A new stress-related diagnosis, Exhaustion disorder (ED), was introduced in the Swedish version of ICD-10 in 2005 and has since then increased rapidly. The condition is long-lasting and debilitating, characterized by considerable and persistent fatigue, insomnia, and impaired cognitive function. The diagnosis is still relatively unexplored and there is no consistent knowledge of, among other things, which interventions that work. Research indicates that physical activity can have positive effects on depression, anxiety, and stress. However, there is little knowledge today about the relationship between the dose of physical activity and stress-related illness. It is also not clear how physical activity can be used in the treatment of stress-related illness. The purpose of this project is to gain increased knowledge about the immediate physiological and psychological effects of physical activity for people with diagnosed ED. The project will investigate the psychological and physiological effects of two different intensities of physical activity in people with ED compared to healthy controls. The information from the study also aims to provide a basis for a second part of the project where treatment including physical activity is carried out with people with ED, in a randomized controlled design.

Background A new stress-related diagnosis, exhaustion disorder (ED), was introduced in the Swedish version of ICD-10 in 2005, and has since then increased rapidly. The condition is long-lasting and debilitating, characterized by considerable and persistent fatigue, insomnia and impaired cognitive function. The diagnosis is still relatively unexplored and there is no consistent knowledge of, among other things, which interventions that work.

There is extensive research on the association between mental health and physical activity in general and exercise specifically. When it comes to long-term, or habitual, exercise, it is established that it has beneficial effects on different aspects of mental health and physical activity interventions are helpful for people with mental illness. The most widely studied mental health-issues are depression, anxiety, and stress, and a recent umbrella review concludes that habitual exercise is beneficial for symptom reduction for depression, anxiety, and stress across different populations. Epidemiological evidence shows that physical activity is associated with lowered risk of experiencing fatigue and reduced energy.

Little is known about how physical activity in general and more specifically different intensities of physical activity affects people with ED. Does it have adverse effects or is it beneficial? This is imperative when it comes to intervention- and treatment planning for these patients. No studies have been done specifically on ED before with this focus. Although an acute study cannot show the optimal physical activity program, it can give insight into the relation between between ED and exercise. This in turn can help us construct better designs of exercise programs for this patient group.

Research aims and questions The purpose of the study is to gain increased understanding of the psychological and physiological response to acute exercise in ED-patients compared to a healthy population, and to determine if that response differs between two different intensities of exercise (low and moderate). The focus is on transient emotional states and how they might fluctuate in response to exercise. Specifically subjective feelings of fatigue, energy, anxiety, psychological discomfort, perceived exertion, recovery, and stress is studied. Salivary cortisol and heart rate variability (HRV) are the biomarkers in focus.

Knowledge from the study is planned to be used in the designing of a physical activity program as part of a treatment program for ED. The design can give us information about whether short bouts of exercise can have mood-altering effects in this patient group, and auonomic reactivity to physical activity.

Research questions:

1. Does level of fatigue, vigor/energy, state anxiety, and perceived stress differ between groups (ED/controls) and/or between exercise intensities (mild/moderate) and/or between timepoints (pre/post/30minpost/6hpost/24hpost)?
2. Does the level of subjective discomfort and perceived exertion differ between groups (ED/controls) and/or between exercise intensities (mild/moderate) and/or between time points (pre/5min/10min/15min)?
3. Does the level of salivary cortisol differ between groups (ED/controls) and/or between exercise intensities (mild/moderate) and/or between time points (pre/post/30 min post)?
4. Does level of heart rate variability (HRV) differ between groups (ED/controls) and/or between exercise intensities (mild/moderate) and/or between timepoints (pre/post/30minpost/6hpost/24hpost)?

If significant differences are found, intercation effects between the different variables will also be studied, as well as potential moderating variables.

Methods Study design The design is a two-armed trial (low and moderate intensity of physical activity) with two groups, one which is patients with ED, and the other an age- and sex matched control group with overall healthy individuals, that include sequential assessments of fatigue and energy states, stress, perceived exertion, perceived psychological distress and state anxiety.

