research paper on traumatic stress disorder

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• Published: 28 September 2018

Posttraumatic stress disorder: from diagnosis to prevention

• Xue-Rong Miao   ORCID: orcid.org/0000-0002-0665-8271 1 ,
• Qian-Bo Chen 1 ,
• Kai Wei 1 ,
• Kun-Ming Tao 1 &
• Zhi-Jie Lu 1  

Military Medical Research volume  5 , Article number:  32 ( 2018 ) Cite this article

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Posttraumatic stress disorder (PTSD) is a chronic impairment disorder that occurs after exposure to traumatic events. This disorder can result in a disturbance to individual and family functioning, causing significant medical, financial, and social problems. This study is a selective review of literature aiming to provide a general outlook of the current understanding of PTSD. There are several diagnostic guidelines for PTSD, with the most recent editions of the DSM-5 and ICD-11 being best accepted. Generally, PTSD is diagnosed according to several clusters of symptoms occurring after exposure to extreme stressors. Its pathogenesis is multifactorial, including the activation of the hypothalamic–pituitary–adrenal (HPA) axis, immune response, or even genetic discrepancy. The morphological alternation of subcortical brain structures may also correlate with PTSD symptoms. Prevention and treatment methods for PTSD vary from psychological interventions to pharmacological medications. Overall, the findings of pertinent studies are difficult to generalize because of heterogeneous patient groups, different traumatic events, diagnostic criteria, and study designs. Future investigations are needed to determine which guideline or inspection method is the best for early diagnosis and which strategies might prevent the development of PTSD.

Posttraumatic stress disorder (PTSD) is a recognized clinical phenomenon that often occurs as a result of exposure to severe stressors, such as combat, natural disaster, or other events [ 1 ]. The diagnosis of PTSD was first introduced in the 3rd edition of the Diagnostic and Statistical Manual (DSM) (American Psychiatric Association) in 1980 [ 2 ].

PTSD is a potentially chronic impairing disorder that is characterized by re-experience and avoidance symptoms as well as negative alternations in cognition and arousal. This disease first raised public concerns during and after the military operations of the United States in Afghanistan and Iraq, and to date, a large number of research studies report progress in this field. However, both the underlying mechanism and specific treatment for the disease remain unclear. Considering the significant medical, social and financial problems, PTSD represents both to nations and to individuals, all persons caring for patients suffering from this disease or under traumatic exposure should know about the risks of PTSD.

The aim of this review article is to present the current understanding of PTSD related to military injury to foster interdisciplinary dialog. This article is a selective review of pertinent literature retrieved by a search in PubMed, using the following keywords: “PTSD[Mesh] AND military personnel”. The search yielded 3000 publications. The ones cited here are those that, in the authors’ view, make a substantial contribution to the interdisciplinary understanding of PTSD.

Definition and differential diagnosis

Posttraumatic stress disorder is a prevalent and typically debilitating psychiatric syndrome with a significant functional disturbance in various domains. Both the manifestation and etiology of it are complex, which has caused difficulty in defining and diagnosing the condition. The 3rd edition of the DSM introduced the diagnosis of PTSD with 17 symptoms divided into three clusters in 1980. After several decades of research, this diagnosis was refined and improved several times. In the most recent version of the DSM-5 [ 3 ], PTSD is classified into 20 symptoms within four clusters: intrusion, active avoidance, negative alterations in cognitions and mood as well as marked alterations in arousal and reactivity. The diagnosis requirement can be summarized as an exposure to a stressor that is accompanied by at least one intrusion symptom, one avoidance symptom, two negative alterations in cognitions and mood symptoms, and two arousal and reactivity turbulence symptoms, persisting for at least one month, with functional impairment. Interestingly, in the DSM-5, PTSD has been moved from the anxiety disorder group to a new category of ‘trauma- and stressor-related disorders’, which reflects the cognizance alternation of PTSD. In contrast to the DSM versions, the World Health Organization’s (WHO) International Classification of Diseases (ICD) has proposed a substantially different approach to diagnosing PTSD in the most recent ICD-11 version [ 4 ], which simplified the symptoms into six under three clusters, including constant re-experiencing of the traumatic event, avoidance of traumatic reminders and a sense of threat. The diagnosis requires at least one symptom from each cluster which persists for several weeks after exposure to extreme stressors. Both diagnostic guidelines emphasize the exposure to traumatic events and time of duration, which differentiate PTSD from some diseases with similar symptoms, including adjustment disorder, anxiety disorder, obsessive-compulsive disorder, and personality disorder. Patients with the major depressive disorder (MDD) may or may not have experienced traumatic events, but generally do not have the invasive symptoms or other typical symptoms that PTSD presents. In terms of traumatic brain injury (TBI), neurocognitive responses such as persistent disorientation and confusion are more specific symptoms. It is worth mentioning that some dissociative reactions in PTSD (e.g., flashback symptoms) should be recognized separately from the delusions, hallucinations, and other perceptual impairments that appear in psychotic disorders since they are based on actual experiences. The ICD-11 also recognizes a sibling disorder, complex PTSD (CPTSD), composed of symptoms including dysregulation, negative self-concept, and difficulties in relationships based on the diagnosis of PTSD. The core CPTSD symptom is PTSD with disturbances in self-organization (DSO).

In consideration of the practical applicability of the PTSD diagnosis, Brewin et al. conducted a study to investigate the requirement differences, prevalence, comorbidity, and validity of the DSM-5 and ICD-11 for PTSD criteria. According to their study, diagnostic standards for symptoms of re-experiencing are higher in the ICD-11 than the DSM, whereas the standards for avoidance are less strict in the ICD-11 than in the DSM-IV [ 5 ]. It seems that in adult subjects, the prevalence of PTSD using the ICD-11 is considerably lower compared to the DSM-5. Notably, evidence suggested that patients identified with the ICD-11 and DSM-5 were quite different with only partially overlapping cases; this means each diagnostic system appears to find cases that would not be diagnosed using the other. In consideration of comorbidity, research comparing these two criteria show diverse outcomes, as well as equal severity and quality of life. In terms of children, only very preliminary evidence exists suggesting no significant difference between the two. Notably, the diagnosis of young children (age ≤ 6 years) depends more on the situation in consideration of their physical and psychological development according to the DSM-5.

Despite numerous investigations and multiple revisions of the diagnostic criteria for PTSD, it remains unclear which type and what extent of stress are capable of inducing PTSD. Fear responses, especially those related to combat injury, are considered to be sufficient enough to trigger symptoms of PTSD. However, a number of other types of stressors were found to correlate with PTSD, including shame and guilt, which represent moral injury resulting from transgressions during a war in military personnel with deeply held moral and ethical beliefs. In addition, military spouses and children may be as vulnerable to moral injury as military service members [ 6 ]. A research study on Canadian Armed Forces personnel showed that exposure to moral injury during deployments is common among military personnel and represents an independent risk factor for past-year PTSD and MDD [ 7 ]. Unfortunately, it seems that pre- and post-deployment mental health education was insufficient to moderate the relationship between exposure to moral injury and adverse mental health outcomes.

In general, a large number of studies are focusing on the definition and diagnostic criteria of PTSD and provide considerable indicators for understanding and verifying the disease. However, some possible limitations or discrepancies continue to exist in current research studies. One is that although the diagnostic criteria for a thorough examination of the symptoms were explicit and accessible, the formal diagnosis of PTSD using structured clinical interviews was relatively rare. In contrast, self-rating scales, such as the Posttraumatic Diagnostic Scale (PDS) [ 8 ] and the Impact of Events Scale (IES) [ 9 ], were used frequently. It is also noteworthy that focusing on PTSD explicitly could be a limitation as well. The complexity of traumatic experiences and the responses to them urge comprehensive investigations covering all aspects of physical and psychological maladaptive changes.

Prevalence and importance

Posttraumatic stress disorder generally results in poor individual-level outcomes, including co-occurring disorders such as depression and substance use, and physical health problems. According to the DSM-5 reporting, more than 80% of PTSD patients share one or more comorbidities; for instance, the morbidity of PTSD with concurrent mild TBI is 48% [ 8 ]. Moreover, cognitive impairment has been identified frequently in PTSD. The reported incidence rate for PTSD ranges from 5.4 to 16.8% in military service members and veterans [ 10 , 11 , 12 , 13 , 14 ], which is almost double those in the general population. The estimated prevalence of PTSD varies depending on the group of patients studied, the traumatic events occurred, and the measurement method used (Table  1 ). However, it still reflects the profound effect of this mental disease, especially with the rise in global terrorism and military conflict in recent years. While PTSD can arise at any life stage in any population, most research in recent decades has focused on returned veterans; this means most knowledge regarding PTSD has come from the military population. Meanwhile, the impact of this disease on children has received scant attention.

The discrepancy of PTSD prevalence in males and females is controversial. In a large study of OEF/OIF veterans, the prevalence of PTSD in males and females was similar, although statistically more prevalent in men versus women (13% vs. 11%) [ 15 ]. Another study on the Navy and Marine Corps showed a slightly higher incidence for PTSD in the women compared to men (6.6% vs. 5.3%) [ 12 ]. However, the importance of combat exposure is unclear. Despite a lower level of combat exposure than male military personnel, females generally have considerably higher rates of military sexual trauma, which is significantly associated with the development of PTSD [ 16 ].

It is reported that 44–72% of veterans suffer high levels of stress after returning to civilian life. Many returned veterans with PTSD show emotion regulation problems, including emotion identification, expression troubles and self-control issues. Nevertheless, a meta-analytic investigation of 34 studies consistently found that the severity of PTSD symptoms was significantly associated with anger, especially in military samples [ 17 ]. Not surprisingly, high levels of PTSD and emotional regulation troubles frequently lead to poor family functioning or even domestic violence in veterans. According to some reports, parenting difficulties in veteran families were associated with three PTSD symptom clusters. Evans et al. [ 18 ] conducted a survey to evaluate the impact of PTSD symptom clusters on family functioning. According to their analysis, avoidance symptoms directly affected family functioning, whereas hyperarousal symptoms had an indirect association with family functioning. Re-experience symptoms were not found to impact family functioning. Notably, recent epidemiologic studies using data from the Veterans Health Administration (VHA) reported that veterans with PTSD were linked to suicide ideations and behaviors [ 19 ] (e.g., non-suicidal self-injury, NSSI), in which depression as well as other mood disruptions, often serve as mediating factors.

Previously, there was a controversial attitude toward the vulnerability of young children to PTSD. However, growing evidence suggests that severe and persistent trauma could result in stress responses worse than expected as well as other mental and physical sequelae in child development. The most prevalent traumatic exposures for young children above the age of 1 year were interpersonal trauma, mostly related to or derived from their caregivers, including witnessing intimate partner violence (IPV) and maltreatment [ 20 ]. Unfortunately, because of the crucial role that caregivers play in early child development, these types of traumatic events are especially harmful and have been associated with developmental maladaptation in early childhood. Maladaptation commonly represents a departure from normal development and has even been linked to more severe effects and psychopathology. In addition, the presence of psychopathology may interfere with the developmental competence of young children. Research studies have also broadened the investigation to sequelae of PTSD on family relationships. It is proposed that the children of parents with symptoms of PTSD are easily deregulated or distressed and appear to face more difficulties in their psychosocial development in later times compared to children of parents without. Meanwhile, PTSD veterans described both emotional (e.g., hurt, confusion, frustration, fear) and behavioral (e.g., withdrawal, mimicking parents’ behavior) disruption in their children [ 21 ]. Despite the increasing emphasis on the effects of PTSD on young children, only a limited number of studies examined the dominant factors that influence responses to early trauma exposures, and only a few prospective research studies have observed the internal relations between early PTSD and developmental competence. Moreover, whether exposure to both trauma types in early life is associated with more severe PTSD symptoms than exposure to one type remains an outstanding question.

Molecular mechanism and predictive factors

The mechanisms leading to posttraumatic stress disorder have not yet been fully elucidated. Recent literature suggests that both the neuroendocrine and immune systems are involved in the formulation and development of PTSD [ 22 , 23 ]. After traumatic exposures, the stress response pathways of the hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system are activated and lead to the abnormal release of glucocorticoids (GC) and catecholamines. GCs have downstream effects on immunosuppression, metabolism enhancement, and negative feedback inhibition of the HPA axis by binding to the GC receptor (GR), thus connecting the neuroendocrine modulation with immune disturbance and inflammatory response. A recent meta-analysis of 20 studies found increased plasma levels of proinflammatory cytokines tumor necrosis factor-alpha (TNF-a), interleukin-1beta (IL-1b), and interleukin-6 (IL-6) in individuals with PTSD compared to healthy controls [ 24 ]. In addition, some other studies speculate that there is a prospective association of C-reactive protein (CRP) and mitogen with the development of PTSD [ 25 ]. These findings suggest that neuroendocrine and inflammatory changes, rather than being a consequence of PTSD, may in fact act as a biological basis and preexisting vulnerability for developing PTSD after trauma. In addition, it is reported that elevated levels of terminally differentiated T cells and an altered Th1/Th2 balance may also predispose an individual to PTSD.

Evidence indicates that the development of PTSD is also affected by genetic factors. Research has found that genetic and epigenetic factors account for up to 70% of the individual differences in PTSD development, with PTSD heritability estimated at 30% [ 26 ]. While aiming to integrate genetic studies for PTSD and build a PTSD gene database, Zhang et al. [ 27 ] summarized the landscape and new perspective of PTSD genetic studies and increased the overall candidate genes for future investigations. Generally, the polymorphisms moderating HPA-axis reactivity and catecholamines have been extensively studied, such as FKBP5 and catechol-O-methyl-transferase (COMT). Other potential candidates for PTSD such as AKT, a critical mediator of growth factor-induced neuronal survival, were also explored. Genetic research has also made progress in other fields. For example, researchers have found that DNA methylation in multiple genes is highly correlated with PTSD development. Additional studies have found that stress exposure may even affect gene expression in offspring by epigenetic mechanisms, thus causing lasting risks. However, some existing problems in the current research of this field should be noted. In PTSD genetic studies, variations in population or gender difference, a wide range of traumatic events and diversity of diagnostic criteria all may attribute to inconsistency, thus leading to a low replication rate among similar studies. Furthermore, PTSD genes may overlap with other mental disorders such as depression, schizophrenia, and bipolar disorder. All of these factors indicate an urgent need for a large-scale genome-wide study of PTSD and its underlying epidemiologic mechanisms.

It is generally acknowledged that some mental diseases, such as major depressive disorder (MDD), bipolar disorder, and schizophrenia, are associated with massive subcortical volume change. Recently, numerous studies have examined the relationship between the morphology changes of subcortical structures and PTSD. One corrected analysis revealed that patients with PTSD show a pattern of lower white matter integrity in their brains [ 28 ]. Prior studies typically found that a reduced volume of the hippocampus, amygdala, rostral ventromedial prefrontal cortex (rvPFC), dorsal anterior cingulate cortex (dACC), and the caudate nucleus may have a relationship with PTSD patients. Logue et al. [ 29 ] conducted a large neuroimaging study of PTSD that compared eight subcortical structure volumes (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle) between PTSD patients and controls. They found that smaller hippocampi were particularly associated with PTSD, while smaller amygdalae did not show a significant correlation. Overall, rigorous and longitudinal research using new technologies, such as magnetoencephalography, functional MRI, and susceptibility-weighted imaging, are needed for further investigation and identification of morphological changes in the brain after a traumatic exposure.

Psychological and pharmacological strategies for prevention and treatment

Current approaches to PTSD prevention span a variety of psychological and pharmacological categories, which can be divided into three subgroups: primary prevention (before the traumatic event, including prevention of the event itself), secondary prevention (between the traumatic event and the development of PTSD), and tertiary prevention (after the first symptoms of PTSD become apparent). The secondary and tertiary prevention of PTSD has abundant methods, including different forms of debriefing, treatments for Acute Stress Disorder (ASD) or acute PTSD, and targeted intervention strategies. Meanwhile, the process of primary prevention is still in its infancy and faces several challenges.

Based on current research on the primary prevention of post-trauma pathology, psychological and pharmacological interventions for particular groups or individuals (e.g., military personnel, firefighters, etc.) with a high risk of traumatic event exposure were applicable and acceptable for PTSD sufferers. Of the studies that reported possible psychological prevention effects, training generally included a psychoeducational component and a skills-based component relating to stress responses, anxiety reducing and relaxation techniques, coping strategies and identifying thoughts, emotion and body tension, choosing how to act, attentional control, emotion control and regulation [ 30 , 31 , 32 ]. However, efficiency for these training has not been evaluated yet due to a lack of high-level evidence-based studies. Pharmacological options have targeted the influence of stress on memory formation, including drugs relating to the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nerve system (especially the sympathetic nerve system), and opiates. Evidence has suggested that pharmacological prevention is most effective when started before and early after the traumatic event, and it seems that sympatholytic drugs (alpha and beta-blockers) have the highest potential for primary prevention of PTSD [ 33 ]. However, one main difficulty limiting the exploration in this field is related to rigorous and complex ethical issues, as the application of pre-medication for special populations and the study of such options in hazardous circumstances possibly touches upon questions of life and death. Significantly, those drugs may have potential side effects.

There are several treatment guidelines for patients with PTSD produced by different organizations, including the American Psychiatric Association (APA), the United Kingdom’s National Institute for Health and Clinical Excellence (NICE), the International Society for Traumatic Stress Studies (ISTSS), the Institute of Medicine (IOM), the Australian National Health and Medical Research Council, and the Department of Veterans Affairs and Department of Defense (VA, DoD) [ 34 , 35 , 36 , 37 , 38 ]. Additionally, a large number of research studies are aiming to evaluate an effective treatment method for PTSD. According to these guidelines and research, treatment approaches can be classified as psychological interventions and pharmacological treatments (Fig.  1 ); most of the studies provide varying degrees of improvement in individual outcomes after standard interventions, including PTSD symptom reduction or remission, loss of diagnosis, release or reduction of comorbid medical or psychiatric conditions, quality of life, disability or functional impairment, return to work or to active duty, and adverse events.

Psychological and pharmacological strategies for treatment of PTSD. CBT. Cognitive behavioral therapy; CPT. Cognitive processing therapy; CT. Cognitive therapy; CR. Cognitive restructuring; EMDR. Eye movement desensitization and reprocessing; SSRIs. Selective serotonin reuptake inhibitors; SNRIs. Serotonin and norepinephrine reuptake inhibitors; MAO. Monoamine oxidase

Most guidelines identify trauma-focused psychological interventions as first-line treatment options [ 39 ], including cognitive behavioral therapy (CBT), cognitive processing therapy (CPT), cognitive therapy (CT), cognitive restructuring (CR), coping skills therapy (including stress inoculation therapy), exposure-based therapies, eye movement desensitization and reprocessing (EMDR), hypnosis and hypnotherapy, and brief eclectic psychotherapy. These treatments are delivered predominantly to individuals, but some can also be conducted in family or group settings. However, the recommendation of current guidelines seems to be projected empirically as research on the comparison of outcomes of different treatments is limited. Jonas et al. [ 40 ] performed a systematic review and network meta-analysis of the evidence for treatment of PTSD. The study suggested that all psychological treatments showed efficacy for improving PTSD symptoms and achieving the loss of PTSD diagnosis in the acute phase, and exposure-based treatments exhibited the strongest evidence of efficacy with high strength of evidence (SOE). Furthermore, Kline et al. [ 41 ] conducted a meta-analysis evaluating the long-term effects of in-person psychotherapy for PTSD in 32 randomized controlled trials (RCTs) including 2935 patients with long-term follow-ups of at least 6 months. The data suggested that all studied treatments led to lasting improvements in individual outcomes, and exposure therapies demonstrated a significant therapeutic effect as well with larger effect sizes compared to other treatments.

Pharmacological treatments for PTSD include antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase (MAO) inhibitors, sympatholytic drugs such as alpha-blockers, antipsychotics, anticonvulsants, and benzodiazepines. Among these medications, fluoxetine, paroxetine, sertraline, topiramate, risperidone, and venlafaxine have been identified as efficacious in treatment. Moreover, in the Jonas network meta-analysis of 28 trials (4817 subjects), they found paroxetine and topiramate to be more effective for reducing PTSD symptoms than most other medications, whereas evidence was insufficient for some other medications as research was limited [ 40 ]. It is worth mentioning that in these studies, efficacy for the outcomes, unlike the studies of psychological treatments, was mostly reported as a remission in PTSD or depression symptoms; other outcomes, including loss of PTSD diagnosis, were rarely reported in studies.

As for the comparative evidence of psychological with pharmacological treatments or combinations of psychological treatments and pharmacological treatments with other treatments, evidence was insufficient to draw any firm conclusions [ 40 ]. Additionally, reports on adverse events such as mortality, suicidal behaviors, self-harmful behaviors, and withdrawal of treatment were relatively rare.

PTSD is a high-profile clinical phenomenon with a complicated psychological and physical basis. The development of PTSD is associated with various factors, such as traumatic events and their severity, gender, genetic and epigenetic factors. Pertinent studies have shown that PTSD is a chronic impairing disorder harmful to individuals both psychologically and physically. It brings individual suffering, family functioning disorders, and social hazards. The definition and diagnostic criteria for PTSD remain complex and ambiguous to some extent, which may be attributed to the complicated nature of PTSD and insufficient research on it. The underlying mechanisms of PTSD involve changes in different levels of psychological and molecular modulations. Thus, research targeting the basic mechanisms of PTSD using standard clinical guidelines and controlled interference factors is needed. In terms of treatment, psychological and pharmacological interventions could relief PTSD symptoms to different degrees. However, it is necessary to develop systemic treatment as well as symptom-specific therapeutic methods. Future research could focus on predictive factors and physiological indicators to determine effective prevention methods for PTSD, thereby reducing its prevalence and preventing more individuals and families from struggling with this disorder.

Abbreviations

American Psychiatric Association

Acute stress disorder

Cognitive behavioral therapy

Catechol-O-methyl-transferase

Cognitive processing therapy

Complex posttraumatic stress disorder

Cognitive restructuring

C-reactive protein

Cognitive therapy

Dorsal anterior cingulate cortex

Diagnostic and Statistical Manual

Disturbances in self-organization

Eye movement desensitization and reprocessing

Glucocorticoids

Glucocorticoids receptor

Hypothalamic–pituitary–adrenal axis

International classification of diseases

Impact of events scale

Interleukin-1beta

Interleukin-6

Institute of Medicine

Intimate partner violence

International Society for Traumatic Stress Studies

Monoamine oxidase

Major depressive disorder

United Kingdom’s National Institute for Health and Clinical Excellence

Non-suicidal self-injury

Posttraumatic diagnostic scale

Posttraumatic stress disorder

Randomized controlled trials

Rostral ventromedial prefrontal cortex

Serotonin and norepinephrine reuptake inhibitors;

Strength of evidence

Selective serotonin reuptake inhibitors

Tumor necrosis factor-alpha

DoD Department of Veterans Affairs and Department of Defense

Veterans Health Administration

World Health Organization

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We thank Jamie Bono for providing professional writing suggestions.

This work was supported by the National Natural Science Foundation of China (31371084 and 31171013 by ZJL), and the National Natural Science Foundation of China (81100276 by XRM).

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Miao, XR., Chen, QB., Wei, K. et al. Posttraumatic stress disorder: from diagnosis to prevention. Military Med Res 5 , 32 (2018). https://doi.org/10.1186/s40779-018-0179-0

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Received : 20 March 2018

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Published : 28 September 2018

DOI : https://doi.org/10.1186/s40779-018-0179-0

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• Cognitive impairment
• Psychological interventions
• Neuroendocrine

Military Medical Research

ISSN: 2054-9369

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Treatment of Posttraumatic Stress Disorder: A State-of-the-art Review

Affiliations.

• 1 Department of Psychiatry, University of Alberta, Edmonton, Canada.
• 2 Department of Occupational Therapy, University of Alberta, Edmonton, Canada.
• 3 ARQ National Psychotrauma Center, Diemen, The Netherlands.
• 4 Department of Psychiatry, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
• 5 School of Medicine, The University of Adelaide, Adelaide, Australia.
• 6 Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
• 7 Department of Psychiatry, New York University Grossman School of Medicine, New York, USA.
• PMID: 37132142
• PMCID: PMC10845104 (available on 2024-07-04 )
• DOI: 10.2174/1570159X21666230428091433

This narrative state-of-the-art review paper describes the progress in the understanding and treatment of Posttraumatic Stress Disorder (PTSD). Over the last four decades, the scientific landscape has matured, with many interdisciplinary contributions to understanding its diagnosis, etiology, and epidemiology. Advances in genetics, neurobiology, stress pathophysiology, and brain imaging have made it apparent that chronic PTSD is a systemic disorder with high allostatic load. The current state of PTSD treatment includes a wide variety of pharmacological and psychotherapeutic approaches, of which many are evidence-based. However, the myriad challenges inherent in the disorder, such as individual and systemic barriers to good treatment outcome, comorbidity, emotional dysregulation, suicidality, dissociation, substance use, and trauma-related guilt and shame, often render treatment response suboptimal. These challenges are discussed as drivers for emerging novel treatment approaches, including early interventions in the Golden Hours, pharmacological and psychotherapeutic interventions, medication augmentation interventions, the use of psychedelics, as well as interventions targeting the brain and nervous system. All of this aims to improve symptom relief and clinical outcomes. Finally, a phase orientation to treatment is recognized as a tool to strategize treatment of the disorder, and position interventions in step with the progression of the pathophysiology. Revisions to guidelines and systems of care will be needed to incorporate innovative treatments as evidence emerges and they become mainstream. This generation is well-positioned to address the devastating and often chronic disabling impact of traumatic stress events through holistic, cutting-edge clinical efforts and interdisciplinary research.

