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Table 1: Contd...
Study Origin Source Population Measure(s) Results Observations
de Brazil (São Paulo, Stanley 29 bipolar, 29 RNA extracted Immune Neuroinflammatory
Baumont SP and Porto Neuropathology schizophrenia, 30 from frontal cortex response‑and microglia activation
et al. [36] Allegre, Rio Consortium nonpsychiatriccontrols to assess gene stress‑related is compatible
Grande do Sul) expression profile; genes were with these data;
and Portugal cloned DNA for differentially the influence of
(Braga and microarray analysis expressed medication has not
Guimarães, between the been ruled out
Braga) control and the
patient group;
bipolar patients
differed from those
with schizophrenia
in that the former
showed an
up‑regulation of
a set of 28 genes
in bipolar disorder
with respect to
schizophrenia
*S100β induces the expression of IL‑1β in cultured ratmicroglia; [37,38] astrocyte synthesis of S100β in AD may be triggered by microglial‑derived IL‑1. [39] BA: brodmann’s
c
area; TNFR2: tumor necrosis factor receptor, type 2; IL‑1β: interleukin‑1 beta; MIP 1α/LD78: macrophage inflammatory protein‑1 alpha/LD78; PrP : cellular prion protein;
QRT‑PCR: quantitative real‑time polymerase chain reaction; MyD88: myeloid differentiation factor 88; NF‑κB: nuclear factor kappa B; GFAP: glial fibrillary acidic protein;
iNOS: inducible nitric oxide synthase; NMDA: N‑methyl‑D‑aspartic acid; HERV: human endogenous retrovirus; HERV‑W: human endogenous retrovirus‑W; AA: arachidonic
acid; cPLA2: cytosolic phospholipase A2; sPLA2‑IIA: secretory phospholipase A2‑IIA; COX: cyclooxygenase; mPGES: membrane prostaglandin E synthase; cPGES: cytosolic
prostaglandin E synthase; TNF‑α: tumor necrosis factor α
It proved to be more tiresome to download all papers, individual that eventually ensued in bipolar behavior
but this allowed us to identify two papers that would and disorder, cannot be probed. In fact, to demonstrate
otherwise have gone undetected. Surprisingly, the causality we need longitudinal study designs, and in
majority of suitable articles regarded postmortem the case of neuroinflammation and bipolar disorder all
studies. These studies (n = 15) [Table 1] favored the relevant articles were based on cross‑sectional articles.
idea of the existence of neuroinflammation in bipolar While this was mandatory for postmortem studies, it
disorder in their majority. Two provided indirect was not for studies investigating living humans. Future
evidence for microglial activation, while four were not studies should be able to tackle the causality question
consistent with the presence of neuroinflammation in by studying the same patients across the various phases
bipolar disorder. However, in one of these, it is possible of their illness. However, the fact that the supposed
[23]
that treatment could have set‑off neuroinflammation. In neuroinflammation was present to some extent also
fact, patients were receiving drugs such as lithium and when bipolar disorder was in its euthymic phases
valproate, which both interfere with the arachidonic strongly argues against the lack of involvement of the
acid cascade, [45] one of the cross‑roads of excitotoxicity brain immune system in bipolar disorder.
and neuroinflammation. [46] The evidence stemming
from in vivo studies (n = 5) is consistent with the The studies included in our review were methodologically
presence of neuroinflammation in bipolar disorder, different, and their sample sizes were much variable.
also in consideration of the fact that most patients were Investigations of neuroinflammatory markers in the CSF
sampled/tested when euthymic. The demonstration were all but one carried out in Sweden and conducted
of peripheral benzodiazepine receptor alterations in by the same Karolinska‑Gothenburg group. One of
bipolar I disorder patients may constitute a definitive these studies had to be excluded due to sample and
demonstration, [43] but it should also be considered data duplication, [21] but all these studies were quite
that such alterations in the brain of people with consistent in their conclusions, supporting the existence
bipolar disorder, which are consistent with microglial of neuroinflammation in bipolar disorder. This might
activation, may not be specifically related to the have introduced a site bias. The markers tested each
pathogenesis of bipolar disorder or any diagnosis, but time in postmortem studies differed, even when the
rather to disease activity. [47] same research groups were involved. Hence, we had no
population overlap, with the same group first reporting on
Causality effects, that is, whether it is bipolar disorder some people and then on a bigger sample that comprised
that once established, triggers neuroinflammation, the formerly reported cases. We found no duplicates even
either through the adoption of a reckless lifestyle when data referred to the same population in postmortem
that is likely to promote a metabolic syndrome that studies. There was a tendency in Bethesda‑based groups
facilitates the onset of neuroinflammation, or rather it to support neuroinflammation while the German groups
is neuroinflammation that has always existed in a given were more skeptical about it [Table 1].

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