Neurobiology and treatment advances for prolonged grief disorder

Prolonged Grief Disorder (PGD) is a recently identified bereavement outcome added to DSM-5-TR in 2022. Loss of someone close is a major stressor, and ~7–10% of bereaved individuals develop PGD [1]. Core symptoms include intense, persistent yearning or preoccupation with the deceased, accompanied by at least 3 of 8 associated symptoms. PGD extends the period of acute grief, impairs functioning, and increases risk for a wide range of negative health outcomes.

The announcement of the new DSM disorder along with increased pandemic deaths has brought public awareness and need for PGD treatments. Targeted psychotherapy using psychological exercises to facilitate acceptance, promote the capacity to thrive, and address impediments to these processes is efficacious and widely used. However, no treatment works for everyone, and there remains a paucity of effective pharmacological interventions. The only randomized pharmacotherapy trial did not find an effect of the SSRI, citalopram [2]. Thus, elucidating biological underpinnings of interpersonal loss can help refine existing treatments and develop efficacious somatic interventions.

Existing research in humans and a handful of studies using animal models indicate remarkably consistent loss-induced disruptions of physiology and behavior across species [3, 4]. For example, loss results in increased HPA axis activity, elevated anxiety levels, impaired parasympathetic regulation, reduced pain thresholds, and sleep disruption (Fig. 1A). This consistency in findings supports the face and construct validity of using bond disruption in non-human animals for studying the molecular and cellular bases of loss. However, few studies to date focus on yearning, the core feature of grief that is central to differentiating PGD from PTSD, depression, and other diagnoses.

Fig. 1. Advances in modeling loss and elucidating the neurobiology of prolonged grief disorder.

A Recent advances in animal models for studying loss highlight consistency in loss-induced physiological and mental phenotypes. B Neuroimaging and other studies indicate that PGD results from a stalling of loss adaptation. For instance, individuals with PGD do not experience an adaptive reduction in yearning and continue to show strong nucleus accumbens BOLD signal upon reminders of the lost loved one. C Bond disruption in monogamous prairie voles provides an opportunity to study loss and adaptation. Prolonged partner separation in this species leads to erosion of pair bond transcriptional signatures in the nucleus accumbens, suggesting that remodeling of reward systems may be required for successful adaptation and the ability to form a new pair bond.

Yearning is a response evoked by loss of an important source of motivation and reward. It is typically strong in the early period of bereavement and diminishes as a bereaved person understands and accepts the finality of their loss, restoring their capacity to thrive. But yearning remains persistent and intense in PGD (Fig. 1B). In human neuroimaging studies, yearning in PGD is associated with enhanced nucleus accumbens BOLD signal when viewing images of the lost loved one; bereaved individuals without PGD show significantly less NAc activity to reminders of the loss [5]. In monogamous prairie voles, pair bonding leads to persistent transcriptional changes in the nucleus accumbens, and erosion of this bond-induced transcription occurs as they adapt to the loss of their partner (Fig. 1C) [6]. Together, these data support a model in which remodeling of reward processes is required to treat PGD, with remodeling acting in a top-down fashion to ameliorate other negative physiological and behavioral effects of loss.

Thus, a promising avenue for treatment development entails identifying molecular and neuronal processes that mediate adaptive reward remodeling. Such work will provide insights that could be used to develop methods for enhancing adaptive processes in patients with PGD and/or ways to assess intervention outcomes. Preclinical research, guided by a reward-driven model of loss, will be instrumental for refining this and other current treatments and for developing and testing new behavioral and somatic interventions that can facilitate this transition.

Author contributions

ZRD and MKS wrote the paper and prepared the figure. Julie Sadino is also acknowledged for contributing to figure conceptualization and generation.

Funding

ZRD is supported by NIH U01NS122124, DP2MH119427, R01MH125423, and NSF IOS-2045348.

Competing interests

The authors declare no competing interests.