Download Non-stimulants

Current Issues in the
Therapeutic Management of
ADHD in Children and
Adolescents
Eric Harvey, PharmD, MBA
Pharmacy Quality Manager
January 15, 2015
Pediatric Attention Deficit Hyperactivity Disorder (ADHD)
http://www.chiro.org/pediatrics/DISCONTINUED/ritalin.gif
Learning Objectives
• Describe the epidemiology of ADHD
• Summarize the etiology and pathophysiology of
ADHD
• Select appropriate treatment modalities
• Compare the advantages and disadvantages of
specific treatment options
• Design or redesign a pharmacotherapy plan within the
bounds of the significant warnings for stimulant use
Epidemiology
• Most commonly diagnosed mental health
condition in children in the United States
• 2-16% prevalence in school-aged children
• Parent reported diagnosis: 7.8% 2003; 9.5% 2007,
11% 2011
• Psychiatric diagnosis: 8.7% 2004
• Prevalence doubles from ages 4-10 to 15-17
• Male > Female, approximately 2:1
Etiology
• Genetic link: 55-90% concordance
• Environmental factors:
• Prenatal alcohol RRI: 2.5
• Smoking pre/post natal RRI: 2.1
• Premature birth RRI: 2.1-2.6
• Suspected association:
• Head injury < 2 yrs (trauma, infection, hypoxia)
• Television viewing age 1-3 yrs, neglect or abuse
• No association:
• Artificial colors or sweeteners, sodium benzoate, sugar
Pathophysiology
• Abnormal central dopaminergic and noradrenergic tone
• Lower activity in brain regions
associated with executive function:
prefrontal cortex, striatum, and
cerebellum
• Smaller brain volume in prefrontal
cortex, caudate nucleus, and
vermis of the cerebellum.
• MRI shows decreased blood flow to precortical area
Complications
•
•
•
•
•
•
Lower academic performance
Increased risk of intentional and unintentional injury
Increased risk of traffic citations and accidents
Earlier initiation or increased likelihood of smoking
Poorer social function
Lower self esteem
Treatment reduces, but does not completely eliminate the
impact of these complications in ~70% of patients
Presenting Symptoms
• Inattention
• Careless mistakes
• Difficulty giving close attention or maintaining
attention
• Trouble organizing tasks, following through,
listening
• Easily distracted, forgetful, loses things
• Avoids or dislikes activities requiring sustained
focus
• Hyperactive/Impulsive
•
•
•
•
•
“Driven by a motor”, “On the go”
Fidgets, unable to remain seated, restless
Talks excessively, blurts out answers
Interrupts or intrudes on others
Difficulty with quiet activities, waiting their turn
H-I-I
• Hyperactivity: observed at 4 years of age
• Ex: excessive fidgetiness/talking
• Impulsivity: occurs in conjunction with hyperactivity
• Ex: difficulty waiting turns; blurting out answers
• Inattention: observed at 8-9 years of age
• Ex: forgetfulness, easily distracted, losing things
ADHD-specific rating scales
• Many scales available
• Connors-EC for ages 2-6 yrs
• Connors Comprehensive and ADHD Rating Scale IV for
•
•
•
•
•
•
ages 4-5 yrs
Connors-3 for ages 6-18 yrs
SNAP IV for ages 5-11 yrs
ADD-H Comprehensive Teacher’s Rating Scale for
kindergarten to eighth grade
Academic Performance Rating Scale for grades 1-6
Home Situations Questionnaire-Revised
School Situations Questionnaire-Revised
• Warning: patient may be outside the population
from which the scale was validated
Diagnosis
• Consensus criteria is published in DSM-V
• Highlights:
• Symptoms must present in two or more settings
• For patients younger than 16 years, 6 or more symptoms must
•
•
•
•
persist > 6 months in at least one of the two categories
• Inattention
• Hyperactivity/Impulsivity
Several symptoms must be present before age 12
Symptoms must impair function in academic, social, or
occupational activities
Symptoms must be disruptive and excessive for the
developmental level of the child (compared to same age peers)
Other mental disorders that could account for the symptoms must
be excluded
Subtypes of ADHD
• Predominantly inattentive type
• Usually diagnosed at 9-10 years of age
• Studied less commonly
• Predominantly hyperactive-impulsive
• Usually diagnosed at 6-7 years of age
• Cognitive performance may be unaffected
• Combined type
• Usually diagnosed at 6-7 years of age
• “Classic” type and most common
Comorbidities
• 50-60% of children with ADHD meet criteria
for another psychiatric diagnosis.
