Deep Transcranial Magnetic Stimulation for Adolescents with Treatment-Resistant Depression: A Preliminary Dose-Finding Study Exploring Safety and Clinical Effectiveness

Abstract

Background:

Transcranial magnetic stimulation (TMS) is an intervention for treatment-resistant depression (TRD) that modulates neural activity. Deep TMS (dTMS) can target not only cortical but also deeper limbic structures implicated in depression. Although TMS has demonstrated safety in adolescents, dTMS has yet to be applied to adolescent TRD.

Objective/Hypothesis:

This pilot study evaluated the safety, tolerability and clinical effects of dTMS in adolescents with TRD. We hypothesized dTMS would be safe, tolerable, and efficacious for adolescent TRD.

Methods:

15 adolescents with TRD (Age, years: M = 16.4, SD = 1.42) completed a six-week daily dTMS protocol targeting the left dorsolateral prefrontal cortex (BrainsWay H1 coil, 30 sessions, 10 Hz, 3.6s train duration, 20s inter-train interval, 55 trains; 1980 total pulses per session, 80% to 120% of motor threshold). Participants completed clinical, safety, and neurocognitive assessments before and after treatment. The primary outcome was depression symptom severity measured by the Child Depression Rating Scale-Revised (CDRS-R).

Results:

14 out of 15 participants completed the dTMS treatments. One participant experienced a convulsive syncope; the other participants only experienced mild side effects (e.g., headaches). There were no serious adverse events and minimal to no change in cognitive performance. Depression symptom severity significantly improved pre- to post-treatment and decreased to a clinically significant degree after 10 treatment sessions. Six participants met criteria for treatment response.

Limitations:

Main limitations include a small sample size and open-label design.

Conclusions:

These findings provide preliminary evidence that dTMS may be tolerable and associated with clinical improvement in adolescent TRD.

Introduction

Depression is a leading cause of disability and global disease burden (Üstün et al., 2004). Depression emerges in adolescence in about 25% of those affected (Kessler et al., 2005). Earlier onset of depression is associated with greater psychosocial dysfunction and suicidality (Hollon et al., 2006; Zisook et al., 2007, 2004). About 30% of adolescents with depression do not respond to currently-available treatments (Kennard et al., 2009b, 2009a; March et al., 2004), many of which were first developed with adults. Since the brain undergoes important maturation during adolescence (Casey et al., 2008; Giedd et al., 2009; Gogtay and Thompson, 2010; Sowell et al., 2002), the neural mechanisms underlying disease and treatment response could vary in this population due to developmental differences (Bylund and Reed, 2007; Gee et al., 2013). Together, these considerations highlight the need to study adolescents separately from adults. Early and effective treatments could prevent long-term morbidity and mortality associated with adolescent depression.

Repetitive transcranial magnetic stimulation (TMS) is a well-established treatment for treatment-resistant depression (TRD) in adults. TMS applies a pulsatile magnetic field to the scalp, which induces electrical currents to the brain (Roth et al., 2007). Typically, TMS is applied to the dorsolateral prefrontal cortex (DLPFC) and neighboring cortical regions (Perera et al., 2016). The first TMS coil to receive US Food and Drug Administration (FDA) approval for use in depression was the figure-8 coil, which can stimulate up to 1 cm into the cortex. More recently, the H1 coil was developed with the goal of stimulating deeper (5 cm depth) brain structures (Roth et al., 2007) (hence referred to as “deep TMS”). The greater depth deep TMS (dTMS) can achieve is promising for the treatment for depression because the stimulation can reach subcortical prefrontal regions and subcortical reward and threat network regions, like the amygdala, thalamus, hippocampus, and nucleus accumbens, that are implicated in the pathophysiology of depression (Bersani et al., 2013; Parazzini et al., 2017; Zibman et al., 2021). dTMS is now also FDA-approved for adults with TRD (Levkovitz et al., 2009), following six open-label studies (Berlim et al., 2014; Feffer et al., 2017; Naim-Feil et al., 2016; Rapinesi et al., 2015; Rosenberg et al., 2010; Tendler et al., 2018) and four randomized controlled trials confirming its benefit compared to sham (Filipčić et al., 2019; Kaster et al., 2018; Levkovitz et al., 2015, 2009). While both coils are now used in standard practice, compared to the figure-8 coil, the H1 coil is less focal and stimulates the DLPFC bilaterally with greater intensity over the left hemisphere (Roth et al., 2007). The FDA-approved dTMS protocol has fewer pulses per session (1980 vs. 3000), a higher frequency (18 Hz vs. 10 Hz), a shorter pulse train (2s vs. 4s), and a shorter intertrain interval (20s vs. 26s) than the FDA-approved rTMS protocol using a figure-8 coil for treating MDD in adults (McClintock et al., 2018). One meta-analysis comparing studies on adults using these different coils with protocols that were matched for stimulation frequency and number of sessions found greater improvement in depression severity in the dTMS studies (Hedges’ g = 1.55) compared to the rTMS studies (Hedges’ g = .97; Gellersen & Kedzior, 2019). Likewise, one head-to-head trial found higher response rates in adults assigned to the H1 coil (dTMS; response rate of 67%) versus the standard figure-8 coil (response rate of 44%; Filipčić et al., 2019).

