piperidines and Attention-Deficit-Disorder-with-Hyperactivity

This review discusses the laboratory and clinical research supporting the rationale for the efficacy of donepezil (Aricept USA) in enhancing cognition in autism, Alzheimer disease, Down syndrome, traumatic brain injury, Attention Deficit Hyperactivity Disorder (ADHD), and schizophrenia. While preliminary animal models have shown effective, human studies exclusive of Alzheimer disease are sparse. Although attention and memory are unlikely a sole operation of the cholinergic system, evidence indicates a promising direction for further examination of this hypothesis in autism. Studies that examine changes in operationally defined behaviors and reliable and valid measure of changes in attention and memory are needed.

Topics: Alzheimer Disease; Animals; Attention; Attention Deficit Disorder with Hyperactivity; Autistic Disorder; Brain Injuries; Donepezil; Down Syndrome; Humans; Indans; Learning Disabilities; Memory Disorders; Mental Recall; Nootropic Agents; Piperidines; Schizophrenia; Treatment Outcome

Several alternatives to psychostimulants have been developed and expanded the variability of the treatment of ADHD. Clonidine is a good option for managing core behavioral symptoms, especially hyperactivity and impulsivity. Bupropion and venlafaxine seem potentially promising. Significant new options include norepinephrine reuptake inhibitors, such as atomoxetine, and possibly selective dopamine agonists. Central anticholinesterases, such as donepezil, may improve core ADHD symptoms.

Topics: Adrenergic alpha-Agonists; Antidepressive Agents, Tricyclic; Attention Deficit Disorder with Hyperactivity; Bupropion; Clonidine; Donepezil; Humans; Indans; Piperidines; Treatment Outcome

There has been substantial development of pharmacological treatments for attention-deficit hyperactivity disorder (ADHD) recently. The greatest change is the approval of new delivery systems for methylphenidate (MPH) and amphetamine (AMP) that permit once a day dosing. There are also a number of new compounds under development for the disorder, including several non-stimulant agents. These compounds target the noradrenergic, histaminergic and dopaminergic systems. The recent developments in the pharmacological treatment of ADHD should increase therapeutic options and the percentage of individuals with the disorder who can be effectively treated.

Topics: Animals; Antidepressive Agents; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Benzhydryl Compounds; Central Nervous System Stimulants; Clinical Trials as Topic; Cyclobutanes; Donepezil; Histamine Agonists; Humans; Indans; Modafinil; Nootropic Agents; Piperidines; Propylamines

Attention deficit/hyperactivity disorder (ADHD) is often a lifelong condition. When untreated or undertreated, it appears to have a deleterious impact upon the daily functioning of the majority of adults that were diagnosed with this condition during childhood. Effective treatment, under the best circumstances, is multi-modal. The recent MTA study staged by the United States government confirmed the primary role of psychostimulants for children with this condition. The findings from this study have been generalised to adults that also have ADHD, particularly in cases where there is a well-defined longitudinal history dating back to early childhood. Psychostimulants remain a viable first-choice strategy for adults with ADHD. There are idiosyncratic differences in response to the various psychostimulants for any given individual with ADHD. Furthermore, the emergence of long-acting, once daily psychostimulant medications is likely to improve the calibre of care for adults with ADHD. A number of alternative pharmacotherapies have been studied, or are being developed, for adults with ADHD. These pharmacotherapies include antidepressant medications that affect dopaminergic and noradrenergic bioavailability, as well as cholinergic agents. In addition, agents that manipulate histaminergic and glutaminergic receptors are being studied as possible non-stimulant alternatives in the management of adult ADHD. More information is needed before any definitive statements can be made concerning the feasibility and utility of these non-stimulant medication approaches.

