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.