• May be primary or secondary
• Conduct disorder
• Tourette syndrome
• Autism
• Depression
• Learning disability
• Anxiety
• Speech problems
• Epilepsy
Treatment Recommendations: American Academy of
Pediatrics
• Children aged <6 years
• First line: parent/ teacher administered behavior training
• Second-line: consider methylphenidate
• Children aged 6-11 years
• First line: stimulants (preferably in combination with parent/teacher
administered behavior training)
• Less evidence for:
• Atomoxetine
• Guanfacine ER
• Clonidine ER
• Adolescents aged 12-18 years
• First line: FDA-approved medications
• Consider adding behavior training
Pharmacotherapy: Stimulants
• Affect the dopaminergic and noradrenergic
transport systems
• Effects: increases attention span and
concentration
Stimulants
• First-line treatments
• Methylphenidate and dexmethylphenidate
• Amphetamines and lisdexamphetamine
• Examples:
• Methylphenidate (Ritalin®, MethylinTM, ConcertaTM,
FocalinTM, Metadate®)
• Dextroamphetamine (Dexedrine®)
• Mixed amphetamine salts (Adderall®)
• Lisdexamphetamine (Vyvanse®)
• No evidence for superiority of one over
another
Stimulants
• Response rate ~ 70%
• CII – high abuse potential
• SE: usually mild, short duration, and reversible
• Common:
• Severe
•
•
•
•
•
•
•
Anorexia/appetite
Suppression
Sleep disturbance
Weight loss
Nervousness/Restlessness
Growth retardation
Increased blood pressure
•
•
•
•
Tics
Arrhythmia
Toxic psychosis
Sudden cardiac death
• Make sure to time dose early enough in day to
prevent sleep disturbance
Stimulants - Significant Warnings
• Serious cardiovascular risks
• Sudden cardiac death reported at usual doses in patients with
underlying serious cardiac problems
• CNS Effects
• psychosis, mixed/manic episode, aggression or hostility,
seizures
• Growth suppression
• Slowing of gain in height (~2cm) and weight (~3 kg) over 3
years of consistent stimulant therapy in patients 7-10 yrs old
• Growth rebound is not guaranteed
• Abuse potential
Methylphenidate
(Ritalin, Methylin)
• Available in immediate and sustained release
• Absorption: From the GI tract, slow and incomplete
• Used frequently for titration and maintenance and in
children <16 kg
• Ritalin dose: 5mg (0.3mg/kg/dose) PO BID before
breakfast and lunch
• Increase by 5-10mg/day (0.2mg/kg/day) at weekly
intervals
• Max = 60mg/day (2mg/kg/day)
• D/C periodically to re-evaluate or if no improvement in 1
mo.
