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Old 02-12-05, 07:54 PM
abre los ojos abre los ojos is offline
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Excellent Research Publication (lots of pieces to the puzzle)

Development of the Cerebral Cortex: XIV.
Stress Impairs Prefrontal Cortical Function

Amy F.T. Arnsten, Ph.D.
J Am Acad Child Adolesc Psychiatry, 37(12): 1337-1339, 1998

A 10-year-old boy has been referred to you at the school’s insistence. For the past 6 months, he has had behavioral problems in class. He has difficulty paying attention, has been easily agitated, and fails to inhibit inappropriate and aggressive impulses. His parents report that he has always been active but he was never like this before. Does he suddenly have attention-deficit/hyperactivity disorder (ADHD)? A little probing reveals that the parents’ marriage is in trouble and that their child’s problems in school coincide with problems at home. Recent advances in neurobiological research may help us understand reactive behavioral problems in children. Neurochemical changes in the prefrontal cortex (PFC) during periods of stress may take this brain region “off-line,” making the child less able to govern his behavior.
The PFC is situated anterior to the motor cortices in the frontal lobe. It is much larger in primates than in other mammals. It continues to develop throughout adolescence. This region of our brains is critical for using “working memory,” a form of memory that is required to appropriately guide behavior. Working memory has been called “scratch-pad” memory, because this type of memory must be constantly updated. Memories can be called up from long-term storage or from more recent buffers. The PFC uses these representations to effectively guide behavior, freeing us from responding only to our immediate environment, inhibiting inappropriate responses or distractions, and allowing us to plan and organize. Animals or humans with lesions to the PFC exhibit poor attention regulation, disorganized and impulsive behavior, and hyperactivity.

Recent research in animals indicates that exposure to stress can produce a functional “lesion” of the PFC. During stress exposure, catecholamines are released in both the peripheral and central nervous systems. In the periphery, the
catecholamines norepinephrine and epinephrine are released from the sympathetic nervous system and adrenal gland, respectively. These catecholamine actions serve to “turn on” our heart and muscles and “turn off” the stomach to prepare for fight-or-flight responses during stress.
In the brain, high levels of the catecholamines dopamine and norepinephrine are released in the PFC during stress exposure, even during relatively mild psychological stress. As basal levels of dopamine and norepinephrine have essential beneficial influences on PFC function, it was originally presumed that high levels of catecholamine release during stress might facilitate PFC function. However, research in monkeys and rats demonstrated the contrary: exposure to stress impairs the working memory functions of the PFC. These findings in animals are consistent with older literature demonstrating that humans exposed to loud noise stress are less able to sustain attention or to inhibit inappropriate responses, functions now known to be carried out by the PFC. As in animal studies, these changes are most evident under conditions in which the subject feels no control over the stress.
A number of studies indicate that stress-induced working memory deficits result from high levels of catecholamine receptor stimulation on neurons in the PFC (Fig. 1). Working memory deficits during stress can be ameliorated by agents that prevent catecholamine release or block catecholamine receptors. For example, stress-induced cognitive deficits can be ameliorated by pretreatment with a2-adrenergic receptor agonists such as clonidine or guanfacine, which decrease stress-induced catecholamine release and enhance PFC function through actions at postsynaptic a2-receptors in the PFC. Stress-induced cognitive deficits can also be prevented by treating with compounds that block either dopamine D1 or noradrenergic a1-receptors, suggesting that dopamine and norepinephrine have their detrimental effects in the PFC through actions at D1 and a1-receptors, respectively. Consistent with this interpretation, intra-PFC infusions of either D1 or a1-agonists impair working memory.

