FIBSER at week 3
BDI-II Beck Depression Inventory 2nd edition, FIBSER Frequency, Intensity and Burden of Side Effects Rating, HR hazard ratio, PHQ-9 Patient Health Questionnaire-9, SE Standard error

Mean (SD)

Mean (SD)

Sertraline prescribed at
week 52 (mg/day)

20.47 (0.23)

17.32 (0.17)

Time to discontinuation of
any treatment by week 25

15.23 (0.32)

Mean (SE)Mean (SE)15.97 (0.30)

263/520 (50.3%)

245/538 (45.5%)

Time to discontinuation of
allocated treatment by week 25

Proportion of remission

4.46 (4.21 to 4.71)

4.34 (4.10 to 4.59)

FIBSER

13.45 (12.49 to 14.41)

14.09 (13.15 to 15.03)

BDI-II

6.37 (5.88 to 6.87)

6.58 (6.09 to 7.07)

Least squares mean (95% CI)

PHQ-9

Combine with mirtazapine
Least squares mean (95% CI)

Continue sertraline

Table 6 Secondary outcomes at week 25 for step 2 randomisation

Kato et al. BMC Medicine (2018) 16:103
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Kato et al. BMC Medicine (2018) 16:103

our results with regard to the initial target dose are consistent with these previous studies.
There are limitations of our study. First, the step 1
cluster randomisation by clinic was performed at thestart of the study. As a result, there was no concealment
at the level of randomisation of individual patients,
which explains the differences in characteristics of patients enrolled in the two arms. Clinicians at study sites
allocated to the lower dose were less inclined to enrol
severe patients or male patients than were clinicians atsites allocated to the higher dose. We dealt with thisprognostic imbalance by adjusting for key variables in
the mixed-model repeated-measures analyses and confirmed robustness of the primary findings against model
assumptions through sensitivity analyses. Unknown confounders may still, however, have biased our findings,
limiting strength of inference in the step 1 findings.
Secondly, the open-label design may have createdsome undetected performance bias that may threaten
the internal validity of both the step 1 and step 2
comparisons, such as differential administration ofco-prescriptions or psychological support. Such bias is,however, likely to be minimal, because the protocol did
not allow any depression-specific psychotherapies suchas CBT or IPT or concomitant administration of
antipsychotics or mood stabilisers up to week 9.
Co-prescription of benzodiazepines was permitted, butthey were prescribed very similarly in all arms (60–70%
of the participants received either anxiolytics or hypnotics). Further, a differential placebo effect associatedwith adding or switching to mirtazapine vs continuingwith sertraline could explain some of the apparent effectof the switching/adding arms in step 2. Blinded assessment of outcomes somewhat ameliorates this concern.
Moreover, the open-label design was consonant with thepragmatic nature of the study, in which we made comparisons including such possible practice variability.
Thirdly, the tapering speed of sertraline in the switching arm was relatively slow and allowed some patients totake the combination of sertraline and mirtazapine forseveral weeks. The efficacy of the switching strategy
might therefore be contaminated by that of the combination treatment. However, gradual tapering was appropriate for this pragmatic trial and allowed us to address
the impact of interventions as clinicians would implement them in the real world.
Fourthly, one might question the generalisability of thecurrent study findings beyond the specific drugs anddosages employed. As the initial target dose of the antidepressant, we compared the minimum and the maximum of the licenced dosage in Japan, 50 mg/day and
100 mg/day of sertraline. The maximum dosage for
sertraline in the USA and in some other countries is
200 mg/day. The study specified dosing for mirtazapine

