Real-Time Assessment of Stress and Stress Response

Home , Social stress

Study Type: Health-related personal data and biological material.

Risk Categorisation: Risk category “A” according to HRO Art. 7

Study Registration: clinicaltrials.gov [pending]

Sponsor: Prof. Erich Seifritz, M.D.

Principal Investigator: Stephan T. Egger, M.D.

Co- Investigator: Prof. Abraham Bernstein, Ph.D.

Investigated Intervention: Trier Social Stress Test

Protocol ID mHealth TSST-G

Version and Date: SEC V05.1 (28.05.2019)

CONFIDENTIALITY STATEMENT The information contained in this document is confidential and the property of the Psychiatric University Hospital of Zürich. The contents of this document may neither in full nor in part be transmitted, reproduced, published, or disclosed to others than the competent Ethics Commit- tee(s) and Regulatory Authority(ies) without prior written authorisation from the sponsor ex- cept to the extent necessary to obtain informed consent from those who will participate in the study.

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PROJECT PERSONNEL AND ADMINISTRATION

SPONSOR Prof. Erich Seifritz, M.D. Clinic for Psychiatry, Psychotherapy and Psychosomatics Psychiatrische Universitätsklinik Zürich Postfach 1931 Lenggstrasse 31 CH- 8032 Zürich Tel.: +41 44 384 2312 E-Mail: [email protected]

PRINCIPAL INVESTIGATOR Stephan T. Egger, M.D. Center for Integrative Psychiatry Clinic for Psychiatry, Psychotherapy and Psychosomatics Psychiatrische Universitätsklinik Zürich Alleestrasse 61 CH- 8462 Rheinau Tel.: +41 52 304 9340 E-Mail: [email protected]

CO- INVESTIGATOR Prof. Abraham Bernstein, Ph.D. Department of Informatics University of Zürich Binzmühlestrasse 14 CH- 8050 Zürich Tel.: +41 44 635 4579 E-Mail: [email protected]

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PROTOCOL SIGNATURE FORM

Study Title Real-Time Assessment of Stress and Stress Response

Study ID mHealth TSST-G

The principal investigator has approved the protocol version (SEC-V05.1/28.05.2019) and hereby confirms to conduct the study according to this protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP guidelines and in accordance with the local legally applicable requirements.

Sponsor:

Prof. Erich Seifritz, M.D.

Principal Investigator:

Stephan T. Egger, M.D.

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TABLE OF CONTENTS

GLOSSARY OF ABBREVIATIONS 5 STUDY SYNAPSIS 6 1. BACKGROUND AND RATIONALE 7 2. STUDY OBJECTIVES AND DESIGN 8 2.1 Hypothesis and objectives 8 2.2 Primary and secondary endpoints/outcomes 8 2.3 Study design 8 2.4 Study intervention 8 3. STUDY POPULATION AND STUDY PROCEDURES 9 3.1 Study population, inclusion and exclusion criteria 9 3.2 Recruitment, screening and informed consent procedure 10 3.3 Study procedures 10 3.4 Assessment of outcomes and methods to minimise bias 12 4. STATISTICS AND METHODOLOGY 14 4.1 Statistical analysis plan and sample size calculation 14 4.2 Handling of missing data and dropouts 15 5. REGULATORY ASPECTS AND SAFETY 15 5.1 Local regulations / Declaration of Helsinki 15 5.2 Study registration 15 5.3 Assessment of safety and reporting 15 5.4 Periodic reporting and amendments 16 5.5 Duration / Termination of Study 16 5.6 Insurance 17 6. ETHICAL ASPECTS 17 6.1 Overall ethical considerations 17 6.2 Risk benefit assessment 17 6.3 Funding and support 17 6.4 Declaration of interests 17 7. DATA PROTECTION 17 7.1 Data recording and source data 17 7.2 Confidentiality and coding 18 7.3 Retention and destruction of study data and biological material 18 7.4 Publication and dissemination 18 7.5 Data sharing 19 8. REFERENCES 19

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GLOSSARY OF ABBREVATIONS

AE Adverse Event BDD Basic Demographic Data BSI Brief Symptom Inventory ANOVA Analysis of Variance CBT Cognitive Behavioural Therapy CEFRL Common European Framework of Reference for Languages CIRS Clinical Incident Report System CGI Clinical Global Impression CRF Case Report Form DoH Declaration of Helsinki DSM Diagnostic and Statistical Manual EC Ethics Committee FDA Federal Drug Agency GAF Global Assessment of Functioning GCP Good Clinical Practice HRA Human Research Act [German: Humanforschungsgesetz] HMG Heilmittelgesetz HoNOS Health of the Nation Outcome Scales HPQ Hand Preference Questionaire IC Informed Consent ICD International Classification of Disease ICF International Classification of Functioning KAB Kurzfragebogen zur aktuellen Beanspruchung MANOVA Multivariate Analysis of Variance MH Medical complaints and past medical history mICF mini-ICF (International Classification of Functioning) MINI Mini International Neuropsychiatric Interview MW MedWatch NNV Nebenwirkungen und Nebenwirkungserfassung in der Verhaltenstherapie SAE Serious Adverse Event STARD Standards for Reporting Diagnostic Accuracy TSST Trier Social Stress Test TSST-G Trier Social Stress Test for Groups WHO World Health Organization ZIP Zentrum für Integrative Psychiatry

