Pharmacotherapy of Adult ADHD Thomas J. Spencer, MD Massachusetts General Hospital Harvard Medical School
Disclosures Dr. Spencer receives research support from Royalties and Licensing fees on copyrighted ADHD scales through MGH Corporate Sponsored Research and Licensing. Dr. Spencer has a US Patent Application pending (Provisional Number 61/233. 686), through MGH corporate licensing, on a method to prevent stimulant abuse. 2
Percent Change (Bmax/Kd) DVR Images Obtained with [ 11 C]Raclopride After Placebo and After Methylphenidate Control ADHD 5 35 30 25 * Controls ADHD Placebo Placebo 20 15 10 5 0 0 Caudate Putamen Ratio Methylphenidate Methylphenidate Volkow, ND et al., Archives of General Psychiatry, 64(8):932-940, 2007.
Mechanism of Action MPH: Insights from PET Imaging Studies (Volkow et al. J Att Dis. 2002;(suppl)1) Because DA enhances task-specific neuronal signaling and decreases noise, MPH-induced increases in DA could improve attention and decrease distractibility Since DA modulates motivation, the increases in DA would also enhance the saliency of the task facilitating the interest it elicits and thus improving performance
Methylphenidate Increases Dorsal ACC & DLPFC in Patients with ADHD MPH-OROS Higher than Placebo at 6 Weeks damcc damcc DLPFC Parietal Bush et al. Archives of General Psychiatry. in press
Average Score MTA: Treatment Effects on Inattention Scores (SNAP) Average Score [MTA Group, Arch General Psychiatry, 1999] CC Beh MedMgt Comb 3 Parent 3 Teacher 2.5 2.5 2 2 1.5 1.5 1 1 0.5 0.5 0 0 0 100 200 300 400 0 100 200 300 400 Assessment Point (Days)
Average Score Teacher SSRS Social Skills 1.5 1.4 1.3 1.2 CC Beh MedMgt Comb 1.1 1 0.9 0.8 0.7 0 100 200 300 400 Assessment Point (Days)
Pharmacotherapy of Adult ADHD N=45 Studies N=6,439 Subjects N=51 Studies N=5,488 Subjects 8 Prince, Wilens 2013
Methphenidate Concentration (ng/ml) Comparison of MPH Concentration Following IR-MPH and OROS-MPH 7 6 5 OROS 18 mg IR-MPH 5 mg 4 3 2 1 0 0 4 8 12 16 20 24 28 32 Time (hours)
Clinical Ratings of ADHD Symptoms (ADHD-RS) Week OROS-MPH mg/day Placebo mg/day 1 36.0 36.0 2 58.7+17.8 66.3+12.8 3 72.6+26.5 82.2+22.4 4 77.9+29.6 92.2+23.8 5 81.3+31.0 94.9+25.5 6 80.9+31.8 96.8+25.9 P=0.04* P=0. 03 P=0.001 P<0.001 Biederman et al Biol psych 2006
BRIEF Impairment Stratified by Executive Function Deficit and Treatment Status at Baseline and Endpoint Biederman et al. Eur Neuropsychopharmacol 2011
Focalin (D-MPH)* An Isomeric Form of MPH H H H H 2 N N 2 Ph 2 COOCH 3 CH 3 OOC 2 Ph H H l (-) Methylphenidate D (+) Methylphenidate *FDA approved for ADHD. Courtesy of T. Wilens, MD.
SODAS d-mph: DAT Occupancy (PET) by Hour and Dose Spencer et al. In Press J Clin Psych 20 mg 30 mg 40 mg
Meta-analysis of Within-Subject Comparative Trials Evaluating Response to Stimulant Medications Spencer et al. Arch of Gen Psych 2001 50 6 studies N=274 40 52% Best Response (Percent) 30 20 25% 23% 10 0 Dextroamphetamine Methylphenidate Equal response to either stimulant 14
Mean ADHD-RS Total Score Mixed Amphetamine Salts: Mean Total Score at Endpoint (ITT) 40 30 20 10 Endpoint = LOCF Baseline Endpoint Change (Endpoint-Baseline) 33.0 31.1 26.4 18.5 ** ** 31.3 32.9 18.4 18.5 ** 0-10 -20 6.6 12.6 Placebo Adderall XR 20 mg **P 0.001 (adjusted Dunnett s test compared with placebo following ANCOVA with baseline score as covariate) 12.9 Adderall XR 40 mg 14.4 Adderall XR 60 mg
Change in ADHD-RS Total Score ADHD-RS Total Score LDX in Adult ADHD: ADHD-RS Total Scores (ITT Population) 60 50 40 30 20 10 0-10 -20 Placebo -8.2 30 mg/d LDX 50 mg/d LDX 70 mg/d LDX -16.2* -17.4* -18.6* Baseline Endpoint Change from baseline (LS mean ± SE) A more negative change in ADHD-RS total score indicates greater improvement. LS=least squares; SE=standard error of the mean. *P<.0001 (adjusted Dunnett s test compared with placebo following ANCOVA with baseline score as covariate).
