Next Article in Journal
The Importance of Antipsychotic Treatment in Severe Mental Disorders
Previous Article in Journal
National Real-Time Surveillance System for Suicide Attempts in Uruguay: Results from the First Year of Implementation
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Psychiatry International
Volume 6
Issue 1
10.3390/psychiatryint6010034
psychiatryint-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Depression in Multiple Sclerosis: Lifestyle Interventions as an Additional Therapeutical Approach: A Narrative Review

by
Matea Hudolin
1,*,
Hrvoje Budinčević
1,2,*,
Dunja Degmečić
1,3 and
Vida Demarin
4
1
Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, 31000 Osijek, Croatia
2
Department of Neurology, Sveti Duh University Hospital, 10000 Zagreb, Croatia
3
Department of Psychiatry, University Hospital Center Osijek, 31000 Osijek, Croatia
4
International Institute for Brain Health, 10000 Zagreb, Croatia
*
Authors to whom correspondence should be addressed.
Psychiatry Int. 2025, 6(1), 34; https://doi.org/10.3390/psychiatryint6010034
Submission received: 2 August 2024 / Revised: 4 March 2025 / Accepted: 12 March 2025 / Published: 20 March 2025
Browse Figure
Versions Notes

Abstract

:
Depression is one of the most common comorbidities in people with multiple sclerosis, which reduces the quality of life and treatment adherence. It enhances the risk of disease relapse. After looking through the literature, we summarized the newest recommendations that might be helpful in reducing depression severity by reviewing publications regarding depression and multiple sclerosis published in the last five years. Physical activity and rehabilitation should be recommended. The ketogenic diet showed promising results, yet there are possible health concerns that might evolve after a longer period and should only be carried out under medical supervision. Mindfulness and cognitive and dialectical behavior therapy reduce depression severity and can be recommended to depressive people with multiple sclerosis.

1. Introduction

Every 5 min, a person is diagnosed with multiple sclerosis somewhere in the world, making the population of people with multiple sclerosis about 2.8 million in 2020 with an incidence rate of 2.1 per 100,000 persons/year [1]. Other than being one of the most common comorbidities in people with multiple sclerosis [2], depression is also the most studied one [3]. Furthermore, the most prevalent comorbidities in people with multiple sclerosis include anxiety, hypertension, hyperlipidemia, and chronic lung disease [2,4], which vary depending on the geographical area. In people with multiple sclerosis, comorbidities cause a higher healthcare resource consumption [5]. Depression, next to osteoarthritis, migraines, anxiety, and allergies, is a comorbidity that limits activities and leads to a productivity reduction in this population [6]. Vorobeychik et al. summarized the negative consequences that comorbid depression might have on people with multiple sclerosis, among them being poorer quality of life and weaker adherence to disease-modifying therapies [7,8,9,10]. A further negative influence on the quality of life can come from fatigue, which affects up to 78% of people with multiple sclerosis [11]. An early reduction in depression severity also improves fatigue [12].
Contrary to past work [13], recent research showed that depression also poses a risk of disease relapse [14].
People with multiple sclerosis show high adherence to undertaking interventions [15] and keep to the tools learned as a part of the intervention, even though they may not be fully satisfied with them [16]. An example of how people with multiple sclerosis can retain existing capabilities and also translate them into new settings can be deduced from the work of Chiaravalotti et al., who showed how the COVID pandemic did not significantly worsen the psychological health of people with multiple sclerosis. The authors hypothesized various reasons, one being diligence with infection protection, thus being more comfortable within the pandemic health regulations [17].
This review aimed to summarize non-pharmacological treatment options and lifestyle interventions in treating depression in people with multiple sclerosis.

2. Methods

We searched PubMed under the term multiple sclerosis and depression for research articles (reviews were excluded) published in the last 5 years to make this review (from 1 July 2019 to 1 July 2024).
To strengthen the level of evidence provided, we kept randomized controlled trials and clinical trials as key publications for this manuscript. We added publications in new PubMed searches regarding different subtopics of proposed lifestyle changes to provide a perspective into previous knowledge or clarify the intervention. Exclusion criteria were pharmacological interventions and interventions not targeting depression in people with multiple sclerosis. We also excluded studies on the subpopulation of people with multiple sclerosis. After the literature review, we divided it into new aspects regarding physical activity and rehabilitation and dietary and psychological interventions.

3. Relevant Findings

This narrative review included 58 articles from 89 PubMed articles. The flow chart of the methodology is shown in Figure 1.

3.1. Physical Activity and Rehabilitation

Exercise reduces depressive symptoms. Even though already active controls show a positive impact on depression levels in people with multiple sclerosis, there is still a difference in favoring physical activity [18].
The positive impact of physical activity can also be achieved in a home setting and provide “clinically meaningful improvements in depressive symptoms”. These effects were shown in a study by Flemming et al., who randomized 80 people with multiple sclerosis into a twice-weekly DVD-supported, at-home Pilates or waitlist control group. Depression, fatigue, and anxiety were primary outcomes measured at the baseline and every 2 weeks during the intervention. Successful randomization made it possible that there were no baseline differences in primary outcomes between groups. Pilates significantly lowered depressive symptoms between baseline and each of the following control measurements. The reduction was significantly lower in the Pilates group than in the waitlist group. Pilates also significantly reduced anxiety symptoms and physical symptoms of fatigue. The same results could also be reproduced in an isolated female sample [19].
One of the therapeutic exercises that could also be translated into a home setting is cycling. Tollar et al. showed how cycling positively impacted motor skills and the quality of life in people with multiple sclerosis. They compared five different therapeutical approaches, exergaming, balance, cycling, proprioceptive neuromuscular facilitation, and standard care, with a wait-listed control group and their impact on, among others, clinical and motor symptoms of multiple sclerosis, quality of life, and depression levels. Even though cycling proved to be effective in relieving motor and psychological problems of people with multiple sclerosis and might be practical since it is also possible at home, in direct comparison, exergaming showed a slightly better improvement. It could, therefore, be a choice of preference in a professional therapeutical setting [20].
Even though exercising in a home setting might be a valid option, there is still a social connection component of exercising, which should be kept in mind [21]. Exercising in a group leads to higher benefits in psychological health aspects compared to exercising alone [22]. In a small research study conducted on 20 people with multiple sclerosis, Grazioli et al. compared the effects of combined endurance-strength training with conventional physiotherapy on motor skills as well as on depression levels and quality of life in people with multiple sclerosis. While both therapies showed significant improvements in quality of life, depression was significantly lower just in the combined therapy group, whereas the physiotherapy group showed a positive trend. The authors commented on the significant impact of the combined therapy to the social component of a group setting [22].
Kocica et al. divided a total of 46 patients into two groups, one that participated in a 12-week-long course of intensive circuit class therapy and the other which was a control group. Apart from assessing the physical improvement, Kocica et al. also tested the patients’ depression and fatigue levels. Pre-testing showed no differences between groups. The intervention was highly effective in reducing motor and depressive symptoms and fatigue. The authors postulated that the social component of the group exercise might also contribute to the intervention’s efficiency [21].
Several authors explored the efficiency of different exercise regimes [23,24,25]. Pan et al. compared the effects of practicing Baduanjin and yoga on depression levels in people with multiple sclerosis. Both of the methods showed significant depression reduction. In direct comparison, Baduanjin proved to be more effective. The extent of the fatigue reduction was not identical; both exercise methods successfully reduced fatigue, yet there was no significant difference between the two [23].
Similar to the above-mentioned research of Tollar et al. [20], Hortobagyi et al. also compared exergaming, cycling, balance, and proprioceptive neuromuscular facilitation and their maintenance programs over 2 years [24]. Over this more extended time period, exergaming, which has proven to be efficient in improving physical and mental health [20], has shown to have the most impact on symptoms and quality of life in people with multiple sclerosis [24].
There is a positive correlation between depression and fatigue levels [23]. Both depression and fatigue can be reduced by high-intensity resistance training, as shown by Englund et al. After randomizing their study population into two subgroups according to an intervention frequency of once or twice a week, they looked for a difference in impact regarding different groups. Both once- and twice-a-week-group participants showed a clinically significant reduction in fatigue without a significant difference between the groups. On the other hand, anxiety and physiological aspects of quality of life improved significantly in the twice-a-week group [25]. High-intensity resistance training can also improve cognitive performance [26].
A method that has unfortunately shown to be ineffective in depression reduction or quality of life improvement is the low-frequency pulsed electromagnetic field therapy. Granja-Dominguez et al. randomized 44 relapsing-remitting multiple sclerosis (RRMS) patients with minimal-to-significant disability into receiving pulsed electromagnetic field therapy or placebo therapy for 4 weeks. The primary outcome was fatigue, secondary to walking function, depression, and quality of life. After the treatment ended and 3 months post-intervention was evaluated, there were no differences between the intervention and control groups regarding fatigue levels. The same result was shown regarding gait, depression, and quality of life [27].
Innovative technologies, such as virtual reality and robot-assisted gait training, which help improve both patients’ physical as well as psychological health compared to conventional rehabilitation methods, could, therefore, in the future, be chosen and individually planned for patients with prominent psychological difficulties [28,29]. Galperin et al. randomized 124 people with multiple sclerosis into a treadmill training with a virtual reality group and a treadmill-alone (active control) group. Over 6 weeks, the patients received the exercise 3 times per week. Of the participants, 108 finished the training program and the post-intervention assessment, and 84 completed the 3-month follow-up. Even though positive progress was seen in both groups, information processing speed and attention improved after treadmill training with virtual reality. They remained higher in the three-month follow-up compared to the treadmill alone. Treadmill training with virtual reality also impacted some cognitive processes like attention and verbal fluency, some of which remained better in the 3-month follow. Gait performance improved similarly in both groups and persisted in the 3-month-control [28]. The physical aspect of quality of life improved in both groups, although more in the treadmill-alone groups. In contrast, the mental aspect of life only showed improvement after treadmill training with virtual reality. This was also the only therapeutical option that improved depressive symptoms [28].
Ozsoy-Unubol et al. published their study performed on 37 people with multiple sclerosis, which aimed to compare the effects of robot-assisted gait training and conventional gait training on depression, anxiety, quality of life, and mobility. Both programs proved to be effective, yet robot-assisted gait training was superior in helping fatigue, depression, and anxiety [29].
Table 1 shows the impact of physical activity on depression in people with multiple sclerosis.

