ADHD: Dopamine, Norepinephrine & Behavior

Attention-Deficit/Hyperactivity Disorder (ADHD) Overview

• ADHD is marked by impulsivity, hyperactivity, and inattention
• Diagnosable in childhood, persistence into adulthood is common
• Symptoms manifest as early as age 3, diagnosis possible from age 4
• Impacts school, work, and relationships
• Increases risk of substance use, STDs, incarceration, and psychiatric disorders
• Can lead to lower occupational achievements and higher divorce rates in adults
• Stimulant medications effectively reduce ADHD symptoms, improving lives

Epidemiology of ADHD

• Affects 7-15.5% of youth and up to 14.6% of adults
• DSM-5 doesn't specify an age cutoff for diagnosis, though guidelines allow diagnosis from age 4
• Symptom persistence reported in 80% of adolescents and 30-50% of adults
• ADHD prevalence in U.S. adults rose from 4.4% in 2006 to 14.6% in 2022
• More prevalent in boys (4:1 ratio) but underrecognized in girls due to differing presentations
• Underdiagnosis in females leads to negative social, educational, and health outcomes
• African American and Latino children are less likely to be diagnosed or treated for ADHD

Risk Factors for ADHD

• Both genetic and environmental risks are factors
• Having a first-degree relative with ADHD increases risk by 4-8 fold
• Likely a combination of thousands of different genes, not just a few specific ones
• Environmental factors include maternal smoking, fetal alcohol syndrome, and lead poisoning

ADHD Physiology

• Involves changes to dopamine (DA) and norepinephrine (NE) systems in the brain
• Two pools of DA release: tonic and phasic
• Tonic pool refers to a small amount of DA release that occurs in the absence of an action potential
• The tonic pool binds primarily to D₂ and D, autoreceptors on the presynaptic membrane
• The tonic pool helps provide feedback inhibition to inhibit further DA release
• Phasic pool refers to large amount of DA released during action potential
• The phasic pool binds primarily to post-synaptic DA receptors, leading to varying downstream effects
• Imbalances in tonic and phasic neurotransmitter release may contribute to ADHD
• A reduced tonic pool coupled with an exaggerated phasic release is thought to contribute to ADHD symptom expression

Etiology and Pathophysiology

• Exact cause of ADHD is unknown, but hyperactive and hypoactive catecholamine hypotheses exist
• Likely a combination of elements from both theories

Hypoactive Catecholamine Hypothesis

• Patients with ADHD have lower than normal density of DA receptors in brain areas like the prefrontal cortex
• Genetic polymorphisms affecting DA receptors and the (DAT) are linked to ADHD
• Hypoactivity of the NE system is also believed to be involved
• Supported by current medications used for ADHD
• Reduced receptor density, especially in the prefrontal cortex, and lower baseline DA/NE levels lead to inattentiveness

Hyperactive Catecholamine Hypothesis

• Suggests that hyperactivity of the DA and NE systems can lead to ADHD
• Genetic studies show links between ADHD genes leading to increased DA release and decreased reuptake of DA
• Pharmacotherapy for ADHD might work by reducing DA release
• If ADHD was simply an effect of decreased DA and NE levels, drugs such as levodopa/carbidopa should ameliorate symptoms, but they do not
• Excessive phasic release (or overactivity) of DA/NE contributes to hyperactivity and impulsivity

A More Complex Relationship for ADHD

• Likely not as simple as too much or too little DA and NE
• The tonic pool is thought to be reduced, leading to excessive buildup of catecholamines in the pre-synaptic cells
• Buildup results in larger than normal phasic release
• A diminished tonic pool causes an accumulation of neurotransmitters, resulting in an overly robust phasic release

Imaging and ADHD

• fMRI studies show abnormal activity in frontal and pre-frontal cortices in patients with ADHD
• A variety of additional brain areas have been implicated

