No two traumas are alike, and neither are two presentations of <scp>PTSD</scp>
Authors: Soraya Seedat
Journal: World Psychiatry (2025)

Significant advances have been made in our understanding of post-traumatic stress disorder (PTSD), and in translating an overwhelming body of research evidence into clinical practice. However, it is time for researchers and clinicians to pause and reflect on whether true progress has been made. Brewin et al1 convincingly distill the complexity of defining, assessing, diagnosing, predicting, preventing and treating PTSD in diverse populations, across several countries, in varying socio-political-cultural and societal-structural contexts, and at different life stages. The review juxtaposes the rapid and exponential growth of knowledge on trauma, PTSD and complex PTSD against the significant knowledge gaps (and possibly "blind spots") that remain. It brings into sharp focus the need for accelerated research and consensus building on a core set of evidence-informed and integrated phenotypes and biotypes, in pursuit of categorical and dimensional solutions to parsing out PTSD heterogeneity, and intervening timeously and effectively. Fine-grained characterization of PTSD phenotypes and biotypes could propel collective global efforts and pave the way for the development of tailored, measurement-based and personalized interventions for adults and youth with PTSD – interventions that yield higher response and remission rates than the current ones. Trauma is ubiquitous, but it is also individual and personal, and its impact and attributions are highly variable. Prevalence rates of PTSD vary considerably by population, demography, social determinants, and ascertainment method. Several decades of research have taught us that the relationship between the nature of a traumatic event (e.g., single or repeated, interpersonal or non-interpersonal, intentional or non-intentional), the peri-traumatic responses it triggers, and the resultant PTSD is non-linear, and, at an individual patient level, may follow a convoluted trajectory. Similarly, evidence – also gathered over decades – on acute stress disorder, first introduced in the DSM-IV as a distinctive early-after-trauma diagnosis and retained in the DSM-5, has been disappointing with regards to its diagnostic utility in predicting PTSD2, 3. Despite an abundant literature on pre-trauma, peri-trauma and post-trauma risk and protective factors, our ability to predict PTSD and apply biological markers (e.g., genotypic, epigenetic, transcriptomic, endocrine, immune) to stratify trauma-exposed individuals by risk remains very limited. Moreover, low- and middle-income country populations are disproportionately under-represented in longitudinal neurobiological studies that aim to track biological signatures alongside PTSD symptom trajectories4. Also central to the challenge is the astounding within-group heterogeneity in PTSD (in symptom patterning, illness course, and treatment outcome) and the high comorbidity with a wide range of psychiatric disorders and physical illnesses. It is plausible that symptom-based subtypes and biotypes could incrementally refine classification and treatment of PTSD. To date, significant empirical strides have been made in delineating the dissociative subtype, the only one recognized in the DSM-5, which has a point prevalence of 38.1% in children and adolescents with a diagnosis of PTSD, and a unique symptom, neurobiological and treatment response profile that is underpinned by fairly robust evidence5, 6. There is still ongoing debate about whether dissociation is a somewhat common phenomenon in PTSD and a marker of PTSD severity, or whether its occurrence is limited to a more circumscribed subgroup of people with the diagnosis. The specificity of the dissociative subtype needs further interrogation, beyond the Global North, and in culturally diverse settings and PTSD populations where dissociative phenomena might be linked to somatization and other culture-bound phenomena. In the vein of delineating unique PTSD symptom profiles that could inform more targeted, personalized treatments, few studies have sought to map the type of index trauma to PTSD symptom clusters in a concerted fashion. Notable is a recent investigation of 4,069 veterans from the 2019-2020 National Health and Resilience in Veterans Study, which applied an alternative phenotypic model to the DSM-5 and ICD-11 symptom structure to plot the relationship of different traumas (categorized into interpersonal violence, combat/captivity, disaster/accident, and illness/injury) to PTSD symptoms7. The resulting eight-symptom PTSD phenotype model comprised internally-generated intrusions (e.g., distressing traumatic memories), externally-generated intrusions (e.g., emotional reactivity to trauma cues), avoidance, negative affect, anhedonia, externalizing behaviors, and anxious and dysphoric arousal. Findings of discriminable symptom profiles between veterans who experienced interpersonal violence or combat/captivity versus those who experienced illness/injury or disaster/accident are encouraging. However, the cross-sectional design of the study precludes addressing the question of whether these trauma-symptom profiles hold out over time in individuals with chronic PTSD. Moreover, these findings will have to be replicated in other trauma-exposed populations, and the biopsychosocial mechanisms that underlie different trauma-PTSD symptom phenotypes will also require deep exploration. The field has for a long time invested in large-scale and costly efforts to identify clinically valid, affordable and scalable PTSD biomarkers that can aid screening and timely intervention, and lead to better outcomes. Several susceptibility and diagnostic markers, and some predictive and therapeutic biomarkers, have been evaluated, including polygenic risk scores and regional brain structural morphology. However, these markers require replication and testing in large samples and across populations before their potential clinical utility can be realized8. The prospect of employing single biomarkers in PTSD is out of question, and discovery of biomarker panels that have the requisite reliability, specificity, sensitivity and reproducibility – and are cost-effective and feasible to employ at point-of-care – is still some way off. For predictive biomarkers, multiple sampling commencing early after trauma and extending beyond a year to account for the evolving dynamics of PTSD symptoms is arguably the best way to map resilient, chronic, delayed onset, and recovery trajectories, and enhance our understanding of causal pathways. For predictors of treatment response and normalization of biological perturbations with treatment, trials that compare psychotherapies, pharmacotherapies and combination treatments are needed. In addition, innovative strategies, such as biomarker-stratified designs (to address the question of what is the best treatment for all patients with PTSD as well as for biomarker-defined PTSD patient subgroups) and biomarker enrichment designs (to address the question of what is the best treatment in biomarker-positive patients with PTSD), will serve to improve efficiency and precision. Though appealing, these designs are hugely challenging to apply. Generative artificial intelligence tools may fast change this landscape, with benefits that extend beyond identifying novel predictors of PTSD treatment outcomes, to bolstering treatment fidelity and boosting patient engagement9. However, these tools also raise a host of ethical, social and legal considerations that clinicians at the coalface of caring for patients with PTSD will be compelled to grapple with. Finally, in seeking to transform scientific endeavors to prevent, diagnose and treat PTSD, it behooves us to remember that no two traumas and no two presentations of PTSD are alike. The art of providing individual-level care should always sit alongside our science.