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ADHD Across the Lifespan: Presentation, Impact, Diagnosis & Pharmacotherapy Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center Metabolism of Methylphenidate vs. Amphetamine MPH AMPH Oxidative Deamination Hydrolysis & Deesterrifcation Parahydroxymethylphenidate Ring Hydroxylation Ritalinic Acid 80% unchanged in urine Hipuric Acid Benzoic Acid Hydroxyamphetamine metabolite MPH does not usually show on routine urine drug screening 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, AMPgenerally 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 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 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 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 Attention Deficit Hyperactivity Disorder Pharmacological Treatment Stimulants Methylphenidate Amphetamine compounds Dextroamphetamine Non-stimulant Atomoxetine Antidepressants Recently Approved Treatment for ADHD 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) 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. 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 » Total » >1 yr Oct 2001 (NDA) 1,982 169 2003 >4,000 >1,000 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 Tolerability of Atomoxetine in Combined Adult Studies Event Atomoxetine (N=269) Placebo (N=263) P Value Discontinuations Dry Mouth 21 6 <.001 0 Insomnia 13 6 .013 3 Nausea 12 5 .005 1 Constipation 10 4 .009 0 Appetite 10 3 <.001 0 Dizziness 6 2 .015 0 Libido 6 2 .010 1 Erectile Disturbance 7 1 .006 1 Dysmennorhea 7 3 .331 0 Urinary Retention 3 0 .015 2 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; Studies of Non-Stimulant Treatments in ADHD (controlled & uncontrolled) N=2 N=1 N=7 N=1 Tricyclics N=33 N=5 MAOIs Includes RIMA Bupropion Venalfaxine =4 Alpha-adrenergic N=7 Tomoxetine ABT-418 N= 1,829 subjects Buspirone Modafanil in Adults with ADHD Response defined as >30% reduction in ADHD sympotoms 50 45 40 35 30 25 20 15 10 5 0 Placebo D-Amphet Modafanil Both Neither Optimal dosing in completers: Dex 22 9 mg/d; Modafanil 207 85 mg/d Taylor et al., (2000) JCAP 10 (4): 311-20 45 40 35 Comorbid Conditions: 40% Children and Adolescents 30-35% 30 (%) 25 20 15 20-25% 15-25% 15-20% 20% 19% 15% 10 5 0 Oppositional defiant disorder1 1MTA Language disorder2 Anxiety Learning Mood Conduct Smoking4 Substance disorders3 difficulties2 disorders2 disorder3 use disorder5 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. Lifetime Psychiatric Diagnoses in Adults with ADHD Substance Use Disorders Anxiety Disorders Bipolar Major Depression LD Antisocial 0 10 20 30 40 50 60 Biederman et al., (1993) AJP 150(12): 1792-8 Shekim et al., (1990) Comprehensive Psychiatry 31(5): 416-25 Lifetime Comorbidity of ADHD with Other Psychiatric Disorders Substance Abuse(4) GAD(3) Bipolar Disorder(2) Major Depression(1) 0 10 20 1Alpert 2Nierenberg 3Pollack 30 40 et al., (1996) Psychiatric Research 62 (3): 213-9 et al., (2002) data presented at APA, Philadelphia, PA et al., (1995) Psych Clinics of North America 18(4): 745-66 4Levin & Kleber (1994) Harvard Rev Psych 2(5): 246-58 Is ADHD Pharmacotherapy a Risk Factor for Subsequent Substance 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 preclinical1,2 and 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. Is ADHD Pharmacotherapy a Risk Factor for Subsequent Substance 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. ADHD+Substance Abuse Treatment 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. ADHD+Substance Abuse Pharmacotherapy 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. Bupropion in Adults With ADHD+SUD Frequency 40 • 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 30 N=19 20 Dropout Rate= 41% 10 0 Baseline Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Prince JB, et al. Presented at: 155th APA Annual Meeting; May 18-23, 2002; Philadelphia, Pa. Week 6 Bupropion SR in Adults With ADHD+SUD (cont.) ADHD Sx SUD Baseline=34 0.0 Baseline=4 -5 (-46%) -10 -15 -20 SUD CGI ADHD RS 0 -0.5 -1.0 (-22%) p.001 -1.5 p.001 -2.0 Reductions in Symptoms for Baseline to Endpoint (LOCF) Prince JB, et al. Presented at: 155th APA Annual Meeting; May 18-23, 2002; Philadelphia, Pa. ADHD+Substance Use Disorders Treatment 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. ADHD+Substance Use Disorders Treatment 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). Diagnosis & Assessment of ADHD Summary • 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 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