Clinical Presentation of ADHD

• Patients experience difficulties with impulse control, hyperactivity, and attention
• Must display at least 6 symptoms from DSM-5 criteria in at least two different settings
• Children may have trouble sitting still, studying, finishing homework, or paying attention
• Adults may struggle with completing tasks, interrupt others, or be easily distracted
• Both may forget appointments/tasks
• Can be described as pushy, easily angered, stubborn, or frequently demanding
• Adults need only 5 symptoms (child diagnosis requires 6) to be defined with ADHD (adult > 17 years of age)
• Inattention symptoms include distractibility, forgetfulness, disorganization, and difficulty sustaining focus
• Hyperactivity/impulsivity features include excessive fidgeting, an inability to stay seated, interrupting others, and acting without forethought

DSM-5 Diagnostic Criteria for ADHD

• Six (or more) of the following symptoms of inattention and/or hyperactivity/impulsivity have persisted for at least 6 months
• Includes symptoms of Inattention & Hyperactivity/Impulsivity
• Symptoms present before 12 years of age and noticeable in at least two settings (e.g., at school [or work] and at home)
• Symptoms should be persistent, inconsistent with developmental level, and negatively impact social, academic, and occupational functioning
• Symptoms are not solely a manifestation of another psychiatric disorder, substance use disorder, or medical condition
• Presentation Types Include: Combined, Primarily Inattentive, Primarily Hyperactive/Impulsive

Typical Presentations & Subtypes of ADHD

• Children may be constantly moving; explosive or irritable; easily distracted; trouble completing tasks, and following directions
• Adolescents includes disorganization, forgetfulness, inattention, overreaction, and procrastination, plus risky behaviors may be observed such as reckless driving
• Adults includes inability to sit through class or work meetings, excessive talking observed by others to talk too much, and need to get places quickly
• Impulsive symptoms consist of frequent job changes, low frustration tolerance, and unstable interpersonal relationships with friends and family
• Inattentive symptoms include poor time management, poor motivation and concentration, forgetfulness, and excessive mistakes.
• ADHD Subtypes: Combined Type, Predominantly Inattentive Type and ADHD Predominantly Hyperactive-Impulsive Type
• Diagnostic criteria requires impairment recognized in at least two different settings

Comorbidities Related to ADHD

• Other psychiatric conditions are present in approximately two-thirds of children with ADHD diagnoses
• Two common comorbidities: oppositional defiant disorder (ODD) and conduct disorder (CD)
• ODD characterized by persistent disobedience toward authority figures
• CD stems from persistently violating the basic rights of others and includes criminal behavior
• Increased risk for anxiety, depression, autism spectrum disorder, and Tourette's disorder
• Adolescents and adults (untreated) are more likely to suffer from a substance use disorder

Negative Consequences of ADHD in Adults

• Adult ADHD leads to suicidality, psychiatric issues, obesity, risky behaviors, and social/financial problems
• In children, untreated ADHD is linked to poor academic performance, social challenges, increased risk of accidents, and higher rates of substance use disorders
• In adults, untreated ADHD can lead to occupational difficulties, relationship problems, and increased risk of comorbid psychiatric disorders

Diagnosing ADHD

• There are no specific laboratory tests
• All children aged 4-18 years who present with academic or behavioral problems and symptoms of hyperactivity, inattention, or impulsivity be evaluated for ADHD
• Documentation of symptoms and impairment in more than 1 major setting must be present
• In adults, requires careful differential diagnosis, as its symptoms overlap with anxiety, depression, mania, bipolar disorder, PTSD, and substance use disorder

ADHD Behavioral Interventions

• Positive Reinforcement: Providing rewards or privileges contingent on the child's performance ex. Child completes an assignment and is permitted to play on the computer
• Time-Out: Removing access to positive reinforcement contingent on performance of unwanted or problem behavior ex.Child hits sibling impulsively and is required to sit for 5 minutes in the corner of the room
• Response Cost: Withdrawing rewards or privileges contingent on the performance of unwanted or problem behavior ex. Child loses free-time privileges for not completing homework
• Token Economy: Combining positive reinforcement and response ex. Child earns stars for completing assignments and loses stars for getting out of seat
• Establish structured environments with consistent routines and clear rules

