Effectiveness and Acceptability of the Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders in People With Long COVID-19. (UP-LONGCOVID-R)

This Randomized Controlled Trial (RCT) aims to assess the effectiveness and acceptability of the Unified Protocol (UP) in an online group format for the treatment of emotional disorders in adults. Participants will be 90 adults (45 in the control group and 45 in the experimental group) with diagnosis of long COVID and comorbid emotional disorders. Participants will be recruited at Hospital Royo Villanova from Zaragoza, Spain.

In this study it will be explored whether the changes obtained after the intervention in emotional disorders and cognitive complaints are maintained over 12 months. Additionally, levels of chronic stress will be longitudinally evaluated in the experimental group through accumulated cortisol levels in hair, before and after the application of the UP.

Study Overview

• Status: Recruiting
• Conditions: Anxiety; Emotional Disorder; Emotion Regulation; Long Covid-19; Depression Disorders
• Intervention / Treatment: Behavioral: Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders; Other: Treatment as Usual (TAU)

Detailed Description

The COVID-19 disease has caused one of the largest pandemics in history, with significant health, social, and economic negative consequences. A significant proportion of the population has not overcome these negative consequences. It has been found that 10-20% of patients with COVID-19 do not recover their previous health status and develop persistent symptoms over time. This condition has been defined by the WHO as post-COVID-19 condition or long COVID-19, characterized by the presence of physical, cognitive, and emotional symptoms that can last for months or even years after the acute COVID-19 infection. Some of the most prevalent symptoms are fatigue, difficulty breathing, and cognitive dysfunction, in addition to significant psychological impairments. Among these, emotional disorders (ED) are the most commonly reported in this population, including anxiety disorders, depressive disorders, and related conditions.

The Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders (UP) is a transdiagnostic Cognitive Behavioral Therapy-based pychological intervention, which has proven to be effective for the treatment of emotional disorders in different populations. The UP is focused on improving emotion regulation skills.

The main objective of this randomized controlled trial is to evaluate the effectiveness and acceptability of the Unified Protocol (UP) in an online group format for the treatment of emotional disorders in 90 adults (45 in the control group and 45 in the experimental group) with long COVID and a comorbid emotional disorder. The researchers hypothesize that the application of the UP will result in a significant reduction in emotional symptoms in the experimental group, compared to the control group. To analyze this results, the evolution of symptoms (i.e., anxiety and depressive symptoms, etc.) will be assessed over time (before and after the intervention, as well as up to 12 months follow-up). Additionally, the acceptability and satisfaction of participants after receiving the UP will be analyzed, and it will be examined whether changes in emotional symptoms are associated with changes in long COVID physical symptoms. Changes in cortisol and cortisona levels will be longitudinally examined in the experimental group.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jorge Osma Jorge Osma, PhD; Phone Number: +34 978645390; Email: osma@unizar.es

Study Locations

• Spain
  • Zaragoza, Spain
    • Recruiting
    • Hospital Royo Villanova
    • Contact: Jorge J Osma, PhD; Phone Number: 861390 978645390; Email: protocolounificadocovid19@gmail.com
  • Zaragoza, Spain, 50015
    • Not yet recruiting
    • Hospital Royo Villanova
    • Contact: Jorge Osma Jorge Osma, PhD; Phone Number: +34 978645390; Email: osma@unizar.es
    • Sub-Investigator: Verónica Martínez Borba Verónica Martínez Borba, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Residing in Autonomous Community of Aragon (Spain).
• Being at least 18 years old.
• Understanding of Spanish.
• Being diagnosed with long COVID-19: documented SARS-CoV-2 infection and persistence of symptoms beyond 12 weeks after the acute infection.
• Symptoms of depression (ODSIS≥7) and/or anxiety (OASIS≥8).
• Meeting the criteria for an emotional disorder diagnosis.
• Having access to Internet.
• Signing the informed consent.

Exclusion Criteria:

