Repetitive Transcranial Magnetic Stimulation for Adolescent Depression: Efficacy, Predictive Biomarkers, and Mechanisms

Adolescents with Treatment Resistant Depression (TRD) (n=30) will be recruited from the
inpatient and outpatient adolescent mental health clinical services at UMN and surrounding
area.

Adolescents and parents will undergo the consent process and initial clinical evaluation.
This initial evaluation will be done using the Kiddie Schedule of Affective Disorders and
Schizophrenia (K-SADS-PL 2009) and the Children's Depression Rating Scale-Revised (CDRS-R).
Participants and their families will also be asked to complete the Antidepressant Treatment
Report (ATR), Beck Depression Inventory (BDI-II), Columbia Suicide Severity Rating Scale
(C-SSRS), Inventory of Depression and Anxiety Symptoms (IDAS), Temporal Experience of
Pleasure Scale (TEPS), Snaith-Hamilton Pleasure Scale (SHAPS), Young Mania Rating Scale
(YMRS), Edinburgh Handedness Scale, the Weschler Abbreviated Scale of Intelligence (WASI) and
the Tanner Pubertal Staging Questionnaire. Participants will also be asked to complete the
NIH Toolbox, Children's Auditory Verbal Learning Test (CAVLT), and the Delis-Kaplan Executive
Function System (D-KEFS) Trail Making Test.

Adolescents with TRD who fit inclusion/exclusion criteria (presence of major depression with
CDRS-R raw score > 40; a history of at least one failed treatment trial with an
antidepressant [as defined by the Antidepressant Treatment Report]; no history of seizure
disorder; no presence of MRI contraindications [e.g. claustrophobia or metallic implants])
will be scheduled for:

A. A baseline MRI (described below)

B. 6 weeks of the series of rTMS visits described below

C. A post-treatment MRI

D. A post-treatment clinical assessment (blinded to treatment assignment)

E. 6 monthly follow up visits

In the first rTMS visit, the study physician will fit the cap, determine the ideal location
for stimulation, and measure MT and MEPa. Adolescents will receive 6 weeks of rTMS, 20
minutes/day, 5 days/week administered by a trained technician. Active treatment will be 43
trains of 10 Hz, stimulation intensity will vary as described above, inter-train interval 20
seconds, 1680 pulses/session. A member of research staff will meet weekly with patients to
complete the CDRS-R, monitor treatment tolerance using the Side Effects Form for Children and
Adolescents, and measure the MT and MEPa. Adolescents will also complete the BDI-II,
C-SSRS-SLV, IDAS, TEPS, YMRS, and SHAPS weekly. At week four, the participants will be asked
to repeat the NIH Toolbox, Children's Auditory Verbal Learning Test (CAVLT), and the
Delis-Kaplan Executive Function System (D-KEFS) Trail Making Test.

Scanning will take place at the Center for Magnetic Resonance Research on a 3T Siemens Prisma
scanner at baseline (after the clinical assessment, before the first treatment) and after the
last rTMS treatment. Participants will complete MRI safety forms and provide a urine sample
to rule out substance use (all participants) and pregnancy (females only). A high-resolution
T1 image will be collected (voxel size=1mm isotropic; TR=2530ms; TE=3.65ms, T1=1100ms, flip
angle=7°, 5 minutes). Functional data will be acquired using the Human Connectome Project
(HCP)38 multiband echo planar imaging sequence (whole brain T2*-weighted functional volumes,
72 contiguous slices; TR=720ms; TE=34.2ms; flip angle=55o, FOV=212mm; voxel size=2mm
isotropic; matrix=106x106; multiband factor=8; 12 minutes) during rest with eyes open while
viewing a fixation cross.

Participants will be asked to complete a task fMRI in which they are presented with a series
of visual stimuli, (human faces of varying emotion expressions with positive, negative or
neutral words printed over the faces). During the task, participants will be asked to decide
whether the words printed over the faces are positive or negative regardless of the emotion
of the face shown. Each subject will complete four distinct blocks of the task.

After the completion of rTMS sessions, all participants will undergo a final assessment
during which they will be asked to meet with evaluators again to complete the CDRS-R. They
will also be asked to complete the BDI-II, C-SSRS, TEPS, SHAPS, IDAS and NIH Toolbox.

After the completion of all rTMS sessions, participants will be asked to return to see
researchers every month for 6 months to assess length of treatment response.

