Sean O’Sullivan, MD, PhD
March 2025
The adolescent mental health crisis remains truly dreadful. The statistics have gone from bad to worse, and calls for help are as acute as ever. Many promising approaches are being investigated and employed to address this emergency, but as a psychiatrist and neuroscientist, I am putting my eggs in the basket of neuromodulation, specifically transcranial magnetic stimulation (TMS). Though psychotherapy and pharmacotherapy have an obvious role to play in ameliorating this crisis, their limitations are evident–these options have been available for generations while the crisis worsens.
Neuromodulation, on the other hand, is relatively new. The FDA only recently cleared TMS for adolescent depression in March of 2024. This clearance has resulted in the rapid adoption and coverage by insurance companies further demonstrating the hunger for options outside of psychotherapy and pharmacotherapy. However, at the time of this writing, the FDA clearance includes only a few TMS stimulators and the protocol covered is the so-called conventional TMS protocol.
The conventional TMS protocol, which was first approved in 2008 to treat adults with treatment-resistant depression (TRD), is quite impressive. It remains the most common form of TMS to date, with response rates around 30% and remission rates around 15% in adults with TRD. Seizure, the most problematic side effect, occurs at a rate of about 1 in 60,000 sessions which is a lower-risk than most antidepressant medications. Many patients benefit from maintenance TMS at varying doses and schedules following initial treatment usually once or twice per year. A major drawback of the conventional protocol is that one treatment is given per weekday over 4-6 weeks, posing a considerable time commitment and similar treatment onset to pharmacotherapy.
A major breakthrough in the field has occurred with the emergence of personalized, accelerated, and so-called optimized TMS. The science is fascinating, but essentially TMS protocols have been improved in tolerability, safety, efficacy, convenience, and time-to-onset. Some protocols have yielded a 90% remission rate after only 5 days of treatment. In a randomized trial, the same protocol had a 66% remission rate with the trial prematurely terminated for FDA clearance. Most recently, a protocol providing only a single day of treatment boasted a 74% remission rate in an open-label trial in adults. These numbers are not unheard of in psychiatry, but have always been coupled with severe side-effects, suboptimal onset, and high cost. With TMS, most patients drive to the clinic, get treated, and drive home with little more than a few uncomfortable minutes and possibly a mild headache afterwards. Almost all of this research has occurred in adults with treatment-resistant depression.
My group at UT Austin is investigating a personalized accelerated TMS protocol for adolescent depression. This innovative study is one of the first to investigate TMS as a first-line treatment for depression. Our trial, NCT06523439, is looking to enroll adolescents aged 13-20 who have received little to no prior treatment. Participants will remain antidepressant-free and psychotherapy for about 7 weeks, and can resume standard of care following this period. Every participant will receive the active treatment which is precision-targeted based on each participant’s neural functional connectivity. That is, all participants will receive an MRI of their brain, and TMS pulses will be targeted based on each individual’s unique neural architecture. Follow-up MRIs after the 5 treatment days will be used to investigate the pathophysiology of depression to understand how TMS modulates functional connectivity.
If my hypothesis is correct, the study will show accelerated, personalized, optimized TMS can be a first-line treatment for adolescent depression, supporting the idea that adolescent depression can be managed without exposure to antidepressant medications. Pharmacotherapy, by the way, has a lower efficacy in this age group compared to adults, along with significant side effects that limit life quality such as emotional numbness, decreased libido, weight gain, and a boxed warning for increased suicidal thoughts. This study will not be definitive as there is no sham group, but it could lay the foundation for future trials. There is a paradigm shift happening in the mental health field, and I encourage anyone to reach out to our study team if interested or know of a possible participant who may benefit from this treatment.
