Pharmacological interventions are recommended by clinical guidelines for ADHD as part of a comprehensive treatment programme (including a behavioural therapy component) if there is insufficient response to non-pharmacological treatment.1-4
The main classes of available ADHD pharmacological treatments include:
- Methylphenidate (e.g. Ritalin®,5 Medikinet®,6 Biphentin®,7 Concerta®,8 Equasym®,9 Focalin®,10 Matoride®11)
- Amfetamine (e.g. Adderall®,12 Amfexa®,13 Dexedrine®,14,15 Elvanse®,16 Elvanse Adult®17).
- Atomoxetine (Strattera®18)
- Guanfacine (Intuniv®19).
The decision about which medication should be used to treat ADHD depends on a range of factors, including: presence of comorbidities; undesirable effects of the medication; individual compliance needs; potential for drug diversion; and the personal preference of patients and their caregivers.1-4
Are there difficult areas of the day when control of ADHD symptoms is particularly important for children and adolescents with ADHD, for example, early morning, late afternoon, weekends, at school? | Dr Robert Findling | Johns Hopkins University and Kennedy Krieger Institute, Baltimore, MD, USA
When choosing the most appropriate treatment for your patient with ADHD, what consideration do you give regarding the flexibility of dosing? | Professor Peter Hill | Independent Child and Adolescent Psychiatrist, London, UK
When choosing a treatment, how big a consideration are the ADHD patients’ comorbid conditions or comorbid symptoms? How do you decide which symptoms to treat? | Professor Peter Hill | Independent Child and Adolescent Psychiatrist, London, UK
When choosing a treatment, how big a consideration are the ADHD patients’ comorbid conditions or comorbid symptoms? How do you decide which symptoms to treat? | Dr Robert Findling | Johns Hopkins University and Kennedy Krieger Institute, Baltimore, MD, USA
How does treating adults with ADHD differ from treating children and adolescents? | Dr Joel Young | Rochester Centre for Behavioral Medicine, Rochester, MI, USA
Are there difficult areas of the day when control of ADHD symptoms is particularly important for children and adolescents with ADHD? | Professor Peter Hill | Independent Child and Adolescent Psychiatrist, London, UK
Mode of action
The modes of action of pharmacological treatments for ADHD are not fully understood; however, agents such as methylphenidate, amfetamine, atomoxetine and guanfacine all appear to have distinct effects on dopamine and noradrenaline signalling pathways in the brain.20-53
Mechanisms of delivery
Pharmacological treatments for ADHD can be delivered by immediate-release54 or extended-release (multiple bead,9,55-57 osmotic-controlled release,58,59 prodrug16,17,60,61) systems.
Pharmacokinetic data are available for all simulant and non-stimulant preparations.5-7,9,10,12,13,16-19,57,62-73
Differential response to treatment
Evidence from crossover studies suggests that some people with ADHD may respond differently to different types of pharmacological treatment, and that particular treatments may be ineffective in some patients.74-77
Adherence to treatment
Adherence to ADHD medication is often suboptimal, which can negatively affect treatment outcomes.78,79
Psychoeducation and knowledge of a patient’s acceptance of their condition may be helpful in encouraging adherence to medication, particularly in adolescents.2
In the absence of direct comparative trials, effect sizes are calculated to allow indirect comparisons of randomised, double-blind, placebo-controlled studies of ADHD medications, and provide data on the relative efficacy of each medication.80,81
- NICE guideline 2018. Attention deficit hyperactivity disorder: diagnosis and management. Available at: https://www.nice.org.uk/guidance/ng87. Accessed February 2019.
- Canadian ADHD Resource Alliance (CADDRA). Canadian ADHD Practice Guidelines. Fourth Edition. Toronto, ON; CADDRA, 2018.
- Banaschewski T, Hohmann S, Millenet S. Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) im Kindes-, Jugend- und Erwachsenenalter. DGKJP, DGPPN and DGSPJ German guidelines. 2018.
- Guías de Práctica Clínica en el SNS. Grupo de trabajo de la Guía de Práctica Clínica sobre las Intervenciones Terapéuticas en el Trastorno por Déficit de Atención con Hiperactividad (TDAH). 2017.
- Novartis Pharmaceuticals UK Ltd. Ritalin Summary of Product Characteristics. Last updated April 2018.
