Accelerated rTMS for existential distress in palliative care: A report of two cases

Psychological suffering is common among patients with terminal illness; up to 30% of patients with cancer meet criteria for clinically significant depression or anxiety [[1]Mitchell A.J. Chan M. Bhatti H. et al.Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview based studies.Lancet Oncol. 2011; 12: 160-174Abstract Full Text Full Text PDF PubMed Scopus (1240) Google Scholar]. As underlying illness progressively impairs function, patients often express a debilitating loss of autonomy, increased anxiety and depression, and a lack of meaning and purpose in life. Taken together, these symptoms are sometimes described as “existential distress” and are associated with decreased quality of life and increased desire for hastened death [[2]Bauereiss N. Obermaier S. Ozunal S.E. Baumeister H. Effects of existential interventions on spiritual, psychological, and physical well-being in adult patients with cancer: systematic review and meta-analysis of randomized controlled trials.Psycho Oncol. 2018; 27: 2531-2545Crossref PubMed Scopus (31) Google Scholar]. Palliative care providers aim to reduce suffering and improve quality of life among patients with terminal illness. Despite existential distress being reported in up to 19% of patients with cancer nearing end of life [[3]Bovero A. Sedghi N.A. Opezzo M. et al.Dignity-related existential distress in end-of-life cancer patients: prevalence, underlying factors, and associated coping strategies.Psycho Oncol. 2018; 27: 2631-2637Crossref PubMed Scopus (17) Google Scholar], few options exist to treat this condition. Studies of pharmacological therapies, including anxiolytics and antidepressants, have shown inconsistent results [[4]Rodin G. Lloyd N. Katz M. et al.The treatment of depression in cancer patients: a systematic review.Support Care Cancer. 2007; 15: 123-136Crossref PubMed Scopus (157) Google Scholar]. Patients with terminal illness are also at increased risk of drug interactions and side effects such as delirium. Psychotherapeutic approaches have shown limited efficacy [[5]Chochinov H.M. Kristjanson L.J. Breitbart W. et al.Effect of dignity therapy on distress and end-of- life experience in terminally ill patients: a randomised controlled trial.Lancet Oncol. 2011; 12: 753-762Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar] and may be too resource-intensive for widespread use. Repetitive transcranial magnetic stimulation (rTMS) is a safe and well-tolerated treatment indicated for major depression and shows promise in other mood disorders where medication has been ineffective [[6]Lefaucheur J.P. Aleman A. Baeken C. et al.Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018).Clin Neurophysiol. 2020; 131: 474-528Crossref PubMed Scopus (278) Google Scholar]. Recent reports using accelerated regimens of up to 10× daily stimulation have achieved full therapeutic effect in as little as 5 days, even in severely ill patients [7Cole E.J. Phillips A.L. Bentzley B.S. et al.Stanford neuromodulation therapy (SNT): a double-blind randomized controlled trial.Am J Psychiatr. 2021; ([Online ahead of print])https://doi.org/10.1176/appi.ajp.2021.20101429Crossref PubMed Google Scholar, 8Konstantinou G.N. Trevisol A.P. Goldbloom D. et al.Successful treatment of depression with psychotic features using accelerated intermittent theta burst stimulation.J Affect Disord. 2021 Jan 15; 279: 17-19Crossref PubMed Scopus (2) Google Scholar]. Such observations raise the question of whether accelerated rTMS might benefit patients with terminal illness and limited life expectancy. Here we offer what is, to our knowledge, the first report on the use of accelerated rTMS for severe existential distress in the palliative care setting. The use of rTMS in these cases is part of an ongoing prospective, open-label study examining the role of accelerated rTMS for psychological distress and existential suffering in an inpatient palliative care unit (Clinicaltrials.gov identifier: NCT04257227) and has been approved by the Bruyère Research Ethics Board (#M16-19-035) and Ottawa Health Science Network Research Ethics Board (#20200017-01). Given the degree and rapidity of the symptomatic improvement in these cases (the first two to complete the protocol), we chose to publish this report. Although both had consented to have their results published as part of the study, we obtained expressed consent from the patient or next of kin in both cases to report their de-identified data in this manuscript, in accordance with the recommendation of our Research Ethics Board. Patient A was a 73-year-old man with advanced lung cancer, anemia, and a remote history of heart transplant for ischemic heart disease. His medical comorbidities were optimized, and his anti-rejection medication (cyclosporin) was at a stable therapeutic level. On admission to the palliative care unit, his most notable symptoms were low mood and demoralization, which he attributed to social isolation and a lack of control over his illness. Other physical symptoms were controlled. We assessed mood using the 17-item Hamilton Depression Rating Scale (HDRS) [[9]Hamilton M. Development of a rating scale for primary depressive illness.Br J Soc Clin Psychol. 1967; 6: 278-296Crossref PubMed Google Scholar] and the Hospital Anxiety and Depression Scale (HADS) [[10]Zigmond A.S. Snaith R.P. The hospital anxiety and depression scale.Acta Psychiatr Scand. 