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Evidence from crossover studies suggests that some people with ADHD may respond differently to different types of pharmacological treatment:

  • Some people respond to more than one type of treatment.
  • Some people respond better to some types of treatment than to others.
  • Some people respond to some types of treatment, but do not respond at all to others.

The possible reasons for such ‘differential responses’ are explored below, alongside the potential implications for treatment approaches.

Arnold conducted searches of the MEDLINE and PsycINFO databases to identify literature published between 1984 and 1996 with the keywords ‘methylphenidate’ and ‘amfetamine’; search results were supplemented with known prior and more recent literature.1

Ten controlled crossover studies comparing methylphenidate and amfetamine were found. These were published between 1974 and 1999. Of the 10 studies, only eight independent samples were represented because of the large overlap in sample size in three of the studies. A further two studies were eliminated for the following reasons:1

  • One study contained non-comparable dosing and contradictions in response rate and mean global score.
  • One study focused on the comorbidity of Tourette’s syndrome.

The final analysis of response to methylphenidate and amfetamine was carried out on six of the studies identified (n=174).1

Of the 174 patients:1

  • 22 (13%) responded to neither methylphenidate nor amfetamine.
  • 152 (87%) responded to methylphenidate and/or amfetamine (the author suggests that this should be considered a lower-bound estimate due to a high non-response rate in two studies in which children were receiving behavioural treatment, which normalised behaviour on placebo).
  • 99 (57%) responded to methylphenidate.
  • 120 (69%) responded to amfetamine.

When considering relative responses to methylphenidate and amfetamine:1

  • 72 (41%) patients were described as ‘double responders’ (the author notes that there may have been more double responders undetected by the reporting methods, and therefore response rates for the individual medications should be considered as lower-bound estimates).
  • 27 (16%) patients responded better to methylphenidate.
  • 48 (28%) patients responded better to amfetamine.
  • Data are not reported for the remaining five (3%) patients.

Adverse events were broadly similar with both medications across the studies.1

Figure: Arnold 2000: patient outcomes following treatment with methylphenidate versus amfetamine. Reproduced with kind permission from Arnold LE. J Atten Disord 2000; 3: 200-211.1

Arnold 2000: patient outcomes following treatment with methylphenidate versus amfetamine

Hodgkins et al conducted PubMed literature searches in March 2011 to identify publications reporting studies of methylphenidate (search terms: methylphenidate, Biphentin, Concerta, Daytrana, Equasym, Focalin, Medikinet, Metadate, Methylin, Ritalin) and/or amfetamine (search terms: amfetamine, Adderall, Dexedrine, Dextrostat, lisdexamfetamine), with results limited to ‘clinical trial’ but no restrictions on publication date; search results were then filtered for relevance.2

The search identified 13 randomised studies comparing methylphenidate and amfetamine, published between 1974 and 2006.2

A total of 318 patients were included in the analysis of eight randomised studies, all published between 1978 and 2000. These comprised seven crossover studies and one parallel-group (head-to-head) study.2

The data suggested that:2

  • Most patients (n=287/316; 91%) responded to methylphenidate and/or amfetamine (Figure).
  • ~29% of patients did not respond to methylphenidate and 20% responded preferentially to amfetamine.
  • ~32% of patients did not respond to amfetamine and 23% responded preferentially to methylphenidate.
  • 9% of patients may have benefited from an alternative to treatment with stimulants.

Regarding responses to the medications, the authors drew the following conclusions:2

  • The proportion of patients responding to either class of stimulant was higher than the proportion responding to each individual stimulant.
  • Non-response was uncommon when a subject was offered both methylphenidate and amfetamine.
  • Response rates with the two classes of stimulant were similar in the overall population, but there was variation between subjects.

Adverse-event profiles were reported to be similar with both medications across the studies.2

  • However, some of the individual studies suggested that the frequency and severity of adverse events may be greater with amfetamine than with methylphenidate when the two stimulant types are compared, and also that the frequency of adverse events may be greater with methylphenidate than with amfetamine when both stimulants are compared with placebo.2
  • Insomnia and appetite suppression were generally the most common adverse events reported for both medications.2
Figure: Hodgkins et al 2012: patient outcomes following treatment with methylphenidate versus amfetamine. Reproduced with kind permission from Hodgkins P et al. Eur Child Adolesc Psychiatry 2012; 21: 477-492.2

Hodgkins et al 2012: patient outcomes following treatment with methylphenidate versus amfetamine

A double-blind crossover study reported by Efron et al was designed to compare methylphenidate and amfetamine in ADHD.3

Children and adolescents (aged 5–15 years) with ADHD received treatment with methylphenidate 0.3 mg/kg twice daily (BID) for 2 weeks and dexamfetamine 0.15 mg/kg BID for 2 weeks (n=125). It should, however, be noted that neither treatment is indicated for use in children aged <6 years.3

Outcomes varied by assessment approach; although Conners’ Teacher Rating Scale-Revised indicated that 20% of patients did not respond to either medication, 124/125 responded to at least one treatment on at least one measure (Figure).3

There were no statistically significant differences in the proportions of patients responding to each medication, although methylphenidate had a significantly greater treatment effect than dexamfetamine according to Conners’ Teacher Rating Scale-Revised.3

