rTMS With and Without iCBT For the Treatment of Resistant Depression (TRD)
Condition: Depressive Disorder, Treatment-Resistant
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
Study type: Interventional

Summary: 
      This is a prospective, two-arm randomized controlled trial. 100 patients diagnosed with
      resistant depression in psychiatric care clinic in Edmonton, Alberta, Canada will be
      randomized to one of two conditions: (1) enrolment in rTMS sessions alone (2) enrolment in
      the rTMS sessions plus iCBT. Patients in each group will complete evaluation measures (eg,
      recovery, general symptomatology and functional outcomes) at baseline, 1 month, 3 months and
      6 months. The primary outcome measure would be changes to scores on the Hamilton Depression
      Rating Scale. Patient service utilization data and clinician-rated measures will also be used
      to gauge patient progress. Patient data will be analyzed with descriptive statistics,
      repeated measures and correlational analyses.
    

Detailed description: 
      BACKGROUND AND RATIONALE:

      Major depression is a severe, disabling, and potentially lethal clinical disorder. While
      there are a wide variety of pharmaceutical agents available as treatments for major
      depression, only about half of patients respond to an initial course of antidepressant
      pharmacotherapy, It has been conservatively estimated that at least 15% of all patients with
      major depressive disorder remain refractory to any treatment intervention. While a complex
      relationship exists between disease chronicity and ineffective treatment, clinical evidence
      suggests that the greater the number of treatment failures, the less likelihood of a good
      treatment response to subsequent interventions. The reported results of the STAR*D study are
      the most vivid example of this clinical phenomenon. In that work, there was a progressive
      likelihood of poorer response with each successive treatment failure. For example, after the
      first treatment attempt, about 30% of patients remitted. By the time that a patient had
      experienced definitive treatment failures, the likelihood of achieving remission with the
      fourth treatment option offered fell below 10%. Taken together, these facts underline the
      clinical urgency for physicians to identify treatment resistant patients as early as possible
      so that alternative treatments with proven efficacies may be offered sooner. In turn, this
      will result in superior treatment outcomes for these treatment resistant patients.

      Technology and the Internet have dramatically changed medicine. According to Statistics
      Canada, 83% of Canadians had Internet access in 2012, and more than 70% use the Internet
      daily; 62% were smartphone users. E-Mental health refers to the use of computers, Internet,
      and mobile devices for mental health information and care. E-Mental health applications are
      now widely available for information, screening, assessment and monitoring, interactive
      self-management, psychotherapy, and social support. Clinicians should be aware that there are
      benefits and potential harms to using and recommending e-Mental health applications and that
      few have good-quality evidence to support effectiveness. Meta-analyses and reviews of
      computer-based psychological treatment for the treatment of MDD, whether delivered over the
      Internet or as a stand-alone program, demonstrate convincing support for these treatment
      modalities. Internet- and computer-delivered cognitive behaviour therapy (iCBT) can also be
      helpful in relapse prevention.

      In 2009, the Canadian Network for Mood and Anxiety Treatments (CANMAT), a not-for-profit
      scientific and educational organization, published a revision of evidence-based clinical
      guidelines for the treatment of depressive disorders. CANMAT has updated these guidelines in
      2016 to reflect new evidence in the field. Neurostimulation, or neuromodulation, is an
      expanding area of research and clinical interest, driven in part by the increasing knowledge
      base on the neurocircuitry of depression. Most of these neurostimulation treatments have been
      studied and are used in patients with TRD who have failed to respond to standard treatments.
      However, there is no previous study which has examined the effect of rTMS plus iCBT in
      comparison to rTMS alone.

      Repetitive Transcranial Magnetic Stimulation (rTMS):

      rTMS uses powerful (1.0-2.5 Tesla), focused magnetic field pulses to induce electrical
      currents in neural tissue noninvasively, via an inductor coil placed against the scalp.
      Therapeutic rTMS is usually delivered by a trained technician or nurse, under physician
      supervision. Unlike Electroconvulsive Therapy (ECT), no anesthesia is required. The
      therapeutic mechanism of rTMS is still under investigation, with mechanisms proposed at both
      cell-molecular and network levels. Repeated rTMS sessions can exert therapeutic effects
      lasting several months. Clinical trials and naturalistic studies have found maximal effects
      at 26 to 28 sessions. Clinical experience concurs in suggesting 20 sessions before declaring
      treatment failure, with extension to 25 to 30 sessions if improvements occur.

