Evaluation of the H1-Coil TMS- Double Blind Placebo Controlled Study in Adolescent Patients Suffering From Major Depression.

Adolescent depression is a severe disorder affecting 5-8% of adolescents. It is a major risk factor for adolescent suicide-one of the 3 most common reasons for death in this age group. It carries with it a heavy burden of harsh comorbidities such as substance abuse, and behavioral problems[1, 2].

The first line treatment of moderate or severe illness includes pharmacotherapy with serotonin reuptake inhibitors (SSRIs) such as fluoxetine, in combination with psychotherapy. However, more than 30% of the patients do not achieve remission (defined as minimal or no symptoms) despite treatment with a combined intervention [3]. In adolescents there is some evidence that as a second line, switching to another SSRI combined with cognitive behavioral therapy (CBT) can be useful [4]. There is no evidence to what should be the third line in therapy. Early intervention in the course of a disease is expected to protect from the grave long term sequelae[9], but in treating adolescent depression our therapeutic tools are extremely limited[10].

There is a necessity to advance our evidence based interventions to treat treatments resistant adolescent depression.

Hypoactivity in the left dorsolateral prefrontal cortex (DLPC) is a key finding in brain imaging of depression[11]. Repetitive transcranial magnetic stimulation (rTMS) is a therapeutic procedure in which a magnetic coil that generates recurrent pulsatile magnetic fields from a rapidly oscillating electrical current is placed on the scalp, to induce recurrent electrical currents in the brain. High frequency rTMS causes activation of the affected brain regions and networks. This is the suggested mechanism of the antidepressant effect of high frequency rTMS to the left DLPC in depression[12]. Recent advances in custom coil technology led to the development of H coils that support stimulation of deeper, limbic structures[13]. Due to the accumulating knowledge on safety and efficacy in adult depression both the custom rTMS and the "deep" H coil TMS are approved (FDA and Israeli ministry of health), for clinical (not just research) use [12, 14-16]. In a large multicenter study of the H1 coil to treat adult depression there were minimal side effects and a large effect size of 0.78 was reported, strengthening the promise of this mode of therapy [5].

The field of brain stimulation and specifically TMS is based on the concept of neuroplasticity, the ability of repeated stimulations to cause a longer lasting neuronal change. In this respect the adolescent developing brain is a period of opportunity for such changes[17, 18] To date, there are no randomized placebo controlled studies on rTMS to treat adolescents suffering from depression, although reports support the safety of rTMS in treating adolescents. Recently, there was a report of a self-limited convulsion in an adolescent treated with deep rTMS at 120% motor threshold-strengthening the necessity for well-structured studies in the field[23].