Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center

1. ADHD Across the Lifespan: Presentation, Impact, Diagnosis & Pharmacotherapy Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center

2. Metabolism of Methylphenidate vs. Amphetamine MPH AMPH Oxidative Deamination Ring Hydroxylation Hydrolysis & Deesterrifcation 80% unchanged in urine Hipuric Acid Benzoic Acid Hydroxyamphetamine metabolite Parahydroxy-methylphenidate Ritalinic Acid MPH does not usually show on routine urine drug screening

3. Use of Stimulants to Treat ADHD “The literature does not help the clinician choose the best stimulant for an individual patient. Group studies of psychostimulants-MPH, DEX, AMP-generally fail to show significant differences between MPH, DEX, AMP. Conversely, there are large individual differences in response to different drugs and doses. Therefore, the best order of their presentation for a particular patient is unknown. MPH, DEX, AMP may be used first, on the basis of the inclination of the physician and the parent.” Practice Parameter for the Use of Stimulant Medication in the Treatment of Children, Adolescents and Adults JAACAP (2002) 41 (2) suppl 26S-49S

4. Treating Adults with ADHD Using Stimulants • Phase 1: Starting a Stimulant • Choose MPH, DEX, AMP • Immediate Release or Extended Delivery (varies per circumstance) • ? Rating Scales vs Anchor points • (baseline and follow-up vs significant other info) • (CAARS, ADHD-RS, SNAP-IV, WRAADDS) Zametkin & Ernst. N Eng J Med 1999;340:40 Wilens, Biederman & Spencer Attention Deficit Hyperactivity Disorder Ann Rev Med (2002) 53: 113-31 Practice Parameter for the Use of Stimulant Medication in the Treatment of Children, Adolescents and Adults JAACAP (2002) 41 (2) suppl 26S-49S

5. Treating Adults with ADHD Using Stimulants • Phase 2: Titrating to Optimal Effect • Forced Titration or Titrate to optimal effect (inverted U) • MTA or Children’s Texas Medication Algorithm • Adjust dose often? • Medication should be given 7 days/week during initiation of therapy and through titration to optimal effect • This strategy allows significant others of adult receiving medication to observe medication effects, benefits, side effects in multiple settings (e.g., home, work) Zametkin & Ernst. N Eng J Med 1999;340:40 Wilens, Biederman & Spencer Attention Deficit Hyperactivity Disorder Ann Rev Med (2002) 53: 113-31 Practice Parameter for the Use of Stimulant Medication in the Treatment of Children, Adolescents and Adults JAACAP (2002) 41 (2) suppl 26S-49S

6. Treating Adults with ADHD Using Stimulants • Phase 3: Monitoring the Stimulant • ? ‘N of 1’ with alternative stimulant (MPH, DEX, AMP) • If choose IR then consider switch to Extended Delivery • ? Rating Scales (baseline and follow-up vs caregiver info) • (CPRS-R, CTRS-R, ADHD-RS, SNAP-IV, IOWA-CTRS) • After titration to optimal dose then continue 7 days/wk or or sculpt to situation? • Monitor for • side effects (frequency & severity) • adherence • comorbidity (adjust stimulant as necessary) Zametkin & Ernst. N Eng J Med 1999;340:40 Wilens, Biederman & Spencer Attention Deficit Hyperactivity Disorder Ann Rev Med (2002) 53: 113-31 Practice Parameter for the Use of Stimulant Medication in the Treatment of Children, Adolescents and Adults JAACAP (2002) 41 (2) suppl 26S-49S

7. Attention Deficit Hyperactivity Disorder Pharmacological Treatment Stimulants Methylphenidate Amphetamine compounds Dextroamphetamine Non-stimulant Atomoxetine Antidepressants Tricyclics Bupropion Antihypertensives Clonidine Guanfacine Miscellaneous Combined pharmacotherapy Magnesium Pemoline (monitor for hepatic toxicity) Modafanil Venlafaxine Cholinergic agents (i.e. donezepil) Neuroleptics (only in severe cases with monitoring) Recently Approved Treatment for ADHD Updated 2003 from Wilens T, Biederman J, Spencer T. ADHD, In Annual Review of Medicine, 2002: 53. And Greenhill L. Childhood attention deficit hyperactivity disorder: pharmacological treatments. In: Nathan PE, Gorman J, eds. Treatments That Work. Philadelphia, Pa: Saunders; 1998:42-64.