3.2. Diet and Supplementation

There is a complex connection between inflammation and multiple psychiatric conditions, among them depression [30]. Mentelzou et al. showed in their review the multiple ways the ketogenic diet could be a promising neuroprotective agent, one of them being a neuroinflammation inhibitor [31]. An influence on neuroinflammatory processes, which has led to antidepressant effects in animal models, has been described for crocin, one of the main components of saffron [32], and N-acetylcysteine [33] in the past. In their study on a mouse model, Xiao et al. hypothesized that the antidepressant activity of crocin stemmed from “suppression of neuroinflammation inhibition and oxidative stress”. Furthermore, crocin also directly increased antioxidant activity [32]. In their study in a rat model, Fan et al. showed, firstly, the detrimental effects and structural damage that chronic stress and depression can produce in rats, such as microglia activation, synapse number reduction, and neural apoptosis. These processes attenuated under N-acetylcysteine supplementation [33]. Furthermore, there was also a reduction of pro-inflammatory cytokines under the N-acetylcysteine supplementation [33], speaking once more for neuroinflammatory pathways underlying depression. Fan et al. concluded that over-activation of oxidative stress is the key step in the neuroinflammatory pathway and that this step should be focused on when trying to prevent further pathophysiological damage to the neurons [33].
Probiotics could also be another approach to modifying the neuroinflammatory processes through the gut-brain axis [34]. In their review article, Suda et Matsuda summarized the pathological (neuroinflammatory) pathways behind depression regarding the gut-brain axis and microbiome but also showed possible therapeutical pathways for the future [34].
New publications regarding the effect of different dietary interventions on depression levels in people with multiple sclerosis are mostly in accordance with the previous research mentioned above: low-saturated fat and modified Paleolithic elimination diets under supplementation [35], ketogenic diet [36], probiotics [37], and saffron [38] supplementation reduce depression in people with multiple sclerosis. That effect could not be seen under N-acetylcysteine augmentation [39].
Shemirani et al. randomized 77 people with multiple sclerosis into groups undergoing low-saturated fat or modified Paleolithic diets over 24 weeks. They analyzed serum B12 vitamin, homocysteine, and folate. The populations of both groups had a significant reduction in depression and anxiety levels. Groups also had significant serum homocysteine reduction and a significant serum vitamin B12 increase. Interestingly, the positive effects on psychological health were not associated with the serum levels of serum homocysteine, folate, or vitamin B12 [35].
Research effects of a ketogenic diet in people with multiple sclerosis showed that age, sex, BMI, prior diet attempts, MS durations, and EDSS were not associated with the likelihood of diet adherence [36], making dietary interventions reasonably feasible in clinical practice. Patients who underwent ketogenic diet intervention over six months had significant BMI, waist circumference, fat mass, fat-free mass, and resting metabolic rate reduction. Their fatigue severity and depression scores were also significantly reduced, and their quality of life increased. Next to the physical aspects of quality of life, the most positive progress was seen in cognitive processes. The ketogenic diet improved the patients’ EDSS and fine motor skills, as the Nine-Hole Peg Test objectively identified. The benefits of the ketogenic diet could also be seen through the reduction of serum levels of leptin, a pro-inflammatory cytokine, with the effects being time-correlated and strongest early in the diet course [36]. Probiotic supplementation over 6 months also impacts serum cytokine levels, next to reducing depression and fatigue levels, as shown by Rahimlou et al. [37].
Bahrami et al. sought to research the effects of saffron supplementation and corrective exercises on depression and quality of life in women with multiple sclerosis. After 12 weeks, they concluded that saffron supplementation or corrective exercises alone already improved depression, but the impact was most significant in the group that received the saffron supplementation in addition to corrective exercises. Therefore, saffron supplementation and physical activity are recommended [38].
Even though previous research showed positive effects of N-acetylcysteine on the attenuation of oxidative stress [33], supplementation with N-acetylcysteine could not reach the depression reduction effect [39]. As shown by Khalatbari Mohseni et al., after 8 weeks of supplementation of 600 mg N-acetylcysteine twice daily, people with multiple sclerosis showed significantly reduced anxiety levels, yet depression levels showed no difference between baseline and post-intervention. As the authors pointed out, when analyzing results, one should consider the study’s limitations (a fairly small sample of 42 patients, relatively short supplementation time, and just one dose in the research) [39].
Kouchaki et al. used high-sensitivity CRP, among others, as a biomarker for successful inflammation reduction under supplementation with saffron components (crocin). Interestingly, and similar to the research conducted with N-acetylcysteine [39], the supplementation that reduces inflammation may still not be sufficient to impact mental health positively or might need more time [40].
Dietary interventions should always be undertaken under supervision, even though a short-term ketogenic diet improved depression levels, fatigue, and quality of life in people with multiple sclerosis, Brenton et al. expressed their reservations about unsupervised and long-term adherence because of potential side effects [36].
Ellagic acid has previously been researched in rodent models of autoimmune encephalitis, representing conditions present in multiple sclerosis, which showed it could relieve neuroinflammation [41]. Supplementation of ellagic acid in humans increases serotonin levels, leads to an improvement in depression scores, and reduces serum levels of nitric oxide, cortisol, and interferon-γ [42], which could indirectly also speak to the (patho)immunological pathway leading to depression.
Table 2 summarizes diet’s impact on depression in people with multiple sclerosis.

