Efficacy of patient education and duloxetine, alone and in combination, for patients with multisystem functional somatic disorder: Study protocol for the EDULOX trial.

BACKGROUND: Multisystem functional somatic disorder is characterized by specific patterns of persistent physical symptoms with a complex biopsychosocial etiology. The disorder can lead to disability and personal suffering. Current treatment options require specialized settings, therefore patients often wait a long time to receive specific treatment. Patient education is considered important in most treatment programs, but has only been investigated sparsely as a stand-alone treatment. Pharmacological treatment is limited to tricyclic antidepressants in low doses with no antidepressant properties. Duloxetine has been found effective in single organ functional disorders. As a treatment for multisystem functional somatic disorder, duloxetine could reduce symptoms and treat comorbid anxiety and depression. It may furthermore enhance the effect of patient education through a hypothesized effect on cognitive functioning. The purpose of the EDULOX trial is to study psycho-EDUcation and duLOXetine alone and in combination. METHODS: This is a nested study design. The parent trial "EDULOX1" (n = 424) will compare a patient education program with enhanced usual care in an open-labelled, randomized controlled trial. In addition to this, eligible participants will furthermore receive either duloxetine or active placebo in the nested, double-blinded, randomized controlled trial, "EDULOX2" (n = 212). Patient and clinician reported outcomes will be collected through questionnaires. CONCLUSION: The EDULOX trial may establish evidence for treatments applicable for the majority of patients with multisystem functional somatic disorder. If effective, duloxetine would be a more tolerable pharmacological treatment option that can target comorbid depression and anxiety, and potentially boost the effect of patient education. Trial registration number The study is registered at www. CLINICALTRIALS: gov (NCT06232473) and the internal list of research projects at the Region of Central Denmark (Case number 1-16-02-305-23). Approval from the Danish Medical Research Ethics Committees (Case number: 2212291) and the Danish Medicines Agency was obtained under EudraCT Number: 2022-002780-30 and Sponsor's Protocol Code Number: 9515.

Increasing transcultural competence in clinical psychologists through a web-based training: study protocol for a randomized controlled trial.

BACKGROUND: In mental health care, the number of patients with diverse cultural backgrounds is growing. Nevertheless, evaluated training programs for transcultural competence are missing. Barriers for engaging in transcultural therapy can be identified in patients as well as in therapists. Besides language barriers, clinical psychologists report insecurities, for example, fear of additional expenses when involving a language mediator, ethical concerns such as power imbalances, or fear of lack of knowledge or incorrect handling when working with patients from other cultures. Divergent values and concepts of disease, prejudices, and stereotyping are also among the issues discussed as barriers to optimal psychotherapy care. The planned study aims to empower clinical psychologists to handle both their own as well as patients' barriers through a web-based training on transcultural competence. METHODS: The training includes 6 modules, which are unlocked weekly. A total of N = 174 clinical psychologists are randomly assigned to two groups: the training group (TG) works through the complete training over 6 weeks, which includes a variety of practical exercises and self-reflections. In addition, participants receive weekly written feedback from a trained psychologist. The waitlist control group (WL) completes the training after the end of the waiting period (2 months after the end of the TG's training). The primary outcome is transcultural competence. Secondary outcomes consist of experiences in treating people from other cultures (number of patients, satisfaction and experience of competence in treatment, etc.). Data will be collected before and after the training as well as 2 and 6 months after the end of the training. DISCUSSION: This randomized controlled trial tests the efficacy of and satisfaction with a web-based training on transcultural competence for German-speaking clinical psychologists. If validated successfully, the training can represent a time- and place-flexible training opportunity that could be integrated into the continuing education of clinical psychologists in the long term. TRIAL REGISTRATION: DRKS00031105. Registered on 21 February 2023.

Endorsing a Biopsychosocial Perspective of Pain in Individuals With Chronic Pain: Development and Validation of a Scale.