• Duration:
• Immediate release: 3-5 hours
Methylphenidate
(Concerta, Metadate, Ritalin LA)
• Once dose is determined, can switch to longer
acting agent
• Concerta ~20% IR and 80% ER
• Metadate ~30% IR and 70% ER
• Ritalin LA ~50% IR and 50% delayed 4hrs
Dexmethylphenidate
(Focalin)
• D-threo-enantiomer of methylphenidate
• Better absorbed (bioavailability of denantiomer: 22% to 25%, l-enantiomer: 5%)
• Initial Dose: 2.5mg PO BID OR 10mg PO Q
AM (for Focalin XR)
• Duration:
• Immediate release: 3-5 hours
• Extended release: 8-12 hours
• Focalin XR ~50% IR and 50% delayed 4hrs
Methylphenidate
(Daytrana)
• Patch approved for 6 yrs and older
• Initial dose = 10 mg/9 hours patch topically QAM and
is worn for 9 hours
• Duration : 12 hours
• May absorb drug for 2 hours after patch removed
Amphetamines
• Available as:
• Dextroamphetamine (single salt) - Dexedrine®
• 5mg PO once or twice daily
• MAX: 40mg/day
• Mixed amphetamine salts - Adderall®
• >6 years old 5mg PO once or twice daily;
MAX:40mg/day (5-6 yo start at 2.5 mg adv. 2.5 mg/wk)
• 10mg PO QAM (for SR product); MAX: 30mg/day
• Lisdexamfetamine (prodrug) - Vyvanse®
• 6-8 years old: 20 mg PO QAM: MAX 70 mg/day
• >8 years old: 30mg PO QAM; MAX: 70 mg/day
• May increase in increments of 10-20 mg/day at weekly
intervals until optimal response is obtain
Atomoxetine (Strattera®)
• MOA: selective norepinephrine reuptake inhibitor
• Only ADHD stimulant NOT listed as C-II
• Second-line treatment or alternative for patients with
history of drug abuse
• Dose: 0.5mg/kg, then titrate up every 3 days to
1.2mg/kg in either 1 or 2 daily doses
• Max = 1.4mg/kg or 100mg (whichever is less)
• Ceiling effect in efficacy demonstrated at 1.2 mg/kg/day
• Metabolism: via P450 2D6
Atomoxetine (Strattera®)
• Side Effects:
• Common: weight loss, abdominal pain, appetite
suppression, sleep disturbance
• Serious: rare but severe liver injury
• Black Box Warning: suicidal ideation
Non-stimulants
• Usually second-line treatments
• If stimulants are poorly tolerated or ineffective
• As monotherapy or adjunct to stimulants
• Examples:
• Clonidine and Guanfacine
• Desipramine (and other tricyclic antidepressants:
imipramine, nortriptyline)
• Bupropion
• No evidence for superiority of one over
another
Non-stimulants
• Clonidine and Guanfacine
• MOA: alpha-2 adrenergic agonist
• Provides modest reduction in ADHD symptoms by
reducing impulsivity, hyperactivity and improving sleep
• Must taper slowly- risk for rebound hypertension
• Desipramine
• MOA: inhibit NE and serotonin
• Superior to placebo, but not stimulants
• SE: anticholinergic effects, lowers seizure threshold, CV
effects
• Bupropion
• MOA: inhibits NE and DA
• Equivalent to methylphenidate
• SE: motor tics, lowers seizure threshold
Non-stimulants
• Zinc
• As monotherapy or adjunct to methylphenidate
• Efficacy demonstrated in two Middle Eastern studies, but
not replicated in one US study
• Iron
• 80mg ferrous sulfate/day monotherapy
• Superior to placebo in RCT of children with ADHD and
serum ferritin <30 ng/mL
• May augment effects of stimulant therapy in adolescent
patients with low ferritin
• Insufficient evidence for: acupuncture, herbal
treatments, meditation, homeopathy or brainwave
entrainment
Outcome Measures
• Follow up:
• Every 1-3 weeks during initial titration
• up to 4 weeks for atomoxetine
• Every 3-6 months thereafter
• Assess treatment response through validated behavioral
ADHD rating scales
• Patients, parents and teachers
• Sensitive to the effects of pharmacologic therapy & correlates w/
global clinician ratings
• Choose scales carefully, otherwise this may lead to a symptomonly assessment and may not fully measure functional impairment
• Monitor height and weight during stimulant therapy
Outcome Measures
• Quality of Life Assessment (CHQ):
• Overall impairment and life functioning
• Sensitive to pharmacologic therapy
• Global assessment, not suitable for tracking individual
treatment gains
• Studies show pts w/ ADHD have QOL deficits similar
to patients with other chronic diseases
• Mixed results as to whether or not pharmacologic
therapy improves QOL (primarily atomoxetine
studied)
Stopping Therapy
• Consider stopping if patient is stable and doing well
• Stop for 1-4 weeks
• Choose time when there are few transitions or changes
• May consider stopping on weekends or summer
•
•
•
•
Not routinely recommended
Predominantly for inattentive type
May be beneficial in children with aberrant growth
Study (n=40) – no difference
Case #1
NM is a 14 year old female who was diagnosed with
ADHD-inattentive at the age of 12 who experienced
improved symptom control when taking Ritalin LA
50mg qAM. She is now having difficulties completing
her homework in the afternoon/evening.