3.3. Psychological Support and Therapies

Psychological education for people with multiple sclerosis helps reduce depression, anxiety, and somatization. It should be recommended regularly to maintain and improve the mental health and quality of life of people with multiple sclerosis [43]. Even though they do not have a general impact on anxiety levels, interventions targeting the ability to tolerate uncertainty enable better acceptance of the diagnosis of multiple sclerosis [44].
Mindfulness-based programs seem to be a successful way to attenuate depression [45,46]. Mindfulness-based treatments focus on acceptance instead of actively taking on the maladaptive attitudes of attenuation [47,48]. Cognitive-behavioral therapy emphasizes goal-setting and strives to achieve them; mindfulness is more about “non-striving” [48,49]. In their research about the effects of mindfulness-integrated cognitive behavior therapy on the psychological health of people with multiple sclerosis, Pouyanfard et al. randomized 20 people with multiple sclerosis into an intervention group receiving mindfulness-integrated cognitive behavior therapy and drug therapy and a control group, which received their usual treatment, and showed how mindfulness-integrated cognitive therapy significantly reduced anxiety and depression. After two months, the therapy’s positive effects persisted in the post-intervention control [45]. Senders et al. measured the effects of mindfulness-based stress reduction after 8 weeks and 12 months, comparing it to an education undertaken in the control group. The comparison showed that each of the interventions made a positive impact on the physical health of the group, which was also primarily visible after 12 months, yet there was no significant difference between the groups [46]. Contrary to the reports of long-term effects of mindfulness-based therapy, according to Senders et al. [46], in a study by Morrow et al., the effects of a mindfulness-based intervention did not last up to the 6-month intervention follow-up [50].
Mindfulness therapy has also been shown to improve emotional dysregulation in people with multiple sclerosis [51]. Schirda et al. showed how this can be reached in just 4 weeks of mindfulness-based training [51]. Sylvia et al. compared the effectiveness of an eight-session, web-based, mindfulness-based cognitive therapy (MBCT) program and a brief three-session mindfulness intervention in over 4000 individuals. The study was not conducted exclusively on people with multiple sclerosis. Still, the authors recruited the population from 17 web-based, patient-powered research networks, including subpopulations with a wide range of diseases and traits, making the overall population extremely broad. The primary goal of the research was to explore if the MBCT was superior to a shorter mindfulness intervention in improving overall well-being. Both groups improved overall well-being, and MBCT showed no superiority in the overall study population. However, younger people and those who underwent more seances seemed to benefit the most from MBCT, so the authors suggested that MBCT should be recommended to young people with adherence habits [52]. In their study, Sesel et al. compared a web-based mindfulness program group to a waitlisted control group of people with multiple sclerosis; the intervention group showed significantly more depression reduction. They also assessed if people in the population had a history of depression and concluded that the benefits in those with recurrent depression were more significant compared to patients with no such history [53].
Another possible therapeutical approach comes from research published by Hughes et al., who compared the effects of dialectical behavior therapy (DBT) to facilitate peer support (FPS) for people with multiple sclerosis and their supportive partners [54]. Dialectical behavior therapy combines “individual psychotherapy, group skills, training, telephone coaching, and a therapist consultation team” [55]. After 12 weeks (post-intervention), participants in the DBT group showed significantly greater depression reduction compared to FPS; the effects were not yet long-term and not seen in the follow-up [54]. For example, mindfulness training, as a core element of dialectical behavior therapy, has been proposed as a key component to improve emotion dysregulation in borderline personality disorder [56].
Turner et al. stressed that future research should focus on behavioral activation, as they postulated it may be “one mechanism by which physical activity improves depression in MS” [57].
Jongen et al. researched the effects of an intensive 3-day social cognitive treatment in 158 people with multiple sclerosis. They found that it significantly reduced depression in the short term (one-month follow-up) [58]. Cognitive therapy also improves cognitive performance [59,60]. In their research about the extent of the effects of cognitive therapy in people with multiple sclerosis, Vilou et al. showed how over half of patients undergoing cognitive treatment show significant improvement in at least one aspect of cognitive function [59].
Another possible web-based therapeutical approach could be seen in the unified protocol intervention [60]. “The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) is an emotion-focused, cognitive behavioral intervention consisting of five core modules or components that target temperamental characteristics, particularly neuroticism and resulting emotion dysregulation, underlying all anxiety, depressive, and related disorders” [61]. Nazari et al. exposed 70 people with multiple sclerosis to the unified protocol intervention, which consisted of 12 weekly 2 h sessions about “motivation, psychoeducation, mindfulness, cognitive flexibility, emotion-driven behavior, emotional avoidance, interoceptive exposure, in vivo exposure and relapse prevention”, or treatment-as-usual. The results showed that the unified protocol is an effective therapy for depression and anxiety reduction, which improves emotional regulation [62].
“Transcranial direct current stimulation (tDCS) is a method of brain stimulation involving passing a weak current (1–2 mA) across the cortex using at least two electrodes” [63]. According to evidence-based guidelines and secondary meta-analysis for the use of transcranial direct current stimulation in neurological and psychiatric disorders, tDCS is effective in reducing depression [64]. In people with multiple sclerosis, it improved fatigue and anxiety, possibly through delayed effect or mediated through fatigue, yet it did not improve depression [65], but it remains an option for pain intensity reduction in people with multiple sclerosis with chronic neuropathic pain [66]. Young et al. showed how 5 days of repetitive transcranial direct current stimulation (tDCS) significantly reduced visual analog scores (VAS) in people with multiple sclerosis with chronic neuropathic pain. The significant improvement could be seen up to 2 weeks post-intervention. Even though the patients had pain alleviation, there was no simultaneous reduction in depression and anxiety scores or improvement in quality-of-life scores [66].
Table 3 summarize psychological interventions on depression in multiple sclerosis.

