Is Ritalin the number one treatment for ADHD in the United States?

Methylphenidate (MPH; MPD) is a psychostimulant drug approved for treatment of ADHD or attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It is better known by its 1948 trademarked name of Ritalin (original owner CIBA, now Novartis Corporation), was first licensed by the FDA in 1955 for treating ADHD, prescribed from 1960, and became heavily prescribed in the 1990s, when the diagnosis of ADHD itself became more widely accepted. ADHD and some other conditions are believed to be linked to sub-performance of the dopamine, norepinephrine, and glutamate processes in the brain responsible for self-regulation functions, leading to self-regulation disorders compromising the sufferer's attention, self-control, behaviour, motivation, and executive function; methylphenidate primarily works by reducing the reuptake of dopamine and norepinephrine which improves the levels and utility of these neurotransmitters in the brain.

Methylphenidate possesses some structural and pharmacological similarities to cocaine, though methylphenidate is less potent and longer in duration. Methylphenidate is produced in the United States, Mexico, Spain and Pakistan. Other brands include Concerta, Methylin, and Daytrana, and generic forms, including Methylin, Metadate and Attenta are produced by numerous pharmaceutical companies throughout the world.

Ritalin is also sold in Canada, Australia, the United Kingdom, Spain, Germany, Israel and other European countries (although in much lower volumes than in the United States). In Belgium the product is sold under the name Rilatine and in Brazil, Portugal and Argentina as Ritalina. In Thailand, it is found under the name Hynidate.

The dextrorotary enantiomer of methylphenidate, known as dexmethylphenidate, is sold as a generic and under the brand names Focalin and Attenade. Methylphenidate was first synthesized in 1944,5 and was identified as a stimulant in 1954. Methylphenidate was synthesized by Ciba (now Novartis) chemist Leandro Panizzon.

His wife, Marguerite, had low blood pressure and would take the drug as a stimulant before playing tennis. He named the substance Ritaline, after his wife's nickname, Rita. Originally it was marketed as a mixture of two racemates, 80% (±)-erythro and 20% (±)-threo.

Subsequent studies of the racemates showed that the central stimulant activity is associated with the threo racemate and were focused on the separation and interconversion of the erythro isomer into the more active threo isomer. Beginning in the 1960s, it was used to treat children with ADHD or ADD, known at the time as hyperactivity or minimal brain dysfunction (MBD). Production and prescription of methylphenidate rose significantly in the 1990s, especially in the United States, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities.

In March 22, 20069 Janssen received U.S. Food and Drug Administration (FDA) approval to market "Concerta". 12 See the "Extended-release" section of this article, below, for more information about Concerta. Methylphenidate is a benzylpiperidine derivative.

It also shares part of its basic structure with catecholamines and phenethylamines. Methylphenidate primarily acts as a norepinephrine-dopamine reuptake inhibitor. Methylphenidate is most active at modulating levels of dopamine and to a lesser extent norepinephrine.

13 Similar to cocaine, methylphenidate binds to and blocks dopamine transporters and norepinephrine transporters. Moreover, MPH is thought to act as a releasing agent by increasing the release of dopamine and norepinephrine, though to a much lesser extent than amphetamine. 15 Methylphenidate's mechanism of action at dopamine-norepinephrine release is still debated, but is fundamentally different from phenethylamine derivatives, as methylphenidate is thought to increase general firing rate, whereas amphetamine reverses the flow of the monoamine transporters.

16171819 While both amphetamine and methylphenidate are dopaminergic, it should be noted that their methods of action are distinct. Specifically, methylphenidate is a dopamine reuptake inhibitor while amphetamine is a dopamine releasing agent. Each of these drugs also has a corresponding and minor effect on norepinephrine.

Methylphenidate has both dopamine transporter and norepinephrine transporter binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed. Methylphenidate may also exert a neuroprotective action.

The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate. Studies confirm that biological and genetic differences of the kinds predicted by low arousal theory are clearly visible in ADHD sufferers, and have been confirmed both genetically and by in vivo scans of ADHD sufferer brains. MRI scans have revealed that people with ADHD show differences from non-ADHD individuals in brain regions important for attention regulation and control of impulsive behavior.

22 Methylphenidate's cognitive enhancement effects have been investigated using fMRI scans even in non-ADHD brains, which revealed modulation of brain activity in ways that enhance mental focus. Methylphenidate increases activity in the prefrontal cortex and attention-related areas of the parietal cortex during challenging mental tasks; these are the same areas that the above study demonstrated to be shrunken in ADHD brains. Methylphenidate also increased deactivation of default network regions during the task.