OBJECTIVES: Patients' beliefs about pain play an important role in their readiness to engage with chronic pain self-management. The central aim of this study was to validate a self-report instrument to assess a specific set of pain beliefs, patients' endorsement of a biopsychosocial model of chronic pain Patients' Endorsement of a Biopsychosocial Model of Chronic Pain Scale (PEB). METHODS: Interdisciplinary experts in the field of pain were involved in creating an instrument, the PEB Scale, to operationalize patients' endorsement of a biopsychosocial pain model. A sample of 199 patients with chronic pain was recruited to evaluate the factorial structure (principal axis factoring), the internal consistency (Cronbach alpha), the convergent and discriminant validity (correlational analyses), incremental validity (multiple, hierarchical regression analyses), and construct validity (differential population analysis) of the instrument. RESULTS: The factor analysis resulted in a unidimensional, 11-item instrument that explained 51.2% of the total variance. Cronbach alpha (=0.92) indicated high internal consistency of the created set of pain-related beliefs. Regression analyses demonstrated that PEB is a strong predictor of patients' engagement with pain self-management ( P < 0.001) after controlling for demographic variables, anxiety, depression, and other pain-related beliefs. DISCUSSION: Our results show that the PEB Scale is a highly reliable self-report instrument that has the potential to predict patients' readiness to adopt pain self-management. Future research should focus on revalidating the scale to operationalize PEB. Moreover, the PEB Scale should be implemented in longitudinal study designs to investigate its ability to predict the transition from acute to chronic pain and patients' long-term pain management.

Nocebo Hypothesis Cognitive Behavioural Therapy (NH-CBT) for non-epileptic seizures: a consecutive case series.

BACKGROUND: Research has demonstrated that implementation of Nocebo Hypothesis Cognitive Behavioural Therapy (NH-CBT) achieved full symptom remission in 93% of people with Functional Neurological Symptoms Disorder (FNSD), most of them exhibiting motor symptoms. The basis for NH-CBT is consistent with a predictive coding aetiological model of FNSD. This idea is transparently shared with people with FNSD in the form of telling them that their symptoms are caused by a nocebo effect, usually followed by some physical activity that aims to change the person's belief about their body. AIMS: To demonstrate that a version of NH-CBT can also be effective in eliminating or reducing non-epileptic seizures (assumed to be a sub-type of FNSD). METHOD: A consecutive case series design was employed. Participants were treated with NH-CBT over a 12-week period. The primary outcome measure was seizure frequency. Numerous secondary measures were employed, as well as a brief qualitative interview to explore participants' subjective experience of treatment. RESULTS: Seven out of the 10 participants became seizure free at least 2 weeks before their post-treatment assessment, and all stayed seizure-free for at least 5 months. Six of those seven remained seizure free at 6-month follow-up. There were large positive effect sizes for the majority of secondary measures assessed. CONCLUSIONS: This case series provides evidence of feasibility and likely utility of NH-CBT in reducing the frequency of non-epileptic seizures.

DNA Methylation Signatures of Functional Somatic Syndromes: Systematic Review.

OBJECTIVE: Functional somatic syndromes (FSS) are highly prevalent across all levels of health care. The fact that they are characterized by medically unexplained symptoms, such as fatigue and pain, raises the important question of their underlying pathophysiology. Psychosocial stress represents a significant factor in the development of FSS and can induce long-term modifications at the epigenetic level. The aim of this review was to systematically review, for the first time, whether individuals with FSS are characterized by specific alterations in DNA methylation. METHODS: MEDLINE and PsycINFO were searched from the first available date to September 2022. The inclusion criteria were as follows: a) adults fulfilling the research diagnostic criteria for chronic fatigue syndrome, fibromyalgia syndrome, and/or irritable bowel syndrome; b) healthy control group; and c) candidate-gene or genome-wide study of DNA methylation. RESULTS: Sixteen studies ( N = 957) were included. In candidate-gene studies, specific sites within NR3C1 were identified, which were hypomethylated in individuals with chronic fatigue syndrome compared with healthy controls. In genome-wide studies in chronic fatigue syndrome, a hypomethylated site located to LY86 and hypermethylated sites within HLA-DQB1 were found. In genome-wide studies in fibromyalgia syndrome, differential methylation in sites related to HDAC4 , TMEM44 , KCNQ1 , SLC17A9 , PRKG1 , ALPK3 , TFAP2A , and LY6G5C was found. CONCLUSIONS: Individuals with chronic fatigue syndrome and fibromyalgia syndrome seem to be characterized by altered DNA methylation of genes regulating cellular signaling and immune functioning. In chronic fatigue syndrome, there is preliminary evidence for these to be implicated in key pathophysiological alterations, such as hypocortisolism and low-grade inflammation, and to contribute to the debilitating symptoms these individuals experience. PREREGISTRATION: PROSPERO identifier: CRD42022364720.