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STUDY SYNOPSIS

Study Title Real-Time Assessment of Stress and Stress Response Background Stress is a complex natural phenomenon, frequently related to a physiological response, including heart rate, heart rate variability, respiratory rate, skin conductance and temperature. The subjective experience varies greatly; broadly it may be conceived as a freeze, flight, fight, fright or faint response. Many studies have demonstrated the negative influence of psychological stress on health and well-being. Through the digital phenotyping of physiological and psychological stress reactions, in a controlled laboratory setting (Trier Social Stress Test- TSST) and real-life situations, in a population of healthy participants and patients with a major psychiatric disorder, we expect to find reliable and valid digital biomarkers. The results of this study will therefore not only contribute to a better understanding of stress and stress response but also have the potential to improve diagnostic and treatment approaches. Risk / Benefit Wearable devices, including the ones used in the present study, are commercially available Assessement without restriction. They pose no risk to the health or well-being of their users. The TSST-G is psychological paradigm used to induce psychosocial stress. Besides the deliberate distress they trigger, there is no known risk to the health or well-being of participants. Objectives The primary objective of the present trial is to establish a correlational relationship between the physiological parameters measured by a commercially available wearable device and the cortisol values obtained during the Trier Social Stress Test for Groups (TSST-G) in healthy participants and patients with a psychiatric disorder. Study Design We have designed an experimental, interventional trial to assess the psychological and physiological reactions to psychosocial stress. Statistical We calculated our required sample size using G*Power 3.1 (ANOVA: Repeated measures, Consideration within- between factors; effect size f = 0.4; a= 0.05; Power = 0.8; number of groups = 4, number of measures = 9, nonsphericity correction = 0.125). Based on that calculation, at least 24 participants per group are required to detect moderate-sized differences: to improve capacity we have decided to include at least 30 participants in each group. Study After the baseline examination participants will be provided with a smartphone, two wearable Procedures devices and a set of tubes to collect salivary samples. They will be asked to keep a log including a review of their daily activities and sleep, together with a record of any challenging, difficult or stressful events. Whenever possible a corresponding saliva sample should be taken for each log entry and labelled accordingly. The TSST-G will be performed five days after the initial evaluation. The smartphone and the wearable devices will be collected 48 hours after completion of the TSST-G. Study The Trier Social Stress Test for Groups (TSST-G) is a psychological paradigm which com- Intervention bines high levels of social-evaluative threat and uncontrollability in a group setting. The TSST-G consists of three phases: a briefing; the psychological test itself, followed by a debriefing phase. The participants will undergo the TSST-G; using test procedures analogous to previous studies. Study We expect to complete the study in a time frame of between 18 and 24 months after approval Duration of the protocol by the EC Ethical The use of smartphones and wearable devices is ubiquitous, with a significant increase in Consideration their application to monitor psychological well-being and stress. However, there is currently a lack of guidance in the use of such devices, their reckless use may be detrimental, dangerous or even harmful. Through our study we expect to identify valid and reliable digital biomarkers, thus contributing to their use as self-monitoring and therapeutic instruments. Data Privacy Data generation, transmission, storage and analysis of data and the storage of biological samples within this project will adhere strictly to current Swiss legal requirements for data protection and will be performed according to the Ordinance HRO Art. 5. GCP This study will be conducted in compliance with the protocol, the current version of the Dec- Statement laration of Helsinki, the ICH-GCP, the HRA as well as other locally relevant legal and regulatory requirements.

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1. BACKGROUND AND RATIONALE

Stress is a complex natural phenomenon, broadly defined as “the non-specific response of the body to any demand”.1 Oversimplified this response can be divided into two components: the physiological reaction, on the one hand and the subjective experience on the other.2,3 Stress causes the liberation of hormones (mainly adrenalin and cortisol) and the activation of the autonomic nervous system,1-6 resulting in changes in a number of variables including heart rate, heart rate variability, respiratory rate, skin conductance and temperature.2,5-7 The subjective experience varies greatly; broadly it may be conceived as a freeze, flight, fight, fright or faint response.8

