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IMMUNE SYSTEM ALTERATIONS AND do not normalize after treatment, suggesting that TNF‑α
EXCITATORY SYMPTOMS IN AFFECTIVE may be considered as a trait marker of disease. [72] This
DISORDERS hypothesis is supported by the finding that serum TNF‑α
concentrations in BD patients are higher than in controls
Inflammation in manic, hypomanic and mixed states both in early (< 3 years) and late stages (> 10 years)
Cytokines are low‑molecular‑weight proteins secreted of the disease, and that TNF‑α levels are higher in
by immune cells, such as white blood cells and late‑stage than in early‑stage patients. [85] However, a
microglia, which play a crucial role in modulating the study from Guloksuz et al. [86] demonstrated by flow
inflammatory response. In the brain, cytokines exert cytometry that measured levels of TNF‑α are higher in
immune protection by promoting the elimination of lithium‑treated, but not medication‑free euthymic BD
damaged neurons and have also been demonstrated to patients compared to healthy controls, suggesting that
influence neurogenesis and cell survival. [71] However, the persistently increased levels of TNF‑α might result
dysregulation of cytokine synthesis and activity is as an effect of lithium therapy rather than reflect a
known to lead to alterations of synaptic transmission persistent pro‑inflammatory inter‑episodic status. It is
and synaptic plasticity, neurotoxicity, and neuronal interesting to note that TNF‑α has been demonstrated to
death. [8] modulate inflammation and neurotransmission in brain
regions regulating impulse control, like the prefrontal
An imbalance between pro‑ and anti‑inflammatory cortex and anterior cingulate cortex (ACC). [87] The
cytokines has been suggested to exist in manic patients expression of some TNF‑related genes correlates with
[72]
versus healthy controls, underlying a more pronounced ACC activation and aggression in BD children and
shift toward a pro‑inflammatory status in acute relapses. adolescents. [88] Moreover, serum TNF‑α concentrations
There is also evidence of an imbalance between correlate with deficits in executive functioning, that
cytokines secreted by type 1 T helper (Th1) lymphocytes is, inhibitory control, in BD patients; [89] inhibitory
and type 2 T helper (Th2) lymphocytes during mania, control is much more impaired in manic/mixed than in
with an increased Th1/Th2 ratio that normalizes after euthymic or depressed BD patients. Levels of sTNF‑R1
[90]
treatment. [73] IL‑1β levels are increased in the CSF of positively correlate with elevated mood, being increased
euthymic bipolar patients with at least one manic/ in manic states compared to depression, [91,92] and are
hypomanic episode in the last year when compared with much higher in BD‑I than in BD‑II patients. [68] Plasma
patients without a recent episode. [74] Peripheral IL‑1β levels of sTNF‑R1 also positively correlate with general
concentrations also positively correlate with suicide disease gravity and psychotic features in BD patients. [93]
risk in BD patients, [75] and suicide risk is now known to
be much higher when excitatory symptoms are present The alterations in the expression of TNF‑α in BD are
during relapses. [76,77] IL‑1 receptor antagonist (IL‑1Ra) quite intriguing since this factor is involved in many
serum concentrations are higher in bipolar patients processes, such as synaptic transmission, synaptic
both in mania and partial remission, whereas they plasticity, neurodevelopment, neurotoxicity, and
normalize when full remission is achieved. [78] Several regulation of neuronal survival. [94,95] Increased expression
studies investigating serum concentrations of IL‑8, of TNF‑α during acute mood episodes is thought to shift
as well as IL‑2, IL‑6 and their soluble receptors: IL‑2 the balance between cellular survival and cellular death
receptor (sIL‑2R) and IL‑6 receptor (sIL‑6R), found toward apoptosis, [96] therefore playing a role in the
that levels are higher in manic patients than in healthy neurodegeneration observed in chronic BD patients and
controls. [79‑81] In particular, peripheral concentrations possibly in cognitive impairment. Furthermore, TNF‑α
[97]
of IL‑2, IL‑6, and their receptors have been found to induces central recruitment of circulating monocytes
positively correlate with the severity of symptoms during peripheral inflammation by cerebral microglia,
[98]
and tend to normalize following treatment and during which in turn produces more pro‑inflammatory
remission. [58,72,79,80,82] A recent study by Tsai’s group [83] cytokines, sustaining the inflammatory status. [99]
also showed that concentrations of serum IL‑6R reflected
illness activity in a BD patient with manic relapses C‑reactive protein is a nonspecific acute‑phase protein,
during a 63‑week observation time. These findings, synthesized by hepatocytes in response to IL‑1 and
though, were only partially confirmed by meta‑analyses IL‑6 secretion during inflammatory processes. CRP
that demonstrated increased peripheral expression levels in BD patients rise during both mania and
of sIL‑2R in manic patients, with just a trend toward depression and remain higher than in controls in partial
the higher expression of IL‑6 and sIL‑6R. [69,70,84] Levels and full remission of symptoms, [78,83,100] suggesting a
of both TNF‑α and its receptor, tumor necrosis factor constant, nonspecific activation of immunomodulatory
receptor type 1 (sTNF‑R1), are increased in manic BD processes. Nevertheless, other studies have found
patients compared to healthy controls and euthymic increased levels of CRP only in manic bipolar patients
patients. [84] Elevated TNF‑α levels observed in mania and not in depressed or euthymic patients, [101] and that

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