777 final ADHD Flashcards
Attention Deficit Hyperactivity Disorder
Persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development
Hyperactive-impulsive type
Inattentive type
Combined type
ADHD
Neurodevelopmental disorder
Preschooler, children, adolescents, and adults
Characterized by a pattern of diminished sustained attention and increased impulsivity
Clear evidence to support a biological basis for ADHD
DSM-5 Changes
ADHD symptoms present by age 12 rather than 7
Inattentive and hyperactive subtypes replaced by 3 specifiers
1. Combined presentation
2.Predominantly inattentive presentation
2. Predominantly hyperactive/impulsive presentation
Comorbid ADHD and ASD
Fewer criteria for adolescents 17 and older and adults
Epidemiology
5% of children, 2.5% of adults
Most frequent psychiatric disorder in childhood
Most cultures
More frequent in males by 2:1 ratio in children and 1.6:1 in adults
Females more likely to have inattentive features
Diagnostic Features
Persistent pattern of inattention and/or hyperactivity-impulsivity
Interferes with functioning or development
Begins in childhood
Manifestations of the disorder present in more than one setting
Symptoms vary depending on setting
Associated Features
Mild delays in language motor or social development
Low frustration tolerance
Irritability
Mood lability
Impaired academic or work performance
Increased risk of suicide esp when co-morbid with mood, substance or conduct disorders
Development and Course
Toddler and preschoolers: excessive motor activity
School age: inattention more prominent
Hyperactivity less obvious in adolescence and adulthood, restlessness, impatience, poor planning feeling like one is driven by a motor, impulsivity
Attention Difficulties
Inattention Lacking persistence Difficulty sustaining attention Disorganization Hyperactivity Excessive motor activity Excessive restlessness, fidgeting, tapping talkativeness Adults wearing others out with activity Impulsivity Hasty actions and decisions with high harm potential and without forethought and consideration for long-term consequences Desire for immediate reward Inability to delay gratification Social intrusiveness
Sustained Attention Deficiencies in ADHD
Executive dysfunction
Inability to sustain attention and solve problems
Hypothetically linked to inefficient information processing in the dorsal lateral prefrontal cortex (DLPFC)
DLPFC activated by the n-back test
Selective Attention Deficiencies in ADHD
Difficulty with selective attention
Inability to focus
Hypothetically linked to the dorsal anterior dorsal anterior cingulate cortex (dACC)
dACC can be activated by the Stroop test
Risk Factors
Environmental Genetic Neurochemical Neurophysiological Neuroanatomical Psychosocial
Environmental Factors
Very low birth weight (< 1500 grams 3.3 pounds) 2-3X the risk Maternal smoking ETOH exposure in utero Lead exposure Dietary: food coloring, additives Disorganized chaotic households Poverty Head trauma
Genetic
Substantial heritability
Increased concordance in monozygotic twins
2-8 times the risk if a sibling or parent has ADHD
Association of dopamine transporter gene (DAT1) with ADHD
Neurotransmitters and ADHD
DA and NE dysregulation prevents normal tuning of pyramidal neurons in the PFC
DA and NE imbalances hypothetically cause inefficient information processing in prefrontal circuits
Hypothetically associated with excessive signaling in prefrontal DA and NE pathways
Neurobiology of Attentional Disorders
ADHD as a disorder of the prefrontal cortex
Trio of symptoms
Inattention
Difficulties with sustained and selective attention
Hyperactivity
Modulated by a cortico-striato-thalamo-cortical loop from PFC to the putamen to the thalamus and back to the PFC