Page 13 of 16

between 7.5 and 45 mg, which is also lower than thedosing sometimes used in other countries. These differences may reflect differences in body weights and otherethnically specific variations in the genetic as well as
non-genetic mechanisms affecting the pharmacokinetics
and dynamics of psychotropic drugs [45]. Up to now,
however, inquiry has failed to identify ethnicity as aconvincing modifier of antidepressant effect [46]. Had
we compared 50 mg/day vs 200 mg/day, or had we
required higher dose ranges for mirtazapine, the results might have differed. However, consistent with
our step 1 findings, RCTs using other drugs have inmost cases also suggested no additional benefit withhigher doses [12, 47, 48]. It is also uncertain whether
results would be similar had we chosen to begin withan antidepressant other than sertraline or chosen to
combine or switch with a drug other than mirtazapine. Our step 2 findings for adding mirtazapine tosertraline are consistent with the previous systematic
review examining various combination strategies [22].
One might consider our step 2 findings for switching
to mirtazapine at odds with the recent meta-analysis
on this topic that found no additional benefit inswitching to various antidepressants [20]. However,
the only study in this review specific to mirtazapine
reported that using mirtazapine was more effective
than continuing the prior medication [49].
A further limitation is that, although it provides evidence that changing therapy after failure to remit at an
early point (in our study 3 weeks) may be preferable towaiting a longer period (e.g. the oft-recommended 6 to
8 weeks), the design did not specifically address the
optimal timing of the decision to switch or combine.
One RCT compared switching to duloxetine immediately
after non-response to 4weeks of escitalopram against
continuing 4 more weeks on escitalopram and thenswitching if non-responsive: the two arms did not differ
in their primary outcome of time to response, while
there was significant increase in a secondary outcome ofremission in the early switch arm than in the later
switch arm [50]. Another recent RCT examined thevalue of switching escitalopram to venlafaxine if patients
have shown minimal improvement after 2 weeks; remission rates were 8% higher in the switched than in thecontinuation arm, but this difference did not reach statistical significance, possibly due to a small sample size(n = 192, p = 0.21) [51]. Thus, the optimal time to combine or switch remains uncertain.
Strengths of this pragmatic trial primarily relate to design features that enhance the real-world application of
the results. We employed a large number of study sites
using broad eligibility criteria, and thus enrolled sufficient patients to achieve high power to establish or refute differences between groups. Because Japan does notKato et al. BMC Medicine (2018) 16:103

have a primary care system, patients with new onset depressive episodes usually consult office practice psychiatrists directly. Thus, in many other countries, primarycare doctors would see and begin treatment of mostparticipants entered in SUN☺D. In comparison to many
multi-centre trials, we were able to enrol a large proportion (2011 of 7895) of potentially eligible patients. Enrolment of patients not yet treated for their current episodeis another strength, eliminating a potential source ofvariability. For step 1 randomisation, we excluded patients who did not tolerate a low dose of sertraline, faithfully addressing the clinical question in which patientsand clinicians are interested: In patients who tolerate an
initial low dose of sertraline, should clinicians titrate to
the maximum dose? For step 2 randomisation, we selected alternative interventions that are recommended inpractice guidelines [4, 10] and are widely used [52].
We limited risk of bias through centralised, blinded,
telephone assessments that allowed us to achieve morethan 95% follow-up through 25 weeks, unique amonglarge trials of psychiatric interventions. The centralised
training of the raters enhanced the reliability and validityof the depression assessments [38]. A pre-publishedprotocol [32], statistical analysis plan [33] and blindedinterpretation of the results to minimise the researchers’interpretation bias further enhance the trustworthinessof this RCT.

Conclusions
The SUN☺D trial suggests that, for the initial antidepressant therapy for a new major depressive episode,titrating sertraline to the maximum over the minimum
within the licenced dosage confers no additional benefit
but increases cost. The confidence in this conclusion islimited by the failure of the cluster randomisation toachieve prognostic balance, and the possible residual
confounding after our adjusted analysis. When patients
fail to remit on this initial treatment, early combinationor switching using mirtazapine resulted in a small benefit in reducing depression without an increase in adverse
effects. Inferences apply to the strategies as implemented, which reflect clinical practice, including gradualtapering of sertraline in the switching arm. Factors bearing on the decision to combine or switch are likely to include costs (combination will be more costly), thecurrent burden of side effects of the first-line treatment,
the expected burden of combination or switching andthe patient’s readiness to change antidepressants.
The many drugs available allow clinicians considerable
options in the selection of an initial antidepressant andof second-line antidepressants to switch to or combinewith. Clinicians and patients may consider starting thetreatment with a low dose of agents for which evidence
suggests satisfactory efficacy and acceptability in the

