Neuroprotective Benefits of Antidepressants in Multiple Sclerosis: Are We Missing the Mark?

The potential of antidepressant medication to have a neuroprotective effect for people with multiple sclerosis (MS) has received increased interest in recent years. The possibility of antidepressants, particularly fluoxetine, for potential repurposing to treat primary progressive and secondary progressive MS is of interest as a result of the relative lack of disease-modifying medications for these subtypes. A number of animal studies have found positive results for a neuroprotective effect of antidepressant use in MS, with human studies showing mixed results. These human studies all have a significant limitation: they exclude people with moderate to severe depressive symptoms, a core symptom of MS beyond that of reactive depression. It is likely that reregulation of the common mechanisms in depression and MS, such as inflammation, serotonin, norepinephrine, glutamate and brain-derived neurotropic factor disruption, and hypothalamic-pituitary-thalamic axis dysregulation, are important to the neuroprotective value of antidepressant medication. Given that MS is known for its heterogeneity, the question might be less about whether antidepressant medication provides neuroprotective benefits to people with multiple sclerosis but for whom they provide benefits and whether we are designing studies that will detect a benefit. To answer these questions, studies must include people with MS and depressive symptoms as well as people with relapsing remitting and chronic subtypes.