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Abstract
Objective: Anxiety is among the most common psychiatric illnesses, and it commonly co-occurs with epilepsy. This review of the existing literature on anxiety comorbid with epilepsy aims to generate new insights into strategies for assessment and treatment. Methods: The authors conducted a narrative literature review to select key publications that help clarify the phenomenology and management of comorbid anxiety and epilepsy. Results: Anxiety symptoms may be relevant even if the criteria for a diagnosis of an anxiety disorder are not met. Associating specific seizure types or seizure localization with anxiety symptoms remains difficult; however, the amygdala is a brain region commonly associated with seizure foci and panic or fear sensations. The hypothalamic-pituitary-adrenal axis may also be relevant for anxiety symptoms, particularly for the selection of treatments. Nonpharmacological treatment is appropriate for anxiety comorbid with epilepsy, particularly because relaxation techniques may reduce hypersympathetic states, which improve symptoms. Medication options include antidepressants and anticonvulsants that may have efficacy for anxiety symptoms. Benzodiazepines are a good choice to address this comorbid condition, although side effects may limit utility. Conclusions: Ultimately, there are numerous treatment options, and although there is a limited evidence base, quality of life may be improved with appropriate treatment for individuals experiencing comorbid anxiety and epilepsy.
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Affiliation(s)
- Jay A Salpekar
- Johns Hopkins University School of Medicine, Baltimore (Salpekar); Department of Psychiatry, Brigham and Women's Hospital, Boston (Ma); Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison (Mietchen, Jones); Howard University College of Medicine, Washington, D.C. (Mani)
| | - Grace J Ma
- Johns Hopkins University School of Medicine, Baltimore (Salpekar); Department of Psychiatry, Brigham and Women's Hospital, Boston (Ma); Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison (Mietchen, Jones); Howard University College of Medicine, Washington, D.C. (Mani)
| | - Jonathan Mietchen
- Johns Hopkins University School of Medicine, Baltimore (Salpekar); Department of Psychiatry, Brigham and Women's Hospital, Boston (Ma); Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison (Mietchen, Jones); Howard University College of Medicine, Washington, D.C. (Mani)
| | - Jeremy Mani
- Johns Hopkins University School of Medicine, Baltimore (Salpekar); Department of Psychiatry, Brigham and Women's Hospital, Boston (Ma); Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison (Mietchen, Jones); Howard University College of Medicine, Washington, D.C. (Mani)
| | - Jana E Jones
- Johns Hopkins University School of Medicine, Baltimore (Salpekar); Department of Psychiatry, Brigham and Women's Hospital, Boston (Ma); Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison (Mietchen, Jones); Howard University College of Medicine, Washington, D.C. (Mani)
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Nikvarz N, Sabouri S. Drug-induced stuttering: A comprehensive literature review. World J Psychiatry 2022; 12:236-263. [PMID: 35317340 PMCID: PMC8900588 DOI: 10.5498/wjp.v12.i2.236] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/29/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced stuttering (DIS) is a type of neurogenic stuttering (NS). Although DIS has not been reported as frequently as other cases of NS in the literature, it is not a negligible adverse drug reaction (ADR) which can significantly affect the quality of life if not treated. This literature review aims to evaluate the epidemiological and clinical characteristics of DIS and suggests some pathophysiological mechanisms for this ADR. Relevant English-language reports in Google Scholar, PubMed, Web of Science, and Scopus were identified and assessed without time restriction. Finally, a total of 62 reports were included. Twenty-seven drugs caused 86 episodes of stuttering in 82 cases. The most episodes of DIS were related to antipsychotic drugs (57%), mostly including clozapine, followed by central nervous system agents (11.6%) and anticonvulsant drugs (9.3%). The majority of the cases were male and between the ages of 31 and 40 years. Repetitions were the most frequent core manifestations of DIS. In 55.8% of the episodes of DIS, the offending drug was withdrawn to manage stuttering, which resulted in significant improvement or complete relief of stuttering in all cases. Based on the suggested pathophysiological mechanisms for developmental stuttering and neurotransmitters dysfunctions involved in speech dysfluency, it seems that the abnormalities of several neurotransmitters, especially dopamine and glutamate, in different circuits and areas of the brain, including cortico-basal ganglia-thalamocortical loop and white matter fiber tracts, may be engaged in the pathogenesis of DIS.
