<p dir="ltr">Background: Persistent physical symptoms (PPS) are distressing bodily complaints present on most days for several months or longer. In primary care, at least one-fifth of consultations are related to PPS. Common examples include persistent - and often comorbid - cardiopulmonary symptoms, fatigue, gastrointestinal complaints, and pain. These symptoms may be related to various health conditions, including somatic diseases, such as asthma or cancer, or functional somatic syndromes, such as fibromyalgia or irritable bowel syndrome (IBS). Causes are often multifactorial and not easily delineated. Regardless of etiology, PPS are associated with substantial disability, aversive emotional experiences, and costs. General practitioners often find PPS difficult to manage, and common treatment options such as symptom-specific or antidepressant medications typically yield insufficient effects. Self-rating scales evaluating somatic symptom burden may aid the assessment and monitoring of PPS, but their measurement properties need to be established. Further, promising psychological treatment options exist, but are typically diagnosis-specific, fear-focused, and rarely offered in routine primary care. Transdiagnostic treatment approaches may improve access to care and benefit many patients with comorbid PPS. Further, investigating the relevance of diverse emotions in PPS may be informative.</p><p dir="ltr">Aims: This thesis aimed to evaluate the measurement properties of two self-rating scales widely used to assess somatic symptom burden: the Patient Health Questionnaire-15 (PHQ-15) and its abbreviated version, the Somatic Symptom Scale-8 (SSS-8) (Study I). The aim was also to evaluate the feasibility of a transdiagnostic, internet-delivered exposure therapy for PPS regardless of symptom domain and etiology (Study II), and its efficacy (Study III). Lastly, Study IV aimed to investigate a broad spectrum of emotions experienced in relation to physical symptoms among clinical trial participants with PPS.</p><p dir="ltr">Methods: Study I was a systematic review and meta-analysis of the measurement properties of the PHQ-15 and SSS-8. Study II was a single-group prospective cohort study evaluating the feasibility of a therapist-guided, internet-delivered exposure therapy for PPS, regardless of symptom type or combination. 33 self-referred adult participants with PPS were included. Primary feasibility outcomes included recruitment, adherence, credibility, acceptance of the measurement strategy, treatment satisfaction, and adverse events; secondary outcomes included within-group reductions in somatic symptom burden (PHQ-15) and symptom preoccupation (the Somatic Symptom Disorder-B Criteria Scale; SSD-12). A randomized controlled trial (RCT; Study III) based at Liljeholmen University Primary Health Care Center in Stockholm, Sweden, further evaluated the treatment by comparing its efficacy to internet-delivered, therapist-guided healthy lifestyle promotion (HLP). 161 adult patients with PPS, ranging from mild, single-symptom to severe, multiple-symptom presentations, were included. Symptoms could be of any etiology, provided that participation was not deemed medically inappropriate. Patients were randomized to exposure therapy or HLP. The primary outcome was somatic symptom burden (PHQ-15), and secondary outcomes included symptom preoccupation, disability, depressive symptoms, and general anxiety. Moderator analyses were performed, focusing on somatic symptom burden and symptom preoccupation. Data from the same RCT were subsequently used to evaluate a broad spectrum of emotions (i.e., anger, disgust, fear, joy, sadness, shame) experienced in relation to PPS and to investigate whether these emotions changed with exposure therapy and HLP (Study IV). A cohort of healthy volunteers was also recruited for Study IV for clinical comparisons.