Effects of psychostimulants

Box 7j5 A Swedish Long-term Study with Amphetamine in ADHD 

A trial published by Gillberg et al. (1997) comprised 62 children (52 males, 10 females), aged 6 11 years and meeting DSM-HI-R criteria for ADHD. The children suffered from severe attention deficits and 42% had comorbid diagnoses including mild mental retardation, autistic features, oppositional defiant disorder and tic disorder. They were included in a parallel-group, randomized, double-blind, place bo-cont ro 1 led study of amphetamine treatment. 

All patients had a 3-month single-blind baseline amphetamine titration period and all 62 patients improved significantly during this time. They were then randomized to amphetamine or placebo. During the 12-month double-blind phase, 71% of the children in the placebo group and 29% in the amphetamine group stopped treatment or were switched to open treatment. Most of these dropouts occurred in the first 3 months of the double-blind trial. Thirty-two children (8 on placebo and 24 on amphetamine) completed the study as planned. Early dropouts were considered in a separate statistical analysis. 

The small but statistically significant effect seen in the amphetamine group on the WISC-R was probably a real finding, i.e. not an artifact of retesting. Overall, this study shows that the positive clinical effects of amphetamine on behavioral symptoms and cognitive performance are maintained after 15 months of treatment. 

6 The MTA Study (Multimodal Treatment Study of Children with ADHD) 

---

Cocaine and desipramine inhibit the reuptake of monoamine neurotransmitters whereas amphetamine, which is a phenylalkylamine - similar in structure to the catecholamines, see Fig. 4 - competes for uptake and more importantly, evokes efflux of the monoamine neurotransmitters. All of them exert antidepressant effects. Cocaine and amphetamine are addictive whereas tricyclic antidepressants and their modern successors are not. The corollaty of the addictive properties is interference with DAT activity. Blockade of DAT by cocaine or efflux elicited by amphetamine produces a psychostimulant effect despite the different mechanisms even the experienced individual can hardly discern their actions. Because of the risk associated with inhibiting DAT mediated dopamine clearance the antidepressant effects of psychostimulants has not been exploited. 

Psychostimulants. Table 3 Acute effects of psychostimulants and the brain regions that are mainly involved in these effects... 

Fleckenstein, A.E., Haughey, H.M., Metzger, R.R. et al. Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function. Eur. J. Pharmacol. 382 45, 1999. 

Drouin, C., Darracq, L., Trovero, F. etal. Alphalb-adrener-gic receptors control locomotor and rewarding effects of psychostimulants and opiates. /. Neurosci. 22 2873-2884, 2002. 

Female rats appear to be more sensitive than males to the toxic and reinforcing effects of psychostimulants that increase DA levels in the synaptic cleft females exhibit greater behavioral responses and sensitization as well (Becker 1999 Becker et al. 2001 Morishima et al. 1993 Dalton et al. 1986 Roberts et al. 1989). 

Shippenberg, T. S., Chefer, V. I., Zapata, A. and Heidbreder, C. A. 2001. Modulation of the behaviour and neurochemical effects of psychostimulants by kappa-opioid receptor systems. Annales on the New York Academy of Sciences, 937 50-73. 

Some of the behavioral effects are a decreased sense of fatigue and an increased alertness and ability to concentrate. In overdose the CNS effects of psychostimulants are agitation, confusion, insomnia, seizures and coma while cardiovascular effects include arrhythmias, palpitations, anginal pain and circulatory collapse. 

Table 3.8 Effects of psychostimulant drugs in healthy subjects...

A frequently used test to assess the effect of psychostimulants is the CPT. Methylphenidate at doses of around 0.3mg/kg usually improves performance, Le. reduces the number of errors, on the CPT whereas the effects of d-amphetamine (at doses between 5 and 20 mg) and pemoline (10 60mg) appear to be less reliable (Riccio et al., 2001). The stimulating effect of caffeine in various areas of performance is of shorter duration than that of... 

The most common adverse effects of psychostimulants include the following ... 

Research studies on human performance have typically involved the administration of cocaine and d-amphetamine in single doses that do not produce toxic psychosis. In the studies reviewed, d-amphetamine was administered orally (PO). Given that the performance effects of D-amphetamine have been studied for more than 60 years and its widespread use during World War II,24 it is not surprising that much is known about the effects of D-amphetamine on vigilance and attention. However, the effect of psychostimulants on higher-order cognitive processes has not been widely studied. 

Cherland, E., Fitzpatrick, R. (1999). Psychotic side effects of psychostimulants A 5-year review. Canadian Journal of Psychiatry, 44, 811-813. 

Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Wong C, Hitzemann R, Pappas NR (1999) Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. J Pharmacol Exp Ther 297 409 415. 

Incentive arousal role of dopamine and the behavioral effects of psychostimulants. An incentive arousal role of DA is best suited to explain many behavioral properties of psychostimulants. Indeed, the notion of an incentive role of endogenous DA is largely derived from the role attributed to DA as the substrate of the effect of psychostimulants on reinforcement and instrumental responding (Di Chiara, 1995). Psychostimulants elicit typical unconditional incentive effects in the form of approach towards stimuli and exploratory behavior related to novelty of the context. Psychostimulants also facilitate conditioned reinforcement (the ability of a Pavlovian CS to elicit responding instrumental to its presentation) (Robbins et al., 1989), an effect involving preliminary Pavlovian association with a reward and therefore related to the incentive properties of the stimulus. 

Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG (1999) Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 255 397-401. 

Side effects of psychostimulant drugs include insomnia, restlessness, irritability, nervousness, dizziness, tremor and sometimes psychosis. 

---