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The ADHD Success Formula

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The Parenting Adhd Resource Guide

You will find: 6 behavioral strategies. 6 behavioral strategies that you can use today to improve your child's behavior (page 52) The key to success. Why being Smart is the key to success with your child (page 53) The absolute best way. The absolute best way to tackle other people who say that Adhd is a myth and cop out for bad parenting (page 55) Rewards to improve your child's behaviors.Discover the exact type of rewards that you can use to improve your child's behaviors .and the exact type of rewards to avoid at all costs (page 57) 10 sure-fire techniques.10 sure-fire techniques to use when your child has problems in keeping attention; that will help them at home and in school (page 58) The real truth about Adhd and playing computer games.The real truth about Adhd and kids playing computer games (and believe me it's not what you might think.) (page 64) 8 practical tips.8 practical tips that you can use to deal with the challenges of a moody teenager with Adhd and reduce the conflict now (page 70) How to overcome the feelings of stress.How to overcome the feelings of stress and being overwhelmed when you are the parent of an Adhd child (page 74) The key actions.The key actions you must take if your Adhd child is becoming a danger at home; to make thing safer all round (page 79).

The Parenting Adhd Resource Guide Summary

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Author: Dave Angel
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Attentiondeficithyperactivity Disorder

ADHD, usually first evident in childhood, is characterized by excessive motor activity, difficulty in sustaining attention, and impulsiveness. A variety of stimulant drugs have been utilized in the treatment of ADHD, and they are particularly indicated in moderate-to-severe cases. Methylphenidate is effective in children with ADHD and is the most common intervention treatment may start with a dose of 5 mg in the morning and at lunch, increasing gradually over a period of weeks depending on the response as judged by parents, teachers, and the clinician. The total daily dose generally should not exceed 60 mg. Methylphenidate has a short duration of action thus, most children require 2-3 doses day, with the timing individualized for effect. Methylphenidate, dextroamphetamine, and amphetamine probably have similar efficacy in ADHD. pemoline appears to be less effective, although like sustained release preparations of methylphenidate (ritalin sr, concerta, metadate) and amphetamine...

Attention DeficitHyperactivity Disorder

The efficacy of the stimulant drugs in treating attention-deficit hyperactivity disorder (ADHD) is well established. The tricyclics, especially desipramine, also appear to be of value. In one study, desipramine, given at doses greater than 4 mg kg for 3-4 weeks, was effective in two-thirds of the children, whereas placebo was effective in only 10 (Biederman et al. 1989). Desipramine was also found to be more effective than placebo in adults with ADHD (Wilens et al. 1996). One of the advantages of desipramine is its low potential for abuse. Unfortunately, five cases of sudden death were reported in the early 1990s in children being treated with desipramine (Riddle et al. 1991, 1993). All were under the age of 12 years. As a result, desipramine is now contraindicated in children younger than 12 years (discussed in greater detail below see section Side Effects and Toxicology ). Given that tricyclics as a group share the same adverse cardiac effects, there is reason to be concerned that...

Membrane Transporters In Therapeutic Drug Responses

PHARMACODYNAMICS TRANSPORTERS AS DRUG TARGETS Membrane transporters are the targets of many drugs. For example, neurotransmitter transporters are the targets for drugs used in the treatment of neuropsychiatric disorders. SERT (SLC6A4) is a target for the selective serotonin reuptake inhibitors (SSRIs), a major class of antidepressant drugs. Other neurotrans-mitter reuptake transporters serve as drug targets for the tricyclic antidepressants, amphetamines (including amphetamine-like drugs used in the treatment of attention deficit disorder in children), and anticonvulsants. These transporters also may be involved in the pathogenesis of neuropsychi-atric disorders, including Alzheimer's and Parkinson's diseases. Transporters that are nonneuronal also may be potential drug targets (e.g., cholesterol transporters in cardiovascular disease, nucleo-side transporters in cancers, glucose transporters in metabolic syndromes, and Na+-H+ antiporters in hypertension).

Dopaminergic Receptors

The D4 receptor has received much interest in psychopharmacological research in recent years because of the fact that clozapine has a high affinity for this receptor. Studies are currently underway that are investigating more selective D4 antagonists as adjunctive agents in the treatment of schizophrenia. Furthermore, considerable attention has focused on the possibility that genetic D4 variants may be associated with thrill-seeking behavior (Zuckerman 1985), attention-deficit hyperactivity disorder (Roman et al. 2001), and responsiveness to clozapine (Van Tol et al. 1992).

Role of Pharmacotherapy

Currently, ADHD is subdivided into three diagnostic subtypes, defined by predominance in inattention, hyper-activity, and impulsivity, or as the combined type that includes both inattention and hyperactivity impulsivity. Pharmacological treatments for ADHD enhance cate-cholaminergic neurotransmission. This repeated observation, combined with neuroimaging evidence strongly implicate fronto-striatal and fronto-cerebellar circuits in deficits affecting behavioral organization and the ability to predict events and behavioral outcomes a further deficit in the fronto-amygdalar loop that assigns emotional significance to predicted and detected events is also hypothesized (Swanson et al. 2007). However, no differences in medication response have been reported among the three subtypes.

Current Concepts and State of Knowledge

ADHD research has long employed animal models in the study of the neural basis of this multifactorial and heterogeneous pathology. The core clinical symptoms of ADHD - namely, inattentiveness, hyperactivity and impulsivity - have been used as constructs in animal research for a long time. Following early attempts to model these symptoms in animals such as dogs and cats, laboratory models of ADHD have been developed mostly in rodents, partly because more is known about their biology and genetics. Several authors have put forward some essential characteristics of a good animal model of ADHD. They can be summarized as follows (1) behavioral symptoms should be evident only in particular environments and stage of development, according to the specific characteristics of ADHD symptom manifestation (2) biochemical and morphological abnormalities - as well as their etiology - should be similar to those shown by ADHD sufferers (3) the model should respond to the same drugs used for the...

