**1. Introduction**

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system. MS presents sexual dimorphism showing importance in the incidence and severity of the disease. The female sex shows a higher incidence of the disease and the male sex shows faster clinical progression [1,2]. Numerous epidemiological studies in the Spanish population indicate that it is a region of medium-high prevalence of the disease throughout the whole country. The cases have been increasing progressively and have reached 80–180 cases per 100,000 inhabitants with the frequency being higher in women [3].

This pathology is characterized by the spread of spatio-temporal lesions, with frequent exacerbations and remissions [4]. In addition to psychomotor signs and symptoms, demyelination has psychological and psychiatric consequences, presenting depressive symptoms in 50% of people with MS [5–7].

The discovery of biomarkers in the blood is a fundamental tool for predicting, diagnosing, and monitoring the efficacy of depression treatment [8]. Biomarkers are present in

**Citation:** Ruiz-Sánchez, F.J.; do Rosário Martins, M.; Soares, S.; Romero-Morales, C.; López-López, D.; Gómez-Salgado, J.; Jiménez-Cebrián, A.M. Impact of Multiple Sclerosis and Its Association with Depression: An Analytical Case-Control Investigation. *Healthcare* **2022**, *10*, 2218. https:// doi.org/10.3390/healthcare10112218

Academic Editors: Athanassios Tselebis and Argyro Pachi

Received: 8 October 2022 Accepted: 3 November 2022 Published: 4 November 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

depressive patients with autoimmune diseases, in whom, in turn, there is a development of the proinflammatory state of cytokines IL-1β, IL-6, and TNF-α [9]. Recent studies have identified that the inflammatory process is closely related to the neurodegenerative pathways associated with depression, with proinflammatory cytokines being important in its pathophysiology [10]. In autonomic diseases such as MS, proinflammatory cytokine production triggers episodes of depression [11]. Another way to measure depression-related biomarkers is through saliva where the anti-inflammatory cytokine IL-10 is significantly associated with depression severity in MS patients [12].

The diagnosis of depression in people with MS is complex as it can have a multifactorial etiology and can be associated with clinical manifestations including euphoria, anxiety, emotional lability, and psychosis [4]. A series of atypical symptoms also must be taken into account, such as peripheral facial paralysis, painless optic neuritis, and encephalopathy [13]. Histological inflammatory changes are also implicated in the etiology [14]. The state of depression represents one of the main determinants of quality of life in MS and can lead to suicidal intent [15,16] as it is related to the intake of interferon alpha and beta [17]. In addition, within the clinical picture, there are motor disorders (spasticity, ataxia, foot drop), sensory disorders (paresthesia, pain), cerebral disorders (dysarthria, gait ataxia, fear, lack of coordination of limbs), alterations of the cranial nerves (decreased visual acuity, facial muscle weakness), disorders of the autonomic nervous system (urinary and intestinal incontinence), and cognitive disorders (decreased attention) [18,19]. A study using magnetic resonance imaging (MRI) in 46 acute MS patients showed that there was a significant correlation between frontal periventricular or non-periventricular white matter lesions and psychopathological conditions such as depression [20].

Cases of depression in subjects with MS are higher in women, tending to decrease with increasing age, with 16.7% of women and 13.1% of men being affected [21]. Depression is significantly related to education, and 89.9% of MS subjects in a recent sample had mild to severe depressive symptoms [22]. There is a significant relationship between the type of MS and depression, where subjects with progressive relapsing MS have a higher risk (100%) of developing depression [23]. Likewise, there were higher depression scores in subjects with relapsing–remitting and secondary progressive MS [24].

However, there are few studies on the Spanish population that evaluate the significance of the resulting levels of depression in its three domains (affective, behavioral, and cognitive) and anxiety in patients with multiple sclerosis. Therefore, after reviewing the published literature, we found that levels of depression have not been described in previous studies comparing subjects with MS and healthy subjects. The objective of this study is to help to improve their well-being and quality of life.

Finally, the study tries to ascertain relative depression risk in people with multiple sclerosis and healthy subjects, thus making it a case-control study.

#### **2. Materials and Methods**

#### *2.1. Design and Sample*

To develop this study, a total sample of 116 subjects was recruited for an analytical, observational, and multicenter study of cases and controls carried out in different MS associations in the province of Malaga and Granada and in the neurology area of the "Hospital de Serrania de Ronda". This research was performed according to the criteria of the Strengthening the Reporting of Observational Studies in Epidemiology guidelines [25].

The subjects who participated were patients with MS (case group *n* = 58) and without MS (control group *n* = 58) with similar socio-economic status. The patients were recruited using a convenience sampling method. Multiple sclerosis patients were taken from reference associations and healthy subjects from the same locality as the cases.

The subjects with MS were chosen once their association and neurologist had informed them of the study on depression and quality of life and they had decided to participate voluntarily.

The inclusion criteria were as follows: Between 18 and 88 years, of both sexes, able to walk, and who authorized their participation in the signing of the consent form.

The exclusion criteria of the subjects were another neurodegenerative disease other than MS, cognitive impairment, and severe mental disorder (measured with the Expanded Disability Status Scale (EDSS)). Cases and controls were matched for age, gender, and BMI.

#### *2.2. Sample Size Calculation*

To calculate the sample size, we used Epidat 4.2 software (Epidemiology Service of the General Directorate of Public Health of the Consellería de Sanidade (Xunta de Galicia) with the support of the Pan American Health Organization (PAHO-WHO) and the University CES of Colombia, thus obtaining specific levels of trust, power, and groups of equal size. A sample of 102 participants (51 per group) was obtained with a confidence level of 70%, an odds ratio of 2.0, a power of 0.80, and an exposure value of 66.67% for the MS group and 50% in the control group. Finally, for operational and safety reasons, a total of 58 patients (in each group) were used in this study.

#### *2.3. Procedure*

Data collection included general health questions associated with demographic variables (age, weight, height, sex, and BMI) and comorbid characteristics such as diabetes, arterial hypertension/hypotension, and ischemic heart disease. In addition, health questions related to the disease were recorded, such as the type of MS, degree of spasticity, years diagnosed, and medication administered.

Next, the participants were given the Spanish version of the Beck Depression Inventory (BDI) questionnaire [26–28]. This questionnaire was validated and translated into Spanish and is one of the instruments used to establish depression levels [29,30]. This version of the instrument consists of a total of 21 items with four alternatives each, which are classified from 0 to 3 points, giving a possible total of 63 points. The results obtained are measured in four ranges: The first category goes from 0 to 13 points (no signs of depression), the second from 14 to 19 points (mild depression), the third from 20 to 28 points (moderate depression), and the fourth from 29 to 63 points (severe depression). This instrument is one of the fastest and most efficient for the correct assessment of signs of depression with a Cronbach's alpha coefficient of 0.889 [31].