Participants Approximately 30 patients with diagnosed exhaustion disorder (F43.8A in ICD-10-SE) and 30 age- and sex-matched healthy control participants are recruited for the study. ED-patients are recruited through occupational health care Avonova and through advertisement in social media Facebook and Instagram. Inclusion criteria in the studies for ED-patients: confirmed primary diagnosis ED by a physician; assessed to not be in the acute phase of ED; age of 35-55 years; considered by a physician and/or a psychologist as suitable for participating in a study including performing physical activity. Healthy control participants are recruited via the same social media channels as ED-patients. Inclusion criteria: age of 35-55 years; self-reported good health (no known somatic or psychiatric disease); considered as suitable for participating in a study including performing physical activity. Mini International Neuropsychiatric Interview 6.0.0. (MINI), as well as an additional diagnostic questionnaire targeting stress-related disorders based on diagnostic criteria from ICD-11, will be conducted with both ED-patients and healthy controls, to ensure the inclusion- and exclusion criteria. MINI is a diagnostic interview for the major DSM-IV psychiatric disorders. The participants will receive thorough written information about the study and written informed consent will be obtained before inclusion. The study was approved by the Regional Ethical Review Board in Linköping, Sweden (Approval Nr. 2022-04943-01) and will be conducted in accordance with the ethical principles of the Declaration of Helsinki.

Procedure The study takes place in a laboratory setting at GIH on three different days, separated by at least one week. Before enrollment, participants complete an online administered screening questionnaire measuring exhaustion, burnout, and diagnostic and general health information. Eligible participants are invited to GIH for a familiarization visit, where a structured clinical interview (MINI and stress diagnoses questionnaire) is performed. Participants will also complete a submaximal cardiorespiratory fitness test (CRF) to estimate maximal aerobic capacity. The test is performed on a calibrated mechanically braked cycle ergometer (model 828E, Monark, Varberg, Sweden) for 8 min. Pedal frequency throughout the test is 60 rpm. Cycling resistance starts at 0,5 kilopond (kp) for 4 minutes and is increased to a personalized higher work rate, which lasts for 4 minutes. VO2max is estimated from these 8 minutes using heart rate data collected during the test. The result on this test will be used in determining each participant's correct intensity level on the two trial conditions.

Conditions The two trial conditions are performed in a counter-balanced and randomly assigned order. The participants perform the two conditions of physical activity bouts at approximately the same time in the morning/forenoon (start time of test visit is either 8:30 or 10:30 a.m.) with at least one week in between conditions. The participants have the same test start time at the two test visits. At each test session participants perform a 22-minute exercise on a cycle ergometer (model 839E, Monark, Varberg, Sweden). Immediately before and at three time points during the exercise (after 5, 10, and 15 minutes on the low or moderate intensity), they rate level of exertion (RPE) and feelings of psychological distress on a VAS-scale. Immediately before, immediately after, 30 minutes after, 6 hours after, and 24 hours after exercise participants fill out questionnaires regarding feelings of fatigue, energy, anxiety, recovery, and stress. Participants wear a H10 heart rate sensor and Vantage M2 monitor (Polar, Kempele, Finland) for a little more than 24 hours, starting approximately 30 minutes before the exercise. HRV parameters will be calculated from 5-min window recordings using the software Kubios HRV (University of Eastern Finland, Kuopio, Finland), immediately before (pre), immediately after (post), 30 minutes after (30 min post), 6 hours after (6h post), and 24 hours after (24h post) exercise. Since HRV is influenced by several factors (caffeine intake, alcohol consumption, circadian rhythm, stress (both mental and physical), exercise, food- and water intake, certain medications, bladder filling, respiratory rate, and posture) these factors will be controlled for when at GIH. Salivary cortisol is collected pre, post and 30 min post exercise using Sarstedt Salivette Cortisol (Sarstedt, Nümbrecht, Germany). The follow-up measurements will determine the trajectory of the cortisol and HRV post-exercise. During the 24 hours following the exercise bout physical activity pattern is measured using a hip-worn accelerometer (Actigraph GT3X). Accelerometer data will be processed in Actilife.