Keywords: Posttraumatic stress disorder; intervention; ketamine; moral injury; neuromodulation.; psychedelic; psychotherapy; psychotropic drugs.

Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Publication types

• Psychotropic Drugs / therapeutic use
• Stress Disorders, Post-Traumatic* / drug therapy
• Substance-Related Disorders* / drug therapy
• Treatment Outcome
• Psychotropic Drugs

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Posttraumatic Stress Disorder Complicated by Traumatic Brain Injury: A Narrative Review

• Published: 28 February 2023
• Volume 5 , article number  92 , ( 2023 )

Cite this article

• Stephen L. Aita   ORCID: orcid.org/0000-0001-7201-3247 1 , 2 ,
• Kaitlyn R. Schuler   ORCID: orcid.org/0000-0002-7866-7310 3 ,
• Steven L. Isaak   ORCID: orcid.org/0000-0002-0311-4527 3 , 4 ,
• Nicholas C. Borgogna   ORCID: orcid.org/0000-0002-5085-3656 5 ,
• Grant G. Moncrief   ORCID: orcid.org/0000-0001-5811-4308 2 ,
• Sean D. Hollis 6 &
• Benjamin D. Hill   ORCID: orcid.org/0000-0002-5797-5082 3  

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We reviewed the phenomenology of Post-Traumatic Stress Disorder (PTSD) and Traumatic Brain Injury (TBI), as well as the combined effects of PTSD + TBI comorbidity on functional outcomes. We also provide a series of research and treatment recommendations based on gaps in the literature with an emphasis on culture, interpersonal trauma, and treatment. Rates of PTSD + TBI are remarkably high. This comorbidity is especially common among combat-exposed military populations (with current estimates among Veterans returning from Afghanistan/Iraq at approximately 48%), as well as individuals who experience motor vehicle collisions (estimated base rate = 12%). These conditions often co-occur primarily because the events preceding the brain injury are both physically and psychologically traumatic. In many cases of PTSD + TBI, especially mild TBI, psychological factors largely account for accompanying functional outcomes (e.g., cognitive sequela, somatosensory health, quality of life, occupational functioning, social engagement). Overall, we suggest the importance of integrative teams in the early assessment, conceptualization, and treatment of PTSD + TBI. Psychological interventions and cognitive rehabilitation may synergistically improve psychological and functional outcomes for this patient population.

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MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial

• Jennifer M. Mitchell   ORCID: orcid.org/0000-0002-7567-8129 1 , 2 , 3 ,
• Marcela Ot’alora G.   ORCID: orcid.org/0000-0001-6174-7317 4 ,
• Bessel van der Kolk 5 ,
• Scott Shannon 6 ,
• Michael Bogenschutz   ORCID: orcid.org/0000-0003-4530-3470 7 ,
• Yevgeniy Gelfand 8 ,
• Casey Paleos 9 ,
• Christopher R. Nicholas 10 ,
• Sylvestre Quevedo 2 , 11 ,
• Brooke Balliett 12 ,
• Scott Hamilton 13 ,
• Michael Mithoefer   ORCID: orcid.org/0000-0002-4267-6135 14 ,
• Sarah Kleiman 15 ,
• Kelly Parker-Guilbert 16 ,
• Keren Tzarfaty 17 , 18 ,
• Charlotte Harrison 13 ,
• Alberdina de Boer 19 ,
• Rick Doblin 20 ,
• Berra Yazar-Klosinski 13 &

MAPP2 Study Collaborator Group

Nature Medicine volume  29 ,  pages 2473–2480 ( 2023 ) Cite this article

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This multi-site, randomized, double-blind, confirmatory phase 3 study evaluated the efficacy and safety of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) versus placebo with identical therapy in participants with moderate to severe post-traumatic stress disorder (PTSD). Changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (primary endpoint) and Sheehan Disability Scale (SDS) functional impairment score (key secondary endpoint) were assessed by blinded independent assessors. Participants were randomized to MDMA-AT ( n  = 53) or placebo with therapy ( n  = 51). Overall, 26.9% (28/104) of participants had moderate PTSD, and 73.1% (76/104) of participants had severe PTSD. Participants were ethnoracially diverse: 28 of 104 (26.9%) identified as Hispanic/Latino, and 35 of 104 (33.7%) identified as other than White. Least squares (LS) mean change in CAPS-5 score (95% confidence interval (CI)) was −23.7 (−26.94, −20.44) for MDMA-AT versus −14.8 (−18.28, −11.28) for placebo with therapy ( P  < 0.001, d  = 0.7). LS mean change in SDS score (95% CI) was −3.3 (−4.03, −2.60) for MDMA-AT versus −2.1 (−2.89, −1.33) for placebo with therapy ( P  = 0.03, d  = 0.4). Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n  = 5 (9.4%); placebo with therapy, n  = 2 (3.9%)). There were no deaths or serious TEAEs. These data suggest that MDMA-AT reduced PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD and was generally well tolerated. ClinicalTrials.gov identifier: NCT04077437 .

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MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

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Post-traumatic stress disorder (PTSD) is a serious neuropsychiatric condition affecting approximately 5% of the US population each year 1 . Managing PTSD is particularly complicated in individuals experiencing the dissociative subtype of PTSD, recurrent exposure to trauma and comorbidities, such as mood disorders and alcohol and substance use disorders 2 , 3 , 4 . Together, these factors are associated with symptom exacerbation, treatment resistance and treatment discontinuation 3 , 5 . Trauma-focused psychotherapies are the gold standard treatment for PTSD. However, many individuals have persisting symptomology, and dropout rates are high 6 , 7 , 8 . Although the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine are FDA approved for treating PTSD, 35–47% of individuals do not respond to treatment 9 . More effective, therapeutic interventions are needed to address the immense individual, societal and economic burdens of PTSD 10 , 11 .

Mounting evidence supports substituted phenethylamine 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) as a treatment for PTSD 12 , 13 . MDMA, an entactogen that promotes monoamine reuptake inhibition and release (primarily by inducing conformational change of pre-synaptic transporters 14 , 15 , 16 , 17 ), effectively modulates fear memory reconsolidation, enhances fear extinction and promotes openness and prosocial behavior 18 , 19 , 20 , 21 , 22 . Several phase 2 trials indicated that MDMA-AT has an acceptable risk–benefit profile in individuals with PTSD 13 . A pivotal phase 3 study (MAPP1) showed that MDMA-AT was generally well tolerated and met the trial’s primary and secondary endpoints of reduced PTSD symptom severity and decreased functional impairment 12 .

Due to disparities in trauma exposure, gender-diverse and transgender individuals, ethnoracial minorities, first responders, military personnel, veterans and victims of chronic sexual abuse have a disproportionately higher risk of developing PTSD 2 , 23 , 24 , 25 , 26 , 27 , 28 . However, these diverse populations are historically underrepresented in clinical trials 29 . Here we report the results of MAPP2, the second, confirmatory phase 3 study that extends the findings of MAPP1 (refs. 12 , 30 ) in an ethnoracially diverse population with moderate to severe PTSD (Supplementary Table 1 ).

Demographics and baseline characteristics

Participants were recruited from 21 August 2020 to 18 May 2022 (last participant visit on 2 November 2022). Overall, 324 individuals were screened, and 121 were enrolled. Of these, 17 individuals did not meet enrollment confirmation after initiation of preparation therapy, and 104 were confirmed for randomization: 53 were assigned to MDMA-AT and 51 to placebo with therapy (Fig. 1 ). Ninety-four participants completed the study, and nine discontinued ( n  = 1 MDMA-AT; n  = 8 placebo with therapy) (Fig. 1 and Supplementary Table 3 ).

CONSORT diagram, indicating participant numbers and disposition throughout the course of the trial. Endpoint assessments (T1, T2, T3 and T4) of CAPS-5 and SDS were conducted after each experimental session. a The number of individuals after an initial phone screening who gave informed consent. b Other reasons for exclusion could include withdrawal of consent, adverse event or death, discontinuation of treatment by investigator, lack of therapeutic rapport and illness or lost to follow-up. c One participant in the placebo with therapy group completed the study but had missing item-level data on the final CAPS-5 assessment, and the final assessment was not included in the analysis of the de jure estimand. AE, adverse event; ITT, intention to treat; mITT, modified intention to treat; T, time of endpoint assessment; T1, baseline; T2, after experimental session 1; T3, after experimental session 2; T4, 6–8 weeks after experimental session 3 (18 weeks after baseline).

Baseline characteristics were generally similar between groups (Table 1 ). In total, 74 of 104 (71.2%) participants were assigned female sex at birth, with a higher proportion in the placebo with therapy group (42/51, 82.4%) than the MDMA-AT group (32/53, 60.4%). Participants were ethnically and racially diverse: 35 of 104 (33.7%) participants identified their race as other than White, and 28 of 104 (26.9%) identified their ethnicity as Hispanic/Latino. The mean (s.d.) duration of PTSD was 16.2 (13.3) years. The mean (s.d.) Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) score at baseline was 39.0 (6.6) and was similar between groups. Overall, 28 of 104 (26.9%) and 76 of 104 (73.1%) participants had moderate and severe PTSD, respectively; the dissociative subtype was present in 24 of 104 (23.1%) participants.

Primary outcomes

MDMA-AT significantly attenuated PTSD symptomology versus placebo with therapy, as measured by a reduction in CAPS-5 total severity score from baseline to 18 weeks. Mixed models for repeated measures (MMRM) analysis of the de jure estimand showed a least squares (LS) mean (95% confidence interval (CI)) change of −23.7 (−26.94, −20.44) for MDMA-AT versus −14.8 (−18.28, −11.28) for placebo with therapy (treatment difference: −8.9 (−13.70, −4.12), P  < 0.001; Fig. 2a ). The Cohen’s d effect size of MDMA-AT versus placebo with therapy was d  = 0.7; the within-group effect sizes were d  = 1.95 for MDMA-AT and d  = 1.25 for placebo with therapy. MMRM analysis of the de facto estimand revealed an LS mean change (95% CI) in CAPS-5 scores of −23.7 (−26.97, −20.47) for the MDMA-AT group versus −14.8 (−18.24, −11.33) for the placebo with therapy group ( P  < 0.001).

a , LS mean change (±s.e.m.) in CAPS-5 total severity score from baseline to after session 3 (primary outcome) for placebo with therapy ( n  = 50) versus MDMA-AT ( n  = 53, P  < 0.001, Cohen’s d  = 0.7). b , LS mean change (±s.e.m.) in SDS total score from baseline to after session 3 (key secondary outcome) for placebo with therapy ( n  = 50) versus MDMA-AT ( n  = 53, P  = 0.03, Cohen’s d  = 0.4).

Source data

Secondary outcomes.

MDMA-AT significantly mitigated clinician-rated functional impairment, as measured by a reduction in the Sheehan Disability Scale (SDS) from baseline. MMRM analysis of the de jure estimand revealed that the LS mean change (95% CI) in SDS total scores was −3.3 (−4.03, −2.60) with MDMA-AT versus −2.1 (−2.89, −1.33) with placebo with therapy (treatment difference: −1.20 (−2.26, −0.14); P  = 0.03, d  = 0.4; Fig. 2b ). Improvements were observed across all domains, including family life, social life and work life (Supplementary Table 4 ).

Exploratory outcomes

In the MDMA-AT group, 45 of 52 (86.5%) participants were responders with a clinically meaningful improvement at 18 weeks after baseline, defined as a ≥10-point reduction in CAPS-5 total severity score, versus 29 of 42 (69.0%) in the placebo with therapy group (Fig. 3 ). By study end, 37 of 52 (71.2%) participants in the MDMA-AT group no longer met DSM-5 criteria for PTSD versus 20 of 42 (47.6%) participants in the placebo with therapy group. Furthermore, 24 of 52 (46.2%) participants in the MDMA-AT group and nine of 42 (21.4%) participants in the placebo with therapy group met remission criteria (Fig. 3 ). The net number of participants needed to treat for each responder analysis group was as follows: responder, six; non-responder, six; loss of diagnosis, four; remission, four.

A ≥10-point reduction in CAPS-5 total severity score was considered to be clinically meaningful. Responders (≥10-point reduction from baseline), loss of diagnosis (≥10-point reduction from baseline and no longer meeting PTSD diagnostic criteria) and remission (loss of diagnosis and CAPS-5 total severity score of 11 or less) were tracked in both groups as a percentage of participants. Non-responders were defined as any CAPS-5 total severity score change <10-point reduction from baseline.

Covariate analyses demonstrated similar responses to treatment regardless of disease severity, risk of hazardous alcohol or substance use disorder, severe adverse childhood experiences or dissociative subtype PTSD. The only measured exploratory covariate with a significant interaction with treatment was lifetime history of SSRI use, which was associated with improved efficacy of MDMA-AT ( P  = 0.02; Supplementary Table 5 ). Covariates significantly impacting the main effect were sex assigned at birth and baseline Beck Depression Inventory (BDI)-II score; female sex assigned at birth and baseline BDI-II score ≥23 were both associated with improved outcomes irrespective of treatment assignment ( P  < 0.05).

A blinding survey conducted at study termination showed that 33 of 44 (75.0%) participants in the placebo with therapy group were certain or thought they received placebo, whereas nine of 44 (20.5%) participants inaccurately thought that they received MDMA, and two of 44 (4.5%) participants could not tell. In the MDMA-AT group, 49 of 52 (94.2%) participants were certain or thought that they received MDMA; one of 52 (1.9%) participants inaccurately thought that they received placebo; and two of 52 (3.8%) participants could not tell (Supplementary Table 6 ). When asked for the reason for their belief in treatment assignment, most participants in the MDMA-AT group reported attributing their response on the blinding survey to experiencing positive mental or emotional effect (45/52 (86.5%)) and positive physical effect (29/52 (55.8%)), whereas most of the participants in the placebo with therapy group reported experiencing no effect (28/44 (63.6%)).

Most participants (102/104, 98.1%) experienced at least one treatment-emergent adverse event (TEAE) during the study (Table 2 ); seven experienced a severe TEAE (MDMA-AT, n  = 5 (9.4%); placebo with therapy, n  = 2 (3.9%)). None had a serious TEAE. Two participants (3.9%) in the placebo with therapy group discontinued treatment due to TEAEs. Frequently reported TEAEs (occurring with incidence >10% and at least twice the prevalence in the MDMA-AT group versus the placebo with therapy group) included muscle tightness, nausea, decreased appetite and hyperhidrosis (Table 2 ). These were mostly transient and of mild or moderate severity. At least one treatment-emergent adverse event of special interest (TEAESI) occurred in six of 53 (11.3%) participants in the MDMA-AT group and three of 51 (5.9%) participants in the placebo with therapy group (Table 2 ). No TEAESIs of MDMA abuse, misuse, physical dependence or diversion were reported.

Eight participants (MDMA-AT, n  = 7; placebo with therapy, n  = 1) experienced cardiac TEAEs, which included palpitations (MDMA-AT, n  = 5 (9.4%); placebo with therapy, n  = 1 (2.0%)) and tachycardia (MDMA-AT, n  = 2 (3.8%)); all were mild. Nine participants (MDMA-AT, n  = 7; placebo with therapy, n  = 2) experienced vascular TEAEs; all were mild, except for one participant in the MDMA-AT group who had a history of hypertension, who was not taking anti-hypertensive medications and who experienced a TEAE of moderate hypertension (Supplementary Table 7 ). Five participants had cardiac TEAESIs: four participants in the MDMA-AT group and one participant in the placebo with therapy group reported palpitations (Supplementary Table 7 ). Participants in the MDMA-AT group experienced temporary dose-dependent increases in mean blood pressure (BP) and pulse during experimental sessions compared to the placebo with therapy group (Supplementary Table 8 ).

Transient increases in heart rate and BP were expected and were observed during experimental sessions in a dose-dependent manner. Greater fluctuations in BP were seen during experimental sessions 2 and 3 in the participants treated with MDMA, most likely due to the higher doses of MDMA administered. These transient elevations did not require clinical intervention, including among the subset of participants with well-controlled hypertension. Because the current dosing regimen involves administering a single, split drug dose under observation, for a limited number of times, each after a lengthy washout, cardiovascular risk is likely to have been sufficiently mitigated by the study procedures and screening measures.

Psychiatric TEAEs occurred at a similarly high frequency in both groups (MDMA-AT, n  = 44 (83.0%); placebo with therapy, n  = 37 (72.5%)), with suicidal ideation, insomnia and anxiety reported most frequently. Psychiatric TEAEs were mostly mild to moderate; three severe events occurred in the MDMA-AT group (5.7%; n  = 1 each: dissociation, flashback and grief reaction) and two in the placebo with therapy group (3.9%; n  = 1 each: agitation and anxiety). No severe TEAEs of suicidal ideation or behavior were reported. Two participants in the MDMA-AT group had suicidality TEAESIs of suicidal ideation, one of whom engaged in non-suicidal self-injurious behavior. Two participants in the placebo with therapy group had suicidality TEAESIs; one engaged in non-suicidal self-injurious behavior, and one had suicidal ideation and trichotillomania (Supplementary Table 9 ).

More than 80% (87/104) of participants had a lifetime history of suicidal ideation; 13 of 53 (24.5%) in the MDMA-AT group and 12 of 51 (23.5%) in the placebo with therapy group reported suicidal ideation during the final preparation session (V4). The number of participants reporting positive suicidal ideation varied throughout the study but collectively never exceeded baseline values in either group (Supplementary Fig. 2 ). Three participants (two MDMA-AT and one placebo with therapy) had treatment-emergent active suicidal ideation with at least some intent to act (Columbia-Suicide Severity Rating Scale (C-SSRS) score of 4 or 5), which was observed on five occasions (MDMA-AT, three events; placebo with therapy, two events) (Supplementary Fig. 2 ). Of these, one participant in the MDMA-AT group with no suicidal ideation at baseline had the emergence of active suicidal ideation with at least some intent to act.

In this confirmatory phase 3 study of participants with moderate to severe PTSD, MDMA-AT significantly improved PTSD symptoms and functional impairment, as assessed by CAPS-5 and SDS, respectively, compared to placebo with therapy over 18 weeks. Notably, 45 of 52 (86.5%) participants treated with MDMA-AT achieved a clinically meaningful benefit, and 37 of 52 (71.2%) participants no longer met criteria for PTSD by study end. In a historic first, to our knowledge, for psychedelic treatment studies, participants who identified as ethnically or racially diverse encompassed approximately half of the study sample. These findings confirm and extend the results observed in MAPP1 (ref. 12 ), with general consistency across endpoints.

Given the diverse population and degree of participant complexity, the replication of efficacy is particularly notable. In our study, 26.9% (28/104) of participants expressed moderate PTSD, whereas, in MAPP1, all participants expressed severe PTSD 12 . A substantial proportion of participants displayed comorbid features associated with high treatment resistance 5 , such as major depression, multiple sources of trauma (including childhood and combat trauma) and dissociative subtype PTSD. In keeping with MAPP1, treatment was not significantly affected by disease severity, risk of hazardous alcohol or substance use disorder, severe adverse childhood experiences or dissociative subtype. Furthermore, there was no observed site-to-site variability and no differential effect if participants stayed overnight after the experimental session. However, lifetime history of SSRIs, female sex assigned at birth and BDI-II score ≥23 at baseline were associated with positive impacts on outcomes and may warrant further study based on the exploratory nature of these analyses.

MDMA simultaneously induces prosocial feelings and softens responses to emotionally challenging and fearful stimuli 19 , potentially enhancing the ability of individuals with PTSD to benefit from psychotherapy by reducing sensations of fear, threat and negative emotionality 18 , 19 . The low dropout rate for MDMA-AT has been replicated across seven studies, suggesting that MDMA induces a true shift in participant engagement 12 , 13 . In contrast, a recent study comparing psychotherapies in veterans with PTSD reported dropout rates of 55.8% and 46.6% for prolonged exposure and cognitive processing therapy, respectively 31 . The MAPP2 dropout rate was 1.9% (1/53) in the MDMA-AT group and 15.7% (8/51) in the placebo with therapy group. The higher proportion of dropouts in the placebo with therapy group relative to MDMA-AT could be attributed to participants receiving less effective treatment and to disappointment from ineffective therapeutic blinding, although blinding survey data showed that not all participants correctly identified the treatment that they received.

Consistent with MAPP1, no new major safety issues were reported. Common TEAEs were similar to previous studies and consistent with expected effects of MDMA 12 , 32 . Rates of cardiac TEAEs were low, and increases in BP and pulse were mild, transient and consistent with MDMA’s sympathomimetic effects 18 , 33 , 34 . Consistent with PTSD, suicidal ideation was observed in both groups. MDMA did not appear to increase this risk, and no suicidal behavior was observed. C-SSRS scores varied throughout the study but never exceeded baseline values for either group. Notably, there were five total events of treatment-emergent C-SSRS scores of 4 or 5: three in the MDMA-AT group and two in the placebo with therapy group. MAPP2 enrolled participants with a history of suicidality but excluded those with a current, serious imminent suicide risk; thus, special attention to this vulnerable population is warranted in future studies. In alignment with MAPP1 (ref. 12 ), there were no reports of problematic MDMA abuse or dependence, including in participants with histories of, or current, alcohol and substance use disorders. However, it is important to note that participants with any substance use disorder other than cannabis or alcohol in the 12 months before enrollment were excluded from MAPP2, as were participants with severe or moderate (in early remission) alcohol or cannabis use disorder. However, exploratory findings from the MAPP1 phase 3 trial indicated that MDMA-AT was actually associated with a significantly greater reduction in mean Alcohol Use Disorder Identification Test change scores compared to placebo with therapy, suggesting that the effects of MDMA-AT on hazardous alcohol use secondary to PTSD should be further studied 35 . Long-term data are also needed to assess the risk of MDMA abuse or misuse after study participation.

Although the sample sizes of the MAPP1 and MAPP2 phase 3 studies had 90% statistical power and were developed with guidance from the FDA to ensure adequate, rigorous testing of outcomes, these evaluations did not extend further than 2 months after therapy and were intended to support an acute treatment course. To support these studies, data from the ongoing follow-up of participants from phase 2 and 3 studies (ClinicalTrials.gov Identifier: NCT05066282 ) will be important for further assessment of the long-term effectiveness of MDMA-AT in participants with PTSD. It is of interest to note that pooled phase 2 analyses of participants with at least 12 months of follow-up after their final MDMA-AT session have shown that LS mean CAPS-IV scores continue to improve between the final session and follow-up 32 .

Several limitations may impact the integration of MDMA-AT into clinical care, including the exclusion of participants with high suicide risk, comorbid personality disorders and underlying cardiovascular disease. Observed effect sizes for MDMA-AT (between-group, d  = 0.7; within-subject, d  = 1.95) were similar to MAPP1 (ref. 12 ) (between-group, d  = 0.91; within-subject, d  = 2.1), and, although higher than those observed in SSRI studies (ranging from 0.09 to 0.56 versus placebo for sertraline and paroxetine 36 ), the superiority of MDMA-AT over SSRIs cannot be assumed without a direct comparison. The complex relationship between SSRI use/history and MDMA-AT treatment efficacy was beyond the scope of the current statistical analysis plan and sample size but will be important to consider in future studies. In addition, further study of MDMA with other forms of psychotherapy for PTSD should be explored.

The notable effect seen in the placebo with therapy arm could suggest the standalone value of the manualized inner-directed therapy that was developed for use with MDMA. Additional head-to-head studies will need to be conducted to evaluate whether this form of manualized therapy provides greater value in the treatment of PTSD than the current first-line cognitive behavioral therapy and prolonged exposure therapy treatments 37 .

Although treatment expectancy, per se, was not measured in this study, prospective treatment expectancy would likely have been high in both study arms, with random assignment expected to distribute this equally between groups. Although expectancy effects are a well-known issue in psychiatric clinical trials and are intertwined with the observation of treatment benefit during a trial 38 , several observations support expectancy mitigation in the current study: (1) the groups did not separate after the first experimental session; (2) placebo with therapy dropouts did not uniformly occur after the first experimental session; and (3) blinding survey data (Supplementary Table 6 ) showed that not all participants correctly identified the treatment that they received.

The therapists who participated in this study were required to complete the sponsor’s training program (see Supplementary Methods for further details). To ensure consistent clinical practice and to mitigate harm, it may be of benefit for prescribers to complete additional training and continuing education if MDMA-AT is approved for use by a regulatory agency.

