Psychological Interventions for Multiple Sclerosis: Effects on Anxiety, Depression, and Cognition. (MS-PSY)

Psychological Intervention in Multiple Sclerosis: Efficacy in the Treatment of Anxiety-depressive Symptoms and Cognitive Impairment.

This study evaluated the efficacy of two structured psychological interventions for patients with relapsing-remitting multiple sclerosis (RRMS). The main goal was to determine whether a Cognitive Behavioral Therapy (CBT)-based program and a Psychophysiological Regulation Therapy (PRT) improved emotional well-being and cognitive functioning compared with Standard Care (SC).

A total of 140 participants with mild to moderate disability and disease duration between 5.5 and 8.5 years were randomly assigned to one of three groups: CBT, PRT, or SC (waiting list). Each intervention was delivered in small groups over 12 weekly sessions. Assessments were conducted before and after treatment using validated clinical and neuropsychological measures.

Results were analyzed to explore the effectiveness of both interventions in reducing anxiety and depressive symptoms and enhancing cognitive performance. The study aimed to provide evidence for the inclusion of psychological therapies as complementary treatments in comprehensive care for multiple sclerosis patients.

Study Overview

• Status: Completed
• Conditions: Depression; Cognitive Impairment; Anxiety; Cognitive Behavior Therapy; Multiple Sclerosis (MS) - Relapsing-remitting; Emotional Well-being
• Intervention / Treatment: Behavioral: Cognitive Behavioral Therapy (CBT); Behavioral: Psychophysiological Regulation Therapy (PRT)

Detailed Description

A randomized controlled trial design will be conducted with allocation to the following groups: treatment group (cognitive-behavioral intervention group, psychophysiological reduction - low performance - and neuropsychological rehabilitation) or control group (waiting list). Assessments will be carried out before and immediately after treatment, and at a six-month follow-up after therapy completion. Additionally, a follow-up magnetic resonance imaging (MRI) will be performed after the intervention, within a period of 1 to 3 months, and again at 6 months post-treatment. This neuroimaging activity is included as part of the clinical practice of the Multiple Sclerosis Unit. Participants: A total of 140 patients with clinically defined relapsing-remitting Multiple Sclerosis (MS) will be studied. Inclusion criteria will include minimal to mild disability according to the Expanded Disability Status Scale (EDSS) (EDSS: 0-3.5), mild to moderate cognitive impairment (BRB-N: up to two subtests with scores <2 SD), and presence of anxiety and/or depressive symptoms (HADS: scores >8 on one or both subscales; BDI-II: scores >8). Participants will be recruited from the Multiple Sclerosis Unit of the University Hospital Nuestra Señora de Candelaria (HUNSC) in Santa Cruz de Tenerife. The sample size calculation was based on the assumption that, to achieve a 90% power for detecting effects on primary measures (BDI-II, HADS, ISRA, BRB-N, etc.). The sample size was calculated based on an ANOVA design (medium effect size, d = 0.5; α = 0.05; power = 80%), estimating a required total of 156 participants (52 per group).

