Which pharmacological therapies are available for ADHD?
Pharmacological interventions are recommended by clinical guidelines for attention-deficit hyperactivity disorder (ADHD), or hyperkinetic disorder (HKD), as part of a comprehensive treatment programme (including a behavioural therapy component) if there is insufficient response to non-pharmacological treatment.1-4 As outlined in the National Institute for Health and Care Excellence (NICE) guidelines 2018, when prescribing pharmacotherapy for ADHD, clinicians are recommended to be aware that effect size, duration of effect and adverse effects may vary from person to person.1 Clinicians prescribing ADHD medication are encouraged to be familiar with the pharmacokinetic profiles of all short- and long-acting preparations available for ADHD and take variations in bioavailability into account to avoid reduced effect or excessive adverse effects.1
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 availability and approved use of these treatments differs between countries. For further information, please consult your local prescribing information.
Childhood/adolescent ADHD and treatment effects in the brain by Dr Mitul Mehta
Psychoeducation and an individual’s acceptance of their ADHD may help adherence to pharmacotherapy, particularly in adolescents.2
How can clinicians improve adherence to pharmacological therapies for ADHD?
The decision regarding which medication is used to treat ADHD may depend on a range of factors, including: presence of psychiatric comorbidities; undesirable effects of the medication; individual compliance needs; potential for drug diversion; and the personal preference of the individual and their family or carers.1-4 Adherence to pharmacological therapy for ADHD can be suboptimal, which may negatively affect treatment outcomes.20,21 For example, individuals with ADHD and their families may think that a pharmacotherapy has less than optimal effectiveness and is associated with intolerable adverse effects, which may contribute to poor adherence.22 Psychoeducation and an individual’s acceptance of their ADHD may help adherence to pharmacotherapy, particularly in adolescents.2 In support of this, adolescents’ perceptions of the degree of stigma associated with ADHD have been reported to affect receptiveness to treatment.23 Multiple daily doses of medication, including dosing during school hours, could also be considered a source of embarrassment for some students with ADHD.20 Moreover, ADHD-related forgetfulness may cause difficulty in adhering to a treatment plan that requires multiple daily doses; therefore, for some individuals once-daily dosing may be more helpful.2
It is recommended that clinicians ensure that individuals with ADHD are fully informed of the balance of risks and benefits of any treatment for ADHD, and check that problems with adherence are not due to misconceptions.1 The following strategies to support adherence to treatment have been recommended by the NICE guidelines 20181:
- Encourage people with ADHD to be responsible for their own health, including taking their medication as needed.
- Provide the individual with clear instructions about how to take their medication in picture or written format. This information may include dose, duration, adverse effects and dosage schedule.
- Advise the individual to use visual reminders to take their medication regularly (e.g. alarms, apps, clocks, pill dispensers or notes on calendars or fridges).
- Suggest that the individual takes their medication as part of their daily routine (e.g. before meals or after brushing their teeth).
- Encourage the individual with ADHD and their family or carers to attend peer support groups and encourage parents or carers to oversee ADHD medication for children and adolescents.
What are the modes of action of the pharmacological therapies for ADHD?
The modes of action of pharmacological treatments for ADHD are not fully understood; however, agents such as methylphenidate, amfetamine, atomoxetine and guanfacine appear to have distinct effects on dopamine and noradrenaline signalling pathways in the brain (Table 1; Figures 1‒4).24-40
Table 1: Hypothesised mode of action of pharmacological treatments for ADHD.24-40
Figure 1: Hypothesised mode of action of methylphenidate.24-31
Figure 2: Hypothesised mode of action of amfetamine.24,25,32-37
Figure 3: Hypothesised mode of action of atomoxetine.38,39
Figure 4: Hypothesised mode of action of guanfacine.40
How does the mechanism of delivery differ between pharmacological therapies for ADHD?
