Transcranial Magnetic Stimulation to Treat Prolonged Grief Disorder

April 29, 2025 updated by: James Downar, Bruyere Research Institute

Transcranial Magnetic Stimulation to Treat Prolonged Grief Disorder: A Single-centre, Single-arm, Open-label Phase I/II Proof-of-concept and Feasibility Clinical Trial

Grief is a normal response after the death of a loved one. With time, the grief response decreases and people learn to cope with their loss. However, for some, the response becomes more intense and distressing. This is called prolonged grief disorder (PGD). People with PGD experience emotional pain and a deep longing for their loved one. PGD normally occurs <10% of people after a loss, but it has become more common since the COVID-19 pandemic (~30%). If left untreated, PGD leads to poor quality of life and increased risk of death. Treatment options such as medication and therapy are available; however, they can cause negative side effects and take a long time to work. To help individuals with PGD, we need treatments that work well and quickly.

Repetitive transcranial magnetic stimulation (rTMS) is a safe, non-invasive treatment that delivers magnetic pulses to brain areas responsible for mood. rTMS has been approved in Canada to treat mood disorders. There is research to show that rTMS is safe and well-tolerated, and that works well in treating Post-Traumatic Stress Disorder (PTSD), a condition with similar symptoms to PGD. To determine whether rTMS is effective for treating PGD, we first need to determine if rTMS as a treatment for PGD is safe and feasible among grieving individuals.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

15

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: James Downar, MDCM, MHSc
  • Phone Number: 1502 613-562-6262
  • Email: jdownar@toh.ca

Study Contact Backup

Study Locations

  • Canada
    • Ontario
      • Ottawa, Ontario, Canada, K1R 7A5
        • Bruyere Health
        • Contact:
          • James Downar, MDCM, MHSc
          • Phone Number: 1502 613-562-6262
          • Email: jdownar@toh.ca
        • Contact:
        • Principal Investigator:
          • James Downar, MDCM, MHSc

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Bereaved individuals >/= 18 years of age
  2. Score >25 on the Inventory of Complicated Grief
  3. Must have a primary care physician
  4. Ability to understand and communicate in English
  5. Ability to provide first-person informed consent

Exclusion Criteria:

  1. Current or previously diagnosed seizure disorder
  2. Documented brain lesions
  3. Contraindications to TMS (i.e., metallic skull plates, clips, stimulators, pacemakers)
  4. Current substance abuse disorder (e.g., schizophrenia)
  5. Pregnancy or lactation, or trying to conceive
  6. Advanced, incurable illness with an expected prognosis of <3 months - bereaved family members are known to be at elevated risk of death from medical illness, but if death is expected in the near future, it would be difficult to justify using an entire week of their limited time for an unproven therapy.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: rTMS Intervention
Device: Repetitive Transcranial Magnetic Stimulation (rTMS)

Eight rTMS sessions will be administer per day at 60-minute intervals for 5 consecutive days.

Each rTMS session will consist of 600 pulses of theta-burst stimulation (iTBS), a pattern of 3 TMS pulses every 200 milliseconds for 2 seconds (i.e., 3 x 50 Hz bursts repeated at 5 Hz) for 3 minutes at 100% of resting motor threshold. The left dorsomedial prefrontal cortex (DMPFC) will be targeted via the Fz EEG site (30% of the nasion-inion distance posteriorly along the nasion-inion line).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Recruitment Rate
Time Frame: Through study completion, up to 9 months
Number of individuals recruited divided by the recruitment period
Through study completion, up to 9 months
Enrollment Rate
Time Frame: Through study completion, up to 9 months
Number of individuals enrolled divided by the number of individuals approached
Through study completion, up to 9 months
Intervention Completion Rate
Time Frame: Through study completion, up to 10 months
Number of participants who complete the intervention divided by the number of participants enrolled
Through study completion, up to 10 months
Withdrawal Rate
Time Frame: Through study completion, up to 16 months
Number of participants who withdrew divided by the number of participants enrolled
Through study completion, up to 16 months
Follow-up Completion Rate
Time Frame: Through study completion, up to 16 months
Number of participants who complete follow-up divided by the number of participants enrolled
Through study completion, up to 16 months
Number of Participants with Adverse Events
Time Frame: Through intervention completion, up to 1 week
Proportion of participants who experience an adverse event
Through intervention completion, up to 1 week

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Measured using the Patient Global Impression of Change (PGIC) scale (score 1-7 on one item; higher scores indicate greater positive change)
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
Measured using the Inventory of Complicated Grief (ICG) (score 0-4 on each item; score of 26 or less or a score reduction of greater than or equal to 4 indicates therapeutic benefits)
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
Measured using the Impact of Event Scale-Revised (IES-R) (score 0-4 on each item; score reduction of 4 indicates therapeutic benefit; score greater than 33 will be considered positive for PTSD)
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
Measured using the Hamilton Depression Rating Scale (HDRS) (score 0-4 on each item; score reduction of 2 from baseline indicates therapeutic benefit)
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
Measured using the Work and Social Adjustment Scale (WSAS) (score of 0-8 on each item; point difference of greater than or equal to 8 indicates therapeutic benefit)
Baseline, day 5 (last day of intervention), 2-week follow-up, 4-week follow-up, and monthly thereafter for up to 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Bruyere Research Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

July 1, 2025

Primary Completion (Estimated)

March 31, 2026

Study Completion (Estimated)

April 30, 2026

Study Registration Dates

First Submitted

April 22, 2025

First Submitted That Met QC Criteria

April 29, 2025

First Posted (Actual)

May 1, 2025

Study Record Updates

Last Update Posted (Actual)

May 1, 2025

Last Update Submitted That Met QC Criteria

April 29, 2025

Last Verified

April 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 23732836368

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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