Page 14 of 16

current trial and in the comprehensive network
meta-analysis [29]. Should they choose to combine antidepressants as the second-line strategy, the relative
merits of potential combinations remain largely untested
in RCTs, and it is implausible that RCTs will ultimately
evaluate all such alternatives. A previous review
suggested that a combination of a reuptake inhibitor
antidepressant and an antagonist of presynaptic alpha-2
autoreceptor is more effective than other combinations[22], and the current findings were consistent with thissuggestion. Those who place a high value in treatmentsthat have been tested in large trials that both minimiserisk of bias and mimic real-world conditions may prefer
the specific strategies used in this trial.

Additional files
Additional file 1: Blinded data analyses statement of interpretation.
(PDF 336 kb)
Additional file 2: Figure S1. Schedule of the assessments. Table S1.
Incidence of suicidality, manic switches or any serious adverse events up
to week 9 for step 1 randomisation. Table S2. Incidence of suicidality,
manic switches or any serious adverse events up to week 25 for step 1
randomisation. Table S3. Two pre-specified subgroup analyses for step 1
randomisation. Table S4. Four pre-specified sensitivity analyses for step 1
randomisation. Table S5. Incidence of suicidality, manic switches or any
serious adverse events up to week 9 for step 2 randomisation. Table S6.
Incidence of suicidality, manic switches or any serious adverse events up
to week 25 for step 2 randomisation. Table S7. Three pre-specified
subgroup analyses for step 2 randomisation. (DOCX 32 kb)
Additional file 3: SUN☺D Investigators and committee members.
(DOCX 17 kb)
Acknowledgements
Group information: A complete list of participating centres and investigatorsin the Strategic Use of New generation antidepressants for Depression(SUN☺D trial) is provided in Additional file 3.
Funding
The study was funded by the Ministry of Health, Labor and Welfare, Japan(H-22-Seishin-Ippan-008) from April 2010 through March 2012 to TAF (http://
www.mhlw.go.jp/english/) and thereafter by the Japan Foundation for
Neuroscience and Mental Health (JFNMH) to TAF (http://www.jfnm.or.jp/).
The JFNMH received donations from Asahi Kasei, Eli Lilly, GlaxoSmithKline(GSK), Janssen, Merck Sharp & Dohme (MSD), Meiji, Mochida, Otsuka, Pfizer,
Shionogi, Taisho and Mitsubishi-Tanabe. The funders of the study had norole in study design, data collection, data analysis, data interpretation or inwriting of the report.
Availability of data and materials
Sharing of identifiable, individual-level data is prohibited by Japanese law.
Fully anonymised, unidentifiable data with age, sex and site deleted are available from the University Hospital Medical Information Network (UMIN-ICDR
http://www.umin.ac.jp/icdr/index.html), an academic network information
centre for biomedical sciences funded by the Japanese Ministry of Education,
Culture, Science, Sports and Technology (MEXT) at https://upload.umin.ac.jp/
cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000034028.
Authors’ contributions
TAF is the principal investigator and had overall responsibility for the
management of the study. TAF, NY, ST and QZ had full access to all the datain the study and take responsibility for the integrity of the data and theaccuracy of the data analyses. TAF conceived the study. YOg, NTa, YH, AT
and KSh performed data curation; NY, ST, QZ and TAF performed the formal