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Affiliation(s)
- Naemeh Nikvarz
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman 7616911319, Iran
| | - Salehe Sabouri
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman 7616911319, Iran
- Department of Pharmaceutical Biotechnology, Kerman University of Medical Sciences, Kerman 7616911319, Iran
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Ota T, Yamamuro K, Okazaki K, Kishimoto T. Evaluating Guanfacine Hydrochloride in the Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Adult Patients: Design, Development and Place in Therapy. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:1965-1969. [PMID: 34007156 PMCID: PMC8123957 DOI: 10.2147/dddt.s221126] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/01/2021] [Indexed: 11/23/2022]
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate and impairing levels of inattention, hyperactivity, or impulsivity, or a combination of these characteristics. It is estimated to affect around 4% of adults worldwide. In the past few decades, prescriptions for ADHD drugs (psychostimulants and non-psychostimulants) have increased significantly. However, the efficacy and safety of adult ADHD medications remains controversial. Guanfacine extended-release (GXR) is a non-psychostimulant ADHD drug that is a selective α2A-adrenergic receptor agonist, first approved for treatment of adult ADHD in Japan in June 2019. Our aim was to provide an overview of GXR pharmacology and review the studies on efficacy and safety that have been conducted in adults with ADHD. The beneficial actions of guanfacine are thought to be attributed to the strengthening of prefrontal cortical network connections, which regulate attention, emotion, and behavior via the activity at post-synaptic α2A receptors. Current evidence of GXR efficacy and safety suggests that GXR is an effective monotherapy treatment option for adults with ADHD.
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Affiliation(s)
- Toyosaku Ota
- Department of Psychiatry, Nara Medical University, Kashihara, Japan.,Faculty of Nursing, School of Medicine, Nara Medical University, Kashihara, Japan
| | | | - Kosuke Okazaki
- Department of Psychiatry, Nara Medical University, Kashihara, Japan
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Que faire devant un enfant ronfleur et hyperactif ? Arch Pediatr 2017; 24 Suppl 1:S28-S33. [DOI: 10.1016/j.arcped.2016.09.049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 09/25/2016] [Accepted: 09/26/2016] [Indexed: 11/18/2022]
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Weitemier AZ, McHugh TJ. Noradrenergic modulation of evoked dopamine release and pH shift in the mouse dorsal hippocampus and ventral striatum. Brain Res 2017; 1657:74-86. [DOI: 10.1016/j.brainres.2016.12.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 11/25/2016] [Accepted: 12/01/2016] [Indexed: 01/24/2023]
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Abstract
Children/adolescents with attention-deficit/hyperactivity disorder (ADHD) may have a poor or inadequate response to psychostimulants or be unable to tolerate their side-effects; furthermore, stimulants may be inappropriate because of co-existing conditions. Only one non-stimulant ADHD pharmacotherapy, the noradrenaline transporter inhibitor atomoxetine, is currently approved for use in Europe. We review recent advances in understanding of the pathophysiology of ADHD with a focus on the roles of catecholamine receptors in context of the α2A-adrenergic receptor agonist guanfacine extended release (GXR), a new non-stimulant treatment option in Europe. Neuroimaging studies of children/adolescents with ADHD show impaired brain maturation, and structural and functional anomalies in brain regions and networks. Neurobiological studies in ADHD and medication response patterns support involvement of monoaminergic neurotransmitters (primarily dopamine and noradrenaline). Guanfacine is a selective α2A-adrenergic receptor agonist that has been shown to improve prefrontal cortical cognitive function, including working memory. The hypothesized mode of action of guanfacine centres on direct stimulation of post-synaptic α2A-adrenergic receptors to enhance noradrenaline neurotransmission. Preclinical data suggest that guanfacine also influences dendritic spine growth and maturation. Clinical trials have demonstrated the efficacy of GXR in ADHD, and it is approved as monotherapy or adjunctive therapy to stimulants in Canada and the USA (for children and adolescents). GXR was approved recently in Europe for the treatment of ADHD in children and adolescents for whom stimulants are not suitable, not tolerated or have been shown to be ineffective. GXR may provide particular benefit for children/adolescents who have specific co-morbidities such as chronic tic disorders or oppositional defiant disorder (or oppositional symptoms) that have failed to respond to first-line treatment options.
