Lecture 12: Stimulants and ADHD Medication

Question 1

Prevalence ADHD (2)

Answer 1

1. 6-9% children, 4% adults
   - boys 2x a likely
2. Kentucky ranks second in percent of 4-17 year olds with prescribed medications for ADHD (10.1%)

Question 2

Diagnostic criteria ADHD

Answer 2

1. persistent pattern if inattention and/or hyperactivity/impulsivity that interferes with functioning or development as characterized by

a. inattention
- 6 + symptoms have persisted for at least 6 months to a degree that is inconsistent with developmental level and negatively impacts directly on social and academic/occupational activities

b. hyperactivity and impulsivity
- 6+ symptoms for 6 months to a degree that is inconsistent with developmental level and negatively impacts social/academic/occupation al activities

Question 3

Signs/Sx ADHD: inattention (9)

Answer 3

1. fail to give close attention to details
   - makes carless mistakes
2. has difficulty sustaining attention in tasks
3. does not seem to listen when spoken to directly
4. does not follow through on instructions and fails to finish schoolwork, chores, duties, in workplace
5. often has difficulty organizing tasks and activities
6. avoids, dislikes, reluctant to engage in tasks that require sustained metal effor
7. losses things
8. easily distracted by extraneous stimuli
9. forgetful in daily activities

Question 4

Signs/Sx ADHD: Hyperactivity/impulsivity (9)

Answer 4

1. fidget or tap hands or feet or squirms in seat
2. often leaves seat in situations when remaining seated ix expected
3. runs about or climbs in situations when it is inappropriate
4. often unable to play or engage in leisure activities quietly
5. “on the go” “driven by motor”
6. talks excessively
7. blurts out answer before question is completed
8. difficulty waiting their turn
9. often interrupts or intruded on others

Question 5

ADHD Screening tools: kids

Answer 5

Vanderbilt ADHD rating scales

• free online
• separate for teachers and parents

Question 6

ADHD Screening tools: adults

Answer 6

Adult ADHD self report scale

• 6 questions, self-rates
• if 4 or more are positive can complete additional 12 questions for further symptom eval

Question 7

ADHD Pathophysiology (7)

Answer 7

1. deficits in function of prefrontal cortex
   a. manifest as impulsivity, poor problem solving, hyperactivity
2. dysfunction of dopamine transmission related to genetic defects in the transporter (DAT) and receptors
3. low dopamine decreases arousal and every signal, inlacing important stimuli as “background noise”
   - inattentiveness, fidgeting
4. increase in dopamine then increases arousal and allows important stimuli to “break through”
   - individual can thus focus on pertinent tasks
5. individuals with ADHD have increased PFC activation, possibly to compensate
   - may come across as “pulses” of DA, in response to environmental cues, possibly manifested as hyperactivity
6. dysfunction of noradrenergic transmission, notably the post-synaptic alpha 2a receptors
7. engaging these receptors helps the prefrontal cortex to identify appropriate stimuli

Question 8

Other conditions from excess dopamine/NE

Answer 8

1. PTSD
2. Schizophrenia
   * balance dopamine/NE key

Question 9

Tx recommendations 4-5 yrs (2)

Answer 9

1. should rx behavior therapy
2. may rx methylphenidate
   - limit for moderate to severe dysfunction

Question 10

tx recommendations 6-11 years (1)

Answer 10

1. Should prescribe FDA approved medications and/or (preferably) behavioral therapy

Question 11

Tx recommendation 12-18 years old (2)

Answer 11

1. should prescribe FDA-approved medications

2. encouraged to prescribe behavioral therapy

Question 12

ADHD into adult hood (2)

Answer 12

1. 60-70% retain the diagnosis after puberty into adulthood
2. less occurrence of hyperactivity, with inattention predominant
   - manifested as legal trouble and difficulties in workplace and classroom

Question 13

DDX ADHD (4)

Answer 13

1. bipolar d/o
   - increased psycomotor activity
2. PTSD
   - negative alterations in cognition
3. Major depressive d/o
   - cognitive impairment
4. Traumatic brain injury (TBI)
   - cognitive impairment

Question 14

Medication Options ADHD (2)

Answer 14

1. stimulants

2. non-stimulant

Question 15

Stimulants for ADHD (5)