Topics: Adult; Amphetamines; Antidepressive Agents; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Donepezil; Dopamine Plasma Membrane Transport Proteins; Humans; Indans; Isoxazoles; Membrane Glycoproteins; Membrane Transport Proteins; Methylphenidate; Nerve Tissue Proteins; Piperidines; Pyrrolidines

Asverin® (tipepidine hibenzate) has been used as an antitussive for > 50 years in Japan. Studies revealed that tipepidine modulates monoamine levels, by inhibiting G-protein-activated inwardly rectifying potassium (GIRK) channels, expecting the potential therapeutic effects of tipepidine for attention-deficit/hyperactivity disorder (ADHD) in recent years. In this study, TS-141, a sustained-release tablet of tipepidine, was developed for the treatment of ADHD through a drug repositioning approach.. The sustained-release profile of TS-141 in healthy adults was investigated, and tipepidine exposure in the plasma after the TS-141 administration was compared to that of Asverin in the phase I study. Phase II study was conducted to examine the effects of TS-141 30 (once a day), 60 (once a day), 120 mg (60 mg twice a day), or placebo, that is within the exposure in the maximum dosage of Asverin, in children and adolescents with ADHD, and was designed as an 8-week treatment, randomized, parallel group, double-blind, placebo-controlled trial recruiting 6-17-year-old children and adolescents diagnosed with ADHD. A total of 216 patients were randomized according to the CYP2D6 phenotype. The primary end-point was ADHD Rating Scale IV-J changes. Furthermore, effects of CYP2D6 phenotype on the efficacy in the subgroup analysis were investigated.. TS-141 had the sustained-release profile, and the CYP2D6 phenotype had effects on the plasma exposure of tipepidine. ADHD RS-IV-J scores in all TS-141 dosages decreased from their baseline scores; however, no significant difference was observed in ADHD RS-IV-J score changes between the placebo and TS-141-administered groups. In patients with intermediate metabolizer CYP2D6, ADHD RS-IV-J score changes in the 120 mg group tended to be larger than that in the placebo group.. ADHD RS-IV-J changes on TS-141 may depend on the interaction between the TS-141 dose and CYP2D6 phenotype, suggesting that further clinical trials should be conducted with careful consideration of polymorphism. Drug repositioning approach of TS-141 was attempted at the same dose as that of antitussive; however, dose setting according to the indication was necessary.. Phase I study: JapicCTI-205235 (Registered 25 March 2020), Phase II study: JapicCTI-163244 (Registered 9 May 2016), https://www.clinicaltrials.jp/cti-user/trial/Show.jsp.

Topics: Adolescent; Adult; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Repositioning; Humans; Japan; Piperidines; Psychiatric Status Rating Scales; Tablets; Treatment Outcome

This study evaluated the efficacy and safety of tipepidine as an add-on to methylphenidate in the drug treatment of attention-deficit/hyperactivity disorder (ADHD).. This study was an 8-week, randomized, parallel group, double-blind, placebo-controlled trial recruiting 53 ADHD-diagnosed children. Patients were randomly divided to receive methylphenidate + tipepidine or methylphenidate + placebo for 8 weeks. Participants were assessed using the parent version of ADHD Rating Scale-IV and the Clinical Global Impression scale at baseline, at week 4, and at the end of the trial. Moreover, the safety and tolerability of the treatment strategies were compared.. On general linear model repeated measures analysis a significant effect was seen for time × treatment interaction on the total and hyperactivity-impulsivity subscales of the Parent ADHD Rating Scale-IV during the trial period (Greenhouse-Geisser corrected: F = 3.45, d.f. = 1.52, P = 0.049, and F = 5.17, d.f. = 1.52, P = 0.014, respectively). The effect for time × treatment interaction, however, was not significant on Clinical Global Impression-Severity scale (Greenhouse-Geisser corrected: F = 1.79, d.f. = 1.43, P = 0.182). The frequencies of adverse events were similar between the two groups.. Eight weeks of treatment with tipepidine, as a supplementary medication, resulted in satisfactory efficacy and safety of the adjuvant therapy in management of patients with ADHD. Rigorous investigations, however, involving larger sample sizes, more extended treatment periods, and dose responses should be considered.

Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Methylphenidate; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome

Striatal cholinergic dysfunction may be important in tics and attention-deficit/hyperactivity disorder (ADHD).. The purpose of this study was to determine the safety profile of donepezil and whether it improves chronic tics in young patients with comorbid ADHD.. This 18-week (14 weeks of open treatment followed by a 4-week washout period), single-center, dose-escalating, prospective, open-label trial was conducted in patients aged 7 to 17 years with tics, including chronic motor or vocal tics and Tourette's syndrome, and ADHD. Patients were treated with once-daily oral donepezil doses of 2.5 mg for 2 weeks, 5 mg for the next 6 weeks, and 10 mg for the last 6 weeks, followed by a 4-week washout period. Patients were evaluated using the Children's Global Assessment Scale; the Yale Global Tic Severity Scale (YGTSS); the Revised Conners' Parent Rating Scale; the Symbol and Digit Wisconsin Card Sorting Test; the Stroop black/white, color, and interference tests; the Rey Complex Figure Test; and the Children's Yale-Brown Obsessive Compulsive Scale at 4 visits: baseline, week 8 (5-mg dose), week 14 (10-mg dose), and week 18 (washout).. Seventeen males and 3 females (mean [SD] age, 11.3 [1.9] years [range, 8-14 years]; tic duration, 5.3 [1.9] years; ADHD duration, 6.5 [1.7] years) were included in this study. Tics were significantly reduced at the 10-mg (week-14) donepezil visit compared with the baseline and washout visits based on the total mean (SD) tic score of the YGTSS (18.6 [9.3] vs 12.2 [11.0]; P = 0.006). Fifty percent of patients withdrew and 65% experienced adverse events.. These preliminary results suggest that donepezil significantly reduced tics in these children and adolescents with comorbid ADHD who completed the study. No significant improvement in the symptoms of comorbid ADHD was found with the use of donepezil 10 mg. Donepezil 5 and 10 mg were not well tolerated in these children and adolescents.

Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Child; Cholinesterase Inhibitors; Comorbidity; Donepezil; Dose-Response Relationship, Drug; Female; Humans; Indans; Male; Pilot Projects; Piperidines; Prospective Studies; Severity of Illness Index; Tic Disorders

Recent studies reported ADHD-like symptoms and cognitive deficits in pervasive developmental disorder (PDD). Because work in dementia documents improvement in executive function deficits with the acetylcholinesterase inhibitor donepezil, the authors reason that similar benefits could be obtained in PDD.. The authors describe eight cases of PDD youth ages 10 to 17 treated with donepezil targeting ADHD-like symptoms associated with PDD.. Most participants improve ADHD-like symptomatology. In addition, improvement in communication and socialization is noted.. Donepezil may have a role in treating ADHD-like symptoms in children with PDD.

Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Child; Child Development Disorders, Pervasive; Cholinesterase Inhibitors; Communication; Donepezil; Drug Administration Schedule; Female; Humans; Indans; Male; Piperidines; Social Behavior

