Indole Tryptophan Metabolism and Cytokine S100B in Children with Attention-Deficit/Hyperactivity Disorder: Daily Fluctuations, Responses to Methylphenidate, and Interrelationship with Depressive Symptomatology

Abstract

Background: Indole tryptophan metabolites (ITMs), mainly produced at the gastrointestinal level, participate in bidirectional gut-brain communication and have been implicated in neuropsychiatric pathologies, including attention-deficit/ hyperactivity disorder (ADHD). Method: A total of 179 children, 5-14 years of age, including a healthy control group (CG, n = 49), and 107 patients with ADHD participated in the study. The ADHD group was further subdivided into predominantly attention deficit (PAD) and predominantly hyperactive impulsive (PHI) subgroups. Blood samples were drawn at 20:00 and 09:00 hours, and urine was collected between blood draws, at baseline and after 4.63 -2.3 months of methylphenidate treatment in the ADHD group. Levels and daily fluctuations of ITM were measured by tandem mass spectrometer, and S100B (as a glial inflammatory marker) by enzyme-linked immunosorbent assay. Factorial analysis of variance (Stata 12.0) was performed with groups/subgroups, time (baseline/after treatment), hour of day (morning/evening), and presence of depressive symptoms (DS; no/yes) as factors. Results: Tryptamine and indoleacetic acid (IAA) showed no differences between the CG and ADHD groups. Tryptamine exhibited higher evening values ( p < 0.0001) in both groups. No changes were associated with methylphenidate or DS. At baseline, in comparison with the rest of study sample, PHI with DS+ group showed among them much greater morning than evening IAA ( p < 0.0001), with treatment causing a 50% decrease ( p = 0.002). Concerning indolepropionic acid (IPA) MPH was associated with a morning IPA decrease and restored the daily profile observed in the CG. S100B protein showed greater morning than evening concentrations ( p = 0.001) in both groups. Conclusion: Variations in ITM may reflect changes associated with the presence of DS, including improvement, among ADHD patients.

Is S100B Involved in Attention-Deficit/Hyperactivity Disorder (ADHD)? Comparisons with Controls and Changes Following a Triple Therapy Containing Methylphenidate, Melatonin and ω-3 PUFAs

“…When comparing S100B values between ADHD patients and controls, our results differed from the first studies presented by Oades et al [ 42 ] and later by our group [ 45 ], in which no significant differences were observed between participants with ADHD and healthy children; indeed, an inverse relationship was reported between peripheral S100B levels and ADHD symptoms [ 43 ]. According to this, Oades et al [ 42 ] supported that the glial damage occurring in ADHD should be differentiated from the one taking place in other neuroinflammatory-based processes, such as schizophrenia [ 33 , 34 , 65 ], depression [ 66 ] or Alzheimer’s disease [ 35 , 36 ].…”

“…However, a cross-sectional study conducted on school-aged children with heavy metal-related ADHD in China revealed a significantly positive correlation between serum S100B levels and ADHD-like symptoms, although the correlation proved negative for the inattention and hyperactivity/impulsivity indexes in the Conners’ rating scale for teachers [ 44 ]. The results obtained by our group in a further clinical trial agreed with Oades et al [ 42 ], as no significant differences in serum S100B levels between ADHD children and controls were found; nevertheless, we also revealed that patients with depressive symptoms were prone to show higher S100B levels [ 45 ]. Given the contradictory results obtained by the few studies measuring S100B in patients with ADHD, further exploration of the involvement of this protein in ADHD could help understand the pathophysiology of this disorder.…”

“…The most striking result was a paradoxically significant increase in S100B concentrations three months after starting therapy (T3) compared to baseline (T0) in the ADHD group, at the same time that a significant improvement in the attention scores (QA/SA) was also observed. In the study conducted by Fernández-López et al [ 45 ], a non-significant increase in S100B levels was reported by our group following MPH treatment, although the lack of noticeable differences was then attributed by the authors themselves to the large dispersion of data. Certainly, we have no clear explanation for the paradoxical increase in S100B levels after three months of treatment onset.…”

“…Instead, astrocytic alteration in ADHD would be characterized by decreased release of S100B, reflecting insufficient energy supply to neurons [ 67 ]. Certainly, in the investigations conducted by Oades et al [ 42 ] and Fernández-López et al [ 45 ], the control group was partly or totally composed of healthy siblings to the ADHD participants; therefore, genetic similarities in S100B values should be taken into consideration. Additionally, these authors excluded patients with neurologic comorbidities, including epilepsy.…”

Evaluation of Serum S100B Levels in Male Children Younger than 6 Years Old with Autism Spectrum Disorder: A Psychiatric and Biochemical Perspective

“…This day/night difference was not seen in the healthy control group or at discharge time in the schizophrenia patients either (27). It has been documented that both ADHD and healthy control groups had higher serum S100B concentrations in the mornings than in the evenings (28). Considering all, it may E a r l y A c c e s s be concluded that whether this is related to a psychiatric disorder pathophysiology or S100B circadian rhythm remains unclear.…”