Goals of ADHD Therapy

• Increase functioning at school and work, including improved interpersonal relationships
• Stimulants can increase attention and impulse control
• Untreated ADHD linked to higher risk of alcohol/drug use, lack of social/academic development
• Goals are to reduce current symptoms and avoid psychosocial complications

Nonpharmacotherapy for ADHD

• Behavioral interventions improve symptoms of ADHD
• Behavior therapy is effective if delivered by parents
• A structured environment, plus consistent limit setting and rules
• Positive reinforcement for good behavior has shown to be helpful in children
• Adults may respond to CBT, organization strategies
• Some evidence suggests omega 3/6 fatty acids and ferrous sulfate can be adjunctive treatments
• Natural products should not be used as monotherapy, as no intervention to date is superior to behavioral techniques and stimulants
• In young children (ages 4–6), behavioral therapy is first‑line—often before medication is introduced

Therapeutic Agents for ADHD

• Two medication classes: stimulants and non-stimulants
• Both classes affect activity at catecholamine receptors
• Stimulants divided into methylphenidate - and amphetamine -based classes
• Increased catecholamine activity in prefrontal cortex appears responsible for therapeutic actions
• Stimulants include methylphenidate-based products like Ritalin®, Concerta®, Daytrana®, Aptensio XR®, and Metadate CD®
• Stimulants also include amphetamine products such as Adderall®, Vyvanse®, Dexedrine®, and Zenzedi®
• Non-stimulants include: atomoxetine (Strattera®), alpha‑2 agonists such as guanfacine (Intuniv®) and clonidine (Kapvay®, Onyda XR®), and viloxazine (Qelbree®)
• Structurally, methylphenidate and amphetamines differ in their chemical backbones (piperidine derivatives versus phenethylamines, respectively)

Stimulants: Formulation, Delivery, and Absorption

• Methylphenidate is available as racemic mixtures of the hydrochloride salt in tablets, capsules, solutions, and chewable tablets, Daytrana is a transdermal formulation of the methylphenidate free base, and Concerta utilizes the OROS® osmotic release tablet system.
• Methylphenidate is readily absorbed upon dissolution in the GI tract and may be delayed by a high-fat breakfast
• Jornay PM™ requires evening dosing with the primary intent of providing early morning control of symptoms
• Dexmethylphenidate (Focalin®) is an enantiomerically pure formulation of the active stereoisomer of methylphenidate and is available as the hydrochloride salt in biphasic release capsules (Focalin XR).
• Azstarys® includes serdexmethylphenidate along with dexmethylphenidate (approved 2021)
• Azstarys comprises two film coatings; the first delays the release of drug throughout the night and the second, extended-release layer controls the rate of release of the active ingredient

Stimulants: Amphetamine Products

• Dextroamphetamine (d-amphetamine; Dexedrine®; Spansule; ProCentra®) is the active enantiomer of amphetamine
• Adderall is available as immediate-release tablets and extended-release (once daily dosing) capsules giving a ratio of 3:1 of the d/l isomer mixture
• All of the immediate-release amphetamine formulations reach peak plasma concentrations in ~ 3 hours, while the sustained-release and extended-release products achieve Cin 7-8 hours
• Lisdexamfetamine (Vyvanse®) delivered as the dimesylate salt and reaches Cmax within ~ 1 hour, metabolism of the prodrug leads to peak plasma concentrations of dextroamphetamine in ~ 3.5 hours max

Stimulants: Action & Effects

• Block presynaptic reuptake of dopamine/norepinephrine by inhibiting DAT/NET
• Inhibit monoamine oxidase (MAO)
• Amphetamine (but not methylphenidate) can access the presynaptic neuron and stimulate the release of stored dopamine/NE
• These actions result in increased synaptic levels of the catecholamines
• Stimulants act by blocking the dopamine transporter (DAT) and norepinephrine transporter (NET), thereby increasing synaptic levels of both neurotransmitters

