1. PSYCHOPHARMACOLOGY OF ADHD Stephen M. Soltys, MD Professor of Psychiatry Southern Illinois University

2. DIRECT OR INDIRECT Clonidine – alpha-selective adrenergic agonist with direct action Amphetamines – release of biogenic amines from nerve terminal storage sites Methylphenidate – also blocks dopamine transporter preventing reuptake

3. FDA APPROVAL FDA approval is focused on regulating the indications for which a company can market its drug Is not based on a constant monitoring of scientific literature Companies will only go for FDA approval if they feel the financial return will be significant

4. FDA APPROVAL As a result the scientific literature may have numerous citations about how a drug may be safely used yet not have FDA approval for advertizing The FDA does not intend “approval” to mean that medications cannot be used for other indications supported by the medical science literature, only that companies cannot advertize for these uses

5. PRINCIPALS OF TREATMENT Core symptoms of ADHD are distractability, hyperactivity and impulsivity These are the only symptoms that respond to ADHD meds Treatment failure can result from diagnosing ADHD when it is not there or not recognizing other disorders along with ADHD

6. DIFFERENTIAL DIAGNOSIS DEPRESSION CONDUCT DISORDER OPPOISIOTNAL- DEFIANT DISORDER LEARNING DISABILITIES BIPOLAR DISORDER (OVER DIAGNOSED) ANXIETY DISORDER TOURETTE’S

7. INFORMATION Patient interview Parent information School or daycare Past tesing Standardized scales (CBCL, Conners, Vanderbilt)

8. TESTING In the absence of clear indications of medical, neurological or environmental issues in the history, tests such as MRI, CAT Scan, EEG, thyroid levels, lead levels are not indicated APA cites lack of validity of tests involving radioactive nucleotides in the diagnosis and treatment of ADHD and thus significant safety issues with radiation exposure Psychological testing not indicated in absence of low IQ or learning disabilities

9. MEDICATIONS Stimulants and atomoxetine are the first line of treatment Behavioral intervention alone ineffective in ADHD as first line treatment Medication not likely to impact behaviors resulting from other co-morbid disorders or conduct and oppositional-defiant disorder need behavioral interventions Clonidine, guanfacine, buproprion, imipramine are second-line or augmenting treatments

10. MEDICATIONS FOR HOW LONG? Summer and long holiday’s can be utilized to assess if meds still needed All meds have side effects, key lowest dose that has benefit without adverse effects Monitor height and weight

11. STIMULANTS Effects on central norepinephrine (NE) and dopamine (DA) Amphetamines increase intersynaptic concentration of DA via indirect mechanisms Methylphenidate with a radioisotope marker occupies the DA transporter the striatal area of the brain

12. STIMULANTS Preparations of methylphenidate and amphetamines have been the mainstay of treatment for ADHD Regular preparations are quickly absorbed, low plasma binding and quickly metabolized extracellularly and hepatically: Onset of action 30 minutes, peak 1-3 hours, duration 4-6 hours Generics may have fast absorption and peak sooner Class II Controlled non-narcotic substance Problems with break-through symptoms between doses, non-compliance with multiple doses

13. STIMULANT TOLERANCE Little evidence for tolerance to ADHD symptoms No evidence to suggest behavioral sensitization to long-term stimulants as used in children Can occur if drug is intermittently administered in high parenteral doses that are then allowed to fall to zero Use as prescribed is low oral intake

14. STIMULANT EFFECTS Can see a rebound in the activity level with stimulants when they wear off Equal general efficacy for MPH, DEX, AMP 70% respond when single stimulant is tried, placebo response of ADHD ranges 3-30% Produce improvement in day to day functioning, retain behavioral problems, no consistent long-term academic achievement or improvement in social skills Positive response does not mean ADHD

15. STIMULANTS AND COMORBIDITY ADHD and anxiety: increased placebo response rates, more side effects, less cognitive improvement ADHD and Tourette’s: generally worsening but a few reports of improvement ADHD and DBH: Generally decreases rate of behaviors