Much less is known about the utility of TMS and dTMS in adolescents with TRD. Available data from children and adolescents suggest similar rates of adverse events as adults (Allen et al., 2017; Krishnan et al., 2015; Rossi et al., 2021). Of particular interest for this still-developing population, side effects tend to be mild and transient and there has been no evidence of TMS-associated cognitive impairments (Bloch et al., 2008; Mayer et al., 2012; Wall et al., 2016). Reported side effects of dTMS in adults include: application site discomfort/pain, muscle twitching, headache, backpain, lightheadedness/dizziness and insomnia (Filipčić et al., 2019; Zibman et al., 2021). There is some evidence of elevated seizure risk in dTMS relative to the rTMS with a figure-8 coil (43/100,000 vs. 8/100,000 sessions; Lerner et al., 2019) but other studies have demonstrated a seizure rate for dTMS to be similar to rTMS and antidepressant medications (Zibman et al., 2021; Tendler et al., 2018). Overall, dTMS has evidence of high tolerability and low dropout rates in adults (Filipčić et al., 2019; Zibman et al., 2021) and rTMS has evidence of high tolerability in children and adolescents (Allen et al., 2017; Krishnan et al., 2015), making TMS a promising treatment for depression in youth.

Key efficacy findings from the literature testing TMS in adolescent MDD are summarized in Supplementary Table S1. Briefly, while the few small studies that have tested TMS in adolescent MDD have shown promising results, with response rates ranging from 33% to 100% (Bloch et al., 2008; Croarkin et al., 2021; Loo et al., 2006; MacMaster et al., 2019; Pan et al., 2018; Wall et al., 2016, 2011; Yang et al., 2014), the field still lacks conclusive data supporting TMS as an intervention for adolescent TRD based on controlled studies. The first randomized, sham-controlled trial of TMS in 103 adolescents with TRD (Croarkin et al., 2021) reported a 42% response rate in the active TMS group and a 36% response rate in the sham group; the group difference was not statistically significant. However, it remains unknown whether alternative strategies in TMS treatment (e.g., H1 coil versus figure-8 coil or altering parameters such as stimulation intensity, frequency, and session number) might be more effective for adolescents with TRD.

Here we report the results of an open-label trial of dTMS treatment for adolescents with TRD. Of note, the current study began as a randomized, sham-controlled trial, utilizing the H1 coil treatment protocol that was FDA-approved for adults. However, following a seizure event in a participant from an initial phase of this study (Cullen et al., 2016), the protocol was modified to enhance safety and shifted to an open-label, dose-finding design (decreasing the stimulation frequency from 18 Hz to 10 Hz and stimulation intensity from 120% of motor threshold (MT) to a stepwise process evaluating safety at 80%, 100% and finally 120%). The first aim was to document the side effect profile and other safety features, including mania and cognitive functioning, for adolescents who underwent a trial of dTMS. The second aim was to examine clinical status across the course of dTMS for adolescents with TRD. We hypothesized dTMS would be safe and well-tolerated and that depression severity would significantly decrease from baseline to post-treatment, which would be sustained during follow-up, and that there would be no decline in neurocognitive performance from baseline to post-treatment.

Material and Methods

Study Design and Setting.

This study explored the safety and efficacy of six weeks of active dTMS in adolescents with TRD (ClinicalTrials.Gov NCT02611206). The study was overseen by the FDA (Investigational Device Exemption # G150132) and was approved by the Institutional Review Board at the University of Minnesota. Data were collected between 2015 and 2021. Participants completed clinical, safety, and cognitive assessments throughout treatment and were invited to return for six monthly follow-up appointments (in-person or via video) to assess their clinical status. Figure 1 shows the timing of assessments across the study. The study protocol included neuroimaging assessments conducted before and after treatment; results from those analyses will be reported separately. After the beginning of the COVID-19 pandemic, all data were collected using REDCap (Research Electronic Data Capture), a secure, web-based software platform (Harris et al., 2019, 2009).

Figure 1. Study Design and Assessments Taken at Visits.

Note. MRI=Magnetic Resonance Imaging, TMS=Transcranial Magnetic Stimulation, CDRS-R=Children’s Depression Rating Scale-Revised, BDI-II=Beck Depression Inventory, C-SSRS=Columbia Suicide Severity Rating Scale, TEPS=Temporal Experience of Pleasure Scale, IDAS=Inventory of Depression and Anxiety Symptoms, YMRS=Young Mania Rating Scale, ATR=Antidepressant Treatment Record, STAI=State-Trait Anxiety Inventory, CVLT-II=California Verbal Learning Test, D-KEFS=Delis-Kaplan Executive Function System, ANT=Attention Network Task, WASI=Wechsler Abbreviated Scale of Intelligence, PHQ-9=Patient Health Questionnaire, SEFCA=Side Effects Form for Children and Adolescents, MT=Motor Threshold

¹Kiddie Schedule for Affective Disorders and Schizophrenia, CDRS-R, BDI-II, C-SSRS, TEPS, IDAS, YMRS, ATR, Tanner Pubertal Staging Questionnaire, STAI

²CVLT-II, D-KEFS Trail Making, ANT, WASI

³BDI-II

⁴PHQ-9 at every session

⁵CDRS-R, BDI-II, C-SSRS, TEPS, SEFCA, MT, YMRS, STAI

⁶CDRS-R, BDI-II, C-SSRS, TEPS, IDAS, YMRS, STAI

⁷D-KEFS Trail Making, CVLT-II, ANT

⁸CDRS-R, BDI-II, C-SSRS, TEPS, IDAS

Participants.