Stimulants: Metabolism and Excretion

• Active (d) isomer of methylphenidate is metabolized in the liver to the inactive d-ritalinic acid - T1/2 = 2-3 hours (children), 2-4.5 hours (adults)
• Half-life of elimination of amphetamine is 9 - 11 hours in children, 11 - 14 hours in adolescents, and 10 - 13 hours in adults.
• Vyvanse converted to dextroamphetamine

Stimulants: Adverse Effects and Contraindications

• Carry a black box warning for cardiovascular issues and misuse potential
• Usually mild and clinically insignificant increase in heart rate and blood pressure can be expected
• Diminished growth is in the range of 1 to 2 cm that occurs over 1 - 3 years of continued use
• Common side effects includes headache, appetite suppression, insomnia, irritability/anxiety, dry mouth, nausea, diarrhea, weight loss
• Contraindications stem from drug-drug interactions with MAOI

Non-Stimulants: Formulation, Delivery, and Absorption

• Non-stimulants typically used for ADHD: atomoxetine, guanfacine, clonidine
• Only extended-release (Intuniv®) is FDA approved for ADHD;
• The oral bioavailability of the immediate-release formulations is 75% to 90%.
• The ER and IR formulations are not bioequivalent, as peak plasma concentrations achieved with the ER formulations are only 50% of those achieved with the IR formulated drug
• absorption with a high-fat meal is decreased so ideally it should be taken on an empty stomach

Non-Stimulants: Distribution, Action, and Effects

• Guanfacine and clonidine: selective a2A adrenergic agonists
• Atomoxetine and viloxazine: selectively inhibit pre-synaptic reuptake of NE via NET
• Non‑stimulants like atomoxetine and viloxazine primarily inhibit the NET
• Alpha‑2 agonists (guanfacine, clonidine) work on post‑synaptic α₂A adrenergic receptors in the prefrontal cortex to modulate NE activity

Non-Stimulants: Metabolism & Excretion

• Atomoxetine is predominantly metabolized in the liver by CYP2D6 and CYP2C19
• Clearance of the parent compound by extensive metabolizers is 0.35 L/hr/kg and the mean half-life is 5.2 hours
• Viloxazine is metabolized by CYP2D6 and renally excreted, although its effects in 2D6 poor metabolizers has not been as well characterized as atomoxetine

Non-Stimulants: Adverse Effects and Contraindications

• Atomoxetine carries a black box warning of an increased risk of suicidal ideation in pediatric patients
• The most common effects experienced with guanfacine are somnolence, dizziness, headache, fatigue, dry mouth, and constipation. Cardiovascular effects such as bradycardia, hypotension, orthostasis, and syncope can occur and are most common during the first month of therapy
• Atomoxetine should not be used in combination with MAO inhibitors or pimozide
• Guanficane or colonidine cause depressive actions on the cardiovascular system may be additive
• Atomoxetine may cause gastrointestinal upset, dry mouth, & fatigue
• Guanfacine and clonidine often produce sedation, dizziness, and hypotension

Evidence Based Medicine & Treatment Approaches

• Treatment options: medication management, behavioral therapy, or both, along with a control group
• If the impairment is mild or if the diagnosis is unclear, behavioral therapies are recommended
• Evidence supports behavioral interventions initially in children aged 4-5 years
• Evidence demonstrates that while both behavioral therapy and medication are beneficial, the combination of both yields the greatest improvement in symptoms
• In preschool-aged children, behavioral interventions may be used as first‑line therapy; in older children and adults, medication is typically the cornerstone of treatment

