Methylphenidate and Attention Deficit Hyperactivity Disorder

Attention Deficit Hyperactivity Disorder: Definition

Attention Deficit Hyperactivity Disorder (ADHD) is a disorder manifested in preschool and early school children. These children often have difficulty controlling their behavior and/or pay attention. The prevalence of ADHD is estimated to be 3-5% (NIMH, 2006.)


The exact etiology of this condition is unknown. Although ADHD is widely considered to be a genetic disorder (ADHD is also seen in 25 % of close relatives (NIMH, 2006)), environmental factors like preterm birth with vulnerable cerebrovascular homeostasis may contribute (Lou et al., 2004). The pathophysiological basis of ADHD is deficient dopaminergic neurotransmission, and it is hypothesized that it could be a result of cerebral ischemia occurring at birth (Lou et al., 2004). Another theory is that defects in serotonin system genes might disrupt normal brain serotonin function, causing an imbalance between serotonergic and dopaminergic neurotransmitter systems, with serotonin levels lesser than dopamine levels (Quist et al., 2000). Other suggested causes of ADHD include: use of cigarettes and alcohol during pregnancy, traumatic brain injury in childhood, food additives, and sugar (NIMH, 2006.)


The symptoms of ADHD include inattention, hyperactivity, and impulsivity, which appear early and over many months in a child’s life. The symptoms of impulsiveness and hyperactivity usually precede that of inattention.

ADHD is usually suspected when the symptoms of hyperactivity, distractibility, poor concentration, or impulsivity start to affect the child’s school performance, social relationships with other children, or behavior at home (NIMH, 2006). However, ADHD may not be easily diagnosable, especially when the primary symptom is inattentiveness.


The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) classifies ADHD into three subtypes: predominantly hyperactive-impulsive type (that does not show significant inattention); the predominantly inattentive type (that does not show significant hyperactive-impulsive behavior); and the combined type (that displays both inattentive and hyperactive-impulsive symptoms).

Some signs of hyperactivity-impulsivity are fidgeting with the hands or feet, restlessness, squirming while seated, running, climbing, or leaving a seat in situations when sitting or quiet behavior is expected, inability to wait in a line or taking turns, and blurting out answers before hearing the entire question.

The signs of inattention are: not paying attention to details and making careless mistakes, rarely following instructions carefully and completely, easy distraction by irrelevant sights and sounds losing or forgetting things like toys, or pencils, books, and tools needed for a task, and skipping from one uncompleted activity to another.

Other disorders that sometimes accompany ADHD are learning disabilities, Tourette syndrome, oppositional defiant disorder, conduct disorder, anxiety and depression, and bipolar disorder (NIMH, 2006).


The treatment of ADHD involves the use of medications and interventional approaches. The medications, which are used include amphetamine and dextroamphetamine (for children aged 3 years and older), methylphenidate, and pemoline (for children aged 6 years and older).

The interventional approaches include psychotherapy, behavioral therapy, social skills training, support groups, and parenting skills training (NIMH, 2006).

The mechanism of action of methylphenidate

The dopamine receptors in the brain may reside in presynaptic locations (e.g., autoreceptors and transporter sites) or postsynaptic locations. The autoreceptor is involved in the regulation, manufacture, and release of dopamine, while the transporter removes dopamine from the synaptic cleft. Methylphenidate (MPH) acts by both promoting the release of stored dopamine from presynaptic vesicles as well as by blocking the reuptake of dopamine into the presynaptic nerve endings.

This combined action of MPH leads to the accumulation of extracellular dopamine in the basal ganglia, cortex, and other regions of the brain (to a lesser extent).

However, there are individual variations in the clinical response to MPH. This may be due to differences in dopamine release and differences in the sensitivity of postsynaptic dopamine receptors to the extracellular increase in dopamine (Lawrence, Deirdre, Kathleen, 2004).

By using Positron Emission Tomography (PET) to investigate the mechanism of action of MPH in the human brain, Volkow et al., 2002, have shown that it takes 60-90 minutes for oral MPH to reach a peak concentration in the brain. Therapeutic doses of MPH block more than 50% of the dopamine transporters (DAT) and significantly enhance extracellular dopamine (DA) in the basal ganglia (Volkow et al., 2002)

Synopsis of the article

Stein et al., 2003, conducted a study to examine the dosage effects of OROS methylphenidate HCL (MPH), which is a recently developed long-acting stimulant to treat ADHD, on ADHD symptoms, its side effects, and the potential moderating effects of ADHD subtype.

The methods involved 47 children aged 5 to 16 years with combined type ADHD (ADHD-CT) or predominantly inattentive type ADHD (ADHD-PI). An adolescent psychiatrist or psychologist conducted a semistructured diagnostic interview with the parents and the child to meet the inclusion criteria (DSM-IV criteria for ADHD). Youths with mental retardation, severe mood disorders requiring medication, Tourette syndrome, seizure disorders, or other medical conditions that mimicked ADHD, and children who were taking systemic medications were excluded from the study.