This confirmatory phase 3 trial showed consistent benefits of MDMA-AT in an ethnoracially diverse group of individuals with longstanding moderate to severe PTSD and numerous comorbidities. The dropout rate was low, and treatment was generally well tolerated. These findings represent the culmination of over two decades of research 39 , and, together with MAPP1, indicate that further consideration of this treatment in individuals with moderate to severe PTSD is warranted.

Study design and oversight

This multi-site, randomized, double-blind, placebo-controlled study assessed the efficacy and safety of MDMA-AT versus placebo with therapy in participants diagnosed with moderate or severe PTSD ( NCT04077437 ). Thirteen study sites (11 in the United States and two in Israel, both institutional and private) participated. The trial was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonization and with the ethical principles of the Declaration of Helsinki. An independent data monitoring committee ensured that the study was conducted safely and had sufficient sample size. The review boards and institutions that approved the study protocol are listed in the Supplementary Methods .

Participants

After written informed consent, participants were screened for eligibility. Adults (≥18 years of age) meeting the full DSM-5 criteria for current PTSD per CAPS-5 assessment 40 , 41 and a CAPS-5 total severity score ≥28 (moderate or higher severity) with symptom duration of ≥6 months were eligible for enrollment confirmation. During the Preparation Period that preceded the Treatment Period, participants were tapered off all psychiatric medications before baseline to avoid potential drug interactions and confounding efficacy (Supplementary Fig. 1 ). Full inclusion and exclusion criteria are outlined in the Supplementary Methods .

Randomization and masking

Participants were randomized in a 1:1 allocation and in a blinded fashion to the MDMA-AT and placebo with therapy groups, stratified by clinical site. Randomization was managed via an interactive web randomization system (IWRS) (IT Clinical version 11.0.1) based on a centralized randomization schedule developed by an independent third-party vendor to maintain blinding.

A central pool of blinded independent assessors was used to mitigate the risk of functional unblinding 42 . Assessors were trained and supervised by independent consultants with expertise in PTSD diagnostics and the CAPS-5 to ensure inter-rater reliability and validity of assessments. Supervision involved reviewing each assessor’s first two assessments as well as 20% of all assessments (chosen at random) throughout the study, with each review resulting in detailed feedback for the assessor. The independent assessors were blinded to the general study design, study visit, treatment assignment, number of treatments received and any safety data for the participant. Participants were instructed to withhold their opinion on treatment group assignment and the number of completed visits from the independent assessors. Each assessor conducted no more than one CAPS-5 assessment with each participant to reduce potential bias and expectancy effect from having conducted repeat CAPS-5s with a participant. Assessors were also vetted before their onboarding to ensure that there were no conflicts of interest (such as other involvement within the Multidisciplinary Association for Psychedelic Studies (MAPS) organization or a bias toward MDMA-AT), and assessors were instructed to not expose themselves to scholarly presentations and papers related to MDMA-AT for PTSD to maintain their blinding to study design.

To ensure that all site and sponsor staff were shielded from study outcomes, the blinded independent assessor pool collected and stored outcome measures in a dedicated database that was separate from the blinded clinical database. A blinding survey was conducted at study termination (visit 20) to assess if participants thought that they received MDMA or placebo.

Trial procedures were consistent with MAPP1 (ref. 12 ). Enrolled participants underwent three 90-min preparation sessions with a two-person therapy team, including at least one licensed therapist, and were then randomized 1:1 to receive MDMA-AT or placebo with therapy for approximately 3 months. The treatment period consisted of three 8-h dosing sessions, in conjunction with therapy, spaced approximately 1 month apart. Therapy was conducted by trained personnel in accordance with the MAPS MDMA-AT treatment manual ( https://maps.org/treatment-manual ) and trial protocol. During experimental sessions, and in keeping with the dosing in MAPP1, participants received a split dose of 120–180 mg of MDMA or placebo. For the first experimental session, the initial dose of 80 mg was followed by a supplemental half-dose of 40 mg. In the second and third experimental sessions, the initial dose of 120 mg was followed by a supplemental half-dose of 60 mg. The supplemental half dose was administered 1.5–2 h after the initial dose. Participants in both treatment groups received identical therapy. The 120-mg (80 mg + 40 mg) split dose was selected for the first experimental session in phase 3 trials to allow patients to acclimate to the treatment regimen using a clinical titration approach based on clinician recommendations from a phase 2 trial in veterans and first responders 13 . During the second and third experimental sessions, doses were escalated to 180 mg (120 mg + 60 mg), as this was the most frequently studied efficacious dose in phase 2 trials. This dosing regimen also provides clinicians with the option of dose adjustments if needed.

Within the MDMA-AT group, three participants did not undergo dose escalation in experimental sessions 2 and 3, and two participants experienced dose administration timing errors (Supplementary Table 2 ). Each experimental session was followed by three 90-min integration sessions to support participants in processing and understanding their experience (Supplementary Fig. 1 ). Full procedures, including details on therapy teams and training, are outlined in the Supplementary Methods .

Independent assessors conducted CAPS-5 and SDS outcome assessments at baseline, after experimental sessions 1 and 2 and 6–8 weeks after experimental session 3 (18 weeks after baseline) via video interviews. Primary and secondary objectives were mean change in CAPS-5 total severity and SDS scores, respectively, for MDMA-AT versus placebo with therapy from baseline to 18 weeks after baseline.

Exploratory outcome measurements included characterization of the treatment response and differences between the treatment groups by demographics and characteristics. Responder analyses were based on categorical diagnostic assessment data and the CAPS-5 total severity score assessment. PTSD severity was defined using the CAPS-5 total severity score as follows: asymptomatic (0–10), mild (11–22), moderate (23–34), severe (35–46) and extreme (47+) (ref. 41 ). A ≥10-point reduction in CAPS-5 total severity score was considered to be clinically meaningful as agreed upon with the FDA through a Special Protocol Assessment. Four responder categories were derived and compared at each post-experimental session visit using CAPS-5 scores. These categories were: non-responder (<10-point reduction from baseline), responder (≥10-point reduction from baseline), loss of diagnosis (≥10-point reduction from baseline and no longer meeting PTSD diagnostic criteria) and remission (CAPS-5 total severity score of 11 or less and no longer meeting PTSD diagnostic criteria).

Safety objectives included assessment of differences between groups in severity, incidence and frequency of TEAEs, serious TEAEs, TEAESIs, suicidal ideation and behavior and vital signs. TEAEs were defined as any adverse event that occurred during the treatment period from the first experimental session to the last integration session. The severity of TEAEs was determined by the site physician as mild (no limitation in normal daily activity), moderate (some limitation in normal daily activity) or severe (unable to perform normal daily activity). A serious TEAE was defined as any unforeseen medical event at any dose of the drug that resulted in death; was life-threatening; required inpatient hospitalization; caused significant disability or incapacity; resulted in a congenital anomaly or birth defect; or required intervention to prevent permanent impairment or damage. Serious TEAEs also included any event, based on medical judgement, that jeopardized the participant or may have required intervention to prevent one of the events listed previously. With the exception of serious adverse event reporting, relatedness to study drug was not assessed by investigators, to preserve blinding. In an effort to identify common adverse events that may be most related to MDMA, TEAEs occurring with incidence >10% and at least twice the prevalence in the MDMA-AT group versus the placebo with therapy group are reported. Suicidality was tracked at each study visit using the C-SSRS (see the Supplementary Methods for more information).

Statistical analysis

SAS version 9.4 (SAS Institute) was used for analyses. Sample size was calculated to achieve a power of 90% at an alpha of 0.0499.

Efficacy was tested using an MMRM analysis comparing the change from baseline to 18 weeks after baseline in CAPS-5 and SDS scores between treatment groups in two-sided tests with alpha set at 0.0499. The alpha was adjusted to account for an administrative interim analysis for sample size re-estimation conducted after all participants were enrolled and 60% of primary endpoint data had been collected. Fixed effects were treatment, visit, treatment group by visit interaction and dissociative subtype; baseline CAPS-5 score was a covariate. Primary and secondary efficacy analyses used a de jure (related to initially randomized treatment) estimand and a supportive de facto (treatment policy) estimand of the modified intention-to-treat population, which required exposure to MDMA or placebo and at least one follow-up CAPS-5 assessment, as in MAPP1 (ref. 12 ). The de jure dataset included all available data, except for 12 (one MDMA-AT and 11 placebo with therapy) outcome measurements taken after treatment discontinuation in analysis of treatment efficacy (Supplementary Table 3 ). Missed observations were considered missing at random (MAR), and choice of this assumption was tested with a tipping point analysis ( Supplementary Methods ).

In additional exploratory analyses, 13 covariates were assessed in the model, with alpha set at 0.0499: age, sex (self-reported), prior use of selective SSRIs, work disability, disease severity, PTSD duration, dissociative subtype, overnight site stay, site ID, moderate depression (as measured by the BDI-II), severe adverse childhood experiences and moderate alcohol and substance use disorder risk (as measured by the Drug Use Disorders Identification Test and the Alcohol Use Disorders Identification Test). Analyses of primary or secondary outcomes by gender were not planned a priori; some exploratory analyses included sex as a covariate ( Supplementary Methods ).

Safety analysis evaluated TEAEs at the participant level, including all participants who received MDMA or placebo. Causal association with MDMA was determined based on relative incidence of TEAEs with at least a two-fold difference between groups.

Adverse events of special interest

In accordance with FDA guidance, special attention was paid to a subset of adverse events, TEAESIs, relating to cardiac function, suicide risk and MDMA abuse, misuse or diversion. TEAESIs involving cardiac function that could be indicative of QT prolongation or cardiac arrhythmias were collected, including torsade de pointes, sudden death, ventricular extrasystoles, ventricular tachycardia, ventricular fibrillation and flutter, non-postural syncope and seizures. TEAESIs involving suicide risk included suicide, suicide attempts, self-harm associated with suicidal ideation, suicide ideation assessed as a score of 4 or 5 on the C-SSRS and suicidal ideation judged by the investigator to be serious/severe. TEAESIs involving terms of MDMA abuse, misuse, drug diversion, dependence or overdose were also collected.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Data availability

The data that support the findings of this study are available from the sponsor beginning 1 year after completion of the trial. However, restrictions apply to the availability of these data, which were used under license for the current study and so are not publicly available. Data are, however, available from the authors upon reasonable request and with the permission of the sponsor. All requests for raw and analyzed data are promptly reviewed to verify if the request is subject to any confidentiality obligations. Participant-related data not included in the paper were generated as part of clinical trials and may be subject to participant confidentiality. Any data that can be shared will be released via a data use agreement. Proposals should be directed to https:/maps.org/datause . Source data are provided with this paper.

Code availability

Commercially available software (SAS version 9.4 or higher, SAS Institute) was used for analyses, in keeping with the statistical analysis plan.

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Acknowledgements

The authors thank all of the participants and their support networks. See the Supplementary Information for acknowledgments concerning study collaborators, including all members of the MAPP2 Study Collaborator Group.

This study was funded by Multidisciplinary Association for Psychedelic Studies (MAPS) with support from the Steven and Alexandra Cohen Foundation and organized by MAPS Public Benefit Corporation (PBC). MAPS PBC was responsible for overseeing the collection, analysis and interpretation of the data. Medical writing assistance was provided by J. Carpenter and M. Yochum of BOLDSCIENCE, funded by MAPS PBC.

Author information

A list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

Neuroscape, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

Jennifer M. Mitchell

Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA

Jennifer M. Mitchell & Sylvestre Quevedo

Department of Veterans Affairs, Research Service, San Francisco VA Medical Center, San Francisco, CA, USA

Aguazul-Bluewater, Inc., Boulder, CO, USA

Marcela Ot’alora G.

Boston University School of Medicine, Boston, MA, USA

Bessel van der Kolk

Wholeness Center, Fort Collins, CO, USA

Scott Shannon

Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA

Michael Bogenschutz

Zen Therapeutic Solutions, Mt. Pleasant, SC, USA

Yevgeniy Gelfand

Nautilus Sanctuary, New York, NY, USA

Casey Paleos

Department of Family Medicine and Community Health, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

Christopher R. Nicholas

San Francisco Insight and Integration Center, San Francisco, CA, USA

Sylvestre Quevedo

New School Research, LLC, Los Angeles, CA, USA

Brooke Balliett

MAPS Public Benefit Corporation, San Jose, CA, USA

Scott Hamilton, Charlotte Harrison & Berra Yazar-Klosinski

Medical University of South Carolina, Charleston, SC, USA

Michael Mithoefer

Kleiman Consulting and Psychological Services, PC, Ivyland, PA, USA

Sarah Kleiman

KPG Psychological Services, LLC, Brunswick, ME, USA

Kelly Parker-Guilbert

University of Haifa, Haifa, Israel

Keren Tzarfaty

MAPS Israel, Hod Hasharon, Israel

Tulip Medical Consulting, LLC, Port Townsend, WA, USA

Alberdina de Boer

Multidisciplinary Association for Psychedelic Studies (MAPS), San Jose, CA, USA

Rick Doblin

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Contributions

S.H., B.Y.-K., C.H. and A.d.B. contributed to data analysis; these authors and J.M.M. directly accessed and collectively verified the underlying data. All authors had full access to the trial data, contributed to the interpretation of the data and contributed to writing the manuscript. The authors attest to the accuracy and completeness of the reported data, accept responsibility to submit for publication and confirm that the trial conformed to the protocol and the statistical analysis plan (available via Nature Medicine ).

Corresponding author

Correspondence to Jennifer M. Mitchell .

Ethics declarations

Competing interests.

J.M.M. has received research support from MAPS; grants/contracts from the Veterans Administration (Merit Award) and the FDA (Research Award); has received royalties/licenses from UCLA (for a patent licensed to UCSF for cell screening); has received payment/honoraria from Stanford (for lecturing to undergraduate students) and Johns Hopkins (for presenting grand rounds); has a patent licensed to UCSF for cell screening; has been a reviewer for NIAAA CTN; has been a member of CA DOJ RAP; and has been a grant reviewer for the Australian Medical Research Council. M.O.G.: Aguazul-Bluewater, Inc has received research support from MAPS PBC and payments from Cybin (training and consultation), from Horizons Conference and from Naropa University. B.v.d.K. has received royalties from Penguin Random House (book, The Body Keeps the Score ) and Guilford Press (book, Traumatic Stress ); has received consulting fees from Meadows Hospital (Wickenburg, Arizona); and has received payment/honoraria from PESI. B.v.d.K. is also the president of the Trauma Research Foundation. S.S. has received grants/contracts from MAPS (research support) and MindMed (research support); has received royalties/licenses from Academic Press and Norton Publishing (professional books); has received honoraria from Scripps, the Integrative Psychiatric Institute and the Institute of Functional Medicine (lectures and presentations); is member of the Maya Health Advisory Board; and previously served as CEO of the Board of Psychedelic Medicine and Therapies. M.B. has received grant support to his institution for the current study from MAPS PBC; has received grants/contracts to his institution from Mend Medicine, Tilray Canada and the Heffter Research Institute; has been paid by AJNA Labs, Journey Colab and Bright Minds Biosciences for advisory board participation; and has received drug to his institution from Tilray Canada for an NIH-funded trial. Y.G. anticipates support from MAPS PBC for congress attendance in the future and has stock in MindMed. C.P. has received grants/contracts (research support) and consulting fees from MAPS PBC (training and supervision/consultation). C.R.N. has received grants/contracts fromm MAPS PBC (research studies); has received payment/honoraria from MAPS PBC and MindMed (training and educational events); has received meeting/travel support from MAPS PBC; and has received funding for contract work as an MDMA-assisted therapy trainer. S.Q. has received grants/contract support for research from MAPS. B.B. has received support for the present study from New School Research and the California Center for Psychedelic Therapy; has received consulting fees from MAPS PBC (training and supervision/consultation); has received payment/honoraria from the Integrative Psychiatric Institute, the California Association of Marriage and Family Therapists, the Los Angeles County Psychological Society and the Palm Springs Art Museum (lectures/speaking events); has received support for meetings/travel from MAPS PBC; and is a trainer representative for the MAPS PBC Commercial Advisory Committee and supervisor and coordinator of the Zendo Project (psychedelic harm reduction). S.H. is an employee of MAPS PBC. M.M. has received support for the present research from MAPS PBC (independent contractor) and is a member of the Awakn Life Sciences Scientific Advisory Board; has received royalties from PESI (video sales of presentations); has received consulting fees from MAPS PBC; has received payment from PESI (speaking) and the California Institute of Integral Studies (training workshops); has received honoraria from Harvard Medical School, Sounds True, the Integrative Psychiatry Institute and Vital (speaking); has received support from MAPS PBC for attending meetings/travel; and owns stock in Awakn Life Sciences. S.K. has received grants/contracts/consulting fees from MAPS PBC, pharmaceutical companies, VA hospitals and university research groups for providing supervision and training to psychodiagnostic assessors on a variety of research studies. K.P.-G. has received consulting fees from MAPS PBC for training assessors in psychodiagnostic assessment on PTSD treatment trials and from other research studies/groups conducting similar work. K.T. has received payment/honoraria from MAPS US (education and study activities in Israel), MAPS PBC (senior trainer and supervisor therapist) and MAPS Israel (co-founder and CEO) and meeting/travel support from MAPS PBC. C.H. is a MAPS PBC employee; has received consulting fees from Cybin (unrelated molecule and indication in the psychedelics field); and has received meeting/travel support from MAPS PBC. A.d.B. was previously an employee of MAPS PBC; has received consulting fees (to Tulip Medical Consulting); has received meeting travel/support from MAPS PBC; and served as CMO (while previously an employee of MAPS PBC) and attended Data Safety Monitoring Board meetings without any voting rights. R.D. is the founder and president (salaried employee) of MAPS and is a member of the Board of MAPS and MAPS PBC. B.Y.-K. is an employee of MAPS PBC, was previously an employee of MAPS and has received support from MAPS PBC and MAPS for attending meetings/travel.

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Mitchell, J.M., Ot’alora G., M., van der Kolk, B. et al. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med 29 , 2473–2480 (2023). https://doi.org/10.1038/s41591-023-02565-4

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Peer-reviewed

Research Article

Post-traumatic stress disorder and associated factors among internally displaced persons in Africa: A systematic review and meta-analysis

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Department of Environmental and Occupational Health and Safety, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

Roles Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft

Affiliation Department of Clinical Pharmacy, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

Roles Methodology, Visualization, Writing – review & editing

Roles Methodology, Supervision, Visualization, Writing – review & editing

Roles Data curation, Investigation, Visualization, Writing – review & editing

Affiliation Department of Nursing, College of Medicine and Health Sciences, Jigjiga University, Jigjiga, Ethiopia

Roles Data curation, Methodology, Supervision, Visualization, Writing – review & editing

Affiliation Department of Environmental Health, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia

Roles Data curation, Methodology, Validation, Visualization, Writing – review & editing

Affiliation Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia

Roles Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing

Affiliation Department of Epidemiology and Biostatistics, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

Roles Data curation, Investigation, Methodology, Supervision, Validation, Visualization, Writing – review & editing

• Amensisa Hailu Tesfaye, 
• Ashenafi Kibret Sendekie, 
• Gebisa Guyasa Kabito, 
• Garedew Tadege Engdaw, 
• Girum Shibeshi Argaw, 
• Belay Desye, 
• Abiy Ayele Angelo, 
• Fantu Mamo Aragaw, 
• Giziew Abere

• Published: April 1, 2024
• https://doi.org/10.1371/journal.pone.0300894
• Peer Review
• Reader Comments

Internally displaced people (IDPs), uprooted by conflict, violence, or disaster, struggle with the trauma of violence, loss, and displacement, making them significantly more vulnerable to post-traumatic stress disorder (PTSD). Therefore, we conducted a systematic review and meta-analysis to assess the prevalence and associated factors of PTSD among IDPs in Africa.

A comprehensive search of electronic databases was conducted to identify relevant studies published between 2008 and 2023. The search included electronic databases such as PubMed, CABI, EMBASE, SCOPUS, CINHAL, and AJOL, as well as other search sources. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Data were extracted using Microsoft Excel, and analysis was performed using STATA 17 software. The quality of the included studies was assessed using the JBI quality appraisal tool. A random-effects model was used to estimate the pooled prevalence of PTSD and its associated factors. The funnel plot and Egger’s regression test were used to assess publication bias, and I 2 test statistics was used to assess heterogeneity. The protocol for this review has been registered with PROSPERO (ID: CRD42023428027).

A total of 14 studies with a total of 7,590 participants met the inclusion criteria. The pooled prevalence of PTSD among IDPs in Africa was 51% (95% CI: 38.-64). Female gender (OR = 1.99, 95% CI: 1.65–2.32), no longer married (OR = 1.93, 95% CI: 1.43–2.43), unemployment (OR = 1.92, 95% CI: 1.17–2.67), being injured (OR = 1.94, 95% CI: 1.50–1.50), number of traumatic events experienced [4-7(OR = 2.09, 95% CI: 1.16–3.01), 8–11 (OR = 2.09, 95% CI: 2.18–4.12), 12–16 (OR = 5.37, 95% CI: 2.61–8.12)], illness without medical care (OR = 1.92, 95% CI: 1.41–2.29), being depressed (OR = 2.97, 95% CI: 2.07–3.86), and frequency of displacement more than once (OR = 2.13, 95% CI: 1.41–2.85) were significantly associated with an increased risk of PTSD.

Conclusions

The findings of this systematic review and meta-analysis highlight the alarming prevalence of PTSD among IDPs in Africa. Female gender, marital status, number of traumatic events, ill health without medical care, depression, and frequency of displacement were identified as significant risk factors for PTSD. Effective interventions and the development of tailored mental health programs are needed to prevent PTSD among IDPs, focusing on the identified risk factors.

Citation: Tesfaye AH, Sendekie AK, Kabito GG, Engdaw GT, Argaw GS, Desye B, et al. (2024) Post-traumatic stress disorder and associated factors among internally displaced persons in Africa: A systematic review and meta-analysis. PLoS ONE 19(4): e0300894. https://doi.org/10.1371/journal.pone.0300894

Editor: Roberto Ariel Abeldaño Zuñiga, University of Helsinki, FINLAND

Received: December 6, 2023; Accepted: March 5, 2024; Published: April 1, 2024

Copyright: © 2024 Tesfaye et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting information files ( S3 File ).

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Internally displaced persons (IDPs) are individuals forced to flee their homes due to conflict, natural disasters, or other man-made or natural events [ 1 ]. These individuals face numerous challenges, including physical and psychological trauma, witnessing violence, loss of livelihoods, and separation from family and friends [ 2 , 3 ]. These challenges can contribute to the development of post-traumatic stress disorder (PTSD), a common mental health condition characterized by flashbacks, nightmares, hypervigilance, avoidance, and emotional numbness [ 4 – 6 ].

PTSD can have a profound and debilitating impact on the lives of IDPs, posing significant challenges to their recovery and reintegration into society [ 3 ]. The impact of PTSD on IDPs extends beyond the individual, affecting their families and communities as well. The emotional turmoil and behavioral changes associated with PTSD can strain relationships within families, leading to conflict, neglect, and further emotional distress [ 1 , 7 ]. PTSD can also lead to secondary problems such as substance abuse, self-harm, and suicide [ 8 , 9 ]. Moreover, the inability of IDPs with PTSD to contribute fully to their communities can hinder collective recovery efforts and exacerbate existing social and economic vulnerabilities [ 1 , 7 , 10 ]. The impact could have been highly significant in Africa because of several factors, including insufficient mental health services, the stigma associated with mental health problems, and the logistical challenges of providing mental health services to IDPs who are often living in remote areas [ 11 – 13 ].

Globally, more than 71 million people are internally displaced as of the end of 2022 across 120 countries because of conflict, violence, and disasters. This number shows an increase of 20% from the previous year [ 14 ]. Human and natural disasters that could potentially cause IDPs have been prominently reported in sub-Saharan Africa [ 15 ]. In 2020, Africa accounted for almost 40% of all new internal displacements globally, with natural disasters being the primary cause of displacement in 32 out of 54 African countries [ 16 ]. According to the United Nations Human Rights Commission (UNHCR), 42% of all IDP people globally have lived in Africa [ 17 ].

The prevalence of PTSD among IDPs varies widely, ranging from 3% to 88% depending on the specific country and population studied [ 18 , 19 ]. The prevalence of PTSD in East Africa ranges from 11% to 80.2% [ 20 – 22 ]. Similarly, a meta-analysis study conducted in sub-Saharan African countries reveals that the magnitude of PTSD ranges from 12.3% in Central Sudan to 85.5% in Nigeria, and the majority of them reported to have more than 50% of the magnitude of PTSD [ 23 ]. This suggests that PTSD is a significant public health problem among IDPs in Africa.

