Pharmacotherapy of ADHD Side Effects of Stimulants Flavio Guzman, MD

Overview Cardiovascular risks Effects on growth Risk of tics Potential for abuse / diversion Sleep disturbances

FDA warning on sudden cardiac death Based on rare reports Warning (as appears in PI): Sudden death has been reported with usual doses of CNS stimulants in children and adolescents with structural cardiac abnormalities or other serious heart problems. Sudden death, stroke , and myocardial infarction have been reported in adults taking CNS stimulants at usual doses. U.S. Food and Drug Administration, Drug Safety and Risk Management Advisory Committee Meeting. February 9-10, 2006

ADHD, stimulants and sudden cardiac death What is the relationship between ADHD, stimulants and sudden cardiac death? No evidence that shows that SCD is more common in: Children with ADHD Children with ADHD receiving stimulants Berger, S. Cardiac evaluation of children receiving pharmacotherapy for attention deficit hyperactivity disorder. In: UpToDate, Triedman, J (Ed), UpToDate, Waltham, MA. (Accessed February, 2015.)

Stimulants, heart rate and blood pressure Stimulants cause slight but clinically insignificant increases in heart rate blood pressure Awudu, G. A., & Besag, F. M. (2014). Cardiovascular Effects of Methylphenidate, Amphetamines and Atomoxetine in the Treatment of Attention-Deficit Hyperactivity Disorder: An Update. Drug Safety, 37(9), 661-676.

Not suggestive of cardiac disease Pharmacotherapy can be initiated or continued without additional evaluation History and examination Not suggestive of cardiac disease Perrin JM, Friedman RA, Knilans TK, et al. Cardiovascular monitoring and stimulant drugs for attention deficit/hyperactivity disorder. Pediatrics 2008; 122:451.

History Special attention to symptoms such as palpitations, syncope or near syncope Family history of sudden death History of loss of consciousness particularly with exercise History of marked exercise intolerance Pharmacological Management of ADHD, in: Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA): Canadian ADHD Practice Guidelines, Third Edition, Toronto ON; CADDRA. Version: November 2014

Physical examination Measurement of: Cardiac auscultation Blood pressure Heart rate Cardiac auscultation Presence of a cardiac murmur Irregular or rapid cardiac rhythm Wilens TE, Prince JB, Spencer TJ, Biederman J. Stimulants and sudden death: what is a physician to do? Pediatrics 2006; 18:1215.

The role of ECG Should we order a screening ECG? Not recommended No data of ECG findings associated with serious cardiac events It may delay treatment Perrin JM, Friedman RA, Knilans TK, et al. Cardiovascular monitoring and stimulant drugs for attention-deficit/hyperactivity disorder. Pediatrics 2008; 122:451. American Academy of Pediatrics/American Heart Association clarification of statement on cardiovascular evaluation and monitoring of children and adolescents with heart disease receiving medications for ADHD.

ECG Cardiac disease Further evaluation (including ECG) History or physical examination suggestive of cardiac disease Further evaluation (including ECG) Consultation with pediatric cardiologist Perrin JM, Friedman RA, Knilans TK, et al. Cardiovascular monitoring and stimulant drugs for attention-deficit/hyperactivity disorder. Pediatrics 2008; 122:451. American Academy of Pediatrics/American Heart Association clarification of statement on cardiovascular evaluation and monitoring of children and adolescents with heart disease receiving medications for ADHD.

Effects of stimulants on growth Appetite suppression Growth retardation Purushothaman, Priti. "What's New with Stimulants?." Child and Adolescent Psychopharmacology News 18.4 (2013): 1-8.

Effects of stimulants on growth Prolonged treatment (more than 3 years) Slower rate of physical development during puberty Poulton, A. S et al (2013). Growth and pubertal development of adolescent boys on stimulant medication for attention deficit hyperactivity disorder. Med J Aust,198(1), 29-32.

