A. Characteristics

1. Also called "Hyperkinetic Disorder" (HKD)
2. Key characteristic is difficulty focusing on particular problem or stimulus
3. Primarily a childhood disorder
   1. Most common in young persons (boys about 2:1 over girls)
   2. Can also occur in adults, where male : female ratio ~1
   3. Prevalence in general population is 2-10% in most studies
4. Learning difficulties are major problem in setting of this disorder
   1. Genetic component to disease has been recognized in twin studies
   2. Reduction in size of frontal basal-ganglia and in frontal lobes on MRI has been found
5. Estimated 3-9% of school-aged persons have ADHD
   1. Typically begins before age 7
   2. Symptoms are continously present, not intermittent
6. Up to 4% of adults have ADHD [1]
7. Three Major Types of ADHD
   1. Predominantly hyperactive-impulsive type (boys to girls 4:1)
   2. Predominantly inattentive type (boys to girls <2 to 1)
   3. Mixed type

B. Etiology

1. Substantial Genetic Component
   1. Inheritability of 0.75-0.91 (>75%)
   2. May be related to variants in genes of the dopamine pathway
   3. Some linkage to Dopamine D4 receptor (DRD4), DRD5, SLC6A3, SLC6A4, HTR1B
   4. No genes with large effect have yet been discovered
2. Decreased catecholamine activity has been reported in ADHD
3. Elevated density of dopamine transporter has been reported [6]
4. Brain Volume [12,15]
   1. Significantly smaller brain volumes in ADHD versus unaffected children
   2. Cerebrum and cerebellar volumes both significantly reduced
   3. Unmedicated ADHD children with ADHD had smaller white matter volumes than medicated ADHD or unaffected children
   4. No progression in differences with age
   5. Male and female patients similar results
5. Region Specific Brain Abnormalities [15]
   1. Frontal, temporal and parietal anomalies demonstrated in ADHD versus normal
   2. Likely represents a distributed neuronal system controlling attention and behavior
   3. Most abnormalities in volume in prefrontal cortex and anterior temporal cortices
   4. Bilateral changes are present
   5. Grey matter increases in large portions of posterior temporal and inferior parietal cortices
6. Smoking during pregnancy - ~3X risk increase in children

C. Components and Diagnosis of ADHD

1. Triad Symptom Complex (ICD-10 and DSM-IV)
   1. Inattention
   2. Hyperactivity
   3. Impulsivity
   4. Diagnosis requires that symptoms be present for 6 months or more
2. Inattention
   1. Fails to attend to details
   2. Difficulty in sustaining attention
   3. Does not seem to listen
   4. Fails to finish
   5. Difficulty organizing tasks
   6. Avoids sustained effort
   7. Loses things
   8. Distracted by extraneous stimuli
   9. Forgetful
   10. Diagnosis require 6 or more from this group
3. Hyperactivity
   1. Fidgets with hands or feet
   2. Leaves seat in classroom
   3. Runs about or climbs
   4. Difficulty playing quietly
   5. Motor excess
   6. Talks excessively
   7. ICD-10 requires 3 or more from this group
   8. DSM-IV requires 6 from hyperactivity OR impulsivity group (combined)
4. Impulsivity
   1. Talks excessively
   2. Blurts out answers to questions
   3. Difficulty waiting turn
   4. Interruprts or intrudes on others
   5. ICD-10 requires 1 or more from this group
   6. DSM-IV requires 6 or more from this group OR from hyperactivity group (combined)
5. Diagnosis for Adult ADHD [1]
   1. Minimum of 6 symptoms under Impulsivity or Hyperactivity
   2. Presence of some symptoms prior to age of 7
   3. Some impairment is present in at least 2 settings due to the symptoms
   4. Evidence of clinically significant impairment in social, academic, or occupational settings
   5. Symptoms do not occur during the course of another major psychiatric disorder

D. Differential Diagnosis [3]

1. Coexisting Conditions
   1. Conduct disorder
   2. Learning Disability
   3. Oppositional Defiant Disorder
   4. Tourette's Syndrome
   5. Speech or Language Disability
2. Disorders Affecting Attention
   1. Anxiety disoders
   2. Mood disorders: depression, mania, manic-depressive illness
   3. Substance Abuse
   4. Pychosis, Schizophrenia
   5. Thyroid disorders

