*2.4. Ethics Procedure*

A favorable assessment was obtained from the Ethics Committee of the University of Malaga (CEUMA) with registration number 32–2021-H and the Ethics Committee of the Provincial Research of Malaga with code 5002V01. Likewise, the participants in this study completed and signed an informed consent form detailing the entire procedure and the protection of their data. This study respected all the ethical principles for experimentation and clinical research in humans of the Declaration of Helsinki (World Medical Association) and other organizations [32].

## *2.5. Statistics*

SPSS 25.0v software (IBM Corp., Armonk, NY, USA) was used to perform the statistical analysis, reporting an alpha error of 0.05 for a confidence interval (CI) of 95%.

The normality of the quantitative data was demonstrated using the Kolmogorov– Smirnov test showing a *p*-value of less than 0.05 and was described as mean ± standard deviation (SD) and range (minimum–maximum). The contrasts were compared with Student's *t*-test or the Mann–Whitney U test for independent samples. The differences between both groups were contrasted with the Chi square test (BDI category).

### **3. Results**

The data obtained showed a normal distribution (*p* > 0.05) except in the ranges of depression. The investigation was completed with a sample of 102 subjects divided into *n* = 51 for the case group and *n* = 51 for the control group, being divided and matched according to age, sex, and BMI. As can be seen in Table 1, there were no statistically significant differences (*p* > 0.05) between both groups for the descriptive data.


**Table 1.** Descriptive and socio-demographic data of the sample.

Comparison of the demographic characteristics of the total sample, MS with foot pain and healthy matched MS with normalized reference values BMI: Body mass index; \* Mean ± standard deviation, range (min-max), and Student's *t* test were applied for independent samples. In all analyses, *p* < 0.05 (with a 95% confidence interval) was considered statistically significant and † Student' *t*-test was applied for independent samples. ‡ The Chi-square test was used.

All the participants (*n* = 116) presented the characteristics described in Table 1. It can be seen that the years of evolution of MS were high according to the mean (12.55 ± 8.53), and the type of MS that was most present in the study was remittent–recurring (93.1%).

Table 2 shows a statistically significant difference (*p* < 0.05) in the BDI scores between both groups. The highest scores correspond to subjects with MS (BDI = 9.52 ± 7.70 points) and the lowest scores for the control group (BDI = 5.03 ± 5.14). Statistically significant differences (*p* < 0.001) were found for the BDI categories in the MS group compared to the non-MS group (Table 2).

**Table 2.** Relationship of scores and categories of the BDI between patients with MS and healthy controls.


\* BDI, Beck depression inventory. Frequency, percentage (%), and Chi-square test (x2) were utilized. BDI domains were divided as follows: (1) 0 to 9 points: Without depression, (2) 10 to 15 points: Mild depression, (3) 16 to 23 points: Moderate depression, and (4) 24 to 57 points: Severe depression. † BDI scores, Median ± interquartile range, range (min–max), and Mann–Whitney U test were used. In all the analyses, *p* < 0.05 (with a 95% confidence interval) was considered statistically significant (bold).

#### **4. Discussion**

This research studied depression in 58 patients with MS compared to 58 healthy subjects, the first case-control study of this type carried out on the Spanish population. The results obtained showed that many of the people with MS (41.4%) are at risk of suffering from depression in at least some range of the BDI.

According to a recent study, treating depression in MS patients significantly improves fatigue [33]. Therefore, it is important for these patients to be evaluated by a multidisciplinary team in order to improve their quality of life.

Depression tends to be related to other symptoms such as pain and fatigue exacerbated by the psychomotor degeneration of these patients [34]. The prevalence of depression in patients with MS is remarkably high, although it is still not properly diagnosed, leading to cognitive impairment causing the risk of suicide [35]. In the review by Claudio Solaro et al., it is stated that for the correct management of depression in subjects with MS, it is necessary to understand the damage in the central nervous system using MRI and relate fatigue and pain with depression [16].