16. STIMULANTS Mixed amphetamine salts and dextro- amphetamine: Maximum 40 mg/day Methylphenidate similar dosing with maximum of 60 mg/day Dexmethylphenidate dosing up to 20 mg/day Maximum dosing should be guided by size of child (mg/kg/day) but not exceed published maximums Behavior /education benefit trade off may be in the 0.3 to 0.8 mg/kg/day range depending on the medication

17. STIMULANTS Long acting preparations developed Methylphenidate was developed with a capsule that had a coating of regular methylphenidate. When the coating was dissolved, moisture absorbed in one end of the capsule caused inert material in capsule to expand at a steady rate, causing release of methylphenidate over twelve hours. Available in 18 mg, 27 mg, 36 mg,and 54 mg tablets.

18. STIMULANTS Methylphenidate marketed as Concerta 18 mg = 10-15 mg/day regular or 20 mg methylphenidate-SR 36 mg = 20-30 mg/day regular or 40 mg methylphenidate-SR 54 mg = 30-45 mg/day regular or 60 mg methylphenidate-SR Also available in 27 mg

19. OROS METHYLPHENIDATE Wilens et al JAACAP 2003 OL study 71% completed one year Start 18mg (29%), 36mg (47%), 54mg (24%). End 18mg (15%), 36 mg (40%), 54mg (45%) No tolerance to beneficial effects 6.9% discontinued because of adverse effects. Most common tics, decreased appetite, insomnia,

20. NEW PREPERATIONS Other long acting methylphenidate preparations developed that have variable sized coatings on granules Patch which bypasses GI absorption and hepatic first pass inactivation

21. STIMULANTS The long acting preparation of mixed amphetamine salts comes in a capsule that dissolves releasing rapid acting and delayed release beads that delivers two pulses of medication. Marketed as Adderall XR. Capsule can be opened and mixed with apple sauce for those with trouble swallowing pills Available in 5 mg, 10 mg, 15 mg, 20 mg, 25 and 30 mg. Not recommended in children under 6.

22. STIMULANTS Decreased appetite is a major problem. Need to monitor height, weight and follow growth chart. Spencer et al 1996 found untreated ADHD children have slower growth rate advances than normal children If taken with food will decrease chance of stomach upset. Headache Document presence or absence of tics Dysphoria

23. LISDEXAMFETAMINE 20 mg to 70 mg capsules Inactive until converted to dextro- amphetamine in gut Longer length of action because of conversion process Ineffective if taken by other routes than oral

24. STIMULANT ABUSE May be abused orally, internasally, parenterally 2-3% of high school seniors annually use recreationally with 13% using at sometime in their lives 16% of all ADHD patients are asked to sell March 2003 JAACAP article suggested a 7X increase in MPH abuse

25. AMPHETAMINE TOXICITY Irritability, hyper-vigilance, situational reactivity, stereotyped behaviors, euphoria, impaired judgment, motor agitation Tachycardia, dilation of pupils, elevated BP, perspiration, nausea/vomiting Severe: weakness, respiratory depression, cardiac arrhythmias, confusion, coma

26. PEMOLINE Class IV controlled substance, Hepatic failure 2 to 17 times that in the general population. Monitor hepatic enzymes q 2 weeks after baseline for duration. Otherwise same potential side effects as stimulants, watch for skin rash Half life 12 hours with steady state at 2-3 days Start at 37.5 mg/day, increase by 18.75/week until therapeutic. Usual dose 56.25 to 75 mg range, maximum 112.5 mg/day.