• What would you recommend?
Case #2
RW is a 8 year old, 23 kg male who was diagnosed
with ADHD-hyperactive/impulsive 1 month ago. He
began methylphenidate therapy at 7 mg twice a day
and experienced improved symptom control, but his
teacher has recently reported that he is still disruptive
in the classroom.
• What would you recommend?
Case #3
AZ is a 10 year old, 33 kg male who was diagnosed
with ADHD-combined 7 months ago. He has been
taking mixed amphetamine salts 7.5mg twice a day
Mon-Fri and his behavior has been less disruptive at
school. AZ’s mom reports that he continues to “run
around like crazy” and cannot play quietly with his
brothers and neighborhood friends, particularly on the
weekends.
• What would you recommend?
Take Home Points
• ADHD is an increasingly common disorder
that may continue on into adulthood
• Stimulants are first line medication therapy
• Requires routine assessment of evolving
risks and benefits
Questions?
References
•
•
•
•
American Academy of Pediatrics; Subcommitee on ADHD disorder. ADHD:
Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of
Attention-Deficit/Hyperactivity Disorder in Children and Adolescents.
Pediatrics. 2011;128:1007-22.
American Psychiatric Association. Diagnostic and statistical manual of
mental disorders. 5th edition. Washington, DC: American Psychiatric
Association, 2013.
Arnold LE, Disilvestro RA, Bozzolo D, et al. Zinc for attentiondeficit/hyperactivity disorder: placebo-controlled double-blind pilot trial alone
and combined with amphetamine J Child Adolesc Psychopharmacol. 2011
Feb;21:1-19.
Cooper WO, Habel LA, Sox CM, et al. ADHD Drugs and Serious
Cardiovascular Events in Children and Young Adults. N Eng J Med.
2011;365:1896-1904.
References
•
•
•
•
Currie J, Stabile M, Jones L. Do stimulant medications improve educational
and behavioral outcomes for children with ADHD? J Health Econ. 2014;37:5869.
Pliszka S, AACAP Work Group on Quality Issues. Practice parameter for the
assessment and treatment of children and adolescents with attentiondeficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry.
2007;46:894-921.
Schelleman H, Bilder WB, Strom BL, et al. Cardiovascular Events and Death
in Children Exposed and Unexposed to ADHD Agents. Pediatrics.
2011;127:1102-10.
Sever Y, Ashkenazi A, Tyano S, Weizman A. Iron treatment in children with
attention deficit hyperactivity disorder. A preliminary report.
Neuropsychobiology. 1997;35:178-80.
References
•
•
•
Shaw M, Hodgkins P, Caci H, et al. A systematic review and analysis of longterm outcomes in attention deficit hyperactivity disorder: effects of treatment
and non-treatment. BMC Med. 2012;10:99.
Visser SN, Danielson ML, Bitsko RH, et al. Trends in the Parent-Report of
Health Care Provider-Diagnosed and Medicated Attention Deficit/Hyperactivity
Disorder: United States, 2003-2011. J Am Acad Child Adolesc Psychiatry.
2014 Jan;53:34-46.
Wolraich M, Brown L, Brown RT, et al. ADHD: clinical practice guideline for the
diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in
children and adolescents. American Academy of Pediatrics (AAP)
Subcommittee on Attention-Deficit/Hyperactivity Disorder, Steering Committee
on Quality Improvement and Management. Pediatrics. 2011;128:1007-22.
Thanks for your time
and attention!