Neuropsychopharmacology: The Fifth Generation of Progress
They also improve maternal-child and sibling interactions. Children with ADHD who are treated with stimulants have increased abilities to perceive peer communications and sit- uational cues and to modulate the intensity of their behav- ior. They also show improved communication, greater responsiveness, and fewer negative interactions. Neuro- psychological studies show that stimulants improve vigi- lance, cognitive impulsivity, reaction time, short-term memory, and learning of verbal and nonverbal material in children with ADHD.
Although stimulants are the mainstay of anti-ADHD pharmacotherapy, tricyclic antidepressants (TCAs) also are effective anti-ADHD agents. TCAs include secondary and tertiary amines with a wide range of receptor actions, effi- cacy, and side effects. Secondary amines are more selective (noradrenergic) with fewer side effects. Most studies of TCAs have found either a moderate or robust response rate of ADHD symptoms (8–10). These studies show anti- ADHD efficacy for imipramine, desipramine, amitriptyline, nortriptyline, and clomipramine. Both short- and long-term studies show that TCAs produce moderate to strong effects on ADHD symptoms. In contrast, neurocognitive symp- toms are do not respond well to TCA treatment. Because of rare reports of sudden death among TCA-treated chil- dren, these drugs are not a first-line treatment for ADHD and are only used after carefully weighing the risks and benefits of treating or not treating a child who does not respond to other agents.
Other noradrenergic agents help to control ADHD symptoms. Bupropion hydrochloride, which has both dopa- minergic and noradrenergic effects, is effective for ADHD in children (11,12)as well as in adults (13). Although they are rarely used because of their potential for hypertensive crisis, several studies suggested that monoamine oxidase in- hibitors may be effective in juvenile and adult ADHD (14). The experimental noradrenergic compound tomoxetine showed efficacy in a controlled study of adults with ADHD (15) and in an open study of children with ADHD (16).
In contrast to the beneficial effects of stimulants and TCAs, there is only weak evidence that either 2-noradren- ergic agonists or serotonin reuptake inhibitors effectively combat ADHD (17). A controlled clinical trial showed that transdermal nicotine improved ADHD symptoms and neuropsychological functioning in adults with ADHD (18). Consistent with this finding, a controlled study found the experimental compound ABT-418 to treat adult ADHD effectively (19). ABT-418 is a potent and selective agonist for 42-subtype central nervous system neuronal nicotinic receptors.
As the foregoing review shows, effective medications for ADHD act in noradrenergic and dopaminergic systems. Stimulants block the reuptake of dopamine and norepi-
nephrine into the presynaptic neuron and increase the re- lease of these monoamines into the extraneuronal space (20). Solanto suggested that stimulants may also activate presynaptic inhibitory autoreceptors and may lead to re- duced dopaminergic and noradrenergic activity (21). The maximal therapeutic effects of stimulants occur during the absorption phase of the kinetic curve, within 2 hours after ingestion. The absorption phase parallels the acute release of neurotransmitters into synaptic clefts, a finding providing support for the hypothesis that alteration of monoaminergic transmission in critical brain regions may be the basis for stimulant action in ADHD (22). A plausible model for the effects of stimulants in ADHD is that, through dopami- nergic or noradrenergic pathways, these drugs increase the inhibitory influences of frontal cortical activity on subcorti- cal structures (22).
Human studies of the catecholamine hypothesis of ADHD that focused on catecholamine metabolites and en- zymes in serum and cerebrospinal fluid produced conflict- ing results (23,24). Perhaps the best summary of this litera- ture is that aberrations in no single neurotransmitter system can account for the available data. Of course, because studies of neurotransmitter systems rely on peripheral measures, which may not reflect brain concentrations, we cannot ex- pect such studies to be completely informative. Neverthe- less, although such studies do not provide a clear profile of neurotransmitter dysfunction in ADHD, on balance, they are consistent with the idea that catecholaminergic dysregu- lation plays a role in the origin of at least some cases of ADHD.
The catecholamine hypothesis of ADHD finds further support from animal studies. One approach has been the use of 6-hydroxydopamine to create lesions in dopamine pathways in developing rats. Because these lesions created hyperactivity, they were thought to provide an animal model of ADHD (25). Disruption of catecholaminergic transmission with chronic low-dose N-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin, creates an animal model of ADHD in monkeys. In this latter work, MPTP administration to monkeys caused cognitive impair- ments on tasks thought to require efficient frontal-striatal neural networks. These cognitive impairments mirrored those seen in monkeys with frontal lesions (26,27). Like children with ADHD, MPTP-treated monkeys show atten- tional deficits and task impersistence. Methylphenidate and the dopamine D2 receptor agonist LY-171555 reversed the behavioral deficits but not the cognitive dysfunction (28, 29).
Several investigators used the spontaneously hypertensive rat (SHR) as an animal model of ADHD because of the animal’s locomotor hyperactivity and impaired discrimina- tive performance. Studies using the SHR have implicated dopaminergic and noradrenergic systems. For example, the dopamine D2 receptor agonist, quinpirole, caused signifi- cantly greater inhibition of dopamine release from caudate-