Fig. 1 Dopamine acting at D1 receptors in the prefrontal cortex (PFC) produces an inverted U dose response whereby either too little or too much D1 receptor stimulation impairs neuronal or cognitive function. A–C: Highly schematic representation of the work of Yang and Seamans (1996) of the electrophysiological effects of dopamine or D1 agonists on PFC pyramidal cell function. Intracellular recordings from PFC slices showed that D1 receptor stimulation diminishes the calcium currents that convey signals from the distal dendrites to the cell body. A: With insufficient D1 receptor stimulation, all signals are conveyed to the soma, resulting in diffuse, unfocused information. This is represented in A by the large arrow of incoming signals. The behavioral correlate is poor working memory and poor attention regulation. B: With optimal levels of D1 receptor stimulation, signal transfer is focused such that only the largest, coordinated signals are conveyed to the cell. This is represented in B by the normal-sized arrow. The behavioral correlate is optimal working memory and attention regulation. C: At very high levels of D1 receptor stimulation such as during stress, calcium currents are blocked and signal transfer is abolished. This is represented by the small arrow. The behavioral correlate is once again poor working memory and attention regulation. D: These electrophysiological results fit very well with cognitive studies, whereby an inverted U is observed with changing levels of D1 receptor stimulation. In this figure, working memory performance in rats was impaired by either insufficient or excessive D1 receptor stimulation in the PFC. Adapted from Zahrt et al. (1997), Supranormal stimulation of D1 dopamine receptors in the rodent cortex impairs spatial working memory performance. J Neurosci 17:8528–8535.

Electrophysiological recordings similarly indicate that high levels of D1 receptor stimulation can interfere with PFC neuronal function. Studies of a1-receptors have not been done. For example, large amounts of D1 agonist abolish the calcium currents that convey signals along dendrites, effectively “strangling” information transfer from dendrite to soma (Fig. 1). Conversely, low levels of D1 receptor antagonists can enhance memory-related neuronal responses in monkeys performing working memory tasks. Thus, high levels of D1 receptor stimulation erode the working memory responses that the PFC uses to effectively guide behavior.
Active neurochemical mechanisms to take the PFC “off-line” during stress may have had survival value in evolution, allowing faster, instinctual mechanisms regulated by subcortical and posterior cortical areas to regulate behavior during stress. However, these brain actions may often be maladaptive in human society when we are in need of PFC regulation to act appropriately, e.g., in the classroom when behavior must be highly controlled.
The reversal of stress-induced cognitive deficits with pharmacological treatments in animals suggests that medication may also be helpful in children with stress-related behavioral problems. The animal research showed that stress-induced PFC deficits could be prevented by pretreatment with very low doses of neuroleptics or with an a2-adrenergic agonist. However, drawing parallels between children and animals should be made with caution for several reasons. The laboratory studies were performed with acute stress exposure in adult animals; the effects of pharmacological interventions have not been tested under chronic stress conditions or in juvenile animals. Furthermore, even in animal studies the results with neuroleptics were problematic: there was a very narrow therapeutic dose window, and even low clinical doses were usually too high to restore PFC function. The danger of tardive dyskinesia and other neuroleptic-related disorders also cautions against the use of these compounds in children.
The usefulness of a2-adrenergic agonists in preventing stress-induced cognitive deficits in animals may have more clinical relevance, as clonidine and guanfacine are already in use for the treatment of ADHD. Animal studies indicate that guanfacine is more effective than clonidine in preventing stress-induced working memory deficits. It is important to note that a2-adrenergic agonists improve working memory performance in animals under conditions of either insufficient (e.g., catecholamine depletion) or excessive (e.g., stress) catecholamine receptor stimulation in the PFC. This quality may enhance the clinical utility of these compounds, but it does not help us distinguish between hypo- versus hypercatecholaminergic states when considering potential etiologies of PFC disorders in children. The animal data indicate that behavioral problems could arise from both states, as either too little or too much catecholamine receptor stimulation results in PFC dysfunction.
Our new neurobiological perspective suggests that behavioral problems in children can arise from PFC dysfunction due to either external factors, such as exposure to a stressful environment, or from inherent changes in PFC circuits, such as genetic changes in dopamine or
norepinephrine transporters. It is possible that we assign the ADHD diagnosis to children with inherent changes, while those with visible causes for their behavioral problems are less likely to be given this diagnosis.
Current research suggests that common neurochemical changes in the PFC may underlie these problems irrespective of the cause. The similarity between ADHD symptoms and stress-induced PFC deficits may help to explain why ADHD is often not taken seriously as a true biological disorder. Our new understanding of stress effects on PFC function may also help to clarify why highly structured, low-stress environments can be especially helpful in treating children with ADHD and related problems. By understanding that behavioral problems may have a neurobiological basis, we may be able to deal with them more compassionately and intelligently.