4. Discussion

Both active controls and regular training activity are effective in reducing depression in people with multiple sclerosis, with training being superior [18]. Active controls are also effective, because regular and more frequent contact with healthcare providers contributes to a well-built relationship between them and patients and ensures a stronger feeling of being supported, thus possibly helping patients cope better with the diagnosis of multiple sclerosis. Illness-related uncertainty in people with multiple sclerosis positively correlates with fatigue, anxiety, and depressive symptoms [3].
Flemming et al. showed how Pilates reduced depression and anxiety in people with multiple sclerosis [19]. It has been identified as an effective method to improve physical performance, cognition, and quality of life in this subpopulation [67]. Recently, Pilates has also been introduced as a successful telerehabilitation method for people with multiple sclerosis [68], making it a neuro (tele)rehabilitation “all-rounder”, a method that is accessible and cost-effective. A recent systematic review and meta-analysis of systematic review and meta-analysis of the effectiveness of telerehabilitation in people with multiple sclerosis pointed out exergaming as the most frequent method used among the studies included in the analysis [69]. As its effects are, if not superior [70], comparable to those of conventional physiotherapy, they are also adaptable to every individual patient’s disability level and needs [71], and exergaming should be used routinely in rehabilitating people with multiple sclerosis.
Learmonth et al. showed how an at-home exercise program for people with multiple sclerosis could be put together and is fairly affordable. As a part of the intervention, the patients received a pedometer, elastic resistance bands, DVD, training manual, logbooks, calendar, video-calls, pedometers, elastic resistance bands, DVDs, training manuals, logbooks, calendars, video calls, and newsletters. The study lasted 4 months, with 90% of the participants finishing the program (51 patients), and the total study costs were USD 5331.03. The demographics of the study are also very interesting; participants were mostly female, with a mean age of 48.4 years, and a mean duration of MS of 13.9. [72], which shows that even relatively older patients who may be diagnosed with multiple sclerosis for even a decade might still be relatively easily motivated to exercise at home, which should be considered and used more in the everyday clinical approach.
Even though, in the past, pulsed electromagnetic field therapy was shown to have positive clinical effects on fatigue and quality-of-life improvement in people with multiple sclerosis [73], a more recent study showed no improvement in quality of life, gait, or depression [27]. A need for further research regarding the use of pulsed electromagnetic therapy and its effects on people with multiple sclerosis certainly still exists, as positive reports of its cognition improvement in people with multiple sclerosis now date almost 30 years back [74]. Electromagnetic stimulation has since been found to play a role in neuromodulation and possibly being neuroprotective [75].
Fatigue, depression, and pain have been named a “symptom cluster”. Dysfunctional reward processing had been identified as a shared underlying cause of all three after reviewing neuroimaging and neuroinflammation findings in people with multiple sclerosis suffering from these three symptoms, which is why further investigations should focus more on shared pathological pathways and their therapeutical implications [76].
According to evidence-based guidelines, transcranial direct current stimulation effectively reduces depression [64], meaning one can find more positive than negative reports on the method’s benefits during a literature search. Burkhardt et al. reported no effect on depression severity in people with major depressive disorder after applying transcranial bifrontal direct current as an add-on to SSRIs [77]. One could speculate about the causes of this specific intervention’s failure, but we would like to point out another finding of the mentioned study to stress the importance of the meticulous choice of patients to undergo specific interventions: not only did the intervention group show no advantage compared to the control, sham group, but they also had significantly more (mild) side effects [77]. Patients should always be carefully evaluated, chosen, and informed about the possible adverse reactions to planned interventions.
Limitations of our review are that we haven’t performed a systematic review or meta-analysis on lifestyle modifications as a therapeutic modality for depression in people with multiple sclerosis. Our review was focused on depression in people with multiple sclerosis, and some other important comorbidities were not covered, such as anxiety or cognitive impairment. We analyzed articles published in the last five years on PubMed, so some articles, such as observational studies and expert opinions and articles, have not been included. There was variability in study designs or population selection, which may cause bias. Our review did not analyze the potential bias of pharmacotherapy in addition to lifestyle modification. Despite these limitations, our review showed the latest lifestyle modification options for the treatment of depression in people with multiple sclerosis.

5. Conclusions and Future Recommendations

Regular physical activity should be encouraged in depressive patients with multiple sclerosis. They should also undergo regular physical rehabilitation programs. Even though some dietary interventions may bring some benefits, they should not be made without medical consultation or supervision. Depressive people with multiple sclerosis would also benefit from completing a psycho-educational program, long-term mindfulness or dialectical behavior therapy, cognitive therapy, or a unified protocol program. Patients undergoing these interventions should be carefully evaluated and meticulously chosen, considering the possible side effects. Table 4 shows a summary of recommendations regarding lifestyle interventions for depression in people with multiple sclerosis.
Neurologists and family medicine physicians should be aware of the numerosity of depressive people with multiple sclerosis and implement screening for depressive symptoms into regular appointments. Upon detection of such symptoms, patients should, next to eventual pharmacological therapy and psychiatrist referral, also be included in regular psychological care, including psychoeducational programs, behavior or cognitive therapy, or unified protocol programs. Furthermore, patients should be encouraged to undertake some of the aforementioned lifestyle modifications while maintaining regular control appointments.
Rehabilitation improvement is an important field of multiple sclerosis research, but everyday difficulties that people with multiple sclerosis face sometimes get overlooked, both in research and everyday practice. Exploring the long-term effects of these lifestyle interventions on depression in people with multiple sclerosis or examining potential barriers to implementing these interventions in clinical practice might be useful for providing better care to people with multiple sclerosis.

