A Double-blind Sham Controlled Trial of rTMS in Treatment Resistant Major Depression
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Study type: Interventional

Summary: 
      The main treatment option for Treatment Resistant Depression is electroconvulsive therapy
      (ECT) which is often effective but complicated by cognitive side effects, need for
      anaesthesia and considerable stigma.

      In recent years considerable efforts have been made to increase public awareness about
      depression and increase access to services. However, the increasing number of patients
      accessing treatment for depression in clinical services is also likely to be accompanied by a
      sizeable increase in the number of patients with TRD. Despite the demand, relatively few
      treatment options are available to such patients. One of the only substantially new
      treatments developed for TRD in recent years has been the advent of repetitive transcranial
      magnetic stimulation (rTMS). Repetitive TMS has been evaluated in over 20 trials conducted
      over the last 10 years. Previous research indicates that rTMS has antidepressant activity;
      however, the proportion of patients who respond to rTMS and the degree of treatment response
      demonstrated in trials to date is limited. The limitations of these studies include
      relatively small samples and limited duration of treatment (i.e., 2 weeks) as well as a lack
      of long term follow-up. As rTMS is gradually entering use in routine clinical practice (for
      example, recent regulation of its use in Canada), research is urgently required to establish
      ways to enhance treatment response both in regards to the extent of response within
      individuals and the proportion of individuals in whom rTMS has effects.

      Stimulation site is another important treatment factor; thus far almost all of the trials of
      rTMS in TRD conducted have evaluated the utility of high frequency left prefrontal cortex
      (PFC) rTMS (HFL-TMS). In addition, several studies have evaluated the treatment efficacy of
      low frequency rTMS to right PFC (LFR-TMS). In a previously published study we have
      demonstrated that these two approaches have similar therapeutic benefit and both were
      superior to sham stimulation.

      A promising new approach to enhance efficacy involves combining LFR-TMS and HFL-TMS in a
      sequential manner. We describe this as sequential bilateral rTMS (SB-rTMS). We have recently
      published the results of the first substantial evaluation of SB-rTMS showing not only a
      superiority to placebo in TRD but also a therapeutic response that is substantially superior
      to response rates in most of the published studies of unilateral rTMS (>50% of patients
      achieving standard criteria for clinical response compared to usually <30% in most studies).
      In this proposed research study, we will directly test the hypothesis that SB-rTMS produces a
      greater therapeutic response than HFL-TMS and compare both of these forms of stimulation to
      placebo (i.e., sham) stimulation.
    

Detailed description: 
      Justification for project

      TRD is clearly a major health issue - depression is common, results in marked morbidity and
      mortality and a large percentage of patients do not respond to, or cannot tolerate standard
      treatment. The development of new treatments for this condition is undoubtedly required.
      International efforts are underway to try and establish the efficacy of HFL-TMS to the point
      where the technique may be approved by regulatory authorities and clinically introduced.
      However, clearly the response rate to HFL-TMS is suboptimal for its widespread use.

      The overall goal of this research program is to develop rTMS methods to the point at which
      they are highly relevant and applicable to clinical practice. None of the substantial
      international studies is focusing on novel applications such as SBrTMS. As an outcome, we
      expect positive results to change the focus of rTMS application and practice nationally and
      internationally. If we can follow our well received initial study of this technique with a
      substantial comparative trail as planned here, it will provide enough evidence for the more
      widespread adoption and testing of SBrTMS as a viable alternative to HFL-TMS. Ultimately,
      this or a modification of it, may become the rTMS administration method of choice.

      Additionally, we will have a sufficient sample size to start to explore meaningful predictors
      of clinical response including biological, psychosocial/personality variable predictors.

      Hypotheses / Research Questions

      Primary Hypothesis

        -  Hypothesis 1: Treatment with left sided and SBrTMS will both result in a greater
           reduction in HAMD and MADRS scores than sham rTMS.

        -  Hypothesis 2: Treatment with SBrTMS will result in a greater reduction in HAMD and MADRS
           scores than left sided rTMS applied alone.

      Secondary Hypotheses

      • Greater than 50% of treatment responders to rTMS will continue to experience clinical
      benefits from rTMS, as indexed by persistently low HAMD and MADRS scores, at 6 months post
      acute treatment.