“ADHD, Stimulant Treatment, and Growth: A Longitudinal Study” Medications did not affect children’s final height as adults Growth spurt at a later age than boys not treated with stimulants Mean age of peak height velocity delayed about 7 months Magnitude not affected Harstad EB et al. ADHD, stimulant treatment, and growth: A longitudinal study. Pediatrics 2014 Sep; 134:1

Effects on growth - Management Monitor: Appetite Weight Height BMI Baseline and every 6 months Purushothaman, Priti. "What's New with Stimulants?." Child and Adolescent Psychopharmacology News 18.4 (2013): 1-8.

Effects on growth - Management Appetite suppression Give medication after meals rather than before If growth concerns occur: Consider drug holidays on weekends or school holidays Consider reducing the dose Consider switching to an alternative class or formulation Purushothaman, Priti. "What's New with Stimulants?." Child and Adolescent Psychopharmacology News 18.4 (2013): 1-8.

Stimulants and tics Do stimulants cause tics? No evidence that stimulants cause tics in children who do not already have them Law SF et al., J Am Acad Child Adolesc Psychiatry 1999;38 (8):944–951; Varley CK et al., Compr Psychiatry2001;42(3):527–536; Tourette’s Syndrome Study Group, Neurology2002;58 (4):527 –53

Pathogenesis: increased DA in the basal ganglia Stimulants and tics Pathogenesis: increased DA in the basal ganglia Theoretically, stimulants could: Increase the risk of tics Worsen the severity of existing tics Purushothaman, Priti. "What's New with Stimulants?." Child and Adolescent Psychopharmacology News 18.4 (2013): 1-8.

Stimulants and tics In children with ADHD + tic disorders: MPH did not seem to worsen tics Supratherapeutic doses of D-AMP were shown to worsen tics Bloch, M. H., et al (2009). Meta-analysis: treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders. Journal of the American Academy of Child & Adolescent Psychiatry, 48(9), 884-893.

Stimulants and tics Cochrane review: Stimulants are effective Will likely continue to be a first-line treatment for children with comorbid ADHD and tic disorders Pringsheim, T., & Steeves, T. (2011). Pharmacological treatment for Attention Deficit Hyperactivity Disorder (ADHD) in children with comorbid tic disorders.The Cochrane Library

Potential for abuse / diversion Stimulants are associated with significant misuse potential Drug diversion is a concern in college and university settings Pharmacological Management of ADHD, in: Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA): Canadian ADHD Practice Guidelines, Third Edition, Toronto ON; CADDRA. Version: November 2014

Potential for abuse / diversion Non-medical use of stimulants improves academic performance Stimulants are more effective at correcting deficits False True Lakhan, S. E., & Kirchgessner, A. (2012). Prescription stimulants in individuals with and without attention deficit hyperactivity disorder: misuse, cognitive impact, and adverse effects. Brain and behavior, 2(5), 661-677.

Potential for abuse / diversion Students are the main source of diversion to other students Bolea-Alamañac, B., Nutt, D. , et al(2014). Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: Update on recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology, 28(3), 179-203.

Potential for abuse /diversion Avoiding risks of abuse Use long-acting formulations Prodrug lisdexamfetamine Bolea-Alamañac, B., Nutt, D. , et al(2014). Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: Update on recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology, 28(3), 179-203.

Sleep disturbances May be associated with ADHD ADHD medication Stimulant effects vary considerably Graham, J., Banaschewski, T., Buitelaar, J., Coghill, D., Danckaerts, M., Dittmann, R. W., ... & Taylor, E. (2011). European guidelines on managing adverse effects of medication for ADHD. European child & adolescent psychiatry, 20(1), 17-37.

Sleep disturbances Management Sleep hygiene Dose adjustment Dose scheduling Medication switch Atomoxetine Graham, J., Banaschewski, T., Buitelaar, J., Coghill, D., Danckaerts, M., Dittmann, R. W., ... & Taylor, E. (2011). European guidelines on managing adverse effects of medication for ADHD. European child & adolescent psychiatry, 20(1), 17-37.

Other side effects Headache Dizziness GI symptoms Precipitation of mania or psychosis Irritability, dysphoric mood

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