Several factors have been identified as being associated with an increased risk of PTSD among IDPs. These factors include: female gender, young age, trauma, experiencing or witnessing violence, depression, anxiety, stress, low level of educational status, lack of social support, and economic hardship [ 20 , 23 , 24 ]. Beyond the previously mentioned factors, a number of other factors may also increase the likelihood of PTSD in IDPs in Africa. These factors include political instability and ongoing conflict, which can prolong the trauma and displacement cycle and make it more challenging for IDPs to find stability and security. This ongoing exposure to stress and uncertainty can exacerbate PTSD symptoms and hinder recovery efforts. Poverty and food insecurity are also common among IDPs in Africa, creating additional stressors and challenges. These socio-economic factors can contribute to feelings of hopelessness, despair, and a sense of being trapped in a difficult situation, further exacerbating PTSD among these vulnerable groups [ 25 – 28 ].

Despite the high prevalence of PTSD among IDPs in different African countries, there is a lack of comprehensive studies that show the pooled impact of PTSD and the nature of risk factors. Thus, a comprehensive study that can address the overall public health impact of internal displacement in terms of causing PTSD could be important to provide mental health services for IDPs. Therefore, the purpose of this systematic review and meta-analysis is to synthesize existing evidence on the prevalence of PTSD and its associated factors among IDPs in Africa. This information will be used to inform the development of interventions to prevent and treat PTSD among IDPs in Africa.

Methods and materials

Study setting.

The study provides a comprehensive synthesis of existing research on PTSD prevalence rates and examines risk factors contributing to the development of PTSD among IDPs in African countries. According to the African Development Bank, there are 54 countries in Africa today [ 29 ].

Protocol and registration

The protocol for this review was registered in the International Prospective Register of Systematic Reviews (PROSPERO), the University of York Centre for Reviews and Dissemination (Record ID: CRD42023428027, May 31 st , 2023).

Data sources and search strategy

This review and meta-analysis were conducted according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The three phases drawn from the PRISMA flowchart were documented in the results to show the study selection process from identification to the included studies [ 30 ]. The PRISMA checklist was also used in the reporting of the systematic review and meta-analysis ( S1 File ).

We extensively searched articles on PubMed/MEDLINE, CABI, EMBASE, SCOPUS, CINHAL, and African Journal Online (AJOL) up to June 11, 2023. According to the African Development Bank, there are 54 countries in Africa [ 29 ]. The search terms were selected to capture relevant articles on PTSD and IDPs in African countries. The search was conducted using a combination of keywords and controlled vocabulary (MeSH terms). The search strategy was adapted for each database as per their specific syntax and indexing terms. For the PubMed search, the following key terms were used in combination with the Boolean operators "AND" and "OR". ("Post-traumatic stress disorder" [All Fields] OR "Posttraumatic stress disorder" [All Fields] OR "PTSD" [All Fields]) AND ("Internally displaced persons" [All Fields] OR "Internally displaced people"[All Fields] OR "Internally displaced individuals" [All Fields] OR "IDP" [All Fields]) AND ("Associated factors" [All Fields] OR "Determinant factors" [All Fields] OR "Risk factors" [All Fields]) AND "Africa" [All Fields].

In addition to these electronic database searches, we searched the grey literature using website searches such as BioMed Central and National Institute of Mental Health, Behavioral and Brain Sciences—Cambridge University Press, etc., Google Search, and Google Scholar. We also searched the reference lists (bibliographies) of the included studies for additional relevant studies.

Eligibility criteria

Inclusion criteria..

Articles that met the following criteria were considered for inclusion in this systematic review and meta-analysis.

• Population: internally displaced persons (IDPs).
• Outcomes: articles reported the quantitative outcome of the prevalence of PTSD and associated factors among IDPs in Africa.
• Study design: a cross-sectional study.
• Study setting: studies conducted in African countries.
• Publication issue: peer-reviewed journal articles published before 11 June 2023.

Exclusion criteria.

Systematic reviews, qualitative studies, letters to editors, short communications, and commentaries were excluded. In addition, articles that were not fully accessible after three personal email contacts with the corresponding author and articles that did not indicate the outcome interest of this study were all excluded.

Study selection process

The Endnote X9.2 (Thomson Reuters, Philadelphia, PA, USA) software reference manager was used to collect and organize search results and to remove duplicate articles. Three investigators (AHT, FMA, and GA) independently screened articles by their title, abstract, and full text to identify eligible articles using predetermined inclusion and exclusion criteria. The screened articles were then compiled together by three investigators (AHT, GSA, and AKS), and the disagreement between authors that arises during data abstraction and selection is solved based on evidence-based discussion and the involvement of other investigators (AKS, GTE, and AAA).

Data extraction and management

Data were extracted using the Joanna Briggs Institute (JBI) data extraction checklist. Four review authors (AHT, FMA, GGK, and BD) extracted the data independently using a Microsoft Excel spreadsheet. The data extraction format included (name of first author, publication year, study country, study design, sample size, response rate, prevalence of PTSD, total number of participants, factors associated with PTSD with their respective OR with 95% CI, and risk of bias). Disagreements between the review authors were resolved by a review by the other review authors based on an evidence-based discussion.

Quality assessment of the studies

The quality of the included articles was assessed using the Joanna Briggs Institute (JBI) quality appraisal tools for analytical cross-sectional studies [ 31 ]. Three investigators (AHT, AKS, and GA) independently assessed the quality of the included articles. The assessment tool contains eight criteria: (1) clear inclusion and exclusion criteria; (2) description of the study subject and study setting; (3) use of a valid and reliable method to measure the exposure; (4) standard criteria used for measurement of the condition; (5) identification of confounding factors; (6) development of strategies to deal with confounding factors; (7) use of a valid and reliable method to measure the outcomes; and (8) use of appropriate statistical analysis. The risks for biases were classified as low (total score, 6 to 8), moderate (total score, 3 or 5), or high (total score, 0 to 2) ( S2 File ). Finally, articles with low and moderate biases were considered in this review. Disagreements that arose during the full-text quality assessment were resolved through evidence-based discussion with the involvement of other review authors (GGK, GA, and BD).

Outcome of interest

The primary outcome of this review was the pooled prevalence of post-traumatic stress disorder (PTSD). It was reported as a percentage (%). The second outcome of this review was the pooled measure of the association between PTSD and associated factors among IDPs in Africa. It was determined using the pooled odds ratio (OR) with a 95% confidence interval.

Statistical methods and data analysis

The extracted data were exported from a Microsoft Excel spreadsheet to STATA version 17 for further analysis. Heterogeneity among the included studies was quantitatively measured by the index of heterogeneity (I 2 statistics), in which 25%-51%, 50%-75%, and>75% represented low, moderate, and high heterogeneity, respectively [ 32 ]. The overall pooled estimate of PTSD among IDPs in Africa was computed using the metaprop STATA command. A subgroup analysis was conducted by a study country to see the difference in the pooled prevalence of PTSD between countries. The influence of a single study on the overall pooled estimate was assessed using a sensitivity analysis. Furthermore, the small-study effect was evaluated using the funnel plot test and Egger’s regression test, with a p-value <0.05 as a cutoff point to declare the presence of publication bias. A p-value <0.05 was used to declare factors associated with PTSD to be statistically significant with a pooled odds ratio (OR) at the 95% confidence level. The results were presented using graphs, tables, text, and a forest plot.

Searching process

A total of 4622 articles were identified using electronic databases and manual searching. After removing duplicate records, 3427 records were screened for this review. Based on their titles and abstracts, 3351 articles were excluded. In addition, 62 articles were excluded based on the exclusion criteria. Finally, a total of 14 articles were included in this review. The PRISMA flow diagram was used to summarize the selection process ( Fig 1 ).

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• TIFF original image

https://doi.org/10.1371/journal.pone.0300894.g001

Characteristics of the included studies

In this review, the publication year, country of study, study design, sample size, and prevalence of PTSD are summarized in Table 1 . By design, all included studies were cross-sectional. This study included a total of 7,590 participants [ 2 , 10 , 20 , 21 , 24 , 26 , 33 – 40 ]. The included articles were published between 2008–2023. The included study sample sizes ranged from 93 to 1291. In this review, a study conducted in Sudan, South Darfur, at the Darfur Campaign study site, showed the lowest prevalence of PTSD (14.9%) [ 35 ], while a study conducted in IDP camps in Yobe State in northeastern Nigeria showed the highest prevalence of PTSD (94.2%) [ 2 ]. Three studies were from Ethiopia [ 20 , 26 , 33 ]; five studies were from Nigeria [ 2 , 24 , 38 – 40 ] and the remaining studies were from Kenya [ 34 ], Somalia [ 10 ], Sudan [ 35 ], South Sudan [ 36 ], Uganda [ 21 ] and the Democratic Republic of Congo (DRC) [ 37 ]. The included studies were categorized as having a low risk of bias (quality score 6 to 8). The description of the included studies is presented in Table 1 .

https://doi.org/10.1371/journal.pone.0300894.t001

Assessment methods of PTSD.

This research review included studies with varying screening methods for PTSD. While standardized questionnaires were common, most lacked clinical confirmation, raising potential concerns about the accuracy of PTSD diagnoses. However, some studies employed both questionnaires and clinical confirmation, offering a more robust approach to assessing PTSD. Details of these assessment methods used in the original studies are summarized in Table 2 .

https://doi.org/10.1371/journal.pone.0300894.t002

Meta-analysis

Pooled prevalence of ptsd among idps in africa.

The pooled prevalence estimate of PTSD was found to be 51% (95% CI: 38–64; I 2 = 99.38%). In this analysis, the lowest prevalence of PTSD was found in Sudan at 15% (95% CI: 9–25) [ 35 ] and the highest prevalence of PTSD was found in Nigeria at 94% (95% CI: 92–96) [ 2 ]. A forest plot shows the prevalence estimates of PTSD among IDPs in Africa ( Fig 2 ).

https://doi.org/10.1371/journal.pone.0300894.g002

Subgroup analysis

Subgroup analysis was done to see the pooled prevalence of PTSD by country. According to the result, of in-country subgroup analysis, the pooled prevalence of PTSD was 62% (95% CI: 41–82) in Nigeria and 54% (95% CI: 36–72) in Ethiopia. Subgroup analysis of the study showed that the highest and lowest prevalence of PTSD was in Nigeria, 62% (95% CI: 41–82), and Sudan, 15% (95% CI: 9–25), respectively ( Fig 3 ). A subgroup analysis was also performed with clinically confirmed cases of PTSD and positive screening cases of PTSD as different subgroups. Accordingly, the pooled prevalence of clinically confirmed cases of PTSD was 31% (95% CI: 15–46) and positive screening cases of PTSD was 55% (95% CI: 44–65) (Figs 4 & 5 ).

https://doi.org/10.1371/journal.pone.0300894.g003

https://doi.org/10.1371/journal.pone.0300894.g004

https://doi.org/10.1371/journal.pone.0300894.g005

Heterogeneity and publication bias

The presence of heterogeneity and publication bias (small study effect) was assessed within the included studies. The included studies had a high degree of heterogeneity (I 2 = 99.38%, p = 0.00). Publication bias was assessed using a funnel plot and Egger’s regression test at a p-value <0.05. The funnel plot showed that the distribution of studies was asymmetrical, whereas Egger’s test was found to be not statistically significant for the estimated prevalence of PTSD (p = 0.063), meaning that there was no evidence of publication bias ( Fig 6 ).

https://doi.org/10.1371/journal.pone.0300894.g006

Sensitivity analysis test

A sensitivity analysis was performed to assess the effect of each study on the pooled estimate of PTSD. However, the results of the sensitivity analysis showed that there was no single study effect on the pooled prevalence of PTSD in the fitted meta-analytic model, as shown in Fig 7 .

https://doi.org/10.1371/journal.pone.0300894.g007

Factors associated with PTSD among IDPs in Africa.

Factors associated with PTSD were identified based on the pooled effect of two or more studies. In this meta-analysis, factors associated with PTSD were assessed using 14 studies [ 2 , 10 , 20 , 21 , 24 , 26 , 33 – 40 ]. The analysis showed that in 4 of these studies [ 20 , 21 , 33 , 36 ], female IDPs were found to have a twofold higher risk of developing PTSD compared to male IDPs (OR = 1.99, 95% CI: 1.65–2.32). The pooled results of three studies [ 21 , 33 , 36 ] revealed that individuals who were no longer married (divorced, separated, widowed, or forcefully separated) had 1.93 times higher likelihood of PTSD compared to those who were married or single (OR = 1.93, 95% CI: 1.43–2.43). Similarly, the pooled findings of two studies [ 10 , 26 ] showed that the likelihood of PTSD was 1.92 times higher for unemployed IDPs compared to employed IDPs (OR = 1.92, 95% CI: 1.17–2.67). Furthermore, two studies’ combined results [ 33 , 36 ] revealed that the likelihood of PTSD was 1.94 times higher for injured IDPs than for uninjured ones (OR = 1.94, 95% CI: 1.50–2.37).

Moreover, the pooled results of two studies [ 20 , 21 ] of this meta-analysis revealed a positive correlation between the likelihood of developing PTSD and the commutative number of traumatic incidents encountered. The odds of PTSD were higher in IDPs who had experienced four or more of the sixteen traumatic events (OR = 2.09, 95% CI: 1.16–3.01), 3.15 times higher in those who had experienced eight to eleven traumatic events (OR = 2.09, 95% CI: 2.18–4.12), and 5.37 times higher in those who had experienced twelve or more traumatic events (OR = 5.37, 95% CI: 2.61–8.12) compared to those who had experienced zero to three traumatic events. The combined findings of two studies [ 21 , 36 ] revealed that the odds of having PTSD were 1.92 times higher for IDPs with poor health who did not receive medical care than for those who did receive medical care (OR = 1.92, 95% CI: 1.41–2.29). Furthermore, the pooled result from four studies [ 2 , 20 , 24 , 26 ] revealed that people with depression had a 2.97-fold increased risk of developing PTSD compared to people without depression (OR = 2.97, 95% CI: 2.07–3.86). Additionally, the current analysis discovered a substantial correlation between PTSD and a higher frequency of displacement. The meta-analysis’s combined findings showed that those who were internally relocated more than once had a 2.13-fold increased risk of developing PTSD ( Table 3 ).

https://doi.org/10.1371/journal.pone.0300894.t003

Internally displaced persons (IDPs) are particularly vulnerable to PTSD because they have often experienced traumatic events such as violence, loss of loved ones, and destruction of their homes [ 41 , 42 ]. They may also have difficulty accessing mental health care, which can make it harder to recover from PTSD. Investigating the overall impact and risk factors might be important to the development of interventions to prevent and treat PTSD among IDPs in Africa. The current review presents comprehensive findings on the pooled magnitude of PTSD and its associated factors among IDPs in Africa.

This systematic review and meta-analysis found that the pooled prevalence of PTSD among IDPs in Africa was 51% (95% CI: 38–64%). The prevalence of PTSD in this review was aligned with the studies carried out in the Kurdistan region of Iraq (60%) [ 43 ], and Sri Lanka (56%) [ 44 ]. Moreover, this finding is in concordance with a systematic review and meta-analysis study in Syria which reported a pooled estimate of 36% PTSD [ 45 ]. On the other hand, the prevalence of PTSD in this review was lower than that of the study done in Medellin, Colombia (88%) [ 46 ]. There are several possible explanations for these disparities. One possibility could be a difference in methodological approaches. Another possibility is that the studies were conducted with different populations in different cultural and social contexts to manage problems related to displacements [ 47 ]. Antithetically, the estimated prevalence of PTSD in the current review was higher than the studies carried out in another study in Sri Lanka (2.3%) [ 48 ], Georgia (23.3%) [ 49 ], Iraq (20.8%) [ 50 ], and India (9%) [ 51 ]. Furthermore, the prevalence of PTSD in the current study is higher than in a systematic review and meta-analysis of an epidemiological study done by Nexhmedin M. et al which reported a 26% pooled prevalence of PTSD among survivors living in war-afflicted regions [ 52 ].

The subgroup meta-analysis of this review showed that the pooled prevalence of clinically confirmed cases of PTSD was 31% (95% CI: 15–46) and positive screening cases of PTSD was 55% (95% CI: 44–65). One possible explanation for the higher prevalence rate among positive screening cases (55%) compared to clinically confirmed cases (31%) could be related to the sensitivity of the screening tool used. Screening tools are designed to identify individuals who may be at risk or likely to have the condition, but they may also capture individuals with false positives those who screen positive but may not meet the diagnostic criteria upon further clinical assessment. These false positives could inflate the prevalence rate among positive screening cases. On the other hand, clinically confirmed cases undergo a more comprehensive diagnostic evaluation, which includes clinical interviews, symptom assessment, and adherence to specific diagnostic criteria. This process is typically conducted by trained professionals such as qualified mental health professional and aims to ensure a more accurate diagnosis of PTSD. By applying stricter criteria, the diagnostic process may exclude individuals who had initially screened positive but do not meet the clinical diagnostic threshold. Consequently, the prevalence rate among clinically confirmed cases may be lower compared to positive screening cases [ 53 – 55 ].

Several factors may also contribute to the differences. The first possible reason could be due to the impact of conflict, mass displacement, and the level of property destruction repeatedly encountered in the African region where this review was conducted. This may include a combination of war and political and ethnic conflict [ 22 ]. In addition, this difference may be related to the differences in the accessibility and affordability of mental health care services in those different settings [ 23 ]. Furthermore, it is also possible that the studies were conducted at different times, and that the prevalence of PTSD has changed over time.

A meta-analysis of this review found that females were at higher risk of PTSD than men. Several factors could contribute to the higher prevalence of PTSD among females compared to males. Numerous studies across different countries have documented the higher prevalence of PTSD among females compared to males [ 13 , 23 , 56 – 60 ]. These factors can broadly be related to biological, psychological, and social factors. Hormonal differences between females and males that estrogen may enhance emotional reactivity and memory consolidation, potentially increasing the risk of PTSD [ 61 ]. Social factors could also contribute to increased PTSD in females because females are more likely to experience interpersonal trauma, such as sexual assault or domestic violence compared with males [ 23 , 62 , 63 ], which are associated with a higher risk of PTSD compared to other types of traumas. Gender roles and expectations of females may also emphasize emotional expressiveness and vulnerability, which could make them more susceptible to developing PTSD symptoms. Furthermore, psychological factors like coping strategies and social support might be among the factors contributing to the occurrence of PTSD among female IDPs. Females may be more likely to use emotion-focused coping strategies, such as rumination and suppression, which may exacerbate PTSD symptoms. Males, on the other hand, may favor problem-focused coping, which may be more effective at managing stress. In addition, females often have stronger social networks, which can provide emotional support and buffer against stress. However, these networks may also expose females to more trauma-related discussions, potentially increasing the risk of PTSD. Therefore, understanding these factors is crucial for developing effective prevention and treatment strategies for PTSD in this population. This finding may also suggest that it could be important to give more attention to females to provide psychological and general support to minimize the impact on their daily lives.

In this review, being divorced, separated, and widowed was found to be more associated with PTSD compared with being married and/or single. The finding is also consistent with previous studies [ 23 , 64 ]. Marital status can influence an individual’s vulnerability to PTSD in several ways: social support and emotional buffer, joint problem-solving and resource sharing, and sociocultural factors that marriage can provide a strong source of social support and emotional buffering, which can help individuals cope with stress and trauma. These findings suggest that marital status can play a significant role in influencing the risk of PTSD among IDPs. The supportive and protective aspects of marriage can help individuals cope with the challenges of displacement and trauma, reducing their vulnerability to PTSD. However, it is important to note that the relationship between marital status and PTSD may not always be straightforward. In some cases, some studies showed that marital strain or conflict can increase the risk of PTSD among married individuals [ 65 , 66 ]. Therefore, the impact of marital status on PTSD may vary depending on individual circumstances, cultural factors, and the specific nature of the traumatic event.

Consistent with earlier findings [ 10 ], employment status was also found to have a significant association with PTSD among IDPs. Several factors contribute to this association: loss of routine and structure that unemployment disrupts an individual’s daily routine and structure, which can be particularly destabilizing for IDPs who have already experienced the upheaval of displacement; financial strain, and economic hardship, adding to the stress and anxiety of displacement; limited access to mental health care that can hinder an individual’s ability to access mental health care, either due to financial constraints or the lack of employer-sponsored health insurance. These findings underscore the importance of employment in promoting mental health and well-being among IDPs. Supporting employment opportunities and providing vocational training can help IDPs regain a sense of normalcy, purpose, and control, reducing their risk of developing PTSD and improving their overall quality of life.

This review revealed that being injured is significantly associated with the existence of PTSD among IDPs, which is in line with other studies [ 23 , 42 , 67 ]. Experiencing physical injury during displacement can significantly increase an individual’s risk of developing PTSD because of direct trauma and physical pain, psychological impact of injury, impact on daily living and functioning, limited access to healthcare and support, trauma reactivation, and reminders of injury. These findings highlight the importance of addressing physical injuries and providing comprehensive support services for IDPs to mitigate the risk of developing PTSD. Timely and effective medical care, rehabilitation services, and psychological support can significantly improve the physical and mental health outcomes of IDPs who have experienced injuries.

The current finding has shown, consistent with earlier evidence [ 23 , 45 , 68 , 69 ], that the number of trauma events experienced was positively associated with the risk of PTSD. There is a well-established relationship between the number of trauma events experienced and the risk of PTSD among IDPs. Research suggests that each additional trauma event increases the likelihood of developing PTSD. This association can be attributed to several factors, such as accumulation of stress and emotional overload. Each trauma event exposes an individual to significant stress and emotional overload, taxing their coping mechanisms and increasing their vulnerability to developing PTSD. The cumulative effect of multiple trauma events can overwhelm an individual’s ability to process and integrate these experiences, leading to the development of PTSD symptoms. In addition, repeated exposure to traumatic events can heighten an individual’s sensitivity to trauma cues, making them more likely to experience flashbacks, nightmares, and intrusive thoughts related to the traumatic experiences. This sensitization can maintain the state of hypervigilance and emotional arousal characteristic of PTSD. These findings may underscore the importance of preventing and addressing trauma exposure among IDPs to reduce the risk of developing PTSD. Providing early intervention and mental health support services can help IDPs cope with the effects of trauma and prevent the development of PTSD.

Illness in the absence of medical care was found to be significantly associated with the presence of PTSD among IDPs and this is in line with other findings [ 21 ]. The absence of medical care significantly elevates the risk of developing PTSD among IDPs. This association stems from several interconnected factors including unmet physical and psychological needs. Lack of access to medical care can lead to the neglect of both physical and psychological needs following a traumatic event. These findings highlight the importance of providing comprehensive healthcare services to IDPs, including both physical and mental healthcare. Addressing their medical needs can significantly reduce the risk of developing PTSD and promote their overall well-being.

In the current review, the presence of depression is found to have a significant association with PTSD among IDPs, which is in line with earlier studies [ 10 , 21 , 23 ]. The co-occurrence of depression and post-traumatic stress disorder (PTSD) is prevalent among internally displaced persons (IDPs). This could be because of shared etiological factors that both depression and PTSD share common risk factors, such as exposure to trauma, genetic predisposition, and neurobiological alterations. Both depression and PTSD involve dysregulation of stress hormones, such as cortisol and norepinephrine. These hormonal imbalances can contribute to the development and maintenance of both conditions. In addition, IDPs face a range of social and environmental stressors, such as displacement, loss of social support, and economic hardship. These stressors can contribute to both depression and PTSD by exacerbating emotional distress and reducing resilience. These findings implicate the importance of addressing both depression and PTSD simultaneously in IDPs. Integrated treatment approaches that target both conditions can significantly improve the mental health outcomes of IDPs.

The current review also revealed that an increased frequency of displacement was also found to be significantly associated with PTSD. The finding is consistent with previous studies [ 21 , 23 , 42 , 67 , 68 ]. The number of times an individual had been displaced was positively associated with the risk of PTSD. Multiple factors contribute to the increased risk of PTSD among IDPs who experience repeated displacements. This could be because each displacement experience exposes an individual to significant stress and emotional overload, taxing their coping mechanisms and increasing their vulnerability to developing PTSD. Repeated displacements lead to an accumulation of traumatic experiences, making it increasingly difficult to process and integrate these experiences, ultimately increasing the risk of PTSD. Frequent displacements can heighten an individual’s sensitivity to trauma cues, making them more likely to experience flashbacks, nightmares, and intrusive thoughts related to the traumatic experiences. This sensitization perpetuates the state of hypervigilance and emotional arousal characteristic of PTSD. These findings suggest the importance of preventing and addressing repeated displacements to reduce the risk of PTSD among IDPs. Providing stable housing, livelihood support, and mental health services can help IDPs cope with the effects of displacement and prevent the development of PTSD.

Strengths and limitations of the study

This study was a first-of-its-kind systematic review and meta-analysis that estimated the pooled prevalence and associated risk factors of PTSD among IDPs in Africa. The study identified several significant risk factors for PTSD among IDPs. This information can be used to develop targeted interventions to prevent PTSD. This study has its limitations. Firstly, it was a cross-sectional study, so it could not establish cause-effect relationships. In addition, the lack of studies from countries other than those included may limit the continental representativeness of the study. Overall, the study is a valuable contribution to our understanding of PTSD among IDPs in Africa. The findings can be used to inform the development of targeted interventions to prevent PTSD among this vulnerable population.

