Design
This study is a randomized controlled clinical trial. The study is registered in ClinicalTrials.gov registry as NCT02611401.
Setting
Participants will be enrolled at the CReSM Unit (Regional Reference Centre for Multiple Sclerosis), affiliated with the San Luigi University Hospital of Orbassano, Italy, which includes about 1500 patients with MS.
The study protocol is approved by the Medical Ethics Committee of San Luigi Gonzaga University Hospital.
Participants
The subjects of the study will be 88 patients with MS and depressive symptoms that will be pre-screened from a catchment group of about 600 patients using the Beck Depression Inventory-II (BDI-II). Those who have a score on BDI-II greater than 13 (considered the best approach to screening for depression in MS patients following the Goldman Consensus Group) [12] will be assessed with the other psychological measures.
Inclusion criteria are as follows:—definite diagnosis of MS (Mc Donald Criteria) [30] evaluated by a neurologist of the CReSM Unit at least 6 months prior the beginning of the study;—relapsing-remitting and secondary progressive disease;—age of 18–65 years;—clinically inactive phase of the disease;—an Expanded Disability Status Scale (EDSS) score lower than 6.5;—fluent Italian speaker;—legal capacity to consent to the treatment;—willingness to abstain from or to suspend all concomitant psychological treatment;—suspension of all psychotropic medications at least 1 month before the treatment or maintenance at baseline level throughout the study.
Exclusion criteria are as follows:—current severe Major Depressive Disorder (as assessed by Structured Clinical Interview-DSM-IV (SCID);—severe suicidality, including ideation, plan, and intent;—current serious psychological and psychiatric disorders, including psychotic disorders, bipolar disorders, active substance abuse (as assessed by the SCID);—presence of overt dementia;—corticosteroid treatment during the previous 30 days;—other serious medical disorders in addition to MS;—current pregnancy.
The research protocol will be proposed to patients who will meet the inclusion criteria, with an explanation of the aims of the study and declaring the possibility that they are assigned by random allocation to MBI group or to control group. Patients who will give informed consent will be included in the study.
Randomization and blinding
Patients will be randomly allocated to one of the two conditions: MBI and active control group. Patients will be randomized to the intervention or control group with a 1:1 ratio, using a block-wise randomization sequence (block size of 4 and 6).
The sequence will be determined by an independent researcher, blind to initial assessment to ensure allocation concealment, using a random number generator (www.randomizer.org).
Treatment assignment will be communicated to the patients by the study coordinator to ensure the blinding of the evaluators.
One family member or caregiver for each patient is asked to join the group the patient has been assigned to. Because it is not possible to stratify for this variable, and as it is not our primary outcome, we expect that due to randomization the proportion of caregivers participating in the study will be distributed randomly and equally in both groups.
Assessments
All patients in the care of the CReSM are evaluated by neurologists with the EDSS (Expanded Disability Status Scale). The psychological assessment will be performed with the same timing and tools: at baseline (T0), after treatment (T1) and 6 months after the end of the group intervention (T2). The psychological assessment of the patients entering the study will be performed by trained Clinical Psychologists with more than 3 years of clinical practice in the liaison setting. The psychological assessment will be independent and blind to treatment, and will encompass the administration of the following clinical interview and self-report questionnaires.
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Structured Clinical Interview-DSM-IV (SCID-IV) [31]: is a well-validated, semi-structured interview, which covers the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for adult psychopathology.
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Beck Depression Inventory-II (BDI) [32]: it is a 21-item self-report instrument that assesses the presence and severity of symptoms consistent with the criteria of the DSM-IV. Each item is scored on a 4 point scale ranging from 0 to 3 with total scores ranging from 0 to 63, where higher scores are indicative of higher levels of depression. The Consensus Group for depression in MS [12] and the American Academy of Neurology [13] stated that the best approach to screening for depression in general MS populations is to use the BDI-II, with a cut-off score of 13.
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Functional Assessment of Multiple Sclerosis (FAMS) [33]: it is a self-report scale designed to assess six primary aspects of QOL of patients with MS: Mobility, Symptoms, Emotional Well-Being, General Contentment Thinking and Fatigue, and Family/Social Well-Being.
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Beck Anxiety Inventory (BAI) [34]: is a 21-item self-report measure that assesses cognitive, somatic, and affective anxiety symptom severity. Each item is rated on a Likert scale from 0 to 3, and the total BAI score can range from 0 to 63, where higher scores are indicative of higher levels of anxiety.
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Fatigue Severity Scale (FSS) [35]: is a self-administered questionnaire with 9 items investigating the severity of fatigue in different situations during the past week. This items are designed to differentiate fatigue from clinical depression.
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Inventory of Interpersonal Problems (IIP) [36]: is a self-report instrument that identifies a person’s most salient interpersonal difficulties. The IIP contains 64 statements describing common interpersonal problems.
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Brief Illness Perception Questionnaire (IPQ-Brief) [37]. It is a nine item self-report measure that is used to assess the major components of illness perceptions. The questionnaire assesses each dimension using a single-item scale from 0 to 10.
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Perceived Stress Scale (PSS) [38]. It is a 10-item measure of the degree to which situations in one’s life are appraised as stressful. The items refer to people’s subjective appraisals of events.
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Post Traumatic Growth Inventory (PTGI) [39], a 21-item instrument for assessing positive outcomes in people who have experienced traumatic events. It measures five domains or factors: relating to others, new possibilities, personal strength, spiritual change, and a deeper appreciation of life.
