Revisiting the Role of Serotonin in Attention-Deficit Hyperactivity Disorder: New Insights from Preclinical and Clinical Studies

Attention-deficit hyperactivity disorder (ADHD) is characterized by core symptoms of inattention, hyperactivity, and impulsivity. Aberrant dopaminergic and noradrenergic neurotransmission are often implicated in the pathogenesis of these symptoms because ADHD treatments increase synaptic levels of these neurotransmitters in brain regions associated with attention and impulse control. However, some ADHD treatments also enhance serotonergic neurotransmission in these regions, which could contribute to their efficacy. Here, we review preclinical and clinical data highlighting functional interactions between the serotonergic and catecholaminergic systems in mediating ADHD phenotypes and responses to treatment. The potential utility of serotonergic compounds for treating distinct behavioral features and psychiatric comorbidities (e.g., depression) is also discussed. Overall, preclinical and clinical studies underscore important neuromodulatory effects of serotonin on the catecholaminergic system in mediating distinct ADHD behavioral phenotypes, notably hyperactivity–impulsivity and emotional dysregulation. Incorporating a basic understanding of dynamic monoaminergic interactions and their contributions to ADHD symptoms may identify new targets for treatment. Beyond ADHD core symptoms, emotional dysregulation, which is closely linked to serotonergic dysfunction, is common in ADHD and significantly contributes to negative outcomes across the lifespan. Therefore, an expanded conceptualization of ADHD that includes emotional dysregulation may facilitate insight into ADHD pathology and treatment.