Author Contributions

Conceptualization, M.H. and H.B.; methodology, M.H. and H.B.; validation, M.H., H.B., D.D. and V.D.; investigation, M.H., H.B. and D.D.; resources, M.H.; writing—original draft preparation, M.H.; writing—review and editing, H.B., D.D. and V.D.; supervision, D.D. and V.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Walton, C.; King, R.; Rechtman, L.; Kaye, W.; Leray, E.; Marrie, R.A.; Robertson, N.; La Rocca, N.; Uitdehaag, B.; van der Mei, I.; et al. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult. Scler. 2020, 26, 1816–1821. [Google Scholar] [CrossRef] [PubMed]
  2. Marrie, R.A.; Fisk, J.D.; Fitzgerald, K.; Kowalec, K.; Maxwell, C.; Rotstein, D.; Salter, A.; Tremlett, H. Etiology, effects and management of comorbidities in multiple sclerosis: Recent advances. Front. Immunol. 2023, 14, 1197195. [Google Scholar] [CrossRef]
  3. Sabin, J.; Salas, E.; Martín-Martínez, J.; Candeliere-Merlicco, A.; Barrero, F.J.; Alonso, A.; Sánchez-Menoyo, J.L.; Borrega, L.; Rodríguez-Rodríguez, M.; Gómez-Gutiérrez, M.; et al. Perceived illness-related uncertainty among patients with mid-stage relapsing-remitting multiple sclerosis. Mult. Scler. Relat. Disord. 2024, 91, 105861. [Google Scholar] [CrossRef] [PubMed]
  4. Marrie, R.A.; Cohen, J.; Stuve, O.; Trojano, M.; Sørensen, P.S.; Reingold, S.; Cutter, G.; Reider, N. A systematic review of the incidence and prevalence of comorbidity in multiple sclerosis: Overview. Mult. Scler. 2015, 21, 263–281. [Google Scholar] [CrossRef]
  5. Cárdenas-Robledo, S.; Otero-Romero, S.; Passarell-Bacardit, M.A.; Carbonell-Mirabent, P.; Sastre-Garriga, J.; Montalban, X.; Tintoré, M. Multiple sclerosis is associated with higher comorbidity and health care resource use: A population-based, case-control study in a western Mediterranean region. Eur. J. Neurol. 2021, 28, 4124–4134. [Google Scholar] [CrossRef]
  6. Chen, J.; Taylor, B.; Winzenberg, T.; Palmer, A.J.; Kirk-Brown, A.; van Dijk, P.; Simpson, S., Jr.; Blizzard, L.; van der Mei, I. Comorbidities are prevalent and detrimental for employment outcomes in people of working age with multiple sclerosis. Mult. Scler. 2020, 26, 1550–1559. [Google Scholar] [CrossRef]
  7. Vorobeychik, G.; Black, D.; Cooper, P.; Cox, A. Multiple sclerosis and related challenges to young women’s health: Canadian expert review. Neurodegener. Dis. Manag. 2020, 10, 1–13. [Google Scholar] [CrossRef] [PubMed]
  8. Berrigan, L.I.; Fisk, J.D.; Patten, S.B.; Tremlett, H.; Wolfson, C.; Warren, S.; Fiest, K.M.; McKay, K.A.; Marrie, R.A.; CIHR Team in the Epidemiology and Impact of Comorbidity on Multiple Sclerosis (ECoMS). Health-related quality of life in multiple sclerosis: Direct and indirect effects of comorbidity. Neurology 2016, 86, 1417–1424. [Google Scholar] [CrossRef]
  9. Tarrants, M.; Oleen-Burkey, M.; Castelli-Haley, J.; Lage, M.J. The impact of comorbid depression on adherence to therapy for multiple sclerosis. Mult. Scler. Int. 2011, 2011, 271321. [Google Scholar] [CrossRef]
  10. Treadaway, K.; Cutter, G.; Salter, A.; Lynch, S.; Simsarian, J.; Corboy, J.; Jeffery, D.; Cohen, B.; Mankowski, K.; Guarnaccia, J.; et al. Factors that influence adherence with disease-modifying therapy in MS. J. Neurol. 2009, 256, 568–576. [Google Scholar] [CrossRef]
  11. Oliva Ramirez, A.; Keenan, A.; Kalau, O.; Worthington, E.; Cohen, L.; Singh, S. Prevalence and burden of multiple sclerosis-related fatigue: A systematic literature review. BMC Neurol. 2021, 21, 468. [Google Scholar] [CrossRef] [PubMed]
  12. Knowles, L.M.; Arewasikporn, A.; Kratz, A.L.; Turner, A.P.; Alschuler, K.N.; Ehde, D.M. Early Treatment Improvements in Depression Are Associated With Overall Improvements in Fatigue Impact and Pain Interference in Adults With Multiple Sclerosis. Ann. Behav. Med. 2021, 55, 833–843. [Google Scholar] [CrossRef] [PubMed]
  13. Kowalec, K.; McKay, K.A.; Patten, S.B.; Fisk, J.D.; Evans, C.; Tremlett, H.; Marrie, R.A.; CIHR Team in Epidemiology and Impact of Comorbidity on Multiple Sclerosis (ECoMS). Comorbidity increases the risk of relapse in multiple sclerosis: A prospective study. Neurology 2017, 89, 2455–2461. [Google Scholar] [CrossRef]
  14. Salter, A.; Kowalec, K.; Fitzgerald, K.C.; Cutter, G.; Marrie, R.A. Comorbidity is associated with disease activity in MS: Findings from the CombiRx trial. Neurology 2020, 95, e446–e456. [Google Scholar] [CrossRef] [PubMed]
  15. Saxby, S.M.; Shemirani, F.; Crippes, L.J.; Ehlinger, M.A.; Brooks, L.; Bisht, B.; Titcomb, T.J.; Rubenstein, L.M.; Eyck, P.T.; Hoth, K.F.; et al. Effects of a Remote Multimodal Intervention Involving Diet, Walking Program, and Breathing Exercise on Quality of Life Among Newly Diagnosed People with Multiple Sclerosis: A Quasi-Experimental Non-Inferiority Pilot Study. Degener Neurol Neuromuscul. Dis. 2024, 14, 1–14. [Google Scholar] [CrossRef]
  16. Alschuler, K.N.; Altman, J.K.; Ehde, D.M. Feasibility and acceptability of a single-session, videoconference-delivered group intervention for pain in multiple sclerosis. Rehabil. Psychol. 2021, 66, 22–30. [Google Scholar] [CrossRef]
  17. Chiaravalloti, N.D.; Amato, M.P.; Brichetto, G.; Chataway, J.; Dalgas, U.; DeLuca, J.; Meza, C.; Moore, N.B.; Feys, P.; Filippi, M.; et al. The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis. J. Neurol. 2021, 268, 1598–1607. [Google Scholar] [CrossRef]
  18. Sadeghi Bahmani, D.; Razazian, N.; Farnia, V.; Alikhani, M.; Tatari, F.; Brand, S. Compared to an active control condition, in persons with multiple sclerosis two different types of exercise training improved sleep and depression, but not fatigue, paresthesia, and intolerance of uncertainty. Mult. Scler. Relat. Disord. 2019, 36, 101356. [Google Scholar] [CrossRef]
  19. Fleming, K.M.; Coote, S.B.; Herring, M.P. Home-based Pilates for symptoms of anxiety, depression and fatigue among persons with multiple sclerosis: An 8-week randomized controlled trial. Mult. Scler. 2021, 27, 2267–2279. [Google Scholar] [CrossRef]
  20. Tollár, J.; Nagy, F.; Tóth, B.E.; Török, K.; Szita, K.; Csutorás, B.; Moizs, M.; Hortobágyi, T. Exercise Effects on Multiple Sclerosis Quality of Life and Clinical-Motor Symptoms. Med. Sci. Sports Exerc. 2020, 52, 1007–1014. [Google Scholar] [CrossRef]
  21. Kocica, J.; Kolcava, J.; Sladeckova, M.; Stourac, P.; Vlckova, E.; Dosbaba, F.; Kratochvilova, J.; Bednarik, J. Intensive Circuit Class Therapy in Patients with Relapsing-Remitting Multiple Sclerosis. J. Rehabil. Med. 2022, 54, jrm00267. [Google Scholar] [CrossRef] [PubMed]
  22. Grazioli, E.; Tranchita, E.; Borriello, G.; Cerulli, C.; Minganti, C.; Parisi, A. The Effects of Concurrent Resistance and Aerobic Exercise Training on Functional Status in Patients with Multiple Sclerosis. Curr. Sports Med. Rep. 2019, 18, 452–457. [Google Scholar] [CrossRef] [PubMed]
  23. Pan, Y.; Huang, Y.; Zhang, H.; Tang, Y.; Wang, C. The effects of Baduanjin and yoga exercise programs on physical and mental health in patients with Multiple Sclerosis: A randomized controlled trial. Complement. Ther. Med. 2022, 70, 102862. [Google Scholar] [CrossRef]
