Repetitive Transcranial Magnetic Stimulation for Adolescent Depression: Efficacy, Predictive Biomarkers, and Mechanisms
Condition: Treatment Resistant Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
Study type: Interventional

Summary: 
      This study will be an open-label 6-week (30 session) trial of active repetitive transcranial
      magnetic stimulation (rTMS) using a fixed frequency (10 Hz) but varying stimulation
      intensities using a 3+3 study design for safety and tolerability amongst adolescents. This
      means that we will only enroll 3 participants at a time and give them rTMS at the stimulation
      intensity energy of 80% of motor threshold (MT). If all three participants complete the 6
      weeks of treatment with no major safety events (i.e. seizure), we will increase the energy
      for the next 3 participants by 20%. If 1 of the 3 participants has a major safety event, we
      will enroll 3 more patients at the SAME energy. We will proceed in this manner, increasing by
      20% after 3 subjects safely complete treatment at that energy, to a maximum energy of 120% of
      motor threshold. If 2 participants in each intensity level cohort experience a major safety
      event, we will discontinue running subjects at that energy level. If this happens at our
      initial energy level of 80% of MT, we will stop the study. If we reach 2 events in any of the
      higher energy cohorts, we will return to the previous energy level and complete the remainder
      of the subjects at that energy level.
    

Detailed description: 
      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.
    

Intervention name(s): Active Repetitive Transcranial Magnetic Stimulation (rTMS): intensity 80% MT; Device: Active Repetitive Transcranial Magnetic Stimulation (rTMS); Stimulation intesity: 100% of MT; Device: Active Repetitive Transcranial Magnetic Stimulation (rTMS); Stimulation intesity: 120% of MT
Intervention type(s): Device; Device; Device
Intervention description(s): rTMS applies a pulsatile magnetic field to the scalp which painlessly induces electrical currents to the brain. Typically, rTMS is applied to the dorsolateral prefrontal cortex (DLPFC), a brain region that is hypoactive in depression. Whereas standard rTMS stimulates superficial (1cm depth) cortical areas, recent advances in rTMS coil technology support stimulation of deeper (5 cm depth) limbic structures that are also relevant to depression.
Other Name: Brainsway rTMS; rTMS applies a pulsatile magnetic field to the scalp which painlessly induces electrical currents to the brain. Typically, rTMS is applied to the dorsolateral prefrontal cortex (DLPFC), a brain region that is hypoactive in depression. Whereas standard rTMS stimulates superficial (1cm depth) cortical areas, recent advances in rTMS coil technology support stimulation of deeper (5 cm depth) limbic structures that are also relevant to depression.
Other Name: Brainsway rTMS; rTMS applies a pulsatile magnetic field to the scalp which painlessly induces electrical currents to the brain. Typically, rTMS is applied to the dorsolateral prefrontal cortex (DLPFC), a brain region that is hypoactive in depression. Whereas standard rTMS stimulates superficial (1cm depth) cortical areas, recent advances in rTMS coil technology support stimulation of deeper (5 cm depth) limbic structures that are also relevant to depression.
Other Name: Brainsway rTMS
Other intervention name(s): Brainsway rTMS
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: rTMS