FIGURE 2.

Pathophysiological theories of depression in MS. The number of green arrows in windows is directly proportional to the importance of each theory in the pathophysiology of the disease. Pathophysiological theories to explain the onset of depressive symptoms in MDD. Depression in the course of MS/EAE presents a wide range of clinical presentations. Compared to MDD, monoamine dysfunction is likely less relevant, although it is fundamental in the genesis of depressive symptoms, as it is supported by a good pharmacological response to SSRIs (anti-inflammatory effect). The neuroendocrine theory, responsible of HPA-cortisol perturbation is less investigated in MS than in MDD. The neuroinflammatory theory stands out of importance in MS depressive disorder, sustained by activated T cells and macrophage/microglia that secrete proinflammatory cytokines, causing demyelination, axonal loss a neurodegeneration. Perturbation of limbic areas has been associated to microgliosis. Finally, the glutamate theory is essential in understanding depressive symptoms associated to MS/EAE, especially in the early phase of the disease even before clinical onset. Increased hyperexcitability, caused by enhanced glutamatergic transmission and by a reduced GABAergic tone, has been associated to early mood disturbances. Altered synaptic plasticity also causes cognitive impairment. The link between the neuroinflammatory theory and the glutamatergic hypothesis has been well characterized in MS and the inflammatory synaptopathy has been recognized as a reliable hallmark of MS/EAE.