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Trial registered on ANZCTR


Registration number
ACTRN12620000952943
Ethics application status
Approved
Date submitted
2/07/2020
Date registered
24/09/2020
Date last updated
30/06/2021
Date data sharing statement initially provided
24/09/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
An observational study of the effect of serotonin re-uptake inhibitors (SSRIs) on both the communication between brain and body and symptoms of anxiety
Scientific title
Breathing and anxiety: Understanding the effect of serotonin re-uptake inhibitors on the possible miscommunication between brain and body in individuals with clinical levels of anxiety
Secondary ID [1] 301683 0
None
Universal Trial Number (UTN)
U1111-1254-6624
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anxiety 318131 0
Condition category
Condition code
Mental Health 316155 316155 0 0
Anxiety

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Brief name: SSRI
This observational study will recruit and measure participants with clinical levels of anxiety who have been prescribed a serotonin re-uptake inhibitor (SSRI) by their physician for a period of 6 weeks. Measurements will be performed within a 4 hour session (including breaks), and will involve completing a set of behavioural tasks that consist of answering questions about emotions and body perceptions, two tasks that involve breathing through a sterile system to detect changes in breathing effort, as well as a visual detection task and emotion recognition task (both performed on a computer). The first measurement session will take place either prior to or within the first week of treatment, and this will then be repeated following 6 weeks of treatment.
Intervention code [1] 317993 0
Not applicable
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 324334 0
Change in self-reported anxiety measured using a combination of the Spielberger Trait Anxiety Score, GAD-7 (Generalised Anxiety Disorder Questionnaire) and ASI-3 (Anxiety Sensitivity Index-3)
Timepoint [1] 324334 0
Within one week (or prior) and 6 weeks post commencement of intervention
Primary outcome [2] 324335 0
Change in breathing perception and related metacognition, measured using a behavioural breathing task (the "Filter Detection Task")
Timepoint [2] 324335 0
Within one week (or prior) and 6 weeks post commencement of intervention
Primary outcome [3] 324336 0
Change in interoceptive learning related to breathing, measured using a behavioural breathing task (the Breathing Learning Task)
Timepoint [3] 324336 0
Within one week (or prior) and 6 weeks post commencement of intervention
Secondary outcome [1] 384371 0
Change in depression measured using the CES-D (Center for Epidemiologic Studies Depression Scale)
Timepoint [1] 384371 0
Within one week (or prior) and 6 weeks post commencement of intervention
Secondary outcome [2] 384372 0
Change in fatigue measured using the FSS (Fatigue Severity Scale)
Timepoint [2] 384372 0
Within one week (or prior) and 6 weeks post commencement of intervention
Secondary outcome [3] 384373 0
Change in general mood measured using the PANAS (Positive Affect Negative Affect Schedule) for affective traits
Timepoint [3] 384373 0
Within one week (or prior) and 6 weeks post commencement of intervention
Secondary outcome [4] 385029 0
Change in general self-reported awareness of body perceptions (interoception) using the MAIA (Interoceptive Awareness Questionnaire)
Timepoint [4] 385029 0
Within one week (or prior) and 6 weeks post commencement of intervention
Secondary outcome [5] 386126 0
Change in catastrophising of breathing symptoms measured using the PCS-resp (Catastrophic Thinking Scale in Pain, substituting the word “breathlessness” or "breathing" for the word “pain")
Timepoint [5] 386126 0
Within one week (or prior) and 6 weeks post commencement of intervention
Secondary outcome [6] 386127 0
Change in vigilance towards breathing symptoms measured using the PVAQ-resp (Pain Awareness and Vigilance Scale, substituting the word “breathlessness” or "breathing" for the word “pain”)
Timepoint [6] 386127 0
Within one week (or prior) and 6 weeks post commencement of intervention
Secondary outcome [7] 387202 0
Change in a visual perception and related metacognition, measured using a visual detection task (the "Perceptual Decision-Making Task")
Timepoint [7] 387202 0
Within one week (or prior) and 6 weeks post commencement of intervention
Secondary outcome [8] 387203 0
Change in response to emotional faces, measured using an emotional faces task previously developed and reported (the "Facial Expression Recognition Task")
Timepoint [8] 387203 0
Within one week (or prior) and 6 weeks post commencement of intervention
Secondary outcome [9] 397621 0
Change in general self-reported resilience using the CD-RISC questionnaire (Connor Davidson Resilience Scale)
Timepoint [9] 397621 0
Within one week (or prior) and 6 weeks post commencement of intervention
Secondary outcome [10] 397622 0
Change in general self-efficacy using the GSS questionnaire (General Self-Efficacy Scale)
Timepoint [10] 397622 0
Within one week (or prior) and 6 weeks post commencement of intervention
Secondary outcome [11] 397623 0
Change in the level of emotional needs, measured using the Institute for Personality-Oriented Management (IPM) algorithm
Timepoint [11] 397623 0
Within one week (or prior) and 6 weeks post commencement of intervention