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Broberg BV, Madsen KH, Plath N, Olsen CK, Glenthøj BY, Paulson OB, Bjelke B, Søgaard LV. A schizophrenia rat model induced by early postnatal phencyclidine treatment and characterized by Magnetic Resonance Imaging. Behav Brain Res 2013; 250:1-8. [DOI: 10.1016/j.bbr.2013.04.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Revised: 04/18/2013] [Accepted: 04/20/2013] [Indexed: 12/15/2022]
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Fox HC, Seo D, Tuit K, Hansen J, Kimmerling A, Morgan PT, Sinha R. Guanfacine effects on stress, drug craving and prefrontal activation in cocaine dependent individuals: preliminary findings. J Psychopharmacol 2012; 26:958-72. [PMID: 22234929 PMCID: PMC3694403 DOI: 10.1177/0269881111430746] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Cocaine dependence is associated with increased stress and drug cue-induced craving and physiological arousal but decreased prefrontal activity to emotional and cognitive challenge. As these changes are associated with relapse risk, we investigated the effects of α2 receptor agonist guanfacine on these processes. Twenty-nine early abstinent treatment-seeking cocaine dependent individuals were randomly assigned to either daily placebo or guanfacine (up to 3 mg) for four weeks. In a laboratory experiment, all patients were exposed to three 10-min guided imagery conditions (stress/stress, drug cue/drug cue, stress/drug cue), one per day, consecutively in a random, counterbalanced order. Subjective craving, anxiety and arousal as well as cardiovascular output were assessed repeatedly. Brain response to stress, drug cue and relaxing imagery was also assessed during a functional magnetic resonance (fMRI) imaging session. In the current study, guanfacine was found to be safe and well-tolerated. Lower basal heart rate and blood pressure was observed in the guanfacine versus placebo group. Guanfacine lowered stress and cue-induced nicotine craving and cue-induced cocaine craving, anxiety and arousal. The guanfacine group also showed increased medial and lateral prefrontal activity following stress and drug cue exposure compared with placebo. Data suggest further exploration of guanfacine is warranted in terms of its potential for reducing stress-induced and cue-induced drug craving and arousal.
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Affiliation(s)
- Helen C. Fox
- The Connecticut Mental Health Center, Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA
| | - Dongju Seo
- The Yale Stress Center, Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA
| | - Keri Tuit
- The Connecticut Mental Health Center, Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA,The Yale Stress Center, Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA
| | - Julie Hansen
- The Yale Stress Center, Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA
| | - Anne Kimmerling
- The Connecticut Mental Health Center, Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA
| | - Peter T. Morgan
- The Connecticut Mental Health Center, Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA
| | - Rajita Sinha
- The Connecticut Mental Health Center, Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA,The Yale Stress Center, Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA,The Child Study Center, Yale University School of Medicine, New Haven, CT, USA
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Neurobiological circuits regulating attention, cognitive control, motivation, and emotion: disruptions in neurodevelopmental psychiatric disorders. J Am Acad Child Adolesc Psychiatry 2012; 51:356-67. [PMID: 22449642 DOI: 10.1016/j.jaac.2012.01.008] [Citation(s) in RCA: 359] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2011] [Revised: 01/06/2012] [Accepted: 01/27/2012] [Indexed: 01/05/2023]
Abstract