1983; 67: 261-370Crossref Scopus (28640) Google Scholar] (Fig. 1). Despite modest baseline scores, Patient A reported severe existential distress, frequent episodes of crying, overwhelming despair and low quality of life. Patient B is a 54-year-old man with metastatic rectal cancer and a history of anxiety. He was followed by community palliative care for abdominal pain. However, during assessments he was noted to have significant existential distress and anxiety which was worsened by social isolation and other stressors. He felt a loss of control related to his illness which often manifested as panic attacks. He was admitted to the palliative care unit for consideration of rTMS. Other physical symptoms, including pain, were controlled. At the time of admission, his baseline HDRS and HADS scores were indicative of depression and anxiety. After thorough discussion of treatment options, including medication augmentation and supportive care, each patient consented to a trial of palliative accelerated rTMS. The treatment regimen was adapted from the recently published SAINT/SNT protocol [[8]Konstantinou G.N. Trevisol A.P. Goldbloom D. et al.Successful treatment of depression with psychotic features using accelerated intermittent theta burst stimulation.J Affect Disord. 2021 Jan 15; 279: 17-19Crossref PubMed Scopus (2) Google Scholar], and comprised a 5-day course of 8 sessions per day delivered at 45-min intervals, 600 pulses of intermittent theta-burst stimulation per 3-min session, at 80% of resting motor threshold, targeting the left dorsolateral prefrontal cortex (BeamF3 technique) using a MagStim Rapid2 device equipped with a D70 figure-8 coil. Importantly, there were no changes to medications which could have impacted symptoms during the treatment course or follow up period (including changes to opioids, corticosteroids, antidepressants, anxiolytics, or medications for medical comorbidities). No serious adverse effects from treatment were reported or observed. Both Patient A and Patient B exhibited marked improvement in depression, and anxiety symptoms over the 5-day treatment course (Fig. 1). With respect to symptoms of existential distress, Patient A reported full resolution of feelings of despair, showing no further crying episodes, markedly increased sociability, and goal-oriented behavior. Patient B demonstrated marked reduction in panic attack symptoms, improved motivation and appetite and reported a renewed sense of control in his life. Despite the continuing presence of end-stage terminal illness and its physical and psychological sequelae in the weeks after treatment, both patients continued to have excellent control of symptoms enduring post-treatment. Clinical care teams noted increased social engagement, and patients and families reported that rTMS had major positive impacts on quality of life. Two days prior to the 28-day follow up, Patient A developed worsening anemia related to his disease. This led to physical symptoms including fatigue and cognitive deterioration. At this time, an increase in HDRS and HADS scores were noted. The patient then experienced a rapid decline in consciousness and died peacefully the following day. Patient B was also noted to have mild increase in HDRS and HADS scores at 28-day follow-up. He attributed this to worsening physical pain and financial stressors. However, both he and his palliative care team maintained that his symptoms of existential distress were substantially improved, and he felt rTMS was extremely beneficial. Of note, while patients did not have formal assessment of HDRS/HADS between 14 and 28 days, clinical teams continued to perform regular informal symptom assessments and felt the effect of rTMS was largely sustained. To our knowledge, this is the first report of the effect of rTMS on psychological suffering in the palliative care population and the first using existential distress as an indication for treatment. We found that symptom control was achieved in a safe and timely manner using an accelerated rTMS protocol; an important consideration in patients with a short prognosis where the time to effect may limit treatment options [[4]Rodin G. Lloyd N. Katz M. et al.The treatment of depression in cancer patients: a systematic review.Support Care Cancer. 2007; 15: 123-136Crossref PubMed Scopus (157) Google Scholar]. Regarding limitations, this report did not specifically employ a validated tool for measuring existential distress as distinguished from standard symptoms of depression/anxiety. The profound and rapid effects of the intervention in relieving despair and psychological suffering were readily apparent to the patients, families, and care teams, yet were incompletely captured by the HDRS/HADS(A) total scores. Future work should therefore employ validated measures of both existential distress (when available) and quality of life. Finally, we do not have data beyond a 28-day follow up. Although this timeframe is still meaningful in the palliative context, we cannot exclude the possibility that this accelerated intervention has limited durability. Our future work will look to determine whether accelerated rTMS could offer rapid, potent and durable benefits to quality of life for patients facing limited life expectancy and profound existential distress in the setting of end-stage terminal illness. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Jonathan Downar has received research support from the Arrell Family Foundation, the Buchan Family Foundation, Brain Canada, the Canadian Biomarker Integration Network in Depression, the Canadian Institutes of Health Research (CIHR), the Klarman Family Foundation, NIH, the Ontario Brain Institute, the Toronto General and Western Hospital Foundation, and the Weston Family Foundation; his lab has received in-kind equipment support for investigator-initiated trials from MagVenture; he has served as an advisor for BrainCheck, Restorative Brain Clinics, and TMS Neuro Solutions. All other authors have no conflicts of interest to declare. This research is funded by the Canadian Cancer Society (grant # 706313 ), generously supported by the Lotte and John Hecht Memorial Foundation . The authors would like to acknowledge Yekta Ansari for providing rTMS to the patients in this report.

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