Kato et al. BMC Medicine (2018) 16:103

analysis. TAF and MY acquired the funding. TK, TAF, AM, KK, HK, SH, HS,
KSu, BC, KI, YI, YS, MK, YOk, HF, MS, SY, NTs, TI, NF, TA, MY, SS, NW, MI,
KM, YOg, NTa, YH, AT, KSh and GHG performed the investigation. TAF,
TA, MY, SS, NW, MI, KM and NY developed the methodology.MK, YOk,
HF, MS, SY, NTs, TI, NF, YOg, NTa, YH, AT and KSh administered the
project. TAF and GHG supervised the project. TAF and GHG wrote theoriginal draft. TK, AM, KK, HK, SH, HS, KSu, BC, KI, YI, YS, MK, YOk, HF,
MS, SY, NTs, TI, NF, TA, MY, SS, NW, MI, KM, YOg, NTa, YH, AT, KSh, NY,
ST and QZ reviewed and edited the manuscript. All authors read andapproved the final manuscript.
Ethics approval and consent to participate
The study protocol was approved by the ethics committees/institutional
review boards of Kyoto University Graduate School of Medicine (C0446),
Nagoya City University Hospital (45–10-0004), Kochi Medical School (22–96),
Kumamoto University (No. 1341), Yatsushiro Kosei Hospital (dated October28, 2011), Yuge Hospital (No. 86), Kurume University Medical School (No.
11151), St. Lucia Hospital (dated January 11, 2012), Hiroshima University
Hospital (Rin 297), University of Tokyo Hospital (P2011062-11X), Toho
University School of Medicine (No. 23053), Hokkaido University Hospital(JI011–0292) and Sapporo Hanazono Hospital (dated June 4, 2014). All
participants provided written informed consent.

Competing interests
TK has received lecture fees from Eli Lilly and Mitsubishi-Tanabe and has
contracted research with GSK, MSD and Mitsubishi-Tanabe. He has received
royalties from Kyowa Yakuhin. TAF has received lecture fees from Eli Lilly,
Janssen, Meiji, MSD, Otsuka, Pfizer and Mitsubishi-Tanabe and consultancy
fees from Takeda Science Foundation. He has received research support from
Mochida and Mitsubishi-Tanabe. AM has received lecture fees from Mochida,
Eli Lilly and Meiji. SH has received lecture fees from MSD, Pfizer, Meiji,
Tanabe-Mitsubishi and Otsuka. HS has received lecture fees from DaiichiSankyo and Mochida. KSu has received lecture and/or consultant fees from
Eli Lilly, Mochida, Eisai, Meiji and Daiichi-Sankyo. BC has received lecture feesfrom Eli Lilly, Meiji and Mitsubishi-Tanabe. KI has received lecture fees from
Dainippon-Sumitomo, Eli Lilly, Otsuka, Takeda, Kyowa Yakuhin, MitsubishiTanabe, Meiji and Shionogi. YI has received lecture fees from Meiji, Eli Lilly,
Janssen and Otsuka. YS has received lecture fees from Janssen, Kyowa
Yakuhin, Meiji, MSD, Otsuka and Mitsubishi-Tanabe. MK has received lecture
fees from Yoshitomi and a research grant from Novartis. YOk has received
lecture fees from Otsuka, Dainippon-Sumitomo, Astellas, Pfizer, Eli Lilly,
Janssen, Meiji, Mochida, Yoshitomi, Eisai and GSK. HF has received lecture
fees from Meiji, Mochida, MSD and Otsuka. SY has received lecture fees from
Daiichi-Sankyo and Otsuka. NTs has received lecture fees from Astellas,
Shionogi, Novartis, Fujifilm RI Pharma, Meiji, Mochida, Janssen, Eli Lilly andDainippon-Sumitomo. TI has received lecture fees from GSK, Mochida, Asahi
Kasei, Shionogi, Otsuka, Dainippon-Sumitomo, Eli Lilly, Eisai, MitsubishiTanabe, Pfizer, AbbVie, MSD, Yoshitomi, Takeda and Meiji. He has received
grants from Shionogi, Astellas, Otsuka, Dainippon-Sumitomo, Eli Lilly, Eisai,
Mitsubishi-Tanabe, Pfizer, AbbVie, MSD, Yoshitomi, Takeda and Meiji. He is on
advisor boards for GSK, Mochida, Otsuka, Eli Lilly, Mitsubishi-Tanabe, Pfizer
and Takeda. NF has received lecture fees from Pfizer, Eisai, Mochida, Ono,
Shionogi, MSD and Otsuka. TA has received lecture fees and/or researchfunds from Daiichi-Sankyo, Eisai, Hisamitsu, Eli Lilly, MSD, Meiji, Mochida,
Otsuka, Pfizer, Novartis and Terumo. MY has received lecture fees from Meiji,
MSD and Asahi Kasei and has contracted research with Nippon Chemiphar.
SS has received lecture fees from Otsuka, MSD, Meiji, Eli Lilly, Mochida andShionogi. MI has received a grant from Novartis Pharma. He has received
lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma,
Daiichi-Sankyo, Meiji and Takeda. KM has received lecture fees from Eisai,
GSK, Meiji, MSD, Otsuka, Pfizer, Eli Lilly, Mochida, Yoshitomi, DainipponSumitomo, Takeda and Shionogi. YOg has received a lecture fee from Eli Lilly.
NTa has received lecture fees from Otsuka and Meiji. YH has received alecture fee from Yoshitomi. AT has received lecture fees from Eli Lilly and
Mitsubishi-Tanabe. ST has received lecture fees from AstraZeneca, Taiho andOno. He has received consultation fees from DeNA Life Science and CanBus.
He has received outsourcing fees from Satt and Asahi Kasei Pharma. His wife
has been engaged in a research project of Bayer. All these fees have beenoutside the submitted work. KK, HK, MS, NW, KSh, NY, QZ and GHG declarethat they have no competing interests.

