Psychomotor Stimulants – Psychostimulants and ADHD

The most important clinical use for psychostimulants is in the treatment of a developmental disorder known as attention-deficit/hyperactivity disorder (ADHD).Children with ADHD exhibit extreme degrees of inattentiveness, impulsivity, and hyperkinesis (excessive motor activity).They have a very short attention span and impulsively turn their attention to almost anything in the environment. DSM-IV identifies three different subtypes of ADHD: a predominantly inattentive subtype, a predominantly hyperactive-impulsive subtype, and a combined subtype. In severe cases of the hyperactive-impulsive or combined subtype, there may be destructiveness, stealing, lying,fire setting, and sexual “acting out.”The child is frequently unruly in the classroom and disruptive of family interactions within the home.

ADHD symptoms sometimes persist into adulthood. Adult ADHD patients show signs of distractibility, impulsivity, restlessness, hyperemotionality, and problems both at work and in interpersonal relationships. Moreover, such individuals are at heightened risk for developing conduct disorder, antisocial personality disorder, and/or substance abuse problems.

The relevance of psychostimulants for the treatment of ADHD is that low doses of these drugs produce a calming effect in more than half of affected children.This phenomenon was first reported by Bradley in 1937 and has since been observed in many other studies. Dextroamphetamine, methylphenidate, and a third stimulant called pemoline (trade name Cylert) are the medications usually prescribed for ADHD. For the best results,concomitant psychotherapy and parental counseling are also required. Stimulants can also cause undesirable side effects in some children, one of which may be reduced growth. Whether or not chronic stimulant treatment suppresses growth has been a matter of intense debate within the scientific community. Despite the amount of research devoted to this issue, a definitive answer has not yet been obtained.

Methylphenidate is currently avail-able in several different pharmaceutical formulations.There is an immediate-release form (Ritalin) that only provides 3 to 4 hours of symptom reliefând therefore must be taken at least twice each day—early in the morning and then again at lunchtime. For children, this means that the midday dose must be administered at school, and symptoms may reappear unless a third dose is taken in the late afternoon or early evening.These disadvantages led to the development of modified-release formulations that deliver the drug over longer periods of time.The first to be developed was a sustained-release version of methylphenidate (Ritalin SR) that lasts for 6 to 8 hours and is generally taken only in the morning. Even longer-acting, however, are the newer extended- release formulations like Ritalin LA and Concerta that are effective for the entire day.

We saw earlier that high doses of psychostimulants are behaviorally activating in both animals and humans. Yet low doses of these compounds can reduce locomotor activity in rodents under the appropriate conditions. A good example of this phenomenon was shown by Kuczenski and Segal (2002), who observed locomotor suppression in adolescent rats given low doses of methylphenidate orally (see figure).When adult humans are given the same low doses of psychostimulants used in the treatment

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Locomotor-suppressive effects of low-dose methylphenidate in adolescent rats Rats were maintained under a reverse day-night cycle and were stud-ied during the dark (active) phase of the cycle.The animals were given oral doses of the drug (MP) or saline vehicle (SAL) three successive times at 3-hour intervals while locomotor activity was measured by crossovers between quadrants of an activity-exploratory compartment.The figure depicts the total activity of the control and two drug-treated groups over the entire 9-hour test period. Note that high doses of methylphenidate (5 mg/kg or more) cause a stimulation of locomotor activity rather than the suppressive effect observed in the present study. (After Kuczenski and Segal, 2002.) of ADHD, the typical effects are increased arousal and hyperactivity.

This has led to the general belief that clinical responses of sharpened attention (which is incompatible with a state of overarousal) and reduced activity following psychostimulant treatment represent a “paradoxical” reaction on the part of ADHD children. It should be mentioned, however, that early work by Rapoport and her colleagues found decreased activity and enhanced attention in both normal and hyperactive boys given typical therapeutic doses of amphetamine (Rapoport et al., 1978; Zahn et al. 1980).Thus it is unclear whether the calming effects of low-dose psychostimulants in ADHD children are paradoxical or whether they represent the typical response at this stage of development.

What do we know about the neurochemical basis of ADHD and the mechanisms underlying the therapeutic effectiveness of psychostimulant drugs? Most investigators believe that ADHD is related to a dysfunction in the dopaminergic system. Brain imaging studies have found that striatal DAT density is elevated in adult ADHD patients compared with normal controls (Dougherty et al., 1999; Dresel et al., 2000; Krause et al., 2000). This might result in enhanced DA clearance from the synaptic cleft and therefore abnormally low DA availability at postsynaptic DA receptors. There is also evidence linking ADHD in children with a particular form of the DA transporter gene. Finally, oral doses of methylphenidate similar to those used in the treatment of ADHD produce a significant blockade of the DA transporter and a consequent elevation of extracellular DA levels (Volkow et al., 1998,2001 b).These findings support an involvement of DA in the therapeutic actions of methylphenidate and possibly other psychostimulants.

Despite this focus on DA, there is also some evidence implicating NE in the effects of ADHD medications. For example, the previously mentioned study of Kuczenski and Segal found that locomotor-inhibiting doses of methylphenidate in rats enhanced extracellular NE levels without affect-ing DA. Moreover, in 2002 the FDA approved the use of atomoxetine (Strattera),a selective NE uptake inhibitor, for the treatment of ADHD. Unlike methylphenidate or amphetamine, atomoxetine is nota psycho-stimulant and does not have abuse potential. Future studies need to determine if the shared effect of NE uptake inhibition underlies the therapeutic effects of psychostimulants and atomoxetine or, alternatively, if these drugs alleviate the symptoms of ADHD by differing neurochemical actions involving the dopaminergic versus the noradrenergic system.

Lastly, it is important to note that abuse of methylphenidate is rising in the United States.When taken orally at standard therapeutic doses, methylphenidate usually does not produce feelings of euphoria, due to its relatively slow uptake from the gastrointestinal tract. However, a “high”can occur when pills are crushed and taken either intranasally (snorted) or by IV injection. Indeed, controlled laboratory studies have shown that the euphoric response to IV methylphenidate is similar to that obtained from IV cocaine (Wang et al., 1997). Both methylphenidate and dextroamphetamine, therefore, have significant abuse potential. Parents of medicated ADHD children need to be vigilant for signs either of abuse by the child or distribution of the medication to siblings for recreational use.

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