OBJECTIVE This article aims to review basic and clinical studies outlining the roles of prefrontal cortical (PFC) networks in the behavior and cognitive functions that are compromised in childhood neurodevelopmental disorders and how these map into the neuroimaging evidence of circuit abnormalities in these disorders. METHOD Studies of animals, normally developing children, and patients with neurodevelopmental disorders were reviewed, with focus on neuroimaging studies. RESULTS The PFC provides "top-down" regulation of attention, inhibition/cognitive control, motivation, and emotion through connections with posterior cortical and subcortical structures. Dorsolateral and inferior PFC regulate attention and cognitive/inhibitory control, whereas orbital and ventromedial structures regulate motivation and affect. PFC circuitries are very sensitive to their neurochemical environment, and small changes in the underlying neurotransmitter systems, e.g. by medications, can produce large effects on mediated function. Neuroimaging studies of children with neurodevelopmental disorders show altered brain structure and function in distinctive circuits respecting this organization. Children with attention-deficit/hyperactivity disorder show prominent abnormalities in the inferior PFC and its connections to striatal, cerebellar, and parietal regions, whereas children with conduct disorder show alterations in the paralimbic system, comprising ventromedial, lateral orbitofrontal, and superior temporal cortices together with specific underlying limbic regions, regulating motivation and emotion control. Children with major depressive disorder show alterations in ventral orbital and limbic activity, particularly in the left hemisphere, mediating emotions. Finally, children with obsessive-compulsive disorder appear to have a dysregulation in orbito-fronto-striatal inhibitory control pathways, but also deficits in dorsolateral fronto-parietal systems of attention. CONCLUSIONS Altogether, there is a good correspondence between anatomical circuitry mediating compromised functions and patterns of brain structure and function changes in children with neuropsychiatric disorders. Medications may optimize the neurochemical environment in PFC and associated circuitries, and improve structure and function.
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Adriani W, Zoratto F, Laviola G. Brain processes in discounting: consequences of adolescent methylphenidate exposure. Curr Top Behav Neurosci 2012; 9:113-143. [PMID: 21956611 DOI: 10.1007/7854_2011_156] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Traits of inattention, impulsivity, and motor hyperactivity characterize children diagnosed with attention-deficit/hyperactivity disorder (ADHD), whose inhibitory control is reduced. In animal models, crucial developmental phases or experimental transgenic conditions account for peculiarities, such as sensation-seeking and risk-taking behaviors, and reproduce the beneficial effects of psychostimulants. An "impulsive" behavioral profile appears to emerge more extremely in rats when forebrain dopamine (DA) systems undergo remodeling, as in adolescence, or with experimental manipulation tapping onto the dopamine transporter (DAT). Ritalin(®) (methylphenidate, MPH), a DAT-blocking drug, is prescribed for ADHD therapy but is also widely abused by human adolescents. Administration of MPH during rats' adolescence causes a long-term modulation of their self-control, in terms of reduced intolerance to delay and diminished proneness for risk when reward is uncertain. Exactly the opposite profile emerges when exogenous alteration of DAT levels is achieved via lentiviral transfection. Both adolescent MPH exposure and DAT-targeting transfection lead to enduring hyperfunction of dorsal striatum and hypofunction of ventral striatum. Together with upregulation of prefronto-cortical phospho-creatine, striatal upregulation of selected genes (like serotonin 7 receptor gene) suggests that enhanced inhibitory control is generated by adolescent MPH exposure. Operant tasks, which assess the balance between motivational drives and inhibitory self-control, are thus useful for investigating reward-discounting processes and their modulation by DAT-targeting tools. In summary, due to the complexity of human studies, preclinical investigations of rodent models are necessary to understand better both the neurobiology of ADHD-like symptoms' etiology and the long-term therapeutic safety of adolescent MPH exposure.