  24. Hortobágyi, T.; Ács, P.; Baumann, P.; Borbély, G.; Áfra, G.; Reichardt-Varga, E.; Sántha, G.; Tollár, J. Comparative Effectiveness of 4 Exercise Interventions Followed by 2 Years of Exercise Maintenance in Multiple Sclerosis: A Randomized Controlled Trial. Arch. Phys. Med. Rehabil. 2022, 103, 1908–1916. [Google Scholar] [CrossRef] [PubMed]
  25. Englund, S.; Piehl, F.; Kierkegaard, M. High-intensity resistance training in people with multiple sclerosis experiencing fatigue: A randomised controlled trial. Mult. Scler. Relat. Disord. 2022, 68, 104106. [Google Scholar] [CrossRef]
  26. Silveira, S.L.; Motl, R.W.; Elmer, D.J.; Botkin, T.; Ontiveros, T.; Williams, S.; Hubbard, E.A. Results of a feasibility and initial efficacy clinical trial of a high-intensity interval training program using adaptive equipment in persons with multiple sclerosis who have walking disability. Mult. Scler. Relat. Disord. 2024, 87, 105695. [Google Scholar] [CrossRef] [PubMed]
  27. Granja-Domínguez, A.; Hochsprung, A.; Luque-Moreno, C.; Magni, E.; Escudero-Uribe, S.; Heredia-Camacho, B.; Izquierdo-Ayuso, G.; Heredia-Rizo, A.M. Effects of pulsed electromagnetic field therapy on fatigue, walking performance, depression, and quality of life in adults with multiple sclerosis: A randomized placebo-controlled trial. Braz. J. Phys. Ther. 2022, 26, 100449. [Google Scholar] [CrossRef]
  28. Galperin, I.; Mirelman, A.; Schmitz-Hübsch, T.; Hsieh, K.L.; Regev, K.; Karni, A.; Brozgol, M.; Cornejo Thumm, P.; Lynch, S.G.; Paul, F.; et al. Treadmill training with virtual reality to enhance gait and cognitive function among people with multiple sclerosis: A randomized controlled trial. J. Neurol. 2023, 270, 1388–1401. [Google Scholar] [CrossRef]
  29. Ozsoy-Unubol, T.; Ata, E.; Cavlak, M.; Demir, S.; Candan, Z.; Yilmaz, F. Effects of Robot-Assisted Gait Training in Patients With Multiple Sclerosis: A Single-Blinded Randomized Controlled Study. Am. J. Phys. Med. Rehabil. 2022, 101, 768–774. [Google Scholar] [CrossRef]
  30. Beurel, E.; Toups, M.; Nemeroff, C.B. The Bidirectional Relationship of Depression and Inflammation: Double Trouble. Neuron 2020, 107, 234–256. [Google Scholar] [CrossRef]
  31. Mentzelou, M.; Dakanalis, A.; Vasios, G.K.; Gialeli, M.; Papadopoulou, S.K.; Giaginis, C. The Relationship of Ketogenic Diet with Neurodegenerative and Psychiatric Diseases: A Scoping Review from Basic Research to Clinical Practice. Nutrients 2023, 15, 2270. [Google Scholar] [CrossRef]
  32. Xiao, Q.; Xiong, Z.; Yu, C.; Zhou, J.; Shen, Q.; Wang, L.; Xie, X.; Fu, Z. Antidepressant activity of crocin-I is associated with amelioration of neuroinflammation and attenuates oxidative damage induced by corticosterone in mice. Physiol. Behav. 2019, 212, 112699. [Google Scholar] [CrossRef]
  33. Fan, C.; Long, Y.; Wang, L.; Liu, X.; Liu, Z.; Lan, T.; Li, Y.; Yu, S.Y. N-Acetylcysteine Rescues Hippocampal Oxidative Stress-Induced Neuronal Injury via Suppression of p38/JNK Signaling in Depressed Rats. Front. Cell Neurosci. 2020, 14, 554613. [Google Scholar] [CrossRef] [PubMed]
  34. Suda, K.; Matsuda, K. How Microbes Affect Depression: Underlying Mechanisms via the Gut-Brain Axis and the Modulating Role of Probiotics. Int. J. Mol. Sci. 2022, 23, 1172. [Google Scholar] [CrossRef] [PubMed]
  35. Shemirani, F.; Titcomb, T.J.; Saxby, S.M.; Eyck, P.T.; Rubenstein, L.M.; Hoth, K.F.; Snetselaar, L.G.; Wahls, T.L. Association of serum homocysteine, folate, and vitamin B12 and mood following the Swank and Wahls elimination dietary interventions in relapsing-remitting multiple sclerosis: Secondary analysis of the WAVES trial. Mult. Scler. Relat. Disord. 2023, 75, 104743. [Google Scholar] [CrossRef] [PubMed]
  36. Brenton, J.N.; Lehner-Gulotta, D.; Woolbright, E.; Banwell, B.; Bergqvist, A.G.C.; Chen, S.; Coleman, R.; Conaway, M.; Goldman, M.D. Phase II study of ketogenic diets in relapsing multiple sclerosis: Safety, tolerability and potential clinical benefits. J. Neurol. Neurosurg. Psychiatry 2022, 93, 637–644. [Google Scholar] [CrossRef]
  37. Rahimlou, M.; Hosseini, S.A.; Majdinasab, N.; Haghighizadeh, M.H.; Husain, D. Effects of long-term administration of Multi-Strain Probiotic on circulating levels of BDNF, NGF, IL-6 and mental health in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled trial. Nutr. Neurosci. 2022, 25, 411–422. [Google Scholar] [CrossRef]
  38. Bahrami, F.; Pour, F.J.; Hassanpour, M.; Saki, M.; Ebrahimzadeh, F.; Jafaripour, L. The effect of saffron and corrective exercises on depression and quality of life in women with multiple sclerosis: A randomized controlled clinical trial. Mult. Scler. Relat. Disord. 2023, 79, 105038. [Google Scholar] [CrossRef]
  39. Khalatbari Mohseni, G.; Hosseini, S.A.; Majdinasab, N.; Cheraghian, B. Effects of N-acetylcysteine on oxidative stress biomarkers, depression, and anxiety symptoms in patients with multiple sclerosis. Neuropsychopharmacol. Rep. 2023, 43, 382–390. [Google Scholar] [CrossRef]
  40. Kouchaki, E.; Rafiei, H.; Ghaderi, A.; Azadchehr, M.J.; Safa, F.; Omidian, K.; Khodabakhshi, A.; Vahid, F.; Rezapoor-Kafteroodi, B.; Banafshe, H.R.; et al. Effects of crocin on inflammatory biomarkers and mental health status in patients with multiple sclerosis: A randomized, double-blinded clinical trial. Mult. Scler. Relat. Disord. 2024, 83, 105454. [Google Scholar] [CrossRef]
  41. Kiasalari, Z.; Afshin-Majd, S.; Baluchnejadmojarad, T.; Azadi-Ahmadabadi, E.; Esmaeil-Jamaat, E.; Fahanik-Babaei, J.; Fakour, M.; Fereidouni, F.; Ghasemi-Tarie, R.; Jalalzade-Ogvar, S.; et al. Ellagic acid ameliorates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis: Involvement of NLRP3 and pyroptosis. J. Chem. Neuroanat. 2021, 111, 101891. [Google Scholar] [CrossRef]
  42. Hajiluian, G.; Karegar, S.J.; Shidfar, F.; Aryaeian, N.; Salehi, M.; Lotfi, T.; Farhangnia, P.; Heshmati, J.; Delbandi, A.A. The effects of Ellagic acid supplementation on neurotrophic, inflammation, and oxidative stress factors, and indoleamine 2, 3-dioxygenase gene expression in multiple sclerosis patients with mild to moderate depressive symptoms: A randomized, triple-blind, placebo-controlled trial. Phytomedicine 2023, 121, 155094. [Google Scholar] [CrossRef] [PubMed]
  43. Oz, H.S.; Oz, F. A psychoeducation program for stress management and psychosocial problems in multiple sclerosis. Niger J Clin. Pract. 2020, 23, 1598–1606. [Google Scholar] [CrossRef] [PubMed]
  44. Molton, I.R.; Koelmel, E.; Curran, M.; von Geldern, G.; Ordway, A.; Alschuler, K.N. Pilot intervention to promote tolerance for uncertainty in early multiple sclerosis. Rehabil. Psychol. 2019, 64, 339–350. [Google Scholar] [CrossRef] [PubMed]
  45. Pouyanfard, S.; Mohammadpour, M.; ParviziFard, A.A.; Sadeghi, K. Effectiveness of mindfulness-integrated cognitive behavior therapy on anxiety, depression and hope in multiple sclerosis patients: A randomized clinical trial. Trends Psychiatry Psychother. 2020, 42, 55–63. [Google Scholar] [CrossRef]
