Watanabe et al. Trials (2015) 16:36
DOI 10.1186/s13063-015-0554-z

TRIALSSTUDY PROTOCOLOpen AccessA mindfulness-based stress management
program and treatment with omega-3 fatty acids
to maintain a healthy mental state in hospitalnurses (Happy Nurse Project): study protocol for arandomized controlled trial
Norio Watanabe1*, Toshi A Furukawa2, Masaru Horikoshi3, Fujika Katsuki4, Tomomi Narisawa1, Mie Kumachi5,
Yuki Oe3, Issei Shinmei3, Hiroko Noguchi6, Kei Hamazaki7 and Yutaka Matsuoka1

Abstract
Background: It is reported that nursing is one of the most vulnerable jobs for developing depression. While they
may not be clinically diagnosed as depressed, nurses often suffer from depression and anxiety symptoms, which
can lead to a low level of patient care. However, there is no rigorous evidence base for determining an effective
prevention strategy for these symptoms in nurses. After reviewing previous literature, we chose a strategy oftreatment with omega-3 fatty acids and a mindfulness-based stress management program for this purpose. We aim
to explore the effectiveness of these intervention options for junior nurses working in hospital wards in Japan.
Methods/Design: A factorial-design multi-center randomized trial is currently being conducted. A total of 120 nurses
without a managerial position, who work for general hospitals and gave informed consent, have been randomly allocatedto a stress management program or psychoeducation using a leaflet, and to omega-3 fatty acids or identical placebo pills.
The stress management program has been developed according to mindfulness cognitive therapy and consists of four
30-minute individual sessions conducted using a detailed manual. These sessions are conducted by nurses with amanagerial position. Participants allocated to the omega-3 fatty acid groups are provided with 1,200 mg/day ofeicosapentaenoic acid and 600 mg/day of docosahexaenoic acid for 90 days.
The primary outcome is the change in the total score of the Hospital Anxiety and Depression Scale (HADS), determinedby a blinded rater via the telephone at week 26. Secondary outcomes include the change in HADS score at 13 and 52
weeks; presence of a major depressive episode; severity of depression, anxiety, insomnia, burnout, and presenteeism;
utility scores and adverse events at 13, 26 and 52 weeks.
Discussion: An effective preventive intervention may not only lead to the maintenance of a healthy mental state in nurses,
but also to better quality of care for inpatients. This paper outlines the background and methods of a randomized trial that
evaluates the possible additive value of omega-3 fatty acids and a mindfulness-based stress management program forreducing depression in nurses.
Trial registration: Clinicaltrials.gov: NCT02151162 (registered on 27 May 2014).
Keywords: Anxiety, Behavior therapy, Depression, Fatty acids, Omega-3, Mindfulness, Prevention and control* Correspondence: noriow@ncnp.go.jp
1
Department of Clinical Epidemiology, Translational Medical Center, National
Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo,
Tokyo 187-8551, Japan
Full list of author information is available at the end of the article© 2015 Watanabe et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.

Watanabe et al. Trials (2015) 16:36

Background
Hospital nurses are vulnerable to psychological stress andmental disorders [1]. In early reports, the suicide rate of female nurses was significantly higher than that of average
workers, and their life expectancy at the age of 45 years was
26.9 years, which is only one year more than that of miners[2]. In a cross-sectional survey conducted in Cyprus, 65% ofnurses reported that their job was stressful, and the prevalence of fatigue was higher in females (93%) than in males(88%) [3].
Consequently, nursing is highly associated with depression. The prevalence of depressive symptoms above a clinical cut-off among hospital-employed nurses is 18% in the
United States [4]. Nurses with depression are not only
likely to suffer personally, but their illness may also havean impact on the quality of care for patients, through anincrease in presenteeism. In terms of the monetary burdenof patient care, the costs due to increased falls and medication errors that are caused by presenteeism are estimated at 1,346 USD per nurse annually [5].
A systematic review conducted on psychological distressamong hospital nurses in the United States reported thatemotional fatigue and burnout in nurses is associated withlack of support from senior management in the form ofsafety programs, and support from supervisors, respectively[6]. Less-experienced junior nurses need support from senior colleagues and require interventions to empower resilience in order to alleviate their psychological distress.
When considering the possible options for intervention in
depression, pharmacological treatments can be discounted
because they are not useful as a preventive intervention due
to their adverse side effects. Instead, lifestyle interventions,such as exercise and diet, are highly likely to be easily implemented and are promising options. With regard to exercise,according to a systematic review of randomized controlled
trials (RCTs), depressive symptoms among patients with achronic illness and functioning problems were reduced [7];however, rigorous evidence has not supported exercise as apreventive measure for depression and anxiety symptoms
among the elderly [8] or children and young people [9]. In
addition, intensive exercise may not be feasible due to thebusy schedule of nurses working in hospitals. In contrast,
the most feasible interventions may be diet. Omega-3 polyunsaturated fatty acids (PUFAs), in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), havebeen most frequently evaluated for their effects on depression and anxiety disorders. Many previous systematic reviews that have accumulated data from RCTs have been
published; however, there are some reviews that show apositive effect of omega-3 PUFAs [10] and others that donot [11]. In addition, these reviews did not focus on preventative interventions.
In a recently published comprehensive meta-analysis [12],omega-3 PUFAs were effective in patients with a diagnosis