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Affiliation(s)
- Walter Adriani
- Section of Behavioural Neuroscience, Department of Cell Biology & Neurosciences, Istituto Superiore di Sanitá, Viale Regina Elena 299, I-00161, Rome, Italy,
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Canese R, Marco EM, De Pasquale F, Podo F, Laviola G, Adriani W. Differential response to specific 5-Ht(7) versus whole-serotonergic drugs in rat forebrains: A phMRI study. Neuroimage 2011; 58:885-94. [DOI: 10.1016/j.neuroimage.2011.06.089] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2010] [Revised: 06/24/2011] [Accepted: 06/29/2011] [Indexed: 10/18/2022] Open
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Sallee FR, Eaton K. Guanfacine extended-release for attention-deficit/hyperactivity disorder (ADHD). Expert Opin Pharmacother 2011; 11:2549-56. [PMID: 20831361 DOI: 10.1517/14656566.2010.517523] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
IMPORTANCE OF THE FIELD Guanfacine extended-release (GXR) is a non-stimulant approved in the US for treatment of attention deficit/hyperactivity disorder (ADHD). GXR is a 'first in class' α(2A)-adrenoceptor agonist reformulated to optimize efficacy. GXR enters a rapidly growing but crowded ADHD market as an alternative not only to psychostimulants but also to atomoxetine. AREAS COVERED IN THIS REVIEW Pharmacodynamics, pharmacokinetics, clinical efficacy and safety of GXR are covered based on a literature review (MEDLINE and EMBASE) from 1980 to 2010. Two large pivotal controlled trials are reviewed along with companion safety studies over 24 months. Collateral studies in ADHD children with oppositional symptoms and combination use of GXR in psychostimulant partial-responders are featured. WHAT THE READER WILL GAIN Novel aspects of apparent GXR mechanism of action may complement existing treatments. Study evidence indicates that GXR is a well-tolerated and effective treatment for children and adolescents with ADHD, and appears efficacious to reduce oppositional symptoms in children with these complicating features. The GXR safety database reflects mild and asymptomatic decreases in both blood pressure and heart rate throughout, with most adverse events being somnolence-related and time-limited. TAKE HOME MESSAGE This review of GXR will allow the reader to determine the place for GXR in the ADHD treatment landscape.
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Affiliation(s)
- Floyd R Sallee
- University of Cincinnati, Department of Psychiatry, OH 45219, USA.
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Marco EM, Adriani W, Ruocco LA, Canese R, Sadile AG, Laviola G. Neurobehavioral adaptations to methylphenidate: The issue of early adolescent exposure. Neurosci Biobehav Rev 2011; 35:1722-39. [DOI: 10.1016/j.neubiorev.2011.02.011] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Revised: 02/21/2011] [Accepted: 02/22/2011] [Indexed: 01/14/2023]
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Russell VA. Overview of animal models of attention deficit hyperactivity disorder (ADHD). ACTA ACUST UNITED AC 2011; Chapter 9:Unit9.35. [PMID: 21207367 DOI: 10.1002/0471142301.ns0935s54] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous, highly heritable, behavioral disorder that affects ∼5% to 10% of children worldwide. Although animal models cannot truly reflect human psychiatric disorders, they can provide insight into the disorder that cannot be obtained from human studies because of the limitations of available techniques. Genetic models include the spontaneously hypertensive rat (SHR), the Naples High Excitability (NHE) rat, poor performers in the 5-choice serial reaction time (5-CSRT) task, the dopamine transporter (DAT) knock-out mouse, the SNAP-25 deficient mutant coloboma mouse, mice expressing a human mutant thyroid hormone receptor, a nicotinic receptor knock-out mouse, and a tachykinin-1 (NK1) receptor knock-out mouse. Chemically induced models of ADHD include prenatal or early postnatal exposure to ethanol, nicotine, polychlorinated biphenyls, or 6-hydroxydopamine (6-OHDA). Environmentally induced models have also been suggested; these include neonatal anoxia and rat pups reared in social isolation. The major insight provided by animal models was the consistency of findings regarding the involvement of dopaminergic, noradrenergic, and sometimes also serotonergic systems, as well as more fundamental defects in neurotransmission.