Page 15 of 16

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.
Author details
1
Aratama Kokorono Clinic, Nagoya, Japan. 2Department of Health Promotionof Human Behavior, Kyoto University Graduate School of Medicine / Schoolof Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
3
Mantani Mental Clinic, Hiroshima, Japan. 4Kabe Mental Health Clinic,
Hiroshima, Japan. 5Kokokara Clinic, Kochi, Japan. 6Hirota Clinic, Kurume,
Japan. 7Harimayabashi Clinic, Kochi, Japan. 8Oji Mental Clinic, Tokyo, Japan.
9
Ginza Taimei Clinic, Tokyo, Japan. 10Sinsapporo Mental Clinic, Sapporo,
Japan. 11Narumi Himawari Clinic, Nagoya, Japan. 12Shiki Clinic, Nagoya, Japan.
13
Department of Psychiatry and Cognitive-Behavioral Medicine, Nagoya City
University Graduate School of Medical Sciences, Nagoya, Japan.
14
Department of Neuropsychiatry, Hiroshima University Graduate School of
Biomedical & Health Sciences, Hiroshima, Japan. 15Center to Promote
Creativity in Medical Education, Kochi Medical School, Kochi University,
Nankoku, Japan. 16Department of Neuropsychiatry, University of Tokyo
Hospital, Tokyo, Japan. 17Department of Neuropsychiatry, Kurume University
Medical School, Kurume, Japan. 18Department of Psychiatry, Toho University
School of Medicine, Tokyo, Japan. 19Department of Neuropsychiatry, Tokyo
Medical University, Tokyo, Japan. 20Department of Neuropsychiatry,
Kumamoto University Graduate School of Medicine, Kumamoto, Japan.
21
Department of Neuropsychopharmacology, National Center of Neurology
and Psychiatry, Tokyo, Japan. 22Department of Neuropsychiatry, Okayama
University Hospital, Okayama, Japan. 23Miki Mental Clinic, Yokohama, Japan.
24
Department of Biostatistics, Kyoto University Graduate School of Medicine /School of Public Health, Kyoto, Japan. 25Department of Clinical Biostatistics,
Kyoto University Graduate School of Medicine / School of Public Health,
Kyoto, Japan. 26Departments of Clinical Epidemiology and Biostatistics and of
Medicine, McMaster University, Hamilton, Canada.
Received: 8 December 2017 Accepted: 5 June 2018

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