Arnsten AFT (1997), Catecholamine regulation of prefrontal cortex. J Psychopharmacol 11:151–162
Arnsten AFT, Goldman-Rakic PS (1998), Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry 55:362–369

Arnsten AFT, Steere JC, Hunt RD (1996), The contribution of alpha-2 noradrenergic mechanisms to prefrontal cortical cognitive function: potential significance to attention deficit hyperactivity disorder. Arch Gen Psychiatry 53:448–455

Barkley RA (1997), ADHD and the Nature of Self-Control. New York: Guilford

Broadbent D (1971), Decision and Stress. London: Academic Press

Goldman-Rakic PS (1992), Working memory and the mind. Sci Am 267:

Yang CR, Seamans JK (1996), Dopamine D1 receptor actions in layers V-VI rat prefrontal cortex in vitro: modulation of dendritic-somatic signal integration. J Neurosci 16:1922–1935

Zahrt J, Taylor JR, Mathew RG, Arnsten AFT (1997), Supranormal stimulation of D1 dopamine receptors in the rodent cortex impairs spatial working memory performance. J Neurosci 17:8528–8535

Accepted August 13, 1998.
Dr. Arnsten is Research Scientist, Section of Neurobiology, Yale University School of Medicine, New Haven, CT.
Correspondence to Dr. Arnsten, Section of Neurobiology, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520; e-mail:
Dr. Lombroso’s e-mail address is
0890-8567/99/3802–0220/$03.00/0q1999 by the American Academy of Child and Adolescent Psychiatry.

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Old 02-12-05, 11:37 PM
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Part 2

Amy F.T. Arnsten, Ph.D.