Inclusion Criteria:

- Diagnosis of Major Depressive Disorder (MDD)

- A CDRS-R score of >40

- Experiencing a current MDD episode with a duration of ≥ 4 weeks and ≤3 years

- Resistance to treatment, defined by failure to respond adequately to at least one
antidepressant treatment, defined by ATR level 1-4 in current episode

- Both child and parent/guardian are English speaking

- Female participants who are sexually active during the course of the study must use a
form of birth control for the duration of the study

Exclusion Criteria:

- Any subject with a clinically defined neurological disorder or insult including, but
not limited to, a condition likely to increase the risk of seizure; such as, space
occupying brain lesion; any history of seizure; history of cerebrovascular accident;
transient ischemic attack within two years; cerebral aneurysm; dementia; brain
surgery; history or stroke or family history of epilepsy

- Any subject with an increased risk of seizure for any reason, including prior
diagnosis of increased intracranial pressure or history of significant head trauma
with loss of consciousness for ≥ 5 minutes

- Positive responses to any question on the Transcranial Magnetic Stimulation Adult
Safety Screening Questionnaire (TASS)

- Subjects with cardiac pacemakers, implanted medication pumps, intracardiac lines, or
acute unstable cardiac diseases

- Subjects with conductive, ferromagnetic, or other magnetic-sensitive metals implanted
in the head within 30 cm of the treatment coil excluding the mouth that cannot safely
be removed should be excluded. Examples include cochlear implants, implanted
electrodes/stimulators, aneurysm clips or coils, stents, bullet fragments, jewelry and
hair barrettes

- Subjects with active or inactive implants (including device leads), including deep
brain stimulators, cochlear implants, and vagus nerve stimulators

- Inability to locate and quantify a motor threshold as defined in the protocol

- History of treatment with ECT or TMS therapy for any disorders

- Participation in any investigational drug trial within 4 weeks of the baseline visit

- Pregnancy

- IQ < 80

- Clinically significant laboratory abnormality or medical condition, that in the
opinion of the investigator would hinder the subject in completing the procedures
required by the study

- Suicide attempt within the previous 6 months that required medical treatment or ≥2
attempts in the past 12 months, or has a clear plan for suicide and states that s/he
cannot guarantee that s/he will inform a family member or call his/her psychiatrist or
the investigator if the impulse to implement the plan becomes substantial during the
study; or, in the investigator's opinion, is likely to attempt suicide within the next
6 months

- Unstable psychotherapy (therapy must be for at least 3 months prior to entry into the
study, with no anticipation of change in the frequency or treatment focus of the
therapeutic sessions over the duration of the study)

- A diagnosis of substance use disorder, Schizophrenia, Bipolar Disorder, or Autism

- Refusal to cooperate with study procedures

- Recent change in dose of antidepressant medication (within 6 weeks prior to initial
evaluation). This includes all antidepressants and any adjunctive psychotropic
medications that are being used to address problems related to mood or anxiety (e.g.
antipsychotic medications, mood stabilizers.) This does not include stimulant
medications that are being used to treat Attention Deficit Hyperactivity Disorder
(ADHD).**

- Current treatment with Bupropion at a dose greater than 150mg per day.

- Current treatment with a stimulant medication as an adjunct medication for
depression.***

- Current treatment with a stimulant medication for ADHD above FDA recommended
dosages.***

(*) If the participant has an insufficient number of trials in the current episode, then
the participant must also have failed ≥1 and ≤4 trials in a previous episode. Subjects who
have been unable to complete an antidepressant trial of adequate dose and duration due to
intolerance to antidepressant therapy may be included if they have demonstrated intolerance
to ≥4 antidepressant medications within one discrete illness episode (current or previous
episode as defined above)

(**) If there has been a recent discontinuation of a medication we will require varying
lapses of time before study entry depending on medication type as follows: Antidepressant
medications = 4 weeks, mood stabilizers (e.g. Lithium, Valproate) = 2 weeks, Antipsychotic
medications = 2 weeks, Stimulant medications = 1 week

(***) If participants are being treated with stimulant medications as an adjunct strategy
for their depression, we will require them to discontinue the stimulant prior to starting
the study treatment and wait 1 week before they begin the study as listed above. If the
participant is taking a stimulant medication to treat ADHD, they will be allowed to
continue the stimulant medication, as long as the dosage is within FDA recommendations.