Trust in the approval process of medicines mediates the effect of an educational intervention on the pain relief induced by a generic analgesic.

BACKGROUND: Generic medicines have been associated with less efficacy compared to originator products. Educational videos explaining generic medicines can have a positive effect on perceptions of generic drugs and their pain-relieving effect. The central aim of the current study was to examine whether trust in the governmental approval process of medicines mediates the effect of educational video interventions on the pain-relieving effect induced by a generic medicine and whether trust can be built by improving individuals' understanding of generic medication. METHODS: This is a secondary analysis of a randomized controlled trial where participants with frequent tension headaches were randomly assigned to either watching a video explaining generic drugs (n = 69) or a video informing about headaches (control group: n = 34). After watching the video, participants took an originator and a generic pain analgesic in a randomized order to treat their next two consecutive headaches. Pain severity was measured before and 1 h after taking the medicine. RESULTS: A multiple serial mediator model showed that improving individuals' understanding of generic medicines is associated with increased trust in medicines. Both factors together, understanding and trust, significantly mediated the effect of the video education about generic drugs on the generic's pain-relieving effect (total indirect effect: coefficient: 0.20, 95% CI: 0.42, -0.0001). CONCLUSION: Results of this study show that improving individuals' understanding of generic medication and trust in the process of approving medicines should be considered as important mechanisms of future educational interventions about generic medicines.

The framework for systematic reviews on psychological risk factors for persistent somatic symptoms and related syndromes and disorders (PSY-PSS).

Introduction: Numerous psychological factors are believed to play a pivotal role in the development and maintenance of persistent somatic symptoms (PSS) in all fields of medicine. However, very few of these factors have been empirically investigated in relation to PSS. The aim of this study is firstly to propose a framework and define search terms for systematic reviews on the empirical evidence and diagnostic value of psychological risk factors for PSS and PSS-related outcomes (PSY-PSS). Secondly, the application of the framework is illustrated using the example of a systematic review on the relevance of psychological factors in somatic symptom disorders (SSD; DSM-5) and bodily distress disorders (BDD; ICD-11). Methods: Following a narrative review approach, two comprehensive lists of search terms to identify studies in (1) relevant patient groups with PSS and (2) relevant psychological factors were generated by reviewing the current literature and employing an iterative process of internal revision and external expert feedback. Results: We identified 83 relevant symptoms, syndromes and disorders for which we defined a total of 322 search terms (list 1). We further comprised 120 psychological factors into 42 subcategories and 7 main categories (list 2). The introduced lists can be combined to conduct systematic reviews on one or more specific psychological factors in combination with any symptom, syndrome or disorder of interest. A protocol of the application of this framework in a systematic review and meta-analysis on psychological etiological factors of SSD and BDD is presented following the PRISMA guidelines. Discussion: This framework will help to gather systematic evidence on psychological factors in order to improve the understanding of the etiology of PSS, to refine future diagnostic conceptualizations of PPS, and to develop optimized mechanism-based interventions for individuals with PPS and related syndromes and disorders.

Aetiological Understanding of Fibromyalgia, Irritable Bowel Syndrome, Chronic Fatigue Syndrome and Classificatory Analogues: A Systematic Umbrella Review.

