ADHD

For > 6 months, a persistent pattern of inattention and/or hyperactivity-impulsivity exists
Several symptoms present before age 12 years and occur in 2 or more settings
Symptoms are not solely a manifestation of another psychiatric disorder, SUD, or medical condition
Can be combined, primarily inattentive, or primarily hyperactive/impulsive

> or equal to 6 of the following symptoms (> or equal to 5 if 17 y/o or older)
Frequently forgets daily activities
Easily distracted by external stimuli
Unable to listen when spoken to directly
Loses items necessary for tasks or activities
Trouble organizing schoolwork and other activities
Difficulty maintaining attention in work or play activities
Unable to follow instructions and fails to finish schoolwork and other tasks
Fails to focus on details or makes careless mistakes in schoolwork or other activities

> or equal to 6 of the following symptoms (> or equal to 5 if 17 y/o or older)
Talks excessively
Difficulty waiting turn
Impulsively blurts out answers
Runs or climbs in unacceptable situations
Inability to remain seated when necessary
Fidgets with hands or feet or squirms in seat
Unable to play or engage in quiet, leisure activates
Often “on the go” or acts as if “driven by a motor”
Interrupts activities or conversations of others or intrudes or takes over for others

estimated 9.4% (6.1 million) among children 2-17, 4.4% of adults

Low birth weight/prematurity
Exposure to smoking during pregnancy
FH of ADHD (2-8x increased risk in first-degree relatives)
Perinatal stress
Fetal alcohol syndrome
Lead poisoning
Traumatic brain injury
Adverse child-parent relationshi

Difficulty being soothed because of irritability, fidgeting, crying
Short periods of sleep/very little sleep
When crawling, in constant motion

Inability to sit through class/work meetings, excessive talking or observed by others to talk too much, need to get to places quickly
Impulsive symptoms such as frequent job changes, low frustration tolerance, unstable interpersonal relationships
Inattentive symptoms include poor time management, poor motivation and concentration, forgetfulness, excessive mistakes

2/3 have comorbid condition
Disruptive/conduct problems (oppositional defiant disorder, conduct disorder, etc.)
Anxiety
Depression
Autism spectrum disorder
Tourette’s disorder/tic disorder

MDD (3x more likely)
Any mood disorder (4x more likely)
SUD (2x more likely)
50% of patients with ADHD have an anxiety disorder (high social anxiety)
Bipolar disorder (9-20% of pts with bipolar disorder have ADHD)
Cluster B and Cluster C personality disorders

Behavior therapy (BT)

FDA-approved medication for ADHD + BT

Methylphenidate (MPH)

Psychological interventions

Psychostimulant (atomoxetine if risk of stimulant misuse)

MPH or AMP (atomoxetine if risk of stimulant misuse)

Psychostimulant (atomox if risk of misuse)

Stimulant + guanfacine

Stimulant + guanfacine

ADHD-focused parent training

ADHD focused information and support

MPH or lisdexamfetamine

Alternative first-line agent, atomoxetine, guanfacine

Behavioral therapies if symptoms mild, diagnosis uncertain, medication not preferred by parents
Stimulants (MPH, AMP)

Alternative first-line (if triedMPH switch to AMP and vice versa)
Atomoxetine
Guanfacine
Clonidine

Bupropion
Modafinil

Stimulants (MPH, AMP)
Atomoxetine if risk of stimulant misuse

Alternative first-line (if tried MPH switch to AMP and vice versa)

Atomoxetine
Stimulant + guanfacine
Bupropion
Guanfacine
Clonidine

Inhibits reuptake of NE and DA by binding to transporters
Blocks reuptake of DA more than NE
Inhibits monoamine oxidase (reduced breakdown of catecholamines)

Inhibits reuptake of NE and DA by binding to transporters
Increases release of DA and NE into synapse from presynaptic nerve terminal
Enhances release of NE in periphery from adrenergic nerve terminals
Inhibits monoamine oxidase (reduced breakdown of catecholamines, more potent than MPH)

Dexmethylphenidate: D-isomer of MPH
More pharmacologically active
Can administer at 50% dose of MPH