  46. Senders, A.; Hanes, D.; Bourdette, D.; Carson, K.; Marshall, L.M.; Shinto, L. Impact of mindfulness-based stress reduction for people with multiple sclerosis at 8 weeks and 12 months: A randomized clinical trial. Mult. Scler. 2019, 25, 1178–1188. [Google Scholar] [CrossRef]
  47. Ellis, A. Rational-emotive therapy and cognitive behavior therapy: Similarities and differences. Cogn. Ther. Res. 1980, 4, 325–340. [Google Scholar] [CrossRef]
  48. Hofmann, S.G.; Gómez, A.F. Mindfulness-Based Interventions for Anxiety and Depression. Psychiatr. Clin. N. Am. 2017, 40, 739–749. [Google Scholar] [CrossRef]
  49. Baer, R.A. Mindfulness training as a clinical intervention: A conceptual and empirical review. Clin. Psychol. Sci. Pract. 2003, 10, 125–143. [Google Scholar] [CrossRef]
  50. Morrow, S.A.; Riccio, P.; Vording, N.; Rosehart, H.; Casserly, C.; MacDougall, A. A mindfulness group intervention in newly diagnosed persons with multiple sclerosis: A pilot study. Mult. Scler. Relat. Disord. 2021, 52, 103016. [Google Scholar] [CrossRef]
  51. Schirda, B.; Duraney, E.; Lee, H.K.; Manglani, H.R.; Andridge, R.R.; Plate, A.; Nicholas, J.A.; Prakash, R.S. Mindfulness training for emotion dysregulation in multiple sclerosis: A pilot randomized controlled trial. Rehabil. Psychol. 2020, 65, 206–218. [Google Scholar] [CrossRef] [PubMed]
  52. Sylvia, L.G.; Lunn, M.R.; Obedin-Maliver, J.; McBurney, R.N.; Nowell, W.B.; Nosheny, R.L.; Mularski, R.A.; Long, M.D.; Merkel, P.A.; Pletcher, M.J.; et al. Web-Based Mindfulness-Based Interventions for Well-being: Randomized Comparative Effectiveness Trial. J. Med. Internet Res. 2022, 24, e35620. [Google Scholar] [CrossRef] [PubMed]
  53. Sesel, A.L.; Sharpe, L.; Beadnall, H.N.; Barnett, M.H.; Szabo, M.; Naismith, S.L. A randomized controlled trial of a web-based mindfulness programme for people with MS with and without a history of recurrent depression. Mult. Scler. 2022, 28, 1392–1401. [Google Scholar] [CrossRef]
  54. Hughes, A.J.; Botanov, Y.; Beier, M. Dialectical behavior therapy skills training for individuals with multiple sclerosis and their support partners: A pilot randomized controlled trial. Mult. Scler. Relat. Disord. 2022, 59, 103481. [Google Scholar] [CrossRef] [PubMed]
  55. Linehan, M.M.; Wilks, C.R. The Course and Evolution of Dialectical Behavior Therapy. Am. J. Psychother. 2015, 69, 97–110. [Google Scholar] [CrossRef]
  56. Schmidt, C.; Soler, J.; Vega, D.; Pascual, J.C. Practice matters: The role of mindfulness skills in emotion dysregulation in borderline personality disorder. J. Context. Behav. Sci. 2024, 32, 100756. [Google Scholar] [CrossRef]
  57. Turner, A.P.; Hartoonian, N.; Hughes, A.J.; Arewasikporn, A.; Alschuler, K.N.; Sloan, A.P.; Ehde, D.M.; Haselkorn, J.K. Physical activity and depression in MS: The mediating role of behavioral activation. Disabil. Health J. 2019, 12, 635–640. [Google Scholar] [CrossRef]
  58. Jongen, P.J.; van Mastrigt, G.A.; Heerings, M.; Visser, L.H.; Ruimschotel, R.P.; Hussaarts, A.; Duyverman, L.; Valkenburg-Vissers, J.; Cornelissen, J.; Bos, M.; et al. Effect of an intensive 3-day social cognitive treatment (can do treatment) on control self-efficacy in patients with relapsing remitting multiple sclerosis and low disability: A single-centre randomized controlled trial. PLoS ONE 2019, 14, e0223482. [Google Scholar] [CrossRef]
  59. Vilou, I.; Bakirtzis, C.; Artemiadis, A.; Ioannidis, P.; Papadimitriou, M.; Konstantinopoulou, E.; Aretouli, E.; Messinis, L.; Nasios, G.; Dardiotis, E.; et al. Computerized cognitive rehabilitation for treatment of cognitive impairment in multiple sclerosis: An explorative study. J. Integr. Neurosci. 2020, 19, 341–347. [Google Scholar] [CrossRef]
  60. Blair, M.; Goveas, D.; Safi, A.; Marshall, C.; Rosehart, H.; Orenczuk, S.; Morrow, S.A. Does cognitive training improve attention/working memory in persons with MS? A pilot study using the Cogmed Working Memory Training program. Mult. Scler. Relat. Disord. 2021, 49, 102770. [Google Scholar] [CrossRef]
  61. Barlow, D.H.; Farchione, T.J.; Bullis, J.R.; Gallagher, M.W.; Murray-Latin, H.; Sauer-Zavala, S.; Bentley, K.H.; Thompson-Hollands, J.; Conklin, L.R.; Boswell, J.F.; et al. The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders Compared With Diagnosis-Specific Protocols for Anxiety Disorders: A Randomized Clinical Trial. JAMA Psychiatry 2017, 74, 875–884. [Google Scholar] [CrossRef] [PubMed]
  62. Nazari, N.; Sadeghi, M.; Ghadampour, E.; Mirzaeefar, D. Transdiagnostic treatment of emotional disorders in people with multiple sclerosis: Randomized controlled trial. BMC Psychol. 2020, 8, 114. [Google Scholar] [CrossRef] [PubMed]
  63. Chase, H.W.; Boudewyn, M.A.; Carter, C.S.; Phillips, M.L. Transcranial direct current stimulation: A roadmap for research, from mechanism of action to clinical implementation. Mol. Psychiatry 2020, 25, 397–407. [Google Scholar] [CrossRef] [PubMed]
  64. Fregni, F.; El-Hagrassy, M.M.; Pacheco-Barrios, K.; Carvalho, S.; Leite, J.; Simis, M.; Brunelin, J.; Nakamura-Palacios, E.M.; Marangolo, P.; Venkatasubramanian, G.; et al. Evidence-Based Guidelines and Secondary Meta-Analysis for the Use of Transcranial Direct Current Stimulation in Neurological and Psychiatric Disorders. Int. J. Neuropsychopharmacol. 2021, 24, 256–313. [Google Scholar] [CrossRef]
  65. Chalah, M.A.; Grigorescu, C.; Padberg, F.; Kümpfel, T.; Palm, U.; Ayache, S.S. Bifrontal transcranial direct current stimulation modulates fatigue in multiple sclerosis: A randomized sham-controlled study. J. Neural. Transm. 2020, 127, 953–961. [Google Scholar] [CrossRef]
  66. Young, J.; Zoghi, M.; Khan, F.; Galea, M.P. The Effect of Transcranial Direct Current Stimulation on Chronic Neuropathic Pain in Patients with Multiple Sclerosis: Randomized Controlled Trial. Pain. Med. 2020, 21, 3451–3457. [Google Scholar] [CrossRef]
  67. Marques, K.A.P.; Trindade, C.B.B.; Almeida, M.C.V.; Bento-Torres, N.V.O. Pilates for rehabilitation in patients with multiple sclerosis: A systematic review of effects on cognition, health-related physical fitness, general symptoms and quality of life. J. Bodyw. Mov. Ther. 2020, 24, 26–36. [Google Scholar] [CrossRef]
  68. Eldemir, K.; Guclu-Gunduz, A.; Eldemir, S.; Saygili, F.; Ozkul, C.; Irkec, C. Effects of Pilates-based telerehabilitation on physical performance and quality of life in patients with multiple sclerosis. Disabil. Rehabil. 2024, 46, 1807–1814. [Google Scholar] [CrossRef]
  69. Doherty, F.; Lynch, P.; Powell, P.; Monaghan, K. Feasibility and effectiveness of telerehabilitation on mobility and balance function in multiple sclerosis: A systematic review and meta-analysis. J. Neurol. Sci. 2024, 466, 123214. [Google Scholar] [CrossRef]
  70. Moeinzadeh, A.M.; Calder, A.; Petersen, C.; Hoermann, S.; Daneshfar, A. Comparing virtual reality exergaming with conventional exercise in rehabilitation of people with multiple sclerosis: A systematic review. Neuropsychol. Rehabil. 2023, 33, 1430–1455. [Google Scholar] [CrossRef]
  71. Elhusein, A.M.; Fadlalmola, H.A.; Awadalkareem, E.M.; Alhusain, E.Y.M.; Alnassry, S.M.; Alshammari, M.; Abdulrahman, E.E.; Fadila, D.E.S.; Ibrahim, F.M.; Saeed, A.A.M.; et al. Exercise-based gaming in patients with multiple sclerosis: A systematic review and meta-analysis. Belitung Nurs. J. 2024, 10, 1–14. [Google Scholar] [CrossRef] [PubMed]
