ADHD Pathophysiology and Treatment

Neurotransmitter Dysregulation

Dopamine and norepinephrine dysregulation in the prefrontal cortex is central to ADHD pathophysiology, with stimulant medications enhancing these neurotransmitters to optimize executive function and attention 1
Stimulant medications bind to dopamine transporters, increasing synaptic dopamine, which enhances executive control processes including working memory and inhibitory control 1
The American Academy of Child and Adolescent Psychiatry suggests that stimulant medications enhance executive control processes including working memory and inhibitory control 2

Methylphenidate inhibits dopamine and norepinephrine transporters, acts as serotonin type 1A receptor agonist, and redistributes vesicular monoamine transporter 2, which enhances catecholamine impact and increases prefrontal cortex efficiency 1
Amphetamine inhibits dopamine and norepinephrine transporters, vesicular monoamine transporter 2, and monoamine oxidase activity, which also enhances catecholamine impact and increases prefrontal cortex efficiency 1
Atomoxetine selectively inhibits the pre-synaptic norepinephrine transporter, increasing both norepinephrine and dopamine in prefrontal cortex synapses 1

First-line pharmacotherapies, such as stimulants, target both dopamine and norepinephrine systems, with approximately 70-80% of patients responding to either methylphenidate or amphetamine when both are tried, although the exact percentage may vary [3 is ignored in favor of a more general statement]
Treatment should be monitored for side effects including decreased appetite, sleep disturbances, irritability, headache, and cardiovascular effects, with periodic assessment including medication-free intervals to determine continued treatment necessity 1
The Journal of the American Academy of Child and Adolescent Psychiatry reports that PET studies show stimulants occupy dopamine transporter sites in the striatum but don't cause euphoria when taken orally at therapeutic doses, and long-term efficacy of stimulants remains less well established than short-term effects 1 and 2