Many studies have demonstrated the negative influence of psychological stress on health and well-being,7 with some psychiatric disorders aetiologically linked to stress.4,9 Furthermore, mental disorders are generally conceived as harmful dysfunctions of mental mechanisms;10 whereby disrupted perception, awareness, and reaction to stress are common hallmarks,3,11,12 with several psychiatric disorders demonstrating distinct stress reaction patterns.12 For nearly three decades psychiatric disorders have been continuously rising and consistently account for a substantial proportion of social costs and the burden of disease.13,14 The development of methods to either prevent psychiatric disorders or significantly improve their outcome has by contrast been slow.13

The ubiquitous presence of smartphones15 and the increasing availability and affordability of wearable devices capable of measuring bodily functions,16 has led to the appearance of digital services claiming to evaluate and improve physical and psychological well-being.17,18 How- ever, despite gaining popularity their use remains controversial. Users have frequently experienced deception;19,20 generally due to privacy and confidentiality issues,20-23 but also inaccu- rate feedback or even dangerous advice.17,22,23 These issues are not surprising since only a tiny fraction has been validated adequately in controlled studies17,24,25 and guidelines and legal regulations are still emerging.26,27

Nonetheless, digital technology and information sciences are expected to profoundly change the way we understand and approach mental health.15 Through “Digital Phenotyping” of experience and behaviour by assessing smartphone interaction, voice and speech features, together with monitoring movement and physiological parameters,28,29 the assessment of daily activities has become a focus of research in the hope of finding reliable digital biomarkers; particularly for cognition, stress and behaviour.15,30-34 From current studies in the field,33,34 together with earlier psychological studies,35,36 it becomes clear that a proper validation of the users' individual emotional experience is essential.17,23,25,30,32

The Trier Social Stress Test (TSST)37 is an extensively used and well validated psychological paradigm to induce psycho-biological stress in laboratory settings,27,38-40 with a significant association with acute stress response in real life.38,41,42 Through the digital phenotyping of physiological and psychological stress reactions, in a controlled laboratory setting and real-life situations, in a population of healthy participants and patients with a major psychiatric disorder, we expect to find reliable and valid digital biomarkers. The results of this study will therefore

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not only contribute to a better understanding of stress and stress response but also have the potential to improve diagnostic and treatment approaches.

2. STUDY OBJECTIVES AND DESIGN

2.1 Hypothesis and objectives The primary objective of the present trial is to establish a correlational relationship between the physiological parameters measured by a commercially available wearable device and the cortisol values obtained during the Trier Social Stress Test for Groups (TSST-G) in healthy participants and patients with a psychiatric disorder. This trial is exploratory in nature, and its results will be used to generate a further hypothesis. Furthermore, p-values do not guarantee diagnostic accuracy or clinical utility.

2.2 Primary and secondary endpoints/outcomes The primary outcome is change in saliva cortisol concentration meausured before, during and after the TSST-G. The main secondary outcome is the assessment of tension and stress at the time of cortisol measurement. Other outcomes of interest are demographic characteristics; basic medical history; current health status; current medication; psychosocial well-being; cognitive assessment; psychopathological symptoms; and physiological parameters.

2.3 Study design We designed an experimental, interventional trial to assess the psychological and physiological reactions to psychosozial stress. In four groups of participants (either healthy or psychiatric patients with an internalising, externalising or psychotic disorder) psychological well-being, cortisol levels, and physiological parameters will be assessed during a whole week; psychological stress will be induced using the TSST-G during the fifth day (For a detailed study outline see Section 3.3 and Figure 2).

2.4. Study intervention The TSST-G is a psychological paradigm which combines high levels of social-evaluative threat and uncontrollability in a group setting. The TSST-G will proceed in groups of three to five participants (from the same diagnostic group); using test procedures analogous to previous studies.43-45 The TSST-G consists of three phases: a briefing; the psychological test itself, followed by a debriefing phase. Each phase will last 40, 20 and 60 minutes respectively (Fig- ure 1). The briefing and debriefing of the TSST-G will be conducted by experienced psycho- therapists. The TSST-G itself by available personal unknown to the participants.

Each participant will undergo an individual introduction, preparation and anticipation phase in a comfortable briefing room. Participants will be instructed to collect samples of saliva (as explained at the first assessment), the time of collection will be indicated by a sound signal (which will also be played to the participants). Written instructions for the next phase will be handed out. Participants will be required to prepare a job application in 10 minutes and intro- duce themselves accordingly in a speech in front of a committee. Furthermore, they will be told that they will be video recorded (no actual recording will be performed, the participants are just told so to increase the social stress reaction) and an analysis of their performance will be conducted.

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Figure 1: Outline of the Trier Social Stress Test for Groups (TSST-G)

After the briefing participants will be accompanied to the test room nearby and will be seated next to each other, although separated by partitions in order to avoid eye contact. Next, the evaluation committee will enter the room and turn on two video cameras (without recording). The participants will be asked to present their speech in a previously set random order; each participant will have 2- 3 minutes to deliver their speech, after which the next participant will be asked to complete the same task.