• Pre-existing emotional symptoms prior to the acute SARS-CoV-2 infection.
• Actually receiving psychological treatment.
• Having a diagnosis of severe mental disorder (e.g., personality disorder, bipolar disorder, etc.).
• Active suicidal ideation at the time of the assessment.
• Individuals on psychotropic medication must maintain their dosage throughout the study, unless medically contraindicated.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Unified Protocol Psychological Intervention; The 45 participants assigned to this condition will receive the Unified Protocol psychological intervention through 12 sessions. Weekly session will be conducted online (via Google Meet). Each sessions will last 2 hours.	Behavioral: Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders; This transdiagnostic psychological intervention is focused on training emotion regulation skills. This program is composed by 8 modules (core modules are 3 to 7). In this study we will use a group online format (videocalls). Each sessin will last 2 hours. The contents of the UP will be distributed in 12 online sessions as follows: Module 1 (session 1): Setting goals and maintaining motivation.; Module 2 (sessions 2 and 3): Understanding your emotions.; Module 3 (sessions 4 and 5): Mindful Emotions Awareness.; Module 4 (sessions 6 and 7): Flexible thinking.; Module 5 (session 8): Emotional baheviors.; Module 6 (session 9): Facing physical sensations.; Module 7 (sessions 10 and 11): Emotionl exposures.; Module 8 (Session 12): Relapse prevention.
Other: Control Group-Waiting list; The 45 participants assigned to this condition will remain as a control group on a waiting list for the 12 weeks of the program that participants in the experimental group receive.	Other: Treatment as Usual (TAU); This intervention will act as a control condition. During the waiting period (12 weeks) participants assigned to this condition will continue receiving Treatment As Usual at the Royo Villanova Hospital. It consists of regular contact with doctors to monitor the physical symptomsof long COVID-19. After the 12 weeks, participants in this conditions will join the experimental group and they will receive the psychological intervention following the same procedure described for the experimental condition.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
General Depression Severity and Interference Scale (ODSIS; Bentley et al., 2014. Validated in Spanish by Osma et al., 2019)	It assesses the frequency, intensity, severity and interference of depressive symptomatology through 5 items. total scores range from 0 to 20 points, higher scores indicating more severe depressive symptoms.	Before the treatment, after the treatment, at three points follow up (3, 6 and 12 months after the intervention ended)
General Severity and Interference Scale for Anxiety (OASIS; Norman et al., 2006. Validated in Spanish by Osma et al., 2019)	It consiste of 5 items that assess the frequency, intensity, severity and interference of anxious symptomatology. Total scores range from 0 to 20 points, higher scores represent more severe anxiety symptoms.	Before the treatment, after the treatment, at three points follow up (3, 6 and 12 months after the intervention ended)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Memory Failures of Everyday, MFE (Sunderland et al., 1983; Montejo et al., 2014)	It assesses the frequency of forgetfulness and memory lapses in daily life. Errors include forgetting names, misplacing objects, difficulties in planning, or lapses in attention.	Before the treatment, after the treatment, at three points follow up (3, 6 and 12 months after the intervention ended)
Multidimensional Inventory for Emotional Disorders (MEDI; Rosellini and Brown, 2019. Validated in Spanish by Osma et al., 2023)	It is composed by 49 items that evaluates the transdiagnostic profile of Emotional Disorders, which is composed of nine dimensions: neurotic temperament, positive temperament, depressed mood, somatic anxiety, arousal activation, social anxiety, intrusive cognitions, traumatic re-experiencing, and avoidance.	Before the treatment, after the treatment, at three points follow up (3, 6 and 12 months after the intervention ended)
Emotional Regulation Difficulties Scale (DERS; Gratz and Roemer, 2004. Validated in Spanish by Hervás & Jódar, 2008)	Evaluation through 36 items of difficulties in emotional regulation by means of 5 subscales: lack of control, rejection, interference, inattention and emotional confusion. Higher scores indicate greater difficulties in emotion regulation.	Before the treatment, after the treatment, at three points follow up (3, 6 and 12 months after the intervention ended)
EuroQol (Brooks, 1996. Validated in Spanish by Badia et al., 1999)	It is composd by 5 items assessing self-perceived health status. Higher scores indicate better quality of life.	Before the treatment, after the treatment, at three points follow up (3, 6 and 12 months after the intervention ended)
Distress Tolerance Scale (DTS; Sandín et al., 2017)	This scale evaluates, through 15 items, distress tolerance in the following dimensions: 1) Tolerance: perceived ability to tolerate emotional distress; 2) Appraisal: subjective assessment of distress; 3) Absortion: attention absorbed by negative emotions; 4) Regulation: strategies to alleviate distress.	Before the treatment, after the treatment, at three points follow up (3, 6 and 12 months after the intervention ended)
Perceived Stress Scale (PSS; Remor y Carrobles, 2001)	This scale consists of 14 items designed to measure the level of perceived stress in daily life over the past month. The items are rated from 0 to 4, where 0 is "never" and 4 is "very often." Higher total scores indicate greater perceived stress.	Before the treatment, after the treatment, at three points follow up (3, 6 and 12 months after the intervention ended)
An adaptation of Client Satisfaction Questionnaire (CSQ-8) of Larsen et al., 1979)	the adaptation made for this study includes 6 of the 8 items of the CSQ-8 (perceived quality, adequacy to previous expectations, recommendation of the treatment to friends or family, usefulness of the techniques learned, general satisfaction with the intervention and probability that they will choose an intervention of this type again) and one additional item related to the discomfort generated by the intervention. Likewise, a change has been made in the Likert response scale from 4 points in the original (0 = "Bad / Not at all" to 4 = "Excellent/Very Much") to 11 in the current one (0 = "Bad / Not at all to 10 = "Excellent/Very Much"). Higher scores represent greater satisfaction with the treatment.	After the treatment is applied (post-assessment; approximately 12 weeks after the intervention starts)