Dysfunction of the prefrontal cortex (PFC) is a fundamental component of attention-deficit/hyperactivity disorder (ADHD). The PFC uses working memory to intelligently guide behavior, inhibiting inappropriate impulses or distractions and allowing us to plan and organize effectively (see previous column). Individuals with ADHD are consistently impaired on tests of frontal lobe function, and both structural and functional imaging studies have shown evidence of altered PFC function in individuals with ADHD. In particular, the right PFC has been shown to be consistently smaller in ADHD subjects than in age-matched controls, and the inability to suppress responses to salient but irrelevant stimuli correlates with reduced volume of the right PFC (Casey et al., 1997).
The cognitive functioning of the PFC is modulated in a critical manner by the neuromodulators norepinephrine (NE) and dopamine (DA). Intriguingly, a recent positron emission tomography study showed reduced fluorodopa binding in the PFC of adults with ADHD, indicative of altered NE and/or DA transmission in the PFC in this disorder (Ernst et al., 1998). Although most previous research has focused on DA mechanisms, NE influences on PFC function are just as powerful. Indeed, as recent research suggests that low doses of the ADHD medication methylphenidate (Ritalint) preferentially release NE in rat brain, NE mechanisms may be particularly relevant to our understanding of ADHD. This column will review the evidence that NE has an essential beneficial influence on the working memory and attention functions of the PFC through actions at postsynaptic, a2A-noradrenergic receptors, while very high levels of NE release appear to engage a1-noradrenergic receptors and impair PFC functions.
NE has been associated with attention regulation for many years. NE cells of the locus ceruleus increase their firing in response to behaviorally relevant stimuli. Selective depletion of NE in the forebrain makes animals more distractible. At least some of these behavioral changes are likely due to altered NE in the PFC. Either global depletion of catecholamines or depletion restricted to the PFC impairs working memory and attention regulation, while having little effect on basic visual discrimination and associative abilities.
Anatomical studies have documented the NE innervation of the PFC in rodents, monkeys, and humans. NE axons from cells of the locus ceruleus terminate throughout the PFC with moderate density. The a- and b-noradrenergic receptor subtypes have been observed in the PFC, and the a2A-noradrenergic receptor has been localized both presynaptically and postsynaptically in the primate PFC. Although previous research focused on presynaptic a2-receptors ("autoreceptors" that decrease NE release), it is now appreciated that the vast majority of a2-receptors in the brain are localized postsynaptic to NE cells. In the monkey PFC, a2A-receptor immunoreactivity has been documented over the postsynaptic thickening of dendritic spines of pyramidal cells, demonstrating an anatomical substrate for postsynaptic actions.
a2-Noradrenergic agonists such as clonidine, guanfacine, and meditomidine have been shown to improve a variety of cognitive functions subserved by the PFC in rodents, monkeys, and humans (Jakala et al., 1999). Systemic administration of these compounds can enhance performance of working memory tasks, response inhibition, and planning, particularly under distracting conditions. These improvements are blocked by cotreatment with a2-antagonists, consistent with actions at a2-receptors. In contrast, a2-agonists have little effect or actually impair performance of tasks that depend on posterior cortices or subcortical structures, indicating functional specificity. a2-Agonists are particularly potent in enhancing PFC functions in subjects with catecholamine depletion due to either experimental manipulations (e.g., the neurotoxin 6-OHDA or reserpine) or natural conditions (e.g., aging, vitamin B deficiency in Korsakoff amnesia). The finding that a2-agonists become more, rather than less, efficacious in subjects with catecholamine depletion is consistent with drug actions at postsynaptic a2-receptors.
Three a2-receptor subtypes have been identified in humans: the A, B, and C subtypes. Pharmacological profiles suggest that the a2A-subtype underlies the PFC-enhancing effects of a2-agonists. Thus agonists such as guanfacine, which are relatively selective for the a2A-subtype, are able to improve PFC function with fewer side effects than nonselective agonists such as clonidine (Arnsten, 1998). Recent studies in mice with a mutation of the a2A-receptor (a "functional knockout") support this hypothesis: guanfacine improves the working memory performance of wild type mice but has no effect in mice with a mutation of the a2A-receptor (reviewed by Arnsten, 2000). In contrast, a2-agonists remain effective in mice with a knockout of the a2C-subtype. Work with the a2B-knockout remains to be done. Thus, studies to date have focused on the importance of the a2A-receptor for PFC function.
Evidence suggests that a2-agonists act directly in the PFC to enhance working memory function. The beneficial effects of a2-agonists disappear in subjects with PFC ablations, suggesting that the PFC is the substrate for drug actions. Consistent with this idea, systemic administration of guanfacine or clonidine has been shown to enhance regional cerebral blood flow in the PFC of both human and nonhuman primates performing PFC tasks. For example, Figure 1 shows the areas of enhanced regional cerebral blood flow in the dorsolateral PFC of a monkey performing a spatial working memory task. Lesions of this same area markedly impair performance of this task.