The findings of this systematic review and meta-analysis highlight the alarming prevalence of PTSD among IDPs in Africa. The estimated pooled prevalence of 51% is significantly higher than the general population prevalence of PTSD, demonstrating the unique challenges faced by IDPs in coping with trauma and displacement. The study’s identification of significant risk factors, including female gender, marital status, traumatic events, ill health without medical care, depression, and frequency of displacement, provides valuable insights for targeted interventions. Effective interventions and the development of tailored mental health programs are needed to prevent and treat PTSD among IDPs, with focusing on the identified risk factors. Future studies focusing on the determinant factors of PTSD and their impacts on IDPs need to be welcomed.

Supporting information

S1 file. prisma checklist used in the reports of systematic review and meta-analysis..

https://doi.org/10.1371/journal.pone.0300894.s001

S2 File. JBI quality appraisal/result of the quality assessment of the studies.

https://doi.org/10.1371/journal.pone.0300894.s002

S3 File. Data set used in generating and analyzing of systematic review and meta-analysis.

https://doi.org/10.1371/journal.pone.0300894.s003

Acknowledgments

The authors would like to thank the University of Gondar, Ethiopia, for providing an office and free internet service. Moreover, the authors thanked and recognized the articles included in this study and used them as a basis for this systematic review and meta-analysis.

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• April 01, 2024 | VOL. 181, NO. 4 CURRENT ISSUE pp.255-346
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Trauma, Resilience, Anxiety Disorders, and PTSD

• Ned H. Kalin , M.D.

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Stress and trauma are well known to be critical factors in the development and maintenance of psychopathology. In some stress-related disorders, such as anxiety and depression, stress can play an etiological role, whereas in other disorders like schizophrenia, stress can precipitate and exacerbate symptoms. Stress occurring early in life in the form of traumatic events is a transdiagnostic risk factor for developing psychopathology, whereas posttraumatic stress disorder (PTSD) is a disorder that is specifically defined as a maladaptive response to traumatic events. In the midst of the COVID-19 pandemic, and certainly to no one’s liking, we currently are involved in a naturalistic experiment linking stress to mental suffering and psychopathology.

Most of us have never experienced stressors of the magnitude and length associated with the global COVID-19 pandemic. Because the pandemic has been so prolonged, and in part as a way to cope, many of us have become inured to its catastrophic effects. It is mind boggling that we have begun to accept as commonplace the fact that 3,000 Americans per day are dying from COVID-19 or that the economic consequences are so dire that 16% of adults with children report not having sufficient food ( 1 ). Although it may be obvious, it is important to enumerate why the COVID-19 pandemic represents the perfect storm of stressors and traumatic events:

A long-term sense of uncertainty about the future coupled with a sense of uncontrollability.

Concerns about contracting COVID-19, becoming gravely ill, and dying.

Worries about losing loved ones and friends, and the grief associated with real losses.

The trauma associated with being gravely ill with COVID-19.

Prolonged physical separation and social isolation from family and friends.

Disruption of regular routines, including work and school for children.

Losses of jobs, business failures, and the profound economic consequences.

Lack of trust in leadership to effectively deal with the crisis.

As mental health care providers, we are in the uniquely challenging position of both personally experiencing the disruptive influences of chronic stress associated with the pandemic and working with patients and other vulnerable individuals to mitigate the consequences of the stress and tragedies that they are experiencing. It is critical to underscore the need to provide additional resources to underprivileged and marginalized individuals, as they are particularly vulnerable to the direct and indirect consequences of the COVID-19 pandemic. For example, Black and Latino households are twice as likely as White households to experience food insufficiency during the pandemic.

The focus of this issue of the Journal is highly relevant, as it provides new insights into the neural alterations associated with trauma, resilience, anxiety disorders, and PTSD as well as insights into new, promising treatment strategies. Dr. Yuval Neria, a PTSD expert from Columbia University, reviews neuroimaging findings in relation to PTSD and addresses how they may relate to the heterogeneity of PTSD symptom presentation and inform selective treatment approaches ( 2 ). Dr. Yair Bar-Haim from Tel Aviv University and his colleagues present a thought-provoking commentary suggesting that symptoms associated with the intrusive reexperiencing of traumatic events should be prioritized as a focus of research efforts to elaborate mechanisms underlying responses to trauma and PTSD ( 3 ). Dr. Dylan Gee and Paola Odriozola from Yale University coauthor a review that uses a translational neuroscience approach to discuss learning mechanisms relevant to the maladaptive regulation of fear and anxiety. In addition to considering conditioned fear learning and extinction, this review emphasizes the importance of safety signal learning, describes its underlying mechanisms, and speculates about the potential utility of using safety signal learning approaches in treating youths with anxiety disorders ( 4 ).

Is Inducing Anxiety in Healthy Individuals a Valid Approach for Understanding Pathophysiological Processes in Patients With Anxiety Disorder?

Numerous studies in healthy individuals have used threat-related paradigms in combination with neuroimaging to characterize the neural correlates of adaptive anxiety responses. The findings from these studies have frequently been used to draw inferences about alterations in neural activation that are associated with maladaptive anxiety responses in individuals with anxiety disorders. Chavanne and Robinson focus on determining whether studying healthy individuals under conditions of threat is a valid approach for understanding brain processes relevant to psychopathology ( 5 ). In their study, the authors first performed a meta-analysis on neuroimaging findings from studies in which patients with anxiety disorders were compared with control subjects when exposed to emotion-related paradigms. The results of this analysis were further compared with a meta-analysis of imaging findings assessing neural responses induced by unpredictable threat paradigms in healthy individuals. Across healthy individuals and those with anxiety disorders, increased activation was found in the insula, cingulate cortex, medial prefrontal cortex, and periaqueductal gray. There were also some differences between individuals with specific disorders and healthy control subjects. Similarities in neural activation between healthy individuals exposed to threat and individuals with anxiety disorders appeared to be greatest for individuals with specific phobias and were least similar for those with generalized anxiety disorder. In an editorial, Dr. Alexander Shackman from the University of Maryland and Dr. Andrew Fox from the University of California, Davis, discuss these findings in relation to the validity of using healthy subjects to understand pathophysiological processes in patients with anxiety disorders. They also point to additional work that needs to be done with animal models and humans to further develop an understanding of the mechanisms underlying pathological anxiety ( 6 ).

Using Brain Network Connectivity to Estimate the Severity of Dissociative Symptoms

Dissociative symptoms are a hallmark of PTSD and can be very disabling. The study by Lebois et al. ( 7 ) presents data demonstrating the capacity to use machine learning with functional connectivity MRI data to modestly estimate individual differences in dissociative symptoms in women with PTSD. In their study involving 65 women, the authors demonstrated that they could estimate about 24% of the variance in an individual’s dissociative symptom severity by using the functional connectivity data. Hyperconnectivity between regions of the default mode network and the frontoparietal network appeared to contribute most to this prediction. Of importance, this brain network connectivity–based estimate controlled for childhood trauma and PTSD symptom severity, suggesting that the connectivity patterns identified to be associated with dissociative symptoms involved distinct neural alterations. In addition to providing a better understanding of the neural underpinnings of dissociative symptoms, the results of this study suggest that in the future it may be plausible to use brain-based neural connectivity measurements as an objective proxy for subjective reports of dissociative symptoms. In his insightful editorial, Dr. Vinod Menon from Stanford University discusses how the functions of the default mode network and frontoparietal network, and their interactions, may relate to the subjective experience of dissociation ( 8 ). In addition, he suggests that interventions aimed at components of the salience network, such as the anterior cingulate cortex, may ameliorate dissociative symptoms by affecting interactions between the default mode and frontoparietal networks.

Patterns of Cortical Thinning Are Shared Across Individuals With Internalizing, Externalizing, and Thought Disorder–Related Symptoms

Brain structural alterations are commonly reported in patients across various psychiatric diagnoses. Romer and colleagues ( 9 ) present data demonstrating overlapping patterns of reduced cortical thickness in individuals with internalizing symptoms (e.g., depression and anxiety), externalizing symptoms (e.g., substance abuse and antisocial behavior), and thought disorder–related symptoms (e.g., delusions and hallucinations). This study used structural imaging data to assess cortical thickness and cortical surface area from 45-year-old individuals who were part of the longitudinally studied Dunedin Cohort. In addition to demonstrating cortical thinning across diagnostic domains, patterns of cortical thinning were related to the general psychopathology dimensional score known as the p factor. It is important to keep in mind that these relations do not address issues of causality. Based on these data, the authors argue that the transdiagnostic nature of pervasive cortical thinning further supports the value of a broad and general approach to study the relations between psychopathology and brain alterations.

Resilience During Pregnancy Is Associated With Increased Telomere Length in Newborns

Telomeres are strands of nucleotides at the ends of chromosomes that have various functions, including protecting the chromosome from degradation. In general, shortened telomeres have been associated with stress exposure, various illnesses, and aging. Verner and colleagues ( 10 ) studied 656 mother-infant dyad pairs and, by using multiple behavioral measures collected during pregnancy, computed factors associated with stress and positivity. Telomere length was assessed in leukocytes collected from cord blood at birth. The findings demonstrate an association between individual differences in pregnant mothers’ stress factor and shorter telomere length in newborns. In contrast, individual differences in the positivity factor during pregnancy were associated with increased telomere length. By statistically accounting for the effects of positivity on stress, the authors derived what they considered to be a measure of resilience, and by using this measure, they demonstrate that maternal resilience is associated with increased telomere length in newborns. The findings from this study are exciting as they suggest that resilience during pregnancy has important implications at the cellular and molecular level for newborns and for their development. In her editorial, Dr. Stacy Drury from Tulane University further discusses the relevance of telomere length and function in relation to health and disease. She also presents possible mechanisms by which stress during pregnancy might affect offspring telomeres ( 11 ).

Ketamine Treatment for PTSD

New and effective treatments are needed for patients with PTSD. Feder et al. ( 12 ) report findings from a randomized clinical trial examining the effects of repeated intravenous ketamine infusions on symptoms in PTSD patients. Ketamine is an N -methyl- d -aspartate receptor antagonist with effects on numerous other systems, including opiate receptors, and when administered in subanesthetic doses, it is effective in rapidly decreasing depressive symptoms. The authors of the present study previously reported that a single dose of ketamine had positive short-term effects in PTSD patients, and they now extend this work by assessing the effects of repeated ketamine administration as a means to provide longer-term efficacy. In the study, 30 chronically ill PTSD patients were randomly assigned to receive, over a 2-week period, either six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) as an active placebo. In the 29 individuals who completed the study, 15 received ketamine. The findings demonstrated rapid responses to ketamine. When assessed at 1 and 2 weeks, ketamine was significantly and robustly more effective in reducing symptoms compared with midazolam. It is important to note that although the repeated ketamine infusions were highly effective, the median time to the loss of the ketamine response was 27.5 days. In their editorial, Dr. Murray Stein from the University of California, San Diego, and Dr. Naomi Simon from New York University emphasize the need to develop more effective treatments for PTSD. They also comment on the renewed interest in psychedelic drugs as therapeutic agents and the possible mechanisms by which ketamine may work in relation to modifying the recall of traumatic memories associated with PTSD ( 13 ).

Conclusions

The imperative to understand how stress and trauma increase the vulnerability to develop psychiatric illnesses could not be more relevant and timelier as the world’s population is experiencing unprecedented levels of stress, trauma, fear, anxiety, and grief. It is also extremely important to focus on, and understand, the factors that promote resilience, as we witness the remarkable capacities of individuals to endure, cope with, and overcome the adversity and challenges presented by the pandemic.

This issue of the Journal provides a comprehensive focus on new research findings relevant to these issues. Highlights from the reports in this issue include findings that there is evidence supporting the dimensionality of anxiety, as there is shared activation of anxiety-related neural circuitry between healthy individuals and those with anxiety disorders; that resilience during pregnancy is associated with greater “healthier” telomere length in newborns; that focusing on safety learning may be a fruitful treatment approach for anxiety disorders, especially for children; that machine learning methods can be employed with imaging data to predict the severity of dissociative symptoms in PTSD patients; and that repeated ketamine administration over a 2-week period robustly decreases PTSD symptoms.

Disclosures of Editors’ financial relationships appear in the April 2020 issue of the Journal .

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• Cited by None

• Posttraumatic Stress Disorder (PTSD)
• Coronavirus/COVID-19
• Anxiety Disorders

ORIGINAL RESEARCH article

The impact of coping strategies and positive resources on post-traumatic stress symptoms among bereaved families of the sewol ferry disaster.

• 1 Department of Psychiatry, National Medical Center, Seoul, Republic of Korea
• 2 Division of Health Administration, College of Software and Digital Healthcare Convergence, Yonsei University, Wonju, Republic of Korea
• 3 Department of International Healthcare Administration, College of Bio and Medical Sciences, Catholic University of Daegu, Daegu, Republic of Korea
• 4 Department of Psychiatry, Seoul St. Mary’s Hospital, The Catholic University of Korea, College of Medicine, Seoul, Republic of Korea

Introduction: This study investigated the long-term prevalence of, and factors associated with, post-traumatic stress disorder (PTSD) among the bereaved families of the Sewol ferry disaster, in which 250 students lost their lives during a school excursion.

Methods: Eight years after the disaster, 181 family members were surveyed, and the prevalence of clinical PTSD symptoms was estimated. The Positive Resources Test (POREST), the Duke-UNC Functional Social Support Questionnaire, and the Brief COPE were evaluated using self-report measures. The multivariable binomial logistic regression was used to identify protective and risk factors for PTSD.

Results: PTSD symptoms were present in 49.7% of the family members 8 years after the incident. A one-point increase in the score on the optimism subscale of the POREST was associated with a 20.1% decreased likelihood of having clinical PTSD symptoms (OR = 0.799; p = 0.027; 95% CI = 0.655–0.975). Conversely, a one-point increase in the score on the avoidant subscale of Brief COPE was associated with a 13.2% increased likelihood of having clinical PTSD symptoms (OR = 1.132; p = 0.041; 95% CI = 1.005–1.274).

Discussion: Our results provide evidence of the need for long-term mental health monitoring of bereaved families of disaster victims, along with valuable insights for the development of mental health intervention programs.

1 Introduction

The sinking of the Sewol ferry in 2014 was a tragic incident that claimed the lives of 250 out of the 325 high school students onboard for a field trip. This disaster is regarded as one of South Korea’s worst social catastrophes, sparking extensive criticisms and conflicts related to issues like inadequate ship management, errors in judgment by the captain and crew, delayed response, misleading announcements, and perceived mishandling by the government. Even today, the incident remains a highly sensitive and contentious topic, underscoring the severity of the tragedy and the need to address the systemic failures and shortcomings that led to such a devastating loss of life.

Notably, the families of the deceased students continue to suffer from various mental health issues, including depression, anxiety post-traumatic stress disorder (PTSD), and complicated grief ( 1 – 3 ). After conducting a cross-sectional study on the mental health of Sewol Ferry disaster bereaved families 18 months after the incident, the results revealed that 94% experienced complicated grief, 50% reported severe depression, and 70% exhibited clinically significant post-traumatic symptoms (PTSS) ( 2 ). When assessing the embitterment of the accident-affected families, it was found to be 63% at 18 months post-incident, increasing to 77% at 30 months. The group experiencing an increase also showed a concurrent rise in anxiety, post-traumatic stress symptoms, and complicated grief ( 3 ). Furthermore, the group diagnosed with PTSD and complicated grief among the accident-affected families was found to be associated with a perception of injustice, according to the analysis results ( 1 ). Understanding the factors related to PTSD might be crucial to improve these disaster-bereaved families’ long-term mental health.

Numerous studies have made significant efforts to identify the risk and protective factors for PTSD ( 4 – 10 ). Coping strategies have been found to play a vital role in mental health outcomes, particularly in individuals who have experienced trauma ( 4 ). Adaptive coping strategies often lead to positive outcomes, while maladaptive strategies, such as substance use, may lead to greater impairment ( 5 ). Additionally, social support has been identified as a protective factor of PTSD. In a study investigating the impact of a tornado on adolescents, social support, extent of tornado exposure, and sex significantly influenced the development of PTSD ( 6 ). Moreover, a meta-analysis study on the influence of social support on PTSS in children and adolescents revealed that most longitudinal studies have indicated that social support is a significant predictor of PTSS ( 7 , 11 ). According to the results of an online survey conducted among medical students who were locked down during the COVID-19 pandemic period, social support mediated the relationship between positive coping and post-traumatic stress symptoms ( 8 ). Furthermore, positive expectancies, self-efficacy, optimism, and hope have been associated with less severe PTSD symptoms. The results of a meta-analysis indicated that positive expectations were predictive of less severe PTSD symptoms ( 9 ). Additionally, hope and positivity were associated with post-traumatic growth in oral cancer patients ( 10 ).

The burden of PTSD following disasters is known to be significant, and it is associated with various factors such as sociodemographic and background factors, event exposure characteristics, social support factors, and personality traits ( 12 ). One of the longitudinal studies on the long-term PTSD symptoms among disaster bereaved families is the research related to the 2011 Utøya terror attack in Norway ( 13 ). According to this study, eight years after the disaster, many bereaved parents and siblings were showing long-lasting health consequences with symptoms of PG (Prolonged Grief) and PTS (Post-Traumatic Stress) as well as functional impairment. Moreover, the results of a study conducted 26 years after the 1990 fire on the Scandinavian Star ferry found that high social support plays a significant role in reducing posttraumatic stress symptoms, particularly among individuals with a ruminative coping style ( 14 ). In addition, when investigating counterfactual thinking among them, it was suggested that vivid counterfactuals about a traumatic event play a role similar to trauma memories in post-traumatic stress, indicating that they are not beneficial ( 15 ).

While various studies have been conducted on the mental health of disaster-bereaved families, there has been relatively limited research on long-term PTSD risk factors and protective factors following disasters. Therefore, this study investigated the plausible predictive role of coping strategies, social support, and positive resources in the long-term prognosis of PTSD in the families of the victims of the Sewol ferry disaster. The study intends to provide valuable evidence that can serve as a foundation for developing mental health-promoting programs tailored to families affected by disasters.

2 Materials and methods

2.1 study sample and design.

This study was conducted in 2022, eight years after the Sewol ferry disaster, targeting parents who lost their children in the accident. With the assistance of the Ansan Onmaeum Center, we met with representatives of bereaved families to explain the purpose and procedures of this study. The representatives understood the intention of our study and promoted it online to the bereaved families, encouraging those interested to participate by sending messages via their mobile phones. Over a period of approximately two months, the research team scheduled individual appointments and conducted surveys with the participants. The analysis included data from 181 participants after excluding 21 individuals with incomplete responses.

2.1.1 Outcome variables

PTSD symptoms were assessed using the PTSD Checklist for DSM-5 (PCL-5), based on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders ( 16 ). We ensured that participants responded to PTSD symptoms related to the disaster by adding the phrase ‘related to the Sewol ferry incident.’. The PCL-5 comprised 20 items, and total scores range from 0 to 80. A total score of 33 indicated a provisional diagnosis of PTSD. The Korean version of the PCL-5 was utilized in this study, and it demonstrated good internal consistency and test-retest reliability in the present study (Cronbach’s alpha coefficient of 0.963) ( 17 ).

2.1.2 Independent variables

In the current study, positive psychological resources were assessed using the Positive Resources Test (POREST), a self-reported instrument for assessing optimism, purpose/hope, self-control, social support, and care ( 18 ). The POREST consists of 23 items, and participants provide their responses on a five-point Likert scale ranging from 1 (not true) to 5 (very true). Total scores on the POREST range from 23 to 115, with higher scores indicating more personal positive resources. The Cronbach’s alpha coefficient for the POREST in this study was 0.919, indicating good internal consistency.

Social support was measured using the Duke-UNC Functional Social Support Questionnaire (FSSQ) ( 19 ). The Korean version of the FSSQ has been validated, demonstrating good psychometric properties ( 20 ). The FSSQ comprises 14 items, and participants rate their responses on a five-point Likert scale ranging from 1 (much less than I would like) to 5 (as much as I would like). Total scores on the FSSQ range from 14 to 70, with higher scores indicating higher levels of perceived social support. The Cronbach’s alpha coefficient for the FSSQ in this study was 0.954, indicating high internal consistency.

Coping strategies were assessed using the Brief COPE, a well-established self-report measure developed by Carver (1997). The Brief COPE was used to assess coping responses to stress and challenging situations. It comprises 28 items that assess coping strategies commonly employed in response to stressors. The Brief COPE assesses three coping categories: problem-focused coping (active coping, planning, and instrumental support), emotion-focused coping (positive reframing, humor, religion, acceptance, and emotional support), and avoidant coping (self-blame, behavioral engagement, substance abuse, self-distraction, denial, and venting). Each item is rated on a four-point Likert scale. Higher scores indicate greater utilization of stress coping strategies. The Cronbach’s alpha coefficient for the Brief COPE in this study was 0.835, indicating good internal consistency.

2.1.3 Covariates

The analyses were adjusted for several covariates, including age, sex, type of health insurance, marital status, and household income. Age was a numeric variable, while sex was dichotomized into male and female categories. The type of health insurance was classified into two groups: national health insurance and “others”. The others category included individuals who were beneficiaries of the medical aid program and those who refused to answer. The South Korean medical aid program is comparable to the Medicaid program in the United States, and its beneficiaries include individuals with low socioeconomic status ( 21 ). Marital status was dichotomized as married and “others” (those who were separated, divorced, widowed, or had never been married). Household income was categorized into four groups: ≤ 1.99, 2.00–3.99, ≥ 4.00, and those who refused to answer. Household income was measured in monthly units of 1 million South Korean Won, approximately equivalent to USD 1,265 as of 2022.

2.2 Analytical approach and statistics

Descriptive analysis was conducted to summarize the baseline characteristics of the participants and clinically classify the PTSD symptoms. The results are presented as mean and standard deviation (SD) for normally distributed numerical data, median and interquartile range (IQR) for non-normally distributed numerical data, and frequency and percentages for categorical data, as appropriate. To assess the relationship based on the clinical classification of PTSD symptoms, the two-sample t-test was used for analyzing normally distributed numerical data, the two-sample Wilcoxon rank-sum test was used for analyzing non-normally distributed numerical data, and Fisher’s exact test was used to analyze the categorical data. Binomial logistic regression was performed to investigate the relationships between related factors for PTSD while controlling for covariates. To assess multicollinearity in the multivariable regression model, the variance inflation factor (VIF) was calculated. Huber-White’s sandwich estimator was employed to calculate the heteroscedasticity-robust standard error ( 22 ). The threshold for statistical significance was set at p < 0.05 for two-tailed tests. All statistical analyses were conducted using Stata/MP 17.0 software (Stata Corp., College Station, TX, USA).

Table 1 presents a summary of the baseline characteristics and clinical classifications of PTSD for the study participants. The study included 181 participants with a median age of 53 years, and 56.9% of the participants were female. The proportion of participants exhibiting PTSD symptoms that required clinical attention was 49.7% (n = 90). Among the non-clinical PTSD group, the mean or median score for the FSSQ, and the total score for the POREST and its subscales (except the care subscale), were significantly higher. However, the mean score for the avoidant subscale of the Brief COPE was significantly higher in the clinical PTSD group. Additionally, household income showed a significant negative association with clinical PTSD symptoms. The mean PCL-5 score of study participants were 32.6 ± 19.7.

Table 1 Clinical classification and baseline characteristics of bereaved family members of the Sewol ferry disaster.

Table 2 presents the results of the multivariable binomial logistic regression, which aimed to identify protective and risk factors for PTSD. A one-point increase in the score on the optimism subscale of the POREST was associated with a 20.1% decreased likelihood of having clinical PTSD symptoms (OR = 0.799; p = 0.027; 95% CI = 0.655–0.975). Conversely, a one-point increase in the score on the avoidant subscale of Brief COPE was associated with a 13.2% increased likelihood of having clinical PTSD symptoms (OR = 1.132; p = 0.041; 95% CI = 1.005–1.274).

Table 2 Protective and Risk Factors associated with post-traumatic stress disorder.

4 Discussion

In this study, we tracked the mental health of the Sewol ferry disaster victims’ families and found that, 8 years after the incident, 49.7% of the families had clinically significant PTSD symptoms. The use of avoidance coping strategies was identified as a risk factor for PTSD, while optimism was a protective factor.