Evaluation questionnaire of the UP modules (Ad hoc)	This questionnaire has been elaborated ad hoc. It is composed of 7 questions; one general question that evaluates the usefulness of the program to improve emotional regulation and six specific questions that separately evaluate the usefulness of each of the techniques that are worked on in the different modules of the UP to better regulate emotions . The response scale ranges from 0 (not at all) to 10 (very much). Higher scores represent higher satisfaction with the treatment.	After the treatment is applied (post-assessment; approximately 12 weeks after the intervention starts)
Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005)	Brief neuropsychological test designed to assess mild cognitive impairment. It evaluates multiple cognitive domains, including visuospatial skills, memory, working memory, attention, concentration, language, executive functions, and orientation. It has a maximum score of 30 points, with a common cutoff score of 25 to identify potential cognitive deficits. A score of 25 or lower is considered indicative of cognitive impairment.	Only in the experimental group: Before the treatment; at two points follow up (3 and 12 months after the intervention ended)
Digit Symbol subtest-Wechsler Adult Intelligence Scale-III (WAIS-III; Wechsler, 1997)	This cognitive test presents a coding matrix in which the digits from 1 to 9 are paired with a symbol. On the same sheet, a series of digits is displayed with a blank space where participants must draw the corresponding symbol. The task must be completed as quickly as possible, with a 120-second limit to match the symbols with their respective numbers. If participants fail to complete the first four lines within the allotted time, they are given additional time to ensure they gain enough experience with the digit-symbol association. The tota score is based on the number of symbols correctly paired within 120 seconds (maximum score: 133). Immediately after completing the task, the researcher provides the participant with a new sheet containing the digits from 1 to 9 arranged in two lines. In this second part, participants must complete the blank spaces by drawing from memory the symbols corresponding to each number, with no time limit.	Only in the experimental group: Before the treatment; at two points follow up (3 and 12 months after the intervention ended)
Digit subtest from Wechsler Adult Intelligence Scale-IV (WAIS-IV; Wechsler, 2008)	The direct order digit task of this subtest evaluates verbal short-term memory and consists of a numeric recall task that measures the mechanical repetition of a sequence of numbers. The reverse order digit task assesses verbal working memory and requires participants to recall a sequence of numbers in reverse order (maximum score: 9). The memory capacity evaluated with these two tasks is defined as the longest sequence that participants can repeat without errors, allowing two attempts for each sequence length (maximum score: 8).	Only in the experimental group: Before the treatment; at two points follow up (3 and 12 months after the intervention ended)
Cortisol and cortisona levels	Hair sample will be collected from the posterior vertex or nape area, where growth is continuous and less exposed to contaminants. For this, a small portion of hair will be tied with thread near the cut area, which will allow identification of the portion closest to the scalp at the time of analysis and prevent hair loss. Using clean scissors, the hair will be cut as close as possible to the scalp, obtaining a segment of approximately 3 cm in length. This will allow for the evaluation of cortisol levels accumulated over the last three months, as hair grows on average 1 cm per month.	Only in the experimental group: Before the treatment; at two points follow up (3 and 12 months after the intervention ended)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Structured interview for anxiety disorders and related disorders, according to the DSM-5 (ADIS-5; Brown & Barlow, 2014)	Diagnostic interview to determine the clinical diagnosis of emotional disorder (ED). The following diagnoses according to the DSM-V are included within the category of emotional disorder: major depressive disorder, dysthymic disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, social anxiety disorder, hypochondria, and adjustment disorders. Patients with anxiety disorders not otherwise specified and those with depressive disorders not otherwise specified will also be included in the study.	Before the treatment is administered to determine inclusion criteria (approximately 2 weeks before the interventions starts)
Sociodemographic information	Ad hoc questionnaire to assess: Sex, age, place of residence, marital status, employment status, lifestyle habits (smoking, alcohol, physical activity, diet), vaccination against SARS-CoV-2 information.	Before the treatment is administered to characterize the sample (approximately 2 weeks before the interventions starts).
Long COVID-19 pre-assessment questionnaire	This questionnaire is designed to assess the symptoms and impact of long COVID-19 symptoms on patients' daily lives. It evaluates information about physical and cognitive function as well as levels of fatigue and COVID-19 infection history.	Before the treatment is administered to characterize the sample (approximately 2 weeks before the interventions starts).

Collaborators and Investigators

• Sponsor: Instituto de Investigación Sanitaria Aragón
• Collaborators: Hospital Royo Villanova de Zaragoza

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: March 28, 2025
• First Submitted That Met QC Criteria: April 14, 2025
• First Posted (Actual): April 15, 2025

Study Record Updates

• Last Update Posted (Actual): May 22, 2025
• Last Update Submitted That Met QC Criteria: May 19, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Long COVID-19; Cognitive Behavioral; Psychological; Unified Protocol; Transdiagnostic; Emotional Disorders; Emotion regulation skills
• Additional Relevant MeSH Terms: Post-Infectious Disorders; Mental Disorders; Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19; Post-Acute COVID-19 Syndrome; Mood Disorders
• Other Study ID Numbers: UP-LONGCOVID-RCT; PROY_S22_24 (Other Grant/Funding Number: Gobierno de Aragón)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Access Criteria: Under reasonable request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No