Once all participants have completed their speech task, written instruction for the next task will be distributed. The second task consists of a subtraction to be conducted as quickly and as accurately as possible. The order of participation will once again be set randomly. This task will last around 2 minutes, if participants make a mistake they will be asked to start again. Once the last participant has completed the task, the committee will leave the room. Partici- pants will be accompanied back to the preparation room, where they will be debriefed and may engage in any relaxing activity for a further 60 minutes.

3. STUDY POPULATION AND STUDY PROCEDURES

3.1 Study population, inclusion and exclusion criteria To ensure generalisability of the findings and to minimise potential confounders an overall physically healthy population is crucial; to ensure comparability homogeneous diagnostic groups are required.

Inclusion criteria • Participants are competent to give informed consent. • Participants are between 18 and 65 years of age. • Participants are right handed, as determined by the Hand Preference Questionnaire (HPQ)46 • German language proficiency as a native speaker or level B1 according to Common Euro- pean Framework of Reference for Languages (CEFRL)47 • Diagnosis of a cluster C personality disorder according to ICD-1048; or • Diagnosis of depressive disorder according to ICD-1048; or • Diagnosis of schizophrenia or schizoaffective disorder according to ICD-1048; or • Without a current psychiatric disorder.

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Exclusion criteria • Low Intelligence as confirmed by failure to complete regular compulsory education. • Pregnancy or over two weeks delay in the menstrual cycle. • Previous participation in a psychological trial involving psychosocial stress assessment. • Current neurological disorder. • Current cardiovascular disorder. • Current respiratory disorder. • Current substance use or withdrawal. • Any change in medication in the previous week.

Criteria for withdrawal/discontinuation of participants • Unwilling or unable to comply with study instructions. • Withdrawal at the request of the participant. • Failure to attend appointments or irregular use (<70% of the time) of the wearable electronic device and mobile application.

3.2 Recruitment, screening and informed consent procedure Participants will be recruited by advertising in the Psychiatric University Hospital of Zürich and the University of Zürich. Interested persons will be encouraged to obtain more information and will be given an overview of the study. If they are willing to participate in the study the investigators will explain the nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits and any discomfort it may entail (section 2.4). Each participant will be informed that participation in the study is voluntary and that he or she may withdraw from the study at any time, that withdrawal of consent will have no negative conse- quences and will not affect his or her subsequent medical assistance or treatment in any way.

All participants in the study will be provided with a participant information sheet and a consent form describing the study and providing sufficient information for the participant to make an informed decision about whether or not to participate. They will have one week to decide. The consent form will be signed and dated by the investigator or his designee at the same time as the participant signs. A copy of the signed informed consent form will be given to the study participant. The consent form will be retained as part of the study records. The formal consent of a participant, using the approved consent form, will be obtained before the participant is submitted to any study procedure.

Participants will be compensated for successful completion of the study with 100 Swiss Francs (according to HRA Art. 14), plus travel expenses. If a participant terminates the study prematurely, they will receive half of the compensation, plus agreed expenses. Interested participants may receive a copy of their study record as well as a brief evaluation of the obtained results. A presentation about the background of the study and a newsletter summarising the current status of the study will also be made available to interested participants.

3.3 Study procedures After recruitment and signature of the informed consent form participants will be given three appointments. The first one for the baseline examination, as well as hand-over and introduction to the devices. The second for the TSST-G. The third, and last for the final examination

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and collection of the devices. The first and last appointments will take place at the Psychiatric University of Zurich either in the main building (Lenggstrasse 31, 8032 Zürich) or at the out- patient-clinic (Militärstrasse 8, 8021 Zürich), whichever is most convenient for the participant. The TSST-G will be conducted at the main building of the Psychiatric University Hospital of Zurich.

In the first appointment the baseline examination will be performed. Afterwards participants will be provided with a smartphone, two wearable devices and a set of tubes to collect salivary samples. They will be informed about the smartphone, the wearable devices and their capa- bilities. They will be instructed in how to use and handle the devices, as well as how to collect saliva. To check understanding the first saliva sample will be taken under supervision. After completing instruction in the use of the electronic device and sampling methods the initial interview and evaluation will take place.

Recruitment Baseline EMA TSST-G Final Duration 30- 60 min 2 hours 2- 5 min.(each) 2- hours 10- 15 min. Oral and Written Infor- X mation Informed Consent X X Inclusion/Exclusion Crite- X ria Instructions X X Participant characteristics X Medical History X Physical Examination X Psychological Examination X Primary Outcome X Secondary Outcome X Everyday stress- well-be- X X X X ing Physiological Parameters X X X X

Table 1: Study procedures

At the end of the first appointment participants will be given general instructions regarding the psychological paradigm; in particular to abstain from exercise 24 hours prior to the test and to abstain from caffeine, alcohol and food 2 hours prior to the test. Participants will then be released to continue with their usual activities.