- Flynn Pharma Ltd. Medikinet Summary of Product Characteristics. Last updated January 2017.
- Purdue Pharma. Biphentin Product Monograph. Last updated April 2017.
- Janssen-Cilag Ltd. Concerta XL 18-36mg Summary of Product Characteristics. Last updated July 2018.
- Shire Pharmaceuticals Ltd. Equasym XL Summary of Product Characteristics. Last updated June 2018.
- Novartis Pharmaceuticals Corporation. Focalin XR US Prescribing Information. Last updated January 2017.
- Sandoz Ltd. Matoride XL Summary of Product Characteristics. Last updated April 2017.
- Adderall XR Canadian Product Monograph. Last updated June 2017.
- Flynn Pharma Ltd. Amfexa Summary of Product Characteristics. Last updated July 2016.
- Paladin Labs Inc. Dexedrine Product Monograph. Last updated March 2016.
- Auden Mckenzie (Pharma Division) Ltd. Dexamfetamine Sulphate Summary of Product Characteristics. Last updated April 2018.
- Shire Pharmaceuticals Ltd. Elvanse Summary of Product Characteristics. Last updated April 2018.
- Shire Pharmaceuticals Ltd. Elvanse Adult Summary of Product Characteristics. Last updated November 2017.
- Eli Lilly and Company Ltd. Strattera Summary of Product Characteristics. Last updated May 2015.
- Shire Pharmaceuticals Ltd. Intuniv Summary of Product Characteristics. Last updated February 2018.
- Volkow ND, Wang GJ, Fowler JS, et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 1998; 155: 1325-1331.
- Volkow ND, Wang G, Fowler JS, et al. Therapeutic doses of oral methylphenidate signficantly increase extracellular dopamine in the human brain. J Neurosci 2001; 21: RC121.
- Rosa-Neto P, Lou HC, Cumming P, et al. Methylphenidate-evoked changes in striatal dopamine correlate with inattention and impulsivity in adolescents with attention deficit hyperactivity disorder. Neuroimage 2005; 25: 868-876.
- Hannestad J, Gallezot JD, Planeta-Wilson B, et al. Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo. Biol Psychiatry 2010; 68: 854-860.
- Volkow ND, Wang GJ, Tomasi D, et al. Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J Neurosci 2012; 32: 841-849.
- Cherkasova MV, Faridi N, Casey KF, et al. Amphetamine-induced dopamine release and neurocognitive function in treatment-naive adults with ADHD. Neuropsychopharmacology 2014; 39: 1498-1507.
- Crunelle CL, van den Brink W, Dom G, et al. Dopamine transporter occupancy by methylphenidate and impulsivity in adult ADHD. Br J Psychiatry 2014; 204: 486-487.
- Schrantee A, Tamminga HG, Bouziane C, et al. Age-dependent effects of methylphenidate on the human dopaminergic system in young vs adult patients with attention-deficit/hyperactivity disorder: a randomized clinical trial. JAMA Psychiatry 2016; 73: 955-962.
- Silberstein RB, Levy F, Pipingas A, et al. First-dose methylphenidate-induced changes in brain functional connectivity are correlated with 3-month attention-deficit/hyperactivity disorder symptom response. Biol Psychiatry 2017; 82: 679-686.
- Liang NY, Rutledge CO. Comparison of the release of [3H]dopamine from isolated corpus striatum by amphetamine, fenfluramine and unlabelled dopamine. Biochem Pharmacol 1982; 31: 983-992.
- Florin SM, Kuczenski R, Segal DS. Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment. Brain Res 1994; 654: 53-62.
- Gonzalez AM, Walther D, Pazos A, et al. Synaptic vesicular monoamine transporter expression: distribution and pharmacologic profile. Brain Res Mol Brain Res 1994; 22: 219-226.
- Wall SC, Gu H, Rudnick G. Biogenic amine flux mediated by cloned transporters stably expressed in cultured cell lines: amphetamine specificity for inhibition and efflux. Mol Pharmacol 1995; 47: 544-550.
- Kantor L, Gnegy ME. Protein kinase C inhibitors block amphetamine-mediated dopamine release in rat striatal slices. J Pharmacol Exp Ther 1998; 284: 592-598.
