Transcranial Magnetic Stimulation for Adolescent Depression
Transcranial Magnetic Stimulation for Adolescent Depression
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.
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.
Inclusion Criteria:

 -  age (12-22 years),

 -  MDD failing to respond to at least one SSRI trial (minimum 8 weeks treatment at an
 adequate dose; determined retrospectively), and

 -  informed consent. Healthy controls with no psychiatric history (who do not receive
 rTMS) will undergo MRI scans to allow for comparison with MDD patients.

 Exclusion Criteria:

 -  previous seizures or epilepsy,

 -  hypertension,

 -  additional neurological or psychiatric diagnoses (specifically: bipolar disorder,
 psychosis, pervasive developmental disorder, eating disorders, and post-traumatic
 stress disorder).

 As 3T MRI will be used, pregnancy is exclusionary.