Study design

This was a 12-week, parallel-group, single blind RCT of a dietary intervention in the treatment of moderate to severe depression (for the protocol see [25]). This trial was registered in the Australia and New Zealand Clinical Trials Register (ANZCTR): (ACTRN12612000251820) prior to commencing recruitment. Participants were recruited from two sites: Barwon Health in Geelong and St. Vincent’s Health in Melbourne (Victoria, Australia) over a 3-year period. Participants were randomised to receive either dietary support or social support (‘befriending’ [26]). Participants in both groups completed assessments prior to program commencement (baseline), with the primary and secondary outcomes measured at program completion (12 weeks, primary endpoint). Approval to conduct the study was received from Human Research Ethics Committees of St. Vincent’s and Barwon Health. Written informed consent was obtained from all participants after they had received a complete description of the study. The study’s protocol was developed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. Reporting of findings pertaining to primary and secondary outcomes was done in accordance with the Consolidated Standards of Reporting Trials (CONSORT) 2010 guidelines and their extension to non-pharmacologic treatments.

Participants

Inclusion criteria

Eligibility criteria included participants who were at screening: aged 18 or over and could provide informed consent; successfully fulfilled the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV-TR) diagnostic criteria for a major depressive episode (MDE); scored 18 or over on the Montgomery–Åsberg Depression Rating Scale (MADRS) [27]; and scored 75 or less, out of a possible score of 104, on a Dietary Screening Tool (DST) [28] modified for Australian food products. The DST was completed to confirm ‘poor’ dietary quality, before enrolment. This screening tool was used to reflect usual daily or weekly intake of specified foods. Broadly defined, participants had to report a poor (low) intake of dietary fibre, lean proteins and fruit and vegetables, and a high intake of sweets, processed meats and salty snacks. If participants were on antidepressant therapy or undergoing psychotherapy, they were required to be on the same treatment for at least 2 weeks prior to randomization. Participants had to be readily available for a 12-week period and have the ability to eat foods as prescribed, without religious, medical, socio-cultural or political factors precluding participation or adherence to the diet.

Exclusion criteria

Participants were ineligible if they had: (1) a concurrent diagnosis of bipolar I or II disorder; (2) two or more failed trials of antidepressant therapy for the current MDE; (3) known or suspected clinically unstable systemic medical disorder; (4) pregnancy; (5) commencement of new psychotherapy or pharmacotherapy within the preceding 2 weeks; (6) severe food allergies, intolerances or aversions; (7) current participation in an intervention targeting diet or exercise; (8) a primary clinical diagnosis of a personality disorder and/or a current substance use disorder.

Sample recruitment

Community-based recruitment strategies were used to identify study participants, including flyers in medical waiting rooms, pharmacies and university campuses; newsletters; and contact with potential referral sources (e.g. general practitioners, private psychiatrists and local psychiatric inpatient units). Media interviews and advertisements in social media (e.g. Twitter, Facebook), Google, local newspapers and radio stations were also employed as recruitment strategies. Ethics committee requirements meant that we needed to be explicit regarding our planned intervention, with the advertisements stating: ‘We are trialling the effect of an educational and counselling program focusing on diet that may help improve the symptoms of depression’.

Interventions

Dietary support

The dietary intervention comprised personalised dietary advice and nutritional counselling support, including motivational interviewing, goal setting and mindful eating, from a clinical dietician in order to support optimal adherence to the recommended diet. This comprised the ‘ModiMedDiet’, developed by RO and CI, which was based on the Australian Dietary guidelines [29] and the Dietary Guidelines for Adults in Greece [30] and is concordant with our previous dietary recommendations for the prevention of depression [31]. The primary focus was on increasing diet quality by supporting the consumption of the following 12 key food groups (recommended servings in brackets): whole grains (5–8 servings per day); vegetables (6 per day); fruit (3 per day), legumes (3–4 per week); low-fat and unsweetened dairy foods (2–3 per day); raw and unsalted nuts (1 per day); fish (at least 2 per week); lean red meats (3–4 per week) [32], chicken (2–3 per week); eggs (up to 6 per week); and olive oil (3 tablespoons per day), whilst reducing intake of ‘extras’ foods, such as sweets, refined cereals, fried food, fast-food, processed meats and sugary drinks (no more than 3 per week). Red or white wine consumption beyond 2 standard drinks per day and all other alcohol (e.g. spirits, beer) were included within the ‘extras’ food group. Individuals were advised to select red wine preferably and only drink with meals. The dietary composition of the ModiMedDiet was as follows: protein 18% of total energy (E); fat 40% of E; carbohydrates 37% of E; alcohol 2% of E; fibre/other 3% of E. The diet was designed to be easy to follow, sustainable, palatable, and satiating. Individuals were advised to consume the diet ad libitum, as the intervention did not have a weight loss focus. The method for scoring the ModiMedDiet is similar to those used in PREDIMED [33] and the Framingham Offspring Cohort [34]. It is a criterion-based diet score that uses pre-defined absolute or normative goals of consumption for specific food items, independent of the individual’s characteristics. It was developed based on the recommended intakes of the 11 food group components that comprise the ModiMedDiet (as above), and of the score has a theoretical maximum value of 120.