Page 2 of 12

of major depressive disorder, but not effective at preventing
depression in healthy subjects. In this analysis, three parallel
design RCTs for the prevention of depression in healthy
subjects were assessed, with a follow-up duration of overthree months. The studies employed a daily dose of 1.093 g
EPA and 0.226 g DHA [13], 3.0 g EPA and 0.6 g DHA [14]or 3.0 g EPA and 0.6 g DHA [15]. However, a high daily
EPA dose of between 1,000 and 1,500 mg/d with a ratio of
2:1 DHA is argued as optimal for affective disorders [16].
Based on the current evidence for omega-3 PUFAs as a preventive tool for anxiety and depressive symptoms, we believethat methodologically rigorous trials employing optimaldoses of EPA and DHA are still needed.
On the other hand, psychological interventions, such as
stress management, problem solving and support should
be considered as possible interventions in workplacesettings because of their feasibility and accessibility. A
Cochrane review [17] has revealed that a psychologicalintervention to alleviate stress among workers in theworkplace can be efficacious according to several small
RCTs; however, this review concluded that the methodological quality of these trials was not sufficient, and further
methodologically sound trials with a larger sample size areneeded to reach firm conclusions.
Among the various types of psychotherapy, mindfulnessbased cognitive therapy and meditation have been given
particular attention by both clinicians and researchers. In asystematic review, mindfulness meditation programs haveshown moderate evidence of improvements in depression,
with an effect size of 0.30 (95% confidence interval (CI): 0.00
to 0.59) at post-treatment), when compared with nonspecificactive controls [18]; however, the review focused on a clinical sample and therefore was not able to conclude any preventive effects of the psychotherapy. To the best of ourknowledge, there has been no systematic review focusing on
the prevention of depression and anxiety symptoms in theworkplace. Although the efficacy of mindfulness-based cognitive therapy in nurses has been examined in a previous
RCT [19], the trial included only a small number of participants and no firm conclusions could be drawn. For this reason, a conclusive RCT is necessary to establish evidence ofan effective psychological intervention that can help tomaintain a healthy mental state in hospital nurses.
Hence, the present study aims to conduct a methodologically rigorous factorial-design trial with 1:1:1:1 allocation to explore the effectiveness of omega-3 PUFAs,
and a mindfulness-based stress management programfor maintaining a healthy mental state in hospital nurses.

Methods/Design
Trial design

A parallel-arms factorial-design RCT with a 52-weekfollow-up period has been planned. Participants will berandomly allocated to one of the four intervention arms:

Watanabe et al. Trials (2015) 16:36

1) mindfulness-based stress management program plus
omega-3 PUFAs; 2) mindfulness-based stress management
program plus placebo; 3) psychoeducation leaflet plus
omega-3 PUFAs and 4) psychoeducation leaflet plus placebo. A total of 30 participants will be allocated to eacharm. These interventions will terminate within threemonths from the registration of the participant. The primary outcome will be the depression and anxiety severity
at 26 weeks (rated blindly), assessed using the 14-item
Hospital Anxiety and Depression Scale (HADS). Aftereach assessment, an assessor will guess which group theparticipant has been assigned to, making it possible toexamine if the blinding is successful.
Inclusion criteria

Page 3 of 12

4. Taking antidepressants, mood stabilizers,
anticonvulsants or antipsychotics at entry;
5. Any history of taking nutrient supplements,
including omega-3 fatty acids, for four or more
weeks within 52 weeks from entry;
6. Clinical depression, based on a total score of 11 ormore on the HADS - Depression Subscale [22] and15 or more on the Primary Health Care Questionnaire [23];7. Consumption of fish as the main course of a mealfour or more times per a week;
8. Taking anticoagulant drugs at entry or history ofstroke or myocardial infarction or
9. Judged ineligible by a clinical research coordinator(CRC) for any reason.

The inclusion criteria for participants are as follows:
Procedures

1. Aged between 20 and 59 years at entry to the study
and of female gender. We will limit participants to thefemale gender because a previous study investigating
the prevention of post-traumatic stress among emergency workers has demonstrated that omega-3 fatty
acids are effective in females but not males [20]. Thisis the first study to examine the effectiveness ofomega-3 fatty acids among nurses, therefore we havedecided to focus on females to maximize the benefit.
2. Nurses who work in inpatient wards at four general
hospitals in the Tama region of Japan, including the
National Center of Neurology and Psychiatry
Hospital, National Disaster Medical Center, Tokyo
Metropolitan Tama Medical Center and TamaHokubu Medical Center.
3. Those who are mainly engaged in caring forpatients, but not in administrative responsibilities.
Thus, head nurses in wards and senior nurses who
are mainly engaged in supporting administrative
work of the head nurses are excluded. A previous
study has shown that senior nurses have lessburnout than junior nurses [21], and senior nurses
are engaged in administrative work in the hospitals
included in our study.
4. Those who have given written informed consent toparticipate in the study.
Exclusion criteria

The exclusion criteria are as follows:
1. Plans to take sick leave, leave for other reasons orretirement within 26 weeks from entry to the study;
2. Already engaging in structured psychotherapy (suchas cognitive behavioral therapy, interpersonal
therapy or brief psychodynamic therapy) at entry;
3. Seeing a physician regularly for the treatment of any
mood or anxiety disorders at entry;