Chemical Intoxication and Physical Trauma Models

Despite its high heritability, some forms of ADHD are thought to be caused by heavy metal exposure, drug intoxication, or physical traumas, at pre-, peri- or post-natal developmental stage. Some environmental factors may in fact have teratogenic effects on the fetus during pregnancy, which will cause ADHD symptoms in the offspring. Although exposure to chemicals and complications during pregnancy and or delivery represent independent risk factors for the development of ADHD, it is useful to create animal models that mimic such conditions. Other chemical-induced animal models are created by pre- or post-natal administration of polychlorinated biphenyls (PCBs), methylazoxymethanol, and transreti-noic acid. However, these conditions have had only limited success as models of ADHD. Prenatal ethanol and nicotine exposure can cause ADHD-like symptoms in humans and other animals. Accordingly, rats prenatally exposed to ethanol display dysregulation of dopaminergic neurons in the VTA, which...

Chemical Lesion and Behavioral Models

Animal models relevant for ADHD research can be created by lesioning of selective brain areas or interfering with neuromodulatory systems. These lesions are mainly created by microinfusion of neurotoxins during animal adulthood or at early postnatal days, to mimic abnormal neurodevelopmental processes. The most widely used neurodevelopmental model of ADHD is the neonatal 6-hydroxydopamine (6-OHDA) lesioned rat. Shaywitz and colleagues, in 1976, showed that rats lesioned 5 days after birth by intracerebroventri-cular infusion of 6-OHDA display marked hyperactivity and other cognitive deficits that were claimed to be attenuated by acute administration of AMPH. Further research demonstrated that the behavioral phenotype of this model also improves after MPH administration, and that these animals (rats or mice) have decreased striatal DAT density, increased dopamine D4 receptor expression, and alterations in central 5-HT neurotransmission. These rats show patterns of hyperactivity similar...

The Importance of Monoamine Transporters in the Development of Psychopharmacology

In addition monoamine uptake inhibitors are used in the treatment of obesity (sibutramine) smoking cessation (bupropion) and attention deficit hyperactivity disorder (ADHD) (atomoxetine). The amphetamines exert their psychostimulant effects by acting as selective ligands for norepinephrine and dopamine uptake, subsequently displacing dopamine and norepinephrine. Amphetamine and the analog methyl phenidate ( Ritalin ) are widely used in the treatment of ADHD. The psychostimulant drug cocaine also acts by virtue of its ability to inhibit the dopamine transporter.

Inhibitors of Monoamine Uptake as Drugs of Abuse

Concern has been expressed that amphetamine and the congener methyl phenidate used to treat ADHD in children might have abuse and dependence liabilities. In practice, however, there is very little evidence for this, probably because when used medically the drugs are administered orally, leading to slow absorption and brain penetration. In contrast, when abused the amphetamines are administered intravenously or by smoking (methamphetamine), routes that lead to the rapid absorption and brain exposure that addicts crave.

Neurotransmitter Reuptake Site Binding Studies

These methods have led to reformulation of clinical algorithms in the management of depressive disorders. Suicide remains a serious risk among all psychiatric patients, and the role of SERT in the expression of suicide has been studied using PET ligands (Purselle and Nemeroff 2003). Dopamine transporter (DAT) ligands have also been used to study cognitive and motor dysfunction in Parkinson's disease (Cropley et al. 2006 Ravina et al. 2005), and the same methods are currently being applied to investigate conditions such as attention-deficit hyperactivity disorder (ADHD).

PET Tracers of Cerebral Metabolism and Blood Flow

PET has been used to assess functional activity of brain regions, both in the resting state and in response to various stimuli. The methods used include use of FDG-PET and radioactive 15O H2O-PET to study metabolic activity and blood flow, respectively. Figure 10-2A shows a picture of increased cerebral blood flow to paralimbic regions during a sad mood induction task (to be described later) using H2O-PET. In contrast, Figure 10-2B shows metabolic activity differences among depressed versus healthy patients using FDG-PET. These modalities have been effectively used to study a variety of mental phenomena and have been of considerable benefit in enhancing our understanding of psychiatric disorders. Of particular interest have been studies using PET to understand the biological basis of schizophrenia (Fujimoto et al. 2007 Lange et al. 2005), bipolar disorder (Post et al. 2003), depression (Mayberg 2003b Neumeister et al. 2004), substance abuse and craving (Kilts et al. 2004), PTSD...

Methylphenidate Synonyms

Methylphenidate (MPH) is the most commonly prescribed psychostimulant for the treatment of attention-deficit hyperactivity disorder (juvenile and adult forms), although it has also been used in the treatment of narcolepsy and postural orthostatic tachycardia syndrome. It was first synthesized in 1944 and is chemically related to cocaine it was originally formulated as a mixture of two racemates, 80 ( )-erythro and 20 ( )-threo, though its efficacy was later realized to derive from the threo isomer. Like most psychomotor stimulants, it acts to enhance dopamine release and block reuptake with additional effects on noradrenaline reuptake it is not thought to affect central serotonin directly, unlike the prototypical psychomotor stimulant amphetamine, or cocaine. Its main cognitive effects are to reduce fatigue, enhance attention, and reduce impulsivity. Experimental studies in non-sleep-deprived healthy humans have indicated beneficial effects on working memory, leading to its current...