Participants received seven individual dietary support sessions of approximately 60 minutes each, delivered by an Accredited Practising Dietician; the first four sessions occurred weekly and the remaining three sessions occurred every 2 weeks. At the first session, the dietician conducted a diet history to assess usual dietary intake. Participants were provided with supporting written information specifically designed for the intervention to assist with achieving dietary adherence. In order to provide examples of serving sizes and exposure to the recommended foods, participants were also provided with a food hamper, incorporating the main components of the diet, along with recipes and meal plans. Subsequent sessions used motivational interviewing techniques, and participants were encouraged to set personalised goals.

Social support

The social support control condition comprised a manualised ‘befriending’ protocol [26], using the same visit schedule and length as the dietary support intervention. Befriending consists of trained personnel discussing neutral topics of interest to the participant, such as sport, news or music, or in cases where participants found the conversation difficult, engaging in alternate activities such as cards or board games, with the intention of keeping the participant engaged and positive. This is done without engaging in techniques specifically used in the major models of psychotherapy. Research assistants (RAs) in this trial completed manual-guided training and also participated in role-playing training exercises to ensure consistent delivery of the protocol. Befriending aims to control for four factors: time; client expectancy; therapeutic alliance; and therapist factors when compared to the intervention group in an RCT and is often used as a control condition for clinical trials of psychotherapy [26]. Participants in the social support control group were provided with movie tickets as compensation for their time and participation in the study and were offered participation in a group dietary counselling session at the conclusion of the trial.

Assessments and outcomes

Once deemed to be eligible, participants completed a 7-day food diary and the Cancer Council of Victoria food frequency questionnaire [35], in the week leading up to baseline assessment. Participants attended a local pathology clinic to provide fasting blood samples before undertaking baseline assessment and randomization.

Baseline and follow-up assessments

Details of baseline and follow-up assessments have been reported elsewhere [25]. Briefly, primary and secondary endpoints were as described in the following sections.

Primary outcome

The MADRS was used to assess the change in depressive symptomatology at baseline and at the primary endpoint of 12 weeks. The MADRS is an interviewer-rated instrument, comprising 10 items, each measured on a 6-point scale (scores range from 0–60 with higher scores depicting greater symptom severity). It has been found to be a robust and psychometrically sound measure of depressive symptomatology [27].

Secondary outcomes

The Hospital Anxiety and Depression Scale (HADS) [36] was administered as a self-report questionnaire. The Profile of Mood States (POMS) was used to assess mood [37], and the Clinical Global Impression - Improvement (CGI-I) Scale [38] was used to assess change in symptoms from baseline to endpoint. The World Health Organization wellbeing scale (WHO-5) [39] and the Generalized Self-Efficacy Scale [40] were used to assess wellbeing and self-efficacy, respectively. Clinical data including height, weight and waist circumference were also collected and the body mass index (BMI) was calculated. Participants were also asked the following: whether they were a current smoker (yes/no); if they had an existing medical condition (physical or mental); and the names and doses of any medications they were taking. Current levels of physical activity were assessed using International Physical Activity Questionnaire (IPAQ) scores, which capture Metabolic Equivalent of Task (MET) minutes per week. A total MET score was calculated for each participant as a summary of Walking, Moderate and Vigorous MET scores [41]. Dietary quality was assessed using the ModiMedDiet score, which was based on consumption of the key food groups (i.e. wholegrains, vegetables, fruits, legumes, nuts, fish, lean red meats, chicken, low fat dairy, eggs, olive oil, extras) and will be presented in more detail, along with the dietary strategy, in a forthcoming publication. Dietary assessments, using 7-day food diaries, were administered at baseline and endpoint to both groups to identify dietary changes and adherence to the recommended diet; this was done by assessing change in the ModiMedDiet score, which is based on the consumption of the key food groups. Biomarkers, including plasma fatty acids, fasting glucose, total and HDL and LDL cholesterol and triglycerides were also assessed.