Ampreloxetine is a novel norepinephrine reuptake inhibitor in development for the treatment of symptomatic neurogenic orthostatic hypotension. The objectives of this analysis were to define the pharmacokinetics of once-daily oral ampreloxetine and provide dose recommendations for clinical development.. We fitted a population pharmacokinetic model to ampreloxetine plasma concentrations from single- and multiple-ascending dose trials in healthy subjects and two phase II studies in adult subjects with attention-deficit/hyperactive disorder or fibromyalgia at doses of 2-50 mg.. Ampreloxetine pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. The terminal half-life was 30-40 h, resulting in sustained drug concentrations for the entire 24-h dosing interval at steady state. Covariates of age, weight, or renal impairment did not impact ampreloxetine exposure. Cytochrome P450 2D6 phenotype had no influence on ampreloxetine exposure. Sex and smoking status were identified as statistically significant covariates, suggesting a role for cytochrome P450 1A2 in the elimination of ampreloxetine. Despite statistical significance, differences in ampreloxetine exposure in male vs female subjects and smokers vs non-smokers were not clinically meaningful at the recommended dose. At the 10-mg dose, > 75% norepinephrine transporter inhibition and < 50% serotonin transporter inhibition are anticipated for adult subjects.. The population pharmacokinetic model effectively described the plasma concentration-time profile of ampreloxetine after single and multiple doses. Population pharmacokinetic/pharmacodynamic analysis justified using a fixed dosing regimen with no dose adjustments across a broad population and can be used to inform dosing strategies in future clinical studies.. ClinicalTrials.gov identifier numbers NCT01693692 (fibromyalgia); NCT01458340 (attention-deficit/hyperactive disorder).

Topics: Adult; Attention Deficit Disorder with Hyperactivity; Case-Control Studies; Female; Fibromyalgia; Humans; Male; Norepinephrine; Pain; Phenyl Ethers; Piperidines

Topics: Adrenergic alpha-2 Receptor Agonists; Attention Deficit Disorder with Hyperactivity; Child; Comorbidity; Delayed-Action Preparations; Drug Therapy, Combination; Guanfacine; Humans; Male; Piperazines; Piperidines; Tourette Syndrome

Attention deficit and hyperactivity disorder (ADHD) is characterized by impaired levels of hyperactivity, impulsivity, and inattention. Adenosine and endocannabinoid systems tightly interact in the modulation of dopamine signaling, involved in the neurobiology of ADHD. In this study, we evaluated the modulating effects of the cannabinoid and adenosine systems in a tolerance to delay of reward task using the most widely used animal model of ADHD. Spontaneous Hypertensive Rats (SHR) and Wistar-Kyoto rats were treated chronically or acutely with caffeine, a non-selective adenosine receptor antagonist, or acutely with a cannabinoid agonist (WIN55212-2, WIN) or antagonist (AM251). Subsequently, animals were tested in the tolerance to delay of reward task, in which they had to choose between a small, but immediate, or a large, but delayed, reward. Treatment with WIN decreased, whereas treatment with AM251 increased the choices of the large reward, selectively in SHR rats, indicating a CB

Topics: Animals; Attention Deficit Disorder with Hyperactivity; Benzoxazines; Caffeine; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Impulsive Behavior; Male; Morpholines; Naphthalenes; Piperidines; Psychotropic Drugs; Purinergic P1 Receptor Antagonists; Pyrazoles; Random Allocation; Rats, Inbred SHR; Rats, Inbred WKY

Cholinergic neurons of the pedunculopontine tegmental nucleus (PPTg) are thought to be involved in cognitive functions such as sustained attention, and lesions of these cells have been documented in patients showing fluctuations of attention such as in Parkinson's disease or dementia with Lewy Body. Animal studies have been conducted to support the role of these cells in attention, but the lesions induced in these animals were not specific to the cholinergic PPTg system, and were assessed by post-mortem methods remotely performed from the in vivo behavioral assessments. Moreover, sustained attention have not been directly assessed in these studies, but rather deduced from indirect measurements. In the present study, rats were assessed on the 5-Choice Serial Reaction Time Task (5-CSRTT), and a specific measure of variability in response latency was created. Animals were observed both before and after selective lesion of the PPTg cholinergic neurons. Brain cholinergic denervation was assessed both in vivo and ex vivo, using PET imaging with [(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV) and immunocytochemistry respectively. Results showed that the number of correct responses and variability in response latency in the 5-CSRTT were the only behavioral measures affected following the lesions. These measures were found to correlate significantly with the number of PPTg cholinergic cells, as measured with both [(18)F]FEOBV and immunocytochemistry. This suggests the primary role of the PPTg cholinergic cells in sustained attention. It also allows to reliably use the PET imaging with [(18)F]FEOBV for the purpose of assessing the relationship between behavior and cholinergic innervation in living animals.