Adolescents with a history of TRD were recruited through the clinical services at the University of Minnesota Medical Center, referrals from local clinicians, and community postings. Inclusion and exclusion criteria are shown in Supplementary Table S2. After an initial telephone screening, participants and their parents/guardians provided informed consent and assent.

Initial Clinical Assessment.

Participants and families underwent a semi-structured clinical interview using the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-PL) (Kaufman et al., 1997) and Children’s Depression Rating Scale-Revised (CDRS-R) (Poznanski and Mokros, 1996). History of “treatment resistance” (defined here as a failure to respond to at least one adequate trial of an antidepressant, following other work in adolescents (Brent et al., 2008; Dwyer et al., 2020)) was determined using the Antidepressant Treatment Response (ATR) form, Neuronetics, Inc., Malvern, PA (Carpenter et al., 2012; Dunner et al., 2014) and a review of any available medical records. Additionally, adolescents completed the Tanner Pubertal Staging Questionnaire (Tanner and Whitehouse, 1976). The two-subtest version of the Wechsler Abbreviated Scale of Intelligence (WASI) was administered to estimate intelligence quotient (Wechsler, 1999).

Safety and Side Effect Measures.

Participants reported treatment side effects using the Side Effects Form for Children and Adolescents (SEFCA) (Klein, 1994). Participants reported the frequency per week (0 days, 1-2 days, 3-4 days, 5-7 days) and severity (mild, moderate, severe) of 43 side effects that fall under eight broad categories (cardiovascular, gastrointestinal, central nervous system, ocular, mouth and nose, genitourinary, dermatology, and musculoskeletal). The Young Mania Rating Scale (YMRS) (Young et al., 1978) was used to assess treatment-emergent mania symptoms. To assess for potential dTMS-related changes in cognitive functioning, we administered the California Verbal Learning Test (CVLT-II) (Delis et al., 1987) (higher scores indicate better performance in learning and memory), Delis-Kaplan Executive Function System (D-KEFS) Trail Making Test (Delis et al., 2001) (shorter completion times for letter-number sequencing indicate better performance in executive function), and Attention Networks test (ANT) (Fan et al., 2005, 2002) (lower values indicate better sustained attention [alerting], attention shifting [orienting], and executive attention [conflict]; we also examined overall mean reaction time and accuracy).

Clinical Outcome Measures.

The primary outcome measure was depression severity as measured by the CDRS-R in terms of dimensional change scores and responder/non-responder status. Clinical response was determined by the following formula: [(baseline raw score - post-treatment raw score)/(baseline raw score-17)]*100 ≥ 50% (Tao et al., 2009). Secondary outcome measures included self-reported depression severity measured by the Beck Depression Inventory (BDI-II) (Osman et al., 2004), Patient Health Questionnaire (PHQ-9) (Kroenke et al., 2001), and Inventory of Depression and Anxiety Symptoms (IDAS) (Watson et al., 2007). Additional secondary outcomes included the State-Trait Anxiety Inventory (STAI) (Spielberger et al., 1971) to assess anxiety symptoms, the Temporal Experience of Pleasure Scale (TEPS) (Gard et al., 2006) to assess anhedonia, and the Columbia Suicide Severity Rating Scale (C-SSRS recent and lifetime versions) (Posner et al., 2011) to assess suicidality.

Intervention protocol.

The intervention protocol consisted of 30 sessions of dTMS across six weeks using the BrainsWay H1 coil. A trained technician administered the stimulation targeting the left DLPFC for 20 minutes/day, 5 days/week (dTMS parameters: 55 trains, 10 Hz, 3.6s train duration, 20s inter-train interval; a total of 1980 pulses/session). At the first intervention visit, the study physician determined the ideal location for stimulation and measured MT according to standard methods (Rossini et al., 2015)

As noted above, following the reported seizure in the first participant from the original protocol (Cullen et al., 2016), we decreased the frequency from 18 Hz to 10 Hz to increase safety and shifted the focus of the study to identifying a safe treatment intensity. To this end, we employed a dose-finding strategy, first testing the dTMS protocol using a lower stimulation intensity of 80% of MT. After three participants completed the protocol at this intensity with no significant adverse effects, we proceeded to the next level of 100% of MT. When three more participants had completed the protocol at this level of intensity with no significant adverse effects, we moved up to 120% for the remainder of the participants (N=8). Intervention protocol is further described in Supplemental Materials Section S1.

Statistical Analysis.

Analyses were conducted in SPSS Statistics version 28 (IBM Corp., 2021) and R version 4.0.3 (R Core Team, 2020). Paired t-tests and Wilcoxon signed-rank tests were used to identify baseline to post-treatment changes in reported frequency and severity of side effects and cognitive performance. One-way repeated measures analysis of variance (ANOVA) tests were conducted to assess changes in clinical outcomes from baseline to post-treatment. The nonparametric alternative of Friedman test was used to verify findings when distributions violated the assumptions of normality or homogeneity. Post hoc pairwise t-tests were used to compare baseline and post-treatment means with a false discovery rate correction. Following these main analyses, a series of follow-up analyses were conducted. To assess the duration of response, we used pairwise t-tests to compare primary and secondary clinical outcomes at each of the follow-up visits to both the baseline and the post-treatment visit. To identify potential individual factors that may relate to treatment response, we conducted Pearson correlations between change in depression symptoms and age as well as baseline depression severity, and compared depression change between participants who were taking medications (N=11) and those who were not (N=3). To assess the potential impact of dTMS on cortical excitability in this developing population, we conducted linear mixed models to measure change over time in the weekly MT measurements and to explore effects of other clinical and demographic variables on changes in MT.