Information about the study will be presented to thehead of the hospital, the director of the nursing service
department and head nurses in explanatory meetings at
the recruiting hospitals. Leaflets with information about
the study will be distributed to nurses in hospital wards
and interested nurses will be contacted by a CRC. Eachnurse will input her data, except the HADS criterion,
into an electronic data capturing (EDC) system via theinternet, with some assistance by the CRC, and if she
satisfies all of the inclusion criteria and none of the exclusion criteria, provisional written informed consent
will be obtained. The participants will then be interviewed using the HADS through their mobile phone bya rater located in Kyoto University. If the nurse does notsatisfy the HADS exclusion criterion, formal written informed consent will be obtained.
The participants will be randomly allocated to one of thefour intervention arms via the EDC using a minimization
method. Minimization is an adaptive stratified allocation
system that is used in clinical trials [24]. Minimization can
reduce the imbalance between the numbers of patients ineach treatment group over possible confounding factors.
The participant’s place of work, total score on the HADS of
11 or higher [22], and whether they have been working as anurse for one year or more will be used as stratification variables (Figure 1).
Interventions
Psychological interventions

In the present factorial-design RCT, the effects of two
forms of psychological intervention will be compared:
mindfulness-based stress management program and a psychoeducation leaflet.
The stress management program has been developed
combining mindfulness-based self-regulation of attention [25] and the cognitive behavioral model of depression adapted from a previously established manual [26].

Watanabe et al. Trials (2015) 16:36

Page 4 of 12

Figure 1 Flowchart of the trial. EDC, electronic data capturing.

Although a previous trial of 41 nursing students [27]employed mindfulness meditation with the non-judgmental
awareness of moment-to-moment experiences as the central axis [28], we extracted the treatment components ofbody scan and breathing meditation from mindfulness
meditation because these techniques are considered easy tolearn and helpful for nurses, in our experience. The stressmanagement program consists of four weekly 30-minuteindividual sessions and is highly structured, with a detailed
manual. The contents of each session are as follows: 1) understanding the cognitive behavioral model of stress andemotion of the participant, 2) reviewing the model and conducting body scanning and breathing exercises, 3) reviewing the results of model and body scanning and thenpromoting awareness of the cognition of the participantand 4) reviewing the model, providing suggestions about increasing pleasant behaviors and planning a strategy to manage future stress. The feasibility of the program has been
examined by employing five nurses as participants in a pilot
run, the protocol of which was approved by the institutional review boards of the National Center of Neurology
and Psychiatry on 15 November 2013 (approval number:
A2013-102). No dropouts due to the program were observed. All the participants reported that the program
might be helpful for nurses to manage stress from theirwork. Some rewordings have been done to the program according to comments from the participants.
The stress management program will be conducted by senior nurses in four individual sessions within the first threemonths. Senior nurses will have taken a seven-hour workshop, including lectures and role-playing sessions. The
detailed manual and videos, including lectures, will be provided to the senior nurses. The senior nurses will be supervised monthly by email once the program commences. Allsessions will be audiotaped and 20% of them will berandomly selected and evaluated by two independent researchers to assess the integrity of the program. They will
check for adherence to the treatment manual with a checklist for each session.
A leaflet has been prepared for the psychoeducation
leaflet groups. This is based on a freely distributed psychoeducation leaflet about healthy mental state writtenby the Japanese Ministry of Health, Labor and Welfare[29]. The leaflet includes information about checking forsigns of stress, relaxation and sleep hygiene, and suggestions for stress management such as exercise, laughterand meeting intimate friends. It also includes a list of
consultants for mental health. We have adapted thisleaflet to be applicable to our study by adding advice
from senior nurses about working without stress. Participants allocated to the leaflet groups will be instructed toread this often, especially when they feel anxious or
stressed.
Supplements interventions

Omega-3 PUFA capsules have been formulated to contain 1,200 mg EPA and 600 mg DHA (Kentech Co. Ltd.,
Toyama, Japan) according to recommendations from experts [16]. The participants will take the capsules once a
day for 90 days from entry into the study. Placebo capsules contain rapeseed oil (47%), soybean oil (25%), olive
oil (25%) and fish oil (3%), and have an identical appearance and similar odor (Kentech Co. Ltd., Toyama,
Japan).
Adherence to the regimens will be checked amongnurses working for the National Center of Neurology
and Psychiatry Hospital and National Disaster Medical
Center from results of blood tests. At baseline and at
the three-month assessment, red blood cells (RBCs) will
be obtained from EDTA-anticoagulated blood (Terumo

Watanabe et al. Trials (2015) 16:36

Corporation, Tokyo, Japan), washed twice with saline
and frozen at −80°C until analysis. The fatty acid composition of the total phospholipid fraction of the RBCs
will be determined as described previously, with slight
modifications [30]. Briefly, the total lipid content will be
extracted from RBCs according to the method used by
Bligh and Dyer [31]. The total phospholipid fraction will
be separated by thin-layer chromatography. After transmethylation with HCl-methanol, the fatty acid composition will be analyzed using a gas chromatographysystem (GC14A Shimadzu Corporation, Kyoto, Japan)
equipped with a capillary column DB-225 (length: 30 m;
internal diameter: 0.25 mm; film: 0.25 μm; J&W Scientific, Folsom, California, United States); the entire system
was controlled using gas chromatography software
CLASS-GC10 version 1.3 (Shimadzu Corporation). In
addition, to assess adherence to the regimen, all theremaining capsules will be collected from all the participants after the three-month assessment.
Participants who decide to leave the allocated intervention due to adverse events or any other reason within
the first 13 weeks will be classified as dropouts from theintervention, but will still be asked to complete the assessments. Participants allocated to the leaflet and placebo capsule groups will not be allowed to take thestress management program and omega-3 PUFA capsules respectively, after 26 weeks. However, they will beallowed to take these interventions thereafter, and information will be collected from these participants.

