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Table 2: Studies in living humans included in this review investigating microglia or neuroinflammation in bipolar disorder
Study Origin Population Design Results Observations
Soderlund Sweden 15 bipolar I, CSF cytokine Higher IL‑1β and lower Evidence for
et al. [40] (Stockholm‑Linköping‑ 15 bipolar II, concentrations IL‑6 levels bipolar than neuroinflammation and
Göteborg) all euthymic, assessed through controls. Patients with for IL‑1β involvement;
30 healthy immunoassay‑based recent manic/hypomanic cross‑sectional design
volunteers protein array multiplex episodes had significantly is a methodological
system; cross‑sectional higher IL‑1β levels than weakness
those without
Stich Germany 40 bipolar Paired CSF and serum Eight patients with bipolar Cross‑sectional design;
et al. [41] (Freiburg, Greifswald) versus 26 samples analyzed through disorder versus 1 control possible that some
controls with ELISA to detect the had AI > 1.4; 5 patients bipolar patients have
pseudotumor concentration of antibodies versus 0 controls had autoimmune disorder; 1
cerebri against Toxoplasma oligoclonal bands of 5 patients with bipolar
gondii, HSV types 1 and 2, disorder show evidence of
CMV, and EBV. Specific neuroinflammation
AI > 1.4 = intrathecal
specific antibody
synthesis; oligoclonal
bands = chronic
neuroinflammation
Isgren Sweden (Göteborg‑ 21 euthymic Measurements of serum CSF IL‑8 only was higher Cross‑sectional design
et al. [42] Stockholm; England bipolar disorder and CSF concentrations in bipolar patients with is a limitation. The study
[London]) patients versus of 11 cytokines; IL‑6 respect to controls; favors the presence of
71 age‑ and measured through validation reanalysis neuroinflammation in
sex‑matched singleplex assay; IL‑1β, showed measurements to bipolar disorder, but
healthy controls IL‑2, IL‑4, IL‑5, IL‑8/ have been valid, but also do not rule out that
CXCL8, IL‑10, IL‑12, showed no correlation medication could account
IL‑13, TNF‑α, and IFN‑γ between serum and CSF for the results; there was
through the MSD 96‑well levels no correlation between
multi‑array and multi‑spot central and peripheral
human cytokine assay; data
validation of IL‑8
measurement re‑analysis:
21 patients and 20
controls with Proseek
Multiplex Inflammation I
Jakobsson Sweden (Göteborg‑ 221 bipolar MCP‑1, YKL‑40, sCD14, MCP‑1, YKL‑40, and Cross‑sectional design
et al. [18] Stockholm; England versus 112 TIMP‑1, and TIMP‑2 TIMP‑2 levels higher is a limitation. The study
[London]) healthy controls measured through in patients with bipolar favors the presence
for serum ELISAs disorder than controls of peripheral chronic
sampling; 125 in CSF; serum and CSF inflammation and
bipolar versus MCP‑1, YKL‑40 levels neuroinflammation in
87 controls for correlated, but differences bipolar disorder, but also
CSF sampling in CSF levels between stresses the fact that the
bipolar patients and two are independent
controls were independent
from serum levels
Haarman The Netherlands 14 bipolar Dynamic 60‑min PET Significantly increased This study provides strong
et al. [43] (Groningen) I versus 11 scan after injecting of [ C]‑(R)‑PK11195 evidence for the presence
11
healthy controls [ C]‑(R)‑PK11195, a binding potential in bipolar of neuroinflammation
11
ligand of the peripheral patients versus controls in bipolar I disorder,
benzodiazepine receptor in the right hippocampus; but the sample was
that constitutes a a trend toward the same small. Furthermore, the
microglial marker finding was present for the cross‑sectional nature of
left hippocampus the design does not allow
to establish causality
ELISA: enzyme‑linked immunosorbent assay; CSF: cerebrospinal fluid; HSV: herpes simplex virus; CMV: cytomegalovirus; EBV: Epstein‑Barr virus; IL‑1β: interleukin‑1
beta; IFN‑γ: interferon‑γ; MCP‑1: monocyte chemoattractant protein‑1; sCD14: soluble cluster of differentiation 14; TIMP‑1: tissue inhibitor of metalloproteinases‑1;
TIMP‑2: tissue inhibitor of metalloproteinases‑2; PET: positron emission tomography; AI: antibody index; TNF‑α: tumor necrosis factor alpha; MSD: meso scale
discovery; YKL‑40: human cartilage glycoprotein‑39

Despite our care to avoid studies of peripheral immunity talked‑about, but not proved. Another striking result
in bipolar disorder, many of these studies appeared of our search is the high number of reviews (n = 96),
through our search. This was due to the fact that many and especially of those focusing on this issue (n = 40).
of these papers speak about neuroinflammation without Most reviews mix‑up peripheral and brain studies,
actually showing it. In many of these fascinating reaching unwarranted conclusions. The activation
and fashionable papers, the question of how chronic of microglia must not be taken only as evidence of
inflammation and immune derangement would “enter” neuroinflammation, because it might also be consistent
the brain and produce neuroinflammation is much with a host of other functions, such as remolding the

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