Results

Participants.

As shown in the consort diagram (Figure 2), 15 adolescents were considered eligible for the study and proceeded to receive treatment. See Table 1 for demographics. One of these adolescents dropped out after 12 treatments. 14 participants completed all treatment sessions as well as pre and post clinical and cognitive assessments. 13 participants completed at least one follow-up visit over six months.

Figure 2. Consort Diagram.

Note. MT=Motor Threshold, TMS=Transcranial Magnetic Stimulation, SAE=Severe Adverse Event, MRI=Magnetic Resonance Imaging, CVLT-II=California Verbal Learning Test, D-KEFS=Delis-Kaplan Executive Function System, ANT=Attention Network Task

Table 1.

Baseline and Demographic Variables

Variable	Total (N=15) n (%)
Age in years, mean (SD)	16.4 (1.42)
Baseline raw CDRS-R score, mean (SD)	62.7 (12.3)
Columbia Suicide Severity Rating Scale - Lifetime, mean (SD)	3.857 (3.06)
Intelligence Quotient Score, mean (SD)	105 (13.3)
Missing	5 (33.3%)
Sex at Birth
Female	9 (60.0%)
Male	6 (40.0%)
Race
White	12 (80.0%)
American Indian or Alaska Native	1 (6.7%)
Black or African American	0 (0%)
Asian or Asian American	0 (0%)
More Than One Race	2 (13.3%)1
Ethnicity
Hispanic or Latin(o/a)/Latinx	1 (6.7%)
Not Hispanic or Latin(o/a)/Latinx	14 (93.3%)
Pubertal development stage (pubic hair)
Tanner Stage 3	1 (6.7%)
Tanner Stage 4	3 (20.0%)
Tanner Stage 5	8 (53.3%)
Missing	3 (20.0%)
Male pubertal development stage (other)
Tanner Stage 4	2 (13.3%)
Tanner Stage 5	2 (13.3%)
Missing	2 (13.3%)
Female pubertal development stage (other)
Tanner Stage 4	3 (20.0%)
Tanner Stage 5	4 (26.7%)
Missing	2 (13.3%)
Treatment-resistance: number of failed treatments2
One failed treatment	2 (13.3%)
Two failed treatments	5 (33.3%)
Three failed treatments	3 (20.0%)
Four failed treatments	3 (20.0%)
Five failed treatments	2 (13.3%)
Any medications during study	11 (73.3%)
Any antidepressant medication	10 (66.7%)
Selective serotonin reuptake inhibitor (SSRI)	7 (46.7%)
Serotonin and norepinephrine reuptake inhibitors (SNRI)	2 (13.3%)
Other antidepressant	4 (26.7%)
Any psychotropic medication (other than antidepressant)	7 (46.7%)
Antipsychotic	3 (20.0%)
Mood stabilizer	4 (26.7%)
Anxiolytic	2 (13.3%)
Stimulant	2 (13.3%)

Note. Data are n (%) of participants unless indicated otherwise. SD = Standard deviation, CDRS-R=Children’s Depression Rating Scale-Revised

¹One participant identified as Black or African American and White, and the other identified as Asian or Asian American and White.

²Based on the Antidepressant Treatment Record

Safety and Side effects.

There was no indication of treatment-induced mania during or after treatment, F(2.63, 31.57) = 0.644, p = .573. Side effects at baseline and during treatment are summarized in Table 2. Headache was the only side effect where mean frequency ratings were greater during the treatment compared to baseline (p = .0237). There were no changes in severity of side effects reported. Additionally, cognitive assessments indicate no treatment-induced impairments in learning, memory, sustained attention, shifting, or executive function (see Table 3). Overall accuracy on the ANT, however, decreased. On the other hand, CVLT-II scores in terms of total words recalled increased, and executive attention on the ANT improved.

Table 2.

Summary of Side Effects Reported on the Side Effects Form for Children and Adolescents

Side Effect	Pre-Treatment (N=15)	During Treatment1 (N=15)
Cardiovascular
Dizziness	3 (20.0%)	6 (40.0%)
Dizziness when standing up	4 (26.7%)	8 (53.3%)
Tachycardia	3 (20.0%)	2 (13.3%)
Headache	6 (40.0%)	14 (93.3%)
Other cardiovascular side effect	1 (6.7%)	3 (20.0%)
Gastrointestinal
Abdominal pain	6 (40.0%)	5 (33.3%)
Constipation	2 (13.3%)	2 (13.3%)
Diarrhea	2 (13.3%)	1 (6.7%)
Heartburn	1 (6.7%)	1 (6.7%)
Nausea	4 (26.7%)	4 (26.7%)
Vomiting	1 (6.7%)	2 (13.3%)
Other gastrointestinal side effect	0 (0%)	1 (6.7%)
Central Nervous System
Convulsions	0 (0%)	1 (6.7%)
Monotonous speech	3 (20.0%)	5 (33.3%)
Pallor	0 (0%)	1 (6.7%)
Slurred speech	0 (0%)	1 (6.7%)
Sweating	1 (6.7%)	2 (13.3%)
Tremor	1 (6.7%)	1 (6.7%)
Excitement	0 (0%)	1 (6.7%)
Outbursts of anger	3 (20.0%)	5 (33.3%)
Motor tics	0 (0%)	1 (6.7%)
Other Central Nervous System side effect	1 (6.7%)	3 (20.0%)
Mouth and nose
Dry mouth	2 (13.3%)	1 (6.7%)
Nasal congestion	1 (6.7%)	3 (20.0%)
Other mouth and nose side effect	0 (0%)	2 (13.3%)
Dermatology
Photosensitivity	0 (0%)	1 (6.7%)
Itching	2 (13.3%)	2 (13.3%)
Rash	0 (0%)	1 (6.7%)
Other dermatology side effect	1 (6.7%)	0 (0%)
Musculoskeletal
Joint aches	2 (13.3%)	4 (26.7%)
Muscular cramps	2 (13.3%)	6 (40.0%)
Other musculoskeletal side effect	1 (6.7%)	1 (6.7%)
Other side effect	0 (0%)	2 (13.3%)