Pharmacological Properties

Several newspapers in the US recently reported the contention that healthy people should have the right to boost their brains with psychoactive drugs, drugs that are normally described for disorders such as attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), narcolepsy, and memory-impairment in older individuals ( dementia). College students are already taking Ritalin as a cognitive enhancer before exams to help them study better, and some students contend that We should welcome new methods of improving our brain function'' and that doing it with pills is no more morally objectionable than eating right or getting a good night sleep (Houston Chronicle, December 8, 2008). But what do we know about this psychoactive drug What is methylphenidate MPD is one of the most prescribed psychostimulants for the treatment of children and adults with ADHD. ADHD is characterized by a persistent pattern of inattention and or hyperactivity, with impulsivity more often...

Animal Models for Studies of Methylphenidate

Methylphenidate is the drug most often used for treating children and adults with ADHD, for many years. It is expected that these patients would be used to study the prolonged effects of methylphenidate on their physiological and behavioral properties. However, there are ethical, methodological, and economic factors that limit research on children and adults exhibiting ADHD and on the therapeutic effects of methylphenidate. Therefore, research uses animal models for the understanding of the disorders. Researchers deal with a simpler system, which yields data that may be easier to interpret than that of a clinical case. In addition, animal models offer the possibility of understanding neurobiological processes that cannot be readily studied in humans. The question is which animal, and if a rat is selected, which strain It has been argued that the most adequate model to study the physiological properties of methylphenidate is the one that best mimics a clinical case of ADHD and is able...

Summary and Conclusions

Future investigations will continue to elucidate the interactions of these drugs in comparison to cocaine at the DAT and to reveal how those differences affect other neural systems and circuitry, so as to provide a better understanding of cocaine's mechanism of action and to feed this information into our drug design. Further, as the BZT analogues do not appear to have significant abuse liability they may also have therapeutic utility in other disorders such as ADHD and obesity, areas in which drug development is an emerging line of investigation.

Performance Deficits By Nicotinic Drugs

Attention deficit hyperactivity disorder (ADHD) is among the most prevalent of childhood and adolescent disorders, accounting for up to 50 of clinic visits in these populations. The predominant characteristics of ADHD, inattention and dis-tractibility, are also among the symptoms associated with prenatal and early postnatal exposure to a variety of toxicants, as well as with a wide variety of neurologic and psychiatric disorders including AD, Parkinson's disease, Huntington's disease, Tourettes syndrome, and schizophrenia. The primary therapeutic agents utilized for ADHD and other disorders where distractibility and inattention are prominent features include methylphenidate, dextroamphetamine, mixed amphetamine isomers, and pemoline. While the efficacy of these agents has been demonstrated, they are also associated with a wide variety of adverse effects including insomnia, decreased Nicotine has been shown in a number of studies to enhance arousal, visual attention, and perception and...

Other CNS indications

Despite clinical trials for several indications, no molecule specifically designed to block the a2-adrenoceptor has been successfully developed as a drug, although a2-adrenoceptor antagonist activity may play an important role in antidepressants such as mirtazepine (Langer 1997). In addition to their use as antihypertensives, selective centrally-acting a2-adrenoceptor agonists are used as adjuncts to general anesthesia, in the treatment of opiate withdrawal, attention-deficit hyperactivity disorder and Tourette's syndrome the anaesthetic and analgesic actions of a2-adrenoceptor agonists appearing to be mediated by the a2A-adrenoceptor.

D2Like Dopamine Receptor Genes 221 D2 Dopamine Receptor Genes 2211 Gene Structure and Organization

At least 19 different repeat unit sequences, used in 25 different haplotypes that code for 18 different unique receptor variants, were identified in the human D4 dopamine receptor gene 83 . More recently, an extra 35 different alleles have been detected in the population having single nucleotide polymorphisms 84 . The 7-repeat allele was initially reported to be associated with the personality of novelty seeking 85, 86 and then more lately with attention deficit hyperactivity disorder (ADHD) 87-90 . A tandem duplication of 120 bp located 1.2 kb upstream from the initiation codon and approximately 850 bp upstream from the transcription start site was identified in the human D4 dopamine receptor gene 95 . This polymorphism has been found to be associated with ADHD 96-98 . Transient transfection in human neuroblas-toma cells and other human cell lines with coupled luciferase reporter gene assays demonstrated that the duplication had lower transcriptional activity in human neuroblastoma...

Cardiovascular Effects

As mentioned earlier (see subsection Attention-Deficit Hyperactivity Disorder ), sudden death has been reported in five children under the age of 12 years who were receiving desipramine (Riddle et al. 1991, 1993). It was suggested that the immature conduction system in some children might render them more vulnerable to the cardiac effects of desipramine. Subsequently, a study was conducted in 71 children with 24-hour cardiac monitoring (Biederman et al. 1993). No cardiac abnormalities were observed. Wilens et al. (1992) examined the possibility that hydroxydesipramine might reach unusually high levels in children and adolescents, but such levels were not found. A study of electrocardiographic parameters in that sample failed to show a relationship between those parameters and concentrations of desipramine or hydroxydesipramine (Wilens et al. 1993). Although these studies failed to reveal a mechanism for the sudden deaths reported, they do suggest that these events are not predictable,...

HT Systems in Other DAAssociated Disorders

In rats lesioned as neonates with 6-OHDA and lesioned again in adulthood with the serotoninergic toxin 5,7-DHT, there was an inordinate increase in hyperlocomotor activity. This combined treatment in rats was proposed to model attention deficit hyperactivity disorder (Kostrzewa et al. 1994, 2008b). Moreover, the hyperlocomotor activity was abated by 5-HT2 receptor antagonists (Nowak et al. 2007 Brus et al. 2004). 5-HT systems are also proposed as an alternate phenotypic system beneficially preserving function in Parkinson disease (Kostrzewa and Moratalla, submitted)).

