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Psychostimulants (methylphenidate and amphetamines) are the drugs of first choice in the pharmacological treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD).We summarize the pharmacological characteristics of amphetamines and compare them with methylphenidate, special emphasis being given to a comparison of effects and side effects of the two substances. Finally, we analyze the abuse and addiction risks.Publications were chosen based on a Medline analysis for controlled studies and meta-analyses published between 1980 and 2011; keywords were amphetamine, amphetamine salts, lisdexamphetamine, controlled studies, and metaanalyses.Amphetamines generally exhibit some pharmacologic similarities with methylphenidate. However, besides inhibiting dopamine reuptake amphetamines also cause the release of monoamines. Moreover, plasma half-life is significantly prolonged. The clinical efficacy and tolerability of amphetamines is comparable to methylphenidate. Amphetamines can therefore be used if the individual response to methylphenidate or tolerability is insufficient before switching to a nonstimulant substance, thus improving the total response rate to psychostimulant treatment. Because of the high abuse potential of amphetamines, especially in adults, the prodrug lisdexamphetamine (Vyvanse) could become an effective treatment alternative. Available study data suggest a combination of high clinical effect size with a beneficial pharmacokinetic profile and a reduced abuse risk.In addition to methylphenidate, amphetamines serve as important complements in the psychostimulant treatment of ADHD. Future studies should focus on a differential comparison of the two substances with regard to their effects on different core symptom constellations and the presence of various comorbidities.

The current pharmacotherapy for attention-deficit hyperactivity disorder (ADHD) is mainly based on the stimulant methylphenidate and to a small extent on amphetamines which are not approved in Germany. The only approved non-stimulant so far is atomoxetin (Strattera®), a norepinephrine reuptake inhibitor. There is no approved pharmacotherapy for adults. The aim of the available medication is a reduction of impulsivity, hyperactivity, and attention deficits. Neurobiological correlates of these effects are still not fully understood, however, a functional implication of dopaminergic and noradrenergic systems is known. To date there is no disease-modifying therapy. The currently available substances have limitations due to the short half-life of stimulants, the unknown pathomechanisms, and the use of stimulants in developing brains with possible long-term side-effects. Moreover, the abuse potential of stimulants is still controversially discussed. The recently developed Lisdexamfetamin and SPD-465 have stimulant effects, too. A number of different developmental substances in preclinical and clinical phases show other mechanisms: SPD-503 represents an α(2)A-adrenozeptoragonist, ABT-089 and ABT-418 have partial agonistic effects to the α(4)β(2)-subtype of nicotinic acetylcholinreceptors, CX-717, -1739, -1942 and -1796 are glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor agonists and PF-3 654 746 exhibits antagonistic properties to histaminergic H(3)-receptors. The α(2)A-adrenoceptor-agonist Guanfacine (Intuniv®) and the hepatic metabolised amphetamine prodrug Lisdexamfetamin (Vyvanse®) are yet approved for ADHD treatment in the USA. The aim of this review is to summarise established pharmacological treatment options and the stage of development of upcoming symptomatic stimulant and non-stimulant substances in ADHD therapy.

As yet, stimulants remain the preferred means of treating attention-deficit/hyperactivity disorder (ADHD) pharmacologically. They are indicated when measures based on behavioural therapy or psychoeducation alone are not sufficient. How-ever, the period of effectiveness of immediate release stimulants is often not satisfactory. A variety of retarded forms of methylphenidate have now been developed and approved for the German market. This paper presents an overview of clinical studies on effectiveness, period of effectiveness and the profile of side effects of different forms stimulants available in Germany. In clinical practice, the new retard products represent effective alternatives. There is an advantage in administering this drug in a once-daily single dose. At the same time, the side effects that are caused by an extended period of effectiveness have to be studied in detail. A more precise adaptation to the daily obligations and needs of children and adolescents is needed. Possibly, a combination with unretareded MPH might lead to a better effect/side-effect profile.

A long existing hypothesis, i.e. that the EEG effects, in lead O2A2, of typical psychotropic drugs are substance class specific, when given as single oral dosages to healthy volunteers, is discussed. Using the technique of pharmacoelectroencephalograhpy, five typical representatives of neuroleptics, anxiolytics, antidepressives, psychostimulants (Fig. 2) as well as placebo were investigated in 75 volunteers, each receiving one representative of each substance class in a double blind 5-fach change over latin square design (Fig. 3). A five minute EEG record for lead O2A2 was obtained pre, 1 h and 3 hrs post drug intake unter RR (Relaxed Recording) conditions. Typical samples of th EEG records are shown in Figs. 4--7. Parametrisation was done using power spectrum analysis. Then 3 x 7 target variables were formed--six relative power values in predetermined frequency bands and the total power between 1.5 and 30.0 Hz for 3 occasions of measurement (Fig. 4--7). Using a (five-group) linear discriminant analysis the substance effects on the EEG were transformed into 5 probability measures for the five substance classes (Fig. 4--7). The present paper should provide a demonstration of some typical examples, using single subjects, of the projection of substance effects onto an electrophysiological level using a vector of 21 components (7 target variables for 3 occasions of measurement) as can be seen from Table 1. Furthermore, the transformation into probability measures of the five substance classes are shown in Table 2. Table 3 shows five examples of projections of substance effects, which do not fit into the classifications to which they belong. An attempt is made to explain, whether single target variables from the power spectrum can contribute differently to the discrimination between single substances of different substance classes. Within the accepted system of 4 psychotropic drug classes, the following variables seem to be of importance: a) The benzodiazepine anxiolytics show a marked increase in beta F1 (12.0--18.0 Hz) power and activity and, related to sedation, an increase in delta F-power and a decrease in alpha-power; b) The psychostimulants of the amphetamine type show an increase in total power and alpha-power, an increase in the power of the frequency ranges near to the alpha-band (slow beta, fast theta) and a decrease in delta F (1.5--5.5 Hz)-power, when delta F-power is high in the pre-values, indicating a stabilization in vigilance; c) The neuroleptics show a marked increase in theta F (5.5--8.5 Hz)-power, some increase in the delta F--and a decrease in the beta F1-and beta F3-power; d) Tricyclic antidepressants show an interaction between delta F-theta F-, alpha- and beta-power, in the sense of a dissociative shift in vigilance.

Intraperitioneal injection of d-amphetamine sulfate, 0.3-3 mg/kg, led to a marked rise in dopa formation in the dopamine rich areas c. striatum and mesolibbic cortex of the rat brain inhibiton of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCL (NSD 1015). However, amphetamine given in a dose of 10 mg/kg decreased the tyrosine hydroxylation rate in the mesolimbic cortex as well as the norepinephrine containing neocortex. In combination with haloperidol the stimulating effect of the neuroleptic on dopa formation was markedly potentiated by amphetamine in rat forebrain. Also, amphetamine potentiated the haloperidol induced increase in dopamine release in vivo measured as 3-methoxytyramine formation. The functional antagonists haloperidol and d-amphetamine appear to have synergistic effects on dopaminergic neurons.

Six manic patients were acutely treated with 30 or 50 mg d-amphetamine, respectively. There was no intensification in any of these patients of gross manic behavior or single manic symptoms. Conversely, there was sedation and considerable reduction of manic symptomatology in all of them. This effect lasted for 1 to 3 h only. The clinical subgroup "elated-grandiose" was significantly, the subgroup "paranoid-destructive" was not significantly influenced. "Drive" and "mood" were similarly reduced. There was, however, no complete recovery from mania.