Stimulant medication
Stimulants include methylphenidate and amphetamine compounds. Stimulants are the most effective medications for the treatment of ADHD, with responsiveness rates in the 70%–80% range (Spencer et al 2005).

Mechanism of action
Our understanding of the mechanism of action of stimulant medications is undergoing constant revision. Although the exact mechanism of action is unknown, these agents are thought to block reuptake of norepinephrine and dopamine into the presynaptic neuron, thereby increasing extraneuronal catecholamines (Fone and Nutt 2005; Arnsten 2006). Norepinephrine is predominantly connected with frontocortical activity, whereas dopaminergic activity is associated with the lower striatal structures. Both stimulants bind the dopamine transporter protein outside of the cell membrane and block dopamine reuptake presynaptically, thus increasing synaptic dopamine (Wilens 2006). It has been demonstrated that striatal dopamine transporter availability in adult patients with ADHD is markedly reduced by methylphenidate, even at a low dose (Krause et al 2000). Besides dopamine reupatke inhibition amphetamine also increases the release of dopamine from presynaptic cytoplasmic storage vesicles and blocks the uptake of dopamine into neuronal cytoplasmic vesicles, making dopamine more available in the presynaptic neuron (Connor 2005). Methylphenidate in low doses, also enhances hippocampal norepinephrine efflux but does not seem to affect dopamine in the nucleus accumbens. The data are consistent with the hypothesis that enhanced noradrenergic neurotransmission, particularly in the prefrontal cortex, contributes to the effects of methylphenidate (Fone and Nutt 2005).

Clinical effects of stimulants
Stimulants have shown a high behavioral efficacy in numerous randomized controlled trials conducted since the 1960s, with improvement noted for 65%–75% of patients in all age groups (Pliszka 2006). Stimulants effectively alleviate the symptoms of ADHD, including poor attention span, distractibility, impulsive behavior, hyperactivity, and restlessness. Stimulants also improve vigilance, cognition, reaction time, response inhibition, and short-term memory (Connor 2005; Hechtman 2005). Methylphenidate in clinical doses improves spatial working memory, set-shifting, and other prefrontal cortex cognitive functions in healthy individuals and in children with ADHD (Arnsten and Dadly 2005). Stimulant medications are also associated with fewer errors on a driving simulator in teens and adults with ADHD. Barkley and colleagues demonstrated that methylphenidate may have a beneficial effect on some aspects of driving, for example less steering variability, slower driving speed, greater use of turn signals, and a fewer impulsive responses (Barkley et al 2005).

Side effects
Side effects of stimulants are dose-dependent, are generally mild to moderate in most patients, and can be managed either by decreasing the dose or changing the time when medication is given (Weiss and Hechtman 1993). Common adverse effects of stimulants include insomnia, anorexia, nausea, decreased appetite, weight loss, headache, increased blood pressure, elevated pulse, abdominal pain, irritability, and mood lability. Stimulants may also cause tics, which is a frequent reason for discontinuing the stimulant medication in children. In rare cases stimulants may cause seizures, hypertension, psychosis, hepatotoxicity, and in children stimulant may effect growth (Power 2000; Greenhill 2001). Many side effects emerge early in the course of therapy with stimulants and decline in intensity over time. Side effects, such as irritability, developing late in the day may present rebound phenomena and in this case giving a small supplemental dose of stimulant in the afternoon may be helpful.
Initial insomnia is a relatively common side effect of stimulants. However, it is important to make sure to differentiate whether insomnia is a side effect of stimulants or predates treatment. Insomnia as a side effect can be minimized by avoiding doses in the afternoon and evening and by establishing good sleep routines and schedules. In the treatment with short-acting methylphenidate or amphetamine, insomnia may be secondary to a behavioral rebound that occurs with the wearing off of the stimulant’s effects on ADHD symptoms (Powers 2000).
Treatment with all stimulants is associated with a mild increase in blood pressure and pulse. Generally, this slight increase is not clinically significant. However, for adults with borderline hypertension and those with antecedent cardiac disease, it could be clinically significant. What to do with patients with borderline hypertension has remained a clinical dilemma. Results of a recent open-label study in adults with ADHD who had a history of treated hypertension or manifest hypertension demonstrated that treatment with mixed amphetamine salt XR did not produce a clinically significant increase of blood pressure and hypertension during the treatment (Wilens et al 2006).
Mood lability may be a result of ADHD rebound symptom or adverse effect of stimulants. If it is a side effect of stimulants, switching to another stimulant (such as methylphenidate or amphetamine) or switching to non-stimulant medication may be warranted. Sometimes, combination therapy with antidepressants may be useful (Weiss et al 1999).
Very rare adverse events can include psychotic symptoms, manic symptoms, aggression, and suicidality. Rarely reports of psychotic symptoms demonstrated visual and tactile hallucinations of insects (Pliszka 2007).
Contraindications for stimulant treatment are: florid psychosis, bipolar I disorder, Tourette’s disorder, severe anorexia, and some medical condition such as hypertension, tachycardia, and arrhytmias (Greenhill 2001).

