Treatment of ADHD with Methylphenidate

1. Treatment of ADHD with Methylphenidate

2. Historical Context • Methylphenidate (MPH) was first synthesized in 1944 • Marketed by Ciba-Geiggy Pharmaceutical Company as Ritalin • Initially used for: chronic fatigue, lethargy, depressive states, disturbed and senile behaviour, & psychosis associated with depression and narcolepsy • Today: use restricted to ADHD (unlabelled use includes depression in the elderly, cancer and post stroke patients) Use of MPH for treatment of ADHD

3. MPH as a stimulant • Methylphenidate (MPH) is a CNS stimulant with structural and pharmacologic properties similar to those of amphetamine • prescription of stimulants is the most common treatment for attention deficit hyperactivity disorder (ADHD) • MPH is the most prescribed stimulant • Amphetamines are a common alternative • Brand names for drugs containing MPH include: Ritalin SR, Ritalin LA, Metadate ER, Metadate CD, Methylin ER, Concerta. Use of MPH for treatment of ADHD

4. Current Statistics • Most studies on MPH have been done on school-age children, and investigated short term effects. But there have also been studies with pre-school children, adolescents, and adults. As well as longer term longitudinal designs. • 2% - 2.5% of school aged children in North America receive pharmacological treatment for ADHD. 90% of them are treated with MPH (Greenhill & Ford, 2002) • Nearly 10% of 10 year old boys in the United States take stimulants. Boys are 4 times more likely to be taking them than grils (Shader & Oesterheld, 2006) Use of MPH for treatment of ADHD

5. Therapeutic effects • In children with ADHD, MPH reduces disruptive behaviour, increases attention and task related behaviour as well as enhancing cognitive performance. • MPH mainly exerts its effects on behaviour by enhancing dopaminergic neurotransmission in the brain Use of MPH for treatment of ADHD

6. Neurology • Action: MPH acts as a reuptake inhibitor to increase the extracellular concentrations of norepinephrine and dopamine. • Increases concentration of DA at the synapse by binding to the DA transporter and blocking it. • Also affects other neurotransmitters (norepinephrine, acetylcholine, serotonin) • MPH’s influence on the release of acetylcholine produces effects that simulate mania. • This is presumed to be achieved indirectly by stimulation of cortical D1 receptors. Use of MPH for treatment of ADHD

7. Neurology – possible mechanisms of action • Stimulant-induced DA increases in the striatum are believed to decrease background firing rates and increase signal-to-noise ratio of striatal cells • This could be a mechanism for improving attention by enhancement of task-related neuronal cell firing. • DA increases in the nucleus accumbens would enhance the saliency of a task by increasing the interest that it elicits, thus improving attention and performance. (since DA also modulates incentive salience and motivation) Use of MPH for treatment of ADHD

8. Possible mechanisms of action (cont’d) • MPH increases metabolism in cerebellum, decreases it in the basal ganglia • metabolismin cerebellum & frontal & temporal cortices is correlated with D2 density. Metabolism increases in people with higher D2 density, but it decreases in people with low D2 density • the cerebellum plays an important role in higher cognitive functions, including memory, learning & attention. So MPH could exert its beneficial effects partially by activation of the cerebello-thalamo-frontal circuits. • MPH enhances cognitive performance on tasks that are sensitive to frontal lobe damage including aspects of spacial and working memory. Use of MPH for treatment of ADHD

9. Dosage • The optimal dose varies considerably across individuals • Differences in weight and metabolism rates are not sufficient to account for this variation. • Dose-response rel’ship: Up to a point, higher doses produce larger clinical responses (reductions in ADHD symptoms) but also result in increased side effects • For children, the modal dose is 10 mg, 2-3 times a day (for immediate-release MPH), but dosage can range from 5 to 20mg per administration • In a typical 30-kg child, the maximum serum concentration occurs about 1.5 to 2 hours afterward, dropping by 50% 2 hours later • The therapeutic effects mimic this, with a maximal reduction of ADHD symptoms about 2 hours after taking a pill, followed by decline which requires another dose about 4 hours after the first. • Duration: since ADHD is a chronic condition, the duration of treatment is unlimited and as necessary (symptoms may gradually disappear, but sometimes persist into adulthood). Use of MPH for treatment of ADHD

10. Side effects • Main: sleep problems, decreased appetite, stomachache, headache • Other: nervousness, nausea and vomiting, dizziness, palpitations, changes in heart rate and blood pressure, skin rashes and itching, weight loss, and digestive problems, toxic psychosis, psychotic episodes, drug dependence syndrome, and severe depression upon withdrawal. • MPH was said to suppress growth, but more recent studies have found such effects to be clinically insignificant • MPH has also been linked to sudden death, but this evidence was found to be anecdotal, as the rate of sudden death linked to MPH was found to be no different than sudden death in the general population. Use of MPH for treatment of ADHD

11. Abuse potential • The increase of DA in the brain is associated with reinforcing as well as therapeutic effects. Thus, there is a potential for abuse. (Schedule II drug) • MPH increases DA in the nucleus accumbens, which is thought to underlie the reinforcing effects of drug abuse. • MPH is self-administered by animals & used recreationally by humans • Abuse in clinical context is said to be limited, and abuse by oral administration of is rare. • When abused, MPH is usually administered intranasally or injected intravenously, so as to produce large increases in DA quickly. This can overactivate the DA system, making the experience of the drug itself very salient • Reinforcing effects of stimulant drugs vary widely across individuals. Abusers have been found to have low levels of striatal D2 receptors Use of MPH for treatment of ADHD

12. Abuse - Context ofadministration • Context differs greatly in abuse and clinical use. • Clinical: controlled, school setting, expectancy doesn’t play a prominent role. • Abuse: response is affected by the context and expectation. • “…within the context of the classroom, methylphenidate appears to make schoolwork more salient but does not elicit drug craving or drug-seeking behavior to recreate this effect, but when it is procured illegally and taken with the expectation of getting high, powerful conditioning factors appear to operate that do elicit drug craving and drug seeking.” (Volkow & Swanson, 2003) Use of MPH for treatment of ADHD

13. Evaluation • MPH is effective in decreasing ADHD symptoms in a majority of individuals • Non-response to MPH occurs in 15% to 30% of children with ADHD • 20% respond but require very high doses • Amphetamines may be an alternative for those who do not respond to MPH (non-response to both MPH & amphetamines is rare) • There are potential decreases in long-term efficiency, which may be due to habituation and tolerance effects Use of MPH for treatment of ADHD

14. Conclusion • Overall, I believe that if each case is looked at individually, and individual variables and side effects are taken into consideration and addressed, MPH can be an effective treatment, especially in the short term, with a good risk-benefit ratio. Use of MPH for treatment of ADHD

15. Chemical structures methylphenidate:amphetamine: cocaine: Use of MPH for treatment of ADHD