More direct evidence for PFC actions comes from animal studies in which the drug is infused directly into the PFC. Infusions of guanfacine into the monkey dorsolateral PFC produce a delay-related improvement in working memory performance. Similarly, infusion of meditomidine into the PFC of aged rats improves working memory as tested by the delayed alternation task. Conversely, infusion of the a2-antagonist, yohimbine, into the PFC of monkeys produces a marked, delay-related impairment in working memory performance. These results indicate that endogenous NE stimulation of a2-receptors in the PFC has a critical influence on behavioral regulation. Infusions of a1- or b-adrenergic antagonists were without effect on performance, highlighting the importance of a2-receptors to PFC function. Recent electrophysiological studies have shown that iontophoretic application of yohimbine onto PFC cells in monkeys performing a working memory task reduces delay-related firing of PFC neurons, the cellular measure of working memory (Li et al., 1999). Conversely, either iontophoretic or systemic administration of an a2-agonist enhances delay-related activity. Thus, a2-receptor stimulation is critical for PFC function at both the cellular and behavioral level.
In contrast to the marked beneficial effects of a2-receptor stimulation on PFC functions, high levels of a1-noradrenergic receptor stimulation impair PFC function (reviewed by Arnsten, 2000). These detrimental actions appear to come into play under conditions of very high NE release, e.g., during uncontrollable stress. In this regard, it is of interest that NE has much lower affinity for a1-receptors than for a2-receptors, suggesting that high levels of NE release may be needed to significantly engage detrimental a1 mechanisms. Administration of a2-agonists can restore PFC cognitive function in stressed subjects with very high levels of catecholamine release, suggesting that both pre- and postsynaptic a2-receptors can contribute to beneficial effects depending upon the state of the subject. Current research is exploring the second-messenger mechanisms underlying the detrimental effects of a1-receptor stimulation. Evidence to date suggests that a1-receptor stimulation impairs PFC function through activation of the phosphatidylinositol/protein kinase C intracellular signaling pathway. It is intriguing that overactivity of this intracellular pathway has been linked to mania, a disorder that shares some similarities to the symptoms of ADHD.
In summary, research in animals demonstrates that either too little a2-receptor stimulation or too much a1-receptor stimulation can impair PFC cognitive function. These findings suggest that altered NE transmission could contribute to symptoms of ADHD. For example, mutations in the synthetic enzymes for NE or in a2A-receptors could lead to insufficient a2A-receptor actions and impaired PFC function. Mutations of proteins such as the NE transporter would lead to higher levels of NE in the synapse and excessive stimulation of a1-receptors that would also impair PFC function. It will be interesting to observe whether genetic studies find associations between these proteins and ADHD symptoms, as suggested by some preliminary studies. Genetic studies have already found a consistent association between DA D4 receptor polymorphisms and ADHD symptoms, particularly in adults. In this regard it is important to remember that NE has very high affinity for D4 receptors; indeed it has higher affinity for D4 than for noradrenergic a- or b-receptors. However, we do not currently understand how either DA or NE may act at D4 receptors to alter PFC function.
The critical importance of NE to PFC function may explain why selective noradrenergic agents have been successful in treating ADHD. The nonselective a2-agonist, clonidine, has had modest success in treating ADHD symptoms. More recently, the selective a2A-agonist, guanfacine, has also reduced symptoms of ADHD and improved performance of PFC tasks in both open-label and controlled trials (reviewed in Arnsten, 2000). Guanfacine likely reduces impulsivity and enhances attention regulation by strengthening PFC control of behavior. Similarly, the nonselective NE reuptake blocker, desipramine, and the new, selective NE reuptake blocker, tomoxetine, have been shown to ameliorate ADHD symptoms. Noradrenergic therapeutics will be the topic of the next column in this series.
The data presented here suggest possible common mechanisms for how these compounds may be helpful in treating ADHD. Both a2-agonists and NE reuptake blockers may serve to normalize NE transmission in the PFC and thus enhance PFC function. In subjects with underactivity of the NE system, these compounds could increase postsynaptic a2-receptor stimulation in the PFC through either direct stimulation of these receptors (guanfacine) or by increasing available NE levels in the synapse (NE reuptake inhibitors). Conversely, in subjects with overactivity of the NE system, actions at presynaptic receptors might predominate to reduce NE tone. However, it is important to remember that agents such as guanfacine can improve PFC performance in normal subjects or in individuals with altered DA activity. Thus, PFC cognitive enhancement with a2-agonists does not necessarily signify altered NE activity. Instead, it is likely that a variety of insults to PFC circuits can result in ADHD symptoms, and enhanced noradrenergic a2-receptor stimulation in PFC may help to overcome these problems irrespective of their cause.