Answer 15

1. Methylphenidate
2. Dexmethylphenidate
3. Amphetamine/dextroamphetamine
4. dextroamphetamine
5. lisdexamfetamine

Question 16

Non-stimulants for ADHD (4)

Answer 16

1. Atomexetine
2. Viloxazine
3. Gluanfacine
4. clonidine

Question 17

Points of focus for rx (4)

Answer 17

1. time to therapeutic effect
2. duration of therapeutic effect
3. potency of dopaminergic and/or noradrenergic activity
4. side effect profile

Question 18

Stimulants: Good pts (3)

Answer 18

1. work via inhibition of reuptake
   - NET
   - DAT
   * affinities differ by individual agent
   * some agents increase dopamine via other mechanism
2. greater affect size as compared to non-stimulants
3. up to 90% children and adolescents will respond to an agent in the class as optimized dose
4. no increase of seizure compared to placebo

Question 19

Stimulants: bad points (8)

Answer 19

1. increased sympathetic tone
2. side effects
   - appetite loss: give medication after meals and provide PM snacks
3. Dysphoria
4. HA
5. abdominal pain
6. sleep disturbances
   - insomnia or somnolence
   - individualze dosing
7. motor tics
8. retardation in growth rates
   - growth rebound?
   - delayed maturation?
   - permanet loss stature?

Question 20

Multimodal Treatment study of ADHD (MTA) (3)

Answer 20

1. RCT started in 1993 in order to determine long term effects of stimulant use
2. assessment at 36 months
   - those that did not receive stimulants where taller and heavier than those that did
   - difference 2cm, 2kg
3. found that beneficial effects of stimulants are not seen after 3 years
   - some later studies have shown sustained benefits

Question 21

Stimulants: ‘ugly’ points (4)

Answer 21

1. risk of abuse
   - recreational v. therapeutic use
   - stimulants>non-stimulants
   - amphetamine>methylphenidate
   - short acting>long acting
2. prediction of future abuse
   - treatment of ADHD with stimulants may or may not affect future risk of substance abuse
   - conflicting data
3. cardiac affect
   - boxed warning for sudden cardiac death though lack of evidence in literature
   - elevation in BP and HR, particularly in sustained use
   - obtain family hx prior to initiation
4. psychosis
   - lack robust evidence
   - if present decrease or hold dose until symptoms subside

Question 22

Benzedrine

Answer 22

1. first released 1933 as decongestant

- contained racemic amphetamine

Question 23

Amphetamine/Dextroamphetamine (4)

Answer 23

1. directly increases dopamine release into synapse
   - in addition to effects on DAT, NET
2. immediate release formulation has FDA approval for children 3-5 year old
3. ER formulation not approved for children < 6 years old
4. IR formulation dosed BID-TID
   - t 1/2 of 6 hours
   - doses spaced 4-6 hours apart

Question 24

Dextroamphetamine (5)

Answer 24

1. manufactures in response to studies noting that dextroamphetamine was the more “potent” form of amphetamine
   - greater affinity for DAT than NET
2. available as immediate-release tablet as well as sustained-release capsule
3. T 1/2 ER of both IR and SR products was 12 hours
4. IR formulation FDA approval for 3-5 years old
5. ER formulation not approved for children < 6 year old

Question 25

Methylphenidate (4)

Answer 25

1. received initial FDA approval in 1960
2. originally formulated exclusively as an immediate release product
   a. multiple daily doses: 4-6 hours duration
   b. consistent (flat) dosing not officiation due to developmental tolerance
3. solved by the osmotic-controlled release oral delivery system and other ER fomrulations
   - 8-16 hr duration, with onset in 1 hour
   - take in am, keeps working into evening
4. delayed release formulation
   - taken in PM, works in AM

Question 26

Methylphenidate MOA (3)

Answer 26

1. blocks dopamine/NE reuptake
   - possible effects on serotonergic 5HTIa receptor
2. supportive data for use in children 3-5 years old
   - currently not FDA approved at this age though data supports using it as a first line
3. once-daily patchy or OROS tablet may have lower abuse potential as compared to other formulations

Question 27

Dexmethylphenidate (4)