8. Atomoxetine in ADHD Background and Rationale • Initially tested as Antidepressant (≈1200 adults) • High affinity for norepinephrine reuptake inhibition • Low affinity for other receptors • (cholinergic, histaminic, serotonergic, a-1,2 adrenergic) • Minimal direct cardiac effect • No apparent effect on lab values, no need to monitor level • Metabolized through 2D6 (but does not inhibit) • Plasma half-life ≈ 5 hours but CNS effects much longer • enables QD dosing in most pts • Patient Experience Oct 2001 (NDA) 2003 • Total 1,982 >4,000 • >1 yr 169 >1,000

9. Dosing of Atomoxetine in Adults with ADHD • PDR Recommendations • Not controlled so can give samples, refills & call in prescriptions Start ≈ 0.5 mg/kg/d Target 1.2 mg/kg/d with max of 1.4 mg/kg/d or 100 mg/d • 185 # man • Start 18, 25 or 40 mg for 4-7 days in AM after food • 25 mg for 4-7 days then increase to 40 mg for 4-7 days then 60 mg • If already on stimulant, typically stop stimulant, introduce ATMX then reevaluate need for stimulant • Available in 10mg, 18mg, 25mg, 40mg, 60mg • Sprinkling not formally tested and may irritate GI tract • Drug Interactions (contraindicated with MAOIs) • Decrease dose if coadminister with strong 2D6 inhibitor (fluoxetine, quinidine) • Coadministration with iv Albuterol (600 ug over 2 hours) associated with mild increases in HR and BP • Coadministration with methlyphenidate appears well tolerated but not fully studied • Cost ≈ $3/capsule

10. Tolerability of Atomoxetine in Combined Adult Studies Events reported by >2% of pts treated with ATMX and at least twice rate of placebo; Nausea Dyspepsia, fatigue observed significantly more often in QD compared to BID trials;

11. Studies of Non-Stimulant Treatments in ADHD (controlled & uncontrolled) N=2 N=1 N=7 Tricyclics N=1 MAOIs Includes RIMA N=33 N=5 Bupropion Venalfaxine N=4 Alpha-adrenergic N=7 Tomoxetine ABT-418 N= 1,829 subjects Buspirone

12. Modafanil in Adults with ADHD Response defined as >30% reduction in ADHD sympotoms % Responders Optimal dosing in completers: Dex 22  9 mg/d; Modafanil 207  85 mg/d Taylor et al., (2000) JCAP 10 (4): 311-20

13. Comorbid Conditions:Children and Adolescents 45 40% 40 30-35% 35 30 20-25% 15-25% 25 (%) 15-20% 20% 19% 20 15% 15 10 5 0 Oppositional defiant disorder1 Language disorder2 Anxiety disorders3 Learning difficulties2 Mood disorders2 Conduct disorder3 Smoking4 Substance use disorder5 1MTA Cooperative Group. Arch Gen Psychiatry. 1999;56:1076-1086. 2Barkley R. Attention-deficit Hyperactivity Disorder. A Handbook for Diagnosis and Treatment, ed 2.New York: Guilford Pr, 1993. 3Biederman J, et al. Am J Psychiatry. 1991;148:565-577. 4Milberger S, et al. J Am Acad Child Adolesc Psychiatry. 1997;36:37-44. 5Biederman J, et al. J Am Acad Child Adolesc Psychiatry. 1997;36:21-29.

14. Lifetime Psychiatric Diagnoses in Adults with ADHD Biederman et al., (1993) AJP 150(12): 1792-8 Shekim et al., (1990) Comprehensive Psychiatry 31(5): 416-25

15. Lifetime Comorbidity of ADHD with Other Psychiatric Disorders 1Alpert et al., (1996) Psychiatric Research 62 (3): 213-9 2Nierenberg et al., (2002) data presented at APA, Philadelphia, PA 3Pollack et al., (1995) Psych Clinics of North America 18(4): 745-66 4Levin & Kleber (1994) Harvard Rev Psych 2(5): 246-58

16. Is ADHD Pharmacotherapy a Risk Factor for SubsequentSubstance Abuse? Summary of Meta-analysis • Concerns linger as to the ultimate risk that stimulant pharmacotherapy begets on the development of SA in ADHD youths growing up • Discordant findings in the literature for preclinical1,2and human3,4 studies • Evaluation of 674 medicated and 360 unmedicated patients with ADHD followed into adolescence(2 studies) or adulthood (4 studies)5 1. Kollins SH, et al. Pharmacol Biochem Behav. 2001;68(3):611-627. 2. Garasimov, et al. J Clin Pharm Ther. 2001. 3. Biederman J, et al. Pediatrics. 1999;104(2):20. 4. Lambert NM, Hartsough CS. J Learn Disabil. 1998;31(6):533-544. 5. Wilens TE, et al. Pediatrics. 2003;111:179-185.

