Byline: Georgios. Kotzalidis, Elisa. Ambrosi, Alessio. Simonetti, Ilaria. Cuomo, Antonio. Del Casale, Matteo. Caloro, Valeria. Savoja, Chiara. Rapinesi
Recent literature based on peripheral immunity findings speculated that neuroinflammation, with its connection to microglial activation, is linked to bipolar disorder. The endorsement of the neuroinflammatory hypotheses of bipolar disorder requires the demonstration of causality, which requires longitudinal studies. We aimed to review the evidence for neuroinflammation as a pathogenic mechanism of the bipolar disorder. We carried out a hyper inclusive PubMed search using all appropriate neuroinflammation-related terms and crossed them with bipolar disorder-related terms. The search produced 310 articles and the number rose to 350 after adding articles from other search engines and reference lists. Twenty papers were included that appropriately tackled the issue of the presence (but not of its pathophysiological role) of neuroinflammation in bipolar disorder. Of these, 15 were postmortem and 5 were carried out in living humans. Most articles were consistent with the presence of neuroinflammation in bipolar disorder, but factors such as treatment may mask it. All studies were cross-sectional, preventing causality to be inferred. Thus, no inference can be currently made about the role of neuroinflammation in bipolar disorder, but a link is likely. The issue remains little investigated, despite an excess of reviews on this topic.
Among the former mood or affective disorders, bipolar disorder is the one that is most intriguing. Its heterogeneity is well-recognized. While traditionally subdivided into bipolar I and bipolar II according to whether there was a history of mania,[sup] some scholars support the existence of more than 10 subtypes.[sup] It is supposed to be pathophysiologically/neurobiologically continuous with other psychiatric disorders such as schizophrenia according to Griesinger's model of Einheitspsychose ,[sup] and with recurrent major depression.[sup],,
Mood disorders along with anxiety disorders are considered as “stress disorders."[sup] The organism responds to stress in an integrated manner, involving the cooperation among the nervous, endocrine, and immune systems,[sup] and stress disorders are believed to be underpinned by derangements in this integration.[sup]
Stress and Inflammation
Inflammation is a process described since antiquity, meaning burning in both Greek (?e?a??e?) and Latin (inflammation), and characterized by swelling (tumor), redness (rubor), heating (calor), pain (dolor), and impaired function (functiolaesa). It is a general reaction to pathogens in a tissue involving an innate response of cells residing within that tissue. In the acute phase, the process entails the extravasation of immune cells, permeability changes in blood vessels, and the production of chemical mediators, including acute phase proteins, vasoactive amines, eicosanoids, bradykinin and other tachykinins, and chemical attractors. The nonspecific response usually leads to resolution and repair, with restitution to integrity. The inability to restore the previous healthy state may ensue in chronic inflammation, characterized by shifts from the main participating cells toward mononuclear (monocytes, macrophages, lymphocytes, and plasma) cells and fibroblasts and from the main participating molecules toward interferon-a, interleukins (ILs), growth factors, nitric oxide, and hydrolytic enzymes.[sup]
The stress concept was developed from the work of Selye,[sup], who viewed the body in Cannon's frame.[sup] Stress,...