- Zhu MY, Shamburger S, Li J, et al. Regulation of the human norepinephrine transporter by cocaine and amphetamine. J Pharmacol Exp Ther 2000; 295: 951-959.
- Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit / hyperactivity disorder. Neuropsychopharmacology 2002; 27: 699-711.
- Johnson LA, Guptaroy B, Lund D, et al. Regulation of amphetamine-stimulated dopamine efflux by protein kinase C beta. J Biol Chem 2005; 280: 10914-10919.
- Kahlig KM, Binda F, Khoshbouei H, et al. Amphetamine induces dopamine efflux through a dopamine transporter channel. Proc Natl Acad Sci U S A 2005; 102: 3495-3500.
- Berridge CW, Devilbiss DM, Andrzejewski ME, et al. Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry 2006; 60: 1111-1120.
- Han DD, Gu HH. Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol 2006; 6: 6.
- Partilla JS, Dempsey AG, Nagpal AS, et al. Interaction of amphetamines and related compounds at the vesicular monoamine transporter. J Pharmacol Exp Ther 2006; 319: 237-246.
- Swanson CJ, Perry KW, Koch-Krueger S, et al. Effect of the attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several brain regions of the rat. Neuropharmacology 2006; 50: 755-760.
- Easton N, Steward C, Marshall F, et al. Effects of amphetamine isomers, methylphenidate and atomoxetine on synaptosomal and synaptic vesicle accumulation and release of dopamine and noradrenaline in vitro in the rat brain. Neuropharmacology 2007; 52: 405-414.
- Wang M, Ramos BP, Paspalas CD, et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 2007; 129: 397-410.
- Hu J, Vidovic M, Chen MM, et al. Activation of alpha 2A adrenoceptors alters dendritic spine development and the expression of spinophilin in cultured cortical neurones. Brain Res 2008; 1199: 37-45.
- Ji XH, Ji JZ, Zhang H, et al. Stimulation of alpha2-adrenoceptors suppresses excitatory synaptic transmission in the medial prefrontal cortex of rat. Neuropsychopharmacology 2008; 33: 2263-2271.
- Ren WW, Liu Y, Li BM. Stimulation of α(2A)-adrenoceptors promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex. Mol Cell Neurosci 2012; 49: 205-216.
- Avelar AJ, Juliano SA, Garris PA. Amphetamine augments vesicular dopamine release in the dorsal and ventral striatum through different mechanisms. J Neurochem 2013; 125: 373-385.
- Yi F, Liu SS, Luo F, et al. Signaling mechanism underlying α2A-adrenergic suppression of excitatory synaptic transmission in the medial prefrontal cortex of rats. Eur J Neurosci 2013; 38: 2364-2373.
- Somkuwar SS, Kantak KM, Dwoskin LP. Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder. J Neurosci Methods 2015; 252: 55-63.
- Heal DJ, Cheetham SC, Smith SL. The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety. Neuropharmacology 2009; 57: 608-618.
- Kahlig KM, Galli A. Regulation of dopamine transporter function and plasma membrane expression by dopamine, amphetamine, and cocaine. Eur J Pharmacol 2003; 479: 153-158.
- Schiffer WK, Volkow ND, Fowler JS, et al. Therapeutic doses of amphetamine or methylphenidate differentially increase synaptic and extracellular dopamine. Synapse 2006; 59: 243-251.
- Sulzer D, Chen TK, Lau YY, et al. Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci 1995; 15: 4102-4108.
- Gupta A, Hunt RL, Shah RB, et al. Disintegration of highly soluble immediate release tablets: a surrogate for dissolution. AAPS PharmSciTech 2009; 10: 495-499.
- Maldonado R. Comparison of the pharmacokinetics and clinical efficacy of new extended-release formulations of methylphenidate. Expert Opin Drug Metab Toxicol 2013; 9: 1001-1014.
- Novartis Pharmaceuticals Corporation. Ritalin LA US Prescribing Information. Last updated April 2018.
- Flynn Pharma Ltd. Medikinet XL Summary of Product Characteristics. Last updated March 2017.
- Conley R, Gupta SK, Sathyan G. Clinical spectrum of the osmotic-controlled release oral delivery system (OROS), an advanced oral delivery form. Curr Med Res Opin 2006; 22: 1879-1892.