. This estimate may be adjusted throughout data collection due to variability in measures specific to this population. Experience with the initial participant groups and their resulting data will allow refinement of these estimates. Evidence highlights that people with MS exhibit unusually low levels of help-seeking behavior for anxiety and depressive symptoms, emphasizing the need for systematic screening. The Multiple Sclerosis Unit currently follows 587 diagnosed patients. This study also aims, based on initial findings, to broaden inclusion criteria according to preliminary results and to establish comparisons among different forms of MS, thereby improving the external validity of the study. This approach is grounded in the reflections of several authors who note that overly restrictive inclusion criteria (e.g., symptoms, comorbidities) may limit the generalizability of clinical trial results to routine clinical practice. They propose ensuring adequate representation of problems, settings, and therapies, along with systematic treatment monitoring and flexibility in interventions-while maintaining detailed information on their active components. Procedure and Timeline Pre-treatment Evaluation Neurological Evaluation: Initial selection of patients will be conducted at the Multiple Sclerosis Unit of the Neurology Service at the University Hospital Nuestra Señora de Candelaria. A standardized neurological protocol will be requested, including the most relevant clinical history data and neurological examination results. Clinical inclusion criteria: clinically defined relapsingremitting MS and minimal to mild disability level. Psychological Evaluation: Among patients meeting clinical inclusion criteria, an interview will be conducted to identify those reporting cognitive and emotional complaints (including an interview with relatives). Motivation and willingness to collaborate will also be assessed. Upon obtaining informed consent, the evaluation protocol will be administered to determine fulfillment of cognitive and emotional inclusion criteria. Patients meeting the criteria will be randomly assigned to either the intervention group or the control group (waiting list without intervention), considering their anxiety and depression scores as well as cognitive impairment levels. The inclusion period will last approximately four months. Treatment Phase Patients in the treatment group will complete the psychological intervention program over 12 weeks (one weekly session lasting 1 hour and 30 minutes), plus two follow-up sessions. The intervention will follow a cognitive-behavioral framework and consist of a specific program tailored to the characteristics of the identified deficits. It will include didactic sessions, group discussions, and practical exercises. Post-treatment Evaluation This will take place during the week following the end of treatment and will include: Neurological Evaluation: assessment of disability level (EDSS).

Psychological Evaluation: assessment of cognitive, emotional, and quality-of-life variables. Follow-up Evaluation A follow-up assessment will be carried out six months after treatment completion, applying the same evaluation protocol as in previous phases.

The control group will be evaluated at the same time points as the intervention group.

All phases of the study will be conducted at the Multiple Sclerosis Unit of the University Hospital Nuestra Señora de Candelaria (HUNSC).

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Spain
  • Santa Cruz de Tenerife
    • San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain, 38200
      • Faculty of Psychology, University of La Laguna Department of Clinical Psychology, Psychobiology and Methodology of Behavioral Sciences Campus de Guajara, Calle Heraclio Sánchez, s/n 38200 San Cristóbal de La Laguna, Santa Cruz de Tenerife Spain

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Diagnosis of relapsing-remitting multiple sclerosis according to standard clinical criteria.
• Expanded Disability Status Scale (EDSS) score between 0 and 3.5.
• Mild to moderate cognitive impairment defined as: up to two BRB-N subtests with scores < -2 SD.
• Presence of anxiety or depressive symptoms defined as:
• HADS: score > 8 on one or both subscales, and/or
• BDI-II: score > 8.
• Stable disease-modifying treatment for ≥ 3 months.
• Ability to provide written informed consent.

Exclusion Criteria:

• Progressive forms of multiple sclerosis (SPMS or PPMS).
• Severe cognitive impairment preventing participation in psychological sessions.
• Active psychiatric or neurological disorders unrelated to MS.
• Participation in another psychological or pharmacological intervention study.
• Recent initiation or modification of disease-modifying treatment (< 3 months).
• Substance abuse or dependence within the past year.
• Inability to provide informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cognitive Behavioral Therapy (CBT); Participants receive a structured 12-week cognitive-behavioral group intervention designed to improve stress coping and reduce anxiety-depressive symptoms. The program includes psychoeducation, mindfulness, behavioral activation, cognitive restructuring, self-instruction training, and social skills development. Intervention: Behavioral: Cognitive Behavioral Therapy	Behavioral: Cognitive Behavioral Therapy (CBT); A structured 12-week group-based cognitive-behavioral intervention including psychoeducation, mindfulness training, behavioral activation, cognitive restructuring, self-instruction training, and social skills development. Designed to improve coping, reduce anxiety-depressive symptoms, and enhance cognitive and emotional functioning.
Experimental: Psychophysiological Regulation Therapy (PRT); Participants receive a structured 12-week group intervention emphasizing psychophysiological self-regulation. The program includes psychoeducation, mindfulness, relaxation, breathing control, and biofeedback-based exercises aimed at reducing emotional distress and enhancing self-regulation.	Behavioral: Psychophysiological Regulation Therapy (PRT); A structured 12-week group-based intervention emphasizing psychophysiological self-regulation through psychoeducation, mindfulness, relaxation, breathing control, and biofeedback-based exercises to reduce emotional distress and promote physiological balance.
No Intervention: Standard Care (SC); Participants in the control group remain on a waiting list and receive standard medical care provided by the Multiple Sclerosis Unit during the study period. After study completion, they are offered participation in one of the active interventions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fatigue Severity Scale (FSS) - Total Score	Description: Change in fatigue severity measured with the Fatigue Severity Scale (FSS; Krupp et al., 1989). Scale range: 9-63 points (9 items scored 1-7). Interpretation: Higher scores indicate greater fatigue severity.	Baseline and 12 weeks.
Multiple Sclerosis Quality of Life-54 (MSQoL-54) - Total and Subscale Scores	Description: Change in quality of life measured with the Multiple Sclerosis Quality of Life-54 (MSQoL-54; Vickrey, Hays, Harooni, Myers & Ellison, 1995), including physical and mental health composite scores and individual subscales. Scale range: 0-100 points. Interpretation: Higher scores indicate better quality of life.	Baseline and 12 weeks.
Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) - Total Score	Description: Change in perceived cognitive functioning measured with the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ; Benedict et al., 2003). Scale range: 0-60 points. Interpretation: Higher scores indicate greater perceived cognitive impairment.	Baseline and 12 weeks.
Verbal Selective Reminding Test (SRT) - Total Recall Score	Change in verbal learning and memory performance measured with the Verbal Selective Reminding Test (SRT), part of the BRB-N (Rao, 1990). (Scale range 0-72). Interpretation: Higher scores indicate better performance.	Baseline and 12 weeks.
10/36 Spatial Recall Test (SPART) - Total Recall Score	Description: Change in visuospatial learning and memory measured with the 10/36 Spatial Recall Test (SPART), part of the BRB-N (Rao, 1990). Scale range: 0-36. Interpretation: Higher scores indicate better performance.	Baseline and 12 weeks.
Paced Auditory Serial Addition Test (PASAT) - 3-Second Version	Description: Change in complex attention and working memory measured with the PASAT (3-second version), part of the BRB-N (Rao, 1990). Scale range: 0-60 correct responses. Interpretation: Higher scores indicate better performance.	Baseline and 12 weeks.
Symbol Digit Modalities Test (SDMT) - Oral Version	Description: Change in attention and processing speed measured with the Symbol Digit Modalities Test (SDMT), part of the BRB-N (Rao, 1990). Scale range: 0-110 correct responses. Interpretation: Higher scores indicate better performance.	Baseline and 12 weeks.
Controlled Oral Word Association Test (COWAT) - Semantic Fluency ("Animals" Category)	Description: Change in semantic verbal fluency measured with the Controlled Oral Word Association Test (COWAT), Semantic Fluency subtest (animals category). Scale range: Number of correct animals named in 60 seconds (typically 0-40). Interpretation: Higher scores indicate better performance.	Baseline and 12 weeks.