Impulsivity
Hypothetically linked to the orbitofrontal cortex (OFC)
Neurodevelopment and ADHD
Classic: onset by age 7
Formation of synapses and the selection of synapses for removal in the PFC occur in childhood
May be a disruption causing prefrontal abnormalities
Some children compensate and “grow out of the ADHD”
Neurodevelopment and ADHD (continued)
Hypotheses
Abnormal synapse formation
Abnormal synaptic neurotransmission
Genes involved are linked to DA neurotransmission
Genes under investigation are linked to a2A adrenergic receptor, serotonin receptors
Synaptogenesis and Development
Age 1: working memory emerges
3-4 years: minimal capability to sustain attention
6-7 years: sustained attention and planning
Synaptic pruning taking place
Comorbidity
Oppositional defiant disorder Conduct disorder Learning disorders Disruptive mood dysregulation disorder Anxiety Depression Substance use
ADHD Symptoms Across the Lifespan
Preschool Behavioral disturbances School age Behavioral disturbances Academic problems Difficulty with social interactions Self-esteem issues Adolescence Academic problems Difficulty with social interactions Self-esteem issues Legal issues Smoking and injury College age Academic failure Occupational difficulties Self esteem issues Substance abuse Injury/accidents Adulthood Occupational failure Self-esteem issues Relationship problems Injury/accidents Substance abuse
Consequences of ADHD
Decreased school/occupational performance and academic/occupational attainment
Increased social and peer rejection
Children more likely to develop conduct disorders
Increased substance use disorders
Increased accidental injuries, traffic violations
Increased interpersonal conflict
Diagnosis and Treatment of ADHD Across the Lifespan
Rates of diagnosis differ
Due to differences in referral patterns
Children: teachers, parents, pediatricians, psychologists
Adults: self-referred and often have a comorbidity
Treatment differences
2/3 of all stimulant use for ADHD is inpatients under 18
2/3 of all atomoxetine use is in adults
ADHD Assessment
Psychiatric evaluation/clinical interview Context in which symptoms occur Age of onset Educational evaluation Family evaluation Rating Scales: Vanderbilt ADHD Parent and Teacher Connors Rating Scales-Revised (CRS-R) Brown Attention Deficit Disorder Scales (BADDS) Adult ADHD Self-Report Scale (ASRS-1) TOVA
American Academy of Pediatrics (AAP) Guidelines for Diagnosis and Treatment
Guidelines address ADHD in ages 4-18 (expanded age range)
Primary care clinicians evaluate any child presenting with behavioral or academic problems as well as hyperactivity, inattention or impulsivity
Includes pre-schoolers
Inclusion of adolescents acknowledges the children that do not “outgrow” ADHD and those dx for the 1st time in their second decade
Diagnosis confirmed by info from parents, teachers and others involved in child’s care
Other causes should be ruled out
Stressful life events and medications can also mimic ADHD symptoms
Assess for co-existing conditions
Chronic condition
Evidence-based parent and/or teacher-administered behavior therapy should be first line
Methylphenidate for those that do not respond to behavioral therapy
ADHD: Psychotherapy
Psychoeducation
Focused behavioral therapy
Set clear limits with clear expectations
Establish/maintain predictable, calm environment with decreased stimuli
Establish eye contact before giving instructions
Ask to repeat what was heard
Limit distractions for homework and encourage one assignment at a time
Develop effective coping skills
Family therapy
School interventions and accomadations
Treatment Principles for Comorbidities in ADHD
What disorder is prioritized?