Topics: Analysis of Variance; Animals; Attention Deficit Disorder with Hyperactivity; Autopsy; Choline O-Acetyltransferase; Cholinergic Neurons; Disease Models, Animal; Fluorodeoxyglucose F18; Male; Neurotoxins; Pedunculopontine Tegmental Nucleus; Phosphopyruvate Hydratase; Piperidines; Positron-Emission Tomography; Rats; Rats, Long-Evans; Reaction Time; Statistics as Topic; Time Factors

Topics: Administration, Oral; Attention Deficit Disorder with Hyperactivity; Child; Follow-Up Studies; Humans; Piperidines; Treatment Outcome

Topics: Antifungal Agents; Attention Deficit Disorder with Hyperactivity; Boron Compounds; Botulinum Toxins, Type A; Bridged Bicyclo Compounds, Heterocyclic; Brimonidine Tartrate; Depression; Dermatitis, Atopic; Food Hypersensitivity; Humans; Immunologic Factors; Ivermectin; Phosphodiesterase Inhibitors; Phototherapy; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinoxalines; Skin Diseases; Societies, Medical; Thalidomide; Triazoles; United States

Nicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of nicotinic agonists improve attention, and nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel nicotinic receptor agonist at α4β2 nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist dizocilpine (MK-801).. Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats were then injected subcutaneously following a repeated measures, counter-balanced design with saline, AZD3480 (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations 30 min before the test. The effect of donepezil on the same pharmacologically induced attentional impairment was also tested. A separate group of rats was injected with donepezil (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations, and their attention were assessed. Saline was the vehicle control.. Dizocilpine caused a significant (p < 0.0005) impairment in percent correct performance. This attentional impairment was significantly (p < 0.0005) reversed by 0.01 and 0.1 mg/kg of AZD3480. AZD3480 by itself did not alter the already high baseline control performance. Donepezil (0.01-1.0 mg/kg) also significantly (p < 0.005) attenuated the dizocilpine-induced attentional impairment.. AZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist dizocilpine. Low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment due to glutamatergic dysregulation and likely other attentional disorders.

Topics: Animals; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Disease Models, Animal; Dizocilpine Maleate; Donepezil; Dose-Response Relationship, Drug; Female; Indans; Molecular Structure; Neurons; Nicotinic Agonists; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Signal Detection, Psychological

Low doses of psychostimulants produce beneficial behavioral effects in ADHD patients but the mechanisms underlying the response are not understood. Here we use the hyperactive mouse mutant coloboma to identify D2-like dopamine receptor subtypes that mediate the hyperactivity and response to amphetamine; we have previously demonstrated that D1-like dopamine receptors are not involved. Targeted deletion of the D2, but not the D3 or the D4, dopamine receptor in coloboma mice eliminated the hyperactivity; depleting D2 dopamine receptors also restored the excess dopamine overflow that may drive the hyperactivity to normal concentrations. Similar to its effects on ADHD patients, amphetamine reduced the hyperactivity of coloboma mice. The D2 dopamine receptor-selective antagonist L-741,626, but not D3 or D4 dopamine receptor-selective antagonists, blocked the amphetamine-induced reduction in locomotor activity. Thus, the D2 dopamine receptor subtype mediates both the hyperactivity and response to amphetamine, suggesting a specific target for novel therapeutics in ADHD.