</p><p dir="ltr">Results: A total of 305 studies conducted across the general population and various healthcare settings were included in Study I. The results suggested that the PHQ-15 is best represented by a bifactor model with a general factor of moderate strength (AVE = 0.19 - 0.45), and the SSS-8 by a hierarchical model with a general factor of moderate strength (AVE = 0.30 - 0.51). Internal consistency and construct validity appeared adequate for both scales. The overall area under the curve for identifying somatoform disorders ranged from 0.63 to 0.79 for the PHQ-15 and was 0.71 and 0.73 in two studies of the SSS-8. Test-retest reliability was inconsistent for the PHQ-15 (r = 0.65, r = 0.93, ICC = 0.87), and probably adequate for the SSS-8 (r = 0.996, ICC = 0.89). Sensitivity to change appeared promising for the PHQ-15, while data were largely lacking for the SSS-8. The feasibility study (Study II) indicated that exposure therapy could be delivered with adequate patient satisfaction, adherence, credibility, acceptance of the measurement approach, and without serious adverse events. The sample was heterogeneous in terms of PPS and psychiatric comorbidity. In the RCT, exposure therapy was not superior to HLP in the average effect on somatic symptom burden (d = 0.14) (Study III). A small advantage was indicated for exposure therapy compared to HLP in the effect on symptom preoccupation (d = 0.31), but there were no significant differences in the effects on disability, depressive symptoms, or general anxiety. Moderator analyses indicated that baseline somatic symptom burden and symptom preoccupation significantly moderated the between-group effect of exposure therapy versus HLP on somatic symptom burden. Compared with healthy volunteers, patients with PPS reported significantly higher levels of negatively valenced emotions related to their physical symptoms (ds = 0.67 - 2.13) and lower joy (d = - 0.22) (Study IV). Emotions with negative valence were significantly correlated with somatic symptom burden and disability, and improved significantly with exposure therapy and HLP (ds = 0.22 - 0.71). Joy increased significantly in exposure therapy (d = 0.73). There were no significant between-group effects on any emotions.</p><p dir="ltr">Conclusions: Self-rated somatic symptom burden according to the PHQ-15 and SSS-8 reflects a complex factor structure, suggesting both shared and domain-specific covariance across symptom domains in PPS. A flexible, internet-delivered exposure therapy appears to be safe and credible for patients with PPS across various symptom domains and etiologies. It may, however, offer limited benefits to patients with mild PPS compared to the lower-threshold intervention of HLP. For patients with pronounced physical symptoms and distress, exposure therapy appears superior to promotion of healthy lifestyle habits for improved somatic symptom burden and reduced symptom preoccupation. A broader consideration of emotions related to PPS may advance research and facilitate personalized care.</p><h3 dir="ltr">List of scientific papers</h3><p dir="ltr">I. <b>Hybelius J,</b> Kosic A, Salomonsson S, Wachtler C, Wallert J, Nordin S, et al. Measurement Properties of the Patient Health Questionnaire-15 and Somatic Symptom Scale-8: A Systematic Review and Meta- Analysis. JAMA Netw Open. 2024; 7(11): e2446603. <a href="https://doi.org/10.1001/jamanetworkopen.2024.46603" rel="noreferrer" target="_blank">https://doi.org/10.1001/jamanetworkopen.2024.46603</a></p><p dir="ltr">II. <b>Hybelius J,</b> Gustavsson A, af Winklerfelt Hammarberg S, Toth-Pal E, Johansson R, Ljótsson B, et al. A unified Internet-delivered exposure treatment for undifferentiated somatic symptom disorder: single-group prospective feasibility trial. Pilot Feasibility Stud. 2022; 8(1): 149. <a href="https://doi.org/10.1186/s40814-022-01105-0" rel="noreferrer" target="_blank">https://doi.org/10.1186/s40814-022-01105-0</a></p><p dir="ltr">III. <b>Hybelius J,</b> af Winklerfelt Hammarberg S, Salomonsson S, Wachtler C, Epstein M, Olsson A, et al. Effect of internet-delivered exposure therapy versus healthy lifestyle promotion for patients with persistent physical symptoms (SOMEX1): a randomized controlled trial with planned moderator analysis. Psychol Med. 2025; 55: e226. <a href="https://doi.org/10.1017/S0033291725101244" rel="noreferrer" target="_blank">https://doi.org/10.1017/S0033291725101244</a></p><p dir="ltr">IV. <b>Hybelius J,</b> af Winklerfelt Hammarberg S, Salomonsson S, Wachtler C, Epstein M, Olsson A, et al. Basic emotions reported by individuals with persistent physical symptoms receiving exposure therapy versus healthy lifestyle promotion in primary care. Sci Rep. 2026; 16(1): 7170. <a href="https://doi.org/10.1038/s41598-026-39962-x" rel="noreferrer" target="_blank">https://doi.org/10.1038/s41598-026-39962-x</a></p>