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Affiliation(s)
- Vivienne Ann Russell
- Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa
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Purper-Ouakil D, Lepagnol-Bestel AM, Grosbellet E, Gorwood P, Simonneau M. [Neurobiology of attention deficit/hyperactivity disorder]. Med Sci (Paris) 2010; 26:487-96. [PMID: 20510147 DOI: 10.1051/medsci/2010265487] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Attention deficit/hyperactivity disorder (ADHD) is a frequent and disabling condition in school children, with cognitive and behavioral symptoms persisting into adulthood in a majority of patients. Etiology of ADHD is considered multifactorial and heterogenous, with an important contribution of genetic factors. Apart from genetic risk factors, emphasis has been put on the early environment, and prenatal exposure to nicotine, alcohol, prematurity and low birth weight have been associated with subsequent ADHD symptoms. This article reviews recent findings in neurobiology, genetics and neuroimaging of ADHD. Despite their clinical heterogeneity and frequent comorbidities, key symptoms of ADHD, such as impulsivity, hyperactivity and inattention are regularly improved by dopaminergic agonists, leading to consider dopaminergic dysfunction a possibly contributing factor in ADHD. Norepinephrine agonists also have clinical efficacy on ADHD symptoms and several other neurotransmission systems are likely involved in the etiology of ADHD. Dysfunction of neurotransmitter systems have been related to impairments of sustained attention, inhibitory control and working memory. Cognitive tasks focusing on reaction time and verbal working memory fit certain criteria for ADHD endophenotypes, offering a pathway to bridge the gap between observed traits and genetic vulnerability. Despite ADHD being a highly heritable disorder, most candidate genes with replicated findings across association studies only account for a small proportion of genetic variance. Neuroimaging studies using treatment effect or cognitive tasks show differential activation patterns in ADHD patients, with trends towards normalization under treatment. Further insight into neurobiological mechanisms involved in ADHD will arise from collaborative networks and combination of imaging, genetic and neurobiological techniques with consideration of the developmental aspects of ADHD.
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Affiliation(s)
- Diane Purper-Ouakil
- Inserm U894, Centre de psychiatrie et neurosciences, Equipe 1, Analyse génétique et clinique des comportements addictifs et psychiatriques, 2 ter, rue d'Alesia, Paris, France.
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Easton N, Marshall FH, Marsden CA, Fone KCF. Mapping the central effects of methylphenidate in the rat using pharmacological MRI BOLD contrast. Neuropharmacology 2009; 57:653-64. [PMID: 19733553 DOI: 10.1016/j.neuropharm.2009.08.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2009] [Revised: 08/10/2009] [Accepted: 08/11/2009] [Indexed: 11/26/2022]
Abstract
Methylphenidate (Ritalin) is a selective dopamine reuptake inhibitor and an effective treatment for attention deficit hyperactivity disorder (ADHD) however the anatomical foci and neuronal circuits involved in these therapeutic benefits are unclear. This study determines the temporal pattern of brain regional activity change produced by systemic administration of a therapeutically relevant dose of methylphenidate in anaesthetised Sprague-Dawley rats using BOLD MRI and a 2.35T Bruker magnet. Following 60 min basal recording separate rats received saline (n = 9) or +/- methylphenidate hydrochloride (2 mg/kg, i.p., n = 9) and BOLD changes were recorded for 90 min using statistical parametric maps. Methylphenidate produced significant positive random BOLD effects in the nucleus accumbens, substantia nigra, entorhinal cortex and medial orbital cortex. Negative random BOLD effects were more widespread and intense, occurring in the motor and somatosensory cortices, caudate putamen, lateral globus pallidus and bed nucleus of the stria terminalis, without accompanying changes in blood pressure or respiratory rate. Methylphenidate-induced negative BOLD in the striatum, and other dopamine terminal areas, may reflect post-synaptic changes produced by blockade of the neuronal dopamine reuptake transporter. While increased positive BOLD in the medial orbital cortex may reflect altered dopamine and/or noradrenaline release indirectly altering striatal activity. The overall pattern of BOLD changes is comparable to that seen in previous studies using guanfacine, amphetamine and atomoxetine, and suggests that although these compounds operate through distinct pharmacological mechanisms the BOLD changes may represent a 'fingerprint pattern' predictive of therapeutic benefit in ADHD.
