Serotonin dysfunction in ADHD

Summary & key facts

This review brings together biochemical, genetic, animal and drug studies that point to problems with serotonin (5-HT) in at least some people with ADHD. The authors report a common finding of reduced serotonin availability and highlight possible weak links in the serotonin production pathway (for example the step from tryptophan to 5-hydroxytryptophan and the cofactor tetrahydrobiopterin). The review notes the evidence is mixed and ADHD is genetically and clinically diverse, so serotonin changes may matter more in some cases than others.

Key facts:

• ADHD affects an estimated 4–7.6% of children and adolescents worldwide, and about 65% of childhood cases persist into adulthood (around 2.5% of the adult population).
• The review finds an overall theme of reduced serotonin (5-HT) availability in ADHD, with several studies reporting significantly lower serum 5-HT levels in people with ADHD.
• Studies report altered levels of the serotonin precursor tryptophan and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in blood and urine in ADHD, suggesting changes in serotonin production and breakdown.
• Genetic work has flagged multiple serotonin-related genes as candidates for ADHD risk, including the serotonin transporter gene (SERT) and tryptophan hydroxylase 2 (TPH2), though the authors emphasize that ADHD likely results from many gene
• A specific serotonin receptor (5-HT1b) has been linked to ADHD-relevant behaviors in animals: rodents without 5-HT1b show more hyperactivity and impulsivity, and restoring the receptor in adulthood reduced impulsivity in those models.
• In a human candidate-gene study (N = 990), a serotonin receptor SNP (rs6296 in 5-HT1b) was significantly associated with higher inattentive scores on the Adult ADHD Self-Report Scale.
• ADHD drugs affect serotonin as well as dopamine and noradrenaline: stimulants (methylphenidate and amphetamines) increase synaptic 5-HT among other monoamines, and amphetamines inhibit multiple monoamine transporters (including 5-HT transpo
• The authors note limits and risks of current treatments: up to about 30% of people may not respond to stimulant medications, stimulant misuse has been reported (5.1 million people aged 12+ in a US survey, ~1.9% of the population), and long-

Abstract

It is well accepted that attention deficit hyperactivity disorder (ADHD) is in part driven by dysfunction in the monoaminergic neurotransmitter system, but both the extent of dysfunction and possible therapeutic avenues presented by serotonergic neurotransmission is frequently overlooked. As such, we present key evidence for dysfunction in serotonergic transmission, as seen from biochemical, genetic and pharmacological perspectives. An overall deficit in serotonin availability is a common theme throughout the literature, thus this review aims to explore possible dysfunctions in the serotonin synthesis pathway which result in this reduced bioavailability, and investigate whether such dysfunctions could be loci of change in ADHD. We have identified several steps in transmission, namely the conversion of tryptophan to 5-hydroxytryptophan and its use of cofactor tetrahydrobiopterin, which could present promising avenues for development of novel clinical interventions for ADHD.

Topics

Attention Deficit Hyperactivity Disorder Bipolar Disorder and Treatment Neurotransmitter Receptor Influence on Behavior

Categories

Health Sciences Medicine Psychiatry and Mental health

Tags

Attention deficit hyperactivity disorder Central nervous system Internal medicine Medicine Monoaminergic Neurochemical Neurochemistry Neurology Neuroscience Neurotransmission Neurotransmitter Psychiatry Psychology Receptor Serotonergic Serotonin