Methylphenidate
Methylphenidate (MPH) is a stimulant that has been clinically available for 50 years, and its efficacy and safety have been thoroughly studied. It is administered orally with a starting dose of 10 mg for adults. The recommended dose is 0.3–1.5 mg/kg/day (Fawcet 2005) and maximum dose for adults ranges from 80 to 108 mg a day. The higher doses of MPH lead to better therapeutic response (Faraone et al 2004).
MPH is rapidly and extensively absorbed after oral administration. After absorption, it undergoes extensive first-pass hepatic metabolism, predominantly by hydrolysis. Eighty percent of the drug is excreted as ritalinic acid, and the remainder is oxidized by a hepatic mixed-function oxidase (Connor 2005).
There are three pharmaceutical formulations of methylphenidate – (1) immediate release or short-acting formulation (brand name Ritalin), (2) sustained release or intermediate-acting methylphenidate (brand name Ritalin SR), and (3) extended release or long-acting methylphenidate (brand names Concerta, Biphentin, Ritalin LA). The release mechanism of the intermediate-acting methylphenidate (Ritalin SR) produces variable results making this preparation less useful.
The main advantage of short-acting MPH products is their usefulness in situations where a supplement to the once daily medication is required or if the patient desires more flexibility over the dosing schedule (CADDRA 2006). The titration schedule is presented later in the paper.
The rates of MPH abuse are minimal compared to those of cocaine and D-amphetamine (Kollins et al 2001). Methylphenidate is most commonly administered orally, which limits its abuse liability compared to the injected or insufflated forms of other stimulants. However, it can be dissolved and injected and, therefore, there is some concern about abuse and diversion of short-acting methylphenidate (Kollins et al 2001).
Clinical trials on short-acting and long-acting MPH formulations are stated in Table 1. Results of these studies have demonstrated that all MPH formulations are safe and effective in the tretment of ADHD symptoms in adults.
Table 1  Clinical trials on stimulant medication in adults with ADHD   *  MPH – methylphenidate   Controlled released methylphenidate (Biphentin) has a unique multi-layer release delivery system with a duration of action of 10–12 hours. The capsule is composed of beads. Each bead has two layers where the outside coat provides immediate release of methylphenidate (40% of the total dose) and then the controlled release layer provides 60% of the total dose.
The initial dose is 10 mg (CADDRA 2006). Controlled released MPH is available in seven different dosages, and the capsule can be opened so that the drug may be sprinkled on food. It is approved for the treatment of ADHD in children, adolescents, and adults. Results of a randomized, multicenter, double-blind, placebo-controlled, crossover study in 39 adults with ADHD demonstrated significant behavioral improvement in those who received controlled released MPH compared with those who received the placebo. The treatment was well tolerated, and there were no serious adverse events (Jain et al 2007).
OROS methylphenidate (Concerta) is an extended release MPH, that uses an oral osmotic release system (OROS). Clinical trials have shown OROS MPH to have continued action throughout a 10–12-hour period. The capsule has two drug compartments and a water absorption compartment. Water is absorbed and pushes the medication out through a lazer hole at the end of the capsule. Twenty-two percent of the drug is coated on the outside of the capsule and is immediately available. The MPH that is released from the first medication compartment is supposed to provide sufficient improvement of symptoms in the morning. If it is not sufficient, a small dose of short-acting MPH may also be added in the morning (CADDRA 2006). The medication is not officially approved for adults, but at times it is used for this population because of its long duration and once daily administration. However, it is only available in four dosages (18, 27, 36, and 54 mg) and adults may require up to 108 mg, thus doubling the cost when two tablets are needed.
An important advantage of OROS-MPH is that it is associated with less risk of diversion and abuse than the immediate release preparations. Whereas immediate release MPH can be crushed and parenterally administered as a common way of abuse, the OROS delivery mechanism does not allow the pills to be crushed and injected or inhaled. Moreover, the gradual enhancement of the concentration of MPH within the OROS formulation leads to a slower onset of the blockade of presynaptic dopamine transporter and, thus, to a less detectable feeling of euphoria (Kollins et al 2001; CADDRA 2005; Biederman et al 2006).
Clinical trials have demonstrated that OROS-MPH is well tolerated and significantly more effective than a placebo in of treating core ADHD symptoms and improving executive functions (Biederman et al 2006; Fallu et al 2006).
The profile of its side effects is similar to those of immediate released MPH. With regard to cardiovascular side effects, only a few patients in this study had systolic blood pressure above 140 mmHg and pulse above 114 bpm (Biederman et al 2006). Adults with borderline hypertension should be carefully monitored in terms of cardiovascular parameters.
Methylphenidate transdermal system is a MPH patch that delivers continuous medication release throughout the day. Clinical trials in children with ADHD have demonstrated that MPH transdermal system is generally well tolerated with mild to moderate side effects (Biederman 2006). This treatment option has been approved by the FDA in the United States and approval is being sought in other countries. There are no clinical trials demonstrating the efficacy of methylphenidate transdermal delivery system in adults with ADHD.