Note. Data are n (%) of participants reporting each side effect at any frequency or severity. “Other” side effects reported by participants not listed in the Side Effects Form for Children and Adolescents (SEFCA) include nose bleeds, chest pain, jaw and tooth pain or soreness, weight gain, anxiety, non-suicidal self injury, dry nose, eczema, and pain in neck and shoulders. Items listed in the SEFCA that were excluded from the above table were depressive symptoms that were better represented by other validated indexes (appetite changes, sleep disturbances, sadness, depression, lethargy, irritability, difficulty in concentration, and drowsiness) and items that were not endorsed by any participants at any time (vocal tics, blurring, delayed urination, frequent urination, enuresis, fever, other ocular side effects, and other genitourinary side effects).

¹Cumulative report of symptoms reported at any timepoint between week one assessment and post-treatment assessment.

Table 3.

Means, Standard Deviations, and Analyses of Variance Results for Changes in Clinical Outcome and Cognitive Assessment Variables from Pre-Treatment to Post-Treatment

Variable	N	Mean Change in Score1 (SD)	p 2	P3 (pre and post-dTMS)	P4 (pre|post dTMS to follow-up 1)	p4 (pre|post dTMS to follow-up 2)	p4 (pre|post dTMS to follow-up 3)	p4 (pre|post dTMS to follow-up 4)	p4 (pre|post dTMS to follow-up 5)	p4 (pre|post dTMS to follow-up 6)
Clinical Outcome Variables
Depression severity
CDRS-R	14	15.57 (9.66)	<.001**	<.001**	<.001**|0.13	<.001**|0.30	.004**|0.33	.01*|0.87	.04*|0.90	.03*|0.72
BDI-II	14	10.14 (8.53)	<.001**	<.001**	.007**|0.63	.004**|0.72	.01*|0.54	.04*|0.71	.008**|0.45	.005**|0.85
PHQ-9	14	4.7 (4.89)	.004**	.003**
Anxiety
STAI: Trait	11	8.45 (8.73)	<.001**	.009**
STAI: State	11	5.91 (9.5)	.37	-
Anhedonia
TEPS	13	0.15 (13.93)	.92	-
Suicidality
C-SSRS	14	2.93 (3.17)	<.001**	<.001**	<.001**|0.97	<.001**|0.58	<.001**|0.83	.005**|0.23	<.001**|0.82	<.001**|0.85
IDAS
General depression	11	12 (13.56)	.02*	.02*	.025*|0.35	.003**|0.53	0.07|0.24	0.12|0.76	.048*|0.84	.017*|0.52
Dysphoria	11	7.36 (7.02)	.006**	.006**	.02*|0.38	.007**|0.74	0.06|0.47	0.11|0.93	.030*|0.91	.010*|0.26
Lassitude	11	4.45 (4.59)	.009**	.009**	.02*|0.93	.004**|0.65	.006**|0.82	.015*|0.84	.023*|0.69	.015*|0.37
Social anxiety	11	2.64 (2.54)	.006**	.006**	0.11|0.31	0.16|.008**	0.24|0.22	0.77|0.19	0.2|0.14	0.35|0.67
Well-being	11	−5 (6.68)	.03*	.03*	0.37|0.27	0.15|0.10	0.12|0.17	.03*|0.62	0.052|0.88	.04*|0.92
Suicidality	11	2.82 (3.74)	.03*	.03*	.045*|0.81	.04*|1	0.88|0.25	0.76|0.36	0.30|0.87	0.39|0.44
Appetite loss	11	0 (4.84)	1	-
Appetite gain	11	0.18 (1.72)	.73	-
Ill-temper	11	1.64 (4.03)	.21	-
Insomnia	11	3.09 (6.20)	.13	-
Panic	11	1.27 (2.00)	.06	-
Traumatic intrusions	11	−0.64 (3.47)	.56	-
Cognitive Assessment Variables
CVLT-II	12
Free recall total		−7.67 (11.48)	.028*	-
SD free recall		−1.08 (2.19)	.14	-
LD free recall		−1.25 (2.22)	.09	-
D-KEFS TMT	12
Switching time		−9.05 (26.3)	.30	-
ANT	10
Alerting		5.38 (27.25)	.85	-
Orienting		5.85 (40.79)	.70	-
Conflict		20.48 (26.61)	.049*	-
Mean RT		−10.42 (63.45)	.70	-
Accuracy		0.014 (0.02)	.04*	-

^*p<.05,

^**p<.01

Note. dTMS = Deep Transcranial Magnetic Stimulation, CDRS-R = Children’s Depression Rating Scale-Revised, BDI-II = Beck Depression Inventory, PHQ-9 = Patient Health Questionnaire-9, STAI = State-Trait Anxiety Inventory, TEPS = Temporal Experience of Pleasure Scale, C-SSRS = Columbia-Suicide Severity Rating Scale, IDAS = Inventory of Depression and Anxiety Symptoms, CVLT-II = California Verbal Learning Test, SD = Short Delay, LD = Long Delay, D-KEFS TMT= Delis-Kaplan Executive Function System Trail Making Test, ANT = Attention Network Task, RT = Reaction Time.