Methylphenidate taken orally has a bioavailability of 11-52% with a duration of action around 3–6 hours for instant release, 3–8 hours for sustained release, and 8–12 hours for extended release (Concerta). The half-life of methylphenidate is between 4–12 hours depending on the individual and the form of methylphenidate taken. The peak plasma time is achieved in 6–8 hours with peak plasma concentration averaging 3.7 ng/mL.

The concentration of methylphenidate or ritalinic acid, its major metabolite, may be quantified in plasma, serum or whole blood in order to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. MPH is the most commonly prescribed psychostimulant and works by increasing the activity of the central nervous system. 25 It produces such effects as increasing or maintaining alertness, combating fatigue, and improving attention.

26 The short-term benefits and cost effectiveness of methylphenidate are well established, although long-term effects are unknown. 2728 The long term effects of methylphenidate on the developing brain are unknown. Methylphenidate is not approved for children under six years of age.

Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, and obesity. Methylphenidate is approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention deficit hyperactivity disorder. 31 The addition of behavioural modification therapy (e.g. Cognitive behavioral therapy (CBT)) has additional benefits on treatment outcome.

3233 While stimulants such as methylphenidate increase attention and concentration, they do not improve learning and academic performance. 34 People with ADHD have an increased risk of substance abuse, and stimulant medications reduce this risk. 3536 A meta analysis of the literature concluded that methylphenidate quickly and effectively reduces the signs and symptoms of ADHD in children under the age of 18 in the short term but found that this conclusion may be biased due to the high number of low quality clinical trials in the literature.

There have been no placebo controlled trials investigating the long term effectiveness of methylphenidate beyond 4 weeks thus the long term effectiveness of methylphenidate has not been scientifically demonstrated. Serious concerns of publication bias regarding the use of methylphenidate for ADHD have also been noted. 37 A diagnosis of ADHD must be confirmed and the benefits and risks and proper use of stimulants as well as alternative treatments should be discussed with the parent before stimulants are prescribed.

38 The dosage used can vary quite significantly from individual child to individual child with some children responding to quite low doses whereas other children require the higher dose range. The dose, therefore, should be titrated to an optimal level that achieves therapeutic benefit and minimal side-effects. 39 This can range from anywhere between 5–30 mg twice daily or up to 60 mg a day.

Therapy with methylphenidate should not be indefinite. Weaning off periods to assess symptoms are recommended. The means by which methylphenidate affects people diagnosed with ADHD are not well understood.

Some researchers have theorized that ADHD is caused by a dopamine imbalance in the brains of those affected. Methylphenidate is a norepinephrine and dopamine reuptake inhibitor, which means that it increases the level of the dopamine neurotransmitter in the brain by partially blocking the dopamine transporter (DAT) that removes dopamine from the synapses. 41 This inhibition of DAT blocks the reuptake of dopamine and norepinephrine into the presynaptic neuron, increasing the amount of dopamine in the synapse.

It also stimulates the release of dopamine and norepinephrine into the synapse. Finally, it increases the magnitude of dopamine release after a stimulus, increasing the salience of stimulus. An alternate explanation that has been explored is that the methylphenidate affects the action of serotonin in the brain.

1642 However, benefits with other stimulants that have a different mechanism of action indicates that support for a deficit in specific neurotransmitters is unsupported and unproven by the evidence and remains a speculative hypothesis. Narcolepsy, a chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden need for sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance.

44 Methylphenidate improves measures of somnolence on standardized tests, such as the Multiple Sleep Latency Test, but performance does not improve to levels comparable to healthy controls. While side-effects and misuse of methylphenidate have been associated with an increased risk of aggression and psychosis, newer studies indicate that it could be useful in the treatment of ADHD in adults with a history of aggressive and criminal behavior. A large clinical study conducted in Sweden found a significant reduction of the criminality rate in males (32%) and females (42%) as compared with the rate for the same patients while not receiving medication.

46 Some of these clinical outcomes have been confirmed in similar studies with children and adolescents. Use of stimulants such as methylphenidate in cases of treatment resistant depression is controversial. 48 In individuals with cancer, methylphenidate is commonly used to counteract opioid-induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve cognitive function.

49 Methylphenidate may be used in addition to an antidepressant for treatment-refractory major depressive disorder. It can also improve depression in several groups including stroke, cancer, and HIV-positive patients. 50 However, benefits tend to be only partial with stimulants being, in general, less effective than traditional antidepressants and there is some suggestive evidence of a risk of habituation.

Stimulants may however, have fewer side-effects than tricyclic antidepressants in the elderly and medically ill. Methylphenidate has shown some benefits as a replacement therapy for individuals dependent on methamphetamine.