The study aims to evaluate the efficacy of CBT combined with MM to treat youth (aged 18-30 years) diagnosed with major depressive disorder. We will enroll 168 subjects, where 50% of the subjects will be from First Nations (FN) background, while the other 50% will be from all other ethnic backgrounds, stratified in 2 intervention groups and 2 (wait-list) control groups (42 subjects per group, where INT¹ and CTL¹ are from FN background and INT² and CTL² are from non-FN background). The intervention groups will be compared with the control groups at baseline, 3 months (mid intervention), and 6 months (post intervention), using validated outcome measures.

Subjects are identified from the wait-lists for services at the Centre for Addiction and Mental Health (CAMH) and through contacts with multiple Toronto-based clinics. Eligible patients interact with a research coordinator who reviews and explains the study. Eligibility is ascertained in person followed by written consent before randomization. The identification of most subjects follows CAMH procedures where research coordinators identify potential participants by prescreening new clinic referrals and notifying the investigative team and the client’s clinician about potential study eligibility. The clinician then asks the client if she/he is willing to meet with a study team member to explore participation. Only when a client agrees, is she/he approached.

A biostatistician at the Department of Biostatistics at University Health Network (G Tomlinson) performed an electronic randomization of participants with study IDs to the different groups (INT¹, INT², CTL¹, and CTL²). The information regarding each study ID with its respective group allocation was transferred onto cards and placed in individually sealed envelopes. After a participant had completed the baseline questionnaires, the research coordinator opened the next envelope in the series to determine participant group allocation and their respective study ID.

On the basis of a careful review of previously successful studies [38,39,41], we determined a sample size of 42 participants per group in 4 groups (total of n=168). Type I error was set at alpha=.05 and power at 80%. Our projected sample size of 168 participants is deemed more than adequate for the detection of small to medium effect size. With an anticipated drop-out rate of up to 20%, we will recruit 208 participants (54 per group).

All subjects are provided standard psychiatric care, involving 1 monthly session that focuses on appropriate medication, with session durations from 15 to 30 min. Experimental subjects receive the additional intervention, consisting of a CBT-M software program (in collaboration with Nex J Health, Inc), which is accessed online. Interactions with the online workbooks is combined with navigation-coaching (total 24 hours duration), primarily delivered in phone and text message interactions. In addition, each participant is given a Fitbit-HR Charge 2 that assesses physical steps and 24-hour heart rate in 5-second (averaged) durations (the software permits daily monitoring). The intervention content builds on 2 prior successful Web-based CBT-mindfulness RCTs with students [9,10,13,15-17] and on effective methods with other populations demonstrated in previous RCTs [52-55]. The online workbook content includes 24 chapters reflecting multiple topics (eg, Living By Your Truths, Overcoming Wired-ness and Tired-ness, Mindfulness and Relationships, Loss and Grief, and Resilience, Befriending Ourselves, Befriending Your Body with Exercise, Body Image and Mindfulness, Intimacy, Forgiveness, Overcoming Procrastination, Dealing with Negative Moods, Stress Resilience, Overcoming Performance Anxiety, and Cultivating Inspiration) covered sequentially on a weekly basis with the navigator-coach. In summary, the key intervention features are 24-hour access and CBT-mindfulness contents that address specific symptoms and generic depressive experiences.

The CBT-M online intervention will be associated with statistically and clinically significant between-group differences (benefits) when treatment groups and control groups are compared, using both intention-to-treat (ITT) and per protocol analyses (PP). The ITT will proceed in a standard manner, whereas the PP will be based on the 24-week and 24-session structure of the intervention. All subjects who fail to attend 50% of the sessions (ie, <12 sessions) will be excluded from the PP.

Data obtained from participants during the study visits are de-identified and stored as electronic case reporting forms (CRFs) on the CAMH REDCap system and physical CRF paper copies in a locked cabinet. Participant characteristics are summarized via descriptive statistics. Group equivalence at baseline in terms of demographic and clinical variables is assessed.

The monthly rate of recruitment is calculated and the level of retention will be presented in the proportion of enrolled participants completing study outcomes at each time point.

The effect of the intervention on the primary clinical and secondary outcomes will be assessed through separate analysis of covariance (ANCOVA) models that have changed from baseline to 6 months as the dependent variable, the baseline value of the outcome as a covariate and the group assignment as a categorical variable. The treatment effect, its effect size (Hedges’ g), and 95% CIs for the treatment effect and within-group changes from baseline to one year will be calculated from the ANCOVA model. The sensitivity of results to missing data will be evaluated by running a purely data-based multiple imputation procedure, as well as the imputation of missing values on a case-by-case basis using expert opinion and patient history.