How Neuroinflammation May Play a Role in Mood Disorders

Consensus exists that there has been a lack of genuinely novel, innovative treatments for individuals with mood and other mental disorders.1 It is categorically true that psychotropic agents discovered and developed during the past three to four decades have provided for patients a clinically significant advance in safety, tolerability, and ease of use.

Notwithstanding these developments, the majority of individuals receiving conventional psychotropic agents for mood disorders do not receive full syndrome recovery.2 Moreover, a highly replicated observation has been that individuals who are in symptomatic remission continue to report consistent improvements in quality of life and function as well as associated comorbidities, e.g. overweight, obesity.

A strategic imperative, as part of a larger framework, towards novel drug development is refinement of disease pathogenesis in mood disorders. The monoamine hypothesis has been the prevailing disease model since the mid-20th century and has provided a platform for a vast array of monoamine-based therapies.

Non-mutually exclusive alternative effector systems have also been implicated in mood disorder disease modelling. For example, alterations in the innate immunoinflammatory system have been implicated in the pathogenesis, phenomenology, comorbidity, and treatment of mood disorders.3 The foregoing collection of observations provides fertile ground for chartering a novel pathway for drug discovery and possibly disease categorization.

For centuries, alterations in the immunoinflammatory system have been implicated as causative for a wide variety of ailments affecting humanity. In modern times, first reports of the critical role of this system as of pathogenetic relevance appeared in the late 19th century. The introduction of malaria fever therapy, which resulted in the awarding of the Nobel Prize in Medicine in 1927, is a historical reminder of the momentum that was given to immunoinflammation as a pathogenetic and therapeutic focus.

During the past two decades, a highly replicated body of evidence now indicates that subsets of people with mood disorders exhibit alterations in the neuroimmunoinflammatory milieu. Subsets of individuals with major depressive disorder (MDD) more likely have abnormalities in the immunoinflammatory systems include — but are not limited to — individuals with MDD who are resistant to conventional methods of antidepressant therapy,  individuals with MDD reporting past history of early life trauma, as well as MDD comorbid with obesity.4,5

There are many effector systems that comprise the immunoinflammatory system including cytokines, chemokines, cell adhesion molecules, chemoattractant proteins, as well as acute phase reactants (e.g. C-reactive peptide).6 Alterations in both pro, as well as anti- inflammatory proteins, have been documented in both symptomatic and remitted individuals with mood disorders. The most replicated alterations are with interleukin-1, interleukin-6, C-reactive peptide, and tumour necrosis factor alpha.

There is suggestive evidence — albeit not confirmatory — that the “biosignature” of immunoinflammatory changes may be different in remitted versus symptomatic phases, hinting of possible use to guide the presence of disease activity. Moreover, immunoinflammatory signatures may differ as a function of illness staging/trajectory, possibly providing insight into the extent to which an illness has progressed.7