Managing Medication Treatment

• Behavioral therapy is recommmended before stimulant therapy in children 4-6 years of age
• FDA approved stimulant are preferred in children aged 6-12
• Recent studies show a demand for ADHD treatment and recommendations
• Approximatley 70% of adults can expect immediate improvement in alertness and distractibility due to stimulants
• For those who don't respond to stimulants , a second choice is considered of atomoxetine due to lack of major adverse affects with medication use bu bupropion is also recommmended if there is a risk of comorbid psychatric disorder

Stimulants & Non-Stimulants

• If a patient is non-responsive to one medication, it is recommended to try the other class of stimulant prior to trialing non stimulants
• Atomoxetine is used as a second best therapy if it's intolerant to stimulant ide effects can take up to 6 weeks before determining the efficacy of atomoxetine
• Special care should be initiated in stimulant therapy concerning suicidal thoughts or self harm and those who are not responding
• Guanfacine and clonidine can be used if all other options in the 3 treatment is exhausted
• These formulations help maintain steadier plasma levels of the drug, minimizing the peaks (which can cause side effects) and troughs (which may lead to breakthrough symptoms)
• SR formulations are calibrated to mimic multiple daily IR doses in a single pill
• SR formulations are calibrated to mimic multiple daily IR doses in a single pill; for example, Aptensio XR approximates 2 doses per day, Concerta mimics 3 doses, and Metadate CD and Ritalin LA are designed to replace 2 daily IR doses
• Many stimulant medications are administered as racemic mixtures (containing both active and inactive stereoisomers) due to manufacturing convenience

Managing Side Effects

• Caloric intake prior to taking a stimulant will reduce GI intolerance and ensure adequate nutrition that may be compromised with a lack of appetite.
• Administering medication earlier in the day can also minimize insomnia if the medication effects dissipate shortly before bedtime, but not too early as to promote mid-day breakthrough symptoms.
• Clonidine is used to battle insomnia due to its sedating effects and can be useful in controlling agitation with associated ADHD.
• Another option for treatment of ADHD is the use of tricyclic antidepressants (TCAs)
• Short‑acting/IR stimulants such as Ritalin®, Adderall IR are taken multiple times per day
• Long‑acting/ER stimulants such as Concerta®, Adderall XR®, Vyvanse®, Daytrana®, Aptensio XR®—each designed to cover a full school or work day with varied dosing schedules
• Use once‑daily ER formulations or alternatives (like transdermal patches) to simplify the dosing regimen
• Coordinate with schools (e.g., arranging medication administration discreetly) and educate parents on the importance of routine

Substance Use Disorders

• Evidence shows ADHD and stimulant use is not a risk factor for future substance
• If not treated, ADHD considered a risk factor ofr maladaptive substance abuse
• Treatment is multimodal, involving behavioral therapy and psychosocial support whether or not stimulants are prescribed
• Although ADHD is associated with a higher inherent risk of substance misuse, treatment with stimulants has not been shown to increase this risk
• Early and appropriate treatment can reduce the risk of later substance abuse
• Careful patient selection, monitoring for misuse, and considering non‑stimulant options when indicated are key parts of a comprehensive treatment plan

Additional Information

• Stimulant medications carry black box warnings for the potential risk of sudden cardiac death and serious cardiovascular events, as well as for their high potential for misuse and dependence
• When prescribing for a school‑aged child (6–12 years): Start with behavioral therapy, if symptoms persist introduce a low‑dose stimulant, and adjust the treatment plan based on tolerability and efficacy
• Regularly monitor height and weight, consider “drug holidays”, optimize dosing, and ensure adequate nutritional intake to reduce the risk of diminished growth in children
• First‑line treatment for adults generally involves long‑acting stimulant formulations to improve focus and reduce distractibility
• Non‑stimulants are particularly useful when stimulants are contraindicated or not tolerated; their slower onset of action and lower misuse potential make them important alternatives or adjuncts
• For patients with significant cardiovascular disease, consider non‑stimulant medications as safer alternatives
• Sustain Release (SR) formulations typically release an initial loading dose followed by a steady release over time; many SR products are considered a subset of ER formulations