In agreement with our study, patients with MS (51%) present clinically significant depressive symptoms [36]. Thus, we compared the control group with the case group, taking all the patients without considering depression as an inclusion criterion, and when reviewing the data obtained, we found that many people with MS (19%) present a mild level of depression.

For our study, the range of depression was obtained with the Beck Depression Inventory (BDI) questionnaire. This document was validated by other authors as having optimal characteristics to establish depression in subjects with MS [27], and furthermore, this questionnaire correlates with other types of questionnaires used to study depression, fatigue, and affect (Hamilton Rating Scale, Yale Single Questionnaire and PDQ) in patients with MS [37–39]. For this reason, studies conducted on depression in MS tend to have different results due to the use of other types of questionnaires and different types of samples.

Other studies carried out on depression in chronic pathologies also recommend the BDI as a good self-assessment tool for screening and evaluation in clinical practice of depression, its intensity, and its evolution in patients with chronic kidney disease [40]. As depression not only affects patients with MS or other chronic diseases but also their family environment, the BDI proved to be a valid and reliable instrument to measure depression in the family caregivers of children with chronic diseases [41]. Shelby et al., in their study on Parkinson's disease, showed that the BDI in clinical practice is suitable for additional psychiatric evaluation and for adopting different therapeutic interventions [42]. This agrees with the study by Ana María Jiménez-Cebrián et al. where, for the first time, it was shown in a sample of subjects with Parkinson's compared to healthy subjects that depression represents a significant potential risk for the increase in symptoms and has a negative impact on these patients compared to healthy subjects [43]. We can, thus, based on previous studies and our results, consider that depression and chronic pathologies have an unwanted effect on the quality of life of people with MS, especially in somatic-vegetative aspects such as fewer hours of sleep, loss of energy, greater tiredness, and loss of appetite [6,24,44].

Taking into account our findings and the bibliographic review, it is necessary for patients with MS to be aware of the importance of depression on their quality of life and to offer them a multidisciplinary team to establish good management of this pathology. In addition, biomarkers have been studied in some research with MS subjects, but all of them refer to the need for a larger sample for better consistency to thus complete the aspects of depressive studies and their possible causes in MS [11,40].

To correctly manage MS and depression, it would be important to use other biomarkers tools (blood or salivary) together with the BDI to provide more consistency and more treatment possibilities for this group of patients, determine the triggers involved, and improve their quality of life.

#### **5. Conclusions**

The results obtained show us that people with MS have higher scores on all levels of depression compared to healthy subjects, with greater differences at the mild and moderate levels. **Author Contributions:** Conceptualization, F.J.R.-S., M.d.R.M., S.S., C.R.-M., D.L.-L., J.G.-S. and A.M.J.-C.; Data Curation, F.J.R.-S., M.d.R.M., S.S, methodology, F.J.R.-S., M.d.R.M., S.S., C.R.-M., D.L.-L., J.G.-S. and A.M.J.-C.; formal analysis, F.J.R.-S., M.d.R.M., S.S., C.R.-M., D.L.-L., J.G.-S. and A.M.J.-C.; investigation, F.J.R.-S., M.d.R.M., S.S., C.R.-M., D.L.-L., J.G.-S. and A.M.J.-C.; writing original draft preparation, F.J.R.-S., M.d.R.M., S.S., C.R.-M., D.L.-L., J.G.-S. and A.M.J.-C.; writing review and editing, F.J.R.-S., M.d.R.M., S.S., C.R.-M., D.L.-L., J.G.-S. and A.M.J.-C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the University of Malaga (CEUMA) with registration number 32-2021-H and the Ethics Committee of the Provincial Research of Malaga with code 5002V01.

**Informed Consent Statement:** Written informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The dataset supporting the conclusions of this article is available upon request to f.ruiz@udc.es in the Research, Health and Podiatry Group, Department of Health Sciences, Faculty of Nursing and Podiatry. Industrial Campus of Ferrol, Universidade da Coruña, 15403 Ferrol, Spain.

**Acknowledgments:** We would like to thank the people who participated in this research.

**Conflicts of Interest:** The authors declare no conflict of interest.

### **References**