      More than 30 systematic reviews and meta-analyses have been conducted on rTMS in depression,
      with most studies involving patients with some degree of treatment resistance (i.e., having
      failed at least 1 or 2 antidepressant trials). Overall, rTMS is considered a first-line
      treatment for MDD for patients who have failed at least 1 antidepressant treatment.

      Cognitive behavioral therapy (CBT) Psychotherapy:

      Cognitive behavioral therapy (CBT) is an evidence-based, structured, intensive, time-limited,
      symptom-focused form of psychotherapy recommended for the treatment of major depression and
      anxiety disorders. Internet-delivered CBT (iCBT) is structured CBT delivered via the
      internet. Cognitive behavioral therapy helps people become aware of how certain negative
      automatic thoughts, attitudes, expectations, and beliefs contribute to feelings of sadness
      and anxiety. People undergoing CBT learn how their thinking patterns, which may have
      developed in the past to deal with difficult or painful experiences, can be identified and
      changed to reduce unhappiness.

      Barriers to face-to-face conventional ways for treatment include stigmas around people
      seeking help in person, geography (distance from health care professional), time, and cost.
      Increasingly, there is a desire to pursue internet delivery as an option to increase access
      to treatment.

      Internet-delivered CBT (iCBT) consists of structured modules with clearly defined goals, and
      is delivered via the internet. Although there are many types of iCBT programs, each are
      goal-oriented sessions that typically consist of 8 to 12 modules and can be guided or
      unguided. Internet-delivered CBT programs are made available by computer, smartphone, or
      tablet, for a fee. With unguided iCBT, patients are informed of a website through which they
      can participate in an online self-directed program. Guided iCBT involves support from a
      regulated health professional (e.g., social worker, psychologist, psychotherapist,
      occupational therapist, nurse, or physician). In guided iCBT, people complete modules and
      communicate (via email, text messages, or telephone calls) their progress to a regulated
      health professional.

      OBJECTIVES A goal of the project is to evaluate the feasibility of implementing rTMS plus
      iCBT for treatment of patients diagnosed with TRD. Another goal of the project is to assess
      the initial comparative clinical effectiveness of rTMS treatments when used with and without
      iCBT.

      Because of the limited availability of data in this specific area, another goal of the study
      is to generate effect size data for these interventions which will help in sample size and
      power calculations for a full randomized clinical trial. The patient's outcomes are organized
      according to: recovery variables (eg, recovery and stigma), functional variables (quality of
      life and employment), symptom variables (psychological symptoms and general outcomes) and
      other outcomes will be service variables (eg, heath service utilization, cost and
      satisfaction).

      METHODS:

      This study will be a prospective, parallel design, two-arm, rater-blinded Randomized
      Controlled Trial (RCT) with a recruitment period of 12 months and applying active treatment
      for 6 weeks and an observation period of 6 months for each participant. The research will be
      carried out in an Addiction and Mental Health clinic in a large, socio-demographically
      diverse city in Western Canada (Edmonton, Alberta).

      INTERVENTIONS Patients would be randomly assigned to receive either rTMS alone or rTMSplus
      iCBT Patients in both arms of the study will be assigned to an introductory visit to
      introduce the rTMS system to them and explain the procedure which will be carried out in each
      visit. All patients will be scheduled to receive 30 sessions of rTMS treatments over a
      six-week period as pre-determined by Alberta Health Services' Strategic Clinical Network for
      Addiction and Mental Health. In addition, patients in the rTMS plus iCBT arm of the study,
      would be assisted to register on the iCBT program (MoodGym) to receive unique login
      information. To reduce in-person contact due to COVID-19 protocols, patients would be
      remotely assisted via phone to participate in 12 one-hour sessions of iCBT at the clinic
      prior to receiving rTMS treatments. These iCBT sessions would be scheduled in about three
      days intervals (ideally Tuesdays and Thursdays) so that patients receive two iCBT sessions
      each week. Patients would also be encouraged to continue with iCBT treatments beyond the
      scheduled sessions.