      Methodology including project design and sequence of procedures

      Experimental Design

      The study will involve a 2 phases of treatment: an acute treatment phase of 3-9 weeks
      duration and a maintenance treatment phase, lasting 52 weeks. In the initial 3 weeks of the
      acute treatment phase the study will be randomised, double blind and sham-controlled with
      three arms:

        1. SBrTMS

        2. Unilateral left rTMS

        3. Sham rTMS

      Prior to randomization, participants will undergo an EEG and MRI (see below for more detail).
      The EEG and MRI will be repeated once during the active treatment phase.

      Randomization will occur via the generation of a single computer number sequence. Subjects
      will be randomised immediately prior to the commencement of the first treatment session,
      after the measurement of bilateral resting motor thresholds with standard means [30].

      Acute treatment will be administered daily, 5 days per week initially for three weeks (i.e.
      15 treatments). Following 3 weeks of treatment response will be assessed and the blind
      broken. At this point non responders (i.e. HAM-D score > 10) who have been receiving active
      treatment will be offered an additional 3 weeks of treatment at the same treatment
      parameters. Responders who have been receiving active treatment will enter the maintenance
      phase. At week 6 treatment response will again be assessed and non responders will be offered
      a final 3 weeks of active treatment while responders will enter the maintenance phase. At
      week 9 response will again be assessed and non responders will cease their participation in
      the trial, while responders will continue onto the maintenance phase. With regard to the sham
      treatment arm, subjects who respond to treatment and received sham treatment will be
      discontinued from the study at week 3. Those subjects who are classified as non responders
      and were in the sham treatment arm will be randomised to one of the two active treatment arms
      and receive an additional 3 weeks of active treatment.

      The maintenance phase will be open labeled and consist of weekly treatments at the same
      parameters to which patients initially responded, for a total of 8 weeks. Maintenance
      treatment will then be further reduced to fortnightly treatments for 44 weeks. Patients will
      be evaluated clinically every 2 weeks. Should patients relapse (i.e. a HAM-D score of >15 for
      2 consecutive weeks), they will be offered active treatment only (i.e. no sham treatment) for
      up to six weeks at the same stimulus parameters to which they previously experienced a
      response.

      Subjects

      Inclusion Criteria: Patients will be included if they:

        1. Have a DSM-IV diagnosis of a major depressive episode (SCID 11).

        2. Aged 18-85.

        3. Have treatment resistant depression at Stage II of the Thase and Rush classification
           [31]; .e. have failed to achieve a clinical response, or did not tolerate, at least two
           separate antidepressant trials of sufficient dose for at least 6 weeks.

        4. Have a Hamilton Depression Rating Scale Score of > 20 (moderate - severe depression).
           Including only a severely ill group of subjects limits the placebo response rate [32].
           Moreover, this will allow us to address the application of rTMS methods in the most
           clinically relevant subgroup of patients (in addition helping to constrain group
           heterogeneity, a major issue in depression research).

        5. Have had no increase or initiation of new antidepressant (or other psychoactive) therapy
           in the 4 weeks prior to screening.

      Additional Exclusion Criteria:

        1. Patients who have an unstable medical condition, neurological disorder or any history of
           a seizure disorder or are currently pregnant or lactating.

        2. In the opinion of the investigator, are a sufficient suicidal risk to require immediate
           electro-convulsive therapy.

        3. Have a current DSM IV diagnosis of substance abuse or dependence disorder, a diagnosis
           of a personality disorder (SCID II) or another axis 1 disorder.

      Please note: several of these criteria (e.g. inclusion criteria 1 & 2, exclusion criteria 3)
      have been selected to explicitly constrain the heterogeneity of the sample to increase the
      likely power of the study to detect differences between the groups given the potentially
      subtle difference between the treatment methods.

      Sample Size Calculations We aim to recruit 40 patients into each group (total n=120). The
      sample size calculation for the study was conducted based on the within group standard
      deviation of 12.9 (this was the standard deviation for baseline to final study visit in our
      SBrTMS study) and between group difference of 5.0 points. With an alpha of 0.05 the study
      will have a power of 0.87 to detect a difference in end scores between the 3 groups
      (calculation in PASS 8.0).

      Clinical Measures Demographic variables and potential co-variates will be recorded at
      baseline following a clinical interview. These will include the duration of the current
      episode, years from first diagnosis, number of previous episodes, type and dose of current
      and previous treatment and family history of mood disorder.

      Clinical measures will be performed at randomization, at 3 and 6 weeks (and 9 weeks in the
      patients in the extension phase) as well as at the follow up assessments. A trained rater who
      is blind to treatment type will administer all measures. Raters will be required to maintain
      >90% reliability on the primary outcome assessments on ratings with 6 monthly assessments
      based on videotaped interviews.

