Differential responses of two related neurosteroids to methylphenidate based on ADHD subtype and the presence of depressive symptomatology.

Rationale: Attention deficit with hyperactivity disorder is a neurodevelopmental disorder associated with alterations in the prefrontal cortex via dopaminergic and noradrenergic neurotransmission. Neurosteroids (e.g. allopregnanolone and dehydroepiandrosterone) modulate the release of multiple neurotransmitters.

Objective: This study aims to determine the baseline concentrations and daily variations in allopregnanolone and dehydroepiandrosterone in children with attention deficit hyperactivity disorder (ADHD) and to determine the effect of chronic administration of methylphenidate on clinical symptoms and on the concentrations of these two neurosteroids.

Methods: We included 148 children aged 5 to 14 years, subdivided into two groups: ADHD group (n = 107, with a diagnosis of ADHD (DSM-IV-TR criteria), further classified in subtypes by an "attention deficit and hyperactivity scale" and subgroups by the "Children's Depression Inventory") and a control group (n = 41). The clinical workup included blood samples that were drawn at 20:00 and 09:00 hours, at inclusion in both groups, and after 4.61 ± 2.29 months of treatment only in the ADHD group, for measurements for allopregnanolone and dehydroepiandrosterone. Factorial analysis, adjusted for age and gender, was performed by using Stata 12.0.

Results: Methylphenidate induced the doubling of allopregnanolone levels in the predominantly inattentive ADHD patients without depressive symptoms (27.26 ± 12.90 vs. 12.67 ± 6.22 ng/ml, morning values). Although without statistical differences, baseline dehydroepiandrosterone levels were higher and slightly increased after methylphenidate in the ADHD subtype with depressive symptoms (7.74 ± 11.46 vs. 6.18 ± 5.99 ng/ml, in the morning), opposite to the lower baseline levels, and further decrease after methylphenidate in the inattentive subtype with depressive symptoms.

Conclusions: Different neurosteroids may have different baseline concentrations and differential responses to methylphenidate treatment as a function of ADHD subtype and subgroup. These differential responses may be a clinical marker of ADHD subtype and/or co-morbidities.