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Affiliation(s)
- Neil Easton
- School of Biomedical Sciences, Medical School, Institute of Neuroscience, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
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Dissociable effects of noradrenaline, dopamine, and serotonin uptake blockade on stop task performance in rats. Psychopharmacology (Berl) 2009; 205:273-83. [PMID: 19404616 PMCID: PMC2705723 DOI: 10.1007/s00213-009-1537-0] [Citation(s) in RCA: 153] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2008] [Accepted: 04/02/2009] [Indexed: 01/17/2023]
Abstract
RATIONALE The stop-signal paradigm measures the ability to stop a motor response after its execution has been initiated. Impairments in inhibiting inappropriate behavior and prolonged stop-signal reaction times (SSRTs) are characteristic of several psychiatric disorders, most notably attention deficit/hyperactivity disorder. While there is relative consensus regarding the anatomical substrates of behavioral inhibition, the neurochemical imbalance responsible for the deficits in stopping displayed by impulsive individuals is still a matter of debate. OBJECTIVE The aim of this study was to investigate the effects of manipulating brain monoamine levels on stop task parameters. METHODS Lister-hooded rats were trained on the rodent version of the stop-signal task and administered different monoamine transporter inhibitors: citalopram, which selectively blocks the serotonin transporter; atomoxetine, which selectively blocks the noradrenaline transporter; and GBR-12909, which selectively blocks the dopamine transporter (DAT), and the alpha-2 adrenergic agonist guanfacine. RESULTS Atomoxetine speeded SSRT and increased accuracy for go-trials. Citalopram slowed go reaction time and decreased go accuracy at the highest dose (1 mg/kg). GBR-12909 speeded go reaction time and impaired both go and stop accuracy. Guanfacine negatively modulated all principal stop and go measures at the highest dose used (0.3 mg/kg). CONCLUSIONS The results suggest that atomoxetine exerts its beneficial effects on SSRT via its action on noradrenaline re-uptake, as the specific DAT blocker GBR-12909 and serotonin reuptake blockade had only minor effects on SSRT. The speeding of the go reaction time by dopamine reuptake blockade is consistent with the hypothesis that the hypothetical stop and go processes are modulated by distinct monoaminergic systems.
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Vaidya CJ, Stollstorff M. Cognitive neuroscience of Attention Deficit Hyperactivity Disorder: current status and working hypotheses. ACTA ACUST UNITED AC 2009; 14:261-7. [PMID: 19072750 DOI: 10.1002/ddrr.40] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Cognitive neuroscience studies of Attention Deficit Hyperactivity Disorder (ADHD) suggest multiple loci of pathology with respect to both cognitive domains and neural circuitry. Cognitive deficits extend beyond executive functioning to include spatial, temporal, and lower-level "nonexecutive" functions. Atypical functional anatomy extends beyond frontostriatal circuits to include posterior cortices, limbic regions, and the cerebellum. Pathophysiology includes dopaminergic as well as noradrenergic neurotransmitter systems. We review the major insights gained from functional brain imaging studies in ADHD and discuss working hypotheses regarding their neurochemical underpinnings.
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Affiliation(s)
- Chandan J Vaidya
- Department of Psychology, Georgetown University, Washington, DC 20057, USA.
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Peculiar response to methylphenidate in adolescent compared to adult rats: a phMRI study. Psychopharmacology (Berl) 2009; 203:143-53. [PMID: 18998111 DOI: 10.1007/s00213-008-1379-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2008] [Accepted: 10/13/2008] [Indexed: 02/02/2023]
Abstract
RATIONALE Adolescent rodents differ markedly from adults in several neuro-behavioural parameters. Moreover, 'paradoxical' responses to psychostimulants have been reported at this age. OBJECTIVES Thus, we investigated the responses of adolescent (post-natal day, PND, 34 to 43) and adult (PND >60) Sprague-Dawley male rats to the psychostimulant drug methylphenidate (MPH). We used pharmacological magnetic resonance imaging (phMRI) performed at 4.7 T under isoflurane anaesthesia. Following anatomical MRI, axial gradient echo images were collected continuously. After baseline recording (32 min), animals received MPH (0 or 4 mg/kg i.p.) and were recorded for further 32 min. RESULTS Region-specific changes in the blood-oxygenation level dependent (BOLD) signal were evident as a function of age. As expected, among adults MPH induced an increase of BOLD signal in nucleus accumbens (NAcc) and prefrontal cortex (PFC), with no effects in the hippocampus (Hip). Notably, among adolescents, MPH induced a marked and generalised decrease of BOLD signal, which occurred earlier in NAcc and PFC whilst being delayed in the Hip. Any bias in BOLD responses was excluded by the measurement of physiological parameters. CONCLUSIONS The present findings highlight the utility of phMRI in animal models. The peculiar negative BOLD effect found in adolescent rats may be suggestive of a reduced cerebro-vascular feedback and/or an increased MPH-induced neuronal activation. Data are relevant for a better understanding of brain/behavioural regulation during adolescent development. Moreover, a greater understanding of the differences between adult and adolescent drug responses will aid in the development of a more appropriate age-specific treatment strategy.
