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Records identified through PubMed search:
neuroinflammat* or glia* or microglia* or
[(CXCL1 or CXCL2 or IL-1b* or IL-6 or
interleukin* or interferon* or tumor necrosis Additional records identified through Reference
factor or TNF* or NKκB) and (brain or lists, other databases and alternative
cerebrospinal fluid or CSF)], and “bipolar search strategies (n = 40)
disorder” or mania or manic or “recurrent
Identification
depression” in July 11, 2015 (n = 316)
Reviews, focused, with reference lists
potentially providing further records (n = 42)
Total records retrieved and evaluated for
inclusion (screened n = 356)
Reviews, unfocused (n = 56)
Reviews/meta-analyses
(n = 98)
Case reports/series (n = 5)
Screening speculative articles (n = 16)
Opinion papers, editorials,

Ethics not respected (n = 0)
Animal studies (n = 55)

Not relevant, unfocused (n = 100)

Eligibility Human original Excluded due to inadequate methodology
investigations (n = 82)
for investigating neuroinflammation in
bipolar disorder (n = 61)

Studies included in qualitative Peripheral markers (n = 50) In vitro experiments
synthesis (n = 21) (n = 4)

Included No separate analysis for bipolar disorder or no
bipolar disorder patients included or
neuroinflammation not investigated (n = 7)
Records after removing studies
using the same or overlapping
samples (n = 20)*
Measurements of
neuroinflammatory
components in the
Post-mortem (n = 15) In living humans (n = 5)
cerebrospinal fluid (n = 4)

Neuroimaging of neuroinflammatory
markers in the brain (n = 1)
Figure 1: Results for search and inclusion and design typology (*Despite the existence of overlapping samples, most studies except one, were not considered
duplicates since they reported on different datasets)

BASED ON THE SEARCH, IS THERE ANY to its anti‑neuroinflammatory, anti‑oxidative stress, or
EVIDENCE FOR NEUROINFLAMMATION IN anti‑apoptotic effect or to its mitochondrial dysfunction
BIPOLAR DISORDER? countering or glutamate/dopamine balancing actions, [44]
unless accompanied by evidence of neuroinflammatory
This review attempted to answer the question of whether markers moving in the desired direction (and the
neuroinflammation plays a role in the pathophysiology demonstration of their alteration at baseline).
of bipolar disorder. Furthermore, the evidence of abnormal peripheral
inflammatory reactivity cannot be taken as evidence
We may not speak of conclusive evidence of of neuroinflammation.
neuroinflammatory mechanisms in bipolar disorder
when the obtained evidence is too indirect. For Our search yielded a high number of interesting
example, when a molecule like N‑acetylcysteine is articles, but few of them suited the purpose of this
found to have some therapeutic activity in bipolar review. This was due to the fact that our search strategy
disorder, we may not specify whether this is related was over‑inclusive to avoid missing any suitable article.

Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 255