      To ensure comparability with previous studies, the primary outcome variable will be the
      17-item Hamilton Rating Scale for Depression (HAMD). Other outcome measures will include the
      Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Questionnaire (BDI), Brief
      Psychiatric Rating Scale (BPRS) and an interview to record the subjective experiences of TMS
      and any adverse events. Final response and remission rates will be measured using standard
      rating scale score criteria but the patients will need to achieve these scores at the study
      end and at the 2 week follow up assessment.

      Assessments made at baseline to explore potential predictors of clinical response will
      include the CORE rating of melancholia [33], the Measure of Parental Styles [34], the
      Depressive Personality Inventory [35] and the Costello and Comrey trait anxiety measure [36].

      A battery of cognitive tests will be administered prior to commencement and at 3, 6 and 9
      weeks in the active treatment phase with a specific focus on attention and memory:

      HVLT, Controlled oral word association, Trail making A&B, Digit Span The inclusion of these
      measures in the will assess the potential beneficial effects of TMS on frontally mediated
      cognitive functions as well as act as a safety check.

      TMS Treatment TMS will be administered with a Medtronic Magpro30 magnetic stimulator using a
      70mm figure of 8 coil. Prior to the commencement of treatment TMS, single pulse TMS will be
      used to measure the resting motor thresholds (RMT) for the abductor pollicis brevis (APB)
      bilaterally in all subjects using standard published methods [30].

      Stimulation parameters rTMS will be administered on a daily basis 5 days per week for all
      subjects:

      Bilateral:

      Left: 10Hz, 100% RMT, 30 Trains, 5 second duration, 25 second inter-train interval Right: 1
      Hz, 100% RMT, 1 Train of 600 pulses

      Left Unilateral:

      Left: 10Hz, 100% RMT, 30 Trains, 5 second duration, 25 second inter-train interval Right: as
      above, BUT, applied with a Medtronic sham coil Sham: the following applied with a sham coil
      Left: 10Hz, 100% RMT, 30 Trains, 5 second duration, 25 second inter-train interval Right: 1
      Hz, 100% RMT, 1 Train of 600 pulses Missed sessions will be 'made up' by an extension of the
      treatment duration but only one missed session will be allowed weekly and only one missed
      session in a row.

      Stimulation localisation This will follow standard procedures. Firstly, the site for the
      optimal activation of the abductor pollicis brevis muscle in the contralateral hand will be
      located whilst stimulating the relevant motor cortical region at supra-threshold intensity.
      This site will be marked on the scalp. We will then measure 6 cm anteriorly on the scalp
      surface and mark it with ink. This point will be then used as the site of stimulation. The
      majority of rTMS studies have measured 5 cm anteriorly. However, this has been shown to
      result consistently in localisation that is posterior to the dorsolateral PFC [37]. The
      measurement described here should result in more consistent treatment of dorsolateral PFC but
      still provide considerable stimulation overlap with the established '5 cm' site.

      Imaging MRI imaging will be conducted before the commencement of treatment (all subjects) and
      at the end of the active treatment phase where possible. Each subject will undergo a 3D
      sagittally orientated T1 weighted structural MR scan on the 1.5 Tesla MRI scanner at the
      Alfred (128 slices). Analysis of scalp to cortex distance in prefrontal cortex and at the
      site of stimulation will be conducted using previously published methods. This will allow the
      post hoc analysis of the relationship between scalp to cortex distance and treatment
      response. In addition, where possible subjects will undergo additional measures of white
      matter tract integrity (diffusion tensor imaging) and activation. None of the scanning
      procedures will involve the administration of contrast.

      Electroencephalography (EEG) EEG before and after the acute phase of treatment will be used
      to examine mean absolute spectral power within 5 frequency bands. The mean absolute power (in
      squared microvolts per hertz) will then be computed within the following 5 frequency bands:
      delta (0.5-3.5 Hz), theta (3.5-7.5 Hz); alpha (7.5-12.5 Hz); beta 1 (12.5-20.5 Hz), and beta
      2 (20.5-32.5 Hz). EEG activation / spectral power will be assessed at rest (eyes open and
      closed) and during cognitive engagement in several tasks.
    

Intervention name(s): TMS; Sham TMS
Intervention type(s): Drug; Device
Intervention description(s): Active Transcranial Magnetic Stimulation; Sham Transcranial Magnetic Stimulation
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment