Psychosis: glia, immunity, and melatonin.

I read with interest the recent article by Duarte et al. reviewing the neurobiological underpinnings of bipolar disorder (BD).1 Such work is part of a growing body of interest on the role of not only glia, but wider immunity, alterations in psychosis.2 This places the regulation of immune responses as an important target in the pathophysiology of schizophrenia and BD. In this context, it should be noted that melatonin plays an important role in the regulation of both immune and glial cell reactivity, including through its autocrine effects, which world-leading work by Markus et al. in Brazil has shown.3

Melatonin is classically associated with night-time release by the pineal gland and thereby with the regulation of the circadian rhythm. However, a plethora of recent data shows that melatonin is synthesized in many, if not all, mitochondria-containing cells.2 As such, the genetic associations of melatonin with BD are likely to be linked to changes in a wide array of organs and tissues, including the gut, as well as in glia and immune cell regulation. Likewise, the general decrease in pineal melatonin levels in schizophrenia is likely to represent alterations in central and peripheral sites, as well as in circadian regulation.

Given that melatonin may decrease the levels of metabolic dysregulation induced by mood stabilizers and antipsychotics, its immediate clinical utility in psychosis should be highlighted.

However, the targeting of local melatonin synthesis in glia and immune cells is now a significant pharmaceutical company target. The recent development of alpha-7 nicotinic receptor agonists as cognitive enhancers in schizophrenia, as well as in Alzheimer’s disease, may also require the careful regulation of melatonin synthesis, given that melatonin regulates the levels and activity of this nicotinic receptor, again as shown by Markus et al.4 The alpha-7 nicotinic receptor is also a significant inhibitor of glial and immune cell reactivity, suggesting that its interaction with levels of melatonin is likely to modulate its clinical utility.

Most general practitioners and psychiatrists have an underappreciation of such wider roles of melatonin, and of its clinical utility across a host of psychiatric and other medical conditions. It is not unlikely that the pathophysiological changes underpinning the data reviewed by Duarte et al. involve alterations in melatonergic pathways.

Disclosure

The author reports no conflicts of interest.