This pilot study aims to examine the feasibility of recruiting depressed adolescents to examine changes in emotional processing and in neural responses to emotional stimuli after one session of rTMS (which is followed by an open-label phase of 4 weeks active rTMS).

Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment for adolescent depression but clinical trials have been hampered by a lack of dose optimization studies and high placebo rates. While rTMS does not produce mood changes until after weeks of treatment, unconscious changes in emotional processing have been found even after one session of stimulation. It is unknown whether one session of rTMS produces changes in neural activity to emotional stimuli in depressed adolescents. If acute rTMS can reliably produce changes in neural activity associated with emotional processing it could be a biomarker to aid future dose-finding studies. A one-session protocol allows experimenters to truthfully reduce expectancy of mood change and reduce placebo effects. This study will examine the feasibility of recruitment and using a one-session protocol to find a biomarker for acute rTMS effects. A single-blinded sham-controlled design will be used. Depressed adolescents will undergo: 1) sham stimulation (n=15) or 2) active stimulation with intermittent theta burst stimulation (iTBS) (n=15) for one session prior to assessment of brain activity in response to emotional stimuli in a fMRI and other emotional processing tasks. This one day randomized controlled phase can then lead into an open-label treatment phase active rTMS for 4 weeks. The primary outcome will be recruitment rates with a secondary outcome of estimating the magnitude of difference detectable in cortico-limbic activity between groups. This study assesses the feasibility of a novel paradigm to help improve clinical trials for neuromodulation in depressed adolescents.

Inclusion Criteria:

1. Female or male patients between ages 14-21
2. Diagnosis of major depressive disorder as defined by the Diagnostic and Statistical Manual fifth edition (DSM-5)
3. Hamilton Rating Scale for Depression (17-item) score of at least 20
4. At least one failed adequate antidepressant trial
5. On a stable antidepressant regimen for at least 4 weeks before treatment which can continue during treatment and agreement to not make changes or additions to psychotropic medications during the course of their participation in the study
6. Ability to provide informed consent and comply with all testing, follow-ups and study appointments and protocols

Exclusion Criteria:

1. Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, delusional disorder, post-traumatic stress disorder, obsessive compulsive disorder, autism spectrum disorder
2. Active neurologic disease
3. Any lifetime history of seizures
4. Alcohol or substance dependence or abuse in the last 6 months, excluding caffeine and nicotine
5. Current active suicidal ideation
6. Personality disorder deemed to be the primary pathology
7. Taking more than 2 mg lorazepam (or an equivalent) or any anticonvulsant
8. Previous rTMS treatment

Single-blinded sham-controlled between-subjects design with two arms.