Page 5 of 12

Japanese version of the HADS has been confirmed, with
Cronbach’s alpha values of the scale at 0.79 for the
HADS-D and at 0.77 for the HADS-A [22]. The total
score will be used as a measure of the severity of depression and anxiety symptoms in the present study.
Secondary outcome measures

All other self-reported measures will be collected
through the EDC system, where the participants canenter their own data at home. Participants will be notified at 13, 26 and 52 weeks to fill in the assessment
questionnaires within the following 14, 30 and 30 days
through the EDC system, respectively.
Depression and anxiety symptoms

The HADS will be administered at baseline, 13 and 52
weeks as secondary outcomes, as well as at 26 weeks(the primary outcome).
Major depressive episode

Information about depression and anxiety symptoms(primary outcome), insomnia, burnout, presenteeism,
quality of life, sick leave, consultation about the mental
state of the participant and oxidative stress will be collected at baseline, three months, six months (primarytime point) and 12 months from registration for eachparticipant (Table 1).

A current major depressive episode, according to (theDiagnostic and Statistical Manual of Mental Disorders,
4th. Edition (DSM-IV) criteria, will be ascertained using
the Primary Care Evaluation of Mental Disorders(PRIME-MD) algorithm in the depression module of thePatient Health Questionnaire (PHQ-9) [23] at baseline,
13, 26 and 52 weeks. The PHQ-9 was developed as aself-report version of the PRIME-MD that aims at a
DSM-IV diagnosis of several common mental disorders.
The PHQ-9 has been used as an assessment of major depressive disorder, according to DSM-5 [34]. The PHQ-9
consists of the nine diagnostic criteria items, whichmake a total score range between 0 and 27. Good testretest reliability (intraclass correlation coefficient (ICC)= 0.92) [35] and internal consistency reliability (Cronbach’s alpha = 0.89) [23] have been reported. The
Japanese version has been established through backtranslation [36].

Primary outcome measure

Anxiety

The primary outcome will be the total depression andanxiety severity changes at week 26 (rated blindly),assessed using the 14-item HADS [32,33] through theirmobile phone by a blinded rater located at Kyoto University. All the patients will be requested not to reveal
the allocated treatment to the assessors, in order to keep
the assessors’ blindness to the groups.
The total score of the HADS (HADS-T) ranges from 0
to 42, with higher scores indicating more symptoms.
The HADS has two sub-scores, each ranging from 0 to
21: HADS-D (depression) and HADS-A (anxiety). The
defined cutoffs were eight or higher for mild to moderate symptoms and 11 or higher for severe symptoms ofanxiety or depression. The reliability and validity of the

The Generalized Anxiety Disorder 7-item scale (GAD-7)[37] will be used to assess the severity of anxiety symptoms in the participants at baseline, 13, 26 and 52 weeks.
The GAD-7 was developed to screen for and evaluate
the severity of generalized anxiety disorder (GAD) in thegeneral population. The GAD-7 consists of seven items
and can give a diagnosis according to DSM-IV and
DSM-5. The internal consistency and test-retest reliability of the GAD-7 were a Cronbach’s alpha of 0.92 andintraclass correlation of 0.83, respectively [37]. Total
scores between five and nine, 10 and 14, or 15 and 21
indicate mild, moderate or severe anxiety symptoms, respectively. According to a recently published systematic
review, the GAD-7 was the best performing test forAssessment measuresEntryKyoto
University

HADS assessed through telephone

CRC

Informed consent, registration to EDC,
information about allocated group

7 to 21 days 13 weeks from entry
26 weeks from entry
52 weeks from entry
after entry(allowing for subsequent 14 days) (allowing for subsequent 30 days) (allowing for subsequent 30 days)x

Allocation guessed by raters

x

x

x

x

x

x

Watanabe et al. Trials (2015) 16:36

Table 1 Schedule for the assessmentsxSocio-demographic variables (such as age, x
academic status, marital status andpartners)
Concentrations of omega-3 fatty acids inmembrane of RBC, oxidative stress, andantioxidant status
Participants’ PHQ-9
input
GAD-7
through EDC
ISI
MBI

x

x

(2
hospitals)(2 hospitals)

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

BSI

x

x

x

x

HPQ

x

x

x

x

EQ-5D

x

x

x

x

Numbers of incidents and accidents

x

x

x

x

Numbers of visits to clinics

x

x

x

x

Numbers of absent days due to any
reasonxxxxHistory of taking psychotropic drugs

x

x

x

x

x

x

x

Adverse eventsx

x

BSI, Bradford Somatic Inventory; CRC, clinical research coordinator; EDC, electronic data capturing; EQ-5D, EuroQol; GAD-7, Generalized Anxiety Disorder 7-item scale; HADS, Hospital Anxiety and Depression Scale; HPQ,World Health Organization Heath and Work Performance Questionnaire; ISI, Insomnia Severity Index; MBI, Maslach’s Burnout Inventory; PHQ-9, Patient Health Questionnaire; PRIME-MD, Primary Care Evaluation of
Mental Disorders.

