Systematic Reviews
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatry. Jan 19, 2022; 12(1): 151-168
Published online Jan 19, 2022. doi: 10.5498/wjp.v12.i1.151
Neurobiological mechanisms underlying delayed expression of posttraumatic stress disorder: A scoping review
Geert E Smid, Jonna Lind, Jens Peter Bonde
Geert E Smid, ARQ Centrum'45, ARQ National Psychotrauma Centre, Diemen 1112XE, Netherlands
Geert E Smid, Department of Humanist Chaplaincy Studies, University of Humanistic Studies, Utrecht 3512 HD, Netherlands
Jonna Lind, ARQ Centre of Excellence on War, Persecution and Violence, ARQ National Psychotrauma Centre, Diemen 1112XE, Netherlands
Jens Peter Bonde, Department of Occupational and Environmental Medicine, Frederiksberg and Bispebjerg Hospital, Copenhagen 2400, Denmark
Jens Peter Bonde, Department of Public Health, University of Copenhagen, Copenhagen 1014, Denmark
Author contributions: Smid G wrote the first draft of the manuscript; Smid G and Lind J searched and selected the literature; Smid G and Bonde JP conceived the study; all authors contributed to the manuscript revision and read and approved the submitted version.
Supported by the Danish Working Environment Research Fund from Arbejdsmiljøforskningsfonden (to Bonde JP).
Conflict-of-interest statement: The authors report no conflicts of interest.
PRISMA 2009 Checklist statement: The authors have read the PRISMA Scoping Review Checklist, and the manuscript was prepared and revised according to the PRISMA Scoping Review Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Geert E Smid, MD, PhD, Professor, ARQ Centrum'45, ARQ National Psychotrauma Centre, Nienoord 5, Diemen 1112XE, Netherlands.
Received: March 30, 2021
Peer-review started: March 30, 2021
First decision: July 15, 2021
Revised: July 30, 2021
Accepted: November 25, 2021
Article in press: November 25, 2021
Published online: January 19, 2022
Research background

Posttraumatic stress disorder (PTSD) with delayed expression occurs in people who develop PTSD at least six mo following exposure to a potentially traumatic event. During the prodromal phase or delay interval between the traumatic event and the onset of the disorder, subthreshold symptoms are often present, although long delay intervals without prodromal symptoms have rarely been reported. This study reviews neurobiological mechanisms underpinning the occurrence of a prodromal phase with or without prodromal symptoms.

Research motivation

Delayed expression of PTSD may present diagnostic challenges in clinical settings as well as in litigation contexts. Insight in neurobiological mechanisms is crucial to optimize diagnostic assessment and management.

Research objectives

To identify and characterize neurobiological mechanisms and pathways underlying delayed expression of PTSD and to obtain an overview of types of supporting evidence.

Research methods

We performed a scoping review of neurobiological studies in humans and animals and reviews of such studies. Records were eligible if they reported about studies on trauma and PTSD, delayed onset, neurobiology, and causal mechanisms or risk factors.

Research results

Following the search and selection, 38 studies were included in the review. Neural, neuroendocrine, and neuroinflammatory mechanisms have been implicated in progressive PTSD symptom expression over time. Neurobehavioral and contextual pathways complement these mechanisms.

Research conclusions

A variety of interconnected systems underlies the heterogeneity in PTSD symptom expression over time, contributing to sensitization, kindling, and generalization.

Research perspectives

Delayed expression of trauma- and stressor-related disorders requires careful individual assessment of the trauma history, intervening stressors, and development of symptoms. Assessment of a history of TBI is mandatory in help-seeking, trauma-exposed individuals, specifically in soldiers and veterans, as this may be associated with symptom progression over time. Efforts to avert foreseeable stressors and resource losses may contribute to secondary prevention of psychological distress. Future research should explore the preventive potential of normalizing immune reactivity by pharmacological means.