Transcranial Magnetic Stimulation for Adolescent Depression
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: University of Calgary

 
NCT01731678 
 
April 29, 2012 
 
Transcranial Magnetic Stimulation for Adolescent Depression (TMSAD)   
 
INTRODUCTION 
Treatment options for major depressive disorder (MDD) in youth are limited, with concerns over 
efficacy (Carvalho et al., 2007) and safety (Adegbite-Adeniyi et al., 2012; Menke et al., 2012; Cipriani 
et al., 2016). Evidence suggests 30-50% of adolescents and young adults with MDD are treatment-
resistant, leading to lifelong consequences (Fava, 2003). Consequently, new interventions for treatment-
resistant MDD in youth are needed (Souery et al., 2011). One potential treatment is repetitive 
transcranial magnetic stimulation (rTMS)(MacMaster et al., 2016). Prior research demonstrates that 
rTMS targeting the left dorsolateral prefrontal cortex (DLPFC) in adults is well-tolerated, safe, and 
effective for MDD (George, 2010; Lefaucheur et al., 2014; Leggett et al., 2015; Milev et al., 2016; 
McClintock et al., 2017). Prior studies (case series and reports) of rTMS in MDD patients below the age 
of 22 are limited but encouraging, but substantial knowledge gaps remain (Donaldson et al., 2014).  
 
OBJECTIVE 
With this in mind, we conducted a trial of LDLPFC rTMS in youth with treatment resistant MDD. We 
hypothesized that rTMS would reduce depressive symptom severity in youth with MDD. 
 
DESIGN 
Open label trial of TMS.  
 
METHODS 
This study was approved by the Conjoint Health Research Ethics Board (CHREB) for the University of 
Calgary.  
 
Participants 
Participants were recruited from the community and clinics in our area. Inclusion criteria were: (1) age 
12-22 years, (2) diagnosis of MDD, based on an interview with the Kiddie Schedule for Affective 
Disorders and Schizophrenia Present and Lifetime version (K-SADS-PL)(Kaufman et al., 1997) with a 
symptom severity of 40 or greater on the Children’s Depression Rating Scale Revised (CDRS-
R)(Poznanski et al., 1985), (3) history of failing to respond to at least one selective serotonin reuptake 
inhibitors (SSRI) trial (minimum 8-week treatment at an adequate dose; retrospectively determined on 
interview), and (4) ability to provide informed consent. Psychotropic medications were allowed if the 
dose has been stable for six weeks with adequate compliance, and with a commitment to not change 

 
medication/dosage during the trial period, unless deemed medically necessary. Exclusion criteria 
included: (1) previous seizures or epilepsy, (2) hypertension, (3) previous neurological or psychiatric 
diagnoses (specifically - bipolar disorder or psychosis) (4) pregnancy, (5) implanted metal or medical 
device, or (6) left-handedness. 
 
Assessments 
Participants were assessed at baseline, weekly during rTMS, and at the completion of treatment. Core 
clinical assessments were designed to confirm diagnosis (baseline), define symptoms, and assess 
treatment response. The K-SADS-PL (Kaufman et al., 1997), was used to assess both present and 
lifetime psychiatric symptomatology. The CDRS-R (Poznanski et al., 1985) was administered at 
baseline and treatment completion to quantify moderate to severe depressive symptom severity in 
participants. The Hamilton Depression Rating Scale (Ham-D)(Hamilton, 1967) and Beck Depression 
Inventory (BDI)(Beck et al., 1997), were used to assess depressive symptoms at baseline, the end of 
each week for safety monitoring, and after treatment completion. The Hamilton Anxiety Rating Scale 
(Ham-A)(Hamilton, 1959), to assess anxiety levels, was also administered at baseline and after treatment 
completion. We endeavored to complete assessments within two weeks of initiation and termination of 
rTMS.  
 
The primary outcome measure of treatment response was defined as a greater than 50% reduction in 
Ham-D scores from baseline to end-point. A secondary exploratory measure of clinically meaningful 
response was also preset at 30% based on American College of Neuropsychopharmacology (ACNP) 
recommendations (Rush et al., 2006). We also examined predefined criteria for remission (Ham-D score 
≤ 7 post-rTMS) and partial remission (Ham-D score ≤ 10 post-rTMS and a  50% reduction in Ham-D 
score). 
 
rTMS 
TMS was performed at the Alberta Children’s Hospital. The TMS intervention utilized a Magstim 
SuperRapid2, air-cooled 90mm figure-of-8-coil (Magstim, Wales UK). Using a neuronavigation system 
(Brainsight2, Rogue Research, Montreal), the TMS coil was monitored in real time and co-registered 
with the individual’s structural MRI. Imaging was performed on a 3T GE MR750w scanner using a 24-
channel head coil. Anatomical scan parameters were: Axial T1-w 3D BRAVO with TR = 8204 
milliseconds, TE = 3.168 milliseconds, flip angle = 10 degrees, 226 slices with 0.8 mm thickness, 300 x 
300 matrix. 
 
On the first day, motor evoked potentials (MEP) were recorded to determine the resting motor threshold 
(RMT) in the standard manner (Kirton et al., 2010). To initially locate the DLPFC target site, the 5-cm 
rule was applied, in which the scalp position 5cm anterior to the hotspot along a line to the nasion was 
marked (George et al., 1995; George et al., 1996; Herwig et al., 2001; Herwig et al., 2003). 
Neuronavigation confirmed accurate DLPFC (adjusted if needed) targeting. The TMS coil was 
subsequently placed tangential to the scalp, and angled at 45 degrees to the midline and fixed over the 
target using a mechanical arm. The target was marked on the neuronavigation system, allowing real time 
targeting and accurate session to session reliability. 

 
 
rTMS was applied at 10 Hz. Each train consisted of 40 suprathreshold (120% RMT) pulses over 4 
seconds with an inter-train interval of 26 seconds. Treatment sessions lasted 37.5 minutes (75 
trains/3000 pulses), and occurred at the same time of day on every weekday for a period of three weeks 
(15 days total). During TMS, only passive activities were allowed (i.e., watching movies or TV, 
listening to music). Three weeks of treatment was selected based on existing rTMS evidence in adult 
MDD and our rTMS experience in pediatric stroke (Kirton et al., 2008; Davis, 2014). Participants were 
monitored for adverse events and tolerability using a Pediatric TMS Safety and Tolerability Measure 
(Garvey, 2005) on days 1, 6, and 11. Items were self-rated.  
 
STATISTICAL CONSIDERATIONS 
For the primary outcome, we hypothesized that rTMS would result in a significant reduction in 
depression symptom severity as measured by the Ham-D. We used a paired t-test comparing baseline to 
post-rTMS with p < 0.005. We increased the threshold in keeping with recommendations designed to 
improve reproducibility (Benjamin et al., 2017). For exploratory measures (i.e., CDRS, BDI, Ham-A) 
we used a paired t-test comparing baseline to post-rTMS with p < 0.01 to correct for multiple 
comparisons (Bonferroni). Analyses were performed with IBM SPSS (version 24; New York, USA). 
 
 

 
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