neuro/psych: ADHD

attention deficit/hyperactivity disorder (ADHD)

• a common neurodevelopment disorder that impacts patients ranging from preschool to adulthood

  • prevalence → 5.29% in children and adolescents and 4.4% in adults 19-45

  • prevalence declines to 1.0-2.8% in older adults (≥ 50 years of age)

• clinical characteristics include:

  • inattention

  • impulsivity

  • hyperactivity

  • or some combination of these symptoms

  • most importantly, these symptoms must cause functional impairment in 2 or more settings

  • symptoms must be present prior to 12 years of age

• caused by dysregulation of both dopamine and norepinephrine

risk factors of ADHD

• boys > girls

  • girls may be underdiagnosed due to having inattentive symptoms, as opposed to boys which may have more hyperactive symptoms that may be easier to recognize

• socioeconomic status

• parental history and heritability

  • 1/3 of patients with ADHD will have a kid with ADHD

• prematurity

  • exposure to nicotine while pregnant

  • low birth weight

executive functioning

• mental processes that allow for one to plan for and take action to accomplish given task

  • prioritization

  • decision-making

  • motor control

  • time and spacial awareness

• stimulation filtering occurs in the pre-frontal cortex

  • in individuals with ADHD, we see dysregulation in the pre-frontal cortex

  • NTs that are affected include dopamine (DA) and norepinephrine (NE)

    • dopamine in the pre-frontal cortex is a reward pathway → dysregulation of dopamine in these reward pathways can cause delayed gratification

      • why you may see patients with ADHD that have substance use disorders

    • dysregulation of NE in the pre-frontal cortex can cause difficulties with attention and the ability to stay on task → in patients with ADHD, they have increased careless errors

diagnosis of ADHD

• according to the DSM-5, you must have 6 or more symptoms of hyperactivity/impulsivity for more than 6 months, which are inappropriate for their developmental age

• symptoms must be present in more than one setting

  • symptoms result in impairment in social, school, home, personal, or work functions

• symptoms must be present prior to age 12

• symptoms are not explained by other diagnoses or medication side effects

comorbidities of ADHD

• screen for comorbid conditions that may affect ADHD symptoms in response to treatment:

  • emotional and behavioral conditions: anxiety, depression, oppositional defiant disorder, conduct disorder, substance use

  • developmental conditions: learning/langugage disorders, autism spectrum disorders

  • physical conditions: tic disorders, sleep apnea

medications commonly used to treat ADHD

• stimulants

  • methylphenidate

  • amphetamines

• noradrenergic reuptake inhibitors

  • atomoxetine

  • viloxazine

• alpha agonists

  • guanface

  • clonidine

MOA of amphetamines

1. blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron, thus increasing the concentrations of these monoamines in the extraneural space

2. inhibits monoamine oxidase (MAO)

3. increases pre-synaptic release of DA 

   1. makes vesicles more “leaky” and more available for neurotransmission 

4. also has affinity (agonism) at 5HT-1A and 5HT-2C receptors

   1. can cause appetite suppression

MOA of methylphenidate

1. blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron, thus increasing the concentrations of these monoamines in the extraneural space

2. also inhibits monoamine oxidase (MAO), but to a lesser degree → displaces monoamines from presynaptic vesicles

MOA of atomoxetine

• a selective NE reuptake inhibitor in the pre-frontal cortex, increasing dopamine levels

  • primary inhibition of NET → decreased NE reuptake → more NE in the synapse

  • however, in certain brain regions, especially the prefrontal cortex, there’s very little dopamine transporters (DAT)

  • instead, dopamine is largely cleared by the norepinephrine transporter (NET)

  • so, in those regions, NET is doing double duty → it removes both norepinephrine and dopamine from the synapse

  • so, inhibition of NET not only increases levels of NE, but also DA

  • as a result, dopaminergic activity is also indirectly increased

• note: does NOT increase dopamine in the nucleus accumbens (the reward center in the brain), so patients do not experience reward

  • has low abuse potential → may be favorable for patients with substance use disorders

MOA of viloxatine

• similar to the pharmacology of atomexetine → selective NE inhibitor, although much less potent at NE reuptake 

  • in vivo data also suggests that it’s a 5HT-B1 and 5HT-2C receptor antagonist

MOA of alpha agonists in ADHD

• they directly stimulate post-synaptic alpha-2A receptors

  • alpha-2 receptors are found in the CNS, pancreas, veins, GIT, sphincters, salivary glands, etc

  • these receptors are inhibitory in nature → stimulation inhibits the release of NE