The Institutional Review Board of Children’s National Medical Center reviewed and approved the consent and assent forms, study protocol, and any advertisements for the subjects.

The study was a placebo-controlled, crossover trial using forced titration with weekly switches at 3 dosage levels. Weekly blister packs were given to each subject; each of the packs contained a 7-day supply of study drugs for each week. The placebo capsules were slightly larger than the OROS MPH preparations. A randomly ordered list was used to assign the dosing schedules.

To evaluate the efficacy of treatment, parent and teacher ratings of ADHD symptoms were used. This included ADHD Rating Scale-IV: Home Version (ADHD RS-IV), Clinical Global Impression-Severity (CGI), Side Effect Rating Scale (SERS), The vital signs (weight, height, blood pressure, pulse, and temperature), and standardized measures of stimulant side effects were also obtained weekly. Along with the parent and child ratings, the teachers were queried every week to assess the response to medication in the school.

The results indicated that when compared to ratings by teachers, the ratings by parents were more sensitive to the treatment effects. In two-thirds to three-fourths of children with ADHD-CT, a clear linear dose-response relationship was observed with clinically significant reductions in ADHD Rating Scale-IV scores with either 36 or 54-mg doses. On the other hand, 60% of children with ADHD-PI responded optimally to 36 mg or lower doses and derived less benefit from higher doses.

At all dosage levels and during placebo, mild stimulant side effects were reported. In both ADHD subtypes, higher doses were associated with parent ratings of increased insomnia and decreased appetite. Higher dose levels also lead to sleep difficulties, decreased appetite, and a slight increase in pulse rate, especially in younger and smaller children.

Strengths of the trial

This study demonstrated a clinically significant reduction in ADHD symptoms with larger doses in ADHD-CT children, within a short period while children with ADHD-PI responded optimally to lower doses. These findings are consistent with other studies. Higher dose levels also lead to sleep difficulties, decreased appetite, and a slight increase in pulse rate, especially in younger and smaller children.

The inclusion and exclusion criteria are mentioned. Consent was obtained for the study. This is important because any clinical research has the potential of causing harm to the subjects, and ethical guidelines must always be followed (South African Medical Research Council, 2001.)

This study also studied the effect of methylphenidate compared with placebo.

This is important because comparing a drug with a placebo is required to know whether it is clinically effective and is safe. Results from placebo-controlled studies provide adequate evidence about a drug’s efficacy relative to that of other clinical treatment approaches.

Weaknesses of the trial

The study was conducted only for a short-term period of 7 days. A longer study period would have been ideal to observe the efficacy and side effects of the drug. The sample size used in the study was small. A large sample size is needed to provide a representative group size and also enables to compare of the efficacy of two or more treatment methods. Small numbers may have an impact on the power of statistical analysis (Polgar & Thomas, 2000).

The measures of ADHD symptoms that were used in the study were rating scales rather than behavioral observations or laboratory measures of attention. Potential expectancy biases or placebo effects could have affected the rating because some parents or patients may have assumed that the larger capsules represented higher dosages.

Suggestions for the future

Future studies can consider using larger sample size and a longer treatment period. The use of more direct and specific measures of cognitive and behavioral symptoms of ADHD and side effects can be considered, which can examine the intermediate and long-term dose-response effects of MPH.


Lawrence, S, Deirdre, C, Kathleen, B (2004). Methylphenidate: Mechanism of Action and Clinical Update. Journal of Child and Adolescent Psychiatric Nursing.

Lou, H.C, Rosa, P, Pryds, O, Karrebaek, H, Lunding, J, Cumming, P, Gjedde, A (2004). ADHD: increased dopamine receptor availability linked to attention deficit and low neonatal cerebral blood flow. Dev Med Child Neurol. 46(3): 179-83. Web.

Polgar, S, Thomas, SA (2000). Introduction to research in the health sciences. 4th ed. Edinburgh, Churchill Livingstone.

South African Medical Research council (2001). Ethics and human rights. 2007. Web.

Quist, J.F, Barr, C.L, Schachar, R, Roberts, W, Malone, M, Tannock, R, Basile, V.S, Beitchman, J, Kennedy, J.L (2000). Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD). Mol Psychiatry. 5(5): 537-41.

Stein, M.A, Sarampote, C.S, Waldman, I.D, Robb, A.S, Conlon, C, Pearl, P.L, Black, D.O, Seymour, K.E, Newcorn, J.H (2003). A Dose-Response Study of OROS Methylphenidate in Children With Attention-Deficit/Hyperactivity Disorder. Pediatrics. 112 (5).

Volkow, N.D, Fowler, J.S, Wang, G, Ding, Y, Gatley, S.J (2002). Mechanism of action of methylphenidate: insights from PET imaging studies. J Atten Disord. 6.