Transcranial Magnetic Stimulation for Adolescent Depression
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Study type: Interventional

Summary: 
      Major depression (or MDD) in adolescents is a major public health problem. MDD affects
      approximately 15% of adolescents; it is associated with impairment in social, family, and
      academic functioning, and it is a major risk factor for suicide - a leading cause of death in
      adolescents . Unfortunately, there is a paucity of treatment options for this age group.
      Selective serotonin reuptake inhibitors (SSRIs) are the only class of medications approved
      for treating MDD in adolescents, but rates of remission following treatment with SSRIs are
      only 30 to 45 percent. Cognitive behavior therapy is associated with similar remission rates
      and access is limited. Most adolescents will require more than one therapeutic intervention
      in order to achieve full symptom control. Collectively, there is overwhelming evidence that
      additional treatment options are urgently needed to improve outcomes for teens with MDD. One
      novel treatment for adolescent MDD is repetitive transcranial magnetic stimulation (rTMS).
      Studies in children have been limited (a total of 23 cases). This is surprising given the
      evidence suggesting younger adult subjects with MDD respond better to rTMS (56% response
      rate) than older subjects. This limited experience with rTMS for adolescent MDD represents a
      substantial gap in the knowledge, recently recognized in publications calling for further
      study of rTMS in adolescent depression. Most importantly, the mechanism of action of rTMS in
      adolescent MDD is not well understood. The objective of this application is to develop an
      understanding of the brain alterations associated with the positive clinical changes that
      occur with rTMS in adolescent MDD. Such knowledge will provide the basis for pursuing rTMS
      for adolescent MDD as a rational therapeutic technique.

      Specific Aim: To compare the effect of rTMS on DLPFC glutamate concentration in adolescent
      MDD. The investigators hypothesize an increase (normalization to controls) in DLPFC glutamate
      after three weeks of rTMS. Furthermore, the change in glutamate concentration will correlate
      with a change in MDD symptoms.
    

Detailed description: 
      PURPOSE: The purpose of this study is to identify neuroimaging, physiological, and clinical
      predictors of response, remission, and recovery to repetitive transcranial magnetic
      stimulation in youth with treatment resistant major depressive disorder.

      BACKGROUND: Major depressive disorder (MDD) is a major public health problem in adolescents.
      Unfortunately, there are no effectively targeted treatment options for this age group.
      Current remedies are limited in their effectiveness in youth with response and remission
      rates no greater than 60 to 30% respectively and treatment effects are not sustained
      throughout the life cycle. Further, ongoing controversies persist regarding the safety of
      antidepressants in youth. Current interventions were developed to solely target the symptoms
      of rather than the underlying neurobiology. Most importantly, there is no way to accurately
      predict an individual patient's response to interventions. Consequently, there is a critical
      need for optimally targeted interventions that directly address the relevant pathophysiology
      of depression.

      Repetitive transcranial magnetic stimulation (rTMS) targeting the left dorsolateral
      prefrontal cortex (DLPFC) is effective in adults with depression. rTMS is twice as likely to
      result in response (relative risk or RR: 2.35 [95% confidence interval or CI: 1.70-3.25]) and
      remission (RR: 2.24 [95% CI: 1.53-3.27] than a sham procedure Evidence in youth is also
      encouraging, with a 66% response rate in our pilot data (see Summary of Progress). The DLPFC
      plays a critical role in emotional regulation, directly connecting it to depressive
      symptomology. Our lab and others have clearly implicated structural and functional deficits
      in the DLPFC in youth with MDD. What is not known is what biomarkers best predict response,
      remission, and recovery with rTMS in youth with treatment resistant MDD. As response is not
      universal, this is a significant gap in our knowledge. Our basic model is that rTMS increases
      expression of BDNF, up-regulates activity of endocannabinoids, increases glutamate
      concentrations, and increases DLPFC activity - correcting the deficit seen in MDD. These
      biologic changes enhance executive control of mood state (see our pilot data in the Summary
      of Progress). These positive effects may be moderated by comorbidity (i.e., social phobia)
      and genotype (i.e., BDNF). How this model fits with response, remission, and recovery has yet
      to be fully tested and this information has the potential to be directly clinically
      meaningful. The central aim of the project is to evaluate predictors of rTMS response,
      remission, and recovery based on integrated neuroimaging, physiological, and clinical
      measures. While not a clinical trial per se (efficacy is not the primary outcome measure), we
      will use a non-randomized sham lead in to a single active (rTMS) arm study design as a
      framework for biomarker discovery.

      To accomplish this goal, we will pursue the following specific aims: The primary aim is to
      identify baseline neuroimaging, physiological, and clinical predictors of response to 3 weeks
      of rTMS treatment in adolescents with treatment resistant MDD.
    

Intervention name(s): Transcranial Magnetic Stimulation
Intervention type(s): Procedure
Intervention description(s): The standardized treatment location will be the left DLPFC. Anatomical T1 images from the pre-intervention MRI will be loaded into our Transcranial Magnetic Stimulation (TMS) lab neuronavigation software (Brainsight2, Rogue Research, Montreal). Following 3D co-registration of the TMS coil with the patient's MRI images and head, the coil will be placed over the left DLPFC (tangential to scalp, angle of 45 degrees to midline). Interventional repetitive TMS (rTMS) (Magstim Rapid2, Wales, UK) will consist of 40 suprathreshold (120% RMT) pulses over 4 seconds (10 Hz) with an inter-train interval of 26 seconds. Treatment sessions will last 37.5 minutes (75 trains/3000 pulses). Treatments will occur on each weekday for three weeks (15 days total).
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment