Is multiple sclerosis-related depression different from depression in general? The data for and against

Depression in people with multiple sclerosis (MS) is two to three times more frequent than in demographically matched people without MS. The MS-depression literature is large and has expanded exponentially over the past few years. This increase in new knowledge is the impetus for assessing whether there is now sufficient evidence to differentiate depression linked to multiple sclerosis from depression alone. Establishing the validity of MS-depression as a distinct diagnosis is important because it would enhance our understanding of the pathogenesis of depression in general, shed light on a clinical course that might diverge from what is expected from depression without MS, and suggest management strategies that may differ from those followed for people with depression alone. A review of the MS-depression literature from January 2018 to December 2024 (generating 114 papers for inclusion in the manuscript) reveals no unique, distinct MS-depression phenomenology. The factors encompassing predictive validity, namely the course of depression, employment, suicide, cognitive impairment and quality of life, are similar in kind but not severity between depressed people with and without MS. The paucity of randomized controlled trial psychotropic data in MS-related depression means it is unclear whether medication plus psychotherapy is the best treatment option for people with MS who are depressed, as it is in general population samples. In terms of construct validity, the posited immune signature of MS depression, namely an increased frequency of circulating CD4+CCR7low central memory T cells with a Th1 predilection, does not appear to be distinct from depression in the general population. There is considerable neuroimaging commonality, particularly in limbic regional involvement. The potential importance of the dopamine-rich ventral tegmental area in a putative MS depression neural circuit suggests a degree of specificity, but the absence of direct comparison between depressed people with and without MS hinders a more definite conclusion. As for personality factors and socio-economic status in depressed people with MS, the findings essentially overlap with the depression literature in the general population. There are, however, a couple of standout constructs suggesting the possibility of two distinct disorders: the equivocal data pertaining to a specific MS genetic diathesis to depression and the absence of a clear sex difference in depressed people with MS. Until these conundrums are explained, one cannot conclude with certainty that depression in people with and without MS is the same disorder. Further research comparing depressed people with and without MS is needed to understand why this difference may exist.