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EFFECT OF PHARMACOLOGICAL TREATMENT severity of both depressive and manic/hypomanic
ON INFLAMMATORY MARKERS IN BD phases, although more pronounced benefits were
noted during depression. [223]
Mood stabilizing agents commonly used in the therapy
of BD have been suggested to partially exert their Tumor necrosis factor‑α has been suggested to play
activity via the regulation of the immune system and a major role in mechanisms related to inflammation,
oxidative stress pathways. [191] A number of studies neurodegeneration, and possibly neuroprogression of
have provided evidence supporting anti‑inflammatory the disease in BD. Another study by Guloksuz et al. [224]
effects of lithium via different mechanisms. [192,193] demonstrated a correlation between higher levels
Lithium decreases the synthesis of pro‑inflammatory of TNF‑α and a poor response to lithium treatment
enzymes and molecules (i.e. IL‑1β, TNF‑α, PG, NO, in BD patients. According to this evidence, TNF‑α
iNOS, COX‑2 and PLA2), and regulates microglial could be considered as a potential new target for
activity in vitro. [194‑199] Similarly, lithium therapy shows the development of new drugs for BD therapy. [96,225]
some immunoregulatory activity in bipolar patients. Antagonism of IL‑6 has also been hypothesized to be a
It has been demonstrated to decrease the number and novel therapeutic option to improve clinical outcome
the activity of inflammatory cytokine‑producing cells in BD. [226]
in BD patients [197,200] and to reduce the synthesis of
Th1 cytokines. [201] Lithium also normalizes elevated CONCLUSION
levels of sIL‑2R and sIL‑26R in rapid‑cycling BD
patients. [202] The literature reviewed provides evidence for a role
of the inflammatory system in the pathophysiology of
As mentioned earlier, valproic acid down‑regulates mood disorders. Nevertheless, a high rate of variability
the AA signaling cascade by inhibiting the synthesis is observed among the different studies, especially
of COX‑1 and COX‑2 in the rat brain. [203] In addition, those focused on evaluating the peripheral expression
valproate and other antiepileptic drugs commonly used of inflammatory markers. There is a general consensus
as mood‑stabilizing agents, namely carbamazepine, that BD patients show higher levels of cytokines in
lamotrigine, oxcarbazepine, and topiramate, blood samples compared to healthy controls; however,
significantly reduces the synthesis of a number of data are inconsistent and comparisons between
cytokines in vitro. [80,204,205] Anti‑psychotic drugs such as peripheral levels of inflammatory markers in manic/
clozapine, quetiapine, risperidone, and ziprasidone also hypomanic/mixed versus euthymic or depressed BD
show some immunoregulatory effect by modulating the patients fail to converge to univocal conclusions.
AA signaling cascade, cytokine and acute‑phase protein This may be explained by a number of reasons. First,
synthesis, and microglial activation both in vitro and studies differ in their methodology; some of them by
in vivo. [80,129,131,206‑217] assessing the expression of cytokines in serum, others
in plasma, and yet others by evaluating cytokine
FUTURE DIRECTIONS production by in vitro stimulation of white blood cells
from BD patients. Second, peripheral cytokine levels
Because of the converging evidence pointing to are influenced by several confounding factors, such as
inflammatory dysregulation in the pathophysiology smoking status, body mass index, sleep disturbances,
of psychiatric diseases, drugs specifically modulating physical activity, and medications. Third, BD is highly
the inflammatory response, such as acetylsalicylic heterogeneous in its manifestations so that a thorough
acid and other nonsteroidal anti‑inflammatory selection of patients and classification of their mood
drugs (NSAIDs), omega‑3 fatty acids, anti‑TNF‑α state might be difficult. Finally, not all studies take into
agents, minocycline, and N‑acetyl cysteine (NAC) account factors such as age at onset and duration of
have been investigated as new therapeutic illness, number of relapses, polarity of the last relapse,
options, with still controversial results. [3,218‑221] In and the time intercurring from the last episode, which
particular, a randomized study proved the efficacy might be of importance in modifying the inflammatory
of adjunctive therapy with celecoxib, a nonsteroidal status.
anti‑inflammatory drug and a selective inhibitor of
COX‑2, in rapidly improving depressive symptoms An enhanced pro‑inflammatory status might partially
in depression and mixed states of BDI and BDII explain the high rate of medical conditions often comorbid
patients. [222] Another study found elevated levels with BD, that is, cardiovascular, cerebrovascular,
of gene transcripts for prostaglandin D synthetase and metabolic diseases. Similarly, smoking, sleep
and prostaglandin D2 11‑ketoreductase during impairment, and alcohol and substance abuse, the
depressive episodes in rapid‑cycling BD patients; prevalence of which is high in BD patients, might
add‑on treatment with celecoxib improved the contribute to the maintenance of a pro‑inflammatory

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