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Mice lacking the alpha‑2 isoform of Na /K ‑ATPase, re‑conceptualized as an “attenuated mixed state”
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also known as the sodium pump, show some belonging to bipolar‑spectrum disorders. [171]
manic‑like behavior (i.e. hyperlocomotion), and
hyperlocomotion is prevented by pretreatment Until date, few studies have specifically focused on
with lithium. [155] Na /K ‑ATPase inhibitors, such immune alterations during the bipolar depression.
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as ouabain, have been extensively used in animal Higher levels of IL‑1β, IL‑2, IL‑6, IL‑8, IL‑10, TNF‑α,
experiments to model BP. [156] The alpha‑2 isoform high‑sensitivity CRP (hs‑CRP), sIL‑2R, sIL‑6R, sTNF‑R1,
is expressed exclusively in glial cells [157] and is and IL‑1Ra have been found in serum and/or plasma of
reduced in postmortem temporal cortex of BD depressed BD patients, [79,81,100,178] although these findings
patients. [158] were not completely confirmed in meta‑analyses. [69,70,84]
Interestingly, some of these markers (i.e. sIL‑R2, TNF‑α,
Inflammation and excitatory symptoms in depression and sTNF‑R1) appear to be elevated during manic/
Markers of increased immune‑inflammatory activity hypomanic phases as well. [41] Depressed BD patients
have been demonstrated in patients diagnosed with the also show alterations in oxidative stress markers and
major depressive disorder or unipolar depression (UD). glial activity. [179]
These findings have been further confirmed by
meta‑analyses, [159,160] but the studies included in the Few studies have compared levels of inflammatory
research, if considered individually, did not present markers between BD and UD patients, and the results
homogeneous results. This might be explained by were mostly nonsignificant. However, a recent
methodological differences in conducting the studies work from Bai et al. [54] found that bipolar patients
and/or by a variety of confounding factors, one of show higher serum levels of sIL‑6R, CRP, sTNF‑R1,
which might be the presence of some subthreshold and monocyte chemotactic protein‑1 (MCP1) than
excitatory symptoms in depressed patients such as patients with different subtypes of UD, hinting that
mood lability, inner tension, irritability, racing and dysregulation of the immune system is more severe
crowded thoughts, talkativeness, sleep disturbances, in BD than in UD.
and psychomotor agitation. [161‑163] These symptoms
are often misidentified in clinical practice, [164‑166] Inflammation in BD prodromes
despite being present in around 40% of patients Excitatory symptoms, although quite nonspecific,
diagnosed with depression. [167,168] In addition, about are also frequent during the prodromal stages of BD
20% of subjects initially diagnosed with the major in adolescents. [180] These symptoms include mood
depressive disorder and without lifetime manic swings, hyperactivity, sleep disturbances, irritability
symptoms develop excitatory features during the and aggressiveness, and anxiety. [181,182] Cytokines
course of their disease. [169] are thought to interact with adrenal and gonadal
hormones during adolescence, therefore influencing
A recent study found significantly elevated baseline neurodevelopment and contributing to subsequent
levels of CRP in patients diagnosed with UD that onset of psychiatric diseases; [183] a role for a preexisting
later developed excitatory symptoms compared to pro‑inflammatory status in adolescents with high‑risk
unipolar depressed patients who did not show manic of developing BD has been suggested. [184] Recently,
symptoms over two years follow‑up. [170] A similar, a prospective study demonstrated alterations in the
but nonsignificant, trend toward higher levels of IL‑6 immune state, such as increased inflammatory gene
and TNF‑α was also observed. [170] Both the presence expression in monocytes during adolescence and
of excitatory symptoms during the depression and increased levels of chemokine ligand 2 (CCL2, also
high levels of serum cytokines before treatment are known as MCP1), a marker of monocyte activation and
associated with a more severe course of the disease migration, during young adulthood in the offspring of
and poor response to antidepressants. [171‑176] It could be BD patients. [185]
therefore hypothesized that an increased inflammatory
status might be responsible, at least in part, for this Inflammation in postpartum psychosis
evidence. There’s a general consensus that postpartum psychosis
may often occur as a first episode of BD. [186,187]
Excitatory symptoms are twice as common in bipolar Pregnancy in itself is considered a period of great
depression than in UD, [165] and patients diagnosed modifications in the function of the immune system
with major depression that also show psychomotor and immune activation has been observed during the
agitation are nearly three times more likely to postpartum period. [188,189] A recent study found reduced
undergo mood‑switching than depressed patients levels of T‑cells, increased levels of monocytes, and
without excitatory symptoms. [177] This is consistent increased expression of monocyte genes in patients
with the theory that agitated depression should be with first‑onset postpartum psychosis. [190]

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