      All patients will be followed up for 6 months and would be encouraged to continue to receive
      whatever community clinic/ program treatments or supports are part of their usual care.

      HYPOTHESIS The investigators hypothesize that patients enrolled in the rTMS plus iCBT
      treatment arm of the study will achieve superior outcomes compared with patients enrolled in
      the rTMS alone arm of the study on each outcome measure used.

      SAMPLE SIZE The study will therefore be limited to a sample size of 100, with about 50
      patients recruited into each arm of the study. Patients transitioning from resistance of the
      pharmacological treatment are vulnerable to severe depressive attacks, and it can reasonably
      be expected that only a small number of eligible participants will enroll in and complete the
      study.

      RANDOMIZATION AND BLINDING Randomization will be stratified by using permuted blocks to
      ensure balance (1:1) between the two follow-up treatment groups. The randomization codes will
      be transmitted by an independent statistician via text message directly to a researcher's
      password-protected phone line with a secure online backup. This will commence as soon as
      participants sign the consent forms.

      Because it will not be possible for participants to be blinded, treatment allocation will be
      made explicit to them as soon as randomization is concluded. Primary outcome assessors will
      be blinded to treatment group allocation by not involving them in discussions about study
      participants and not granting them access to the database which contains the randomization
      code. After data collection is complete, all data will undergo a blind review for the
      purposes of finalizing the planned analysis.

      FOLLOW-UP ASSESSMENT At 1, 3 and 6 months, a blinded researcher will contact all study
      participants and assist them to complete a range of assessment tools relating to the primary
      and secondary outcome measures. They will be offered the opportunity to complete the
      assessments face to face or over the phone. At 6 months, data related to each person's
      clinic/ programme attendance rates and utilization of health services will be compiled from
      administrative records by the blinded researcher.

      PATIENT AND PUBLIC INVOLVEMENT This study was designed to address the clinical urgency to
      identify and respond to early evidence of treatment resistance using treatments that have
      proven efficacy in these more difficult-to-treat psychiatric patients. The study is designed
      as patient-oriented research with the active involvement of a patient representative who will
      be a coauthor of the study protocol. The randomized trial offers patients the opportunity to
      provide feedback regarding the burden of the intervention through a focused group workshop
      involving a cross section of patients in the two arms of the study.

      ETHICS AND DISSEMINATION The study will be conducted in accordance with the Declaration of
      Helsinki (Hong Kong Amendment) and Good Clinical Practice (Canadian Guidelines). Written
      informed consent will be obtained from each participant. The study results, expected 18
      months after commencement of recruitment, will be disseminated at several levels, including
      patients, practitioners, academics/researchers, and healthcare organizations.
    

Intervention name(s): Repetitive Transcranial Magnetic Stimulation (rTMS); Internet-Delivered Cognitive Behavior Therapy (iCBT)
Intervention type(s): Device; Other
Intervention description(s): rTMS uses powerful (1.0-2.5 Tesla), focused magnetic field pulses to induce electrical currents in neural tissue noninvasively, via an inductor coil placed against the scalp.; Cognitive behavioral therapy (CBT) is an evidence-based, structured, intensive, time-limited, symptom-focused form of psychotherapy recommended for the treatment of major depression and anxiety disorders. Internet-delivered CBT (iCBT) is structured CBT delivered via the internet.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a prospective, two-arm randomized controlled trial. 100 patients diagnosed with resistant depression in psychiatric care clinic in Edmonton, Alberta, Canada will be randomized to one of two conditions: (1) enrolment in rTMS sessions alone (2) enrolment in the rTMS sessions plus iCBT.
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Repetitive Transcranial Magnetic Stimulation; Internet-Delivered Cognitive Behavior Therapy; Treatment of Resistant Depression; Patient - Centered Randomized Controlled Pilot Trial