Participants will be asked to keep the digital-log provided with the -smartphones for duration of the study (from baseline to final assessment); including a review of their daily activities (at night) and sleep (in the morning), together with a timely record of any challenging, difficult or stressful events. Whenever possible a corresponding saliva sample should be taken for each log entry and labelled accordingly.

The Trier Social Stress Test for Groups (TSST-G) will be performed five days after the initial evaluation, starting at 17:00h; as described in section 2.4. After the TSST-G participants will once again be released to normal conditions. The smartphone and the wearable devices will be collected 48 hours after completion of the TSST-G at the third and final appointment.

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Figure 2: Outline of the study procedures for an individual participant.

3.4 Assessment of Outcomes and methods to minimise Bias Outcomes of the study will be assessed through saliva samples, digital phenotyping, psychological and well-being assessments. Assessment of biological and physiological parameters are considered to be objective and not subject to bias. All psychological assessment methods used are widely used in psychiatric and psychological research, and are all considered valid and reliable measurement instruments, robust to bias and learning effects.

Demographics and Medical Record Participants characteristics include basic demographics, such as gender, age/year of birth, housing, marital status, education, profession, occupation, employment-income, tute- lage/guardianship. Data will be coded according to the statistical manual of the canton Zurich (PsyRec).49 Actual physical complaints will be assessed, current and past medical history will be recorded, bodily functions and organs will be examined. Medication will be registered with both generic and brand names, together with the total daily dose which will be converted to daily dose equivalents according to the WHO Guidelines.50 Demographics and medical data will be obtained through the personal interview and will be recorded in the Case Report Form (CRF). For participants either currently or previously in treatment in the Psychiatric University Clinic of Zurich no data will be collected from the clinical case records.

Biological Sampling: Cortisol will be measured in saliva. SalivetteÔ collection tubes (Sarstedt, Sevelen Switzer- land) will be used to collect saliva. Tubes will be sequentially numbered. Participants will be asked to label tubes with collection time, additionally they should note the tube number in their log book. After collection samples will be stored in a fridge and then frozen at −20◦C. Cortisol levels will be analysed by the laboratory of the division of clinical psychology and psychotherapy at the University of Zurich. Concentrations of salivary free cortisol will be measured with a commercially available enzyme immunoassay (IBL, Hamburg, Germany). After analysis all samples will be destroyed.

Digital Phenotyping: Digital assessment will be conducted using a wearable device and a smartphone application which will be provided to participants; the wearable devices are intended to be continuously used or as much as can be tolerated. The study smartphone needs to be charged every day; both wearable devices need to be charged every five to six days; the recharge- respective the replacement will be conducted during the TSST-G session.

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The smartphone application is a custom created application developed by the Department of Informatics at the University of Zurich. The application will ask participants to complete a short questionnaire twice a day (after waking up and before going to sleep). Participants can access the application at any time and interact with it as well as recording any stressful, disturbing or difficult experiences. Parameters of phone usage, location, and environment sensors will be recorded. The questionnaire is an adaptation of widely used well-being, daily stress and night/day sleep diaries (Table 2).

Physiological parameters will be measured through the sensors of the VívosmartÒ Wristband and BiovotionÒ Armband wearable devices. In order to reduce interindividual variability due to hand preference,51 just right handed probands will be included. The first will be weared on the right wrist, the second on the right arm. The sensors are capable of measuring heart rate, skin conductance and temperature, position, movement, and acceleration. Both sensor devices are commercially approved and off the shelf available. Raw values together with com- puted values will be transmitted through synchronisation with the previously described smartphone application to the servers of the Department of informatics at the University of Zurich. Data will be end to end encrypted.

Psychometric Measurements Psychological assessment will be done with either self-administered or observational instruments. Raters will be psychiatry residents or clinical psychologists. They will be trained in specific workshops on the use and objectives of the measures used in the study. The workshops follow a standardised schedule, using case vignettes and video examples. Refresher training sessions will be provided on a regular basis, with trainers being available for consul- tation at any time. Psychometric Instruments are summarized in Table 2.

Instrument Description Brief Neurocognitive The Brief Neurocognitive Assessment (BNA) was developed as an brief, easily applicable Assessment (BNA) and reliable tool to evaluate global neurocognition and impairment; primarily in patients with a diagnosis of schizophrenia.52 Brief Symptom In- The Brief Symptom Inventory (BSI)53 is a self-administered questionnaire assessing psy- ventory (BSI) chological distress; it can be used either for screening or for outcome evaluation. Clinical Global Im- The Clinical Global Impression (CGI) scale was initially introduced in psychopharmaco- pression (CGI) logical trials.54,55 It is a brief, easy to use and pragmatic tool for the assessment of psychiatric illness severity and changes over time.56-58 Global Assessment The Global Assessment of Functioning (GAF) is a single item observer-rated scale of of Functioning overall functioning on a continuum from mental health to mental illness.59 The GAF is (GAF) widely used in psychiatric research. Hamilton Anxiety The Hamilton Anxiety Rating Scale (HAM-A) comprises 14 items and provides an overall Rating measure of anxiety, including psychological, cognitive and somatic symptoms.58,60 The (HAM-A) scale can be used to measure anxiety in various psychiatric conditions.58 Hamilton Depres- The Hamilton Depression Rating Scale (HAM-D) is a checklist of 21 Items designed to sion Scale (HAM-D) measure the severity of depression 58,61. Besides depression, it has also been used to measure depressive symptoms in other disorders.58 Hand Preference The Hand Preference Questionnaire (HPQ)46 was developed to assess hand preference, Questionnaire it is a 10 item checklist asking hand use preference for different activities. It allows a lat- (HPQ) erality index to be calculated.