Page 6 of 12

Watanabe et al. Trials (2015) 16:36

GAD, with a positive likelihood ratio of 5.1 (95% CI: 4.3
to 6.0) and a negative likelihood ratio of 0.13 (95% CI:
0.07 to 0.25) [38]. A Japanese version of the GAD-7 has
been developed [39] and the agreement rate of diagnosis
compared to the Mini International NeuropsychiatricInterview was reported as satisfactory.
Burnout

The Maslach’s Burnout Inventory (MBI) [40] will be
used to assess burnout in nurses. The MBI is a tool for
detecting and measuring the severity of burnout syndrome. It is a 22-item questionnaire that assesses thedegree of burnout in terms of three subscales: emotional
exhaustion (EE), depersonalization (DP) and personal accomplishment (PA). EE represents feelings of being
emotionally exhausted and having a lack of energy, DP
represents feelings of impersonal responses towards recipients of the service and PA represents feeling of incompetence. The original English version has a good
validity and reliability, with a Cronbach’s alpha of 0.71 to
0.90 [41,42]. The Japanese version also has good reliability, with a Cronbach’s alpha of 0.77, 0.76 and 0.60 for
EE, DP and PA, respectively [43].
Insomnia

The Insomnia Severity Index (ISI) [44,45] will be used toassess insomnia at baseline, 13, 26 and 52 weeks. The
ISI is now considered a standard global measure forassessing the severity of insomnia and is used in manystudies [46,47]. Total scores between eight and 14 and15 and 28 indicate subthreshold insomnia and clinicalinsomnia, respectively. The internal consistency of the
ISI has a Cronbach’s alpha of 0.90 in a community population [48]. In a clinical population, a difference in scoreof −8.4 points (95% CI: −7.1 to −9.4) was associated witha moderate improvement, as rated by an independent
assessor after treatment [48]. The Japanese version has
been validated [49].
Somatic symptoms

The Bradford Somatic Inventory (BSI) will be used tomeasure somatic symptoms at baseline, 13, 26 and 52
weeks. The BSI is a 44-item questionnaire for female subjects about symptoms experienced in the previous month,which was designed to detect physical symptoms commonly related to depressed patients [50]. We selected the
BSI as a measurement for somatic symptoms because
there are no other assessment tools for this purpose in theJapanese language. The original English version of the BSI
was translated into Japanese by two Japanese psychiatrists(NW and YM) and back-translated into English by one
psychiatrist (TAF). The translations were then checked by
the original author of the BSI (Professor David B
Mumford). The number of positive items in the BSI will

Page 7 of 12

be used as a measure of the severity of somatic symptoms
in this study. Data from the BSI will be collected throughthe EDC on days seven to 21 from entry into the study tocheck the test-retest reliability.
Presenteeism

The World Health Organization Heath and Work Performance Questionnaire (HPQ) will be used to assess
presenteeism at baseline, 13, 26 and 52 weeks. The HPQ
is a self-report instrument designed to estimate the workplace costs of health problems in terms of self-reported
reduced job performance (presenteeism). The HPQ measures of presenteeism can be used to calculate two scores:
the absolute presenteeism score, obtained by multiplying
the respondent’s response to the second question by 10,
and the relative presenteeism score, obtained by dividing
the first response by the second response, then multiplying by 100. Absolute and relative presenteeism scores will
be used in this study.
The validity of the scale has been confirmed in previous studies [51,52]. The Japanese version of the HPQ
was used in the World Mental Health Survey in Japan[53]. The area under the curve values for absolute andrelative presenteeism in relation to future absences due
to mental disease were 0.71 (95% CI: 0.62 to 0.80) and
0.65 (95% CI: 0.55 to 0.75), respectively [54].
Quality of life

The EuroQol (EQ-5D) [55] will be used to assess healthrelated quality of life (QoL) at baseline, 13, 26 and 52
weeks. The EQ-5D is a standardized instrument used asa measure of health outcome and is applicable to a wide
range of health conditions and treatments. The five domains include mobility, self-care, usual activities, pain
and/or discomfort, and anxiety and/or depression. There
are three levels of severity: no problems, some or moderate problems and severe or extreme problems. Each pattern of responses is allocated to an individual utility
score, which ranges from 0 (death) to one (perfect
health). The Japanese version has been developed [56].
The test-retest reliability of the Japanese version was
0.996, and Cronbach’s alpha was 0.827 [57].
Oxidative stressOxidative stress and antioxidant levels will be evaluated at
the baseline and three-month assessments among thenurses working for the National Center of Neurology andPsychiatry Hospital and National Disaster Medical Center.
Oxidative stress is the imbalance between oxidative stressand antioxidant defenses. High oxidative stress or low antioxidant status are becoming increasingly recognized as biological mechanisms associated with poor health outcomes
and the progression of a wide range of diseases [58,59]. An
association between depression and oxidative stress has

