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the increase in CRP levels positively correlates with the signaling pathway enzymes, such as phospholipase
severity of manic symptoms. [102,103] A2 (PLA2) and membrane prostaglandin E synthase,
are higher in the postmortem frontal cortex of
The complement system is a part of the innate immune bipolar patients than in healthy controls. [118] A recent
system. It consists of over 30 different proteins and its study suggests that some of these alterations might
activation ultimately leads to a massive amplification of be due to epigenetic mechanisms. [119] Among other
the immune response. Increased levels of complement pro‑inflammatory stimuli, COX‑2 expression is
factors C3, C4, and C6 have been found in BD patients induced by TNF‑α, [120,121] the production of which has
during mania. [104] been found to be increased during manic relapses of BD
as already described. Lamotrigine and valproic acid,
Several studies have demonstrated an abnormal two widely used mood stabilizing agents, decrease
activation of T‑cells in bipolar patients, regardless of COX‑2 expression in rat frontal cortex. [122,123] Unlike
the phase, [58] whereas others have found an increase lamotrigine, [124] however, agents known to be effective
in T‑cell proliferation and activation during manic in treating mania, such as lithium, carbamazepine,
states that normalized after full remission. [105,106] A valproate, and the anti‑psychotic drugs clozapine
recent study demonstrated an increased proportion and olanzapine, also decrease AA turnover in rat
of circulating monocytes in BD patients, [107] and a brain, [125‑135] eventually modulating dopaminergic and
correlation between a subcluster of monocyte glutamatergic transmission. [136‑138] On the other hand,
proinflammatory gene (i.e. CCL2 and CCL7) expression the antidepressants fluoxetine and imipramine, but
and excitatory symptoms was found. [108] Interestingly, not bupropion, increase AA signaling and turnover
total leukocyte counts are higher in mixed states than in the rat brain. [139‑141] These findings are intriguing,
in pure manic states, and this difference appears to be considering that antidepressant treatment in bipolar
due mainly to an increased number of neutrophils and patients often leads to a switch from a depressive
monocytes. [109] to a manic/hypomanic state [142,143] and that, among
antidepressants, bupropion is the drug associated
Oxidative stress is defined as the imbalance with the lowest risk of inducing switching. [144,145] Taken
between oxidant and anti‑oxidant agents, provoking together, these findings suggest that manic/hypomanic
macromolecular and cellular damage and ultimately phases might be associated with a higher rate of
inducing impairments in neuronal survival, plasticity, AA signaling, an interesting hypothesis that would
and signal transmission. [110] Alterations in the oxidative need more in‑depth research. [146] Novel neuroimaging
status have been found to differ within mood states techniques such as positron emission tomography
in BD patients. Peripheral levels of nitric oxide (NO), with 11C‑labeled fatty acids might help to better
a powerful oxidant agent, are higher in BD patients, clarify the AA turnover and signaling cascade in the
especially during mania, and also positively correlate brain of BD patients and its role in the development
with the number of lifetime manic episodes. [111,112] of symptoms. [147]
When compared with euthymic subjects or healthy
controls, manic patients show higher levels of Microglial cells are the resident macrophages of the
thiobarbituric acid reactive substances (TBARS) and central nervous system and play critical roles both
protein carbonyl content (PCC), peripheral markers of in physiological and pathological functioning of
lipid peroxidation and oxidative damage to proteins, the brain, as well as during neurodevelopment. [148]
respectively. [113] TBARS levels normalize after treatment One of the most important activities of microglial
with mood stabilizers and anti‑psychotic drugs. [114] cells is to regulate inflammation within the CNS
Levels of superoxide dismutase, a main component via the production of pro‑inflammatory cytokines
of the anti‑oxidant defense system, are also higher in and free radicals, as well as anti‑inflammatory
BD patients during mania, suggesting a compensatory components. [149] Aberrant microglial cell number
response to increased oxidative stress. [115] The and function are involved in the pathophysiology
imbalance in the oxidative state of manic BD patients of psychiatric disorders, including BD, [28,66,150‑153]
is normalized by lithium treatment. [116] possibly modulating GSK‑3β/Wnt pathway activity
through neuroinflammation. [67] However, to date,
Arachidonic acid is one of the most abundant fatty little is known about direct correlations between
acids in the brain and is a precursor in the production excitatory symptoms and glial activity. [67] During
of prostaglandins (PG). PG are hormone‑like lipid acute manic states, alterations in neuronal/glial
compounds, synthesized from AA by cyclooxygenase interactions and glutamatergic transmission have
(COX) isoenzymes, and play crucial roles in the been demonstrated by proton magnetic resonance
promotion of systemic inflammation. [117] Protein and spectroscopy. [154] Some additional evidence on this
mRNA levels of COX isoform‑2 (COX‑2) and other AA issue has been provided by animal experiments.

218 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015