Jacka et al. BMC Medicine(2018) 16:237
https://doi.org/10.1186/s12916-018-1228-y

CORRESPONDENCE

Open Access

The SMILES trial: an important first step
Felice N. Jacka1,2,3*, Adrienne O’Neil1,4, Catherine Itsiopoulos5, Rachelle Opie6, Sue Cotton7,8,
Mohammadreza Mohebbi1,9, David Castle10,11, Sarah Dash1, Cathrine Mihalopoulos12, Mary Lou Chatterton12,
Laima Brazionis5,13, Olivia M. Dean1,10,14, Allison Hodge15,16 and Michael Berk1,7,10,14

Abstract
The SMILES trial was the first intervention study to test dietary improvement as a treatment strategy for depression.
Molendijk et al. propose that expectation bias and difficulties with blinding might account for the large effect size.
While we acknowledge the issue of expectation bias in lifestyle intervention trials and indeed discuss this as a key
limitation in our paper, we observed a strong correlation between dietary change and change in depression scores,
which we argue is consistent with a causal effect and we believe unlikely to be an artefact of inadequate blinding.
Since its publication, our results have been largely replicated and our recent economic evaluation of SMILES
suggests that the benefits of our approach extend beyond depression. We argue that the SMILES trial should beconsidered an important, albeit preliminary, first step in the field of nutritional psychiatry research.
Keywords: Diet, Nutrition, Depression, Randomised controlled trial
Dear editor
We appreciate the interest that Drs Molendijk, Friedand van der Does [1] have shown in our recently published SMILES study [2]. Drs Molendijk and colleagues’
concerns highlight the methodological complexity inherent in nutrition research (and lifestyle and behavioural
medicine more broadly) as compared to other areas ofmedical research. Within the framework of a conventional randomised controlled study design, we attemptedto address these methodological constraints in the development and execution of the trial.
Expectation bias is a key issue associated with
non-pharmacotherapeutic-based intervention studies, including nutrition, physical activity and many psychotherapeutic trials. Our ethics committees wereintractable on the issue of concealing our hypotheses; indeed, our previous research in the field of nutrition andmental health had already received much high-profile
media coverage both locally and nationally. We acknowledged the possibility of expectation bias as the primary
limitation in our study. We also acknowledged the limited sample size and the difficulties we had in recruiting* Correspondence: f.jacka@deakin.edu.au
1
IMPACT Strategic Research Centre, Deakin University, Geelong, VIC, Australia
2
Centre for Adolescent Health, Murdoch Children’s Research Institute,
Parkville, VIC, Australia
Full list of author information is available at the end of the article

participants. We would like to address some further
points in regard to the authors’ concerns.
 The use of a website, media, or advertisements toseek a positive effect. Use of a website, media oradvertisements is a common recruitment strategy
utilised in community-based trials. Our recruitment
website was not initiated until the latter stages of
the trial (June 2014, 2 years after study recruitmentcommenced), after which we recruited only 12 moreparticipants. Of these, only one reported the website
as their recruitment point. Use of a website, media
or advertisements to deliberately and selectively seek
a positive effect would have been a poor strategy; expectation bias that may have arisen from our recruitment materials would have affected both active
and control conditions. While we were concerned
about the possibility of expectation bias in those
eventually randomised to the dietary condition, wewere equally, if not more, concerned with the potential for contamination of the psychosocial support
control condition—an evidence-based supported
comparison of known benefit. It is well recognisedthat one of the main challenges in conducting lifestyle interventions relates to the fact that those in
the control condition also often make changes andimprovements to their lifestyles, based on the© 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.

Jacka et al. BMC Medicine(2018) 16:237

expectation of benefit [3]. As such, our recruitment
materials would have been as least as likely to dilutethe main effects of the intervention, creating a bias
towards the null hypothesis.
The fruity smiley face (https://dietdepressionstudy.com/)and the local newspaper article to which Molendijk etal. [1] refer were from media interviews. The extensive
observational literature in this field that predated andprovided the rationale for the SMILES trial had
already received very extensive coverage in both theAustralian and international media. Thus, the ideathat a healthy diet may be of benefit in patients withdepression was widely understood by the public prior
to the trial, and well before either that single article or
our website. Three human research and ethics
committees approved our study, including our media
communications plans, materials and media
interviews.
Molendijk et al. [1] query our primary outcome, the“interviewer-rated Montgomery–Åsberg Depression
Rating Scale (MADRS)”. In fact, this is the goldstandard tool for assessing depressive symptoms inclinical trials and is the most widely used outcome
measure. It is true that all subjective outcomes are
sensitive to expectancy and hence may overestimate
the effect. One of the acknowledged difficulties in
psychiatry research is the lack of biomarkers or objective measures of mental health. As such, we are
all restricted to the use of clinical assessments. Thisis a generic limitation of our trial and all others in
the field. Including an active control with previous
evidence of benefit is the best way to try and address
this issue, and this is what we did. As reported in
our original paper, all three mental health measures
showed improvement in the diet group, relative tocontrols. We regard the correlation between changes
in the modified Mediterranean diet score andMADRS in the intervention group as being consistent with a causal effect.
Loss of blinding in our study is a possibility and weagree that a loss of blinding will bias towards abigger effect. However, we made considerable efforts
to conceal group allocation from independent blindraters who were formally trained in theadministration of the MADRS.
The dropout rate was higher in the befriending
group, which may be a random finding, a marker ofefficacy differential or a function of the trial designthat is common to behavioural, psychological andlifestyle medicine trials. We confirm that we
conducted thorough sensitivity analyses to examine
the impact of non-random dropouts. The sensitivity
analysis assumed dropouts were correlated with better outcomes in the control group and worse