Topics: Amphetamine; Animals; Attention Deficit Disorder with Hyperactivity; Benzopyrans; Corpus Striatum; Dihydroxyphenylalanine; Disease Models, Animal; Dopamine; Dopamine Agents; Dopamine D2 Receptor Antagonists; Extracellular Space; Indoles; Locomotion; Mice; Mice, Knockout; Mice, Mutant Strains; Piperidines; Pyridines; Pyrroles; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Dopamine D4

Cannabis preparations are the most widely consumed illicit drugs, and their use typically begins in adolescence. The prevalence of cannabis abuse is higher in patients with attention deficit/hyperactivity disorder (ADHD) than in the general population, yet, knowledge about the motivational properties of cannabinoids in animal models of ADHD are lacking.. To compare the motivational effects of the synthetic cannabinoid agonist WIN55,212-2 (WIN) in adolescent and adult spontaneously hypertensive rats (SHR), a validated animal model of ADHD, and Wistar rats, representing a "normal" genetically heterogeneous population. We also asked whether the effects of WIN depended (1) on the activation of the cerebral subtype of cannabinoid receptors, namely, the CB(1) cannabinoid receptor and (2) on putative changes by WIN in blood pressure.. WIN was tested under an unbiased conditioned place preference (CPP) paradigm. Blood pressure after WIN administration was also monitored in additional groups of rats.. In the Wistar rats, WIN produced place aversion only in the adult but not adolescent rats. In contrast, WIN produced CPP in both adolescent and adult SHR rats. The behavioral effects of WIN were CB(1)-mediated and not related to blood pressure.. The contrasting effects of WIN in Wistar and SHR, and the higher resistance of adolescent rats to the aversive and rewarding effects of WIN in these two strains suggests that both adolescence and the ADHD-like profile exhibited by the SHR strain constitute factors that influence the motivational properties of cannabinoids.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Benzoxazines; Blood Pressure; Cannabinoids; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Morpholines; Motivation; Naphthalenes; Piperidines; Pyrazoles; Rats; Rats, Inbred SHR; Rats, Wistar; Spatial Behavior

Converging evidence points to adolescence as a critical period for the onset of a wide range of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and drug abuse. Spontaneously hypertensive rats (SHR) are generally considered to be a suitable genetic model for the study of ADHD, since they display hyperactivity, impulsivity, poorly sustained attention, cognitive deficits and increased novelty seeking. Despite the high prevalence of ADHD among adolescents, studies using SHR have mainly been performed on adult animals. The aim of the present study was to evaluate the effect of acute intraperitoneal (i.p.) administration of the cannabinoid receptor agonist WIN 55,212-2 (0.25-2.5 mg/kg) on locomotor activity and anxiety-like behavior in male adolescent and adult SHR and Wistar rats using the open field and elevated plus-maze tests. WIN 55,212-2 at doses of 0.25 and 1.25 mg/kg (i.p.) selectively promoted locomotor stimulation in adolescent SHR in the open field, but not in adult SHR or Wistar rats (regardless of age). The effect of WIN 55,212-2 (0.25 mg/kg, i.p.) on locomotion of adolescent SHR was reversed by pretreatment with the selective cannabinoid CB1 receptor antagonist AM 251 (0.25 mg/kg, i.p.). Moreover, although the present doses of WIN 55,212-2 had no effect on anxiety-related behaviors in any of the animal groups evaluated in the open field (central locomotion) or elevated plus-maze (time and entries in open arms), the highest dose of WIN 55,212-2 tested (2.5 mg/kg, i.p.) significantly decreased the number of closed-arm entries (an index of locomotor activity) of adolescent rats of both the Wistar and SHR strains in the elevated plus-maze. The present results indicate strain- and age-related effects of cannabinoids on locomotor activity in rats, extending the notion that adolescence and ADHD represent risk factors for the increased sensitivity to the effects of drugs.