Effect Size Stimulant Tx of Executive Function Lisdexamfetamine in Adult ADHD + GEC > 65 Adler et al. JCP 2013 17
Score Controlled Trial of Lisdexamfetamine Collisions 30 25 20 * TX Group Placebo 15 10 5 0 Baseline 2nd Simulation
Adverse Effects of Stimulants Adverse effects (AEs) are similar for all stimulants Decreased appetite Insomnia Headache Stomachache Irritability/rebound phenomena Rates of these AEs may be high prior to any medical intervention; thus, baseline levels should always be obtained Wilens T, Spencer T. In: Child and Adolescent Psychiatric Clinics of North America. Philadelphia, Pa: Saunders Press; 2000:573-604.
Concerns Associated with Use of Stimulants Substance abuse Diversion Tics Growth Cardiovascular risk
Screening for Cardiac Risk: AHA Guidelines Medical history Personal congenital or acquired cardiac disease history Family history of cardiac disease (<50 years of age) Palpitations, chest pain, fainting, seizures, post-exercise symptoms Ask about other medications (including OTC) Routine medical exam Monitor BP and pulse at baseline and follow-up, especially in adults ECG is reasonable but not mandatory Routine check of Holter, ECHO is not necessary Gutgesell H, et al. Circulation. 1999:99:979-982. Schubiner H, et al. J Atten Disord. 2006;10:205-211.
Medication for ADHD and Criminality (Lichtenstein et al. NEJM 2012: 367:2006-2014) Women-41% reduction Men- 32% reduction Swedish national registers (N= 25,656 with ADHD-about 50% on medications) Ca. 40% of convictions related to drug offenses (Tx OR=0.6). No difference in type of ADHD medication (stimulants, nonstimulants) or level of crime.
Norepinephrine Effects Attentional Systems Posterior Resulting Activity Disengage from stimuli Change focus to new stimuli Engage attention to new stimuli Posterior Anterior Anterior Working memory Analyze data Prepare for response Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry. 1996;35(3):264-272. Mefford IN, Potter WZ. Med 24 Hypotheses. 1989;29(1):33-42.
fmri of Atomoxetine: MSIT shows activation of dorsolateral prefrontal, parietal, cerebellum Bush, et al. Psychiatry Research. Volume 211, Issue 1, 30 January 2013
Mean CAARS Change Atomoxetine: Long-term Efficacy in Adults (34 Weeks) 35 30 Discontinuation Phase Acute Phase Extension Phase 25 20 26 15 10 Placebo Atomoxetine Atomoxetine-EXT Atomoxetine-EXT 0 2 4 6 8 10 0 2 4 6 10 14 18 22 34 Weeks N = 384; Adler L et al. J Clin Psych. 2006.
Improvement Least Squares Mean Change Atomoxetine Treatment in Adults with ADHD and Comorbid Social Anxiety Disorder Adler et al. Depression Anxiety 2009 0-5 -10-15 * ** Placebo Atomoxetine -20-25 -30 ** ** *** Week 0 2 4 6 10 14 *p<.05 **p<.01 ***p<.001 Overall tx effect p<.001
Atomoxetine in Adults with ADHD: Common Side Effects* Side Effect Atomoxetine (%) Placebo (%) Dry mouth 21 7 Insomnia 21 9 Nausea 12 5 Decreased appetite 12 3 Decreased libido 7 2 Erectile difficulty 10 1 Dizziness 6 2 Increased BP (systolic, diastolic): 1-3 mm Hg Increased HR: 5 bpm Michelson *All significant D, et versus al. Biol placebo. Psychiatry. 2003;53:112-120.
Atomoxetine: Black Box Warnings Hepatotoxicity Two cases in 4 million exposures of elevated liver enzymes (one had autoimmune disease); no clinical predictors Symptoms: Abdominal pain and jaundice Resolved with discontinuation of medication No screening or blood tests necessary Suicidal ideation/behavior is a concern in children only and is extremely rare 2004 Strattera Safety Guide: Revised Label. FDA MedWatch Web site. http://www.fda.gov/medwatch/safety/2004/strattera_pi.pdf.
Medications that are not FDA approved for ADHD
Bupropion XL (Wellbutrin XL ) in Adults With ADHD: Percent Responders % of Responders 60 50 40 Placebo n = 81 Bupropion XL n = 81 * * * 30 20 10 0 1 2 4 5 8 Time in Study (Weeks) *P.01, P<.05, 30% reduction from baseline. Wilens et al. Biol Psych 2005
Armodafinil Intrasynaptic Dopamine (Rt Caudate) by Dose Spencer et al. Biol Psych 2010 Volkow et al. JAMA 2009 Volkow 200/400 mg modafinil nucleus accumbens Volkow 200/400 mg modafinil caudate
Memantine: Clinical ADHD Rating (AISRS) Surman et al. Annual Meeting AACAP 2010
Summary: Pharmacotherapy of ADHD Efficacy in adults consistent with efficacy in children A variety of effective drugs Commonality: dopaminergic or noradrenergic mechanism of action Preliminary evidence of cholinergic mechanism