¹Change in score was calculated by subtracting post-treatment score from pre-treatment score. For clinical outcome variables, a positive value indicates an improvement in all measures except anhedonia and well-being; for anhedonia and well-being, negative change scores indicate improvement. For cognitive assessment variables, a negative value indicates improvement in performance for CVLT-II and a decrease in performance in D-KEFS. For ANT, a positive change score indicates increased performance in all areas except accuracy.

²One-way repeated measures ANOVA or Friedman tests for clinical outcome variables and paired t-tests/Wilcoxon signed-rank test for cognitive assessment measures.

³Post hoc pairwise t-tests comparing clinical outcome variables at baseline and post-treatment with a false discovery rate correction.

⁴Pairwise t-tests comparing clinical outcome variables at the follow-up visits to both the baseline and the post-treatment visit.

The participant who completed only 12 dTMS sessions experienced a convulsive syncope at the first dTMS session after receiving 13 trains at 100% of MT. The adverse event involved a loss of consciousness followed by upper arm flexion, explained by transient loss of perfusion to the brain caused by a drop in blood pressure. The staff epileptologist evaluated the patient, conducted a neurological physical exam, and noted no focal findings. To rule out potential intracranial pathology suggesting risk for seizure, an EEG was administered. The participant had no past experiences of lightheadedness nor a history of seizures and was not taking any medications. The participant decided to continue treatment after a week with a lowered stimulation intensity of 80-86%. The participant continued to report discomfort during sessions, including lightheadedness, dizziness, and anxiety. The participant ultimately discontinued the study and was given referrals to alternative treatments.

Primary Clinical Outcomes.

Out of the 14 participants who completed all dTMS sessions, six (42.86%) achieved clinical response by the end of treatment. Five of the responders received stimulation at 120% of MT, while one received 80%. CDRS-R scores significantly decreased (Percent Change: M = 39.2%, SD = 25.75%) from baseline (M = 61.79, SD = 12.26) to post-treatment (M = 46.21, SD = 18.75), F(6,78) = 11.293, p < .001 (Table 3 and Figures 3a and 3b); CDRS-R scores decreased as early as the second week of treatment (p = .008).

Figure 3. Mean Children’s Depression Rating Scale-Revised (CDRS-R) Scores with +/− 2 Standard Error Bars Across Treatment Period and Monthly Follow-Ups.

Note. A) Whole sample, B) by Stimulation Intensity and C) Between Medication and No-Medication Groups

Secondary Clinical Outcomes.

Secondary measures of depression (BDI-II, PHQ-9) and suicidality (C-SSRS recent version) also decreased from baseline to post-treatment (Table 3). We observed baseline to post-treatment decreases in IDAS subscales of general depression, dysphoria, lassitude, social anxiety, and suicidality, as well as an increase in well-being. There were no changes in the IDAS subscales of insomnia, appetite gain or loss, ill-temper, panic, and traumatic intrusions. Anxiety (STAI state) and anhedonia (TEPS) also did not change (Table 3).

Additional Analyses.

Follow-up visit data suggest that treatment gains in depression severity and suicidality were sustained: at each follow-up visit, scores on CDRS-R, BDI-II, and C-SSRS did not differ significantly from post-treatment and remained significantly lower than baseline (Table 3). With respect to individual factors related to treatment response, lower baseline depression severity correlated with greater improvement in CDRS-R scores, r(12) = −0.676, p = .0079. The degree of clinical improvement was not related to age, r(12)= −0.35, p = .214. Participants taking antidepressant or psychotropic medications (N=11) appeared to have greater and more sustained symptom improvement across treatment and follow-up periods (not statistically tested due to small group sizes) (Figure 3c). 4/6 responders and 6/8 non-responders were taking antidepressant medications (see Supplementary Table S7 for more details). Finally, there was no significant main effect of treatment week (indexing progress through dTMS treatment) on MT, F(5,65.811) = 0.769, p = .575. Additional models tested effects of clinical and demographic variables on MT across the dTMS course; there were no significant effects on MT of interactions between week × age, week × sex, week × baseline depression severity, or week × responder status. However, week × stimulation intensity (80% MT vs. 100%MT vs. 120% MT) had a significant effect on MT, F(5,58.875) = 3.628, p = .006. Additional details of MT analyses are available in Supplemental Materials Section S2 and Figure S19.

Discussion

To our knowledge, the current study is the first clinical trial examining safety and clinical effects of dTMS in adolescents with TRD. In this small sample, dTMS was tolerated by most (14 of 15) participants. Further, results suggest that dTMS (especially at the higher intensity of 120% of MT) may be effective in reducing depression symptoms with durable effects.

Safety and Side effects.