  • because of this, post-synaptic binding can cause:

    • sedation, drowsiness, dizziness

    • decreased HR and BP

    • decreased anxiety and sweating

    • dry mouth

    • decreased insulin secretion

    • platelet aggregation

• they don’t affect dopamine concentrations so there’s really no concern of misuse, but in terms of their efficacy, they’re less efficacious compared to other ADHD meds like stimulants

first-line therapy for ADHD → children ages 4-6

• behavioral therapy

  • methylphenidate can be used as a second-line agent, but AVOID extended-release formulations in this population

first-line therapy for ADHD → children ages 6-12

• FDA-approved ADHD medication + behavioral therapy

first-line therapy for ADHD → adolescents (ages 12-18)

• FDA-approved ADHD medication

• behavioral therapy is not required, but encouraged

treatment algorithm for ADHD in adults (≥ 18 years) → stimulants are NOT contraindicated

1. start with a short-acting amphetamine, usually mixed amphetamine salts (Adderall IR)

   1. if this fails, switch to dextroamphetamine

2. if the patient prefers a long-acting amphetamine for convenience or to prevent between-dose crashes → start (or switch to) extended-release mixed amphetamine salts (Adderall XR)

   1. if this fails, switch to lisdexamfetamine (Vyvanse)

3. if the patient is experiencing too many side effects while on amphetamine → switch to methylphenidate IR (Ritalin)

   1. if this fails, switch to dextromethylphenidate (Focalin)

   2. if the patient would benefit from a long-acting methylphenidate for convenience or to prevent between-dose crashes → switch to methylphenidate ER (Concerta), adding 20% to the dose for equivalance

      1. if this fails, switch to dexmethylphenidate ER (Focalin XR)

treatment for ADHD in adults (≥ 18 years) → stimulants ARE contraindicated

1. if the patient ONLY has ADHD

   1. initiate atomoxetine

2. if the patient has comorbid depression:

   1. initiate buproprion

3. if the patient has prominent insomnia, nightmares, PTSD, tic disorder, or hyperactivity:

   1. initiate alpha agonists

      1. clonidine ER

      2. guanfacine ER

precautions + contraindications for stimulants

• history of a heart attack or arrhythmia → REQUIRES cardiology clearance first before initiation

• avoid in patients with stimulant use disorder/abuse

  • eg. cocaine or other stimulant medications

• contraindicated in patients currently taking MAOIs or use within 14 days following discontinuation of MAOIs

  • includes MAOIs such as linezolid and IV methylene blue 

treatment for ADHD in adults (≥ 18 years) with comorbid depression

• initiate stimulant + antidepressant

  • consider bupropion monotherapy as a “two-in-one”

treatment for ADHD in adults (≥ 18 years) with comorbid bipolar disorder

• initiate a stimulant + mood stabilizer…

  • lithium

  • VAP

  • carbamazepine

  • lamotrigine

  • atypical antipsychotics (just to name a few):

    • olanzapine

    • quetiapine

    • aripiprazole

    • paliperidone

    • risperidone

    • cariprazine

treatment for ADHD in adults (≥ 18 years) with comorbid psychosis

• avoid stimulants

treatment goals for ADHD

• education to child and family of the causes, symptoms, effects on school performance, and long-term consequences 

• securing resources and assistance

  • parent training in behavioral management (PTBM)

  • special education services

  • transitions

• individualized goals for academic performance, interpersonal relationships, safety, and etc

• revisit and revise over time

non-pharmacologic and alternative treatment options

• play therapy or sensory-related therapy

  • little efficacy in pre-schoolers, tends to work better in older patients

• cognitive behavioral therapy (CBT)

  • little efficacy for children < 7

  • may have some benefit in ages 7-17

• bibliotherapy → book therapy

non-pharmacologic options that have limited evidence/no recommendations

• mindfulness training

• cognitive training

• diet modifications

• EEG biofeedback

• supportive counseling

• CBD

• external trigeminal nerve stimulation (eTNS)