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Five Facet Mindfulness Questionnaire (FFMQ) [40], a 39-item self-report questionnaire measuring five unique facets associated with the overarching construct of mindfulness disposition. The facets included are observing, describing, acting with awareness, nonjudgment, and nonreactivity.
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A clinical diary of the homework practice: it is a clinical diary regarding frequency and duration of homework assigned in the group sessions, that patients are asked to fill out every time they spent time on homework practice.
Caregivers will be asked to complete the same self-report measures administered to the patients, except for the FSS and the IPQ-Brief, which are related to the disease. Instead of FAMS, caregivers will complete the WHO-Quality of Life Brief [41].
Intervention
Treatments will be independent and blinded from the clinical psychologists conducting the clinical assessments. The experimental group will undergo a 8 weekly sessions of 3 h each with a group based Mindfulness Based Intervention. The control group will follow the same structure as the Mindfulness Based Intervention.
Mindfulness based intervention (MBI)
The MBI is based on Mindfulness Based Stress Reduction (MBSR) [42] and Mindfulness Based Cognitive Therapy (MBCT [43] protocols. The MBI comprises an 8-week group program. Participants will took part in a 3 h single weekly sessions, and there will be also an additional all-day session of 7 h. Each session will cover specific exercises and topics within the context of mindfulness practice and training (body scan, breath meditation, walking meditation, yoga exercises). Participants will be required to carry out daily 45-min homework assignments, which consist on mindfulness exercises and mindfulness applications in everyday life. We will attempt to objectively verify the execution of homework practice through the clinical diary.
In order to maximize the clinical utility in people with MS suffering from depressive symptoms, we will tailor mindfulness intervention on the needs of this specific population [44].
We will apply a modified MBSR protocol integrated with techniques from Sensorimotor Psychotherapy (SP) [45], in which:
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particular emphasis will be paid to somatic resources (grounding, centering, boundaries, lengthening the spine, body self-soothing techniques, etc.) to stabilize the emotional state to prepare and sustain the mindful disposition;
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explanation of stress response will be integrated with the concept of “window of tolerance” [46], that is the range of optimal arousal which is necessary to stay in touch with the present moment experience. This concept allows a more precise awareness of the arousal state, recognizing hyper-arousal and hypo-arousal symptoms, and consequently to manage them more effectively;
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considering the attention deficits, which may be due both to neuropsychological deficits and to the depression itself, great attention is paid to attention training;
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considering interpersonal deficits in depression, interpersonal mindful listening is specifically addressed, developing the capacity to listen in a mindful state, creating a space inside to observe in a compassionate and non-judgmental way sensations, emotions and thoughts evoked by the other’s narration;
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great treatment emphasis will be paid on acceptance and self-compassion, and specific tools are used to increase it, such assessment and decentering of negative cognitions, and mindful body self- touch, becoming aware of sensations, feelings, thoughts and needs in the intimate relationship with the self.
MBI groups will be delivered by a psychotherapist with mindfulness training experience, who is experienced in working with people with MS.
Active control group
Our control group is based on the active control group of the study of Grossman et al. [47].
This intervention was designed to control for the non-specific elements of the MBI treatment. It will be based on a psycho-educational framework and will include some relaxation techniques.
In each session is discussed a MS-related topic. Relaxation and gentle stretching exercises will be proposed at the end of each session. Homework and the material (photocopies, slides, etc.) discussed in group sessions is left to each participant to encourage participants to practice exercises between sessions. This intervention will follow the same structure and weekly format of the MBI intervention. The only difference will be the absence of an all-day session. Each component has its counterpart in the MBI curriculum, but emphasis is placed upon not describing or training mindfulness skills to the control group. The groups will be delivered by a psychotherapist with relaxation training experience, who is experienced in working with people with MS.
Outcome measures and statistical analysis
Primary outcome measures will be: 1) the improvements of BDI-II score from T0 to T2; 2) the proportion of participants at T2 that do not have a BDI-II score greater than 13.
Secondary outcome measures will be the comparison of the scores of FAMS, BAI, FSS, IIP, IPQ-Brief, PSS, PTGI and FFMQ of the two groups at T0, T1 and T2. Another secondary outcome aim will be the reduction of psychological symptoms (BDI-II, BAI, IIP, PSS, PTGI) and a reduction in QoL (WHOQoL-Brief) in caregivers of patients with MS.
The efficacy of MBI will be evaluated by comparing the results to different instruments administered to patients before participating at MBI (T0), after MBI (T1) and at the 6-month follow-up (T2) and by comparing these results with those of patients who were included in the active control group. Intention to treat analyses will be used.
A longitudinal (within subjects) and cross sectional (between subjects) evaluation of our outcome measures will be performed through a repeated measures multivariate analysis of covariance (ANCOVA) using the SPSS GLM procedure. The pre-treatment value will be the covariate, and the treatment condition will be the inter-subjects factor. The intra-subject factor will be a time condition, relating to changes from post-treatment to 6-month follow-up.
The proportion of participants at T1 and T2 no longer meeting the BDI-II cut-off criteria for depression will be evaluated through the Chi square test.
Power calculation
The sample size calculation is based on the primary outcomes for patients with MS.
Statistical power calculation was based on previous studies [28, 48]: assuming power =0.80 and 0.05 significance, a minimal sample size of 44 patients/group will be required, based on an effect size of 0.54.
To obtain the 88 patients needed for the study, it is expected to do the screening of at least 600 patients. On the basis of the information that is available on the prevalence of depression in MS patients, on the average 25 % in previous studies, this number should guarantee there will be at least 150 participants. The number of refusals and treatment interruptions is estimated at not above 40 % which leads to about 90 cases.