Adverse events considered to be side effects of stimulant medication were present at baseline and diminished with medication treatment. Amfetamine was associated with a significantly greater severity of adverse events than methylphenidate, in particular negative emotional side effects (e.g., irritability, tearfulness, anxiety).3

The authors acknowledged that:3

  • Response may vary by baseline symptom severity.
  • The fixed doses may not have been optimal for all patients.
Figure: Efron et al 1997: patient outcomes following treatment with methylphenidate versus amfetamine. Reproduced with kind permission from Efron D et al. Pediatrics 1997; 100: E6.3

Efron et al 1997: patient outcomes following treatment with methylphenidate versus amfetamine

Reproduced with permission from Pediatrics, Vol. 100, Page E6, Copyright © 1997 by the AAP

Crossover studies of stimulants and non-stimulants

A literature search was completed using OVID SP and PubMed to search the databases EMBASE (1988 to present) and MEDLINE (1946 to present), using terms relating to atomoxetine, guanfacine and crossover studies.

The only relevant study from this search was Newcorn et al 2008.4

The randomised controlled study reported by Newcorn et al examined treatment response in a subset of children and adolescents (aged 6–16 years) with ADHD who were randomised (3:3:1) to receive treatment with osmotic-controlled release oral delivery system (OROS) methylphenidate 18–54 mg/day, atomoxetine 0.8–1.8 mg/kg per day or placebo for 6 weeks.4

  • Patients met Diagnostic and Statistical Manual of Mental Disorders – 4th Edition criteria for ADHD, any subtype.
  • Response to treatment was defined as a decrease from baseline of 40% or more in total ADHD Rating Scale score at Week 6.

Exploratory data were also collected for patients who received OROS methylphenidate 18–54 mg/day in the main comparison trial, and were then switched to atomoxetine 0.8–1.8 mg/kg per day for a further 6 weeks (n=178).4

  • It is important to note that there was no washout period between the two treatments, and the reverse switch (from atomoxetine to methylphenidate) was not investigated; due to such limitations, the authors described the results as ‘preliminary’.

The only adverse event that was significantly different from placebo for both drugs was decreased appetite. Insomnia (“any report of insomnia”) was more common for patients assigned to methylphenidate than for those taking placebo. Somnolence was reported more often for atomoxetine than for methylphenidate, whereas insomnia was reported more often for methylphenidate than for atomoxetine.4

Figure: Newcorn et al 2008: OROS methylphenidate versus atomoxetine. Reproduced with kind permission from Newcorn JH et al. Am J Psychiatry 2008; 165: 721-730.4

Newcorn et al 2008: OROS methylphenidate versus atomoxetine

Possible reasons for different response: potential contribution of neurobiological factors

Although multiple factors may be involved, neurobiological variations may help to explain why only some individuals respond to a particular treatment.

  • Studies have suggested that certain polymorphisms in dopamine (DA) receptor genes, or DA, noradrenaline or serotonin transporter genes, may be associated with response to methylphenidate.5-8
  • Medication-induced changes in synaptic neurotransmitter levels may be subject to natural differences between individuals. For example, evidence from healthy adults (n=10) suggests that the degree to which synaptic levels of DA are increased following blockade of DA transporters by methylphenidate may depend on inter-individual variability in the amount of DA released by neurons.9

However, with limited data, the neurobiological profile of an individual likely to respond to a particular treatment remains undefined.9

  • Notably, data are particularly limited for ADHD medications other than methylphenidate, although even in the case of methylphenidate there is still not enough evidence to characterise likely responders.
  • Since there is no evidence for rational treatment selection based on neurobiological profile, established treatment guidelines10-13 should be followed and a patient-centred management plan put into place in order to identify an effective treatment for that patient.
  1. Arnold LE. Methylphenidate vs amphetamine: comparative review. J Atten Disord 2000; 3: 200-211.
  2. 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.
  3. 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.
  4. 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.
  5. Froehlich TE, Epstein JN, Nick TG, et al. Pharmacogenetic predictors of methylphenidate dose-response in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2011; 50: 1129-1139.
  6. Yang L, Wang YF, Li J, et al. Association of norepinephrine transporter gene with methylphenidate response. J Am Acad Child Adolesc Psychiatry 2004; 43: 1154-1158.
  7. Thakur GA, Grizenko N, Sengupta SM, et al. The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD. BMC Psychiatry 2010; 10: 50.
  8. Winsberg BG, Comings DE. Association of the dopamine transporter gene (DAT1) with poor methylphenidate response. J Am Acad Child Adolesc Psychiatry 1999; 38: 1474-1477.
  9. Volkow ND, Wang GJ, Fowler JS, et al. Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications. Synapse 2002; 43: 181-187.
  10. NICE guideline 2018. Attention deficit hyperactivity disorder: diagnosis and management. Available at: Accessed February 2019.
  11. Canadian ADHD Resource Alliance (CADDRA). Canadian ADHD Practice Guidelines. Fourth Edition. Toronto, ON; CADDRA, 2018.
  12. Banaschewski T, Hohmann S, Millenet S. Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) im Kindes-, Jugend- und Erwachsenenalter. DGKJP, DGPPN and DGSPJ German guidelines. 2018.
  13. 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.
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