Transcranial Magnetic Stimulation for Psychological Distress in Patients With Advanced Illness: A Phase 2a/2b Dose-finding and Feasibility Clinical Trial

Patients with advanced illness commonly experience symptoms of depression, anxiety, loss of autonomy, hopelessness, and diminished meaning and purpose. Often referred to as existential distress, these symptoms are associated with poor outcomes, including reduced medication adherence, lower quality of life, increased desire for hastened death, and suicide risk. Affecting up to 19% of patients with advanced cancer, existential distress is also a leading reason individuals pursue medical assistance in dying (MAiD), underscoring its impact at the end of life.

Treatment options for existential distress in palliative care (PC) are limited. Antidepressants and anxiolytics have modest evidence of benefit, may take weeks to work, and can cause adverse effects such as falls and confusion. Psychotherapeutic interventions have also shown limited efficacy in randomized trials and are often too time consuming for patients with limited life expectancy. Given the prevalence and consequences of existential distress, there is an urgent need for brief, scalable, and rapidly effective interventions for patients receiving PC.

Repetitive Transcranial Magnetic Stimulation (rTMS) is a Health-Canada- and FDA-approved safe and non-invasive brain stimulation intervention used to treat major depression, post-traumatic stress disorder, and other mood and anxiety disorders where medication has been ineffective. The technique uses trains of powerful, focused magnetic pulses, applied via a handheld inductor placed against the scalp, to induce changes in the activity of frontal lobe circuits responsible for regulating cognition and emotion. The most common stimulation protocols target the dorsolateral prefrontal cortex (DLPFC), using high-frequency (10-20 Hz) to the left DLPFC or low-frequency (1 Hz) to the right DLPFC, or both. With therapeutic rTMS, multiple sessions of treatment are delivered daily over 20-30 visits, to achieve durable symptomatic improvements. Clinical studies have shown rTMS can achieve a response (>50% symptom reduction) in half of patients and sustained remission rates in approximately 1/3 of patients whose depression has been refractory to 2 or more medications.

rTMS is generally well-tolerated with very few complications; about 95% of patients are able to complete a full course of treatment. However, there are obvious barriers to using traditional rTMS in the terminal population. First, the need to come to an rTMS clinic for a 60-minute session daily for 4-6 weeks is too great a time commitment for most patients nearing the end-of-life. Second, rTMS was only recently approved for public funding in many Canadian provinces, limiting the availability of rTMS to research settings and private clinics until now. Third, rTMS devices have been historically costly and difficult to transport, making it unfeasible for inpatient PC facilities to purchase an rTMS device or share one with a psychiatric clinic nearby. All of these factors have changed in the past couple years. New protocols of patterned rTMS have shortened treatment sessions yet preserve efficacy. Other "accelerated rTMS" protocols have given up to 10 sessions per day and shown symptom remission in just 2-5 days. The cost of these devices has also decreased dramatically in recent years (~$25,000 CAN), while the portability and availability have also improved, to the point that it is now feasible to use them in palliative settings.

The current body of literature presented above has studied the effectiveness of rTMS in patients with treatment-refractory depression and other mental illness. Essentially, the current treatment protocols have been designed to be effective in populations who are the most difficult to treat clinically. As such, there is no evidence as to whether or not patients with clinically less severe psychological distress (depression and anxiety), would require the same intensity and duration of treatment to achieve a clinically relevant therapeutic effect.