Background: This umbrella review systematically assesses the variety and relative dominance of current aetiological views within the scientific literature for the three most investigated symptom-defined functional somatic syndromes (FSS) and their classificatory analogues within psychiatry and psychology. Method: An umbrella review of narrative and systematic reviews with and without meta-analyses based on a search of electronic databases (PubMed, Web of Science, Embase, PsychINFO) was conducted. Eligible reviews were published in English, focused on research of any kind of aetiological factors in adults diagnosed with fibromyalgia syndrome (FMS), irritable bowel syndrome (IBS), chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), and somatic symptom disorder (SSD)/somatoform disorder (SFD). Results: We included 452 reviews (132 systematic reviews including meta-analyses, 133 systematic reviews, 197 narrative reviews), of which 132 (29%) focused on two or more of the investigated health conditions simultaneously. Across diagnoses, biological factors were addressed in 90% (k = 405), psychological in 33% (k = 150), social in 12% (k = 54), and healthcare factors in 5% (k = 23) of the reviews. The methodological quality of the included systematic reviews (k = 255) was low (low/critically low: 41% [k = 104]; moderate: 49% [k = 126]; high quality: 10% [k = 25]). The high-quality systematic reviews suggest that deficient conditioned pain modulation, genetic factors, changes in the immune, endocrinological, gastrointestinal, cardiovascular, and nervous system, and psychosocial factors such as sexual abuse and pain catastrophizing increase the risk for FSS. Conclusion: Only very few systematic reviews have used comprehensive, biopsychosocial disease models to guide the selection of aetiological factors in FSS research. Future research should strive for higher scientific standards and broaden its perspective on these health conditions.

Is Therapist Support Needed? Comparing Therapist- and Self-Guided Internet-Based CBT for Somatic Symptom Distress (iSOMA) in Emerging Adults.

Persistent somatic symptoms of varying etiology are very common in emerging adults and can lead to distress and impairment. Internet-delivered interventions could help to prevent the burden and chronicity of persistent somatic symptoms. This study investigated the impact of therapist guidance on the effectiveness of a cognitive-behavioral Internet intervention for somatic symptom distress (iSOMA) in emerging adults, as a secondary analysis of a two-armed randomized controlled trial. We included 149 university students (83.2% female, 24.60 yrs) with varying degrees of somatic symptom distress who were either allocated to the 8-week intervention with regular, written therapeutic guidance (iSOMA guided) or to the control group (waitlist), which was afterwards crossed over to receive iSOMA with guidance-on-demand (iSOMA-GoD). Primary outcomes were somatic symptom distress (assessed by the PHQ-15) and psychobehavioral symptoms of the somatic symptom disorder (assessed by the SSD-12) at pre- and post-treatment. Secondary outcomes included depression, anxiety, and disability. Both treatments showed statistically significant pre-post improvements in primary (iSOMA-guided: d = 0.86-0.92, iSOMA-GoD: d = 0.55-0.63) and secondary outcomes. However, intention-to-treat analysis revealed non-significant between-group effects for all outcomes (ps ≥ .335), after controlling for confounding variables, and effect sizes were marginal (d = -0.06 to 0.12). Overall, our findings indicate that Internet-delivered cognitive behavioral therapy with regular guidance is not unequivocally superior to guidance-on-demand in alleviating somatic symptom distress and associated psychopathology in emerging adults. As a next step, non-inferiority studies are needed to test the robustness of these findings and their impact on clinical populations.

Progress feedback narrows the gap between more and less effective therapists: A therapist effects meta-analysis of clinical trials.

OBJECTIVE: Some psychotherapists are more effective than others, which means that patients' treatment outcomes partly depend on therapist effects (TEs). This study investigated whether the use of progress feedback influences TE. METHOD: Data from N = 4,549 participants and 131 therapists across six clinical trials of progress feedback were analyzed. All trials used the Outcome-Questionnaire-45 (OQ-45) outcome measure and assigned psychotherapy patients to a usual psychological care condition or feedback condition. We examined whether feedback utilization moderated TE using multilevel modeling and random-effects meta-analysis. RESULTS: TE explained a small proportion (intracluster correlation coefficient [ICC] = .011) of variability in posttreatment OQ-45 scores in the pooled multistudy sample, after controlling for intake severity. Feedback utilization was associated with a statistically significant reduction of the magnitude of the TE (ICC = .009) by approximately 18.2%. Secondary analyses of OQ-45 subscales indicated that TEs were statistically significant in relation to symptom distress, but not interpersonal relations or social role. Feedback was associated with better treatment outcomes and narrower variability between therapists. CONCLUSIONS: Feedback-informed treatment reduces the gap between more and less effective therapists, leading to more equitable and effective psychological care. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Using clinical patient characteristics to predict treatment outcome of cognitive behavior therapies for individuals with medically unexplained symptoms: A systematic review and meta-analysis.