factors to consider for pharmacotherapy

• comorbid conditions

• pharmacokinetic parameters

• efficacy and safety of treatment

• psychosocial factors + home environment

• pharmacogenetics

• cost

• palatability

• swallowing difficulties

  • developmental disabilities

  • dysphagia

• match the formulation with the needs of the patient and family

  • considerations may be different for adults vs children and adolescents

stimulants → drugs

• methylphenidate

  • IR and ER formulations

• amphetamine containing products

  • IR and ER formulations

brand name for mixed amphetamine salts (amphetamine/dextroamphetamine) IR

• brand name

  • Adderall IR

brand name for mixed amphetamine salts (amphetamine/dextroamphetamine) ER

• brand name

  • Adderall XR

brand name for dextroamphetamine

• brand name

  • Dexedrine

brand name for lisdexamfetamine

• brand name

  • Vyvanse

brand name for methylphenidate IR

• brand name

  • Ritalin IR

brand name for methylphenidate ER

• brand name

  • Concerta

brand name for dextromethylphenidate IR

• brand name

  • Focalin

brand name for dextromethylphenidate ER

• brand name

  • Focalin XR

noradrengeric reuptake inhibitors → drugs

• atomoxetine

• viloxazine

  • avoid concomitant treatment with MAOI, or within 14 days following discontinuing an MAOI

brand name for atomoxetine

• brand name

  • Strattera

brand name for viloxazine

• brand name

  • Qelbree

alpha-2 agonists used in ADHD → drugs

• clonidine ER

• guanfacine ER

brand name for clonidine ER

• brand name

  • Kapvay

brand name for guanfacine ER

• brand name

  • Intuniv

brand name for bupropion

• brand name

  • Wellbutrin

PK of methylphenidate

• 10-30% protein bound

• duration of action:

  • 3-4 hours for IR formulations

  • 10-12 hours for most ER formulations

• metabolism:

  • de-esterification via carboxylesterase to inactive metabolites

• elimination (half-life):

  • kids → 2.5 hrs

  • adults → 2-7 hrs

• impact of food:

  • may delay absorption with high fat meal

PK of amphetamines

• no protein binding

• duration of action:

  • ≈ 4-6 hours for IR formulations

  • ≈ 8-12 hours for ER formulations

  • ≈ 16 hours for triple-beaded ER formulations

• metabolism:

  • CYP 2D6 hydroxylation to active metabolites

    • genetic testing available

  • oxidative deamination

• elimination (half-life):

  • urinary excretion of parent drug and metabolites dependent on pH

  • kids → 9-11 hrs

  • adults → 10-13 hrs

• impact of food:

  • may delay absorption with high fat meal

PK of atomoxetine

• 98% protein bound

• duration of action:

  • delayed

• metabolism:

  • CYP 2D6 and CYP 2C19 to active and inactive metabolites

  • oxidative deamination

• elimination (half-life):

  • urinary excretion → 5 hours

PK of guanfacine

• 70% protein bound

• metabolism:

  • 50% via CYP 3A4

• elimination (half-life):

  • 50% unchanged in urine → 10-30 hrs

PK of clonidine

• 20-30% protein bound

  • lipid soluble

  • large Vd

• metabolism:

  • hepatically metabolized to inactive metabolites

• elimination (half-life):

  • 40-60% unchanged via urine

  • kids → 6 hrs

  • adults → 12-16 hrs

considerations for methylphenidate

• the d-enantiomer (dextro) is twice as potent as the L-enantiomer 

• high fatty foods can delay its absorption

• can cause rare priapism (prolonged erection)

• can cause rare hepatitis

considerations for amphetamines

• the d-enantiomer (dextro) has higher activity on dopamine transporters (DAT)

• the L-enantiomer has higher activity on norepinephrine transporters (NET)

• high fatty foods can delay its absorption

methylphenidate vs amphetamines in children/adolescents

• amphetamine tends to be preferred by clinicians, while methylphenidate tends to be preferred by teachers

• both have similar tolerability

• methylphenidate is considered a first-line stimulant

methylphenidate vs amphetamines in adults

• amphetamines tend to be preferred by clinicians because it has better efficacy

• both have similar tolerability

• either can be used as a first-line stimulant

PK of immediate and short-acting stimulants

• onset of action → 20-60 minutes

• duration of action → 3-8 hours

PK of long-acting stimulants

• onset of action → 20-60 minutes

• duration of action → 10-12 hours

• examples (not exhaustive):

  • methylphenidate osmotic release oral system (OROS)

  • mixed amphetamine salts XR

  • Daytrana

  • Cotempla XR ODT

  • quillivant XR

  • quillichew ER

  • Vyvanse

  • Dayanavel XR

  • Mydayis

considerations for long-acting stimulants

• they’re harder to abuse

• they work for the entire day

• they may decrease some of the peak side effects

• they can affect sleep

acute side effects of stimulants

• irritability

• headache

• insomnia or sleep disturbances

  • give earlier in the day to prevent or switch to an IR formulation

• loss of appetite

  • encourage eating meals before administration

• abdominal pain

chronic side effects of stimulants

• elevated resting HR and BP

  • 1-2 bpm and 1-4 mmHg

• anorexia

• decreased growth velocity → more significant for children that are still growing