Can be split/crushed
Simple to discontinue
Generic available
Can be added to longer-acting formulations in afternoon

Half-life of ~2.5 hours
Dosed 2-3 times/day, requires second dose at school

Less abuse potential
Half-life ~8 hours: Less frequent dosing (1-2x/day)
Fewer ADEs than IR

Delayed peak (effect may not start until afternoon)
Cannot be split/crushed

Some products can be opened and sprinkled on applesauce
Less abuse potential
Dosed once/day

Not optimal for pts who do not require all-day coverage
Increased risk of insomnia

30 minutes

3-6 hours

60-180 minutes

3-8 hours

30-120 minutes

6-12 hours

Poor oral absorption, should be taken 30-45 minutes before a meal.
Not a CYP450 substrate, minimal DDIs

under 16kg

weekly

Dextro-amphetamine (d-amphetamine, d-AMP), more potent, most AMP products contain only d-AMP
Levo-amphetamine (l-amphetamine, l-AMP)

prodrug of AMP
L-lysine (amino acid) bound to d-AMP, then metabolized in bloodstream
May have less abuse potential

Good oral absorption, high-fat meals may delay time to peak concentration by up to 2 hours
Dextroamphetamine metabolized by CYP2D6
~30% excreted unchanged in urine  may be affected by urine pH

Norephedrine
4-hydroxyamphetamine

20-60 minutes

4-8 hours

60-90 minutes

6-10 hours

30-60 minutes

8-12 hours

weekly

two times daily

under 5 years old

Advanced arteriosclerosis
Symptomatic CV disease
Moderate to severe htn
Cardiac arrhythmias
Heart failure
Recent myocardial infarction

Hyperthyroidism
Glaucoma
Agitated states
H/o SUD
MAOI within 14 days
Tic disorder for lisdexamfetamine

Effect may be largest at lunchtime, recommend patient eat nutritious, high calorie breakfast and dinner

administer with food

Reduce afternoon doses or give earlier in day
Change to a shorter-acting stimulant or a non-stimulant
If persists: Melatonin, diphenhydramine, trazodone before bed
Clonidine, guanfacine also manage evening hyperactivity

Divide dose, decrease dose, or give with food

Rotate application site to avoid worsening erythema
If continues for > 2 days recommend evaluation by provider

Height most impacted early in treatment but often normalizes over time
Discontinuation of treatment can result in rebound of growth to compensate for the loss of height
Often recommend drug holidays (i.e. over summer breaks) or switch to non-stimulant

Additive effects (htn, tachycardia)

Stimulants may counteract antihypertensive effect

contraindicated within 14 days of stimulants, causes massive increase in blood pressure

MPH can increase TCA concentrations

Can affect absorption of MPH (especially MPH-LA)

AMP concentrations may be increased

May increase exposure to mixed AMP salts

Patient does not respond to or tolerate stimulants
Families who want to avoid controlled substances for child
Patients or families with history of substance use disorder

Inhibits pre-synaptic reuptake of NE in CNS (not DA)

Half-life of active metabolites 6-8 hours
Can increase to 34-40 hours in CYP2D6 poor metabolizers

Pharmacogenomics: Polymorphism of CYP2D6 can result in clinical differences:
Lower doses needed to achieve symptom control
Increased risk of ADEs
Greater increases in HR and BP

2-4 weeks

24 hours

Hepatotoxicity

Inhibit pre-synaptic NE release and increase blood flow in prefrontal cortex

2-4 weeks (may see effects in first week)

Clonidine XR: 12 hours
Guanfacine XR: 8-14 hours

Dizziness
Hypotension
Sedation
ADEs are dose-related, can administer at bedtime to decrease risk

Additive antihypertensive effect
Additive sedating effect with other CNS depressants
Mirtazapine: Inhibits alpha2 effects of clonidine, guanfacine
Valproic acid: Guanfacine may increase concentration
Strong CYP3A4 inhibitors: Must use reduced dose of guanfacine

Bupropion or TCAs
• Takes up to 4 weeks for maximal effect
Modafinil
• Lacking strong data
Polyunsaturated fatty acids
• Omega-3 and omega-6 may be low in ADHD
• Adjunctive therapy