ADHD treatment often seen as secondary
Keep an index of suspicion for ADHD in the presence of mood, anxiety, substance abuse
ADHD treatments as augmenting agents to first line tx of mood, anxiety and substance
Treat nicotine dependence
Principles of Stimulant Treatment
Increase release of DA and NE
Stimulants and by some noradrenergic agents
Adults with anxiety, depression, substance abuse
Augment antidepressant or anxiolytic therapies
NET inhibitor (NRI’S)
a2A –adrenergic agonist (Guanfacine, Clonidine)
Methylphenidate (D)
Mechanism of action
Blocks reuptake of DA and NE
Enhances DA and NE in the DLPFC: increased attention, concentration, executive function and wakefulness
Enhances DA in basal ganglia: may improve hyperactivity
Enhances DA and NE in medial prefrontal cortex: may improve depression, fatigue sleepiness
Side effects Insomnia, headache, exacerbation of tics, nervousness, irritability, anorexia, weight loss, palpitations, increased B/P High abuse potential Dosing IR: 2.5 – 10mg BID ER: 10 – 20mg/day
Drug interactions
May inhibit metabolism of SSRI’s, anticonvulsants, tricyclic antidepressants, coumarin
Serious adverse effects may occur if combined with clonidine
Not advised for use with MAOI’s
Precaution
Hypertension, hyperthyroidism, drug abuse
Methylphenidate (D) Special Populations
Elderly: lower doses Children: not approved under 6 Monitor weight and height Pregnancy: Category C Breast feeding: not recommended
Methylphenidate (D, L)
IR formulations: 2-4 hour duration of action
Ritalin, Methylin, generic methylphenidate
Chewable tablets
Oral solutions
Dosing initial 5mg QAM 5mg at lunch increase 5-10mg each week max dose 60mg
SR formulations
Older ER: Ritalin SR, Methylin SR, Metadate ER: duration of action 4-6 hours, dosing 20-30mg/day in divided doses
Newer ER: Concerta up to 12 hours initial dosing 18mg to 72mg, Ritalin, LA Metadate CD up to 8 hours 20-60mg/day
Transdermal formulation
initial dosing 10mg/9 hours increase by 5mg max dose 30mg
Apply patch 2 hours before needed effect, wear for 9 hours
May be possible to dose only during the school week
Drug holidays
Avoid dosing late in the day
Amphetamine
Blocks transporters for DA and NE
Competitive inhibitor and pseudosubstrate for NET and DAT
d and l-isomer
d- isomer more potent for DAT binding
d and l-isomers equally potent for NET binding
SR Stimulants
SR stimulants optimize rate, amount, and length of time that a stimulant occupies NET and DAT
Goal: occupy enough of the NET in the PFC
At a slow enough pace and long enough duration to enhance tonic NE signaling via a2A receptors
Increase tonic DA signaling via D1 receptors
Occupy little enough of the DAT in nucleus accumbens not to increase phasic signaling
Amphetamine (D)
Dexedrine, Dexedrine Spanules, Dextro Stat Mechanism of action Increases NE and DA by blocking reuptake and facilitating release Enhances DA and NE in DLPFC Enhances DA in basal ganglia Enhances DA and NE in medial PFC Pharmacokinetics half-life 10-12 hours High abuse potential May be able to give drug holidays
Monitor B/P
Children monitor height and weight
Drug Interactions
MAOI’s slow absorption of amphetamines
Can raise corticosteroid levels
May antagonize hypotensive effects of veratrum alkaloids and other antihypertensives
May increase analgesic effects of meperidine
Amphetamine (D) Special Populations
Elderly: caution, lower dose Children Not approved for under 3 Acute effects on growth hormone Ages 3-5 (ADHD) initial 2.5mg Pregnancy Category C Breast-feeding: not recommended
Amphetamine (D,L)
Adderall and Adderall XR
Pharmacokinetics
Mixture of d-amphetamine and l-amphetamine salts in a ratio of 3:1
Adult ½ life of d-amphetamine = 10 hours and l-amphetamine = 13 hours
Children ½ life of d-amphetamine = 9 hours and l-amphetamine = 11 hours
Lisdexamfetamine
Mechanism of Action
Prodrug of dextroamphetamine
Increases NE and DA actions by blocking reuptake and facilitating their release
Enhances DA and NE in DLPFC
Enhances DA in basal ganglia
Enhances DA and NE in medial PFC
Pharmacokinetics: duration of action 10-12 hours
Dosing
Initial 30mg QAM increase 10-20mg/week up to 70mg
Lisdexamfetamine Special Populations