- Immediate-release tablets or capsules are the most widely used drug-delivery systems. They are designed to undergo disintegration in the stomach into smaller granules and subsequent dissolution in the fluids of the gastrointestinal tract.41
- Extended-release formulations are designed to produce slow, uniform absorption of the drug.42
- Multiple bead system consists of a water-soluble gelatin capsule that dissolves quickly once swallowed, releasing drug-containing beads of two different dissolution rates.9,43,44 Multiple bead formulations release a steady level of drug into the bloodstream, allowing for once-daily dosing.9,43,44 Once-daily dosing has practical advantages, particularly in young individuals, and the potential for stimulant abuse may be lower for extended-release formulations compared with immediate-release formulations.45
- Osmotic-controlled release oral delivery system is designed to provide a longer duration of effect than the multiple bead system.46 For example, methylphenidate is available in this formulation. The outer layer of the capsule is coated with methylphenidate, which quickly releases once the pill is ingested.46,47 The inner layers are set up along an osmotic gradient; the first compartment, with a small amount of the drug, releases via simple diffusion, but the second compartment, with a higher amount of the drug, releases as a result of the osmotic pressure created when water reacts with the third compartment.47
- Prodrugs are pharmacologically inactive molecules that are converted into one or more active metabolites through a natural metabolic process.48,49 Prodrugs are designed to enhance the attributes of the active drug, such as enhanced solubility, increased or enhanced absorption and distribution and prolonged systemic availability.48,49 Lisdexamfetamine dimesylate is a prodrug where lysine is covalently linked to amfetamine and the drug only becomes active after lysine is cleaved by enzymes in the bloodstream.17,50 The lisdexamfetamine prodrug becomes active only after it has been absorbed by the intestinal tract and has been converted to dextroamphetamine and l-lysine.45
- NICE guideline 2018. Attention deficit hyperactivity disorder: diagnosis and management. Available at: https://www.nice.org.uk/guidance/ng87. Accessed January 2021.
- Canadian ADHD Resource Alliance (CADDRA). Canadian ADHD Practice Guidelines. Edition 4.1. Toronto, ON: CADDRA, 2020.
- 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 January 2021.
- Flynn Pharma Ltd. Medikinet Summary of Product Characteristics. Last updated December 2020.
- Purdue Pharma. Biphentin Product Monograph. Last updated August 2020.
- Janssen-Cilag Ltd. Concerta XL 18-36mg Summary of Product Characteristics. Last updated October 2020.
- Shire Pharmaceuticals Ltd. Equasym XL Summary of Product Characteristics. Last updated January 2021.
- Novartis Pharmaceuticals Corporation. Focalin XR US Prescribing Information. Last updated January 2017.
- Sandoz Ltd. Matoride XL Summary of Product Characteristics. Last updated November 2020.
- Takeda Canada Inc. Adderall XR Canadian Product Monograph. Last updated December 2020.
- Flynn Pharma Ltd. Amfexa Summary of Product Characteristics. Last updated April 2018.
- Paladin Labs Inc. Dexedrine Product Monograph. Last updated October 2020.
- Brown & Burk UK Ltd. Dexamfetamine Sulfate Summary of Product Characteristics. Last updated September 2020.
- Shire Pharmaceuticals Ltd. Elvanse Summary of Product Characteristics. Last updated November 2020.
- Shire Pharmaceuticals Ltd. Elvanse Adult Summary of Product Characteristics. Last updated November 2020.
- Eli Lilly and Company Ltd. Strattera Summary of Product Characteristics. Last updated June 2015.
- Shire Pharmaceuticals Ltd. Intuniv Summary of Product Characteristics. Last updated July 2020.
- 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.
- Charach A, Fernandez R. Enhancing ADHD medication adherence: challenges and opportunities. Curr Psychiatry Rep 2013; 15: 371.
- Bussing R, Zima BT, Mason DM, et al. Receiving treatment for attention-deficit hyperactivity disorder: do the perspectives of adolescents matter? J Adolesc Health 2011; 49: 7-14.
- Heal DJ, Cheetham SC, Smith SL. The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety. Neuropharmacology 2009; 57: 608-618.
- Han DD, Gu HH. Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol 2006; 6: 6.
- 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.
- 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.
- 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.
- 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.
- 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.
- Volkow ND, Wang G-J, 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.
- 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.
- 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.
- 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.
- Teng L, Crooks PA, Dwoskin LP. Lobeline displaces [3H]dihydrotetrabenazine binding and releases [3H]dopamine from rat striatal synaptic vesicles: comparison with d-amphetamine. J Neurochem 1998; 71: 258-265.
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- 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.
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- Novartis Pharmaceuticals Corporation. Ritalin LA US Prescribing Information. Last updated November 2019.
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