These results have important implications. First, they highlight the lasting impact of traumatic events on mental health, with the prevalence of PTSD being significantly higher in our sample compared to families affected by other disasters in previous studies. For example, families who experienced the 2004 tsunami disaster had a PTSD prevalence of 34.5%, while bereaved survivors of the 2008 Sichuan earthquake had a prevalence of 16.8% at 18 months after the event ( 23 , 24 ). The higher prevalence in the Sewol ferry case may be attributable to the nature of the incident, which was a tragic accident during a school excursion (rather than a natural disaster) potentially worsened by the sense of preventability and the role of human error. A systematic literature review on PTSD following man-made disasters reported PTSD prevalence rates ranging from approximately 20% to 75% among survivors or rescuers ( 12 ). Bereaved families from the 2011 Utøya terror attack in Norway still showed clinical levels of PTSS in approximately 46% of cases eight years after the disaster ( 13 ). While there may be differences in results depending on the research methodology, the prevalence of PTSD tends to be lower following natural disasters compared to human-made and technological disasters ( 12 ). Additionally, it should be considered in the interpretation of the results that the participants of this study are parents who have lost children in disasters. According to the review study, bereaved parents exhibited a higher prevalence of mental health issues compared to bereaved spouses and parents who have not experienced loss ( 25 ). Furthermore, the study’s focus on PTSD symptoms 8 years after the disaster emphasizes the long-term nature of mental health consequences. This underscores the importance of continued monitoring and support for affected families over extended periods, as trauma-related symptoms may manifest or change over time.

Second, the identification of avoidance coping strategies as a risk factor for PTSD among bereaved families aligns with the existing research on maladaptive coping in response to trauma. A meta-analysis revealed that high occupational stress and avoidant coping strategies significantly increase the risk of PTSD among police officers ( 26 ). This finding underscores the importance of addressing and modifying avoidance behaviors in therapeutic interventions to promote healthier coping mechanisms and better mental health outcomes for traumatized individuals.

Third, optimism was found to be a protective factor against PTSD, which is encouraging. Previous studies have demonstrated that positive expectancies, such as hope, self-efficacy, and optimism, act as protective factors against PTSD ( 9 , 10 ). In our study, we specifically found that among the positive resources including optimism, hope, self-control, social support and care, optimism was significantly associated with less severe PTSD symptoms. This suggests that, in the process of striving for nearly a decade to uncover the truth of the tragedy of the Sewol ferry accident, where parents of the victims lost their children, the factor of optimism would be beneficial to their mental health by alleviating feelings of injustice and resentment. This implies that fostering a sense of optimism could play a crucial role in promoting resilience and reducing the impact of trauma on mental health. Integrating optimism-focused interventions into mental health programs may prove beneficial for families affected by disasters.

Fourth, it was noteworthy that this study did not find evidence that social support influences PTSD in the bereaved families of the Sewol ferry disaster. This result contrast with previous research findings in disaster-experienced individuals, suggesting that social support may be one of the protective factors for PTSD ( 6 – 8 ). The bereaved parents have reported experiencing profound embitterment after losing their children in the human-made ferry accident, going through feelings of being cheated, injustice, incompetence, wrongdoing by a perpetrator, and the destruction of their belief and value system ( 27 ). In a qualitative analysis of interviews with Sewol ferry disaster bereaved families, it was revealed that they are maintaining only minimal interpersonal relationships due to social withdrawal ( 28 ). They reported difficulties trusting others and expressed caution when someone tries to get closer to them since the incident. Survivors who directly witnessed the 2016 attacks in Belgium reported experiencing changes such as aggression, guilt, distrust, or psychosomatic factors like migraine attacks after the incident ( 29 ). They felt that others would not understand them, leading to a deterioration in interpersonal relationships. In that regard, it has been suggested that for the improvement of PTSD symptoms, it is important to make clients feel safe in therapy settings and that therapeutic relationships play a role similar to social support ( 30 ). Furthermore, the socio-ecological model of resilience has been proposed, suggesting that the best care for trauma survivors is not limited to assisting the individual alone but is achievable when a combination of interpersonal relationships and societal services they belong to is provided. There have been longitudinal studies on the relationship between social support and PTSS depending on the timing after a disaster. Initially after the disaster, it was possible to explain the relationship through social causation (more social support leading to less PTSD), whereas later on, it was found that social selection (more PTSD leading to less social support) was the operative mechanism ( 31 ). Therefore, it can be interpreted that, perhaps, bereaved families have experienced significant negative impacts on interpersonal relationships after the incident. As a result, the positive effects of social support on mental health may have been negligible.

The study had several limitations. First, the limited sample, which comprised only 181 families out of an estimated 500 bereaved parents of the 250 deceased students, may impact the generalizability of the findings. Participant recruitment was challenging given the families’ anger and skepticism after the accident, which limited the sample size. Nonetheless, the fact that about half of the families registered for the study engaged in long-term follow-up surveys was significant. Second, the method of participant recruitment may have introduced sampling bias, potentially affecting the representativeness of the target population. Therefore, there may be differences between the participating families and those who did not participate. Participants in the study may be more adversely affected by the negative impacts of the incident compared to non-participants. Third, the cross-sectional nature of the study may limit the ability to establish causality between variables, as associations were analyzed at a specific time point. Fourth, even though participants were asked to respond to symptoms related to the Sewol ferry disaster when evaluating PTSD, it is not possible to completely exclude the influence of other events and incidents over the span of eight years. In this regard, given the significantly high prevalence of PTSD among Sewol ferry bereaved parents, follow-up longitudinal studies are necessary.

Despite its limitations, this study provides valuable insights into the mental health challenges faced by parents who lost their children in a human-made disaster and the factors influencing long-term PTSD. The results have practical implications for mental health practitioners and policymakers involved in designing interventions for disaster survivors and victims’ families.

Data availability statement

The datasets presented in this article are not readily available because we did not obtain permission from the subjects to disclose the dataset. Requests to access the datasets should be directed to So Hee Lee, [email protected].

Ethics statement

The studies involving humans were approved by the Institutional Review Board of the National Medical Center (registration No. NMC-2022-07-079). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

SL: Conceptualization, Funding acquisition, Project administration, Supervision, Writing – original draft, Resources, Writing – review & editing. JN: Data curation, Formal analysis, Methodology, Software, Validation, Writing – original draft. KK: Formal analysis, Investigation, Methodology, Resources, Software, Writing – original draft, Visualization. JC: Project administration, Writing – review & editing, Conceptualization, Supervision, Validation.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by a grant of the R&D project, funded by the National Center for Mental Health (grant number: MHER22B01).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: Sewol ferry disaster, bereaved families, post-traumatic stress disorder, avoidance coping, optimism

Citation: Lee SH, Noh J-W, Kim K-B and Chae J-H (2024) The impact of coping strategies and positive resources on post-traumatic stress symptoms among bereaved families of the Sewol ferry disaster. Front. Psychiatry 15:1367976. doi: 10.3389/fpsyt.2024.1367976

Received: 09 January 2024; Accepted: 18 March 2024; Published: 02 April 2024.

Reviewed by:

Copyright © 2024 Lee, Noh, Kim and Chae. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jin-Won Noh, [email protected] ; Jeong-Ho Chae, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Dogs can detect trauma stress by smelling humans’ breath, study shows

NEW YORK, March 28 (UPI) -- Service dogs trained to recognize oncoming flashbacks of post-traumatic stress disorder, or PTSD, in people also can be taught to detect these episodes by sniffing their breath, a new pilot study shows.

The study, conducted at Dalhousie University in Halifax, Nova Scotia, Canada, was published Thursday in Frontiers in Allergy.

Earlier research already established that canines' sensitive noses can detect the early warning signs of many potentially dangerous medical situations, such as an impending seizure or sudden low blood sugar.

But until this investigation, it was unknown whether dogs' heightened sense of smell can interrupt a PTSD episode or alert their human companions to these oncoming symptoms spurred by reminders of trauma, the study's first author, Laura Kiiroja, a doctoral student at Dalhousie University, told UPI via email.

The researchers described PTSD as "an impairing mental health condition with high prevalence among military and general populations alike."

PTSD service dogs "are trained to respond to minute behavioral and physical cues, such as fidgeting, fist-clenching, muscle-twitching or elevated respiration and heart rate," Kiiroja said. "Our study showed that at least some dogs can also detect these episodes via breath."

If dogs reacted to stress markers on the breath, researchers suspected the canines could potentially halt PTSD episodes at an earlier stage, making their interventions more effective.

All humans have a "scent profile" of volatile organic compounds -- molecules emitted in secretions such as sweat and influenced by genetics, age, activities and other variables.

Some evidence suggests that dogs may be capable of detecting these compounds, which are linked to human stress. However, earlier studies had not looked into whether dogs could learn to detect these compounds associated with PTSD symptoms.

The study is a collaboration between two distinct sets of expertise -- the clinical psychology lab led by Sherry Stewart and the canine olfaction lab spearheaded by Simon Gadbois, both at Dalhousie University. Neither one could have conducted this research on their own, Kiiroja said.

To carry out this investigation, the researchers recruited 26 humans as scent donors. These individuals also were participating in a study about the reactions of people who experienced trauma to reminders of a catastrophic event, and 54% met the diagnostic criteria for PTSD.

To donate scents, they attended sessions at which they were reminded of their trauma experiences while wearing different facemasks. Participants also answered a questionnaire about their stress levels and emotions.

Meanwhile, the scientists recruited 25 pet dogs to train in scent detection. Two of them -- Ivy and Callie -- were skilled and motivated enough to complete the study.

Both dogs were taught to recognize the target odor from pieces of the facemasks, achieving 90% accuracy in discriminating between a stressed and a non-stressed sample.

The dogs then were presented with a series of samples, one at a time, to determine if they could still correctly detect the volatile organic compounds associated with stress. In this second experiment, Ivy's rate of accuracy was 74% and Callie's was 81%.

"Perhaps the most interesting is the result that our two dogs appeared to respond to different olfactory biomarkers. Stress is not just about cortisol, and our dogs attested to that," Kiiroja said.

"Although they both performed at very high accuracy, they seemed to have a slightly different idea of what they considered a 'stressed' breath sample," she added. "Ivy's performance was correlated with participants' self-reported anxiety and Callie's performance was correlated with participants' self-reported shame."

Kiiroja, a native of Estonia, said she enrolled in the doctoral program at Dalhousie University to pursue her passion of studying canine behavior and cognition.

"It made me all the more happy that my Ph.D. project enabled contributing to the welfare of our own species both by expanding our knowledge on dogs' potential in biomedicine, particularly in mental health, and adding to the evidence base of service dogs as a complementary treatment for PTSD," she said.

Dr. Jerry Klein, chief veterinarian at the American Kennel Club in New York City, who was not involved in the research, told UPI via email it "is intriguing and hopeful that dogs may one day be able to offer assistance to people suffering from PTSD or perhaps other forms of trauma. These tests will need to be validated on a greater level."

One thing is clear, though: Dogs typically possess a much greater sense of smell than humans, with 300 million olfactory receptors in their noses compared to humans' six million receptors, Klein said.

However, "not all dogs may have the same ability or inclination to use these natural gifts in the same way," he said, noting that service dogs are chosen based on their skills and willingness to be trained for utilizing these factors.

"Often, these dogs come from similar breeds or types of dogs, or even subsets of families of dogs, though there are exceptions to every rule," Klein added.

A few small studies have shown that dogs can support people with PTSD in having greater independence, more confidence, lower hypervigilance and higher success in relationships, Alice Connors-Kellgren, a clinical psychologist at Tufts Medical Center in Boston, told UPI via email.

"Hypervigilance refers to the heightened awareness of possible danger that people who have experienced trauma develop," Connors-Kellgren said.

She added that "dogs can be an incredible support to people with all kinds mental health diagnoses." However, "therapy dogs and service dogs are trained from a young age to be on the lookout for signs of distress and to respond to people's signals that they need help with a task."

Other dogs can use smell to detect cancer and have been specifically trained for this purpose. It's not something that any dog would be able to do without training, Connors-Kellgren noted.

Nancy Smyth, a professor in the University at Buffalo School of Social Work, told UPI via email that the current study is "too small to have much significance except to encourage more research investigating whether or not more dogs, especially service dogs, can be trained to detect human scent profiles associated with PTSD."

Smyth added that if future research proves the reliability of trained canines' usefulness in performing this task, "it could really enhance the ability of these dogs to provide support to people struggling with PTSD symptoms."

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To Predict, Prevent, and Manage Post-Traumatic Stress Disorder (PTSD): A Review of Pathophysiology, Treatment, and Biomarkers

Ghazi i. al jowf.

1 Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands

2 Department of Public Health, College of Applied Medical Sciences, King Faisal University, Al-Ahsa 31982, Saudi Arabia

3 European Graduate School of Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands

Ziyad T. Ahmed

4 College of Medicine, Sulaiman Al Rajhi University, Al-Bukairyah 52726, Saudi Arabia

Rick A. Reijnders

Laurence de nijs, lars m. t. eijssen.

5 Department of Bioinformatics—BiGCaT, School of Nutrition and Translational Research in Metabolism (NUTRIM), Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands

Associated Data

Not applicable.

Post-traumatic stress disorder (PTSD) can become a chronic and severely disabling condition resulting in a reduced quality of life and increased economic burden. The disorder is directly related to exposure to a traumatic event, e.g., a real or threatened injury, death, or sexual assault. Extensive research has been done on the neurobiological alterations underlying the disorder and its related phenotypes, revealing brain circuit disruption, neurotransmitter dysregulation, and hypothalamic–pituitary–adrenal (HPA) axis dysfunction. Psychotherapy remains the first-line treatment option for PTSD given its good efficacy, although pharmacotherapy can also be used as a stand-alone or in combination with psychotherapy. In order to reduce the prevalence and burden of the disorder, multilevel models of prevention have been developed to detect the disorder as early as possible and to reduce morbidity in those with established diseases. Despite the clinical grounds of diagnosis, attention is increasing to the discovery of reliable biomarkers that can predict susceptibility, aid diagnosis, or monitor treatment. Several potential biomarkers have been linked with pathophysiological changes related to PTSD, encouraging further research to identify actionable targets. This review highlights the current literature regarding the pathophysiology, disease development models, treatment modalities, and preventive models from a public health perspective, and discusses the current state of biomarker research.

1. Introduction

Post-traumatic stress disorder (PTSD) is a chronic mental disorder resulting in a reduced quality of life and increased economic burden. Exposure to a traumatic stressor is the trigger for PTSD development [ 1 ]. For that, a distinction between ordinary and traumatic stressors (those that have the potential to result in PTSD) is necessary. PTSD was first introduced in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), and further updates to the diagnostic criteria have been introduced in subsequent versions. Traumatic stress relates to the exposure to real or threatened injury, death, or sexual assault. Intrusion symptoms, avoidance/numbing, hyperarousal, sensitisation to stressors, and detrimental cognitive and affective changes are all symptoms of PTSD [ 1 ].

Although exposure to stressors is common in the general population, only a small proportion of susceptible individuals develop PTSD [ 2 ]; however, the underlying mechanism of susceptibility and resilience is still unclear. In the last decade, etiological models have been developed to explain the interplay between biology, environment, and mind in manifesting the disease. Examples of those models include the diathesis–stress and the biopsychosocial models [ 3 ]. In parallel, extensive research aiming to identify the pathophysiological mechanism of PTSD has found the association between genetic variants and an increased risk of PTSD, hypothalamic–pituitary–adrenal (HPA) axis dysfunction, neurotransmitter dysregulation, and alterations in brain circuits [ 4 ]. Research has advanced over the last years in aiming to connect the alterations at the genetic, molecular, chemical, cellular, and circuitry levels into a biological systemic view, while also aiming to discover diagnostic and prognostic biomarkers.

Psychotherapies and pharmacotherapies are two effective PTSD treatments. However, significant subsets of individuals who do seek treatment have symptoms that are difficult to treat. Changing to another treatment modality or combining treatment modalities (combining psychotherapy with pharmacotherapy) is frequently required. Trauma-focused psychotherapy is the first line of treatment for most individuals with PTSD, as opposed to other therapies or pharmacological medication. Cognitive behavioural therapy (CBT), prolonged exposure therapy (PET), and eye movement desensitization and reprocessing (EMDR) therapy are trauma-focused psychotherapies that have been shown to be useful in the treatment of PTSD [ 5 , 6 ].

This review provides an introductory and overall overview of the current concept of findings on the etiology and disease models of PTSD, pathophysiology, treatment, prevention, and lastly biomarkers, including diagnostic and prognostic biomarkers. A literature search was performed using keywords to find papers in PubMed, Cochrane Library, Scopus, and Embase. The literature was then summarized with the aim to provide a comprehensive overview of these topics, and representative examples of research findings were selected. The preferred studies were meta-analyses, systematic reviews, and randomised controlled trials (RCTs), as well as the most recent studies relevant to the presented perspective. Abstracts were then screened for their relevance. Once selected, the limitations of the studies were assessed for their impact on informed clinical decisions. Original studies were preferred for models and concepts. The literature was then summarised with the aim to provide an up-to-date, comprehensive overview of the available data (a graphical summary of the main findings is given in Figure 1 ).

A graphical summary of the main findings of the paper. The entirety of the pre-, peri- and post-traumatic factors can be biological, psychological, or social, according to the biopsychosocial model.

2. Epidemiology and Models of PTSD Development

2.1. epidemiology of ptsd.

The public health perspective of traumatic stress takes a population-based approach and formulates policies based on it. Epidemiological studies concern the distribution and determinants of traumatic stress and stress-related mental disorders in specified populations. They have shown that traumatic stress often occurs among the war-surviving population, refugees, especially females, public health workers, and indigenous populations [ 7 ].

The war-surviving population has a high prevalence of PTSD and depression. This statement is supported by a systematic literature search and meta-analysis of interview-based epidemiological surveys including samples from 43 war-ridden countries with a recent war history (1989–2019) [ 8 ]. Specifically, these war survivors diagnosed with PTSD or depression are primarily living in low/middle-income countries [ 8 ]. Therefore, income or social status may have an impact on the response to traumatic stress. A meta-analysis and the Millennium Cohort study support the association between low socioeconomic status and PTSD [ 9 , 10 ]. Sex/gender has also been linked to risk, e.g., in a refugee population, females who experienced sexual trauma had a higher prevalence of PTSD than males [ 7 ].

Differences between groups of people have been reported. For example, indigenous populations in various countries show a higher prevalence of traumatic stress-related mental health problems than others. The standardized prevalence of 12-month PTSD in the Australian indigenous population was three times the Australian rates [ 11 ]. The independent predictors (determinants) of PTSD among Australian indigenous populations are female gender, rural residence, trauma under age 10, and sexual and/or physical violence [ 11 ]. Such findings might be attributed to the fact that the Australian indigenous population is disadvantaged in different aspects [ 12 ].

Public health workers have been experiencing huge traumatic stress during the COVID-19 pandemic [ 13 ]. Among 26,174 surveyed public health workers in the US, 53.0% reported symptoms of at least one mental health condition in the previous two weeks, especially those unable to take time off or those experiencing overwork [ 13 ]. This result indicates that overworking is associated with the negative impact of traumatic stress.

The studies above demonstrate that specific populations with certain characteristics are more likely to suffer from exposure to traumatic events. These characteristics can be environmental factors like traumatic events including war/violence and workload, social factors like social status, or biological factors like female sex. A dual influence of social and biological factors on females is suggested. Females are more likely to experience physical and sexual violence. Additionally, clinical evidence points to the possibility that cyclical oestrogen discharges throughout the reproductive cycle may contribute to women’s greater susceptibility to and severity of PTSD symptoms following psychological stress [ 14 , 15 ].

2.2. Models of Disease Development

2.2.1. diathesis–stress model for ptsd.

The initiation and maintenance of the disorder are heterogeneous, differing between individuals with the same level of trauma and presenting with varying degrees of disease severity. An explanation for this obvious variation is the diathesis–stress model, tested for PTSD in different studies. According to the model, the pre-trauma state of the individual (risk factors) constitutes a condition of susceptibility (diathesis) that can produce the disorder after a traumatic experience (stress).

In PTSD, the trauma represents the stressor that activates certain processes in an individual with pre-traumatic vulnerability, thereby leading to the expression of psychopathology and social dysfunction. Vulnerability factors may involve aspects like genetic predisposition, psychiatric history, a history of child abuse, a stressful and unhealthy lifestyle, and others. The individual’s diathesis represents a hypothetical threshold, and the impact of a stressor on the individual depends on the diathesis; the less favourable the diathesis, the less severe the stressor needs to be to initiate the disorder.

Not only pre-trauma (e.g., a risk of developing PTSD, genetic, and biological factors), but also peri-trauma (e.g., emotional distress), and post-trauma factors should be considered. McKeever and Huff state that the peri-traumatic perception of trauma and post-traumatic conditions can affect the severity and symptoms. Furthermore, different types of vulnerabilities (e.g., biological and psychological) may interact with one another [ 3 ].

Here, we provide a few examples of research findings in line with the diathesis–stress model. As the diathesis–stress model contends that the interplay of hereditary, biological predisposition, and environmental stress results in the development of mental disorders, researchers have hypothesized that during military service the onset of major psychopathology may be precipitated by psychosocial stress, leading to an increase in psychiatric hospitalisations during the first months of the military service period for those with greater sensitivity or a lower stress tolerance [ 16 ]. In a sample of 118 hospitalised subjects starting their military service assessed for the expression of psychopathology, 59.3% of the subjects were diagnosed with an anxiety disorder, especially PTSD, out of the total sample due to traumatic stress exposure, implicating the nature of warfare stress in the increased risk of anxiety and stress disorders. Intriguingly, the risk of disorder onset within the first two months and hospitalisation was also higher for psychotic spectrum disorders. As the sample was exposed to similar stress levels, these findings suggest that individuals with psychotic spectrum disorders have increased stress sensitivity [ 16 ].

Another study for testing the model in the emergency department (ED) was carried out by Edmondson in 2014. A sample of 189 acute coronary syndrome patients was observed for the effect of ED crowding, depression status, and their interaction on the subsequent development of PTSD. ED crowding significantly affected the 1-month development of PTSD symptoms, as patients treated during ED crowding times scored significantly higher than those treated during times with medium or little ED crowding. Similarly, depression status and the interaction between ED crowding and depression status significantly affected the subsequent development of PTSD [ 17 ].

Another example of findings supporting the diathesis–stress model of PTSD comes from Elwood and colleagues, who investigated the connection between cognitive abilities/vulnerabilities and exposure to sexual assault. Negative attributional style (NAS) and anxiety sensitivity (AS) were used as cognitive vulnerabilities and sexual assault as the negative life event. NAS is the individual’s inference that current negative events will have negative effects, and that a negative event reflects one’s worthlessness, while AS is the extent of fear of the harmful consequences that can result from anxiety and anxiety symptoms [ 18 , 19 ]. In line with the diathesis–stress model, the authors hypothesized that people who had both high levels of cognitive vulnerability and high levels of negative life experiences would have the highest levels of symptoms. The relation between these cognitive vulnerabilities and negative life events was examined for PTSD symptom clusters [ 20 ]. As expected, negative life events significantly predicted changes in avoidance, numbness, and dysphoria symptoms when both NAS and AS were present. The biggest symptom increase was recorded by participants who exhibited high levels of cognitive vulnerability and more traumatic life events. Correspondingly, a low frequency of bad life events and high levels of cognitive insensitivity, however, were linked to reductions in symptoms [ 20 ]. Findings from this study support the role of cognitive vulnerabilities as predictors of the development of PTSD symptoms after exposure to traumatic stressors.

2.2.2. Biopsychosocial Model

Formulated by Engel in 1977, the biopsychosocial model emerged from the view of the insufficiency of the biomedical model alone in explaining illnesses [ 21 ]. Engel explained a need for a new medical model to extend the biomedicine model to account for all the factors influencing the patient’s condition. The biopsychosocial model poses that biological (e.g., genetics, chemical changes, and organ damage), psychological (e.g., stress, mental illness, behaviour, and personality), and social factors (e.g., peers, socioeconomic status, beliefs, and culture) interact with each other in the expression of health and illness. Engel’s justification for his criticism was made in several points:

• Biological disturbance alone is insufficient to cause the disease, as disease appearance results from multi-factor interaction.
• Vulnerability is better accounted for by psychological and social factors than by biological changes.
• The effectiveness of biological treatments is influenced by the psychological status of a “placebo effect.”
• Health outcomes are affected by the doctor–patient relationship to a great extent.

The biopsychosocial model would consider these factors altogether, not only in terms of the expression of illness but also at the level of the social functioning of the individual. It also considers the cultural perception of illness, circumstances in which the patient does not acknowledge their illness, and other circumstances in which the patient admits their illness, as marked by their entry into the healthcare system [ 22 ].

2.2.3. Animal Models of PTSD

In 1993, Yehuda and Antelman proposed a list to systematically evaluate stress models of stress in animals for their relevance to PTSD [ 23 ]. To determine how applicable a model is to PTSD, at least five distinct factors might be applied, according to this list:

• (1) Even very brief stressors should cause biological or behavioural symptoms of PTSD;
• (2) The stressor should be able to produce symptoms in a dose-dependent manner;
• (3) Produced biological alterations should persist or become more pronounced over time;
• (4) Alterations should have the potential to express biobehavioural changes in both directions;
• (5) Interindividual variability in response is present as a function of experience and/or genetics.