Watanabe et al. Trials (2015) 16:36

been reported in a recently published meta-analysis [60];however, the conclusions seem inconsistent due to large
heterogeneity among the included studies, with an I2 of
80% and possible selection bias as the studies did not covera broad range of depression. Moreover, the meta-analysis
included only cross-sectional studies; therefore, associations
between changes in depression and oxidative stress remain
unclear.
In the present study, we will use reactive oxygen
metabolite-derived compounds (d-ROMs) and biologicalantioxidant potential (BAP) tests [61] to evaluate oxidative
stress and antioxidant levels, respectively, as used in previous studies [62,63].
Adverse events

An adverse event is defined as any unwanted or unintended signs (including laboratory exams, suicidal andself-harm behaviors and very unstable mental states),
symptoms or disease seen in trial participants, regardlessof the causal relationship with the study intervention.
Information about any possible adverse events will becollected during the intervention period through the
EDC. Participants will be encouraged to input these data
via emails at fixed intervals. Information about the severity and degree of adverse events affecting normal life will
also be collected. When the severity of severe for adverse
events or the degree affecting usual life of moderate orsevere due to adverse eventsis presented, the participant
will be contacted through telephone or email by a CRC,
and termination of the intervention will be discussed.
Adverse events will be classified into major adverse
events if they may lead to death or to enduring severe
impairment, depending on participants’ conditions andcircumstances. Major adverse events shall be reported to
the relevant section of the Ministry of Health, Labor andWelfare, as well as to the heads of all research centersand recruiting hospitals.
Other outcomes

Information about sick leave, consultations on personalmental state and about discontinuation of the allocatedinterventions will be collected through the EDC.
Sample size

The sample size was based on a power analysis conducted
for the HADS scores. There are no previous reports associated with the stress management program, in terms ofnurse-to-nurse interventions, that can contribute to thepower calculation of our trial. Based on trials that haveused nurses as therapists and the HADS as the primary
outcome, one trial has examined the efficacy of cognitive
behavioral therapy conducted by nurses for depression in
the elderly after lumber fracture operations, and a difference of 3.7 was found compared with treatment as usual

Page 8 of 12[64]. To the best of our knowledge, there have been noreports assessing treatment with omega-3 fatty acids fordepression or anxiety in nurses. One systematic review
and meta-analysis has shown that treatment with omega3, ≥60% EPA and ≤40% DHA led to an effect sizeof −0.026 (95% CI: −0.200 to 0.148), when compared witha placebo [65]. Therefore, the mean difference in the
HADS scores was estimated to be 4 ± 6 (SD) between the
stress management program and leaflet groups, and between the omega-3 fatty acids and placebo groups. To detect a significant difference at P = 0.05 (two-tailed) with apower of 0.9, it was calculated that 48 patients would be
required for each of the arms in both comparisons. Thus,
allowing for a 20% dropout rate, 60 participants would
need to be recruited per group. In the present factorialdesign RCT, 30 participants would be necessary for eachof the four groups.

Data management and analysis

All of the participants who are randomized at baseline will
be included in the primary analyses (intention-to-treat(ITT)). First, a descriptive analysis of the variables at baseline will be performed. We do not plan any statistical tests
to detect a difference at baseline among the trial arms because we aim to avoid multiple tests, and the decision toadjust for baseline data in RCTs should not be determinedby whether baseline differences are statistically significant[66]. However, when clinically important differences atbaseline are noted from a clinician’s point of view, a sensitivity analysis will be performed by adjusting for all suchpossible confounds.
Second, for the primary outcome and all the continuous outcomes assessed at 26 and 52 weeks, differencesamong groups will be examined using a mixed-model
repeated measures analysis. When missing data exist for
categorical variables, which are all negative outcomes,an ITT principal will be applied by assuming that all
dropouts did not satisfy the outcomes. However, perprotocol analyses, where only data from completers areincorporated, will also be presented according to a recent recommendation [67]. We also plan to calculate anumber needed to treat (NNT) with a 95% CI if a statistically significant difference among the groups is observed in dichotomous data.
A P value of <0.05 will be set to test the null hypothesis
for all analyses. Although we understand that this decision
might lead to errors in multiple tests, the present trial is
the first of its kind to examine prevention interventions inthis type of workplace; therefore, we have considered thatavoiding beta errors is preferable over alpha errors. However, 95% CIs will always be presented for differencesamong groups. We will not perform interim analyses to
examine the study hypotheses.

Watanabe et al. Trials (2015) 16:36

Sensitivity analysis

Per protocol analyses, where only data from completers
are incorporated to an analysis of covariance that adjustsfor baseline data, will be performed as sensitivity analyses for all the continuous outcomes.
Data monitoring

The trial will be supervised by the Data Monitoring and
Safety Management Committee. The committee consistsof three independent experts in research on psychotherapy and nutrient interventions and research methodology. Data regarding all outcomes will be sent to thecommittee twice a year and inspected. The members of
the committee are independent from the sponsor andcompeting interests of the present study.
Publication policy

The protocol and the results of all outcomes will be
published in a peer-reviewed medical journal. The results shall be reflected in treatment guidelines and systematic reviews.
Study period

The study period of this trial will be between June 2014
and March 2016, with the participant entry period being
between June 2014 and March 2015.
Ethical issues

The present study complies with the ethical guidelines forclinical studies published by the Japanese Ministry of
Health Labor and Welfare, as well as the ethical principles
established for research on humans stipulated in the Declaration of Helsinki and further amendments thereto.
The study protocol has been approved by the institutional review boards of the National Center of Neurology
and Psychiatry on 16 May 16 2014 (approval number:
A2014-017) and of Toyama University on 16 June 2014
(approval number: 26–24). If important protocol modifications such as changes to eligibility criteria, outcomes oranalyses are needed for any reason, the investigators willcommunicate this with the review boards.
Written informed consent will be obtained from allparticipants included in this study. Participants will be
informed that they can withdraw from the study at any
time without stating the reason, and that their withdrawal will never lead to refusal of any other services.
Data for each participant will be handled with sequentially allocated numbers to keep participant’s confidentiality. Participants’ personal information will also beanonymized with sequentially allocated numbers.