OBJECTIVE: For individuals with medically unexplained symptoms (MUS), cognitive behavioral therapy (CBT) is the best-evaluated treatment. This systematic review and meta-analyses identify clinical patient characteristics associated with the treatment outcome of CBT for MUS. METHODS: A systematic literature search (PubMed, PsycInfo, Web of Science) resulted in 53 eligible studies; of these 32 studies could be included in meta-analyses. Pooled correlation coefficients between predictors and treatment outcome were calculated with a random-effects model. Moderator analyses were conducted to examine differences between subgroups of MUS and different levels of methodological study quality. RESULTS: Meta-analyses demonstrated that individuals with higher symptom intensity (r = 0.38; p < 0.001), lower physical functioning (r = -0.29; p < 0.001), lower emotional and social functioning (r = -0.37; p < 0.001), more potential symptom-related incentives (r = -0.15; p = 0.001), or longer symptom duration (r = 0.10; p = 0.033) at the beginning of treatment reported less change of symptom severity until the end of therapy or higher end-of-treatment symptom severity. The pooled effect sizes did not differ between certain subgroups of MUS or between different levels of methodological quality. CONCLUSION: Our findings indicated that clinical characteristics of MUS patients are associated with treatment outcome of CBT. We discuss how the results can be used to optimize and personalize future treatments for MUS.

Internet-based CBT for somatic symptom distress (iSOMA) in emerging adults: A randomized controlled trial.

OBJECTIVE: Persistent somatic symptom distress is common in emerging adults and is associated with adverse health outcomes and impairment. Internet-based interventions could help to prevent burden and chronicity. This randomized controlled trial tested the efficacy of a guided, cognitive-behavioral internet intervention for somatic symptom distress (iSOMA) in emerging adults at risk for somatic symptom disorder compared to a waitlist control condition. METHOD: 158 participants (N = 156 analyzed; 24.53 years, 83.3% female) with multiple somatic symptoms were recruited among German-speaking universities and randomly allocated to either receive the 8-week iSOMA intervention with psychologist support or the waitlist, both with access to treatment as usual. Primary outcomes were somatic symptom distress Patient Health Questionnaire, somatic symptom scale (PHQ-15) and psychobehavioral features of somatic symptom disorder-12 (SSD-12), assessed at baseline and 8-weeks postrandomization. Secondary outcomes included depression, anxiety, illness worries, functional impairment, and attitudes toward psychological treatment. RESULTS: Participants in the iSOMA group showed significantly greater improvements (ps < .001) in primary outcomes (PHQ-15: d = 0.70 [0.36, 1.05], SSD-12: d = 0.65 [0.30, 0.99], and secondary outcomes (ps < .05; d = 0.41-0.52) compared to the waitlist, except for attitudes toward psychological treatment (p = .944). Satisfaction with iSOMA was high (91.0%), most participants (72.8%) completed at least 4 of 7 modules and negative treatment effects were infrequent (14.9%). CONCLUSIONS: Our intervention had a substantial positive impact on somatic symptom distress across a broad range of persistent physical symptoms in a vulnerable target group, opening up promising possibilities for indicative prevention and blended care for somatic symptom disorders. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Somatosensory amplification moderates the efficacy of internet-delivered CBT for somatic symptom distress in emerging adults: Exploratory analysis of a randomized controlled trial.