A sixth criterion has been proposed by Whitaker et al., which is the model’s capacity to generate co-morbid states, such as an increase in alcohol consumption, an increase in compulsive drinking, and hyperalgesia [ 24 ]. Although these models do not fully replicate the human condition, they simulate the symptoms and neurobiology of PTSD, allowing the evaluation of behavioural changes, neurobiological and epigenetic alterations, and the development of biomarkers and treatment. According to the type of stressor, the models can be categorised as physical, social, or psychological. Table 1 , provides a summary for the commonly used animal models in PTSD, which are mostly conducted in rodents.

Summary of the commonly used preclinical animal model in PTSD.

3. Pathophysiology

While much about the pathophysiology of PTSD is unknown, research into the pathophysiological aspects of PTSD is in rapid development. Preclinical investigations of animal models of stress and evaluations of biological variables in populations with the condition have all contributed to the identification of biological factors and mechanisms involved in PTSD, which can be described on the levels of brain circuits, neurochemical factors, and HPA axis, as discussed in this section.

3.1. Brain Circuits

The core features of PTSD are fear and worry in conjunction with other features and symptoms, including arousal, avoidance, sleep disturbance, and intrusion symptoms (e.g., flashbacks and nightmares) [ 35 ]. Neural circuitries and biological processes underlying these features involve brain structures such as (i) the amygdala, anterior cingulate cortex, and the insula in dysfunctional threat detection; (ii) frontoparietal regions (the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, and medial prefrontal cortex) in emotional regulation; (iii) the medial prefrontal cortex and the hippocampus in contextual processing [ 35 ].

A range of structural magnetic resonance imaging (MRI) studies has reported structural abnormalities in the hippocampus and anterior cingulate cortex (ACC) in patients with PTSD [ 36 ]. Additionally, functional magnetic resonance imaging (fMRI) studies have reported increased activity of the amygdala, which processes fear and emotion, and decreased prefrontal cortex activity when completing tasks that use either trauma-related or unrelated stimuli (script-driven recollections of trauma-related and unrelated stressful events) [ 37 , 38 ].

While hippocampal alterations have been observed in patients with PTSD, including lower volumes and lower levels of activation [ 39 ], impaired connectivity in the frontoparietal areas, both inside and between executive function networks, has also been observed in patients with PTSD [ 40 ]. The aforementioned findings suggest that a disrupted connection within these circuits may reflect a vulnerability factor for PTSD. In contrast, people who were exposed to traumatic events but who do not develop PTSD were reported to exhibit higher prefrontal cortex activity during extinction recall [ 41 , 42 ], and stronger connections between the ACC and the hippocampus, compared to patients with PTSD [ 43 ].

The novel findings by Borgomaneri et al. support the idea that the dorsolateral prefrontal cortex (dlPFC) plays a crucial role in the neural network that mediates the reconsolidation of fear memories in humans by showing that non-invasive repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex after memory reactivation interferes with the expression of fear towards a previously conditioned threatening stimulus. These results enhance our understanding of the processes behind fear memory reconsolidation, and also have potential therapeutic applications in treating fear memories [ 44 ]. Identifying the brain regions involved in the reconsolidation of emotional memories and their particular interactions within the overall fear-processing network remains a challenge for non-invasive brain stimulation (NIBS) and reconsolidation-based interventions, which are increasingly applied to conditions like PTSD [ 45 ].

3.2. Neurochemical Factors

3.2.1. dysregulation of the noradrenergic system.

Catecholamine noradrenaline is a critical transmitter in the autonomic nervous system, and has been linked with the development of the autonomic symptoms associated with PTSD. Noradrenaline is found in the central nervous system’s (CNS) cell nuclei and certain noradrenergic pathways that are implicated in the pathophysiology of the illness. One area with a high concentration of noradrenaline is the locus coeruleus (LC), which is located in the rostral pons and serves as the hub of the neurochemical activity associated with PTSD [ 46 ]. Clinical and preclinical evidence suggests that the dysregulation of noradrenergic signalling is involved in the pathophysiology of PTSD. The increased noradrenergic tone in PTSD arises from increased central and peripheral sympathetic activity leading to increased resting heart rates and systolic blood pressure [ 47 ]. In addition, noradrenaline levels are higher in the urine of individuals with PTSD than in healthy individuals, but recent studies have failed to establish such findings in the cerebrospinal fluid (CSF) [ 48 , 49 ].

Many of the symptoms of PTSD emerge from an increased CNS noradrenergic tone [ 49 , 50 ]. Increased noradrenaline activity has been linked with dysfunction of the medial prefrontal cortex (through impairing prefrontal signalling via α1- and β-AR in the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex) and disturbed fear extinction, which may underlie the increases in behavioural measures of anxiety and PTSD symptom severity [ 51 , 52 ]. Excessive noradrenaline release was found to be increased in the hyperactive amygdala and LC, resulting in intrusion symptoms and autonomic hyperactivity [ 53 ].

Altered noradrenergic function is also associated with night-time and sleep symptoms in PTSD. Increased sympathetic activity during sleep, e.g., an increased heart rate, is found in individuals with PTSD [ 54 ]. Additionally, during rapid eye movement (REM) sleep, people with high levels of PTSD-like symptoms showed an increase in the ratio of low-frequency to high-frequency heart rate variability, which is associated with an elevated sympathetic tone [ 55 ].

3.2.2. Dysregulation of Serotonin Signalling

Serotonin (5-HT) is a monoamine neurotransmitter with multiple biological functions related to mood, cognition, memory, and behavioural regulation [ 56 ]. The 5-HT signalling in the amygdala has been linked to fear regulation and threat responsiveness. Several 5-HT receptors, including 5-HT 1A , 5-HT 1B , 5-HT 2A , and 5-HT 2C have been linked to PTSD and anxiety [ 57 , 58 ].

According to reports from pharmacological studies, blocking the serotonin 5-HT2C receptor in rodents increases locomotion and reduces anxiety [ 59 , 60 ], and in addition, the 5- HT 1A receptor agonist induces anxiogenic responses to the elevated plus maze (EPM) test in mice [ 61 ]. A recent study found that both 5-HT 1A and 5-HT 2A in the hippocampus mediate anxiety-like behaviour in a mouse model of PTSD via the ERK pathway [ 62 ]. Clinical evidence showed higher 5-HT 1A binding potential in people with PTSD, particularly in those with comorbid MDD [ 63 ].

3.2.3. Dopamine

Another prevalent neurotransmitter in the brain is dopamine, primarily synthesised in midbrain areas [ 64 ]. Dopamine is a neurotransmitter that is involved in the regulation of motor activity, limbic functions, attention, and cognition, particularly executive function and reward processing [ 65 , 66 ]. It makes a significant contribution to the anticipatory processes required for planning voluntary action after intention as well as behavioural adaptability [ 67 ]. A range of studies have investigated links between the dopaminergic system and PTSD. For example, several studies have attempted to link PTSD with genetic variants in certain dopamine receptor genes (e.g., DRD2) [ 68 , 69 , 70 ]. Other studies have focused on dopamine-beta-hydroxylase (DBH), which catalyses the conversion of dopamine to noradrenaline, and have reported that high-plasma DBH levels may be linked to the development of intrusion symptoms [ 71 , 72 ], yet other studies have focussed on the dopamine transporter SLC6A3 (solute carrier family 6, member 3), a member of the sodium- and chloride-dependent neurotransmitter transporter family which mediates the transport of dopamine from the synaptic cleft. The 9R allele of the SLC6A3 locus has been identified as a risk allele for PTSD [ 73 ]. Additionally, the epigenetic state of the promoter region of SLC6A3 has been identified as a potential risk factor for/indicator of PTSD [ 74 ].

3.2.4. Gamma-Aminobutyric Acid (GABA)

The inhibitory neurotransmitter GABA is widely distributed throughout the entire brain. A complex pattern of results has been found in studies comparing GABA levels in numerous brain areas between those with and without PTSD. A proton magnetic resonance spectroscopy (MRS) study reported lower GABA-levels in the temporal cortex, parieto-occipital cortex, and insula and higher GABA levels in the dorsolateral prefrontal cortex in people with PTSD compared to trauma-exposed healthy controls [ 75 ]. In times of extreme stress, low plasma levels of GABA are related to PTSD and may lead to the overload of hyperadrenergic response regulation [ 76 ].

There are three primary classes of GABA receptors: GABA-A, GABA-B, and GABA-C. Human research has revealed that Vietnam War combat veterans with PTSD had lower GABA-A benzodiazepine binding ability. According to these findings, changes in the GABA receptor’s expression or binding ability may have an impact on mental diseases linked to stress, including PTSD [ 77 , 78 ].

3.2.5. Neuropeptide Y (NPY)

NPY is a neuropeptide that is expressed throughout the brain, including the forebrain, limbic system, and brainstem. It is involved in several physiological processes including the regulation of emotional and stress-related behaviours [ 79 ].

Early research developed a concept that NPY counteracts the actions of the corticotropin-releasing factor (CRF), terminating the stress response and countering the HPA axis [ 79 , 80 , 81 ]. Studies have demonstrated that plasma NPY levels rise in response to stress, and that higher NPY levels are associated with better behavioural performance under stress [ 82 , 83 ].

Plasma NPY levels were assessed in soldiers who took part in a survival course meant to mimic the conditions that prisoners of war would encounter. Within a few hours of being exposed to military interrogations during the survival course, their serum NPY levels increased. Furthermore, compared to the non-Special Forces or regular soldiers, the majority of Special Forces members who had received resilience training had much higher NPY levels [ 84 ].

Several preclinical and clinical research reports point to an association between PTSD and decreased NPY in the CNS [ 79 , 85 ]. Moreover, NPY levels appear to increase after PTSD remission, suggesting that NPY may act as a biomarker of PTSD or at the very least as a resilience element [ 86 ].

Together, these investigations show that NPY levels in PTSD patients closely mirror the disease course and that NPY can operate as a stress buffer in response to stressful experiences by lowering noradrenergic hyperactivity [ 87 ]. The most prevalent SNP for NPY investigated is the rs16147 (399T > C) polymorphism, which is linked to low levels of NPY and has been linked to hyperarousal, changes in the HPA axis response to stress, and the activation of the hippocampus and amygdala [ 79 ]. Another NPY SNP is 1002T > G, associated with low NPY content in the CSF and amygdala, which is linked to higher levels of anxiety, arousal, addictive behaviours, and decreased stress resilience [ 79 ].

3.2.6. Brain-Derived Neurotropic Factor (BDNF)

BDNF, the richest neurotrophin in the brain, was first characterised for its involvement in the formation of the CNS. It has the ability to participate in neural activities such as survival, differentiation, development, and neuronal plasticity. It preserves synaptic plasticity, which is necessary for extinction learning and fear memory storage [ 88 ]. Variations in BDNF expression or in genetic background have been linked with a risk of various psychiatric disorders such as anxiety, depression, and PTSD [ 89 ].

In US military personnel deployed throughout the conflicts in both Iraq and Afghanistan, PTSD patients had higher BDNF protein levels in their peripheral blood plasma than non-PTSD controls. In the inescapable tail shock rat model of PTSD, increased BDNF levels were found in both blood plasma and hippocampus tissue. Furthermore, the polymorphism Val66Met in BDNF has been linked with an increased risk of PTSD, exaggerated startle response, and alterations in fear extinction [ 90 , 91 ]. The same polymorphism was also found to affect hippocampal volume and memory [ 92 ]. Together, these findings emphasise that BDNF and related molecules may be interesting candidates for biomarker studies and for more fundamental studies aiming to identify actionable biological targets related to the onset or course of PTSD [ 89 , 93 ].

3.2.7. Cannabinoid and Opioid Receptors

Endogenous cannabinoids, including anandamide (AEA) and 2-arachidonolyflycerol (2-AG), work via cannabinoid (CB) receptors (CB1R, CB2R), which are implicated in the pathogenesis of PTSD [ 94 ]. Preclinical data showed that AEA levels are decreased in the brain in chronic stress models [ 95 ]. This is in agreement with the human data showing that endocannabinoid plasma levels are reduced in PTSD patients [ 57 , 96 ]. In addition, defective endocannabinoid signalling is correlated with glucocorticoid dysregulation associated with PTSD [ 96 ].The CB1 receptors are the most abundant G-protein-coupled receptors in the CNS and are highly expressed in a fear circuit of the cortical and subcortical brain regions associated with PTSD [ 97 ]. Interestingly, the disruption of the CB1 receptor gene (knockout models) was found to increase anxiety, whereas a pharmacological blockade of the receptor had anxiolytic effects [ 98 , 99 ]. Animal stress studies also showed that CB1 receptor expression was increased in female but not male animals [ 100 , 101 ].

3.2.8. Oxytocin

Oxytocin is a neuropeptide produced in hypothalamic periventricular and supraoptic nuclei. It emerges from the posterior pituitary and enters the bloodstream. Oxytocin is transported to different parts of the brain through neuronal projections from the hypothalamus. The amygdala, brainstem, olfactory nucleus, and anterior cingulate cortex are among the human brain areas that express the oxytocin receptor and are therefore likely to be impacted by oxytocin [ 102 ]. As it acts on brain areas involved in PTSD, and as oxytocin appears to have anti-stress and anxiolytic effects, oxytocin is thought to be involved in the constellation of dysregulations found in PTSD [ 103 , 104 ].

3.3. Dysfunctional HPA Axis

The hypothalamus, pituitary, and adrenal glands make up the HPA axis, a hierarchical system that controls how the body responds to stress from the environment while maintaining homeostasis [ 105 , 106 ]. As the axis is one of the main stress response systems that controls the release of cortisol and stress hormones, it has received a lot of attention. Exposure to stress causes increased corticotropin-releasing hormone (CRH) production from the hypothalamus [ 107 , 108 ]. The HPA axis is first activated by the production of CRH, which travels through the infundibular stalk’s hypophyseal portal arteries to the anterior pituitary, where it binds to CRH type 1 receptors (CRF1) to trigger the release of adrenocorticotropin (ACTH) into the bloodstream. Cortisol, the main HPA axis effector chemical, is released when ACTH binds to melanocortin 2 receptors in the zona fasciculata of the adrenal cortex. In order to promote the stress response, cortisol has a number of physiological impacts throughout the body, including blocking insulin signalling and increasing glucose availability, controlling immune system operations, and altering electrolyte balance [ 109 , 110 , 111 ].

Upon CRH administration, rodents exhibit PTSD-associated behaviours [ 112 ]. In addition, CRF-1 knockout mice showed impaired responses to stress and reduced anxiety [ 113 , 114 ]. At the same time, CRF-2 knockout mice showed hypersensitivity to stress and augmented anxiety [ 113 , 115 ]. PTSD patients have high CSF levels of CRH and a dysfunctional HPA axis [ 107 , 116 , 117 ]. Studies indicate CRH hyperactivity with subsequent glucocorticoid receptor (GR) hypersensitivity, resulting in higher negative feedback inhibition of cortisol and CRH release [ 118 , 119 ]. In a meta-analysis, Morris et al. reported significantly lower basal cortisol levels in PTSD and trauma-exposed controls without PTSD compared to non-traumatised individuals. Additionally, individuals who had experienced childhood trauma had significantly lower morning cortisol levels compared to those exposed to adulthood trauma [ 120 ]. Figure 2 provides a general overview of the information about the HPA axis discussed in this section.

Basal activity of the HPA axis with or without PTSD. CRH secretion from the hypothalamus increases in PTSD (represented by a thicker black line). The release of ACTH from the anterior pituitary, and hence cortisol from the adrenal cortex, is decreased in PTSD (represented by a thinner black line). Cortisol’s negative feedback inhibition of the HPA axis is increased in PTSD (represented by thicker red lines).

3.4. Conclusive Remarks

Despite the extensive discoveries, the current understanding of the neurochemical factors in PTSD is still limited and requires more research. There is a number of understudied yet significant subjects in the discipline, such as variables that affect susceptibility and resiliency. For instance, one such subject is whether or not the exogenous administration of oxytocin and NPY, two neurobiological components that protect against stress, can foster resilience. Additionally, determining relationships between heritable variables (genetics and epigenetics) and trauma exposure is crucial to understanding PTSD risk, and predicting treatment response. It is important to thoroughly evaluate how trauma affects gene expression, neural plasticity (across the CNS), circuit remodelling, and neurotrophic factors. Future studies should focus on the characterisation of proteomic and transcriptomic abnormalities in PTSD, with the integration of GWAS and EWAS studies, in order to map out novel networks, and allow the development of reliable biomarkers.

Likewise, current controversies and conflictions in the studies assessing HPA axis function and diurnal cortisol levels can be a result of the methodological heterogeneity and limitations of the studies (e.g., different methods of cortisol measurement, different timings of cortisol measurement, and different methods in establishing PTSD in addition to other statistical limitations). Further studies with greater homogeneity are required to draw definite conclusions.

4. Prevention Model of PTSD

PTSD has a predictable development pattern and follows a specific triggering event, unlike other mental diseases. Early PTSD symptoms appear days after exposure to stress. Emergency care providers and helpers are made aware of a lot of traumatised people. These circumstances present exceptional chances for identifying those who are in danger and offering preventive measures. Despite these benefits, the effective prevention of PTSD remains challenging, and the disorder’s incidence in both military members and civilians over the past decades has been relatively steady [ 121 ]. With enough understanding of the condition, preventive and interventional measures can be used to enhance quality of life and reduce the disease’s financial and medical burdens. This is supported by the development of prevention models, but also by the modern digital support of their implementation by e-health approaches (the latter will be explained in the treatment section).

The Social-Ecological Model for PTSD Prevention

A social-ecological model as a framework for prevention is proposed by the US Centers for Disease Control and Prevention, which emphasises risk factors at multiple levels, including the individual level, relationship level, community level, and societal level [ 122 ] ( Figure 3 ). Risk factors on the individual level are about personal characteristics, which are the model’s core. Furthermore, the risk factors on the relationship level are about the quality of relationships for the individual in the family, friends, or other interpersonal interactions. In addition, the risk factors on the community level could be the feeling of safety and economical status. Lastly, the risk factors on the societal level could be social norms, cultural background, and tolerance [ 123 ].

Social-ecological model for traumatic stress and related preventive interventions.

Therefore, preventive measures on the individual and relationship level should be individualised and personal. For instance, emergency hotlines and psychological counselling services should be available in the way that is easiest to reach. Accordingly, preventive measures on the community and societal level are public, legitimacy-related, and educational. For instance, the community or public health sector should increase the awareness of the impact of traumatic stress, and it could organise lectures, campaign movements, or give out brochures about traumatic stress, first-aid help information, and preventive measures ( Figure 3 ). Community-based interventions to improve mental health for people in low- and middle-income countries usually use lay community members as intervention deliverers, and apply transdiagnostic approaches and customized outcome assessment tools [ 124 ]. Furthermore, the public sector should formulate laws, legislation, and policies to prevent discrimination and racism to protect specific populations [ 125 ].

Additionally, preventive measures should also be taken during different stages of traumatic exposure [ 123 ]. Before exposure, the primary prevention is of the actual occurrence of disease or illness. After stress exposure, the secondary form of prevention is to intervene early in the disease process for a cure, and for the reversal of illness or for optimal outcomes. When a disorder occurs, tertiary prevention steps are taken to prevent the disability that often accompanies an illness or disease [ 123 ] ( Figure 3 ). For optimal outcomes, primary, secondary, and tertiary prevention measures should be evidence-based as they are part of disease management [ 126 ].

5. Treatment Modalities for PTSD and E-Mental Health

PTSD is often a chronic and disabling disorder. Many patients fail to seek medical care, and others have symptoms resistant to treatment. Early treatment as soon as the diagnosis is made is recommended to prevent chronicity and disability [ 127 ]. The main goal of treatment is to improve quality of life, maintain patient and others’ safety, reduce distressing symptoms, and reduce hyperarousal and avoidant behaviours. The first-line intervention for PTSD patients is psychotherapy, either trauma-based psychotherapy (CBT, exposure therapy (ET), or EMDR) or non-trauma-focused psychotherapy (present-centred therapy, interpersonal therapy, or mindfulness therapy). In the case of psychotherapy failure, pharmacotherapeutic treatment options are the next choice. Additionally, if the patient has a disability that impairs the success of trauma-focused psychotherapy, pharmacotherapy is considered the appropriate choice until psychotherapy can be initiated [ 5 , 6 ]. In addition to current therapies, e-health is gaining attention as it has interesting potential for providing training, assessment, prevention, and the treatment of negative effects after trauma exposure on a global scale [ 128 ].

5.1. Trauma-Based Psychotherapy

As mentioned earlier, trauma-based psychotherapy includes CBT, ET, and EMDR. CBT has a cognitive and behavioural component. The cognitive component is mainly focused on the cognitive reconstruction of the effects of a traumatic event on one’s life, by addressing all maladaptive beliefs and thoughts about safety, power, trust, and control, while the behavioural component is about learning how to deal with and challenge these thoughts through thinking or real experience, in order to achieve symptom reduction [ 129 ].

ET can be imaginal exposure, in vivo exposure, or virtual reality exposure. All of these focus on putting the patient in confrontation with their traumatic event and memory for these to become less distressing. In PET, multiple sessions of education on reactions to trauma, processing traumatic material, and breathing training are undertaken. It was shown to be effective in patients with comorbid conditions such as psychosis, personality disorders, and substance use [ 130 , 131 ]. In written ET, the patient writes about their traumatic events in response to certain stimulations and discusses them with the therapist to pay attention to the thoughts and events that evoke the patient’s symptoms, with exposure being imaginal [ 132 ].

EMDR is a combination between cognitive behavioural therapy and ET in addition to saccadic eye movements during the therapy. The patient remembers the traumatic event, and while focusing on the cognition aspects simultaneously, the therapist moves their fingers in front of the patient and asks the patient to follow them repeatedly until the anxiety subsides [ 133 ].

5.2. Non-Trauma Focused Psychotherapy

This approach includes present-centred therapy, interpersonal therapy, and mindfulness-based stress reduction. Present-centred therapy focuses on the current life stressors and how to cope with them [ 134 ]. Interpersonal therapy focuses on a specific symptom and impairment in the context of interpersonal relationships [ 135 ]. Mindfulness-based stress reduction mainly teaches the patient how to be fully focused on the current moment, not think about the traumatic event, and attend to the present in a non-judgmental manner [ 136 ].

5.3. Pharmacological Therapy

The pharmacotherapy treatment is preferred in the case of psychotherapy treatment resistance, different patient preferences, or a patient’s inability to participate in the former, and mainly comprises selective serotonin reuptake inhibitors (SSRI) and serotonin-noradrenaline reuptake inhibitors (SNRI). Occasionally, second-generation antipsychotics (SGAs) such as risperidone or olanzapine can be used. If effective, pharmacotherapy should be continued for at least six to twelve months to prevent relapse [ 137 ].

Due to their efficacy at reducing symptoms of PTSD, SSRIs and SNRIs are the first-line agents in the pharmacotherapy of PTSD. Treatment with SSRIs resulted in a higher reduction in the Clinician-Administered PTSD Scale (CAPS) score than treatment with a placebo in a meta-analysis of 12 studies including 1909 PTSD patients, with paroxetine and sertraline being most effective among SSRIs [ 138 ]. The approach to the usage of SSRIs is to “start low and go slow” until the response is achieved, in order to avoid unwanted side effects. However, failure cannot be determined until the maximum therapeutic dose is given and a period of 6–8 weeks is completed, with at least two different agents being used before documenting failure [ 139 , 140 , 141 ]. Although few studies have compared SSRIs to SNRIs, randomised trials have indicated that venlafaxine was superior to a placebo in decreasing PTSD symptoms [ 142 ]. Second-generation antipsychotics can be used as a monotherapy or as augmentation therapy in the case of concomitant psychosis or in the case of failed SSRI/SNRI [ 127 , 143 , 144 ]. In a trial involving 247 United States military veterans from the US who did not respond to two or more trials of SSRI and SNRI, participants received either 4 mg of risperidone or a placebo. However, no significant difference was observed between the two groups between the CAPS scores [ 145 ]. In another study, eighty United States military veterans with persistent PTSD were given quetiapine monotherapy as opposed to a placebo in a randomised clinical study. After 12 weeks, the individuals who received quetiapine had higher mean reductions in their CAPS total score than those who received a placebo [ 146 ]. RCTs and systematic reviews conducted on other SGAs (i.e., olanzapine, aripiprazole) show that these agents are reasonable either as monotherapies or augmentation therapies [ 147 , 148 ].