Application of DAT Imaging

Attention Deficit Hyperactivity Disorder (ADHD) Another area of application with the DAT imaging agents is in detection of attention deficit hyperactivity disorder (ADHD) (Dresel et al., 2000 Krause et al., 2000). It was found that compared with age-matched normal controls, ADHD patients showed a 30 higher density of DAT in the brain. The density of DAT was reduced significantly after treatment of methylphenidate (Ritalin ), demonstrating the mechanism of drug action in vivo. It also points out the possibility that the in vivo imaging method could be used to differentiate the young patients with genuine ADHD before subjection to an indiscriminate drug treatment.

Summary of Considerations When Having a Positive Urine Test

Therapeutic uses for amphetamine and methamphetamine include attention deficit disorder, treatment of exogenous obesity, and treatment of narcolepsy and CNS disorders 59 . Examples of prescription medications that contain amphetamine or methamphetamine are Adderall , Benzedrine , Dexedrine , and Desoxyn .

Clinical Implications

Nowadays it is recognized that serotonin-dopamine interactions may have important clinical implications since they are involved in pathophysiological mechanisms of some neurological and psychiatric diseases (like schizophrenia, Parkinson and Huntinton diseases, ADHD, Alzheimer disease, anxiety, depression, and drug addiction) that may evolve with cognitive dysfunctions besides motor, mood, or behavioral disturbances and may able to be improved by drugs acting on dopamine or serotonin neurotransmission (Araki et al. 2006 Boulougouris and Tsaltas 2008 Cools 2006 Di Pietro and Seamans 2007 Gray and Roth 2007 Kostrzewa et al. 2005 Remington 2008 Scholes et al. 2007 Scholtissen et al. 2006). Further, even though derangement of different brain dopaminergic neurotransmission systems has been mainly implicated in these pathologies, they also affect other nondopaminergic neuronal structures, including neurotransmitter receptors underlying synaptic serotonergic activity. On the other hand,...

HT2C Effects on Factors Influencing Learning Processes 2451 Anxiety

Impulsiveness is defined as an action without adequate forethought in addition, alterations in the impulse control or lack of behavioral inhibition are part of disorders such as OCD, attention deficit hyperactivity disorder (ADHD), schizophrenia, antisocial behavior, and addictive behavior (American Psychiatric Association 1994).

Modulation of Neurotransmission by Docosahexaenoic Acid

In addition, DHA modulates expression of genes for cytokines and their receptors, cell adhesion molecules, cytoskeleton proteins, and hormone receptors. The effect of DHA is sustained as long as DHA remains in the diet. Thus, DHA acts like a hormone to control the activity of key transcription factors, and modulates a variety of neural cell functions 44, 4850 . Collective evidence suggests that DHA modulates the expression of a number of genes with such broad functions as DNA binding, transcriptional regulation, transport, cell adhesion, cell proliferation, raft formation, membrane protrusions and membrane localization. These effects, in turn, may significantly modify cell function, development and or maturation. Collective evidence suggests that n-3 fatty acid-deficient diet through interactions with various neurotransmitter receptors produces symptoms of chronic locomotor hyperactivity, disturbance in melatonin rhythm, and striatal hyperdopaminergia. It is suggested that an n-3...

Human Dopamine Transporter Hdat Slc6A3 31 hDAT Cloning and Gene Organization

Dopamine (DA) systems are important mediators of motor function, mood, reward, and cognition (60). DA systems are believed to play a role in many diseases including ADHD, schizophrenia, drug abuse, Parkinson's disease, and TS and hDAT gene variation could potentially contribute to many of these disorders (61). An important role for DAT in DA physiology and behavior is supported by findings with DAT-knockout mice (see also Chapter 5). Clearance of DA from the extracellular space of the striatum of DAT-knockout mice is 300x slower than in intact animals, supporting the importance of the uptake mechanism, particularly in brain regions with a high density of DA neuron terminals (10). Furthermore, DAT-knockout mice are hyperactive, demonstrate stereotypical behaviors, and do not respond to cocaine administration with a further increase in locomotion. The similarity of the DAT-knockout phenotype to symptomatology of disorders such as attention deficit hyeractivity disorder (ADHD) and...

Norepinephrine Transporters NETs

The NET is a target for many pharmaceuticals, especially antidepressants, and for a number of drugs of abuse, such as cocaine. A diagnostic imaging tool for the study of NET would provide information on the noradrener-gic system in the brain, and a suitable PET ligand would be beneficial in studies of the pathophysiology of a number of neurologic and psychiatric disorders. For example, our knowledge of the central mechanisms underlying disorders such as anxiety, depression, attention-deficit hyperactivity disorder (ADHD), personality disorders, pain, and Parkinson's and Alzheimer's dis-

The Role of Mixed Action Antidepressants in Therapeutics

In addition to the efficacy of non-SSRI agents in depression, studies support efficacy in anxiety disorders (especially venlafaxine, mirtazapine, nefazodone) and ADHD (venlafaxine, bupropion). Bupropion's role in smoking cessation is well recognized (211) but it has also been used to treat neuropathic pain (212). Duloxetine and milnacipram are the preferred antidepressant agents in fibromy-algia. Bupropion and mirtazapine have become the agents of choice if SSRI-induced sexual dysfunction limits continued treatment with that class of drugs.

Neuroimaging Synonyms

Neuroimaging is a family of techniques used for obtaining images of the structure or the function of the human brain. Neuroimaging studies investigate structural and functional brain maturation in health or in diseases of the brain, such as schizophrenia, bipolar disorder, depression, ADHD, drug dependence, and autism. These studies often aim to find genetic and environmental markers of variance in brain structure and function over time. Through additions to diagnostic radiology, neuroimaging has broadened to become a distinct field in neuroscience. The neuroimaging techniques that are currently used in research include single-photon emission computerized tomography (SPECT), positron emission tomography (PET), distinct forms of magnetic resonance imaging (MRI) including structural and functional MRI, MR spectroscopy (MRS), and diffusion tensor imaging (DTI).