Controlled Oral Word Association Test (COWAT) - Phonemic Fluency (F-A-S Letters)	Description: Change in phonemic verbal fluency measured with the Controlled Oral Word Association Test (COWAT), Phonemic Fluency subtest (letters F, A, and S). Scale range: Total number of correct words generated across the three letters in 60 seconds each (typically 0-60). Interpretation: Higher scores indicate better performance.	Baseline and 12 weeks.
Hospital Anxiety and Depression Scale - Anxiety Subscale (HADS-A)	Description: Change in anxiety symptoms measured with the Hospital Anxiety and Depression Scale - Anxiety Subscale (HADS-A; Zigmond & Snaith, 1983). Scale range: 0-21 points. Interpretation: Higher scores indicate greater anxiety severity.	Baseline and 12 weeks.
Beck Depression Inventory-II (BDI-II) - Total Score	Description: Change in depressive symptoms measured with the Beck Depression Inventory-II (BDI-II; Beck et al., 1996). Scale range: 0-63 points. Interpretation: Higher scores indicate greater depressive severity.	Baseline and 12 weeks.
Inventario de Situaciones y Respuestas de Ansiedad (ISRA) - Total Score	Description: Change in cognitive, physiological, and motor anxiety responses measured with the Inventario de Situaciones y Respuestas de Ansiedad (ISRA; Miguel-Tobal & Cano-Vindel, 1994). Scale range: 0-100+ (higher scores = greater anxiety response). Interpretation: Higher scores indicate greater anxiety reactivity.	Baseline and 12 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recent Life Changes Questionnaire (RLCQ) - Total Score	Description: Change in perceived stress measured with the Recent Life Changes Questionnaire (RLCQ; Holmes & Rahe, 1967; Spanish adaptation: González & Morera, 1983). Scale range: 0 to 100+ life change units (LCUs), depending on the number and weight of events endorsed. Interpretation: Higher scores indicate greater perceived stress and higher adjustment demand.	Baseline and 12 weeks.
Symptom Checklist-90-Revised (SCL-90-R) - Global Severity Index (GSI)	Description: Change in general psychopathological symptoms measured with the Symptom Checklist-90-Revised (SCL-90-R; Derogatis, 1994), using the Global Severity Index (GSI). Scale range: 0-4 (mean item score across 90 items rated 0 to 4). Interpretation: Higher scores indicate greater psychopathological symptom severity.	Baseline and 12 weeks.
Cognitive Triad Inventory (CTI) - Total Score	Description: Change in depressive cognitive schemas measured with the Cognitive Triad Inventory (CTI; Beckham et al., 1986). Scale range: 36-252 points (36 items scored 1-7). Interpretation: Higher scores indicate more negative/depressive cognitive schemas about self, world, and future.	Baseline and 12 weeks.
Intolerance of Uncertainty Scale (IUS) - Total Score	Description: Change in intolerance of uncertainty measured with the Intolerance of Uncertainty Scale (IUS; Freeston et al., 1994). Scale range: 27-135 points (27 items scored 1-5). Interpretation: Higher scores indicate greater intolerance of uncertainty.	Baseline and 12 weeks.
Social Support Questionnaire (SSQ-6) - Total Score	Description: Change in perceived social support measured with the Social Support Questionnaire (SSQ; Sarason et al., 1983). Scale range: Typically 0-9 for the number of supports (SSQ-6) and 1-6 for satisfaction (SSQ-S), depending on the scoring method used. Interpretation: Higher scores indicate greater perceived social support (more available supports and/or higher satisfaction).	Baseline and 12 weeks.
Pittsburgh Sleep Quality Index (PSQI) - Total Score	Description: Change in sleep quality measured with the Pittsburgh Sleep Quality Index (PSQI). Scale range: 0-21 points. Interpretation: Higher scores indicate worse sleep quality.	Baseline and 12 weeks.
MRI Lesion Activity and Lesion Load	Change in brain lesion activity (number of new/enlarging T2 lesions and gadolinium-enhancing lesions) and total lesion load (total T2 lesion volume) obtained from routine clinical magnetic resonance imaging (MRI) scans.	Baseline and 12 weeks.
Duke-UNC Functional Social Support Questionnaire (DUFSS) - Total Score	Description: Change in functional social support measured with the Duke-UNC Functional Social Support Questionnaire (DUFSS; Broadhead et al., 1988; Spanish validation by Bellón et al., 1996). Scale range: 5-55 points (11 items scored 1-5). Interpretation: Higher scores indicate greater functional social support.	Baseline and 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-Modifying and Symptomatic Treatment Status	Changes in disease-modifying therapies (DMTs) and symptomatic treatments recorded at each assessment point. Includes initiation, discontinuation, or dose adjustments of any MS-related medication.	Baseline and 12 weeks.

