During the progression of MS, axonal demyelination causes a constant state of inflammation in the brain, exacerbated by the activation of microglia . The anxiety and depression that occur during MS have been considered a consequence of the awareness that the patient has of the disease; however, it is now known that their relationship is more complex, pointing to inflammatory factors typical of MS and the presence of depressive and/or anxiety symptoms.
In this study, we found a 100% estimation for the probability of ruling out a psychopathological process in MS with Remission patients when the MSSS was < 4, with low anxiety symptoms (HADS, the subscale of anxiety < 7) and serum levels of IL-1b < 1.4 measured by western blot analysis.
Using a statistical multivariate model, we found that, when we have a result < 4 on the MSSS scale, psychopathological processes can be ruled out in patients with MS with remission, with low levels of anxiety (HADS, the subscale of anxiety < 7) and with low levels of IL-1b in serum.
The golden standard for depression diagnosis relies on a personal semi-structured interview using DSM5 criteria (). No biomarkers are currently used for the clinical diagnosis of depression with or without comorbidities even though several molecules have been found in experimental studies [11–13]. Finding a biomarker that can be used independently of the comorbidity is essential and extremely difficult since depression is commonly found simultaneously with other medical conditions .
Other studies have found an association between inflammatory biomarkers and depression in comorbidity. However, most of these studies do not use the DSM5 criteria nor the gold standard for the diagnosis of depression [15–17] and only use depression symptoms, this could explain the low association margin obtained for depression and the given comorbidities. Here we found a huge gap of association when using the clinical diagnosis (ORP = 28.5) or the Beck Depression Inventory with two cut-off points (ORP = 8.6 and ORP = 3.1). In order to find a proper biomarker for depression, the clinical diagnosis must be taken into account.
We found that IL-1b can be used to discriminate psychopathology (depression and/or anxiety) from Multiple Sclerosis. Ruling out this comorbidity would allow the clinicians to infer a favorable short-term prognostic as has been seen in studies where an association of depression with the worst outcome has been seen .
Regarding IL-1b, it is known that its administration, whether systemic or central, causes depressive-type symptoms in animals, and it has been speculated that this is because cytokines have an effect on glutamatergic transmission, as well as on the function of various neurotransmitters .
On that matter, IL-1b is also the link between the immune system and the CNS , it modulates the metabolism of tryptophan by increasing the activity of 2,3-IDO, generating a lower availability of tryptophan for the production of serotonin, and indirectly increasing the production of potentially neurotoxic metabolites . Increased central IL-1b activity has also been reported to contribute to cortisol resistance seen in several cases of patients with depression. It can also influence neuronal plasticity through the activation of microglia .
On the other hand, we did not find an association between TNFα, a pleiotropic cytokine that plays an important factor in the early stages of the inflammatory response , and the presence of depression and/or anxiety. On the matter, when TNFα was systemically administered in rodents they found that although they showed signs of sickness-like behavior (body weight loss and a reduced locomotor activity), none showed depressive or anxious symptoms (anhedonia), concluding that the increase in TNFα is not directly related to this type of symptoms . Also, one of our inclusion criteria was not being treated with interferon-beta because it is an independent risk factor for depression and anxiety in patients with multiple sclerosis .
As with other comorbidities, depression in MS is normally ignored. For example, the Expanded Disability Status Scale (EDSS) gives a minimal value to depression which by itself does not affect the EDSS punctuation and is merely mentioned as part of other symptoms related to MS. This exclusion affects the patient in more than one aspect. A proper diagnosis of depression would allow proper treatment, and as mentioned before, depression affects prognosis in diseases such as Rheumatoid Arthritis , Chronic Kidney Disease , type 2 diabetes , irritable bowel syndrome , and Multiple Sclerosis .
One of the main issues with this study is the sample size, nonetheless, the statistical power (P = 0.8) was enough to conclude that the diagnosis of depression can use biomarkers such as IL-1b as part of its clinical characterization even when comorbidity such as MS is present, with the possibility of conjointly using other clinical variables to exclude the possibility of a psychopathological process with a P = 0.7. Other comorbidities with depression need to be evaluated in order to achieve a real biological diagnosis that can accompany the Gold Standard in Psychiatry.
A follow up of the patients that present these risk factors (MSSS was > 4, HADS subscale of anxiety > 7, and levels > 1.4 in the serum values of IL-1b) would be advisable in order to identify if these variables are also associated with a worst prognosis of MS due to the presence of inflammatory depression.
Inflammation caused by the presence of MS can induce depressive symptoms. Inflammation is, therefore, a biological event, which must be taken into account alongside the traditional psychosocial factors implicated in this kind of mood disorder.
Using serum IL-1b measurements we obtained a 100% estimation for the probability of ruling out a psychopathological process in MS with Remission patients. A logistic model where MSSS was < 4, HADS subscale of anxiety was < 7, and serum IL-1b values were < 1.4 allowed a clinical approximation for the use of biomarkers in depression diagnosis.