Discussion
To the best of our knowledge, this study represents thefirst study to investigate the effectiveness of preventive

Page 9 of 12interventions on depression and anxiety symptoms amonghospital nurses. In addition to these symptoms, approximately one in four nurses who are shift workers in Japansuffer from shift work disorder [68], which is characterized
by excessive sleepiness and/or insomnia associated with
their shift work schedule [69]. The high prevalence of
these common psychiatric symptoms is probably due tothe high responsibility, need for high levels of expertiseand relatively low reward associated with the nursing profession. A significant association was found between depressive symptoms and effort-reward imbalance, with anodds ratio (OR) of 10.8, and between esteem-reward imbalance, with an OR of 3.2 in nurse managers working in
hospitals in France [70].
It would be hard to restructure the proportion of hospital workers and increase the number of nurses, or to reduce the responsibility and increase the salary of nurses.
However, realistic interventions are needed to empower
resilience in order to alleviate psychological distressamong nurses. Lifestyle interventions, such as diet andpsychotherapeutic approaches, are highly desirable options. When an effective preventive intervention has been
established, the results may not only lead to the maintenance of a healthy mental state in nurses, but also a better
quality of care for inpatients. We believe that the present
study will be able to contribute to this goal.
The present study is not without methodological limitations. First, a previous observational study with a large
sample size has reported that an increase in a nurses’
workload by one patient, and no bachelor’s degree-level
education led to an increase in preventable hospital
deaths [71]. We do not plan to collect information about
patient outcomes, because inpatients from the hospitals
included in the study are usually discharged within approximately 14 days, and many nurses are involved in
the care of each patient. Therefore, we have decided apriori not to investigate the efficacy of interventions onpatient outcomes.
Second, some essential organizational characteristics,
including decision-making latitude and quality andquantity of support from peer nurses, are not consideredin the study. All of the hospitals that are enrolled in the
study are funded by national or local government andlocated in the capital city of Japan. Neither private nor
rural hospitals are included. These may have an effecton the mental health of nurses and therefore these impose a negative impact on the applicability of findings
from the study. However, the methodology of quantitatively measuring decision-making latitude, and quality
and quantity of support from peer nurses in various disciplines has not been confirmed [6]. The hospitals in thisstudy are core general hospitals in the district and webelieve that they are representative among hospitals indeveloped countries.

Watanabe et al. Trials (2015) 16:36

Third, because fish consumption is higher in Japan thanin other countries, one may doubt the applicability of thefindings about omega-3 PUFAs from the present study. Ahigh consumption of fish has been reported to be correlated with a lower countrywide prevalence of major depression, according to a study published in 1998 [72].
However, the Japanese diet has been changing to a more
Western diet similar to countries in other parts of theworld. Moreover, we have excluded participants who consume fish as the main course of a meal four or more times
per week. Therefore, we believe that our findings can beapplied to the other countries.
In conclusion, this paper outlines the background andmethods of a randomized trial evaluating the promisinginterventions for maintaining a healthy mental state in
hospital nurses.

Page 10 of 12

Suntory Wellness Ltd., Otsuka Pharmaceutical Co. Ltd. and the DHA and EPA
Association. All the other authors report no conflicts of interest.
Authors’ contributions
All authors contributed to the manuscript as follows: NW obtained funding,conceived of and design the study, acquired data, conducted statisticalanalyses and drafted the manuscript. TAF contributed to study design,acquisition of data and statistical analyses and critically revised themanuscript for important intellectual content. MH contributed to study
design and administrative, technical or material development. FK contributed
to study design and administrative, technical or material development. TN
contributed to study design and drafting the manuscript, acquired data, andcontributed to administrative, technical or material development. MK
contributed to study design, acquisition of data and administrative, technicalor material development. YO, IS and HN contributed to study design andadministrative, technical or material development. KH contributed to study
design, acquisition of data, drafting the manuscript, administrative, technicalor material development and critical revision of the manuscript for important
intellectual content. YM contributed to study design, drafting themanuscript, administrative, technical or material development and criticalrevision of the manuscript for important intellectual content. All authors
have read and approved the final manuscript.

