Anxiety, Cognitive Behavior Therapy, Cognitive Impairment, Depression, Emotional Well-being, Multiple Sclerosis (MS) - Relapsing-remitting
Conditions
Keywords
Multiple Sclerosis, Relapsing-Remitting Multiple Sclerosis, Cognitive Behavioral Therapy, Psychophysiological Regulation Therapy, Anxiety, Depression, Cognitive Impairment, Emotional Well-being, Quality of Life, Fatigue, Randomized Controlled Trial, Psychological Intervention
Brief summary
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.
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).
Interventions
BEHAVIORALCognitive 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.
BEHAVIORALPsychophysiological 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.
Sponsors
University of La Laguna
Moisés Bermúdez Hernández
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Outcome assessors were blinded to participants' group allocation. Participants and therapists were aware of the assigned intervention, but evaluators conducting clinical and neuropsychological assessments did not have access to treatment information to minimize bias in data collection.
Intervention model description
This study employed a three-arm randomized controlled design with participants allocated to Cognitive Behavioral Therapy (CBT), Psychophysiological Regulation Therapy (PRT), or Standard Care (waiting list). Interventions were group-based over 12 weekly sessions, with assessments at baseline and post-intervention. Both CBT and PRT followed structured programs aimed at improving stress coping and reducing anxiety-depressive symptoms through psychoeducation, mindfulness, and psychophysiological regulation. Sessions combined didactic content, group exercises, and homework. CBT emphasized behavioral activation, cognitive restructuring, self-instruction, and social skills training, whereas PRT focused on psychophysiological self-regulation, relaxation, breathing control, and biofeedback exercises.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Inventario de Situaciones y Respuestas de Ansiedad (ISRA) - Total Score | Baseline and 12 weeks. | 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. |
| Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) - Total Score | Baseline and 12 weeks. | 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. |
| Verbal Selective Reminding Test (SRT) - Total Recall Score | Baseline and 12 weeks. | 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. |
| 10/36 Spatial Recall Test (SPART) - Total Recall Score | Baseline and 12 weeks. | 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. |
| Paced Auditory Serial Addition Test (PASAT) - 3-Second Version | Baseline and 12 weeks. | 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. |
| Symbol Digit Modalities Test (SDMT) - Oral Version | Baseline and 12 weeks. | 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. |
| Controlled Oral Word Association Test (COWAT) - Semantic Fluency (Animals Category) | Baseline and 12 weeks. | 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. |
| Controlled Oral Word Association Test (COWAT) - Phonemic Fluency (F-A-S Letters) | Baseline and 12 weeks. | 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. |
| Hospital Anxiety and Depression Scale - Anxiety Subscale (HADS-A) | Baseline and 12 weeks. | 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. |
| Beck Depression Inventory-II (BDI-II) - Total Score | Baseline and 12 weeks. | 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. |
| Fatigue Severity Scale (FSS) - Total Score | Baseline and 12 weeks. | 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. |
| Multiple Sclerosis Quality of Life-54 (MSQoL-54) - Total and Subscale Scores | Baseline and 12 weeks. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recent Life Changes Questionnaire (RLCQ) - Total Score | Baseline and 12 weeks. | 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. |
| Symptom Checklist-90-Revised (SCL-90-R) - Global Severity Index (GSI) | Baseline and 12 weeks. | 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. |
| Cognitive Triad Inventory (CTI) - Total Score | Baseline and 12 weeks. | 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. |
| Intolerance of Uncertainty Scale (IUS) - Total Score | Baseline and 12 weeks. | 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. |
| Social Support Questionnaire (SSQ-6) - Total Score | Baseline and 12 weeks. | 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). |
| Pittsburgh Sleep Quality Index (PSQI) - Total Score | Baseline and 12 weeks. | 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. |
| MRI Lesion Activity and Lesion Load | Baseline and 12 weeks. | 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. |
| Duke-UNC Functional Social Support Questionnaire (DUFSS) - Total Score | Baseline and 12 weeks | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Disease-Modifying and Symptomatic Treatment Status | Baseline and 12 weeks. | 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. |
Countries
Spain
Outcome results
None listed