Design: TIDE is an open-label randomized trial with two parallel arms and long-term
follow-up.
Participants: Youth and young adults with major depressive disorder will participate.
Recruitment: Young people aged 12 to 25 will be recruited through family physicians,
child and adolescent mental health services (NSHA, IWK Central referral), student health,
traditional advertisement (posters), and social media advertisement (Instagram, Facebook,
Reddit, and Twitter).
Random allocation: Consenting eligible participants will be randomly allocated in 1:1
ratio to intervention A (cognitive-behavioral therapy) or intervention B (optimized
antidepressant treatment), by an independent statistician using random blocks (block size
4 to 8), stratified by participant age (<18; ≥18). The allocation sequence will be held
by a statistician at a separate location (the Research Methods Unit) and will remain
concealed from the assessment and treatment team until the baseline assessment is
completed.
Interventions: It is our aim to personalize the choice between established active
treatments, not to test an active treatment against an inactive control. Therefore, the
investigator will offer every participant entering the study an intervention that is
established as safe and effective. Within the established interventions, the investigator
chose two that have the largest amount of evidence for efficacy: cognitive-behavioural
therapy and the antidepressant fluoxetine. These two interventions are at equipoise,
meaning that the investigator has equally high expectation of treatment success from both
approaches. Yet the two treatment strategies represent distinct choices, with
intervention A relying on intensive psychological treatment and intervention B on
optimized delivery of the best-established medication treatment for depression in youth.
Because the first episode of depression is a dynamic state with a variety of outcomes,
the intervention will proceed in stages.
Stage 0: Lead in. Participants may enter the study at different stages of the first
episode onset, with some starting at a point where the indications for treatment or
eligibility criteria are uncertain or at a time when the participant is undecided on
whether they need or want to start active treatment. To accommodate these early stages,
there is a lead-in of 1-4 weeks to establish the diagnosis, assess severity and support
the participant while deciding on whether they want to start active treatment. This stage
will include up to four weekly meeting with a clinician (psychiatrist, psychologist, or
CBT therapist) that may involve information gathering, information provision, risk
monitoring and supportive contact, but no cognitive-behavioural therapy or
pharmacotherapy. If the participant and the clinician agree that treatment is indicated,
the participant can transition to Stage 1 (active intervention). Stage 0 is not
randomized. If the participant recovers and no longer meets inclusion criteria or decides
that they do not need active treatment, they may transition directly to Stage 3
(Follow-up).
Stage1: Active interventions. At this stage, all participants will be offered active
treatment for depression. Radom allocation will occur at the beginning of Stage 1 and
will determine whether the participant is offered Intervention A or Intervention B.
Intervention A: Cognitive-behavioural therapy (CBT). This intervention starts with a
course of 20 sessions of individual CBT, offered over 16 weeks. The sessions will be
conducted one-on-one, with a trained and supervised CBT therapist giving full attention
to one participant at a time. Over the course of treatment participants will develop an
understanding of the cognitive, behavioural, emotional, and environmental factors which
contribute to maintaining their depression. They will learn and apply skills to interrupt
unhelpful cognitive and behavioural patterns and engage in guided exploration to improve
self-understanding. CBT is a structured and collaborative treatment and, as such, each
session will follow a similar pattern and commence with a collaboratively set agenda.
Weekly "homework" will be used to maximize opportunities for practice and consolidation
of new skills with the aim of the participant being able to apply these skills well
beyond the termination of therapy. The individual sessions can be combined with optional
family/parent/partner sessions, depending on the situation and preferences of the
participant. All sessions will be video-recorded to allow high-quality supervision,
fidelity- and quality-assurance. This way of delivery corresponds to the best evidence
available for CBT for adolescents and young adults that is established as the best
practice through rigorous trials.
Intervention B: Antidepressant pharmacotherapy. The choice of antidepressants follows the
best established evidence for treating depression in adolescents and young adults. The
investigator will initially offer treatment with fluoxetine, starting at 10mg once daily
and increasing to 20mg once daily after one week if tolerated, a protocol established as
safe and effective in both adolescents and adults across multiple trials. Additional dose
increases to 40 or 60mg will be possible based on balance of positive effects and
side-effects and clinical judgement, consistent with recommendations in this age group.
In cases of intolerance or adverse reaction to fluoxetine, the investigator will switch
to sertraline (25 to 200mg) or escitalopram (5 to 20mg), the other two antidepressants
licensed by the Food and Drug Administration for major depressive disorder in
adolescents. The treatment with fluoxetine (or sertraline, or escitalopram) will be
optimized over 16 weeks, a time-frame comparable to the CBT intervention. The
investigator expects that most participants will only use the antidepressant for as long
as required to minimized overall exposure to pharmacotherapy. Pharmacotherapy will be
managed and prescribed by qualified psychiatrists, referred to as pharmacotherapists
through this protocol. The pharmacotherapist will hold appointments when starting the
treatment, after 1 week, two weeks and then in two-weekly intervals for the reminder of
the 16 weeks acute treatment period.
Stage 2. Continuation treatment and cross-over options: After completion of a course of
CBT or antidepressant, further decisions depend on the outcome of the initial treatment
and will be personalized, based on a discussion between the participant and a clinician.
If a full remission of depression is achieved, the next stage may involve continuation of
the same treatment (up to 4 booster sessions of CBT, continued treatment with an
antidepressant). If a remission is not achieved, the best recommended next step is the
cross-over to (or the addition of) the other established treatment. Therefore,
participants who received CBT in Stage 1 and did not reach remission will be offered
treatment with an antidepressant, and participants who received the antidepressant in
Stage 1 will be offered CBT. The decision of whether to continue Stage 1 treatment will
be based on the balance of benefits and adverse effects for the participant. Participants
who started antidepressant in Stage 1 and did not achieve full remission may decide to
continue the antidepressant while also receiving CBT or to stop the antidepressant with
coordinated support from the pharmacotherapist and the CBT therapist.
Stage 3: Follow-up. The investigators will follow participants once every 3 months for up
to 2 years. The purpose of this follow-up stage is to monitor the stability of remission
and functional outcomes. If the investigators identify re-emergence of depressive
symptoms, the investigators will offer Stage 2 interventions or appropriate clinical
referral as appropriate based on consultation with the principal investigator or other
qualified psychiatrist. For participants who do not achieve remission in stages 1 and 2,
the clinically advisable next steps may involve augmentation with additional treatment.
Such augmentation treatment is beyond the scope of the present protocol. Participants
will be allowed to remain in the follow-up stage even if they receive additional
treatment through regular clinical services or additional studies.