Trial status

The randomized trial is currently in the phase of participant enrolment and follow-up.
Abbreviations
BAP: Biological antioxidant potential; BSI: Bradford Somatic Inventory;
CI: confidence interval; CRC: Clinical research coordinator;
DHA: Docosahexaenoic acid; DSM: Diagnostic and Statistical Manual of
Mental Disorders; EPA: Eicosapentaenoic acid; EDC: Electronic data capturing;
EQ-5D: EuroQol; GAD-7: Generalized Anxiety Disorder 7-item scale;
HADS: Hospital Anxiety and Depression Scale; ICC: Intraclass correlation
coefficient; ISI: Insomnia Severity Index; ITT: Intention-to-treat; MBI: Maslach’s
Burnout Inventory; NNT: Number needed to treat; OR: Odds ratio;
PHQ-9: Patient Health Questionnaire; PUFA: Polyunsaturated fatty acid;
PRIME-MD: Primary Care Evaluation of Mental Disorders; RCT: Randomized
controlled trial; d-ROM: Reactive oxygen metabolites-derived compound;
RBCs: Red blood cell; HPQ: World Health Organization Heath and Work
Performance Questionnaire.
Competing interests
The authors have no conflicts of interests to declare that may be affected by
the publication of the manuscript. NW has research funds from the Japanese
Ministry of Health Labor and Welfare and the Japanese Ministry of Education,
Science, and Technology. He has also received royalties from Sogensha, andspeaking fees and research funds from Asahi Kasei, Dai-Nippon Sumitomo, Eli
Lilly, GlaxoSmithKline, Janssen, Meiji, MSD, Otsuka and Pfizer. TAF has received
lecture fees from Eli Lilly, Meiji, Mochida, MSD, Pfizer and Tanabe-Mitsubishi, andconsultancy fees from Sekisui and the Takeda Science Foundation. He is a
diplomate of the Academy of Cognitive Therapy. He has received royalties from
Igaku-Shoin, Seiwa-Shoten and Nihon Bunka Kagaku-sha. The Japanese Ministryof Education, Science and Technology, the Japanese Ministry of Health, Laborand Welfare and the Japan Foundation for Neuroscience and Mental Healthhave funded his research projects. MH has research funds from the Japanese
Ministry of Health, Labor and Welfare and the Japanese Ministry of Education,
Science and Technology. He has received royalties from Igaku Shoin, Shogakukan
Shueisha Production, Shindan to Chiryosha, Sogensha, Kangokyokai Shuppan,
Kitaoji Shobo and Kongo Shuppan. KH has received research support from an
Intramural Research Grant for Neurological and Psychiatric Disorders from the
National Center of Neurology and Psychiatry, the Japan Society for the Promotionof Science, the Tamura Foundation for Promotion of Science and Technology andthe Ichiro Kanehara Foundation for Promotion of Medical Sciences and Medical
Care; consultant fees from Polyene Project, Inc.; scholarship donations from Otsuka
Pharmaceutical Co. Ltd and speaking fees from the DHA and EPA Association. YM
has received research grants from the Japan Science and Technology Agency; theNational Center of Neurology and Psychiatry, Japan; and the Ministry of Health,
Labor and Welfare of Japan. He has been a paid speaker for Ono Pharmaceutical
Co. Ltd., Mochida Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Ltd.,

Acknowledgements
This study was funded by Intramural Research Grant (number: 25–8) for
Neurological and Psychiatric Disorders of National Center of Neurology andPsychiatry, Japan. The funding organizations had no role in the design andconduct of the study, collection, management, analysis and interpretation of
the data, and preparation, review or approval of the manuscript.
We thank all the collaborators (Miyuki Makino, CP, RN at the National Centerof Neurology and Psychiatry, and Masato Usuki, MD, PhD at the National
Disaster Medical Center), technical assistant staff (Shizuko Takebe at the
University of Toyama), the administrative staff (Mayuko Yamano at the
National Center of Neurology and Psychiatry) and the members of the Data
Monitoring and Safety Management Committee (Masaki Kato, MD, PhD at
Kansai Medical University, Atsuo Nakagawa, MD, PhD at Keio University
School of Medicine and Daisuke Nishi, MD, PhD at the National Center of
Neurology and Psychiatry). We also thank Shinako Ushijima, RN at the
National Center of Neurology and Psychiatry Hospital, Keiko Osada, RN and
Masami Harasawa, RN at the National Disaster Medical Center, Miyuki Hatada,
RN and Noriko Miyajima, RN at the Tokyo Metropolitan Tama Medical Centerand Chieko Kosaka, RN and Masako Tanaka, RN at the Tama-Hokubu Medical
Center for their decisions to participate in the study.
Author details
1
Department of Clinical Epidemiology, Translational Medical Center, National
Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo,
Tokyo 187-8551, Japan. 2Departments of Health Promotion and Human
Behavior and of Clinical Epidemiology, Kyoto University Graduate School of
Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto
606-8501, Japan. 3National Center for Cognitive Behavior Therapy andResearch, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi,
Kodaira, Tokyo 187-8551, Japan. 4Department of Psychiatric and Mental
Health Nursing, Nagoya City University School of Nursing, 1 Kawasumi,
Mizuho-ku, Nagoya 467-0001, Japan. 5Department of Clinical Research,
Translational Medical Center, National Center of Neurology and Psychiatry,
4-1-1 Ogawa-higashi, Kodaira, Tokyo, Japan. 6Correspondence Division,Musashino University, 1-1-20 Shinmachi, Nishitokyo, Tokyo 202-8585, Japan.
7
Department of Public Health, Faculty of Medicine, University of Toyama,
2630 Sugitani, Toyama 930-0194, Japan.
Received: 27 August 2014 Accepted: 7 January 2015

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