Topics: Aging; Animals; Anxiety; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Benzoxazines; Brain; Cannabinoid Receptor Agonists; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Male; Morpholines; Motor Activity; Naphthalenes; Piperidines; Pyrazoles; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Cannabinoid; Species Specificity

Despite available pharmacotherapeutics, a number of youths with attentiondeficit/ hyperactivity disorder (ADHD) continue to experience residual symptoms and prominent executive function (EF) deficits resulting in impairment in multiple domains. We sought to determine if donepezil, used adjunctively to stimulant medication, would improve residual symptoms of ADHD and EF deficits.. In a 12-week open trial, we treated 7 children and 6 adults who had ADHD and evidence of further EF deficits with adjunctive donepezil. All subjects were stabilized on stimulants, at which time donepezil was initiated at 2.5 mg daily and increased to a maximum of 10 mg over the 12-week trial.. Of 13 subjects receiving medication, 7 completed the trial. There was no clinically or statistically significant improvement in the ADHD Rating Scale and the Executive Function Checklist, our primary outcome measures. A majority of individuals experienced nonserious adverse events.. Results of this small open study suggest that donepezil augmentation of stimulants is not well tolerated and does not appear useful for the treatment of residual ADHD and/or EF deficits.

Topics: Adolescent; Adult; Amphetamines; Antimanic Agents; Attention Deficit Disorder with Hyperactivity; Child; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Female; Humans; Indans; Male; Methylphenidate; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychometrics; Treatment Outcome

Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Child; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Inpatients; Male; Piperidines; Urinary Incontinence

Despite well-documented improvement in attention deficit hyperactivity disorder (ADHD) in youths with the available single and combined pharmacologic agents, a number of youths remain with residual symptomatology causing impairment in multiple domains. Recent work has suggested a potential cognitive-enhancing role of cholinergic agents in ADHD. We describe five cases of ADHD youths aged 8-17 years being treated for ADHD with the acetylcholinesterase inhibitor donepezil (Aricept), all of whom demonstrated improvement.

Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Child; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Male; Piperidines

Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Child; Comorbidity; Donepezil; Humans; Indans; Male; Nootropic Agents; Piperidines; Tourette Syndrome

Topics: Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Child; Drug Therapy, Combination; Humans; Isoxazoles; Male; Methylphenidate; Piperidines; Risperidone; Schizophrenia; Treatment Outcome

The clinically tested reversible inhibitors of monoamine oxidase A (RIMAs) include brofaromine, moclobemide and toloxatone. Moclobemide has shown unequivocal antidepressant activity against serious depressive illness in 4 placebo-controlled double-blind trials. It has been compared with amitriptyline, imipramine, clomipramine, desipramine, maprotiline, fluoxetine, fluvoxamine, tranylcypromine, toloxatone, mianserin and amineptine in the treatment of depressive disorders. Meta-analysis showed convincing evidence of moclobemide efficacy, comparable with the most potent antidepressants available. The efficacy of moclobemide has been demonstrated in psychotic and non-psychotic depression, in depression with and without melancholia, in endogenous depression (both unipolar and bipolar), in retarded depression and in agitated depression. The efficacy of moclobemide, allied to the unusually benign side effect profile, has led to exploration of its use in other disorders. Two small studies have given encouraging results in the treatment of attention-deficit hyperactivity disorder. Large placebo-controlled studies have shown the activity of moclobemide in the depression that accompanies dementia (such as senile dementia of Alzheimer type). The results also suggested that, in this patient population, cognitive ability improved in parallel. Social phobia has also been shown to improve on treatment with either moclobemide or brofaromine. Clinical trials are in progress on the effect of moclobemide in chronic fatigue syndrome. Moreover, there are encouraging results with the use of brofaromine and moclobemide in panic disorder. Other disorders in which treatment with RIMA is of interest include agoraphobia, bulimia, borderline personality disorder, post-traumatic stress disorder, compulsive hair pulling (trichotillomania), dysmorphophobia, kleptomania as well as various anxiety syndromes.

Topics: Alzheimer Disease; Antidepressive Agents, Tricyclic; Attention Deficit Disorder with Hyperactivity; Benzamides; Humans; Moclobemide; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Panic Disorder; Phobic Disorders; Piperidines