E. Treatment [4]

1. Overview of Agents
   1. Psychostimulants and newer norepinephrine reuptake inhibitor (SNRI) approved
   2. Atomoxetine is an SNRI, only non-controlled non-stimulant approved for AHDH [13]
   3. Methylphenidate short (Ritilin®) and long (Concerta®) acting forms
   4. Dextroamphetamine, lisdexamfetamine, and other amphetamines
   5. Pemoline (Cylert®) stimulant, originally for somnolence, used for ADHD (56.25mg in AM)
   6. Bupropion (Wellbutrin® SR or XL) - not FDA approved for pediatric use
   7. Tricyclic antidepressants (TCA) generally less effective
   8. Desipramine (Norpramin®), a TCA, may reduce tics and are effective in mixed disorders
   9. Clonidine improves tics and possibly sleep in ADHD [5,11]
   10. Psychosocial intervention therapy is preferred in some parts of Europe
   11. Combination modality therapy may be beneficial
   12. Methylphenidate and amphetamines are Schedule II controlled substances
2. Methylphenidate (Ritilin®, Concerta®, Focalin®, Methylin®, MethyPatch®, Metadate®) [8,9]
   1. Overall this is an excellent drug and is preferred agent in USA
   2. Allows patient to focus on particular stimulus, improves accomplishments, focus
   3. May cause tics, tremors, anorexia, insomnia, abdominal pain
   4. May be combined with clonidine which can reduce tics and improve sleep [3]
   5. Long term use appears to be effective without tachyphylaxis
   6. Social skills and learning may not improve substantially
   7. Socially unacceptable behavior is definitely reduced
   8. Methylphenidate is more effective than behavioral therapy
   9. Longer acting methylphenidates are generally preferred
3. Dosing Methylphenidates [10]
   1. Ritalin® (short acting): 10mg 8Am and 12PM, 5mg at 4PM
   2. Methadate® ER, Methylin® ER, Ritalin® SR (intermediate acting): 40mg in AM
   3. Metadate® CD (long acting): 40mg in AM
   4. Concerta® (long acting): 36mg in AM
   5. Dexmethylphenidate (Focalin®): 10mg bid, 4 hours apart
   6. No clear clinical advantage of dexmethylphenidate over methylphenidate [16]
4. Lisdexamfetamine Dimesylate (Vyvanse®) [17]
   1. Prodrug in which D-amphetamine is covalently linked to L-lysine
   2. Pediatric starting dose 30mg qAM; maximum up to 50mg qAM
   3. Duration of action ~10 hours, similar to other long-acting amphetamines/derivatives
   4. Similar side effects and no clear benefits over other ADHD agents
5. Atomoxetine (Strattera®) [13,14]
   1. First non-stimulant drug approved for ADHD
   2. Selective norepinephrine reuptake inhibitor (SNRI)
   3. Efficacy slightly less than methylphenidate and amphetamine (Adderall XR®) [14]
   4. May be especially effective with concommitant anxiety, mood, or tics
   5. Begin 0.5mg/kg qam and increased to target 1.2mg/kg qam or divided bid
   6. Available in 10, 18, 25, 40 and 60 mg capsules
   7. Side effects: abdominal pain, reduced appetite, nause, dizziness, somnolence, vomiting
   8. Constipation, dry mouth, urinary retention and sexual dysfunction have occurred in adults
   9. Metabolized by CYP 2D6 and higher drug levels in poor metabolizers
   10. Now second line for intolerance to other drugs
   11. Very low risk (~2/2 mllion) of liver injury
6. Buproprion (Wellbutrin®)
   1. Aminoketone antidepressant
   2. Not approved for us in children by FDA, but clearly safe in adults
   3. Reduces impulsivity and inattention
   4. Improves smoking cessation rates which is important in ADHD patients
   5. Not as effective as methylphenidate in children and adolescents
   6. Only the SR (100-150mg qd-bid) or XL (150-300mg qd) forms should be used
   7. Side effects include seizures, bulimia, anorexia
7. St. Johns wart (Hypericum perforatum) of no benefit in adolescents with ADHD [18]
8. Behavioral Therapy [2]
   1. Not as effective alone as medication therapy alone
   2. Some conflicting results with combination pharmacological - behavioral therapy
   3. Behavior therapy combined with methylphenidate may be most effective treatment [7]
   4. However, combination therapy is not recommended for most school-aged children
   5. Medical therapy is usually sufficient for children
9. In Tourette's Syndrome, combination methylphenidate and clonidine effective [11]

F. Prognosis

1. In past, prognosis has been poor
2. ADHD is a major risk factor for psychosis
3. Presence of ADHD at any age increases risk of behavioral and emotional problems
4. Medications provide symptomatic and academic improvement
5. Unclear long-term effects of stimulant medications
6. Combination modality therapy including psychosocial interventions are most effective [1]

References

1. Wilens TE, Faraone SV, Biederman J. 2004. JAMA. 292(5):619
2. Rappley MD. 2005. NEJM. 352(2):165
3. Zametkin AJ and Ernst M. 1999. NEJM. 340(1):40
4. Elia J, Ambrosini PJ, Rapoport JL. 1999. NEJM. 340(10):780
5. Clonidine. 1996. Med Let. 38(989):109
6. Dougherty DD, Bonab AA, Spencer TJ, et al. 1999. Lancet. 354(9196):2132
7. Jensen PS, et al. 1999. Arch Gen Psychiatry. 56:1073
8. Methylphenidate for ADHD. 2000. Med Let. 42(1086):80
9. Metadate CD. 2001. Med Let. 43(1114):83
10. Dexmethylphenidate. 2002. Med Let. 44(1130):45
11. Tourette's Syndrome Study Group. 2002. Neurology. 58:527
12. Castellanos EX, Lee PP, Sharp W, et al. 2002. JAMA. 288(14):1740
13. Atomoxetine. 2003. Med Let. 45(1149):11
14. Atomoxetine Revisited. 2004. Med Let. 46(1189):65
15. Sowell ER, Thompson PM, Welcome SE, et al. 2003. Lancet. 362(9397):1699
16. Sterioisomers. 2003. Med Let. 45(1159):51
17. Lisdexamfetamine. 2007. Med Let. 49(1265):58
18. Weber W, Stoep AV, McCarty RL, et al. 2008. JAMA. 299(22):2633