Neuroinflammation in Bipolar Depression

Abstract

Bipolar disorder (BD) is a leading cause of worldwide disability among mood disorders. Pathological mechanisms are still vastly unclear, and current treatments with conventional medications are often unsatisfactory in maintaining symptoms control and an adequate quality of life. Consequently, current research is focusing on shedding new light on disease pathogenesis, to improve therapeutic effectiveness. Recent evidence has suggested a prominent role of inflammation in mood disorders. Elevated levels of peripheral proinflammatory mediators have been reported in BD, as well as in other mood disorders, and people with systemic autoimmune diseases have an increased risk of developing BD. These immunological alterations are stable, and current medications are unable to alter peripheral concentrations even when clinical improvement is evident. These findings have also been replicated in the central nervous system (CNS) milieu, whereas genetic studies have shown that these immune alterations are not due to the disorder itself, being detectable before the illness onset. Moreover, these inflammatory modifications seem to be affected by and linked to other biomarkers of the disorder, such as alterations of white matter (WM) microstructure, metabolism, kynurenine pathway, and circadian rhythmicity. Finally, these immune variations seem to be useful as predictors of therapeutic responsiveness to medications, and in discriminating between clinically different outcomes. The objective of this review is to summarize available evidence on the connection between inflammation and BD, focusing on peripheral inflammatory markers and recent findings on their connection with other typical features of BD, to outline a general overview of the disorder. Moreover, it is meant to analyze the issues with data gathering and interpretation, given the partially contradictory and inconsistent nature of results.

Role of Oxidative Stress and Neuroinflammation in Attention-Deficit/Hyperactivity Disorder

“…Inflammation of the nervous system, commonly known as neuroinflammation, can be characterized by the activation of microglia (which play a role in pathological and physiological conditions), astrocytes, oligodendrocytes, and ependymal cells, by increasing levels of proteases, glutamate, ROS, NO, chemokines, toxic cytokines, and prostaglandins and by infiltration of T and B cells, neutrophils, monocytes/macrophages and dendritic cells [ 96 , 97 , 98 , 99 ]. The role of neuroinflammation has been associated with several neuropsychiatric disorders, such as autism [ 100 ], bipolar disorder [ 101 ], depression [ 102 ], and schizophrenia [ 103 ]. Thus, growing interest points to neuroinflammation as a factor involved in the pathophysiology of ADHD [ 3 , 39 , 40 ].…”

Gut microbial clues to bipolar disorder: State‐of‐the‐art review of current findings and future directions

“…Additionally, neuroinflammation stimulates the expression of KYN enzymes and modulates the metabolic degradation of tryptophan in the CNS 35 . Tryptophan is an essential amino acid that in vivo can be converted into various substances in an enzyme‐dependent manner, including neurotransmitters (eg, serotonin and melatonin) and KYN metabolites (eg, kynurenic acid, quinolinic acid, and xanthurenic acid) 36,37 . Generally, kynurenic acid is considered to be neuroprotective while quinolinic acid has neurotoxic effects.…”

The Challenge of Assessing Mild Neuroinflammation in Severe Mental Disorders

“…The research on the signaling role of exosomes in CSF represents such a new area of interest in neurology and psychiatry, but is just beginning (79)(80)(81)(82). An intriguing yet widely neglected immune regulatory part herein may be played by the exosomes and cells passaging along cranial and peripheral nerves with CSF outflow into peripheral tissues, where CNS specific immune responses are generated then (11,(83)(84)(85), to be considered with ME and mild neuroinflammation in future research. Another obvious example for such ambiguity of findings in SMDs are the confirmed immune and neuroinflammatory aberrations in bipolar disorders (11,(86)(87)(88)(89): the respective interpretation of immune cell aberrations in blood may make sense only in context with the role of changing environment and possibly the immune response to infectious agents and other factors involved, as these immune aberrancies do not simply correlate with the diseased state of bipolar depression or mania specifically, rather are changing over time in contrarious way (9, 10), which might be interpreted as a slight primary immune defect followed by partially exaggerated and later exhausted immunity (9).…”

“…Given such ambiguity and pleiotropy of single factors found aberrant and representing risk factors of disease, it is not surprising, that there seems little direct (in time periods of actual diseased states) correlation in between these known risk factors and changing clinical pictures in the individual case (at least on the known level of systemic inflammation and/or immune dysregulation), which may heavily depend from environmental factors, eg. infections and stress (9)(10)(11). Relevant clinical syndromes included those on the affective to schizophrenic spectrum (not reviewed here), which is unsurprising with regard to often voiced issue of "non-specificity" in psychiatric research as a general problem and relates to the new approach with Research Domain Criteria (RDoCs) in psychiatric research [see (12)].…”