Agents For ADHDBrian J. Piper, Ph.D., M.S.

piperbj@husson.edu

February 12, 2013

Goals

• Pharmacy students should be:– familiar with ADHD-I, ADHD-HI, and ADHD-C– able to contrast the MOA, AE, and abuse potential

of stimulant and non-stimulant pharmacotherapies for ADHD

History of ADHD

• ≈1910: Minimal Brain Damage: inattentive, distractible, hyper/hypoactive

• 1980: Attention Deficit Disorder: normal IQ, poor sustained attention, added to DSM III

• 1994: ADD is removed from DSM IV• 2013: “Symptoms present by age” changed

from 7 to 12

Taylor (2011). Attention Deficit Hyperactivity Disorder, 3, 69-75.

ADHD: Inattentive

ADHD: Hyperactive/Impulsive

AHDH Epidemiology• Very common in children (6%) & adults (4%)• Substantial regional variability (Maine = 9.6%)• Males (4) > Females (1)• Moderate genetic component in males

Visser et al. (2010) MMWR, 59(44), 1439-1433. http://www.cdc.gov/ncbddd/adhd/prevalence.html

ADHD Combined: ↓Cortical Volume

Castellanos et al. (2002). JAMA, 288(14), 1740-1748.

<- Controls<- ADHD

Dopamine

• Neuroanatomy:– Somas: substantia nigra– Axons: striatum

• Functions: movement, mood, reward, cognition

Dopamine Transporter (DAT)

Dopamine

• Neuroanatomy:– Somas: Ventral Tegmental Area (VTA) – Axons: Nucleus Accumbens

• Functions: movement, mood, reward, cognition

Dopamine• Neuroanatomy:

– Somas: Ventral Tegmental Area (VTA) – Axons: Prefrontal Cortex (PFC)

• Functions: movement, mood, reward, cognition

Modified from Meyer & Quezner (2008). Psychopharmacology.

Norepinephrine• Neuroanatomy– somas: Locus Coeruleus– axons: Forebrain+

• Receptors: α1A,1B,1D, α2A,2B,2C, β1, β2, β3

• Function: attention, cardiac

Modified from Meyer & Quezner (2008). Psychopharmacology.

Amphetamine• History: – synthesized in 1883– benzedrine in 1933

• Indications: ADHD (age 3+ ), narcolepsy• MOA: – DAT inhibition & reversal– NET inhibition & reversal– VMAT2 inhibition– MAO inhibition (weak)

Amphetamine Neurobehavioral Effects ≠ Paradoxical

• 14 Boys (age 6-12, IQ = 131) randomized to receive 5 mg/kg dextroamphetamine or placebo

• Cognitive battery completed at 30 – 150 min post drug

Rapoport, J. et al. (1978). Science, 199, 563-566.

Methamphetamine• History: synthesized in 1893• Indications: ADHD, obesity• Metabolite: amphetamine• MOA: – DAT inhibition & reversal– NET inhibition & reversal– SERT inhibition & reversal– VMAT2 inhibition– MAO inhibition ( ? )

Methylphenidate

• History: synthesized in 1944• Adverse Effects: – nervousness– ↓ appetite/weight– ↑blood pressure/heart rate

• MOA: – DAT/NET inhibition– DA/NE release (moderate)

Leandro (& Marguerite)Panizzon

http://www.cesar.umd.edu/cesar/drugs/ritalin.asp

Comparison (All Schedule II)• Amphetamine (Adderall):

• Methamphetamine (Desoxyn):

• Methylphenidate (Ritalin SR):

Monitoring the Future: “Amphetamines” = Adderall & Ritalin

Recreational Methamphetamine & DAT Depletions

[11C]d-methylphenidate

Volkow et al. (2001). Journal of Neuroscience, 21(23), 9414-9418.

Stimulants & Neurotoxicity• Rats received doses, chosen to

produce 2-5X plasma therapeutic levels of:– amphetamine (AMPH)– methamphetamine (METH)– methylphenidate (MPH)

• Animals monitored for hyperthermia

• Dopamine at 1 week:– MPH = controls– ↓ METH– ↓ AMPH

Levi et al. (2012). Neurotoxicology & Teratology, 34, 253-262.

Diversion Proof?Lisdexamfetamine Guanfacine Atomoxetine

MOA DAT/NET,D-amphetamine prodrug α2A agonist

NRI

Indications ADHD (>6 yrs), ADHD,hypertension

ADHD

Scheduled Yes, II No No

Warning Abuse potential,sudden death No Suicidal

thoughts/behavior

Total estimated number of outpatient prescriptions for ADHD drug market drug products dispensed to the US children (ages 0–17 years) from US retail pharmacies.

Chai G et al. (2012). Pediatrics, 130, 23-31.

↓

↓

↑↑

---------------------------------------------------------------------------------------------------

--------------------------------------------------------------------------------------------------

Treatment for ADHD (DiPiro)

• “Multimodal treatment (parent training, family training, classroom interventions, contingency management) is crucial for an overall positive therapeutic outcome.”

• Pharmacotherapies– 1st Line: methylphenidate or amphetamine– 2nd Line: atomoxetine or guanafacine or bupropion– 3rd Line: combine above or add tricyclic

antidepressant

Copheide & Pliszka (2011). In DiPiro’s Pharmacotherapy: A Pathophysiological Approach, p. 1088.

Treatment for Hyperkinetic Disorder (European)

• 1st Line: Psychoeducation• 2nd Line: methylphenidate• 3rd Line: other stimulant• 4th Line: TCA, nicotine patch

Taylor et al. (2004). Eur Child & Adolescent Psychiatry, 13(S1), DOI 10.1007/s00787-004-1002-x

Multimodal Treatment Study of Children With ADHD (MTA)

• Children (7-10 y.o.) with ADHD-C (N=579) randomized for 14 months to:– Medication Management (MM): methylphenidate (37.7

mg/day), monthly monitoring of adverse effects (parent)– Behavioral Therapy (BT): summer camp (9 hours/day x 5

weeks) + parent training + teaching aid (60 days)– Combined (MM & BT): methylphenidate (30.5 mg/day),

monthly monitoring of adverse effects (parent & teacher)– Community Care: treatment as usual in the community (67%

pharmacotherapy)

MTA Group (1999). Archives of Psychology, 56(12), 1073-1086.

Interpretation?• 1) All groups improved relative to baseline.• 2) Behavioral Treatment doesn’t work• 3) Medication Management > Other• 4) Behavioral Treatment = Community Care

--------------------------------------------------------------------

MTA Group (1999). Archives of Psychology, 56(12), 1073-1086.