Transcranial Magnetic Stimulation to Treat Prolonged Grief Disorder

Prolonged Grief Disorder (PGD) is an important challenge among bereaved individuals. While the grief response following loss is typically acute, with symptoms diminishing over time, it can sometimes lead to prolonged grief disorder (PGD). PGD is characterized by persistent longing and preoccupation with the decedent, emotional pain, as well as cognitive and functional impairment that persists for more than 6 months after a loss. Prevalence rates for PGD vary; systematic reviews show pooled prevalence rates of 10% after death due to natural causes, but rising as high as 49% after death due to sudden or violent causes (e.g., suicide, homicide, mass casualty event). We found that the incidence of PGD in the COVID-19 pandemic rose to \~30% of bereaved family members, regardless of the cause of death (COVID-19 or other illness), and that the prevalence remained unchanged more than 18 months post-loss. PGD is also more common among women, people with severe pre-loss grief or depressive symptoms, those who have lost a child, and those with structural vulnerability (e.g. lower education level and income). Recently, PGD was included as a diagnostic entity in the International Classification of Diseases (ICD), and the Diagnostic and Statistical Manual of Mental Disorders (DSM).

PGD is associated with serious physical and mental health problems, including increased incidence of cardiovascular events, sleep disturbances, substance abuse, and suicidal ideation, resulting in poor overall quality of life and increased risk of mortality. Alongside the physical and psychological symptoms of bereavement, there is a concomitant increase in healthcare utilization, contributing to increased healthcare expenditure. PGD has been associated with increased emergency department visits, general hospital admissions, psychiatric hospitalizations, general practitioner, psychiatrist, and psychologist visits, as well as use of medications such as antidepressants and anxiolytics. Studies have shown that bereaved individuals have increased healthcare expenditures compared to non-bereaved controls, and widowed individuals spend 40% more on healthcare during the first 2-years post-death compared with pre-death expenditures. Moreover, bereaved individuals are less economically productive, particularly when they have PGD. In response to the accumulating evidence showing the wide-reaching consequences of PGD, several organizations (e.g., Canadian Grief Alliance, Canadian Virtual Hospice), are calling for the development and implementation of a national grief strategy to address this "hidden and urgent public health crisis."

Existing treatment options for PGD are limited. Pharmacotherapies such as antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors) are often prescribed for PGD, though their efficacy for grief-related symptoms is minimal, and time to effect and side effects (e.g., headaches, dry mouth, insomnia, flashbacks, palpitations) are barriers to uptake. Psychotherapy (including Complicated Grief Therapy) has shown moderate effectiveness in symptom reduction in a small number of trials, but issues with homogenous (e.g., primarily Western countries) and small samples and variable inclusion criteria raise questions about the generalizability of the evidence. Additionally, psychotherapy is resource-intensive and time-consuming with delayed effectiveness. There is an acute need for feasible, effective, and scalable treatment options to respond to PGD.

Repetitive Transcranial Magnetic Stimulation (rTMS) may be a feasible and efficacious treatment for PGD. rTMS is a safe, tolerable, and non-invasive brain stimulation technique approved by Health Canada in 2002 for the treatment of major depression, post-traumatic stress disorder (PTSD), and other mood and anxiety disorders. Using an inductor coil placed against the scalp, rTMS employs powerful, focused magnetic pulses to induce an electrical current that depolarizes the underlying neuronal tissue and causes action potentials which, depending on the stimulation parameters (high-frequency vs. low-frequency), increase or decrease cortical excitability. When administered repetitively, TMS can cause long-term neuromodulation and subsequent therapeutic benefit.

rTMS is effective for treating post-traumatic stress disorder (PTSD). To date, over 15 studies (10 RCTs) have demonstrated safety, tolerability, efficacy, and durability for treating PTSD with high- and low-frequency rTMS stimulation at different sites (e.g., right dorsolateral prefrontal cortex (DLPFC), left DLPFC, and medial prefrontal cortex).Notably, one open-label case series reported \>50% improvement in PTSD symptoms in 57% of patients following rTMS to the dorsomedial prefrontal cortex. However, rTMS has never been evaluated for the treatment of PGD. Clinically, experiences associated with PGD (i.e., trauma associated with the dying and grief experience) and its symptoms are similar to PTSD, with several overlapping characteristics (e.g., intrusive thoughts or images, avoidance, emotional numbness), raising the question of whether rTMS may be efficacious for treating PGD too.

Objective:

To determine if accelerated rTMS is a safe and feasible treatment for PGD among bereaved individuals. The secondary objective is to examine the preliminary efficacy of accelerated rTMS for treatment of PGD.

Sample Size:

As the main objective of this study is to demonstrate safety and feasibility, no formal sample size calculation was performed. The goal of this study is to provide estimates, along with margins of error, of the enrollment rate and efficacy outcomes to inform a subsequent sham-controlled clinical trial.

Statistical Analysis:

Analysis of safety and feasibility outcomes will be descriptive, with point estimates and 95% confidence intervals. The efficacy analysis will follow an intent-to-treat approach. We will compare the proportion of participants with a minimal clinically important difference in secondary efficacy outcomes at 2-week follow-up.

Details of Eligibility, Intervention Protocol, and Outcome Measures are provided elsewhere.

• Prolonged Grief Disorder - Global Impression of Change [Time frame: Day 5 (last day of intervention), 2-week follow-up, 4-week follow-up, and monthly thereafter for up to 6 months]
• Change in Prolonged Grief [Time frame: Baseline, day 5 (last day of intervention), 2-week follow-up, 4-week follow-up, and monthly thereafter for up to 6 months]
• Prolonged Grief - Change in Post-Traumatic Stress [Time frame: Baseline, day 5 (last day of intervention), 2-week follow-up, 4-week follow-up, and monthly thereafter for up to 6 months]
• Prolonged Grief - Change in Depression [Time frame: Baseline, day 5 (last day of intervention), 2-week follow-up, 4-week follow-up, and monthly thereafter for up to 6 months]
• Prolonged Grief - Change in Work and Social Functioning [Time frame: Baseline, day 5 (last day of intervention), 2-week follow-up, 4-week follow-up, and monthly thereafter for up to 6 months]