Eligibility
Key inclusion criteria
Diagnosed with any clinically significant anxiety disorder AND prescribed with a course of an SSRI by their medical practitioner
Male or female aged between 18 and 45 years
Ability to provide written and informed consent
Ability to adhere to the study protocol
Minimum age
18 Years
Maximum age
45 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Evidence of severe acute or chronic medical disorders, including a neurological disorder, current or past history of a severe brain injury or severe respiratory disorder e.g. severe asthma, chronic obstructive pulmonary disease etc.
Past or current diagnoses of schizophrenia, bipolar disorder, drug addiction or psychosis
Colour blindness
Female patients who are pregnant or breastfeeding
Current significant suicidal ideation
Participants must be free of recreational drug and alcohol use at the time of testing

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Sample size:
To investigate changes in anxiety symptoms over the course of 6 weeks of an SSRI e.g. citalopram, we will aim to recruit 71 participants with a clinically-diagnosed anxiety disorder who have been prescribed a course of an SSRI into this study. We will conduct regression analyses comparing changes in symptoms with changes in our interoceptive measures, and 71 participants would allow us to determine a moderate regression effect size (0.15) with 90% power and an alpha-level of 5%, while 54 participants would be required for a standard level of 80% power. Therefore, to maintain a minimum of 80% power in the final dataset, data collection will continue until at least 54 participants have completed the study. To establish all study procedures, we will additionally require up to 10 pilot participants. All pilot participants will be subject to the same study inclusion and exclusion criteria as for the main study, and will be used for both checking study procedures and model calibrations (if required).

Analysis overview:
Full details of all planned statistical analyses will be documented and time-stamped before being uploaded to an open-access database prior to commencement of any data analysis. Any alterations to these plans will be clearly recorded.
1) Demographic and summary data: Demographic and Background Characteristics: Patient demographic characteristics will be descriptively summarised for all subjects.
2) Questionnaires: Questionnaires will be scored according to their respective manuals. For statistical analysis of this data we will use the statistical analysis software packages of MATLAB, EXCEL or R. For the analysis of questionnaires and other measured variables (below), we will perform analyses in the framework of the General Linear Model (GLM), e.g., multiple regression, analysis of variance (ANOVA), t-tests, and correlation analyses. In these classical (frequentist) statistical analyses, the significance level will be set to an alpha of 0.05 or less, after appropriately correcting for multiple tests.
3) Filter Detection Task (FDT) and Visual Perception Task (VPT)
The FDT and VPT will be analysed using the hierarchical HMeta-d statistical model, with model fits implemented in MATLAB and sampling conducted JAGS. This model firstly utilizes signal detection theory to provide single subject parameter estimates for task difficulty and response bias (akin to symptom over- or under-reporting), as well as using a hierarchical Bayesian formulation of metacognitive efficiency (calculated by fitting metacognitive sensitivity and normalizing by single subject values for sensitivity measures). The task protocol has been designed to generate comparable task difficulty for each participant, by finding the number of filters at which performance was maintained at approximately 75% accuracy.
4) Breathing learning task: To analyse the behavioural data gathered within this task, we will use established generative models of behavioural data, e.g., Hierarchical Gaussian Filter (Mathys et al. 2011) and variants of traditional reinforcement learning models, such as the Rescorla Wagner. Implementation of these models will be carried out in statistically oriented programming languages such as MATLAB, R, or Python.
5) Emotional faces task: This task will be analysed using a statistical program such as MATLAB, EXCEL or R. Summary measures from the emotional faces task will be calculated, such as percentage of correct responses (i.e. the number of faces correctly identified as containing any intensity of a particular emotion), percentage of misclassifications (false hits), and reaction times (RTs) (to emotions correctly identified).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 22710 0
New Zealand
State/province [1] 22710 0
Otago

