Molendijk et al. BMC Medicine(2018) 16:243
https://doi.org/10.1186/s12916-018-1221-5

CORRESPONDENCE

Open Access

The SMILES trial: do undisclosed recruitment
practices explain the remarkably large effect?
Marc L. Molendijk1,2*, Eiko I. Fried1,3 and Willem Van der Does1,2,4Abstract
The SMILES trial showed substantial improvement ofdepressive symptoms following seven consultations on
healthy dieting. The very large effect size on depression
reduction seems remarkable and we suggest that
selectively induced expectancy and a loss of blinding
have contributed to the observed effect.
The recently published SMILES study [1] is the first randomized controlled trial (RCT) to assess the efficacy of amanipulated diet on depression, extending previous studies on single nutrients. The authors conclude that “… dietary improvement guided by a clinical dietician may
provide an efficacious treatment strategy for the management of this highly prevalent mental disorder” ([1], p. 1),
and that “clinicians should […] consider promoting thebenefits of dietary improvement and facilitating access todietetics support for their patients with depression” ([1], p.
11). At the same time, the authors acknowledge the needfor replication while referring to the small sample size of
their study (N = 56; about one-third of the sample size
pre-specified as required for adequate power).
Studying the effects of diet on depression is of considerable public interest [1–4], and we agree that the topic
warrants attention. However, we argue below that the results of the SMILES study should not be taken as evidence for diet efficacy given various issues regarding
study recruitment and blinding. In the SMILES study,
participants were randomized to seven sessions of either
dietary support or social support. The dietary condition
outperformed the control condition (social support)with an effect size (Cohen’s d) of 1.2, which is four
to five times larger than established depression* Correspondence: molendijkml@fsw.leidenuniv.nl
1
Institute of Psychology, Clinical Psychology Unit, Leiden University, Leiden,
The Netherlands
2
Leiden Institute of Brain and Cognition, Leiden University Medical Center,Leiden, The Netherlands
Full list of author information is available at the end of the article

treatments (e.g., cognitive behavioral therapy, d = 0.2–0.3[5]; antidepressants, d = 0.3 [6, 7]). The pre–post effectsize of the diet condition was very large (d = 1.98),
whereas the social support condition had an effect size ofd = 0.63.
Since its publication, the SMILES trial has received
considerable attention [8, 9], likely due to the very large
effect and the conclusion from SMILES’ senior author ina follow-up article that the trial provides “… intervention
evidence supporting causality [for dietary improvement
as a treatment strategy for major depressive episodes]”([4], p. 26). This aligns with other work by some of theSMILES trial team members in which diet and nutrition
are conceptualized as a “… central determinant of mental health” ([2], p. 271).
The primary outcome in the SMILES trial was change
in the severity of depression symptoms, in this caseassessed via the interviewer-rated Montgomery–Åsberg
Depression Rating Scale (MADRS) [10]. Such outcomesare subjective in nature (the participant is queried aboutsymptoms), and thus susceptible to expectancy effects(defined as results biased by the communication of theexpected results [11–14]). When the intervention is
non-pharmacological – herein the advice of following ahealthy diet – the blinding of conditions in an RCT ishardly possible. In order to minimize expectancy bias,
the authors describe that they masked the hypothesis
and used a neutral recruitment strategy. Participants
were approached (in social media, local newspapers, andradio interviews) with the following message: “We aretrialing the effect of an educational and counseling program focusing on diet that may help improve the symptoms of depression” ([1], p. 2). The paper further statesthat “several strategies were employed to reduce the riskof bias” ([1], p. 5) and that “significant effort was madeto mask our hypothesis” ([1], p. 10).
In this letter, we argue that there is a mismatch between the reported and the actual recruitment strategy,
which becomes clear when comparing the reported andactual recruitment strategies. Through a hyperlink to an© 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.

Molendijk et al. BMC Medicine(2018) 16:243

external website on the study’s recruitment website [15](note that there are some differences with current andprevious versions), potential participants are presented
to a ‘fruit smiley’, composed out of two green apples aseyes, a mandarin as nose, and a banana with the edges
pointing up as a smiling mouth [16]. Messages such as:“Bananas look like a smile but can also help you smile
because they contain tryptophan which is a moodstabilizer” and “Banana, brazil nuts, broccoli, they all
have something in common apart from starting with theletter B. They all contain nutrients which can stabilize
mood” are presented alongside. Since no benefits of thecontrol conditioning (befriending) were described, wethink that this is anything but a neutral description,
which has likely affected expectancy in participants. The
study hypothesis was provided at recruitment to potential participants ‘on a platter’, so to speak. Website visitors also learned that “the fear that we are eating ourway to depression is prompting governments to take action” [15]. This was accompanied by testimonials, suchas “The solution to my depression is good quality food”.
In a local newspaper article entitled ‘Diet, Depression,
Hope’ [17], published in the recruitment catchment area
at time of enrolment, the senior author wrote “if you eat
a healthier diet then it reduces your risk on depression”.
This article was accompanied by an invitation to participate in the trial and contact details. In summary, the report of the SMILES trial does not seem to adequately
describe how study recruitment took place in practice.
The befriending condition had a four-time higher
drop-out rate than the dietary condition and its pre–posteffect size (d = 0.6) is lower than the effect size usually reported for pill–placebo (d = 0.9) [6, 7], likely due to the selective induction of expectancy. This implies that thecontrol condition was not perceived as an equally attractive
condition by many participants, indicating selection bias.
Given that a purpose of randomization is to prevent thisbias from happening [18], we argue that the SMILES trial
has essentially lost some of the benefits of randomization
and, further, that conclusions that can be drawn from
RCTs do not directly follow from the SMILES trial.
The SMILES trial investigators discuss that, despite theuse of blinded raters, blinding may not have been sufficient.
Additionally, the data contains evidence that blinding wasimperfect, yet this is not discussed in the article. The pre–post effect sizes of the self-report Hospital Anxiety andDepression Scale and the interviewer-based MADRS areequal in the control condition. However, in the dietary condition, interviewer-rated improvement is much higher thanself-reported improvement (d = 0.8 vs. d = 0 in the control
condition), suggesting a loss of blinding.
In sum, the limitations outlined above, along withwhat we consider a serious mismatch between the actualand published recruitment strategies [1], means that thePage 2 of 3

SMILES trial does not meet all criteria for an RCT. It
must be noted, however, that the notion that a healthy
diet may benefit depression has been discussed in media
prior to the SMILES trial, and not always with the mostcritical scientific eye (e.g., [19]). Accordingly, Jacka et al.
[1] mention the existence of expectancy effects as a potential limitation in the interpretation of the trial results.
Pre-existing expectancies make any trial more difficult
and this is certainly not the responsibility of the SMILES
investigators, yet what we do consider their responsibility is a correct description of the study procedures. We
believe that the SMILES trial falls short in this regard.
Funding
Marc Molendijk, Eiko Fried, and Willem van der Does report to have received
no funding for their participation in this project.
Authors’ contribution
All authors contributed and participated sufficiently in the conception anddesign of this letter, were involved in drafting it, gave approval of the final
version of the letter to be published, and are responsible and accountable
for the content and all aspects of the letter.
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
Institute of Psychology, Clinical Psychology Unit, Leiden University, Leiden,
The Netherlands. 2Leiden Institute of Brain and Cognition, Leiden University
Medical Center, Leiden, The Netherlands. 3Department of Psychology,
University of Amsterdam, Amsterdam, The Netherlands. 4Department ofPsychiatry, Leiden University Medical Center, Leiden, The Netherlands.
Received: 11 June 2018 Accepted: 15 November 2018

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