Assessing Impulsivity and Attention Deficits in Rodents

The diagnosis of ADHD is based on behavioral criteria. Many behavioral tests commonly used in human neuro-psychology have been modeled in animals. Though relatively simple tasks have been extensively used to measure locomotor activity (e.g., open field test), anxiety (e.g., elevated plus-maze), and learning and memory (e.g., radial-arm maze) in animal models of ADHD, more sophisticated tasks have been developed to specifically measure impulsivity and sustained attention. Tasks assessing impulsivity can be broadly divided into those measuring impulsive decision-making and those measuring behavioral inhibition (Winstanley et al. 2006). Both subtypes of impulsivity are highly relevant to ADHD research, given the fact that affected individuals react differently to reinforcers when compared with normal subjects and that one of the core deficits in ADHD is response inhibition. The most widely used tests of behavioral inhibition are the go no-go task and the stop-signal reaction time task...

Trace Amine Associated Receptors

A single functional TAAR9 gene has been identified in mouse, rat, cow and human genomes 6,7,9 , although one study failed to identify a human TAAR9 gene 12 . The opossum genome contains 7 TAAR9 genes (TAAR9, TAAR9a-f) 9 . The chimpanzee TAAR9 gene however, is a pseudogene 6 . Thus, the human genome contains 3 sub-class II TAAR genes (TAAR2, 8 and 9) that are not functional in the chimpanzee. On this basis it has been suggested that these may represent loci for diseases that uniquely affect humans 7 , possibly including cardiovascular disease and the major psychoses 69 . A single nucleotide mutation of TAAR9 resulting in premature termination and a presumed non-functional receptor has been identified in humans 70 , though it is not associated with a disease phenotype, and the prevalence of the mutation was found to be the same among control, attention deficit disorder and bipolar populations.

NS2359GSK372475 SEP225289 Amri Cns1 2 and Acenta Series

NeuroSearch has developed potent, tropane-based uptake inhibitors 42-44 . Some of the analogs are shown in Fig. 5 and their inhibition data are shown in Table 8. NS-2359 (GSK-372475) is another triple-uptake inhibitor that went into clinical development. This compound was discovered at NeuroSearch and was subsequently licensed to GlaxoSmithKline (GSK) as part of a 5-year R&D alliance in CNS diseases. Although the structure of NS-2359 (GSK-372475) is not yet published, it is believed that NS-2359 is a tropane analog (Fig. 5). Phase I trial results of NS-2359 are reported in NeuroSearch's press release. In an imaging study involving six healthy volunteers receiving daily doses of NS-2359 (0.25-1.0 mg), SPECT showed very clear and specific binding in relevant areas of the brain and clear dose-dependency 45 . In a singledose phase I trial in the UK, this compound is well tolerated 46 . In a clinical trial in 54 volunteers, NS-2359 increased attention and improved the ability to recall...

Indirect Sympathomimetics

These clinical properties have been utilized as psychostimulants (an alerting effect), antidepressants (especially before the development of the real antidepressants discussed in Chapter 2), and appetite suppressants (anorexiants or anorectics), the last mentioned ideally part of weight loss regimens for short periods of two months or so. The compounds in which all these properties are most pronounced are amphetamine (No. 5) and methamphetamine (No. 6). Unfortunately, these are the two most abused and habituating compounds in this category. As the doses tend to increase, stereotypical behavior arises in patients as well as increased locomotor activity. Release of DA from central dopaminergic neurons may also be implicated. At even higher doses psychotic behavior and loss of perception becomes manifest. Because of these bizarre consequences and dependence potential, strong controls have been placed on the use of these and several related drugs.11 Their complete ban, at least as...

Noradrenaline Reuptake Inhibitors

Selective inhibition of noradrenaline reuptake has been shown to be an attractive approach for the treatment of a number of diseases. For example, reboxetine 14 (Sect. 4.1.1) is used clinically for the treatment of depression and atomoxetine 13 (Sect. 4.2.1) is a new therapy for the treatment of ADHD (Fig. 30). Furthermore, NRIs are under investigation as potential therapies for chronic pain, urinary incontinence, fibromyalgia and a variety of other indications 64,65 . A number of reviews have been published that summarize discoveries of NRIs 66-69 .

Computerized Assessment

Sample Conners Cpt

The principal computerized test found useful for determining nicotine effects on cognitive function in adults with ADHD is the Conners continuous performance test (CPT).5,6 To characterize possible effects on other aspects of neurobehavioral function, components of the Automated Neuropsychological Assessment Metrics (ANAM) battery have also been used simple reaction time, spatial mental rotation, and delayed matching to sample.3435 The Conners CPT has been validated as an assessment tool for diagnosing ADHD and is sensitive to stimulant therapy 5,6 it has previously been shown to be sensitive to the effects of acute nicotine treatment in adults with ADHD.726 This is a 14-minute test in which the subject is instructed to respond as quickly as possible to a target stimulus, but to refrain from responding to a more rarely occurring nontarget stimulus. This differentiates the Conners CPT from other CPTs in which the subject must respond to rarely occurring stimuli and makes it sensitive...

Physiology and disease relevance

The dopaminergic system has been the focus of much research over the past 40 years because several pathological conditions such as Parkinson's disease, schizophrenia, bipolar disorder, manic depression, Tourette's syndrome, and hyperprolactinaemia are believed to be associated with either dopaminergic system dysfunction or side effect profiles of drugs used to treat these disorders. Extensive work has also been performed to analyse the genetic relationship between dopamine receptors and the diseases mentioned above (reviewed in Missale et al. 1998). However, the results that have been produced are equivocal. Thus no linkage of D2 and D4 receptors to bipolar disorder has been found (Missale et al. 1998) and the association between the dopamine D2 receptor gene and susceptibility to alcoholism is controversial (Missale et al. 1998). More recently, some evidence has been reported for the genetic association of dopamine D4 receptor polymorphisms with behavioural disorders such as...

