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In humans, treatment with interferon (IFN)‑α induces markers, both in the blood and in the brain, that
depressive symptoms such as anhedonia, fatigue, suicidal is, abnormal T‑cell and monocyte‑macrophage
thoughts, cognitive impairments, loss of appetite, and sleep activation, alterations in chemokine, cytokine,
alterations, [9,10] therefore hinting that IFN‑α may contribute prostaglandin, and acute‑phase protein synthesis,
to the development of mood disorders. [11,12] Healthy aberrant inflammatory‑related gene expression,
volunteers injected with Salmonella abortus equi endotoxin increased oxidative stress markers, and microglial
show increased circulating levels of inflammatory activation. [28,52‑67] The vast majority of studies focused
mediators and develop psychiatric symptoms, such as on assessing peripheral cytokine levels. Despite some
anxiety and depressed mood, as well as mild, transient mixed results, globally BD patients show higher
cognitive impairments. Depressed patients with no serum concentrations of TNF‑α, soluble TNF‑receptor
[13]
other concomitant medical conditions show alterations 1 (sTNF‑R1), IL‑1β, IL‑4, soluble IL‑2 receptor (sIL‑2R),
in the levels of many pro‑inflammatory cytokines and and sIL‑6 receptor (sIL‑6R) compared to healthy
acute‑phase proteins, both in peripheral blood and controls, as well as a nearly‑significant trend for
cerebrospinal fluid (CSF). In particular, variations in IL‑6. [54,68‑70] These results refer to both euthymic and
[14]
the concentration of IL‑1, IL‑6, TNF‑α, and C‑reactive symptomatic BD patients and do not emphasize
protein (CRP) have been observed in patients diagnosed the possible differences in the cytokine expression
with depressive disorders when compared to healthy patterns correlated with the presence of excitatory
controls. [15‑20] Glial abnormalities, [21‑23] increased oxidative symptoms. We, therefore, performed an analysis
stress, [24‑27] macrophage activation, [28‑30] and alterations of the literature aimed at highlighting the possible
in the arachidonic acid (AA) signaling cascade [31‑35] have presence of alterations in immune system activity,
also been described in depressed patients. Taken together, specifically in relation to excitatory symptoms of
these results confirm the substantial involvement of BD. We also briefly examined the possible use of
the immune system in the mechanisms of depressive anti‑inflammatory drugs as add‑on therapies to
disorders, possibly via interactions between the immune improve clinical outcomes.
system and the neuroendocrine and autonomic nervous
system. [36‑40] We performed a literature review through a careful
search of articles using PubMed. We conducted an
Starting from these observations, the role of the immune initial search using keywords such as “affective
system has been investigated in other neuropsychiatric disorder” or “major depression” or “bipolar dis*”
diseases, including bipolar disorder (BD), schizophrenia, and “inflammat*” to provide context. Subsequent
anxiety disorders, and personality disorders. A chronic searches were performed using the following key
inflammatory state that exacerbates during symptomatic words: “bipolar dis*” and/or “mania” or “manic” or
relapses has been suggested to be involved in the “mixed” or “depressi*”, cross‑referenced with a set of
pathophysiology of BD. [41] Interestingly, therapy with inflammation‑related terms, such as “cytokine”, “IL”,
IFN‑α has been reported several times to induce “glia”, “oxidative stress”, and “AA”. To examine the
manic/hypomanic or mixed states in nonpsychiatric role on the immune system of drugs commonly used
patients. [42‑45] One study highlighted the higher to treat excitatory symptoms, we cross‑referenced
prevalence of mild excitatory symptoms (i.e. irritable the above‑mentioned set of inflammatory‑related
mood, racing thoughts, distractibility, agitation, and keywords with “lithium”, “mood‑stabilizing agents”,
insomnia) associated with anhedonia and fatigue and “antipsychotics”. Finally, to identify studies on
in IFN‑α treated patients, rather than typical major the possible role of anti‑inflammatory drugs in the
depressive or euphoric symptoms. [46] Another study management of affective episodes, we cross‑referenced
found that nonpsychiatric patients are more likely to the mood‑related keywords mentioned earlier with
develop depressive symptoms following a therapy with the terms “anti‑inflammatory drugs”, “coxib” and
IFN‑α if they experienced lifetime subthreshold manic/ “anti‑TNF‑α”.
hypomanic symptoms. [47] Similarly to what has been
observed in depression, there is a high rate of comorbidity Reference lists from selected papers were
between BD and other inflammation‑related medical subsequently searched to identify further relevant
conditions, such as diabetes, metabolic syndrome, and literature. We limited the search to papers written
cardiovascular and cerebrovascular diseases, [48‑50] which in English. There were no timeframe limitations in
led some authors to question if BD could be considered our searches. Data on alterations of the inflammatory
as a multi‑system inflammatory illness. [51] system in excitatory phases of BD (mania, hypomania
and mixed states) are presented together because
Many studies conducted on BD patients have most of the studies do not specifically differentiate
demonstrated increased levels of pro‑inflammatory between the three.

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