Collaborators and Investigators

• Sponsor: Moisés Bermúdez Hernández
• Collaborators: University of La Laguna

Publications and helpful links

General Publications

• Cuijpers P, Karyotaki E, Weitz E, Andersson G, Hollon SD, van Straten A. The effects of psychotherapies for major depression in adults on remission, recovery and improvement: a meta-analysis. J Affect Disord. 2014 Apr;159:118-26. doi: 10.1016/j.jad.2014.02.026. Epub 2014 Feb 24.
• Scandiffio J, Langer LK, Senthilnathan V, Feng G, Sureshkumar A, Bromberg M, Babineau J, Donkers SJ, Knox KB, Bruno T, Walker LAS, Bayley MT, Simpson R. Effects of psychological therapies in people with multiple sclerosis: a systematic review and network meta-analysis of randomized controlled trials. J Neurol. 2025 Aug 20;272(9):584. doi: 10.1007/s00415-025-13315-6.
• Lucien A, Francis H, Wu W, Woldhuis T, Gandy M. The efficacy of cognitive behavioural therapy for depression and anxiety in multiple sclerosis: A systematic review and meta-analysis. Mult Scler Relat Disord. 2024 Nov;91:105858. doi: 10.1016/j.msard.2024.105858. Epub 2024 Sep 3.
• Moss-Morris R, McCrone P, Yardley L, van Kessel K, Wills G, Dennison L. A pilot randomised controlled trial of an Internet-based cognitive behavioural therapy self-management programme (MS Invigor8) for multiple sclerosis fatigue. Behav Res Ther. 2012 Jun;50(6):415-21. doi: 10.1016/j.brat.2012.03.001. Epub 2012 Mar 13.
• De Meo E, Portaccio E, Bonacchi R, Giovannoli J, Niccolai C, Amato MP. An update on the treatment and management of cognitive dysfunction in patients with multiple sclerosis. Expert Rev Neurother. 2025 Feb;25(2):227-243. doi: 10.1080/14737175.2025.2450788. Epub 2025 Jan 16.
• Amato MP, Langdon D, Montalban X, Benedict RH, DeLuca J, Krupp LB, Thompson AJ, Comi G. Treatment of cognitive impairment in multiple sclerosis: position paper. J Neurol. 2013 Jun;260(6):1452-68. doi: 10.1007/s00415-012-6678-0. Epub 2012 Nov 23.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2015
• Primary Completion (Actual): January 1, 2019
• Study Completion (Actual): January 1, 2019

Study Registration Dates

• First Submitted: November 19, 2025
• First Submitted That Met QC Criteria: November 27, 2025
• First Posted (Estimated): December 9, 2025

Study Record Updates

• Last Update Posted (Estimated): December 9, 2025
• Last Update Submitted That Met QC Criteria: November 27, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Depression; Multiple Sclerosis; Quality of Life; Anxiety; Relapsing-Remitting Multiple Sclerosis; Fatigue; Cognitive Impairment; Randomized Controlled Trial; Psychological Intervention; Emotional Well-being; Cognitive Behavioral Therapy; Psychophysiological Regulation Therapy
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Autoimmune Diseases; Immune System Diseases; Behavioral Symptoms; Neurocognitive Disorders; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Cognition Disorders; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Anxiety Disorders; Multiple Sclerosis; Cognitive Dysfunction; Depression; Fatigue; Multiple Sclerosis, Relapsing-Remitting; Behavior Therapy; Psychotherapy; Behavioral Disciplines and Activities; Cognitive Behavioral Therapy
• Other Study ID Numbers: HUNSC_ULL_MS_PSY2015; PI-60/14 (Other Identifier: Universidad de La Laguna (ULL) and Hospital Universitario Nuestra Señora de Candelaria (HUNSC))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) will be made available upon reasonable request to the corresponding author, Dr. Moisés Bermúdez Hernández (mbermudh@ull.edu.es), for academic and non-commercial research purposes. Data will be fully anonymized in compliance with institutional and ethical regulations and the European General Data Protection Regulation (GDPR).
• IPD Sharing Time Frame: IPD and supporting documents will be available beginning 12 months after publication of the main results and will remain accessible for 5 years thereafter.
• IPD Sharing Access Criteria: Qualified researchers affiliated with academic or non-profit institutions may request access to de-identified individual participant data (IPD) and supporting documents (protocol, SAP, ICF, CSR) for scientific and non-commercial purposes. Requests must be submitted to the corresponding author, Dr. Moisés Bermúdez Hernández (mbermudh@ull.edu.es). Access will be granted following review and approval by the study's ethics committee and in compliance with GDPR and institutional data-sharing policies.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No