There are two experimental exercise conditions, where participants will exercise at two different intensity levels. The intensity levels are standardized across participants by using results from EKBLOM-BAK test to determine a low and moderate intensity. Low intensity is defined as 40% and moderate intensity is defined as 55% of the participant's individual estimated VO2max. The 22-minute exercise starts with a 6-minute warm-up, with a load increase after 1 and 3 minutes and lowered load at the last minute. Then follows a 15-minute bout on either low or moderate intensity, that ends with a 1-minute cool-down. One of the researchers will be present during the complete test to assure correct intensity and length.

Baseline measures

In the week before the familiarization visit each participant completes a digitally administered questionnaire that includes socio-demographic and general health information together with the following questionnaires:

• Exhaustion disorder. Karolinska Exhaustion Disorder Scale (KEDS) was developed for the assessment of ED symptoms. It consists of nine items with a scale range of 0-54 and a cut-off of 19 has been proposed in the discrimination between healthy subjects and patients with ED.
• Burnout. Shirom-Melamed Burnout Questionnaire/Measure (SMBQ/SMBM) is widely used in measuring burnout. SMBM-12 is a short version with twelve items which captures core concepts of burnout: emotional and physiological exhaustion (e.g., "I feel tired"), and cognitive weariness (e.g., "I feel I am not thinking clearly"). A global score of burnout is calculated. SMBM-12 has good composite reliability and convergent validity.
• Trait anxiety. The trait subscale of The State-Trait Anxiety Inventory (STAI). Respondents rate how they generally feel on a 4-point Likert Scale (e.g., "I feel nervous and rested"). A global score of a general and enduring trait anxiety is calculated.
• Depression. Patient Health Questionnaire (PHQ-9) measures depression in line with DSM-IV. Respondents rate depression symptoms the last two weeks on a 4-point Likert Scale (e.g., "Little interest or pleasure in doing things").
• Sleep. Pittsburgh Sleep Quality Index (PSQI) is widely used in measuring sleep quality. It consists of 19 items that form seven components of retrospective sleep quality (1 month) and a global score.
• Physical activity. Saltin-Grimby Physical Activity Level Scale (SGPALS) is a four-level single-item instrument which has acceptable validity for measuring level of physical activity.
• Exercise attitudes. Two subscales of the Exercise Benefits/Barriers Scale (EBBS) were included: Psychological Outlook Subscale (benefits), and Physical Exertion Subscale (barriers).

2-3 days after the familiarization visit, heart rate variability (HRV) and physical activity pattern is measured during a 24-hour baseline measurement. Participants get oral and written instructions on the familiarization visit on how to initialize and conduct this measurement with a H10 heart rate sensor and Vantage M2 monitor together with a hip-worn accelerometer (Actigraph GT3X). Twice during the 24h-measurement, digital questionnaires including Single Item stress Question (SISQ), the vigor and fatigue subscales of Profile of Mood States (POMS), single-item recovery question, and state subscale of The State-Trait Anxiety Inventory (STAI-Y1) are completed.

Data analysis For each of the psychological variables (perceived exertion, psychological discomfort, fatigue, energy/vigor, state anxiety, and stress) a three factorial (group, time, intensity) ANOVA with repeated measures design will be the first hand choice if parametric assumptions are met. A secondary stratified analysis will be performed exploring potential variables that influenced the primary and secondary psychological variables.

For the data analysis of physiological variables, data analysis are yet to be decided. This will be done though before looking at the data.

Inclusion Criteria:

For ED-patients:

• Confirmed primary diagnosis ED by a physician
• Assessed to not be in the acute phase of ED
• considered by a physician and/or a psychologist as suitable for participating in a study including performing physical activity
• Age of 35-55 years

For control group:

• Self-reported good health (no known somatic or psychiatric disease)
• Age of 35-55 years

Exclusion Criteria:

• Chronic fatigue syndrome (CFS)
• Post-covid
• Dementia
• Bipolar and/or psychotic disorder
• Current substance abuse
• Fibromyalgia
• Elevated suicide risk
• Medication with beta-blockers

Following exclusion criteria is also used, since it is not suitable to perform the EKBLOM-BAK-test:

• chronic obstructive lung disease
• hypertension/dyslipidemia
• cardiovascular disease

If participant has ongoing infection (such as a cold) on testday, testing is delayed until she/he is recovered.