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imbalance between peripheral levels of pro‑ and medications, including aspirin, nonsteroidal
anti‑inflammatory cytokines with proteomic analysis anti‑inflammatory drugs, TNF‑α antagonists, and omega‑3
revealing that inflammatory pathways are associated fatty acids, in the treatment of mood disorders. [30‑34]
with BD and modified by mood‑stabilizing lithium
treatment. [1,11] Furthermore, adult subjects with BD are Given the increasing interest in the field of
at higher risk of developing comorbid medical illnesses neuroinflammatory mechanisms and mood disorders,
such as diabetes, metabolic and cardiovascular diseases we carried out a systematic review of literature
that are also associated with elevated levels of pro‑ analyzing the potential pathogenic role of inflammatory
inflammatory markers. [12,13] Potentially involved cytokines processes, decreased neurotrophin levels and oxidative
include tumor necrosis factor (TNF), interleukin‑2 (IL‑2), stress in the pathogenesis of juvenile BD.
IL‑6, IL‑8, IL‑13 and apolipoprotein A1. [14‑18]
SEARCH ALGORITHM AND INCLUSION CRITERIA
Finally, growing evidences are showing that increased
levels of oxidative stress may be linked to inflammatory We performed a literature search through PubMed using
and neuroplasticity pathways [19] and play a role in the following search algorithm: (bipolar disorder OR
the pathophysiology of BD. [20] A meta‑analysis found mania OR bipolar depression) AND (child* OR adolesc*
a significant elevation of oxidative stress biomarkers, OR youth) AND (neuroinflamm* OR inflamm* OR
such as thiobarbituric acid reactive substances (TBARS) neurovascular OR neurotrophin* OR oxidative stress).
and nitric oxide, during all phases of bipolar illness and Reports found through cross‑references were also
preliminary data indicated that oxidative stress may be reviewed and added if they met established search
corrected with pharmacological treatments. [5,6] criteria.

We included only original studies specifically reporting
As mood disorders have a relatively young median age
of onset, in the last 30 years pediatric mood disorders measurements of inflammatory markers or oxidative
[21]
have been studied more systematically, especially stress markers or neurotrophins in subjects diagnosed
depression and BD. [22‑24] In addition, studying clinical with BD. We used the following inclusion criteria:
features of mood disorders at onset in the offspring of (1) original research; (2) diagnosis of BD; (3) measurement
adults with depression or BD has become a promising of at least one inflammatory marker or neurotrophin or
research approach. [25,26] oxidative stress marker; (4) subjects’ age younger than
35 years; (5) reports in English language.
Several reports have shown a relationship between: (1) the Two psychiatrists screened the article titles for potential
dysregulation of inflammatory markers (increased levels of relevance, reviewed the identified abstracts and
IL‑6, IL‑1β, IL‑2, IL‑10, INF‑α and TNF); (2) genetic variation selected the full‑text papers potentially meeting the
in inflammatory genes [C‑reactive protein (CRP)‑gene inclusion criteria. The papers not meeting established
polymorphism] and pediatric major depressive criteria were excluded.
disorder; (3) changes in gene expression among subjects
[16]
[16]
with active mood disorders; (4) preliminary evidences The following variables were extracted from the
of an association between inflammation and suicidality reviewed reports: study sample size, type of study,
in depressed youths (decreased TNF‑α levels in suicidal subject age range, subject diagnosis, type of rating
compared to nonsuicidal depressed adolescents ) as scales and diagnostic interviews, measurement method
[27]
well as increased mRNA and protein expression of IL‑1β, and type of inflammatory marker investigated and main
IL‑6 and TNF‑α in Brodmann area 10 of suicide victims findings of the report.
relative to controls. [28]
MAIN FINDINGS
Among children and adolescents with BD, there
is a high prevalence of conditions associated with Nine papers were identified through the initial
inflammation, such as asthma, cardiovascular database search, and three adjunctive reports were
disorders, diabetes and obesity, [12] often associated found from cross‑references leading to a total of 91
with inflammatory markers, [13] including elevated screened papers [Figure 1]. Twelve reviews were
high‑sensitivity‑C‑reactive protein (hsCRP) and IL‑6. [29] excluded during the abstract screening. Thirty‑four
This is even more striking considering that subjects with full‑text papers were assessed for eligibility and 30
asthma, allergies, and other inflammatory conditions of them were excluded due to either (1) failure to
were routinely excluded from psychiatric samples. report on inflammatory or oxidative stress markers
or neurotrophins (n = 3); (2) included subjects with
Furthermore, recent studies have also examined the age > 35 years (n = 19); or (3) included nonaffected
potential psychiatric applications of anti‑inflammatory bipolar offspring (n = 3). Thus, 9 studies met all our

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