HT and the Signal Attenuation Task

Modulation in the mPFC and the NAc can increase attentional selectivity and decrease impulsivity via 5-HT1A and 5-HT2A receptors. These findings bear clinical relevance, given that some atypical antipsychotics have 5-HT2A receptor antagonist actions that may potentially contribute to a procognitive effect in schizophrenia (Meltzer et al. 2003). The opposing effects of 5-HT2A and 5-HT2C receptor antagonism on premature responding in the 5CSRTT (Winstanley et al. 2004) indicate that selective 5-HT2A receptor antagonists and or 5-HT2C receptor agonists may have beneficial effects in psychiatric disorders where coexisting impulsivity is often present, including attention deficit hyperactivity disorder, schizophrenia, and substance abuse.

Transporters as Targets for Drug Discovery

Whitlock et al. describe progress in the discovery of SSRIs, noradrenaline reuptake inhibitors (NRIs), and SNRIs from 2000 to the present day. Whilst Chen et al. focus on recent developments in the search for triple SERT, NET and DAT reuptake inhibitors. The interest in these areas stems not only from the potential for improved antidepressant efficacy and side effect profiles, as has been proposed for the triple reuptake inhibitors 38 , but the recognition that by tweaking the transporter profile potential therapies for other diseases associated with neurotransmitter imbalance can be developed. For example, although duloxetine 6 (Fig. 1), a dual SNRI, was initially launched in 2004 for the treatment of major depressive disorder (MDD) 39 , since 2004 additional approvals have been granted for pain associated with diabetic neuropathy 40 and fibromyalgia 41 , for stress urinary incontinence 42 and generalised anxiety disorder 43 . NRIs have been licensed for the treatment of attention...

Pharmacotherapy Of Anxiety

OTHER THERAPEUTIC USES OF THESE DRUGS The various antidepressant agents have found broad utility in other disorders that may not be related psychobiologically to the mood disorders. Current applications include rapid but temporary suppression of enuresis with low (e.g., 25 mg) pre-bedtime doses of tricyclic antidepressants, including imipramine and nor-triptyline, by uncertain mechanisms in children and in geriatric patients, as well as a beneficial effect of duloxetine on urinary stress incontinence. Antidepressants have a growing role in attention-deficit hyperactivity disorder in children and adults, for which imipramine, desipramine, and nortriptyline appear to be effective, even in patients responding poorly to or who are intolerant of the stimulants (e.g., methylphenidate). Newer NE selective reuptake inhibitors also may be useful in this disorder atomoxetine is approved for this application. Utility of SSRIs in this syndrome is not established, and bupropion, despite its...

Dopamine

Attention-deficit-hyperactivity disorder (ADHD), makes its appearance in childhood, and is characterized by increased motor activity and impulsive behavior and difficulty in maintaining attention and focus. Recent evidence suggests that ADHD may result from reduced levels of dopamine in the hippocampus and amygdala. Amphetamines and methylphenidate increase the postsynaptic levels of dopamine and have long been used to effectively treat ADHD 15 . Dopamine inhibits prolactin release, and D2-antagonist antipsychotic drugs stimulate lactation, a side effect seen even in male patients. There are many physical and chemical causes of nausea and vomiting. Drugs that enhance dopaminergic activity, such as those used to treat Parkinson's disease, cause emetic effects, while dopamine antagonists, including some antipsychotics and metoclopramide, have antiemetic properties.

Cognitive Effects

Consequentially, and in light of the above findings, it is important to question whether atomoxetine can enhance cognition and ameliorate cognitive deficits in the context of neuropsychiatric disorders. Most translational studies to date have focused on measuring the effects of short-term atomoxetine treatment on laboratory-based measures of impulsivity, assessed in terms of inappropriate and or premature motor responses on cognitive tasks. This focus on impulsivity stems from the utility of atomoxetine in the treatment of ADHD (discussed in the following section). On the five-choice serial reaction time task (5-CSRT), atomoxetine reduced premature impulsive responses in rats across three studies (Robinson et al. 2008). In humans, atomoxetine was found to improve impulse control on the stop signal reaction time task (SSRT) in healthy volunteers, and in adult patients with ADHD (Chamberlain et al. 2006,2007). By combining the SSRT with functional magnetic resonance imaging (fMRI), it...

Summary

The SNRI atomoxetine is playing a growing role in the treatment of ADHD. Translational studies indicate that this agent modulates prefrontal noradrenaline (and dopamine), and is capable of improving response inhibition, a cognitive function dependent on the right inferior frontal gyrus and under likely noradrenergic control. Further clinical trials are required to explore the efficacy and safety of atomoxetine into the longer term in the treatment of ADHD, in children and in adults, and to evaluate the efficacy of this agent in the treatment of other disorders. For example, registered ongoing trials are exploring the utility of atomoxetine in the treatment of alcohol substance abuse, Parkinson's disease, and Binge Eating disorder (www.clinicaltrials.gov). In addition to further clinical trials, it will also be important to explore the role of different components of the brain noradrenaline system in cognition (i.e., sub-receptors) in translational research and to evaluate the effects...