The alpha-1 blocker prazosin is mainly used for symptom relief, especially during sleeping. It is the preferred agent in patients experiencing nightmares or sleeping disorders. It can be used as an adjunct to SSRI/SSNRI [ 149 ]. There are some preliminary clinical studies on riluzole (a glutamatergic modulator), 3,4-methylenedioxymethamphetamine (MDMA), and ketamine. The results of these studies are promising, but these agents are not yet approved [ 150 , 151 , 152 ]. As there is no clear benefit, benzodiazepines are not recommended, as they have been shown to decrease the effectiveness of psychotherapy by diminishing the extinction effect, and they should be avoided, especially in patients with substance use disorders [ 153 , 154 ]. The effectiveness of anticonvulsant drugs with mood-stabilising effects to lessen PTSD symptoms has not been adequately explored in clinical studies. Few sufficiently powered, randomised trials have been released, and the results have largely been unfavourable [ 155 , 156 , 157 , 158 ]. On the other hand, intranasal oxytocin administration has been found to be a promising approach to preventing and reducing PTSD symptoms. Frijiling et al. found that repeated intranasal oxytocin administration in the early post-trauma period reduced the development of PTSD symptoms [ 159 ]. Additionally, intranasal oxytocin was found to reduce symptom severity in females with PTSD upon a trauma-script challenge [ 160 ]. Oxytocin has also been suggested to enhance the outcomes of psychotherapy, although adequately powered RCTs are still needed to assess this use of oxytocin [ 161 ].

A novel method of treating PTSD involves the disruption of memory reconsolidation [ 162 ]. Pharmacologically, this could be done through trauma memory reactivation with the administration of an amnesic drug, resulting in the disruption of memory consolidation. One drug showing promise in such an approach is propranolol, as it has been shown to disrupt fear memory reconsolidation in the amygdala in rodents [ 163 ]. Despite the limitations, such as short-term follow-up and the conflicting results of the recent studies, propranolol shows promise as an early preventative measure for PTSD.

5.4. E-Mental Health and Virtual Reality (VR)

To integrate our understanding of traumatic stress as a public health problem, interdisciplinary and modern approaches can facilitate the mission, including health service research [ 164 ], internet-based digital approaches like e-health [ 165 ], and artificial intelligence applications like virtual reality (VR) [ 166 ].

In the area of traumatic stress, e-mental health, defined by Riper et al. as “the use of information and communication technology to support and improve mental health conditions and mental health care”, has enormous potential to provide instruction, assessment, prevention, and treatment for negative effects following trauma exposure globally [ 167 ]. It is possible and effective to give intensive, trauma-focused treatment for severe or complicated PTSD via home-based telehealth. This can be a substitute for trauma-focused treatment that is delivered in person [ 168 ]. E-health being offered in times of pandemics (such as with COVID-19) has shown to be an efficient way to support prevention and possibly intervention at times of shortage [ 169 ]. This suggests that also in global PTSD care, this could be effective. However, several challenges arise in convincing patients to undergo such a new method of care. Bakker et al. propose three ways in which the application of e-health can be accelerated. First, optimising adherence and the engagement of users (including patients, clinicians, and relatives) can be achieved by designing approaches that meet the requirements of the users and implementing a holistic approach instead of focusing on a single disorder, in addition to featuring designs that engage the patients, such as real-time engagement, rewarding systems, and the involvement of VR and augmented reality (AR) programs. Second, increasing the field’s research with clinical and high-quality studies to help test evidence-based medicine for effective interventions. Lastly, the wide implementation of such interventions could be of great benefit, especially when local expert clinicians and clinics are unavailable. However, such a wide implementation must overcome several dilemmas, including physician and patient avoidance of internet interventions and patients’ preference of therapist-guided interventions [ 165 ].

VR for ET or psychophysiological assessment and resilience training could reduce negative impacts or enhance well-being in response to traumatic stress in public health [ 166 ]. Studies show the promising and wide usage of VR in trauma management from combat scenarios to the COVID-19 pandemic [ 166 ].

5.5. Conclusive Remarks

Although recent developments utilising methodologically sound designs have increased confidence in the effectiveness of PTSD therapy, a sizable proportion of patients fail to respond to treatment, stop receiving it, or never receive it. Research on agents that can target disrupted circuits in PTSD can improve both prevention and treatment. Therefore, there is definitely room for more research on PTSD therapies and delivery methods. With the wide range of available modalities of psychotherapy and pharmacotherapy, the scheme of individualising treatment, according to the severity and personal symptom profiles of PTSD, comorbid conditions, and the use of predictive therapeutic biomarkers, can greatly enhance the efficacy of treatment. With the rapid development of new technology, research in the field of e-mental health is advancing. In light of these quick advancements, future research should concentrate on preserving a high standard of assessment of the effectiveness and acceptability of new technologies, while the evaluation of side effects and hazards should not be disregarded.

6. PTSD Biomarkers

A biomarker is a measurable characteristic, which can be a substance (molecular or histological), response (physiological), or structure (radiographic); it is an indicator of biological or pathological processes, or responses to exposures or interventions [ 170 ]. Recently, the identification of biomarkers for PTSD has received increasing focus [ 171 ]. PTSD biomarkers are currently used for research purposes, but they might soon assist in screening and supporting the early detection of the disorder, resulting in timely intervention and better outcomes [ 172 ]. These biomarkers could be structural changes, substances, and responses which can help assess the disease risk, diagnosis, prognosis, and response to treatment. Here, we explore the different biomarkers of PTSD.

6.1. Susceptibility Biomarkers

Susceptibility markers comprise those that assess the risk of developing the disorder, and are assessed before and after trauma exposure in individuals at risk [ 173 ]. Perhaps a person’s vulnerability to developing PTSD is hard to measure, and many models have been developed to explain the complexity of its evolution [ 174 ]. As discussed earlier, both pre-traumatic, peri-traumatic, and post-traumatic factors can affect disease development and progression. In terms of these, researchers have investigated several susceptibility biomarkers in the pre-traumatic and post-traumatic periods as predictors of disease. Table 2 provides a summary of the susceptibility biomarkers implicated in PTSD.

Summary of the susceptibility biomarkers implicated in PTSD.

A study, the Prospective Research in Stress-Related Military Operations (PRISMO) study, investigated vulnerability markers in Dutch Armed Forces soldiers. The study included a cohort of Dutch military members deployed to Afghanistan for 4 months who experienced trauma and developed PTSD, those who did not develop PTSD, and healthy (unexposed) individuals. It was found that the number of GR in lymphocytes and monocytes before military deployment was significantly higher in soldiers who developed high amounts of PTSD symptoms after deployment which remained high for several months after deployment [ 175 ]. Moreover, T-cells’ high glucocorticoid sensitivity (GCs) (dexamethasone) before deployment was associated with high amounts of PTSD symptoms without comorbid depressive symptoms. Additionally, different patterns of GR sensitivity were associated with different presentations (e.g., severe fatigue and depressive symptoms) [ 176 ]. Furthermore, the study explored the roles of GR pathway components in disease prediction. It was found that low mRNA levels of FKBP5 (a cochaperone modulator of receptor sensitivity to cortisol) before deployment were associated with high amounts of PTSD symptoms after deployment [ 177 ]. High glucocorticoid-induced leucine zipper mRNA levels before deployment were also associated with high amounts of PTSD symptoms post-deployment [ 177 ].

Other studies report the findings of HPA axis involvement, including one on 103 children in the USA, which concluded that polymorphisms in the CRH type 1 receptor gene were associated with PTSD development in these subjects [ 178 ]. These findings elaborate on the importance of the HPA axis, and dysregulation, and how biomarkers related to the axis can be used as disease predictors. As mentioned before, the BDNF polymorphism Val66Met also appears to increase the risk of PTSD, as it results in a decrease in BDNF expression, which obtunds conditioned fear extinction [ 91 , 182 ]. Studies have shown an increased frequency of the Met allele in those who develop PTSD compared to controls [ 93 , 183 ]. However, recent meta-analyses have found that there is no significant correlation between the Met allele and PTSD symptomatology [ 90 , 184 , 185 ].

The markers mentioned above comprise molecular ones, but other non-molecular susceptibility markers have also been investigated, especially in the post-traumatic period. Heart rate has been considered a secondary risk marker of the disease, as increased heart rates in the post-traumatic period have been associated with PTSD development [ 179 ]. Additionally, nightmares in the pre-traumatic period were associated with disease susceptibility in Dutch combat soldiers [ 180 ]. Additionally, increased skin conductance, a psychophysical marker of hyperarousal, in the immediate aftermath of trauma, was also associated with the subsequent development of PTSD [ 181 ]. As patients with PTSD tend to have higher rates of hypertension, as well as higher resting systolic and diastolic blood pressure, blood pressure is considered a candidate risk marker of PTSD [ 186 , 187 ]. However, a recent meta-analysis showed no association between elevated blood pressure and the subsequent development of PTSD symptoms [ 188 ].

6.2. Diagnostic Biomarkers

Diagnostic biomarkers are those used to assess and classify people that are already exposed to traumatic experiences, and are identified in PTSD patients in comparison to those exposed to trauma but who are disorder-free [ 189 ]. Currently, the diagnosis of PTSD is clinical, and it does not depend on its pathophysiology and underlying biological changes. Rather, it depends on the disease’s manifestation and the fulfilment of certain criteria. This is because PTSD, like all mental disorders, is complex, and phenotype manifestation differs greatly between individuals with the same level of traumatic experience [ 190 ] and even between those with similar biological and neurological activity changes. Consequently, this discrepancy might contribute to the limited applicability of such biomarkers. Therefore, biomedical biomarkers are not yet clinically used to diagnose the disorder [ 172 ], but based on scientific advances they may provide diagnostic evidence soon. In the literature, these biomarkers are classified as structural (e.g., neuroanatomical changes), peptides (e.g., monoamines and cortisol), neuroendocrine (e.g., HPA axis activity), responses (e.g., arousal, startle response), genetic and epigenetic biomarkers, and other classifiers [ 173 , 191 , 192 ]. Table 3 provides a summary of the diagnostic biomarkers implicated in PTSD.

Summary of the diagnostic biomarkers implicated in PTSD.

Several studies have been conducted on the levels of monoamines in individuals with PTSD, which have indicated a rise in their levels, specifically in the case of noradrenaline, both peripherally and centrally. Hawk et al. examined the rise in catecholamines and cortisol in the urine of 55 participants who experienced serious motor vehicle accidents. They found that increased NE levels were associated with PTSD development. However, these findings were in men only, which might indicate gender differences for this biomarker [ 193 ]. Studies point to increased monoamine levels also being found in other anxiety disorders and that they are not specific to PTSD [ 204 ].

The HPA axis is the main neuroendocrine regulator in the body and is dysregulated in PTSD [ 205 ]. Several studies have concentrated on the difference in cortisol levels in individuals with PTSD, but the results were considerably variable. Meewisse et al. conducted a meta-analysis and indicated that cortisol levels are inconsistent and insignificant in patients with PTSD [ 206 ]. Interest has increased in FKBP5 and cortisol levels in response to stress. Yehuda et al. explored gene expression alterations in 35 participants who experienced the 9/11 attack on New York City. It was found that patients with PTSD had reduced levels of FKBP5 compared to controls [ 194 ]. As BDNF regulates synaptic plasticity, which is essential for fear learning and extinction, studies have suggested its role as a potential biomarker in PTSD. A systematic review and meta-analysis compared the peripheral blood levels of BDNF in patients with PTSD compared to controls without PTSD. Plasma BDNF levels were significantly higher in PTSD groups when compared to controls [ 202 ]. However, this increase in BDNF levels appears to follow a descending pattern, as BDNF levels tend to fall again in the long-term [ 207 ].

In a pilot study by Snijders et al., participants from the PRISMO study were divided into PTSD subjects, resilient subjects (trauma-exposed with no PTSD diagnosis), and non-exposed healthy controls. In this work, several miRNAs were identified as candidate diagnostic biomarkers. Five miRNAs (miR-221-3p, miR-335-5p, miR-138-5p, miR-222-3p, and miR-146-5p) were able to perfectly separate PTSD subjects from controls after adjusting for confounders [ 197 ]. Furthermore, the downregulation of miR-1246 was shown to be significant in PTSD patients compared to resilient subjects, suggesting its potential as a diagnostic biomarker [ 197 ]. Another study also suggested miRNAs as potential biomarkers, identifying a panel of nine stress-responsive miRNAs (miR-142-5p, miR-19b, miR-1928, miR-223-3p, miR-322*, miR-324, miR-421-3p, miR-463*, and miR-674*) [ 208 ].

As mentioned earlier, circuits involving the amygdala are dysregulated in PTSD. One important neuroanatomical finding in PTSD patients is amygdala over-activation [ 42 , 195 ]. Several studies reported increased amygdala activity in PTSD patients responding to fearful and traumatic stimuli during functional neuroimaging [ 209 ]. This hyperactivity might be due to decreased control and inhibitory signals from regulatory structures, such as the medial prefrontal cortex and the hippocampus [ 210 ]. In mentioning the hippocampus, hippocampal volume loss is a common anatomical change in patients with PTSD [ 196 ]. However, using hippocampal volume loss as a biomarker is unreliable, as it might be a direct consequence of exposure to trauma itself [ 211 ]. NPY, which is implicated in the pathophysiology of PTSD, could also serve as a diagnostic marker. Studies have shown lower NPY levels in the CSF of combat-exposed subjects with PTSD when compared to combat exposed subjects that did not develop PTSD [ 200 , 201 ]. Additionally, trauma exposure and PTSD are associated with diminished baseline plasma levels of NPY [ 198 , 199 ].

Of new interest is the role of oxytocin and its receptor expression patterns in patients with PTSD. Hofmann et al. compared serum oxytocin and oxytocin receptor mRNA (OXTR mRNA) levels at the baseline and during a Trier Social Stress Test (TSST). Serum oxytocin was found to be higher, while OXTR mRNA levels were found to be lower in the PTSD patients at the baseline compared to the healthy controls. During TSST, an increase in OXTR mRNA was markedly correlated with PTSD symptoms. It should be noted, however, that these findings apply only to the HPA axis hyporesponsive subtype of PTSD in the study [ 203 ]. However, due to the small sample size and opposing findings in other studies [ 212 ], it is still early to consider oxytocin a reliable biomarker for PTSD. Future studies should clarify its role in PTSD pathophysiology and its reliability in aiding the diagnosis.

Some psychophysical markers in patients with PTSD were also investigated. One promising candidate is skin conductance (SC), which was found to be increased in patients with PTSD [ 213 , 214 ]. Although resting blood pressure was found to be elevated in PTSD patients [ 186 , 187 ], further studies are needed to assess its feasibility as a biophysical marker. Other biomarkers suggested to help predict and diagnose PTSD include the rise in inflammatory markers and mediators (CRP, IL-2, IL-6, etc.), an increased startle response, symptoms of hyperarousal, and impaired cognitive function, among others [ 173 , 191 ].

6.3. Therapeutic Biomarkers

Therapeutic biomarkers are those that allow the prediction/monitoring of the response to the delivered treatment, and are assessed throughout the treatment process [ 173 ]. Both diagnostic and susceptibility biomarkers can contribute to the treatment process. However, a set of biomarkers that can specifically monitor treatment effectiveness and others that can predict responses to the different modalities of “stratification” have also been investigated [ 215 , 216 ]. Establishing a reliable and cost-effective biomarker for treatment monitoring can lead to significant improvement in PTSD management [ 172 ]. Table 4 provides a summary of the therapeutic biomarkers implicated in PTSD.

Summary of the therapeutic biomarkers implicated in PTSD.

Many studies have been conducted on biomarkers predicting the response to treatment and progression. In PTSD patients, successful cognitive behavioural therapy was observed to decrease right amygdala activity while increasing right anterior cingulate cortex activity [ 217 ]. Additionally, a cerebral blood flow alteration, made evident by a difference in 99mTc-HMPAO uptake was observed between responders and non-responders to EMDR treatment. Compared to controls, patients had increased uptake in the medial temporal cortex, temporal pole, and orbitofrontal cortex. After treatment with EMDR, the uptake difference in the medial temporal cortex was not present anymore but extended to the lateral temporal cortex and the hypothalamus [ 218 ]. The medial temporal cortex is involved in memory encoding, consolidation and retrieval, and re-experiencing symptoms [ 222 , 223 ]. A larger rostral anterior cingulate cortex (rACC) volume was also found with a reduction in PTSD symptoms [ 219 ]. In the same study, Bryant et al. additionally found that a larger volume of rACC was present in those who responded to CBT. They also found that a greater activation of the bilateral amygdala and ventral anterior cingulate was associated with a poorer response to treatment [ 219 ]. A polymorphism in the serotonin transporter gene promoter LL 5HTTLPR was found to be associated with a better response rate to sertraline compared to the other genotypes (SS and SL) [ 220 ]. Interestingly, lower serum levels of BDNF were associated with a decrease in PTSD symptoms in chronic PTSD patients on the SSRI escitalopram [ 221 ].

As described, a significant advancement in therapeutic care will be the discovery of accurate PTSD biomarkers. Nevertheless, the ultimate therapeutic utility of biomarkers as a component of precision medicine will augment rather than replace current decision-making procedures since specific treatment needs are established through a collaborative process between patient and physician.

6.4. Conclusive Remarks

There are now a variety of biomarkers linked to the risks, symptoms, and course of PTSD. Despite this relationship, there is a limited prospect of employing a single marker either diagnostically or prognostically, due to the prevalent comorbidity with other mental illnesses and the limitations of studies. For instance, it is possible that decreased hippocampus volume is linked to both PTSD and comorbid depression and can act as a biomarker of the constellation of symptoms connected to both conditions. For this, biomarker panels (as opposed to the use of a single biomarker) are needed in order to maximise the specificity, sensitivity, and repeatability of diagnostic tools. Future research must examine the biological and psychological aspects of PTSD in more detail in order to meaningfully identify a combination of biomarkers that may cluster around symptoms and symptom development, for example by the use of (multi-)omics data and machine learning approaches.

7. Limitations and Future Directions

Since the introduction of PTSD as a diagnosis four decades ago, our understanding of the disorder has grown tremendously. However, the ability to aid recovery and enhance the quality of life of PTSD patients is still lagging behind. A lot of patients are not diagnosed timely, if at all. Although efficacious treatment regimens have been developed, many patients do not receive their treatment, and others fail to optimally respond.

Recent research on neurobiological models has given unparalleled insight into the potential underlying causes of PTSD. Yet, it is crucial to emphasise that a collection of condensed working models is unlikely to adequately describe the full intricacy of the illness. These neural models’ ability to pave the way from new pathophysiological understanding to ground-breaking treatments for PTSD may be their most important contribution. Limitations to current studies are mostly concerned with study designs and methodology, as mentioned earlier. For example, the mixed results observed in studies evaluating the HPA axis function can largely be due to traumatic exposure in the control groups being a confounder in some studies. As a result, further studies evaluating the association between trauma exposure (as opposed to PTSD) and HPA axis dysfunction are needed. The standardisation of study designs, techniques, and protocols for obtaining diurnal cortisol should be another main goal of future research. For instance, Ryan et al. suggested measuring the salivary diurnal rhythm of cortisol over a period of at least two days before and after the given intervention, as this can characterise the function of the HPA axis and the relationship between diurnal cortisol and PTSD in greater detail [ 224 ].

With the introduction of DSM-5 and ICD11, considerable modifications have been made to the diagnostic criteria and categorisation of illnesses linked to trauma and stressors. In addition to highlighting the enormous research that has gone into understanding these phenomena, the repeated revisions in diagnostic criteria and categorisation also draw attention to the difficulties that occur when evaluating disorders that are caused by traumatic experiences. Given the current understanding, there are a number of necessary next steps to comprehend how to best classify trauma- and stressor-related disorders, including, but not limited to: (1) further clarifying partial PTSD phenotypic expression and determining whether categorisation under a dimensional vs. a categorical approach would be beneficial; (2) continuing to refine assessments to ensure that traumatic experiences are thoroughly assessed and symptoms after these experiences are best captured; (3) examining possible phenotypes of stress- and trauma-related diseases in further detail. In addition, research needs to take into consideration the possible biological subtypes of HPA axis responsiveness in PTSD, as they have been found to differ significantly in symptom intensity and comorbid anxiety symptoms [ 225 ].

Because PTSD has no cure and exposure to trauma is unpredictable, it is crucial to reveal susceptibility in order to find effective resilience-building techniques and avoid PTSD from ever occurring. As only a small portion of the trauma-exposed population has PTSD, susceptibility does exist. One of the promising fields to aid this goal is the genetics and epigenetics field. New discoveries in this field can greatly aid not only the detection of susceptible individuals but also diagnosis and new routes of targeted pharmacological treatment. In a review by Al Jowf et al., we highlight the recent advancements in epigenetics and epigenomics, drawn from EWAS and GWAS studies [ 106 ]. A major limitation of these studies is the fact that a lot of these studies are preclinical studies based on animal models of PTSD. Still, a number of human cohort EWAS and GWAS studies have also been conducted, leading to candidate (epi)genetic markers [ 226 , 227 , 228 , 229 ]. This highlights the need for translational studies in humans that can make clinical use of these markers, which can aid in the detection of susceptibility and early diagnosis.

Biological indicators cannot yet independently validate the evaluation of PTSD, drawing a clear contrast from other medical conditions like cancer, hypertension, and autoimmune diseases that have objective biological testing procedures for diagnosis, assessing the severity of illness, and response to therapy. Instead, self-report screening tests and clinical interviews are used to diagnose PTSD rather than an identification of the underlying pathology. The growing interest in PTSD biomarkers shows significant potential and promise; however, it is currently challenging to make inferences that can be used practically from the existing fundamental and translational research on PTSD biomarkers. Once enough data are collected, machine learning approaches can help combine biomarkers in reliable, valid, and cost-effective integrated panels that can greatly enhance the prediction, diagnosis, and monitoring of the disorder.

Likewise, instead of addressing the biological etiology, treatment has mostly been restricted to symptom control and behavioural adaptation techniques. Drug development for PTSD has thus far been mostly opportunistic, based almost entirely on empirical findings using medications already licensed for other disorders. A single pharmaceutical therapy for PTSD has not yet been created as of the time of this writing. For now, future studies should pinpoint strategies for enhancing effective treatments, such as in specific populations (e.g., military personnel), for the further investigation of recommended and promising treatments, for developing strategies to individualize treatment, for maintaining patient engagement in treatment (i.e., preventing dropout), and for identifying individual factors predicting response/nonresponse. For instance, there are interventions that hold promise in improving PTSD symptoms, including repetitive transcranial magnetic stimulation (rTMS), biofeedback, exercise (e.g., yoga, and aerobic and resistance exercise) and deep brain stimulation (DBS) [ 230 , 231 , 232 , 233 ]. However, a lot of these studies are preclinical, while others are controversial and inadequately powered, creating a need for the further assessment for their efficacy in PTSD treatment. In the future, research on PTSD treatment should be guided by discoveries of the disruptions underpinning the development of the disorder, so that targeted and more effective interventions can be developed.

8. Conclusions and Perspectives

PTSD is usually associated with chronicity and disability. Although the underlying neurobiology might be elusive, several established mechanisms have been studied, which have had significant implications on management. These dysregulations include brain circuit disruption through the dysregulated release of neurotransmitters, namely NE and serotonin among many others (e.g., dopamine, GABA, and NPY), a dysfunctional HPA axis, and disordered cannabinoid and opioid activity. Although PTSD is partly attributed to these dysregulations, models such as the biopsychosocial model and the diathesis–stress model have been developed to emphasise that underlying biology is not the only contributor to the disorder, yet there is an interplay between biological (e.g., genetics, chemical changes, and organ damage), psychological (e.g., stress, mental illness, behaviour, and personality), and social factors (e.g., peers, socioeconomic status, beliefs, and culture) in the manifestations of the disease. The current treatment for PTSD involves two main modalities, namely psychotherapy and pharmacotherapy. While psychotherapy is considered the treatment of first choice, when needed, pharmacotherapy can be used as an alternative or in conjunction with psychotherapy. Preventing the disease at different time points (primary, secondary, and tertiary prevention) can significantly reduce the disease’s burden on patients’ quality of life and economic and medical burdens. Thus, the development and application of disease prevention models are of great importance. In the end, further research on susceptibility and resilience, pathophysiology, and possible targeted intervention is needed for better understanding and treatment. Over the past decade, the identification of disease biomarkers has gained more interest. Establishing reliable and cost-effective biomarkers can greatly enhance primary prevention, diagnosis, the monitoring of therapy, and the prevention of disability. None of the putative PTSD biomarkers reported so far are being used in clinical settings, which highlights the urgent need for additional studies on PTSD biomarkers with large sample sizes and for translational research strategies aiming to understand the underlying molecular causes of PTSD.

Acknowledgments

We would like to thank Bart Rutten for providing us with valuable suggestions and input for our manuscript. Additionally, we wish to thank Mahmoud Elbatreek and Maher Al-Omar for their support in the exchange of thoughts in the preparation of this paper.

Funding Statement

Ghazi I. Al Jowf was supported by personal funding from King Faisal University, Employees Scholarship Program from the Saudi Arabian Government (no. 1026374049).

Author Contributions

G.I.A.J. drafted the initial manuscript. Moreover, Z.T.A., R.A.R., L.d.N. and L.M.T.E. revised the final manuscript and provided comments/suggestions. G.I.A.J. and L.M.T.E. are the corresponding authors. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

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