Funding & Sponsors
Funding source category [1] 306119 0
Charities/Societies/Foundations
Name [1] 306119 0
Royal Society of New Zealand
Address [1] 306119 0
11 Turnbull Street
Thorndon
Wellington 6011
Country [1] 306119 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
Centre for Innovation
Level 1 (East Wing)
87 St David St
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 306588 0
None
Name [1] 306588 0
Address [1] 306588 0
Country [1] 306588 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306336 0
Central Health and Disability Ethics Committee (HDEC-Expedited Review Pathway)
Ethics committee address [1] 306336 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 306336 0
New Zealand
Date submitted for ethics approval [1] 306336 0
18/07/2020
Approval date [1] 306336 0
20/08/2020
Ethics approval number [1] 306336 0

Summary
Brief summary
Anxiety disorders are the most common mental health disorders in New Zealand. One effective intervention for anxiety is the prescription of a serotonin re-uptake inhibitor (SSRI) as an anxiolytic medication. This project aims to understand how SSRI treatment for anxiety is related to changes in breathing perception, as an impaired ability to monitor bodily state has been proposed to exist within anxiety. We will therefore employ breathing tasks in an observational study, both before and after 6 weeks of SSRI treatment for anxiety. These breathing tasks measure a number of important factors, such as perceptual accuracy and self-awareness, symptom reporting, and how an individual learns about their breathing within a changing environment. Participants undergoing treatment for anxiety will be recruited, and individuals who are prescribed a serotonin re-uptake inhibitor (e.g. Citalopram, Sertraline) by their physician and will perform the breathing tasks at the beginning and end of this period. These datasets will allow us to apply state-of-the-art computational models of perception, investigating how anxiety can interrupt the brain’s processing of internal bodily states, and how current interventions may target these disruptions.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103538 0
Dr Olivia Harrison
Address 103538 0
School of Pharmacy
University of Otago
Adams Building
18 Frederick Street
Dunedin 9054
Country 103538 0
New Zealand
Phone 103538 0
+64 3 479 7272
Fax 103538 0
Email 103538 0
olivia.harrison@otago.ac.nz
Contact person for public queries
Name 103539 0
Dr Olivia Harrison
Address 103539 0
School of Pharmacy
University of Otago
Adams Building
18 Frederick Street
Dunedin 9054
Country 103539 0
New Zealand
Phone 103539 0
+64 3 479 7272
Fax 103539 0
Email 103539 0
olivia.harrison@otago.ac.nz
Contact person for scientific queries
Name 103540 0
Dr Olivia Harrison
Address 103540 0
School of Pharmacy
University of Otago
Adams Building
18 Frederick Street
Dunedin 9054
Country 103540 0
New Zealand
Phone 103540 0
+64 3 479 7272
Fax 103540 0
Email 103540 0
olivia.harrison@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results (after de-identification)
When will data be available (start and end dates)?
Following completion of data collection and analyses, with no end date
Available to whom?
Researchers who provide sound research proposals
Available for what types of analyses?
All
How or where can data be obtained?
Access subject to approvals by Principal Investigator (liv.faull@gmail.com)
What supporting documents are/will be available?
Statistical analysis plan
Analytic code
How or where can supporting documents be obtained?
Type [1] 8394 0
Statistical analysis plan
Citation [1] 8394 0
Link [1] 8394 0
Email [1] 8394 0
olivia.harrison@otago.ac.nz
Other [1] 8394 0
Analysis plans will also be uploaded to public-access repositories once analyses are submitted to Academic Journals for publishing
Attachment [1] 8394 0
Type [2] 8395 0
Analytic code
Citation [2] 8395 0
Link [2] 8395 0
Email [2] 8395 0
olivia.harrison@otago.ac.nz
Other [2] 8395 0
Attachment [2] 8395 0
Summary results
No Results