Treatment Stimulants

The first-line pharmacological treatment for all types of ADHD consists of the psychostimulants methylpheni-date (MPH) or amphetamines (Table 1). The overall short-term efficacy and tolerability of these compounds have been conclusively demonstrated in both children and adults (Findling 2008 Stein 2008). About 70-80 of the patients showed improved attention when treated with a stimulant (Rappley 2005). Owing to its lower cost, the generic amphetamine, dextroamphetamine, is most frequently used in developing countries. However, between 30 and 50 of patients discontinue pharmacotherapy due to adverse effects or inadequate response. In most such cases, the next step should include changing to the other type of stimulant. Also widely approved for the treatment of ADHD is the nonstimulant, noradrenergic reuptake inhibitor atomoxetine (ATX). Guanfacine is an alpha2A adrenoceptor agonist indicated for the treatment of essential hypertension that also appears to be efficacious as monotherapy,...

Nonstimulants

Nonstimulant medications that modulate noradrenergic neurotransmission have also been found to be efficacious for ADHD. The first class of such medications are the tricyclic antidepressants, which have comparable efficacy with MPH. However, purely noradrenergic compounds such as desipramine may be more cardiotoxic than mixed noradrenergic serotonergic drugs, although all tricyclics also produce prominent anticholinergic side effects (Biederman and Faraone 2005). The use of tricyclics, in general, and desipramine, in particular, has diminished sharply following reports of deaths of four children who were treated with recommended doses of desipramine. the strongest at the highest doses tested (1.2-1.8 mg kg per day Table 1). Trials sponsored by the manufacturer found no significant differences in efficacy between ATX and IR-MPH, but other trials, also commercially sponsored, have found XR-MAS and OROS-MPH to be somewhat more efficacious than ATX. In clinical practice, ATX is rarely...

Comorbidities

The NIMH Multimodal Treatment Study of ADHD found that children with ADHD and disruptive behavior disorders benefit from stimulant treatment, showing a significant decrease in aggressive behaviors (Kunwar et al. 2007). Nevertheless, behavioral intervention is recommended to promote social integration and academic performance. Though stimulants may be an effective treatment for aggressive or antisocial behavior in ADHD, mood stabilizers or atypical antipsychotics have become widely used with the intent of treating manic symptoms or aggression. Concerns are being raised regarding the serious potential for metabolic derangements with such treatments, especially with certain atypical antipsychotics. Stimulants exacerbate psychotic symptoms in a sizeable proportion of such patients. While stimulants may be modestly helpful for children with learning disabilities without prominent hyperactivity impulsivity, they are never sufficient. Such children require additional educational support....

Conclusions

Methylphenidate and amphetamines, preferably in extended release formulations, are the recommended first choice in children, adolescents, and adults with ADHD, including those with comorbid disruptive behavior. In cases of history of substance abuse, the use of nonstimulants or LDX maybe preferred. Medications for ADHD are chronically administered over years, and require sometimes subtle adjustments in dosing, timing, and adjuncts. Establishing and maintaining a therapeutic alliance with adolescents remains one of the greatest challenges of providing psychopharmacological care for ADHD.

Genetic Models

One of the most investigated animal models of ADHD is the spontaneously hypertensive rat (SHR), an inbred genetic model derived from the Wistar Kyoto (WKY) rat. Hyperactivity and impulsivity in the SHR develop over repeated testing and are particularly evident in settings with a low rate of reinforcement (Sagvolden 2000). These traits are present before the SHR develops hypertension and remain stable during adulthood. Compared with Sprague-Dawley (SD) rats, SHR show a neurochemical profile characterized by subcortical hyperdopaminergic tone and reduced noradrenaline (NE) function in the Attention Deficit Hyperactivity Disorders Animal Models. Table 1. Summary of selected models of ADHD, their behavioral characteristics, and tasks used to assess them.

Therapeutic Uses

The capacity of clonidine to activate postsynaptic a2 receptors in vascular smooth muscle has been exploited in a limited number of patients whose autonomic failure is so severe that reflex sympathetic responses on standing are absent postural hypotension is thus marked. Since the central effect of clonidine on blood pressure is unimportant in these patients, the drug can elevate blood pressure and improve the symptoms of postural hypotension. Among the other off-label uses of clonidine are atrial fibrillation, attention-deficit hyperactivity disorder (ADHD), constitutional growth delay in children, cyclosporine-associated nephrotoxicity, Tourette's syndrome, hyper-hidrosis, mania, posthepatic neuralgia, psychosis, restless leg syndrome, ulcerative colitis, and allergy-induced inflammatory reactions in patients with extrinsic asthma.

Methylphenidate

Methylphenidate (ritalin, others), structurally related to amphetamine, is a mild CNS stimulant with more prominent effects on mental than on motor activities. However, large doses produce signs of generalized CNS stimulation and convulsions. Its pharmacological properties are essentially the same as those of the amphetamines, including the potential for abuse. Methylphenidate is a schedule Il-controlled substance in the U.S. Methylphenidate is effective in the treatment of narcolepsy and attention-deficit hyperactivity disorder (see below). Racemic methylphenidate is readily absorbed after oral administration and reaches peak concentrations in plasma in 2 hours. The more potent (+) enantiomer has a t122 of 6 hours. Concentrations in the brain exceed those in plasma. The main urinary metabolite is a deesterified product, ritalinic acid, which accounts for 80 of the dose. Methylphenidate is contraindicated in patients with glaucoma. Dexmethylphenidate (focalin) is the d-threo...

Pharmacology

Gained attention as possible therapeutic drugs CX 516, a relative of aniracetam, is undergoing clinical trials to counteract cognitive problems in schizophrenia and attention-deficit hyperactivity disorder (ADHD), and LY503430 has shown potential to slow the progress of Parkinson disease (253,255) and improve cognitive function in Alzheimer disease (256). Both of these benefits are proposed to be via an increase in brain-derived neurotrophic factor (BDNF) production, an effect that has lead to speculation that AMPA modulators may also show antidepressant action (257).