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Old 02-13-05, 04:15 AM
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Part 3

Joseph Biederman, M.D., and Thomas J. Spencer, M.D.

Dysregulation of the central noradrenergic network has long been hypothesized to underlie the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) (Arnsten etal., 1996). This hypothesis is derived largely from pharmacological data documenting that drugs which selectively modulate noradrenergic function show efficacy in treating ADHD. However, a noradrenergic hypothesis of ADHD is compelling in its own right because the noradrenergic system has been intimately associated with the modulation of higher cortical functions including attention, alertness, and vigilance. As recently reviewed by Solanto (1998), preclinical and clinical research has implicated the noradrenergic effects of stimulants in enhancing capacities such as delayed responding, working memory, and attention. Furthermore, executive function and noradrenergic activation are known to profoundly affect the performance of attention, especially the maintenance of arousal, and the ability to sustain attention on a subject, particularly a boring one.
Current neuropsychological, genetic, imaging, and pharmacological data emerging in ADHD research provide compelling support for a noradrenergic hypothesis of ADHD (Arnsten etal., 1996). Figure 1 Attention and vigilance depend on adequate modulation by catecholamine neurotransmitters of prefrontal, cingulate, and parietal cortices, thalamus, striatum, and hippocampus. These brain networks all have a high density of catecholamine terminals.
Perhaps the most compelling evidence for a noradrenergic hypothesis for ADHD derives from psychopharmacological data (Spencer etal., 1996). Preclinical studies have shown that stimulants block the reuptake of dopamine and norepinephrine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Early animal studies used 6-hydroxydopamine to lesion dopamine pathways in developing rats. Because these lesions created hyperactivity, they were thought to provide an animal model of ADHD. Although not entirely sufficient, changes in dopaminergic and noradrenergic function appear necessary for the clinical efficacy of the stimulants. Also, 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, providing support for the hypothesis that alteration of monoaminergic transmission in critical brain regions may be the pharmacological basis for the effects of stimulants in ADHD. A plausible model is that these medications increase the inhibitory influences of frontal cortical activity on subcortical structures through dopaminergic and noradrenergic pathways (Zametkin and Rapoport, 1987). Indeed, Kuzcenski recently found that low doses of methylphenidate preferentially release norepinephrine. In contrast, effects on serotonin metabolism appear minimally related to the clinical efficacy of the stimulants.
Evidence for noradrenergic actions also comes from studies of antidepressant compounds used to treat ADHD. While the tertiary amines (imipramine and amitriptyline) are more selective for the serotonin transporter than for the norepinephrine transporter, the secondary amines (desipramine, nortriptyline, and protriptyline) are more selective for the norepinephrine transporter. It is assumed that the activity of the tricyclic antidepressants (TCAs) in ADHD stems from their actions on catecholamine reuptake, particularly that of norepinephrine. Advantages of this class of drugs include their relatively long half-lives (approximately 12 hours), obviating the need to administer medication during school hours and lowering the potential for drug abuse or side effects, and their potentially positive effects on mood and anxiety symptoms.
Of 33 studies (21 controlled and 12 open) evaluating TCAs in hyperactive children, adolescents (n = 1,139), and adults (n = 78), 30 reported positive effects on ADHD symptoms. Imipramine and desipramine are the most studied TCAs; there are a handful of studies on the others. The largest controlled study of a TCA in hyperactive children found favorable results with desipramine (DMI) in 62 clinically referred children with ADHD, most of whom had previously failed to respond to psychostimulant treatment (Biederman etal., 1989). The study was a randomized, placebo-controlled, parallel-design, 6-week clinical trial. Clinically and statistically significant differences in behavioral improvement were found for DMI over placebo, at an average daily dose of 5 mg/kg. Specifically, 68% of DMI-treated patients were considered very much or much improved, compared with only 10% of placebo patients (p < .001). Although the presence of comorbidity increased the likelihood of a placebo response, neither comorbidity with conduct disorder, depression, or anxiety nor a family history of ADHD yielded differential responses to DMI treatment. In addition, DMI-treated patients showed a substantial reduction in depressive symptoms compared with placebo-treated patients.