Treatment was tolerable and safe for most participants. The most common side effects were mild headaches followed by dizziness, dizziness when standing up, and muscular cramps. These patterns are similar to the literature on adults receiving dTMS and adolescents receiving TMS (Bloch et al., 2008; Levkovitz et al., 2015, 2009; MacMaster et al., 2019; Tendler et al., 2018). Although TMS-induced seizures, while rare, are a major concern and the most serious known side effect (Rossi et al., 2009), no seizures were reported in this sample. The seizure experienced by a participant in a previous version of the current study (prior to protocol changes) is described in detail in a published case report (Cullen et al., 2016). The frequency of 10 Hz in this current study (as opposed to 18 Hz in the case report (Cullen et al., 2016)) may have reduced seizure risk. One participant experienced a convulsive syncope, which is rare but more common than seizures (Epstein, 2006; Ferrulli et al., 2021; Fitzgerald and Daskalakis, 2013), with cases reported in adults (Gillick et al., 2015; Kesar et al., 2016) and adolescents (Kirton et al., 2008). Syncopal reactions are brief and without long-term consequences (Fitzgerald and Daskalakis, 2013). TMS can induce bradycardia which may lead to syncope (Rouwhorst et al., 2022). Syncopes are also often related to psychophysical discomfort and anxiety during sessions (Ferrulli et al., 2021; Rossi et al., 2009).

We found no evidence of treatment-related increases in suicidality or mania, nor was there evidence of cognitive side effects in terms of learning, memory, sustained attention, shifting, or executive function. We found evidence of a small decrease in overall accuracy on the ANT, although accuracy only decreased by 1%, and accuracy post-intervention was still high (95%). This post-intervention accuracy rate is consistent with baseline performance in another adolescent MDD sample (Sommerfeldt et al., 2016). As such, this slight change in ANT accuracy performance may be due to factors like lower task engagement related to reduced task novelty or fatigue from attending 30 TMS session visits. Results also suggest improvement in some aspects of cognitive functioning, although practice effects on the CVLT-II and ANT may account for these findings.

Clinical Outcomes.

The severity of depression symptoms was significantly reduced following dTMS in this sample, with a response rate identical to the 42% response rate observed in the active TMS group in a randomized controlled trial in adolescents with TRD (Croarkin et al., 2021) and consistent with dTMS studies in adult TRD and TMS studies in adolescent TRD (30%-70%) (Bloch et al., 2008; Feffer et al., 2017; Levkovitz et al., 2009; MacMaster et al., 2019; Tendler et al., 2018; Wall et al., 2016). The low response rate to dTMS in our study, consistent with other TMS and pharmacologic trials in TRD populations, may reflect the generally lower responses in TRD compared to treatment-naïve populations (Fekadu et al., 2009). Although participants were not assigned equally or randomly to the three stimulation intensities, higher intensity dTMS may have been more effective since 83.33% (N=5) of responders received a stimulation intensity of 120% of MT. The higher effectiveness of a 120% stimulation intensity compared to lower intensities was also documented in a dTMS study in adults (Levkovitz et al., 2009). Given that we did not find differences in side effects reported by participants across the different stimulation intensities, our data tentatively point towards dTMS at 120% of motor threshold as a potentially optimal stimulation intensity in protocols for larger studies conducted in the future. Other rTMS research, however, has shown efficacy at lower intensity treatments as well. Chen et al. (2021) found no differences in improvement in depression severity or remission status between theta burst rTMS applied at 80% vs. 120% of MT in adults with depression. Likewise, accelerated TMS has also shown large effect sizes with a stimulation intensity of 90% of MT (Cole et al., 2022). As such, greater treatment intensities may not always be more efficacious across all TMS protocols. Treatment intensity may interact with other factors that also contribute to the antidepressant effect of TMS, like depth of a brain target in an individual or frequency of TMS sessions.

Clinically significant improvements emerged as early as the end of the second week of treatment (10 dTMS sessions), with half of the responders (N=3) achieving clinical response by the end of the third week (15 sessions). This pattern is similar to TMS studies in adolescents with TRD, in which depression significantly improved after 10–15 sessions (Wall et al., 2016; Yang et al., 2014). This time frame is remarkable considering the treatment-resistant sample and is notably shorter than the 4-6 weeks it takes for standard antidepressant medications to improve symptoms (Malhi et al., 2020). Hastening treatment response by even 2-4 weeks can make a meaningful difference in MDD populations, as slow recovery from depression is associated with a higher risk for suicidal events and non-suicidal self-injury (Emslie et al., 2010; Vitiello et al., 2010, 2009; Wilkinson et al., 2011; Zubrick et al., 2017). Moreover, since anhedonia and avolition are common features of depression that can interfere with treatment engagement (Khazanov et al., 2022), faster improvements can facilitate treatment adherence.

Results suggested some symptom domains improved (general depression, sadness, dysphoria, suicidality, poor concentration), while others (anhedonia, anxiety, insomnia, appetite changes) did not. This falls in line with other work on adolescent depression indicating residual symptoms are common even in responders (Kennard et al., 2006). Since sad mood and concentration have been found to be most impairing to psychosocial functioning (Fried and Nesse, 2014), dTMS may be a promising intervention to positively impact quality of life. The improvement in suicidality is consistent with one prior adolescent TMS study (Wall et al., 2011) but not others (Bloch et al., 2008; Wall et al., 2016). Although we found no statistically significant changes in anhedonia, one of the most debilitating depressive symptoms (Fried and Nesse, 2014), anecdotal evidence from participants’ parents suggested increased activity levels, such as spending time with friends and family and engaging in pleasant activities and school work. It is possible that other modes of assessment, such as behavioral observation or parent report measures, would better detect changes in behavioral domains (Cohen et al., 2019). TMS’s antidepressant effects may also facilitate engagement in adjunctive treatments like Behavioral Activation Therapy (Webb et al., 2022) to address the remaining symptoms.

