Prolonged Grief Disorder: Unveiling Neurobiological Mechanisms for a Shared Path Forward

In the early days of the COVID-19 pandemic, amidst unforeseen losses and tragedy, a unique exhibit, “Reflections on Grief and Child Loss,” debuted in fall 2020 at President Lincoln’s Cottage. This first-of-its-kind display bridges the grief experienced by the Lincolns over their children’s deaths with that of modern bereaved families who have lost their children to illness, violence, and other tragic circumstances. The exhibit is intended to resonate with anyone navigating the profound pain of losing a loved one. Two articles that followed captured our attention: one, in the Washington Post, titled “Mary Lincoln wasn’t ‘crazy.’ She was a bereaved mother, new exhibit says,”¹ and the other, a thought-provoking piece from Smithsonian Magazine titled, “Why historians should reevaluate Mary Todd Lincoln’s oft-misunderstood grief.”² In 1862, President Abraham Lincoln and First Lady Mary Lincoln faced the sudden loss of their 11-year-old son, William, to illness. Historical depictions suggest their grief responses to this tragedy diverged sharply. Despite grieving the loss, President Lincoln immersed himself in work, issuing the Emancipation Proclamation only a few months later, and became regarded as one of the nation’s greatest presidents. In contrast, Mary Lincoln, labeled an “altered woman,” endured further traumas, including losing other children, and witnessing her husband’s assassination. Grief profoundly shaped her life, impacting her daily functioning, and eventually being deemed mentally ill and committed to a sanitarium. The historical narrative of how the Lincolns coped with their son’s loss serves as a poignant reminder of the diverse ways family members navigate grief after losing a loved one.

The current issue features an article by Prigerson et al.³ that delves into the misconceptions about Prolonged Grief Disorder (PGD), and succinctly summarizes the evidence supporting its recognition as a distinct diagnostic entity. Grief is a universal human experience with no predefined endpoint and can occur across the lifespan. Consequently, the inclusion of PGD as a psychiatric diagnosis in the American Psychiatric Association’s DSM-5-TR in 2022 sparked swift and intense discussion. Opponents argue that such diagnostic labeling pathologizes normal grief, a natural and essential process, and can lead to stigma and unwarranted medication exposure for those grieving. The DSM-5-TR’s stipulation of at least a 1-year timeframe following loss to diagnose PGD raises concerns about psychiatry imposing arbitrary timelines on normal grief and encouraging the development of novel pharmacotherapies. However, overlooked in the uproar are crucial factors. Supported by a mounting body of evidence stemming from decades of research, there exists a robust international consensus advocating for a PGD diagnostic classification. In 2018, PGD was formally listed as a diagnosis in the World Health Organization’s International Classification of Diseases, Eleventh Revision (ICD-11). There are some notable differences between the ICD-11 and DSM-5-TR criteria. Specifically, DSM-5-TR provides a stricter diagnostic criterion for PGD. Conversely, ICD-11 provides a simpler clinical guideline for PGD diagnosis, without specifying the number of required symptoms, and necessitating only a minimum of 6 months of persistent symptoms. The public health burden is clear: A small minority of bereaved people experience prolonged and debilitating grief, often lingering for years, and face substantial risks such as significant distress, declines in physical health and cognition, poor quality of life, and premature mortality, including suicide. In such cases, a PGD diagnosis holds great clinical relevance, supported by strong evidence from randomized controlled trials across the lifespan revealing that PGD responds well to targeted grief-specific psychotherapy.⁴⁻⁶ Prolonged Grief Disorder Therapy (PGDT), the most rigorously validated among them in three NIMH-funded clinical trials involving a combined 641 PGD participants aged 20−93, demonstrated over 70% effectiveness in resolving PGD symptoms compared to 44% to depression-specific interventions.⁷ In the largest of the three trials, augmenting PGDT with an antidepressant (citalopram) resulted in superior resolution of co-occurring depressive symptoms, but with no discernable difference between citalopram and placebo in PGD symptom resolution.⁵ PGDT focuses on loss- and restoration-oriented coping strategies, effectively addressing derailing symptoms of PGD, fostering acceptance of the finality of loss, restoring meaning and purpose in life, and engaging in fulfilling activities and relationships, while facilitating a continuing bond with the deceased. The effectiveness of antidepressants appears confined to alleviating distressing depressive symptoms, rather than reducing the intensity of grief. Despite this compelling evidence, skepticism toward PGD persists. In this context, the article by Prigerson et al.³ offers cautious optimism as it may initiate a dialogue aimed at setting aside differences to collectively aide those enduring intense, protracted grief and causing significant dysfunction exceeding the individual’s social, cultural, or religious norms.