Atomoxetine

Atomoxetine 13 (Fig. 2, Table 18) ATX (R) enantiomer of tomoxetine Strat-tera is an orally active, selective NRI developed and launched by Eli Lilly as a new treatment of child, adolescent and adult ADHD. Atomoxetine hy-drochloride was first launched in the USA in 2003 and is the first non-stimulant marketed for the treatment of ADHD. The pre-clinical, clinical and pharmacokinetic profile of ATX has been extensively reviewed 86-91 .

Clinical Assessment

The positive diagnosis of ADHD was made by an experienced clinical psychologist using standard criteria for ADHD in adults as described in the DSM-IV manual.10 Other useful measures for characterizing the presence of adult ADHD are the Wender Utah rating scale,46 the Conners Wells adolescent and adult self-report (CASS),8 and the Barkley's adult ADHD semi-structured interview.2 The benchmark clinical outcome measure of ADHD symptoms is the clinical global impression (CGI) scale, which is scored through a structured interview by a trained clinician. In research studies it is essential that the interviewing clinician be blind to treatment condition. The CGI is a standard seven-point scale widely used in clinical studies in which higher scores indicate more severe clinical states.28 On the CGI scale are 1 normal, 2 borderline, 3 mildly ill, 4 moderately ill, 5 markedly ill, 6 severely ill, and 7 extremely ill. It was found that the CGI was significantly reduced by acute nicotine...

Clinical Disorders

A third classification of disorders related to nicotinic function is those where there is no known loss or genetic alteration of nicotinic receptors, but there is evidence that stimulating nicotinic receptors may have therapeutic value. These disorders include ADHD, anxiety and depression, and Tourette's syndrome. Attention deficit hyperactivity disorder (ADHD) is a clinical syndrome usually diagnosed in childhood. While to date no firm evidence of nicotinic system dysfunction in this disorder exists, current pharmacological treatments are psychostimulants, which are presumably effective via their interactions with dopamine. The primary deficits of this disorder involving attention are affected by nicotine administration in other clinical populations.25 Pilot studies administering nicotine to patients with ADHD have shown improvements in clinical global impressions (CGI) of symptoms, and on attentional tasks.26

Gender

Administration,46 while studies using impaired subjects (either from sleep deprivation, tobacco withdrawal, or diagnosis of AD, ADHD, Schizophrenia, etc.) show larger improvements following nicotine administration.16,18 26 47 48 The effects of baseline performance on the magnitude and direction of the effects of nicotine administration can be seen on a number of dependant variables including mood, behavioral ratings, and tests of cognition, and have been shown in subjects using a wide variety of methodologies.45 One investigator demonstrated that subjects who had lower initial arousal levels experienced a greater stimulant effect of nicotine than subjects whose baseline arousal was already high.49 Although it is possible that this may represent ceiling or floor effects, due to the finding that many effects involving responding exist well within the upper and lower limits of the dependent measure,50 this explanation does not explain away the findings relevant to baseline dependency....

Measures

Tasks that measure sustained or continuous attention performance appear to show the most robust nicotinic effects. Tasks such as the rapid visual information processing task or the Connor's continuous performance test have shown sensitivity to nicotinic stimulation in normal volunteers,60,61 patients with ADHD, and patients with Alzheimer's disease.6263 Measures of selective attention have produced more mixed results. For example, the Stroop task is a measure of conflict between verbal and color processing. While some studies have demonstrated a reduction in the Stroop effect with cigarettes or nicotinic stimulation64 others have shown inconsistent results60 or results suggesting that nicotine enhances the Stroop effect.23 Measures which examine attentional performance over very long periods of time have shown positive effects of nicotine,65 especially in preventing performance decrements. Nic-otinic stimulation has been shone to improve attentional performance in primates,...

Psychostimulants

Agents which are used in patients with attention deficit disorder, parkinsonism, narcolepsy, workshift sedation, and treatment-resistant depression to augment antidepressants, to counter iatrogenic sedation from opioids and other adjunctive medications, and to treat fatigue or sedation in terminal illness. The majority of psychostimulants are amphetamine based and can cause dopamine release in increasing doses, which can result in behavioral changes. Care must be taken with these drugs since significant abuse potential can occur. Amphetamine Dextroamphetamine (Adderall ) Extended release action 1040 mg day, used for adult attention deficit disorder if patient had favorable response to Ritalin R .

Opioids

Impulsivity is a characteristic of normal everyday behavior, but excessive impulsiv-ity may take on a pathological nature that is exhibited in a diversity of psychiatric disorders including aggression, attention deficit hyperactivity disorder (ADHD), drug abuse, and eating disorders (Hollander and Rosen 2000 Moeller et al. 2001). Impulsivity is not a unitary construct and encompasses a variety of different types of behavior, which may well be independent of each other (Evenden 1999). Two forms of impulsivity have been especially well studied in animal models. Impulsive action, which refers to the tendency to make premature responses in anticipation of an expected event, reflects a loss of inhibitory control over behavior. Impulsive choice is a description of the situation in which individuals prefer a small reward that is available immediately to a larger reward that is available after a delay. Operationally, this is studied in animals tests by allowing subjects to choose between one...

Abstract

Dopaminergic pathways and two families of dopamine receptors (D1-like and D2-like) in the brain that influence motor function, behavior, reward and drug dependence, attention-deficit-hyperactivity disorder, and prolactin release. A depletion of dopamine exists in the substantia nigra and striatum in Parkinson disease. One leading model of schizophrenia suggests that schizophrenia is associated with an increase in the functional activity of dopamine in the limbic system. Typical antipsychotic agents are potent D2-antagonists, while atypical antipsychotics have dopamine and serotonin receptor blocking actions.