In a similarly designed controlled clinical trial in 41 adults with ADHD, DMI, at an average daily dose of 150 mg (average serum level of 113 ng/mL), was statistically and clinically more effective than placebo. Sixty-eight percent of DMI-treated patients responded compared with none of the placebo-treated patients (p < .0001). Moreover, the average severity of ADHD symptoms at the end of the study was reduced to below the level required to meet diagnostic criteria. Importantly, while the full DMI dose was achieved at week 2, clinical response improved further over the following 4 weeks, indicating a latency of response. Response was independent of dose, serum DMI level, gender, or lifetime psychiatric comorbidity with anxiety or depressive disorders (Wilens etal., 1995).
In a prospective, placebo-controlled discontinuation trial, we recently demonstrated the efficacy of nortriptyline in doses of up to 2 mg/kg daily in 35 school-age youths with ADHD. In that study, 80% of youths responded by week 6 in the open phase. During the discontinuation phase, subjects randomly assigned to placebo lost the anti-ADHD effect compared with those receiving nortriptyline, who maintained a robust anti-ADHD effect. There was again a lag in response to medication and also a lag in loss of response after medication discontinuation. Although the full dose was achieved by week 2, the full effect evolved slowly over the ensuing 4 weeks. ADHD youths receiving nortriptyline also were found to have modest but statistically significant reductions in oppositionality and anxiety. Nortriptyline was well tolerated, with some weight gain. Weight gain is frequently considered to be a desirable side effect in this population. In contrast, a systematic study in 14 treatment-refractory ADHD youths receiving protriptyline (mean dose of 30 mg) reported less favorable results. We found that only 45% of ADHD youths responded or could tolerate protriptyline because of its adverse effects (Wilens etal., 1995).
The potential benefits of TCAs in the treatment of ADHD have been clouded by concerns about their safety stemming from reports of sudden unexplained death in 4 children with ADHD treated with DMI (Biederman etal., 1989), although the causal link between DMI and these deaths remains uncertain. A rather extensive body of literature evaluating cardiovascular parameters in TCA-exposed youths consistently identified mostly minor, asymptomatic, but statistically significant increases in heart rate and electrocardiographic measures of cardiac conduction times associated with TCA treatment. A recent report estimated that the magnitude of DMI-associated risk of sudden death in children may not be much larger than the baseline risk of sudden death in this age group. However, because of this uncertainty, prudence mandates that until more is known, TCAs should be used as second-line treatment for ADHD and only after carefully weighing the risks and benefits of treating or not treating an affected child.
Bupropion hydrochloride is a novel-structured antidepressant of the aminoketone class related to the phenylisopropylamines but pharmacologically distinct from known antidepressants. Bupropion appears to possess both indirect dopamine agonist and noradrenergic effects. Bupropion has been shown to be effective for ADHD in children in a controlled multisite study (n = 72) and in a comparison with methylphenidate (n = 15). In an open study of adults with ADHD, sustained improvement was documented at 1 year at an average of 360 mg for 6 to 8 weeks. In a placebo-controlled 6-week trial of sustained-release bupropion (up to 200 mg b.i.d.) in adults with ADHD,sustained-release bupropion was well tolerated and effective. Of 38 completers, 76% improved (>30% reduction of symptoms) compared with 37% receiving placebo (p = .012). While bupropion has been associated with a slightly increased risk (0.4%) for drug-induced seizures relative to other antidepressants, this risk has been linked to high doses, a previous history of seizures, and eating disorders.
Although a small number of studies suggested that monoamine oxidase inhibitors (MAOIs) may be effective in treating juvenile and adult ADHD, their potential for hypertensive crisis associated with the irreversible MAOIs (e.g., phenelzine, tranylcypromine), due to dietary transgressions (tyramine-containing foods, i.e., most cheeses) and drug interactions (pressor amines, most cold medicines, amphetamines), seriously limits their use. This "cheese effect" may be obviated with the reversible MAOIs (e.g., moclobemide) that have shown promise in one open trial, although they are not yet available in the United States.
Promising results have been associated with the experimental noradrenergic-specific compound, tomoxetine. One controlled clinical trial in adults documented efficacy and good tolerability. These initial encouraging results, coupled with extensive safety data in adults, fueled efforts at testing this compound in the treatment of pediatric ADHD. An initial open study documented clinical benefits with excellent tolerability, including a safe cardiovascular profile.
