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.