Answer 27

1. d-enantiomer of methylphenidate
   - double potency of methylphenidate (i-entantiomer is essentially inactive)
2. not studied in children <6
3. available in immediate and extended-release formulations
4. may open capsule (XR form only) and sprinkle contents over spoonful of applesauce for immediate use

Question 28

Lisdexamfetamine (3)

Answer 28

1. prodrug of dextroamphetamine
2. may have lower abuse potential relative to other stimulants
   - does no become active molecule until first reaching the liver and intestines
3. more consistent drug levels from lower upate
   - less euphoria and lower potential for abuse by injection/snorting

Question 29

Atomoxetine (4)

Answer 29

1. inhibits reuptake of NE
2. side effects:
   - somnolence
   - GI upset
   - insomnia
3. no known abuse potential
4. slower onset of action compared to stimulant medication
   - 2-4 weeks vs. 1 hour

Question 30

Atomexetine boxed warning (3)

Answer 30

1. increased rx suicide ideation in children and adolescents
2. 5/1357 (0.4%) of patients receiving atomexetine in studies, compared with 0/851 receiving placebo
3. other psychiatric symptoms have been reported
   - concern that these could lead to suicidality

Question 31

Additional warnings atomoxetine (2)

Answer 31

1. severe liver injury, including liver failure
   - d/c agent if jaundice occurs or laboratory parameters (LFTS, bilirubin) become elevated
2. use with caution in patients with serous structural cardiac abnormalities, symptomatic CV disease, hypertension, tachycardia

Question 32

PGx and ADHD (2)

Answer 32

1. 02/2019 atomoxetine became first ADHD medication with CPIC guidelines on dosing based on PGx testing
   - simple weight based dosing has been shown to have 30x range in AUC
2. affects dose titration, length of time between dose increases

Question 33

Viloxazine

MOA

Answer 33

1. approved 2021 for treatment ADHD in children 6-17 years old

a. MOA: NE reupatke inhibitor
- may have additional effects 5HT2 receptors

3. functions as a strong CYPIA2 inhibitor
   - weak 2D6/3A4 inhibitor

Question 34

Viloxazine dosing/warnings (4)

Answer 34

1. available in ER capsules
   - t1/2 7 hours
2. starting dose of 200mg once daily titrated as necessary to max of 400 mg/day
3. warnings/precautions similar to atomoxetine
   - monitor heart rate, BP
   - N/V
   - decreased appetite
   - insomnia
   - somnolence
   - irritabilty
4. boxed warning for increased risk of sicidal ideation/behavior
   - 2x that of placebo though overall rates low (0.4%)

Question 35

Clonidine ER (4)

Answer 35

1. centrally acting alpha 2 receptor agonist
   - blocks NE release and increases blood flow in prefrontal cortex
2. useful for patients with aggressive behavior as well as ADHD
3. onset of activation 1-2 weeks is slower than stimulants but faster than atomoxetine
4. side effects include somnolence, hypotension, bradycardia, dry mouth

Question 36

Guanfacine ER (2)

Answer 36

1. centrally acting alpha 2a receptor agonist
   - potentially more selective for receptor subtype than clonidine
   - may convey less effect on BP
2. side effects include
   - somnolence
   - bradycardia
   - hypotension
   * more sedating than atomexetine or stimulant medications

Question 37

Off-Label ADHD medication (6)

Answer 37

1. bupropion
2. modafinil
3. amitriptyline
4. nortriptyline
5. compiramine
6. trancycypromine

Question 38

Evidence Based Practice for rxing ADHD(5)

Answer 38

1. first, consider comorbities
   - treat underlying schizophrenia, bipolar d/o. or severe dperession/anxiety FISRT with appropriate agent for specificities condition
2. then treat ADHD while being careful to not destabilize other conditions
3. SUD may be treated alongside ADHD but should be initially stabilized
4. methylphenidate proffered in children and adolescents
   - similar efficacy to mixed amphetamines, fewer side effects
5. mixed amphetamine salts preferred in adults
   - higher efficacy, similar rates of side effects

Question 39

monitoring while on stimulants (7)

Answer 39

1. weight
2. height
3. BMI
4. appetite
5. HT
   - consider q 3 months
6. BP
   - consider q 3 months
7. At f/u
   - sleep diary
   - liver function

*every 6 months, consider 3 months on HT and BP