Additional Analyses.

Our exploratory analyses suggest that dTMS may be most effective for participants with less severe depression and those on antidepressant medications. Because psychotropic medications and TMS may interact (e.g., Hunter et al., 2019), the effects of medication on TMS efficacy and the mechanisms underlying potential synergistic effects to optimize treatment response should be explored in future studies. We found no effect of age on improvements in depression. Importantly, improvements in depression and suicidality were maintained at six months following the end of treatment, indicating the potential for long-lasting benefits of dTMS in adolescents with TRD, even in the absence of maintenance dTMS sessions. Long-term effects of TMS in adults and adolescents (Rapinesi et al., 2015; Wall et al., 2016) may suggest durable treatment-induced neuroplastic changes, similar to the increase in synaptic plasticity induced by high frequency (>5 Hz) TMS through long-term potentiation (LTP) (Brown et al., 2020; Huang et al., 2017; Vlachos et al., 2012). Cortical excitability, as indicated grossly by MT assessed weekly during treatment, was stable throughout the dTMS course, and MT changes did not vary by factors such as age, sex, depression severity, and responder status. However, change in MT did vary with stimulation intensity, with greater MT change in those who received 120% MT stimulation, which is particularly intriguing since this group also contained the majority of responders. This falls in line with prior work indicating that cortical connectivity and excitability changes correspond to TMS antidepressant outcomes (Eshel et al., 2020). Prospective dose-finding studies in larger samples of depressed youth, with direct measurement of DLPFC excitability via EEG (Cash et al., 2017), are needed to determine the extent to which stimulation intensity impacts neurophysiologic changes in the maturing adolescent brain and, more broadly, what stimulation parameters create optimal changes in neural circuit functioning that correspond to rapid symptom improvement.

Limitations and Future Directions.

Most importantly, the sample size was small, and the study design did not include a randomized sham control. Sham TMS control conditions are necessary to account for potential placebo effects as well as acoustic and somatosensory side effects (e.g., peripheral nerve stimulation and sounds) associated with TMS (Duecker & Sack, 2015). Ideally, TMS experimental designs should include an active TMS control condition applying stimulation to a control brain region in order to strengthen claims that results are due to stimulation of a proposed brain region. Therefore, the results must be considered preliminary, and any trends observed here require confirmation through future studies that are sufficiently powered and that employ randomized, sham-control designs to demonstrate causality. Larger samples will also be required to identify predictors (e.g., clinical symptom profiles or biomarkers) of response to dTMS and to identify treatment mechanisms that could guide clinicians in personalized treatment planning to select adolescents likely to respond to dTMS and guide clinicians’ decision-making during the treatment course (e.g., when to discontinue treatment early without risk of relapse, reducing burden and cost to the family or when to switch treatments). Larger samples are also needed, and longer follow-up periods to ascertain the duration of response or remission and to assess whether maintenance sessions may be helpful to prolong improvement.

Further research is required to address remaining questions with regard to optimizing the TMS protocol for adolescents: coil type; intensity, frequency and number of pulses per session; number of, frequency of, and interval between sessions. While the H-coil for dTMS enables stimulation of deeper brain regions, this comes with the cost of reduced focality (Deng et al., 2013; Guadagnin et al., 2015). Future studies (such as head-to-head trials) will be required to better understand which coil type may be most suitable for which adolescents with depression. Because our study design had a focus on establishing safety at different stimulation intensities (80%, 100%, and 120% of MT), we have few participants at each intensity, prohibiting formal comparative testing. Other TMS parameters require similar testing to optimize safety and efficacy in adolescents. Accelerated TMS, in particular, may be a promising approach as it has shown large antidepressant effects over a short treatment period (e.g., five days) and a stimulation intensity (90% of MT) in adults with depression (Cole et al., 2022), and it may be safe and efficacious in younger patients (Dhami et al., 2019).

Participants in this study were not instructed on what to do during their daily dTMS sessions. Due to the activity-dependent nature of LTP and plasticity changes induced by TMS, the behavior and mental state of the participant during dTMS sessions may influence how the plastic changes unfold (George et al., 2022). An important avenue may be to consider adjunctive treatment (such as cognitive training or cognitive behavioral therapy) that could be employed to harness the period of increased neuroplasticity induced by dTMS to facilitate further improvement. “On-line” TMS administered during cognitive tasks can improve performance (see (Luber and Lisanby, 2014) for a review), and TMS has been combined with cognitive training for Alzheimer’s Disease (Rabey et al., 2013).

Conclusions.

We report the first results from a prospective trial of dTMS for treatment-resistant depression in adolescents. dTMS is generally well tolerated and may be effective for most adolescents. Of the three stimulation intensities studied here, 120% of MT appeared to be the most efficacious. Although previous research shows that risks tend to increase with stimulation intensity and frequency (Rossi et al., 2009), we did not find an increase in reported side effects at 120%, suggesting this may be an appropriate treatment threshold for adolescents. While preliminary and with a small sample size, the findings are encouraging for future research on dTMS in this population.

Highlights for “Deep Transcranial Magnetic Stimulation for Adolescents with Treatment-Resistant Depression: A Preliminary Dose-Finding Study Exploring Safety and Clinical Effectiveness”.

• dTMS may be helpful for some adolescents with treatment resistant depression (TRD).

• dTMS was tolerable for most adolescents with TRD in this sample.

• Clinical improvements were observable within two weeks of treatment.

• Additional research to test efficacy and to inform parameter selection is needed.