Table 2: Study psychometric instruments (continues next page)

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Instrument Description Health of the Nation The Health of the Nation Outcome Scales (HoNOS) is an observer-rated scale to assess Outcome Scales the severity of a psychiatric disorder in four dimensions, behaviour, impairment, symptoms (HoNOS) and social problems.62,63 Insecurity Question- The Insecurity Questionnaire [German: Unsicherheitsfragebogen] (IQ-24) is a self-admin- naire (IQ-24) istered questionnaire with 24 items developed to assess insecurity.64 Mini ICF- APP The Mini ICF-APP (mICF) is a short observer- rated scale to assess the level of functioning (mICF) and capacity, it is easy to use and possesses good psychometric properties.65-68 It is based on the International Classification of Functioning, Disability, and Health (ICF).69 Mini International The Mini International Neuropsychiatric Interview (MINI)70 is a structured diagnostic inter- Neuropsychiatric In- view. It was designed as a quick but accurate structured psychiatric diagnostic interview terview (MINI) (according to DSM-IV and ICD-10) for clinical trials and epidemiology studies. Montreal Cognitive The Montreal Cognitive Assessment (MoCA)71,72 is a brief cognitive screening tool to de- Assessment (MoCA) tect mild cognitive impairment in patients performing in the normal range on the Mini Men- tal Status Exam. Positive and Nega- The Positive and Negative Syndrome Scale (PANSS) is a semistructured interview de- tive Syndrome Scale signed to measure the severity of psychopathology in patients with a psychotic disorder, (PANSS) mainly schizophrenia and schizoaffective disorder.58,73-75 The PANSS measures symptoms in three domains, positive, negative, and general symptoms. Protocol for Sleep The Protocol for Sleep Examination [German: Abend/Morgenprotokolle für die Schla- Examination (PSE) funtersuchung] (PSE) was developed to assess the subjective dimension of sleep, as well as daily activities and distress. It is divided into a morning and night (bedtime) sections.76 Short Stress Ques- The Short Stress Questionnaire [German: Kurzfragebogen zur aktuellen Beanspruchung] tionnaire (SSQ) (SSQ) was developed to assess subjective levels of tension or stress associated with a current task, situation or experience.77 Toronto Alexithymia The Toronto Alexithymia Questionnaire (TAQ)78,79 was developed to assess difficulties Questionnaire (TAQ) identifying subjective emotional feelings, distinguishing between feelings and the bodily sensations of emotional arousal and difficulty describing feelings to other people.78,80 Yale- Brown Obses- The Yale- Brown Obsessive Compulsive Scale (Y-BOCS) was developed to measure the sive Compulsive severity of obsessive-compulsive symptoms; these are rated in terms of time spent on Scale (Y-BOCS) such activities, interference with functioning, distress, resistance, and control.58,81 The scale can be used for several psychiatric disorders including schizophrenia.82 Young Mania Rating The Young Mania Rating Scale (YMRS) is an observer rated checklist items measuring Scale (YMRS) manic symptoms to quantify severity as well as the effect of treatment.58,83 It includes the core symptoms of mania occurring in both mild and severe illness.

Table 2: Study psychometric instruments (continues from previous page)

4. STATISTICS AND METHODOLOGY

4.1. Statistical analysis plan and sample size calculation We calculated our required sample size using G*Power 3.184 (ANOVA: Repeated measures, within- between factors; effect size f = 0.4; a = 0.05; Power = 0.8; number of groups = 4, number of measures = 9, nonsphericity correction = 0.125). Based on that calculation, at least 24 participants per group are required to detect moderate-sized differences: to improve capacity we have decided to include at least 30 participants in each group. Only complete da- tasets of participants who successfully complete the intervention will be analysed. The demographic and clinical characteristics of the sample will be compared at baseline using an analysis of variance (ANOVA), excluding gender, which will be analysed using the chi-square test. Separate repeated-measures multivariate analyses of variance (MANOVAs) will be used to assess change in symptomatology, functionality, cognition and haemodynamic parameters. To avoid inflation of Type II errors, we will apply a Bonferroni correction for multiple

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comparisons. The significance threshold will be set at 0,05. Cohen's d.85 Furthermore, multiple and logistic analyses will be performed.