  • drug holidays → can initiate a period (usually during the summer for kids) where they stop receiving therapy so that they can get caught up on growth

• motor tics

  • can consider switching to an alpha agonist

• rebound phenomenon → due to an abrupt discontinuation of medication

  • can cause an increase in ADHD symptoms

  • if initiating a drug holiday, you want to slowly taper off (~ 1 month)

“niche” stimulants

• methylphenidate osmotic release oral system (OROS)

• lisdexamfetamine → prodrug of amphetamine, bioactivated when ingested

  • harder to abuse, inject, or snort

• Daytrana patches → methylphenidate

• Mydayis → triple beaded formulation of mixed amphetamine salts

• Adhansia XR → methylphenidate

• liquids

• ODTs

considerations for atomoxetine

• FDA approved for ages 6+

• 2nd line monotherapy

• dosed by body weight

• titrated based on tolerability and response

• non-controlled substance → low abuse liability

• may be useful for those with comorbid substance misuse or failure to stimulant therapy

• has a delayed onset of action compared to stimulants

• CYP 2D6 substrate → pharmacogenomic testing

• can increase HR and BP

• do NOT combine with antidepressants

side effects of atomoxetine (Strattera)

• increased heart rate and BP

• GI effects → nausea, abdominal pain

• constipation

• urinary retention

• decrease in appetite → decreased weight

• dry mouth

• dizziness

• headache

• insomnia, drowsiness, fatigue

BBW for atomoxetine

• rare hepatoxicity

• increased suicidal thoughts, particularly in children and young adults

considerations for viloxazine (Qelbree)

• can be considered a serotonin-norepinephrine modulating agent (SNMA) in addition to its noradrenetic reuptake blocking

  • recall its serotonergic properties (5HT-2B antagonism and 5HT-2C agonism)

• ER formulation is indicated for ADHD in children and adolescents aged 6-17

• non-controlled substance → low abuse liability

• potent CYP 1A2 inhibitor

contraindications for viloxazine

• drugs that are sensitive 1A2 substrates (eg.):

  • duloxetine (Cymbalta)

  • ramelteon (Rozerem)

  • tasimelteon (Hetlioz)

  • tizanidine (Zanaflex)

  • theophylline

• adjust the dose of clozapine (a 1A2 substrate) if coadministered

considerations for alpha-2 agonists

• ER formulations are approved for treating ADHD in kids aged 6-17

  • limited studies in adults

• primarily works post-synaptically, but can also alter the tone of neuronal firing (on autoreceptors)

• also, by decreasing the activity of these receptors, we can see decreases in the pre-frontal cortex networks, leading to changes in affect/emotion

  • recall that it’s an inhibitory receptor (mediated by Gi GCPRs → agonism = decreased NE and sympathetic activity)

• good for patients with hyperactivity

• 2nd line → can be used adjunctively with a stimulant or as monotherapy

• often considered treatment of choice for patients with comorbid tic disorders and autism spectrum disorders

side effects of alpha-2 agonists

• dry mouth

• dizziness

• decreased BP and HR

• sedation, drowsiness

  • much more so with clonidine

• fatigue

• insomnia or changes in sleep patterns

• can increase tic frequency

• rebound HTN

other treatments used for ADHD

• bupropion

  • effective for treatment of adults with ADHD

  • ideal for patients with comorbid depression

  • FDA approved

  • is CNS activating → look out for potentially symptoms of anxiety or akathisia/restlessness

• caffeine

  • not enough quality evidence to recommend for ADHD

• modafinil

  • some positive effects in ADHD

  • NOT used in pediatric patients due to risk of rash

• IR alpha agonists

  • has worse tolerability compared to XR formulations, although have classically demonstrated efficacy

  • alternative if XR products are unavailable

• tricyclic antidepressants

  • desipramine (Norpramin)

considerations for desipramine (Norpramin)

• can be used off-label for treatment of ADHD

  • blocks the reuptake of NE and DA

• has a messy pharmacology…

  • antihistamine

  • anticholinergic

  • alpha-1 blockade

  • sodium channel blocking properties

  • these cause a worse side effect profile

• should be avoided in children under 12 due to cardiovascular risks, particularly arrhythmias, as it can lead to sudden death

• has a delayed onset of action

• reserved treatment

  • may be used for adult patients with comorbid depression after failing other medications, but still rarely used