  72. Learmonth, Y.C.; Adamson, B.C.; Kinnett-Hopkins, D.; Bohri, M.; Motl, R.W. Results of a feasibility randomised controlled study of the guidelines for exercise in multiple sclerosis project. Contemp. Clin. Trials 2017, 54, 84–97. [Google Scholar] [CrossRef] [PubMed]
  73. Lappin, M.S.; Lawrie, F.W.; Richards, T.L.; Kramer, E.D. Effects of a pulsed electromagnetic therapy on multiple sclerosis fatigue and quality of life: A double-blind, placebo controlled trial. Altern. Ther. Health Med. 2003, 9, 38–48. [Google Scholar] [PubMed]
  74. Sandyk, R. Progressive cognitive improvement in multiple sclerosis from treatment with electromagnetic fields. Int. J. Neurosci. 1997, 89, 39–51. [Google Scholar] [CrossRef]
  75. Guerriero, F.; Ricevuti, G. Extremely low frequency electromagnetic fields stimulation modulates autoimmunity and immune responses: A possible immuno-modulatory therapeutic effect in neurodegenerative diseases. Neural Regen. Res. 2016, 11, 1888–1895. [Google Scholar] [CrossRef]
  76. Heitmann, H.; Andlauer, T.F.M.; Korn, T.; Mühlau, M.; Henningsen, P.; Hemmer, B.; Ploner, M. Fatigue, depression, and pain in multiple sclerosis: How neuroinflammation translates into dysfunctional reward processing and anhedonic symptoms. Mult. Scler. 2022, 28, 1020–1027. [Google Scholar] [CrossRef]
  77. Burkhardt, G.; Kumpf, U.; Crispin, A.; Goerigk, S.; Andre, E.; Plewnia, C.; Brendel, B.; Fallgatter, A.; Langguth, B.; Abdelnaim, M.; et al. Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): A triple-blind, randomised, sham-controlled, multicentre trial. Lancet 2023, 402, 545–554. [Google Scholar] [CrossRef]
Psychiatryint 06 00034 g001
Figure 1. Flow chart of the methodology.
Figure 1. Flow chart of the methodology.
Psychiatryint 06 00034 g001
Table 1. Physical activities in depression reduction.
Table 1. Physical activities in depression reduction.
AuthorsInterventionOutcomes
Flemming et al. (RCT) [19]DVD Pilates 2×/week vs.
wait-listed control		Pilates significantly reduced depression, anxiety, and fatigue
Tollar et al. (RCT) [20]Exergaming vs. cycling vs. balance
vs. PNF		All, but PNF improves motor symptoms and quality of life
Grazioli et al. (RCT) [22]Combined endurance-strength
training vs. conventional
physiotherapy		Both improve quality of life,
depression significantly reduced under combined-therapy
Kocica et al. (RCT) [21]Intensive circuit class therapy vs.
control		Reduced motor symptoms,
depression and fatigue after
intervention
Pan et al. (RCT) [23]Baduanjin vs. yogaDepression reduced
(Baduanjin > yoga)
Hortobayagi et al. (RCT) [24]Exergaming vs. cycling vs.
balance vs. PNF		exergaming most impact on
quality of life and
symptom-improvement
Englund et al. (RCT) [25]High-intensity resistance
training 1×/week vs. 2×/week		Both reduce fatigue, anxiety and quality of life better in the 2×/week group
Galperin et al. (RCT) [28]Treadmill training with vs.
without virtual reality		Information processing speed and attention better with virtual reality
Ozsoy-Unubol et al.
(RCT) [29]		Robot-assisted vs. conventional
gait training		Both effective, robot-assisted
superior in depression and
anxiety reduction
PNF—Proprioceptive neuromuscular facilitation; RCT—randomized controlled/clinical trial.
Table 2. Dietary interventions in depression reduction.
Table 2. Dietary interventions in depression reduction.
AuthorsInterventionOutcomes
Shemirani et al. (RCT) [35]Low saturated fat and modified
Paleolithic elimination diet
under supplementation
over 24 weeks		Reduced depression and anxiety
Brenton et al. (RCT) [36]Ketogenic diet over 6 monthsReduced depression and anxiety, quality of life increased
Rahimlou et al. (RCT) [37]Probiotic supplementation
over 6 months		Reduced depression and anxiety
Bahrami et al. (RCT) [38]Saffron supplementation vs.
corrective exercises vs saffron
+ corrective exercises
over 12 weeks		All reduce depression, combined intervention superior
Khalatbari Mohseni et al.
(RCT) [39]		N-acetylcisteine
supplementation over 8 weeks		Reduced anxiety
Hajiluian et al. (RCT) [42]Ellagic acid over 12 weeksReduced depression
RCT—randomized controlled/clinical trial.
Table 3. Psychological interventions in depression reduction.
Table 3. Psychological interventions in depression reduction.
AuthorsInterventionOutcomes
Oz et al. (RCT) [43]Psychological educationReduced depression, anxiety, and somatization
Pouyanfard et al.
(RCT) [45] 		Mindfulness-integrated
cognitive behavior therapy
and drug therapy		Reduced depression and anxiety
Senders et al.
(RCT) [46]		Mindfulness-based stress
reduction		Improved perceived stress,
anxiety, depression, fatigue
Morrow et al. (RCT) [50]Mindfulness-based
intervention		Improved depression and coping
Schirda et al. (RCT) [51] Mindfulness-based training
or adaptive cognitive training		Mindfulness reduced emotional
dysregulation
Sesel et al. (RCT) [53]Web-based mindfulness
program group		Reduced depression
Hughes et al. (RCT) [54]Dialectical behavior therapyReduced depression
Jongen et al. (RCT) [58]3-day social cognitive treatmentReduced depression
Nazari et al. (RCT) [62]Unified protocolReduced depression and anxiety,
improved emotional regulation
RCT—Randomized controlled/clinical trial.
Table 4. Summary of recommendations regarding lifestyle interventions for depression in people with multiple sclerosis.
Table 4. Summary of recommendations regarding lifestyle interventions for depression in people with multiple sclerosis.
Lifestyle ModificationRecommendation
Physical activityRegular home or group exercises
regular physical rehabilitation
Diet *Ketogenic diet, probiotics, saffron
Psychological careEducation, mindfulness-based
interventions, dialectical behavior therapy, cognitive therapy,
unified protocol intervention
* under medical supervision.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Hudolin, M.; Budinčević, H.; Degmečić, D.; Demarin, V. Depression in Multiple Sclerosis: Lifestyle Interventions as an Additional Therapeutical Approach: A Narrative Review. Psychiatry Int. 2025, 6, 34. https://doi.org/10.3390/psychiatryint6010034

AMA Style

Hudolin M, Budinčević H, Degmečić D, Demarin V. Depression in Multiple Sclerosis: Lifestyle Interventions as an Additional Therapeutical Approach: A Narrative Review. Psychiatry International. 2025; 6(1):34. https://doi.org/10.3390/psychiatryint6010034

Chicago/Turabian Style

Hudolin, Matea, Hrvoje Budinčević, Dunja Degmečić, and Vida Demarin. 2025. "Depression in Multiple Sclerosis: Lifestyle Interventions as an Additional Therapeutical Approach: A Narrative Review" Psychiatry International 6, no. 1: 34. https://doi.org/10.3390/psychiatryint6010034

APA Style

Hudolin, M., Budinčević, H., Degmečić, D., & Demarin, V. (2025). Depression in Multiple Sclerosis: Lifestyle Interventions as an Additional Therapeutical Approach: A Narrative Review. Psychiatry International, 6(1), 34. https://doi.org/10.3390/psychiatryint6010034

Article Metrics

Back to TopTop