OBJECTIVE: While studies mainly provide positive evidence for the efficacy of internet-delivered cognitive-behavioral therapy (ICBT) for various persistent somatic symptoms, it remains largely unclear for whom these interventions work or not. This exploratory analysis aimed to identify moderators for the outcome between ICBT for somatic symptom distres and a waitlist control group (WL) in a vulnerable target group of emerging adults. METHODS: Based on data from a randomized controlled trial on 156 university students with varying degrees of somatic symptom distress who were allocated to either an eight-week, therapist guided ICBT (iSOMA) or to the WL, we examined pretreatment demographic characteristics, health-related variables (e.g., somatic symptom duration), mental distress (e.g., depression, anxiety) and cognitive-emotional factors (emotional reactivity, somatosensory amplification) as candidate moderators of the outcome, somatic symptom distress (assessed by the Patient Health Questionnaire, PHQ-15) from pre- to posttreatment. RESULTS: Somatosensory amplification (assessed by the Somatosensory Amplification Scale, SSAS) moderated the outcome in favor of iSOMA (B = -0.17, SE = 0.08, p = 0.031), i.e., higher pretreatment somatosensory amplification was associated with better outcome in the active compared to the control intervention. No significant moderation effects were found among demographic characteristics, health-related variables, or mental distress. CONCLUSION: Our findings suggest that an internet-delivered CBT for somatic symptom distress should be preferred over no active treatment particularly in individuals with moderate to high levels of somatosensory amplification, which as a next step should be tested against further treatments and in clinical populations. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00014375).

Reliability and clinical utility of the chronic pain classification in the 11th Revision of the International Classification of Diseases from a global perspective: results from India, Cuba, and New Zealand.

ABSTRACT: Chronic pain affects 1 in 5 persons and contributes substantially to the global burden of disease. The 11th Revision of the International Classification of Diseases (ICD-11) includes a comprehensive classification of chronic pain. The aim of this ecological implementation field study was to evaluate the classification's interrater reliability and clinical utility in countries with different income levels. The study was conducted in 4 pain clinics in Cuba, India, and New Zealand. Twenty-one clinicians used the ICD-11 to diagnose and code n = 353 patients with chronic pain. Of these, 111 were assessed by 2 clinicians, and Fleiss' kappa was calculated to establish interrater reliability for any diagnosis assigned to ≥15 patients. The clinicians rated the clinical utility of all diagnoses. The interrater reliability could be calculated for 11 diagnoses. It was substantial for 10 diagnoses and moderate for 1 (kappa: 0.596-0.783). The mean clinical utility of the ICD-11 chronic pain diagnoses was rated as 8.45 ± 1.69/10. Clinical utility was rated higher for ICD-11 than for the commonly used classification systems (P < 0.001, η2 = 0.25) and differed between all centers (P < 0.001, η2 = 0.60). The utility of the ICD-11 diagnoses was rated higher than the commonly used diagnoses in Dunedin and Havana, and no difference was found in Kolkata and Hyderabad. The study showed the high interrater reliability of the new chronic pain diagnoses. The perceived clinical utility of the diagnoses indicates their superiority or equality compared with the classification systems currently used in pain clinics. These results suggest the global applicability of the classification in specialized pain treatment settings.

Network Analysis of Persistent Somatic Symptoms in Two Clinical Patient Samples.

OBJECTIVE: Previous attempts to group persistent somatic symptoms (PSSs) with factor-analytic approaches have obtained heterogeneous results. An alternative approach that seems to be more suitable is the network theory. Compared with factor analysis, which focuses on the underlying factor of symptoms, network analysis focuses on the dynamic relationships and interactions among different symptoms. The main aim of this study is to apply the network approach to examine the heterogeneous structure of PSS within two clinical samples. METHODS: The first data set consisted of n = 254 outpatients who were part of a multicenter study. The second data set included n = 574 inpatients, both with somatoform disorders. Somatic symptom severity was assessed with the Screening of Somatoform Disorder (SOMS-7T). RESULTS: Results indicate that there are five main symptom groups that were found in both samples: neurological, gastrointestinal, urogenital, cardiovascular, and musculoskeletal symptoms. Although patterns of symptoms with high connection to each other look quite similar in both networks, the order of the most central symptoms (e.g., symptoms with a high connection to other symptoms in the network) differs. CONCLUSIONS: This work is the first to estimate the structure of PSS using network analysis. A next step could be first to replicate our findings before translating them into clinical practice. Second, results may be useful for generating hypotheses to be tested in future studies, and the results open new opportunities for a better understanding for etiology, prevention, and intervention research.