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outcomes in the intervention group. Our findings
withstood even extreme assumptions about the potential impact of non-random dropouts. Again, thenature of dropouts and potential biases were thoroughly addressed in our original manuscript.
Additional file 1: Table S1 provides data on thecharacteristics of those who completed the followup and dropouts according to allocation groups.
Encouraging insights from our study were that participants were able to make positive changes to their diet,despite their illness, and that these improvements werecorrelated with improvements in depressive symptoms.
Furthermore, qualitative feedback from participants revealed that the support and education from a dietician
was highly valuable in helping participants make sustained improvements to their diet and, accordingly, theirmental health. Undoubtedly, further efficacy and effectiveness trials in this space are warranted to refine anddevelop this approach, both for the betterment of people
with depression as well as for scientific advancement.
As the first randomised controlled trial of its type, weopenly acknowledge the limitations of our study and thefield in general [4]. However, these limitations were thoroughly addressed in the original manuscript to the satisfaction of the reviewers and the journal, and we believe
our trial should be considered an important, albeit preliminary, first-step in this field. In this regard, we would
note that the findings of the SMILES study have now
been largely replicated—an essential next step in the scientific process. The HELFIMED study employed agroup-based intervention with a larger sample size
(n=152), producing very similar findings to ours [5]. In
both studies, the degree of dietary change correlated
closely with the degree of improvement in depression
symptoms. Further, the recent economic evaluation of
our trial suggests large cost savings for our approach [6].
Taken together, these data may support broader implementation of this approach to depression managementin the future.

Additional file
Additional file 1: Table S1. Comparing baseline characteristics of all
those randomised to the dietary support (DS) and social support (SS)groups according to dropout status. (DOCX 23 kb)

Acknowledgments
FNJ is supported by a National Health and Medical Research (NHMRC) CouncilCareer Development Fellowship (2) (#1108125). MB is supported by an NHMRC
Senior Principal Research Fellowship (#1059660). AO is supported by a Future
Leader Fellowship (#101160) from the Heart Foundation, Australia. OD issupported by a R.D. Wright Biomedical Research Fellowship (#1145634).

Jacka et al. BMC Medicine(2018) 16:237

Authors’ contributions
FNJ led, and all other authors contributed to, the drafting of the manuscript
and critical revision for important intellectual content. All authors read andapproved the final manuscript.
Competing interests
The authors declare that they have no competing interests.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.
Author details
1
IMPACT Strategic Research Centre, Deakin University, Geelong, VIC, Australia.
2
Centre for Adolescent Health, Murdoch Children’s Research Institute,Parkville, VIC, Australia. 3Black Dog Institute, Randwick, NSW, Australia.
4
School of Population Health, The University of Melbourne, Melbourne, VIC,Australia. 5Department of Rehabilitation, Nutrition and Sport, La Trobe
University, Melbourne, VIC, Australia. 6Institute for Physical Activity andNutrition, Deakin University, Geelong, VIC, Australia. 7Orygen, The National
Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia. 8Centrefor Youth Mental Health, The University of Melbourne, Melbourne, VIC,Australia. 9Biostatistics Unit, Faculty of Health, Deakin University, Geelong, VIC,Australia. 10Department of Psychiatry, The University of Melbourne,Melbourne, VIC, Australia. 11St Vincent’s Hospital, Melbourne, VIC, Australia.
12Centre for Population Health Research, Deakin University, Geelong, VIC,Australia. 13Department of Medicine, The University of Melbourne,Melbourne, VIC, Australia. 14The Florey Institute of Neuroscience and MentalHealth, Parkville, VIC, Australia. 15Cancer Intelligence and Epidemiology
Division, Cancer Council Victoria, Melbourne, VIC, Australia. 16Centre for
Epidemiology and Biostatistics, Melbourne School of Population and Global
Health, The University of Melbourne, Melbourne, VIC, Australia.
Received: 14 August 2018 Accepted: 30 November 2018

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