Sample size

Our original sample size calculation required 88 people per group, assuming an attrition of 15%, with 8 predictors. For a one-tailed analysis with type I error or alpha set at the .05 level, the study would have been powered at 80% to detect a true difference in rating scale score between the diet and befriending groups if the effect size was 0.15 or greater on the MADRS.

Randomization

The randomization sequence was computer generated by an independent person (OD) using a 2 × 2 block design. The sequence was saved to a password-protected spreadsheet, and groups were coded A and B. The randomization allocation was managed by the trial dieticians or ‘befrienders’, in order to ensure that the research assistants responsible for mental health assessments were blind to participants’ group allocations, and the randomization schedule and coding of group allocations were not, at any time, accessible to the research assistants conducting the assessments, or to the biostatistician (SC). At the conclusion of the baseline appointment, the dietician/befriender would meet privately with the participant and inform them of their group allocation in order to maintain blinding of the research assistants.

Blinding

Although full blinding of participants to condition in this study was not possible, several strategies were employed to reduce the risk of bias. First, participants were provided with only partial information on the study hypothesis; the social support control condition was termed ‘befriending’ and research assistants emphasised the link between social support and mental health as an outcome of interest; and participants in both the intervention and the social support control group were provided with standardised care, with all participants attending appointments in the same location and with the same format, as well as similar duration and frequency. All communication between participants and research staff during the period of intervention (i.e. scheduling concerns, questions regarding intervention) was done directly between participants and their respective ‘clinician’. Participants were clearly instructed only to contact the dietician/befriender personally and to avoid contact with the research assistant, and voice messages were checked daily by the dietician/befriender to avoid unintended contact or information on participants’ allocation. Research assistants did not have direct contact with participants for the duration of the intervention. Final assessments were organised by the dietician or befriender, and research assistants remained blind to condition for the final assessment of outcomes. Prior to assessment, participants were reminded not to reveal the group to which they had been assigned. Statistical analyses were conducted by an external statistician (SC), who was blind to group allocation prior to analysis.

Data analyses

The analyses were conducted in accordance with the International Conference on Harmonization E9 statistical principles. Independent samples t tests and chi-square (χ 2) analyses were used to compare participants who completed and did not complete the 12 weeks of the trial.

Intention-to-treat (ITT) analyses were adopted. The primary efficacy analysis was based on between-group differences in average change from baseline to 12 weeks for the primary outcome measure (MADRS); these analyses were conducted using planned comparisons within a restricted maximum likelihood (REML)-based mixed-effects model, repeated measures (MMRM) approach. Within the MMRM, treatment and assessment occasion and the interaction between treatment group and assessment occasion were included as fixed factors. The MMRM approach is the preferred method of dealing with clinical trial data in psychiatry [42]. The benefits of these MMRM methods are that all available participant data are included in the model [42]. By planning to use MMRM, we made the a priori assumption that missing data were missing at random (MAR); however, we tested these assumptions in sensitivity analyses (as below). The Toeplitiz covariance structure was used to model the relations between observations on different occasions. Planned comparisons using MMRM were also conducted to examine group differences in mean change on the secondary outcome measures from baseline to 12 weeks. Cohen’s d as a measure of effect size was calculated based on observed data. Supplementary sensitivity analyses with the MMRM models were conducted, controlling for relevant confounding variables such as gender, education, physical activity, baseline BMI and baseline ModiMedDiet score. All tests of treatment effects were conducted using an alpha level of 0.05 and reporting 95% confidence intervals. Pearson’s product-moment correlations were calculated to determine whether changes in MADRS scores correlated to changes in biomarkers. Analysis of covariance (ANCOVA) was implemented to evaluate interactions between group allocation and change adherence to ModiMedDiet on MADRS scores at 12 weeks, adjusting for MADRS at baseline. Whilst acknowledging the increased potential for type 1 errors, given that reported comparisons for all primary and secondary outcomes were pre-planned comparisons that were determined a priori and documented in the trial protocol, we did not make adjustments for multiple comparisons.

Sensitivity analyses

We compared demographic, health measures, current treatment, diet quality and psychological measures at baseline between participants with complete follow-up and those with missing data at follow-up, using the chi-squared test for categorical data and t tests for continuous measures. To test departures from missing at random (MAR), a weighted sensitivity analysis using the Selection Model Approach was applied to the main outcome findings [43, 44]. Briefly, once data had been imputed under MAR (n = 5), parameter estimates from each imputed dataset were reweighted to allow for the data to be missing not at random (MNAR). The chosen constant values used to add to the imputed missing data to account for MNAR were multiplications of standard error (i.e. 1.6) for main outcome comparison under MAR assumptions. To evaluate the robustness of our findings, different degrees of departure from the MAR assuming plausible values ranging from 10*SE to –8*SE were considered.