Drugs that mimic norepinephrine at the a2-receptor are also used in the treatment of ADHD. Despite its wide use in children with ADHD, there have been very few studies (n = 4 studies [2 controlled]; n = 122 children) supporting the efficacy of clonidine. Treatment with clonidine appears to have mostly a behavioral effect in disinhibited and agitated youths, with limited impact on cognition. Several cases of sudden death have been reported in children treated with clonidine plus methylphenidate, raising concerns about the safety of this combination. Limited literature exists for guanfacine, a more selective a2A-receptor agonist with fewer side effects. There are 3 small open studies of guanfacine in children and adolescents with ADHD. In these studies, beneficial effects on hyperactive behaviors and attentional abilities were reported. In addition, in a controlled study in normal adults, guanfacine, but not clonidine, improved planning and spatial working memory. In another controlled study in adults with ADHD, guanfacine was reported to improve ADHD symptoms (K. Fletcher, personal communication, 2000). Most recently, a controlled trial in children with ADHD and tics has shown that guanfacine can improve ADHD symptoms and reduce tics (L. Scahill, personal communication, 2000). Thus a variety of noradrenergic agents can improve ADHD symptoms.
In contrast, serotonergic antidepressants are less effective in the treatment of ADHD. While a single, small, open study suggested that fluoxetine may be beneficial in the treatment of children with ADHD, the usefulness of selective serotonin reuptake inhibitors in the treatment of core ADHD symptoms is not supported by clinical experience (NIMH, 1996). Similarly uncertain is the usefulness of the mixed serotonergic/noradrenergic atypical antidepressant venlafaxine in the treatment of ADHD. While a 77% response rate was reported in completers in open studies of adults with ADHD, 21% dropped out because of side effects (n = 4 open studies; n = 61 adults). In addition, a single open study of venlafaxine in 16 children with ADHD found a 50% response rate in completers with a 25% rate of dropout due to side effects, most prominently increased hyperactivity.
In summary, although there is no single pathophysiological profile of ADHD, data implicate dysfunction in the fronto-subcortical pathways that control attention and motor behavior. Moreover, the effectiveness of stimulants, along with animal models of hyperactivity, point to catecholamine dysregulation as at least one source of brain dysfunction in persons with ADHD. There is a great need for more research on the role of norepinephrine in ADHD. As most existing research on stimulants has focused on dopamine, it will be important for basic research to examine norepinephrine mechanisms altered by stimulants and other medications. There is also a need for genetic studies to include the norepinephrine transporter, norepinephrine synthetic enzymes, and norepinephrine receptors in ADHD families. Despite their chemical differences, the various compounds with documented anti-ADHD activity share a common noradrenergic/dopaminergic activity. In this regard, it is notable that both noradrenaline as well as dopamine are potent agonists at the D4 receptor, a gene that has been implicated in the etiology of this disorder (Lanau etal., 1997). It is hoped that advances in the understanding of the underlying neurobiology of ADHD will lead to the development of a new generation of safe and effective treatments for this disorder. Such developments have the promise of revolutionizing the field and improving the quality of life of the millions of affected patients and their families worldwide.

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"Current research suggests that common neurochemical changes in the PFC may underlie these problems irrespective of the cause. The similarity between ADHD symptoms and stress-induced PFC deficits may help to explain why ADHD is often not taken seriously as a true biological disorder. Our new understanding of stress effects on PFC function may also help to clarify why highly structured, low-stress environments can be especially helpful in treating children with ADHD and related problems. By understanding that behavioral problems may have a neurobiological basis, we may be able to deal with them more compassionately and intelligently."

This could also explain why symptoms may appear differently, to a lesser or greater degree, in equally affected individuals.
Thanks for sharing.
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Old 02-14-05, 01:46 PM
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Great articles, do you have the URL's by any chance?
Time is the school in which we learn, time is the fire in which we burn.
~ Delmore Schwartz
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Old 02-15-05, 01:58 AM
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Here's another article that discusses NE as a solution for ADD:

Found at:

Look at the "Brainstorm" articles...Several great articles that most people should find pretty interesting.
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