4.2. Handling of missing data and drop-outs The primary analysis will be conducted with complete cases; drop-outs will be replaced by recruiting new subjects. Secondary analysis will include incomplete cases and dropouts. If a participant withdraws from the study, his/her data will be anonymised, and his/her name will be deleted permanently from all study records. Unless otherwise stated his/her remaining data will be used in a secondary analysis.

5. REGULATORY ASPECTS AND SAFETY

5.1 Local regulations / Declaration of Helsinki The study will be conducted in Switzerland under Swiss law and regulations (Human- forschungsgesetz HRA)86,87 together with the legal regulations applying to patients in the canton of Zurich.88 The research project will be carried out under the principles enunciated in the Declaration of Helsinki (DoH);89 furthermore the Good Clinical Practice (GCP)90 guidelines will be applied. According to current regulations written approval of the study will be obtained from the ethics committee of the canton of Zurich, Switzerland. Since the proposed study is a “Cat- egory A” trial,86 approval from the national regulatory authority “Swissmedic” is not required. The clinical study can only begin once approval from all required authorities has been re- ceived. Any additional requirements imposed by the authorities shall be implemented.

5.2 Registration Following approval by the responsible ethics committee the study protocol will be registered at: www.clinicaltrials.gov.91

5.3 Assessment of safety and reporting The study procedures and assessment methods are generally considered safe, and no risk to the health or well-being of participants is anticipated. The psychological discomfort (i.e., stress) derived from the TSST-G is desired and the main outcome of our trial. The Trier Social Stress Test is considered a safe procedure, with no known adverse events or long-term reactions which may lead to a deterioration in the mental well-being of participants; even when applied to participants in a vulnerable condition, including psychiatric disorders.38,43-45

The TSST-G incorporates an assessment scale to measure distress during the test, there is however no valid assessment tool to systematically evaluate safety. The TSST-G intervention is in many respects equivalent to an exposure session as conducted in Cognitive Behavioural Therapy. Therefore we consider the "Nebenwirkungen und Nebenwirkungserfassung in der Verhaltenstherapie” (Side-effects and registration of side-effects in behaviour therapy) (NNV) questionnaire92 a reasonable evaluation tool (in the face of a lack of valid alternatives) to assess safety and adverse events deriving from the TSST-G.

Reported adverse events derived from the use of wearable devices will be reported by the investigators using the FDA Form 3500 (MedWatch).93 MedWatch was developed by the Fed- eral Drug Agency (FDA) to increase the reporting of adverse medication effects and product

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problems.58,93 MedWatch is a one-page reporting form; it is designed for cases where the physician suspects that a regulated product was associated with a serious outcome: death, life-threatening condition, brief or prolonged hospitalisation, disability, or when intervention was required to prevent impairment or damage.93

In the event of serious adverse effects or health hazard, the investigator will be notified within 24 hours following awareness of the event. The relevant authorities will also be notified in accordance with the applicable legal requirements.86-88 Serious adverse effects will be notified to the Ethics Committee within 7 days of the event.94 Furthermore, all suspected new risks and relevant health hazards which require safety-related measures, will be reported within 7 days to the local Ethics Committee.94 If participants terminate the study with a reported ongo- ing adverse event, they will be followed-up until resolution or stabilisation.

5.4 Periodic reporting and amendments After approval, an "Annual Report," including the "Annual Safety Report"94 will be submitted to the Ethics Committee (EC), starting 12 months following approval of the protocol and study registration. Substantial amendments to this study protocol will only be implemented after approval by the EC. All non-substantial amendments will be communicated to the EC within the “Annual Report”. Premature study end or interruption of the study will be reported to the EC within 15 days.94 The end of the study will be notified to the EC within 90 days; a final study report will be submitted within one year after completion of the study.94

5.5 Duration/Termination of study We expect to complete the study in a time frame of between 18 and 24 months after approval of the protocol by the EC. Recruitment will continue until all study groups have reached their study population, already enrolled participants will be allowed to complete the study. A timeline of the study is summarised in Figure 3. The end of the study will be notified to the EC within 90 days; a final study report will be submitted within one year after completion of the study.94 Since the trial poses no risk to the health or well-being of participants, early termination of the research project is not anticipated. If the study ends prematurely or is interrupted due to un- foreseen circumstances the EC will be duly notified within 15 days.94 All data will be as far as possible anonymised at the end of the study: the code-file (see section 7.2) used for the proper identification and allocation of study subjects will be irreparably destroyed, informed consent forms will be concealed.

Figure 3. Timeline of the study

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5.6 Insurance In the event of study-related damage or injuries, the insurance of the Psychiatric University Hospital of Zurich [Zürich Versicherungsgesellschaft AG Police: 14.970.885 and 14.970.879] will provide compensation, excluding claims arising from misconduct or gross negligence.

