4. Discussion
The relationship between inflammation and OCD is unclear. The fact that
children show signs of OCD and tic disorder after a bacterial throat
infection suggests that neuroinflammation plays an important role in the
etiology of OCD [15]. The most important hypotheses explaining this
relationship involve guanosine triphosphate (GTP) cyclohydrolase I and
indoleamine 2,3 dioxygenase (IDO) activation.
IDO is activated by many proinflammatory cytokines. As a result of IDO
enzyme activation, tryptophan, the primary amino acid precursor of
serotonin, is converted to kynurenine, resulting in the potential
depletion of serotonin [16] (Fig. 1).
GTP cyclohydrolase I is also activated by many proinflammatory
cytokines, especially IFN-ɣ. With the activation of GTP cyclohydrolase
I, the production of neopterin increases and that of BH4 decreases in
response to GTP. Therefore, neopterin is considered a biochemical marker
of the cell-mediated immune response. BH4 in this pathway is the main
cofactor for rate-limiting steps in the formation of serotonin,
noradrenaline, and dopamine. In addition, BH4 plays an important role in
regulating the presynaptic release of neurotransmitters from nerve
terminals [5,7]. The pathway of cytokine–neopterin and BH4 affects
the formation of NO by increasing reactive oxygen species such as NOX
and O2- and activating iNOS [8]
(Fig. 1).
In this study, all proinflammatory cytokine levels were found to be low,
but this decrease was statistically significant only for TGF-1β. There
are few previous studies examining the relationship between OCD and
cytokine levels in children. In a study in which comorbidities were not
excluded but drug use was, TNF-α levels were significantly higher in
children with OCD compared with healthy controls; TGF-1β, IL-1β, and
IL-17 levels were also low, but not significantly so [17]. In a
study of adults with OCD, in which comorbidities and drug use were
excluded, the IL-1β level was significantly higher in the OCD group
compared to the healthy control group, whereas IL-2, IL-6, and TNF-α
levels were significantly lower; no difference was found in IL-10 levels
[18]. Considering these findings, the relationship between OCD and
proinflammatory cytokines identified in this study is compatible with a
recent meta-analysis [19]. Differences among these findings may be
explained in terms of the exclusion of psychiatric comorbidities, which
might affect cytokine levels, the effect of OCD on stress levels, and
the decrease in immune system cell levels and cytokine levels due to
increased the hypothalamic–pituitary–adrenal (HPA) axis activity and
cortisol levels as a result of this effect [20,21]. In addition,
most studies in the literature were conducted in adult patients, and
cytokine production in adults may differ from that in children [22].
To our knowledge, this study is
the first to find that circulating TGF-1β levels are significantly lower
in OCD patients. The relationship between blood concentration of TGF-1β
and pediatric OCD must be investigated through additional studies.
In this study, the neopterin level was significantly higher and BH4
significantly lower in children with OCD compared to the healthy control
group. A prior study conducted in adult patients with OCD found that the
neopterin level in the OCD group was not significantly different from
that in the control group, but there was a significant decrease in the
level of neopterin following the dexamethasone suppression test
performed to suppress the immune system [23]. Only a few studies in
the literature have investigated the relationship between neopterin
levels and psychiatric disorders. In recent years, as a result of
studies conducted in adult patients diagnosed with major depressive
disorder, neopterin levels have been among the candidates for relevant
immune markers in major depressive disorder [6]. A study of children
diagnosed with autism spectrum disorder (ASD) found that neopterin
levels were significantly higher in children with ASD compared to the
control group [24]. In a study of adult patients diagnosed with
bipolar disorder, neopterin levels were significantly higher in the
bipolar group compared to the control group [25]. We found no study
investigating the relationship between OCD and BH4 levels. When
psychiatric diseases other than OCD were examined, BH4 levels were found
to be significantly lower (e.g., in patients with adult schizophrenia)
compared to healthy controls [26]. Although the proinflammatory
cytokine levels did not increase in this study, activation of the
neopterin– BH4 pathway could have been due to elevated IFN-ɣ levels and
decreased 6-pyruvyl-tetrahydropterinsynthase levels [5,27].
In this study, NO levels were found to be significantly higher in
children with OCD compared to the healthy control group. A review of the
literature identified no studies
examining the relationship between
OCD and NO levels in children. A
review of studies and meta-analyses conducted in patients with adult OCD
revealed that NO levels were significantly increased, in keeping with
this study [28–30]. It was thought that increased neopterin levels,
and possibly increased IFN- ɣ levels and iNOS activation, may induce an
increase in reactive oxygen species and thus in NO levels [8].
The results of this study indicate that
the activity of the neopterin–BH4
pathway and changes in inflammatory and oxidative parameters may
underlie OCD. In addition, the
correlations of TGF-1β (r<0.3, weak), neopterin, BH4
(r<0.3, weak), and NO (r<0.3, weak) levels with
C-YBOCS total scores suggest that
this pathway may be involved in the etiology of OCD. Furthermore,
the positive correlation between
illness duration and C-YOCBS obsession and total scores indicates that
illness severity increases over time. Consequently, the results of this
study show that the importance of early diagnosis and treatment of OCD,
and the levels of TGF-1β and NO and the activation of the neopterin–BH4
pathway may be implicated in the pathophysiology of OCD. Additionally,
anti-oxidant and BH4 adjuvant therapies should be investigated as
treatment options for OCD.
In this study, TGF-1β, IL-2, IL-17, and NO levels were evaluated, which
have been examined in few previous studies in children with OCD, and the
levels of neopterin and BH4, which have not been previously investigated
in children with OCD. In addition, we excluded psychiatric and physical
comorbidities and the use of psychotropic and non-psychotropic drugs
that might have influenced the biological results.
The present study has some limitations. The cross-sectional study design
allowed the measurement of cytokine levels at only a single time point.
The small sample size was inadequate to be representative of the general
population. Also, TGF-1β, TNF-α, IL-6 and neopterin levels resulted in
high standard deviations due to extreme values and the small sample
size, and this may have affected the statistical results. However, these
extreme values were not excluded from this study because they were
within the measuring range of the kits used. In addition, we did not
assess the serum levels of neurotransmitters (e.g., serotonin, dopamine,
and noradrenaline), cortisol, IFN- ɣ, and
6-pyruvyl-tetrahydropterinsynthase. Further studies involving a larger
population and addressing the limitations of this study are needed, and
the causal link between TGF-1β, neopterin, BH4 and NO and pediatric OCD
requires further investigation.