Elderly lower doses Children and Adolescents Safety and efficacy not established under 6 Acute effects on growth hormone Pregnancy Category C Breast Feeding Not recommended
Noradrenergic Treatments
Atmoxetine
Buproprion
Desimprimine
Nortriptylene
Atomoxetine
Mechanism of Action
Boosts NE/NA and my increase DA in PFC
Block NE pumps
Increases noradrenergic neurotransmission
Side Effects
Sedation, fatigue, increased heart rate, increased B/P, sexual dysfunction
Dosing
Children: over 70kg or less initial 0.5mg/kg/day after 7 days increase to 1.2mg/kg/day up to 100mg/day
Adults: 40mg/day after 7 days increase to 80mg/day up to 100mg/day
Pharmacokinetics
Metabolized by CYP450 2D6
½ life 5 hours
Drug Interactions
Plasma concentrations of Atomoxetine may be increased by drugs that inhibit CYP 450 2D6 (paroxetine, fluoxetine)
Do not use with MAOI’s (21 days after discontinuation)
Atomoxetine and Special Populations
Elderly Lower dose Reduction of suicidality with antidepressants in adults over 65 Children and Adolescents Approved to treat ADHD in 6 and over Do not use with serious cardiac problems Monitor for suicidal ideation Pregnancy Category C Breast-Feeding Not recommended
Alpha-2A-Adrenergic Agonists
Alpha 2-A receptors primary mediators of NE in PFC
2 direct acting agonists for a2 receptors
Guanfacine
Guanfacine ER
Clonidine
Treatment with Guanfacine and Clonidine
Clonidine more side effects, less selective agonist on a2 receptors
Guanfacine 15-20X more selective for a2 receptors, 10X weaker than Clonidine at inducing sedation and lowering B/P
25X more potent in enhancing PFC function
Can be used adjunctively with stimulants to treat patients with oppositional symptoms
ADHD caused by low NE in PFC without additional impairments in DA neurotransmission good candidates for Guanfacine ER monotherapy (no way to ID these patients other than a trial of meds)
Guanfacine
More selective for a2A receptors
Guanfacine ER once a day dosing
Guanfacine ER approved for ADHD ages 6-17
Treatment of Tic disorders
Mechanisms of Action
Central action on postsynaptic alpha 2A receptors in PFC
10-15X more selective for alpha 2A than alpha 2B or 2C
Side Effects
Hypotension B/P lowered 30-60 minutes after first dose; greatest reduction after 2-4 hours
Sedation
Rebound HTN with abrupt termination
Dosing: IR and ER
IR: 1mg/HS after 3-4 weeks increase to 2mg
ER: 1mg/HS; increase 1mg/week; max dose 4mg/day
Guanfacine (continued)
Pharmacokinetics
Metabolized by CYP450 3A4
Drug Interactions
CYP450 3A inhibitors (nefazodone, fluoxetine, fluvoxamine and ketoconazole) may decrease clearance thereby increasing guanfacine levels
CYP450 3A inducers may increase guanfacine clearance
Do not administer ER with high fat meals
Guanfacine and Special Populations
Elderly Elimination ½ life may be longer More sensitive to sedative effects Children and Adolescents Safety and efficacy not established in children under 6 Pregnancy Category C Breast-Feeding No recommended
Clonidine
Mechanisms of Action
Nonselective agonist at a2 receptors with actions on a2A, a2B and a2C receptors
Interacts at imidazoline receptors which may be the cause of sedating and hypotensive actions
Side Effects
Sedation
Hypotension B/P lowered 30-60 minutes after first dose; greatest reduction after 2-4 hours
Dosing
Initial 0.1mg/bedtime, can increase by 0.1mg/week in divided doses with increased dose at HS max dose 0.4mg/day
Taper
Clonidine (continued)
Pharmacokinetics
½ life 12-16 hours
Metabolized by the liver
Excreted renally
Drug Interactions
Increased CNS depressive and sedative effects when combined with other CNS depressants
Severe discontinuation rxn when combined with beta blockers
Clonidine and Special Populations
Elderly
Lower doses
More sensitive to sedative effects
Caution with beta blockers
Children and Adolescents
Safety and efficacy not established under 6
May be more sensitive to hypertensive effects of withdrawal
More likely to experience CNS depression with OD, may have signs of toxicity at 0.1mg
Pregnancy
Category C
Breast-Feeding
No adverse effects have been reported in nursing infants
Future Treatments
H3 antagonists
Boosting acetylcholine function in PFC
a-nicotinic receptor agonists
a4B2-nicotinic receptor