17. Is ADHD Pharmacotherapy a Risk Factor for SubsequentSubstance Abuse? (cont.) Summary of Results of Meta-analysis • 5/6 studies do not support that stimulants increase SA • 4/6 studies indicate reduced risk for SA in treated vs untreated ADHD individuals (odds ratio=1.9) • No difference in drug or alcohol disorder risk reduction • Risk reduction greater in adolescents than adults Treatment of ADHD reduces the risk for SA by one-half Wilens TE, et al. Pediatrics. 2003;111:179-185.

18. ADHD+Substance AbuseTreatment Strategies: Pharmacotherapy Initiating Pharmacotherapy: How Soon? • If adolescent engaged in substance treatment/motivated with good alliance; and evidence of abstinence or significant reduction in use (UA and self report) • May initiate pharmacotherapy early in treatment if mechanism to closely monitor: • compliance with meds, target symptom response • substance treatment and progress • urine toxicology results Riggs, et al. J Am Acad Child Adolesc Psychiatry. 1998;37.Riggs. Science and Clinical Perspectives. vol. 2 , in press. Wilens TE. Alcohol Health Res World. 1998;22(2):127-130.

19. ADHD+Substance AbusePharmacotherapy Choose Medications with lowest abuse potential • Antidepressants • Bupropion • Other • Atomoxetine ? • Stimulants • Magnesium pemoline • Methylphenidate • Amphetamine compounds • Alternatives • Antihypertensives (juveniles) • Combined pharmacotherapy Riggs, et al. J Am Acad Child Adolesc Psychiatry. 1998:37. Waxmonsky & Wilens. Adolesc SUD in Pediatric Psychopharmacology. 2003.

20. Bupropion in Adults With ADHD+SUD • Open study of adults with ADHD+mixed SUD • Referred out for SUD counseling • Dosing with bupropion to 200 mg SR bid by week 4 Retention in Trial N=32 N=19 Frequency Dropout Rate= 41% Prince JB, et al. Presented at: 155th APA Annual Meeting; May 18-23, 2002; Philadelphia, Pa.

21. Bupropion SR in Adults WithADHD+SUD(cont.) ADHD Sx SUD Baseline=4 Baseline=34 (-22%) (-46%) SUD CGI ADHD RS p.001 p.001 Reductions in Symptoms for Baseline to Endpoint (LOCF) Prince JB, et al. Presented at: 155th APA Annual Meeting; May 18-23, 2002; Philadelphia, Pa.

22. ADHD+Substance Use DisordersTreatment Strategies: Pharmacotherapy • Pharmacotherapy—important aspect of multimodal treatment • Pharmacotherapy—first-line treatment for ADHD • Weigh risk/benefit of pharmacotherapy for ADHD/comorbidity • Adverse interactions-medications with drugs of abuse versus • Delay in diagnosis & treatment ADHD (other comorbidity) may • Result in poor substance treatment retention/outcomes • Legal consequences vs treatment Riggs, et al. J Am Acad Child Adoles Psychiatry. 1998;37.Wilson & Levin. Curr Psych Rep. 2001;3:497-506.Waxmonsky & Wilens. Adolesc SUD in Pediatric Psychopharmacology. 2003.

23. ADHD+Substance Use DisordersTreatment Considerations • If no improvement in 2 months (or clinical deterioration), consider: • Medication change • adverse effects of medication / interaction with substances of abuse? • ? efficacy • ? compliance with medication/other psychiatric treatment? • Reassess psychiatric diagnostic formulation (e.g., ADHD vs bipolar?) • Reassess substance abuse • ? escalation in use; polydrug use • Compliance with substance treatment? • Deterioration in psycosocial functioning? • More intensive treatment • Increased frequency of therapy, monitoring • Increased level of care (e.g., residential; inpatient) • Consultation/referral to treatment specialist Riggs and Davies, 2002; Riggs. Science & Clinical Perspectives. 2003;vol 2 (in press).

24. Diagnosis & Assessment of ADHDSummary • ADHD • affects millions of people of both genders • persists through adolescence and adulthood in a high percentage of cases • Adversely Impact Development across lifespan • Family • Academics/Occupation • Behavior • Diagnosis relies strongly on DSM-IV criteria in domains of • inattention • impulsivity • hyperactivity • Diagnostic assessment includes a thorough gathering of information from multiple sources

25. Summary: Update on Pharmacotherapy of ADHD • Stimulants and Atomoxetine are FDA approved first line agents • Antidepressants (TCAs & Bupropion) are second line agents • Antihypertensives are alternative agents • typically used adjunctly with other meds • Combined pharmacotherapy for incomplete response or comorbid cases • Current research • New stimulant delivery systems (patch) • Modafanil • Cholinergic agents: Achetylcholinesterase inhibitors