Dextroamphetamine
Dextroamphetamine is a common used stimulants, which has been available and studied for many decades. Currently, there are three different formulations regarding the duration of action: (1) Immediate-release dextroamphetamine (Dexedrine), (2) Sustained-release dextroamphetamine (Dexedrine spansule), and (3) Extended-release mixed amphetamine salts (Adderell XR). Dextroamphetamine immediate-release has a short half-life of 4–6 hours and requires multiple dosages two or three times a day. Therefore, it may be considered a second-line agent for adults with ADHD. It is recommended in situations where supplement to the once daily medication is required or if the patients request more flexibility over the dosing schedule (CADDRA 2006). Starting dose for dextroamphetamine is 5 mg and recommended doses are 0.3–1.5 mg/kg with a maximum of 60 mg a day for adults (Wilens et al 2002). After oral administration dextroamphetamine is quickly adsorbed. About a half of a given dose is eliminated unchanged in the urine, while the other half is broken down into various metabolites, mostly benzoic acid (Powers 2000).
Clinical trials on amphetamine compunds are described in the Table 1. Results of these studies have showed that all preparations are safe and effective in the tretment of ADHD symptoms in adults.
Dextroamphetamine sustained release (Dexedrine spansules) releases the active drug substance in a more gradual fashion than the standard formulation. A spansule is a capsule in which part of dose is released promptly, and remaining of dose is released gradually. Thus, its duration of action is a little bit longer, lasting about 6–8 hours (CADDRA 2006). Therefore, the dextroamphetamine sustained release may be given once daily. However, similar to short-acting formulations, dextroamphetamine sustained release is also considered as a second line agent for treatment of ADHD because their duration of action is shorter than that of long-acting formulations. However, in one child study which compared the efficacy of immediate-release and extended-release amphetamine formulations, dextroamphetamine sustained release were significantly more effective at controlling ADHD symptoms than short-acting formulations during the afternoon and in the early evening (James et al 2001).
Unfortunately, there are a few studies which evaluate the efficacy of dextroamphetamine sustained release in adults with ADHD.

Mixed amphetamine salts extended release (Adderall XR)
This formulation includes neutral salts consisting of 75% dextroamphetamine and 25% levoamphetamine, and it comes in a capsule with long and short-acting beads (James et al 2001). An important advantage of extended released mixed amphetamine salts is its extended duration of action. This stimulant formulation covers patients for a period from 10–12 hours. Mixed amphetamine salts XR is available in 6 dosages (5, 10, 15, 20, 25 and 30 mg). Fifty percent of the dose is immediately available resulting in significant improvement in symptoms in the morning without need for augmentation (CADDRA 2006).
Mixed amphetamine salts XR has a good cardiovascular tolerability and may be administered in patients with a mild hypertension who are on stable antihypertensive medication (Wilens et al 2006).
The most common side effects are insomnia, decreased appetite and weight loss, headache, dry mouth, and nervousness (Biederman et al 2005).