27. ATOMOXETINE Approved for use in individuals 6 years or older with Attention Deficit- Hyperactivity Disorder Norepinephrine Reuptake Inhibitor Significant increase of dopamine in prefrontal cortex but not in nucleus accubens (stimulant and euphoric properties) or striatum (tics)

28. ATOMOXETINE Rapidly absorbed with peak plasma concentrations in 1-2 hours Half-life 5 hours with metabolism via the cytochrome P450 2D6 pathway 80% excreted through urine and rest via feces Brain concentrations may differ from plasma as therapeutic effects persist after drug has cleared

29. ATOMOXETINE Impacts both distractibility and hyperactivity- impulsivity with 24 hour length of action Insomnia about same as placebo Appetite can decrease with gastric upset. occasional headache or dizziness Heart rate increase of 6 bpm, BP increase 1.5 mmHG for systolic and diastolic No effects on QTC interval, no requirements for ECG monitoring Lab monitoring not required

30. ATOMOXETINE Used with MAO inhibitors is contraindicated No inhibition or induction of cytochrome P450 enzymes Decrease dosing when giving to patient on paroxetine, fluoxetine and quinidine: all potent P450 2D6 inhibitors Co-administration with IV albuterol may cause increase in blood pressure and heart rate Non-stimulant, non-controlled substance

31. ATOMOXETINE Dosing: 40-62 lbs18mg X 4 days, then 25 mg 63-93 lbs25 mg X 4 days, then 40 mg 94-126lbs40 mg X 4 days, then 60 mg 127+ lbs40 mg X 4 days, the 80 mg Starting dose is in range of 0.5 mg/kg/day, target dose is 1.2 mg/kg/day Doses above target dose or 100 mg in adults have little benefit

32. ATOMOXETINE LONG-TERM Kratochvl et al did metaanalysis of 13 studies treating children age 6-7 with atomoxetine for 24 months JAACAP 8/2006 25.7 % stopped because of lack of efficacy 4% stopped because of side effects Weight went from 63 to 51 percentile with height from 54 to 43, loss of 2.7 cm

33. ALPHA-ADRENOCEPTOR AGONISTS Prefrontal cortex is involved with behavioral inhibition and working memory Stimulation of these receptors may help in ADHD control Clonidine and guanfacine have been used as adjunctive treatments since late 1980’s off-label, FDA advertizing approval only this year for guanfacine

34. CLONIDINE Over 200,000 prescriptions for clonidine are written for ADHD per year, not an approved indication. About 20% of ADHD children are on clonidine Unknown mechanism of action in ADHD Dosing recommendations vary but Hunt (1987) recommended a limit of.005 mg/kg/day Peak is 2 to 6 hours after administration, 12 hour half life, excreted in urine

35. CLONIDINE Alpha 2-adrenergic agonist Hypotension, sedation, bradycardia Activates alpha receptors in cardiovascular control center in CNS with suppressed sympathetic activity Also binds central imidazoline receptors

36. CLONIDINE 2 OL and 2 DBPC studies showed improvement in ADHD children. Has been suggested that it may decrease the need for stimulants but not proven. Four sudden deaths on stimulant-clonidine combination and 17 non-fatal cardiac events on clonidine alone. If child has questionable cardiac status, may want baseline and follow-up EKGs

37. CLONIDINE AND PSYCHOSTIMULANTS Hazell and Stuart 2003 JAACAP DBPC Patients were on.6-.7 mg MPH /mg/kg/day or its equivalent in amphetamine salts Clonidine up to.2 mg/day given Significant impacts in the clonidine group beginning week 5 especially in CD vs ADHD symptoms Main side effect transient dizziness and sedation but decreased the number of stimulant side effects

38. CLONIDINE 4 out of 5 PC studies of clonidine in Tourette’s or tic disorders fail to show any benefit Few uncontrolled studies of efficacy in aggression but may be due to sedation. Clonidine frequently used for sedation in ADHD

39. GUANFACINE 2/2009 DPC study on 210 children showed extended release guanfacine significantly more effective than placebo on ADHD scales Side effects somnolence, headache, fatigue, sedation, dizziness, irritability, upper abdominal pain and nausea Sedation side effects resolve after two weeks