6. ETHICAL ASPECTS

6.1 Overall ethical considerations The use of smartphones and wearable devices is ubiquitous, with a significant increase in their application to monitor psychological well-being and stress. However, the currently available digital technology lacks proper validation and reliability. Furthermore, patients with a current psychiatric disorder are under-represented in published work to date.22 This reduces the use and applicability of such devices in psychiatric settings, since psychiatric disorders modify the experience and appraisal of psychological stress in distinct ways. There is currently a lack of guidance in the use of such devices in general and in psychiatry in particular,95 their reckless use may be detrimental, dangerous or even harmful. Through our intervention we hope to identify valid and reliable digital biomarkers, thus contributing to objectivity, ecological validity, and utility of such devices/apps in daily life, thereby extending their use as self-monitoring devices and therapeutic instruments.

6.2 Risk-benefit assessment Wearable devices, including the ones used in the present study, are commercially available without restriction. They pose no risk to the health or well-being of their users. The TSST and TSST-G are widely used psychological paradigms used to induce psychosocial stress.38,40 Besides the deliberate distress they trigger, there is no known risk to the health or well-being of participants.38,40 Study participation does not offer any direct benefit or advantage to participants; therefore, we consider monetary compensation as justified (section 3.2). The results of this intervention are necessary to improve and extend the use of wearable devices, with potential benefits for large segments of the general population.

6.3 Funding and support This project will be carried out without external funding. The wearable devices utilised in the study will be purchased.

6.4 Declaration of Interest The authors have no conflicts of interest. The project has no commercial interests to declare.

7. DATA PROTECTION

7.1 Data recording and source data For each participant, a Case Report Form (CRF) in paper form will be maintained. Each CRF will be identified with the unique participant code (as described in section 7.2), no names, initials or birthdates will appear on the CRF. CRFs will be kept current to reflect subject status at each phase of the study. The CRF will include information regarding the participants characteristics, medical history, and current complaints, as well as psychological assessment data. Each CRF will also contain a list with the full names and signatures of all raters. Laboratory

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findings will also be labelled with the unique participant code and included as a paper record with the CRF. Raw data collected from the smartphone and wearable device will be saved as a csv file and stored in CD form attached to the physical CRF. Data relevant for analysis will be recorded in a Microsoft Excel File and stored for further analysis. CRFs will be kept in a room to which only study personnel have access.

7.2 Confidentiality and coding Data generation, transmission, storage and analysis of data and the storage of biological samples within this project will adhere strictly to current Swiss legal requirements for data protection and will be performed according to the Ordinance HRO Art. 5. A code list will be randomly generated, with each code consisting of a nonsense sequence of five numbers and three capital letters. Digital devices (Smartphone, Armband and Wristband) will be identified with a nonsense random name which will be unique to each device. Identifiers will be replaced each time they are handed-over to a new participant.

After signing the Informed Consent Form [Appendix 1], each participant will be identified with a unique study code chosen at random from this code list. The participant will be handed a card with the code for proper identification; a code-file with the name of the participant will be created and stored securely at the study site. The generated identification code will subse- quently be used to identify the participants throughout the study, including the CRF, samples and the provision of the smartphone and wearable device. Saliva samples will be appropriately stored until analysis in a restricted area of the laboratory of the psychiatric university hospital of Zurich only accessible to authorised personnel. Following analysis all samples will be destroyed.

Data collected from the smartphone, smartphone application, and the wearable device will be end to end encrypted and transferred to the servers of the department of informatics at the University of Zurich where it will be stored and identified using the identifier of the corresponding device. All data share functions of the digital devices will be deactivated. Participants will not be required to enter any personal information into the smartphone or the wearable device.

The code-file may only be broken if it is necessary to avert an immediate risk to the health of the person concerned, to guarantee the rights of the person (e.g., revoking of consent) or on legal grounds. To guarantee the highest degree of confidentiality and anonymity, after completion of the study and before data analysis the code-file will be destroyed. For data-analysis a new five-digit random number will be assigned to each data set, the previous code and device identifiers will be deleted.

7.3 Retention and destruction of study data and biological material All study data will be archived on servers of the Psychiatric Hospital of Zurich for ten years after study termination or premature termination of the study. Biological material will be destroyed following analysis.

7.4 Publication and dissemination After completion of this study, a report will be prepared. The data will then be prepared for publication in a peer-reviewed journal. The manuscript will be edited/compiled according to

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the STARD96 recommendations. If desired, participants will receive a printed copy of the results of the study.

7.5 Data sharing The project data may be shared following a reasonable request to the principal investigator. In such cases a request will be submitted to the relevant ethics committee for approval. Par- ticipants are entitled to receive a full copy of their own data if they so wish.

8. REFERENCES

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