Are the concerns raised about the potential for prescribing inappropriate pharmacotherapy for those experiencing PGD valid? The short answer is that it is premature to draw definitive conclusions. Nevertheless, an ongoing clinical trial, supported by the National Cancer Institute and focused on the use of naltrexone to treat PGD, has reignited this debate.⁸ The trial is based on the premise that PGD as a reward dysfunction disorder, drawing parallels to addiction, where individuals with this condition crave a connection with the deceased. Naltrexone, a treatment for alcohol use disorder, was chosen for its proposed mechanism of action through the reward pathway, with the objective of diminishing feelings of social bonding, particularly with the deceased, and mitigating yearning for them. Critics argue that this approach is misguided and potentially hazardous.⁹ They contend that maintaining the connection with the deceased, coupled with social support from living loved ones, is crucial for successful adaptation and the transition to integrated grief. These concerns merit careful consideration, call for caution, and underscore the necessity for thoughtful trial designs when testing novel or repurposed interventions for PGD. Drawing insights from historical perspectives on pharmacotherapeutic interventions in other psychiatric disorders can also be instructive. The common practice of prescribing benzodiazepines to those with post-traumatic stress disorder (PTSD) provides a relevant example. While these medications offer short-term relief from distressing symptoms (such as insomnia and anxiety) in individuals with PTSD, it is now generally agreed upon that their long-term use is relatively contraindicated due to adverse effects, including impeding recovery from this disorder and elevating risk of dependence, among others.¹⁰

We assert that embracing a biopsychosocial framework is crucial to comprehend the entire spectrum of responses to loss, from adaptive grief to PGD, and to delineate what constitutes “normal” versus “pathological.” Multiple factors before (e.g., early-life trauma, insecure attachment style, history of psychiatric disorders), during (e.g., nature of death, relationship type), or after (e.g., changes in social network structure, financial problems) bereavement can heighten the likelihood of developing PGD.¹¹ The risk may also be elevated in those bereaved who experience increased medical illness burden, disability, and cognitive dysfunction—factors that become more prevalent with advancing age. While this is the case, our understanding of the neurobiological underpinnings of the development and course of PGD is still in its early stages. Preliminary findings of aberrant neural activity in brain regions linked to reward, emotional regulation, and autobiographical memories to reminders of the deceased in acute and prolonged grief¹² await systematic validation through robust experimental designs using reliable clinical and neuroimaging tools. Furthermore, PGD often co-exists with other psychopathologies, including major depressive disorder (in 50%) and PTSD (in over 30%), resulting in heterogeneous clinical phenotypes. While intense longing or yearning for and/or preoccupation with thoughts and memories of the deceased are gateway symptoms for PGD diagnosis, a combination of associated symptoms is also necessary. A strict PGD diagnostic classification might overlook subsyndromal prolonged grief cases causing significant dysfunction. These complexities call for a transdiagnostic dimensional approach to biological research in grief, transcending boundaries and linking neurobiology with behaviors. Animal research (e.g., pair bond disruption model) mirroring some aspects of human experience of loss and adaptation can offer unique insights into molecular and cellular neural disruptions, informing future studies on the grieving brain.¹³ Integrating biological, clinical, psychological, and social components is vital for understanding grieving along a continuum from adaptive grief to PGD, and to identify those extreme cases where interventions are beneficial.

A thorough appraisal of the human biological processes involved in PGD has the potential to expedite the identification of treatment targets and the development of mechanistically informed interventions. Understanding what changes in the brain and the body during acute grief can help us to see how those biopsychosocial processes differ when loss is not integrated well, and these may serve as predictive markers for PGD, indicating the need for robust preventative interventions. While PGD responds well to PGDT, it is unlikely to be universally efficacious, accessible, or acceptable to all individuals. Therefore, establishing a repertoire of effective interventions can significantly alleviate pain and suffering in those with PGD. Psychotherapeutic, social and lifestyle interventions that have undergone pilot feasibility trials in PGD could be initial candidates for larger-scale trials.¹⁴ This is not to negate the role of targeted pharmacotherapy for PGD or advocate waiting to explore the utility of medications until we have a complete understanding of neurobiological mechanisms. In reviewing the history of treatment identification in psychiatry, waiting for full clarity on the neurobiology of mood or psychotic spectrum disorders would have hindered the identification of effective pharmacological treatments. Despite an incomplete understanding of their biological mechanisms, these interventions have significantly reduced disability and suicides in affected individuals. The complexities surrounding PGD necessitate an ongoing, healthy dialogue between advocates and critics of the diagnosis. Initiatives like the National Institute on Aging-supported Neurobiology of Grief International Network (NOGIN)¹⁵ are essential for fostering collaboration. In a recent NOGIN workshop, grief experts convened to explore common biological metrics as potential biomarkers of integrated (or adaptive) grief. As a group, we discussed difficult questions concerning both the impact that specific pharmacological compounds might have on the grieving brain and the ethical considerations of using psychopharmacological treatments for PGD, echoing the sentiments mentioned here as well as those outlined in the Prigerson et al. and Thieleman et al articles.^3,9

Undoubtedly, the perception of how Mary Todd Lincoln dealt with grief was influenced by culture, gender, race, and class. While the absence of sufficient details precludes us from diagnosing Mary Lincoln with PGD or asserting that Abraham Lincoln transitioned seamlessly to integrated grief, their responses to loss were undeniably unique. Still, in recognizing the profound grief endured by Mary Lincoln, we advocate for significant funding to research the psychosocial determinants of PGD.¹⁶ This investment, we believe, will guarantee identification of innovative psychotherapeutic and social interventions, akin to meticulously identified pharmacological treatments. PGD can be a valid and reliable diagnosis, yet it can also be impacted by structural oppression when socially and culturally relevant resources are unavailable for those acutely grieving. Effectively reducing stigma from all types of diagnosis, and not limited to PGD, demands unwavering advocacy from psychiatry and psychology, as well as from the broader public.

DATA STATEMENT

The data has not been previously presented orally or by poster at a scientific meeting.