40. BUPROPRION Anti-depresseant targeting dopamine Expanding literature showing benefit for ADHD symptoms in adults, adolescents and children Serious risk of seizures if dose is over 6 mg/kg/day Risk may be there at lower doses if seizure history present

41. IMIPRAMINE DOSING Off label use Baseline EKG Start low: 1 – 2 mg/kg/day in divided doses Increase once a week while monitoring response Watch for anticholinergic side effects If going above 3 mg/kg/day repeat EKG one week after each dosing change

42. IMIPRAMINE DOSING Cardiac limits to titration: PR interval greater than 0.21 sec, QT interval greater than 450 msec, QTc prolongation greater than 60 msec, QTC widening greater than 10% over baseline, Heart rate greater than 130. Maximum dose: 5 mg/kg/day Check blood level one week after each dose change. Therapeutic 150-250 ug/dl (Half life 10 to 17 hours) Always recheck two weeks after patient on stable dose with good therapeutic response Treat patient, not blood level

43. LITHIUM INDICATIONS - ESTABLISHED Bipolar I (Mania/Depression): Adult, adolescent Bipolar II (Hypomania/depression): Adult Treat manic episodes, stabilize mania and ? depression Impulsive aggressivity: Adults Supplement antidepressants: Adults. adolescents Not approved for use in youth 12 years and under

44. LITHIUM - PROBABLE INDICATIONS Bipolar I in child, mania treatment, ? stabilization Cyclothymia Major depression, recurrent depression Schizoaffective disorder Cluster headaches Neutropenia Prevent cycling Inappropriate antidiuretic hormone secretion Recurrent genital herpes

45. Lithium - Conjectural Uses (Questionable) Rapid cycling Child impulsive aggression Conduct disorder Non-Bipolar I disorders in children Nonpsychotic behavior disorders Impulsivity Trichotillomania Acute agitation Panic Disorder Obsessive- compulsive disorder Kids of bipolar parents with negative behavior

46. Lithium - Mental Retardation and Pervasive Developmental Disorder Popper notes that there are only case reports on this population. Aggressivity and agitation may be improved in these individuals if they have evidence of bipolar disorder. Otherwise lithium does not help.

47. Lithium - Common Side Effects Anti-thyroid: fatigue, dry-rough hair, hair loss, hoarseness, depression, cold sensitivity, edema Weight gain: due to thyroid, fluid retention, polydipsia, carbohydrate metabolism Diabetes insipidus: 60% adults initial, 20% maintenance, higher in kids (enuresis) Tremor GI upset, diarrhea, nausea

48. Lithium - Toxicity Very common in children, in dehydrated individuals, thiazide diuretics, low salt Side effects seen at levels 1.5-2.5 mEq/L, above this is extremely serious In some may appear at 1 mEq/L The difference between therapeutic levels and toxic is small. One needs to constantly be looking for toxic symptoms

49. Lithium-Degrees of Toxicity Mild: Tremor, drowsiness, diarrhea, vomiting, diabetes insipidus Moderate: Mild confusion, slurred speech, muscle twitching-weakness-rigidity, lethargy, appetite loss, nystagmus, coarser tremor Severe: Ataxia, blurred vision, confusion, hypothermia, hyperreflexia, seizures, arrhythmia, hypotension, tinnitus, collapse, coma, death

50. Lithium - Initial Medical Monitoring PE, HPI, VS, Weight, height. Enuresis and bladder control, tremor Labs: CBC+diff, SMAC-20 (Ca and Ph, Creat, BUN), UA, Thyroid panel, EKG if 40 or CV disease Pregnancy test and assure birth control EEG and neurology approval with seizure disorder

51. Lithium-Follow Up I Li level q M and Th before AM dose until therapeutic and stable. Li level monthly Q 3 months: Thyroid panel, UA (SG Baseline call renal), body weight and height