- Modi NB, Lindemulder B, Gupta SK. Single- and multiple-dose pharmacokinetics of an oral once-a-day osmotic controlled-release OROS (methylphenidate HCl) formulation. J Clin Pharmacol 2000; 40: 379-388.
- Pennick M. Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat 2010; 6: 317-327.
- Sharman J, Pennick M. Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells. Neuropsychiatr Dis Treat 2014; 10: 2275-2280.
- Novartis Pharmaceuticals Corporation. Ritalin LA Summary of Product Characteristics. Last updated April 2018.
- Wong YN, Wang L, Hartman L, et al. Comparison of the single-dose pharmacokinetics and tolerability of modafinil and dextroamphetamine administered alone or in combination in healthy male volunteers. J Clin Pharmacol 1998; 38: 971-978.
- Adjei A, Teuscher NS, Kupper RJ, et al. Single-dose pharmacokinetics of methylphenidate extended-release multiple layer beads administered as intact capsule or sprinkles versus methylphenidate immediate-release tablets (Ritalin((R))) in healthy adult volunteers. J Child Adolesc Psychopharmacol 2014; 24: 570-578.
- Schapperer E, Daumann H, Lamouche S, et al. Bioequivalence of Sandoz methylphenidate osmotic-controlled release tablet with Concerta® (Janssen-Cilag). Pharmacol Res Perspect 2015; 3: e00072.
- Gonzalez MA, Pentikis HS, Anderl N, et al. Methylphenidate bioavailability from two extended-release formulations. Int J Clin Pharmacol Ther 2002; 40: 175-184.
- Haessler F, Tracik F, Dietrich H, et al. A pharmacokinetic study of two modified-release methylphenidate formulations under different food conditions in healthy volunteers. Int J Clin Pharmacol Ther 2008; 46: 466-476.
- Janssen Inc. Concerta XL Summary of Product Characteristics. Last updated July 2018.
- Tuerck D, Wang Y, Maboudian M, et al. Similar bioavailability of dexmethylphenidate extended (bimodal) release, dexmethyl-phenidate immediate release and racemic methylphenidate extended (bimodal) release formulations in man. Int J Clin Pharmacol Ther 2007; 45: 662-668.
- Krishnan S, Zhang Y. Relative bioavailability of lisdexamfetamine 70-mg capsules in fasted and fed healthy adult volunteers and in solution: a single-dose, crossover pharmacokinetic study. J Clin Pharmacol 2008; 48: 293-302.
- Haffey MB, Buckwalter M, Zhang P, et al. Effects of omeprazole on the pharmacokinetic profiles of lisdexamfetamine dimesylate and extended-release mixed amphetamine salts in adults. Postgrad Med 2009; 121: 11-19.
- Witcher JW, Long A, Smith B, et al. Atomoxetine pharmacokinetics in children and adolescents with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 2003; 13: 53-63.
- Swearingen D, Pennick M, Shojaei A, et al. A phase I, randomized, open-label, crossover study of the single-dose pharmacokinetic properties of guanfacine extended-release 1-, 2-, and 4-mg tablets in healthy adults. Clin Ther 2007; 29: 617-625.
- Arnold LE. Methylphenidate vs amphetamine: comparative review. J Atten Disord 2000; 3: 200-211.
- Hodgkins P, Shaw M, Coghill D, et al. Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options. Eur Child Adolesc Psychiatry 2012; 21: 477-492.
- Efron D, Jarman F, Barker M. Methylphenidate versus dextroamphetamine in children with attention deficit hyperactivity disorder: a double-blind, crossover trial. Pediatrics 1997; 100: E6.
- Newcorn JH, Kratochvil CJ, Allen AJ, et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. Am J Psychiatry 2008; 165: 721-730.
- Marcus SC, Wan GJ, Kemner JE, et al. Continuity of methylphenidate treatment for attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 2005; 159: 572-578.
- Barner JC, Khoza S, Oladapo A. ADHD medication use, adherence, persistence and cost among Texas Medicaid children. Curr Med Res Opin 2011; 27(Suppl 2): 13-22.
- Faraone SV. Using meta-analysis to compare the efficacy of medications for attention-deficit/hyperactivity disorder in youths. P T 2009; 34: 678-694.
- Faraone SV. Interpreting estimates of treatment effects: implications for managed care. P T 2008; 33: 700-711.