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Effects of methylphenidate on the catecholaminergic system in attention-deficit/hyperactivity disorder. J Clin Psychopharmacol 2008; 28:S46-53. [PMID: 18480677 DOI: 10.1097/jcp.0b013e318173312f] [Citation(s) in RCA: 192] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Stimulants are part of the standard-of-care treatment for attention-deficit/hyperactivity disorder (ADHD). Methylphenidate, with a history of use spanning approximately 5 decades, is a first-line stimulant treatment for ADHD. Methylphenidate chiefly affects the prefrontal cortex and striatum, the mechanism of action being modulation of catecholaminergic tone. Methylphenidate treatment produces an increase in dopamine (DA) signaling through multiple actions, including blockade of the DA reuptake transporter and amplification of DA response duration, disinhibition of DA D2 autoreceptors and amplification of DA tone, and activation of D1 receptors on the postsynaptic neuron. The actions of methylphenidate may also be mediated by stimulation of the noradrenergic alpha2 receptor and DA D1 receptor in the cortex. The role of other neurotransmitters such as histamine, acetylcholine, serotonin, and alpha-agonists in modulating catecholamine pathophysiology in ADHD and ADHD treatment needs to be elucidated. Overall, the changes in catecholaminergic tone clinically manifest as improvements in attention deficit, distractibility, and motor hyperactivity in patients with ADHD.
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Posey DJ, McDougle CJ. Guanfacine and guanfacine extended release: treatment for ADHD and related disorders. CNS DRUG REVIEWS 2008; 13:465-74. [PMID: 18078429 DOI: 10.1111/j.1527-3458.2007.00026.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Guanfacine, an alpha(2A) adrenoceptor agonist, is U.S. Food and Drug Administration (FDA)-approved for the treatment of hypertension in adolescents and adults. It also has been used "off-label" for several years in children as a possible treatment for attention-deficit/hyperactivity disorder (ADHD) and pervasive developmental disorders (PDDs). Small placebo-controlled trials support the use of guanfacine for the treatment of ADHD. There is more limited research on the use of guanfacine in treating hyperactivity occurring in children diagnosed with PDD. Recently, guanfacine extended release (GXR), a once-daily formulation has been manufactured and studied in phase III clinical trials. Based on preliminary scientific presentations, it also appears to be efficacious in improving ADHD in children. The most common adverse effects associated with guanfacine and GXR treatment is sedation. Adverse cardiovascular effects are uncommon, although modest reductions in blood pressure and heart rate are common. If GXR is FDA-approved, it would be the first alpha(2A) adrenoceptor agonist marketed for ADHD.
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Affiliation(s)
- David J Posey
- Christian Sarkine Autism Treatment Center, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
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Levy F. Pharmacological and therapeutic directions in ADHD: Specificity in the PFC. BEHAVIORAL AND BRAIN FUNCTIONS : BBF 2008; 4:12. [PMID: 18304369 PMCID: PMC2289834 DOI: 10.1186/1744-9081-4-12] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/21/2007] [Accepted: 02/28/2008] [Indexed: 01/22/2023]
Abstract
BACKGROUND Recent directions in the treatment of ADHD have involved both a broadening of pharmacological perspectives to include nor-adrenergic as well as dopaminergic agents. A review of animal and human studies of pharmacological and therapeutic directions in ADHD suggests that the D1 receptor is a specific site for dopaminergic regulation of the PFC, but optimal levels of dopamine (DA) are required for beneficial effects on working memory. Animal and human studies indicate that the alpha-2A receptor is also important for prefrontal regulation, leaving open the question of the relative importance of these receptor sites. The therapeutic effects of ADHD medications in the prefrontal cortex have focused attention on the development of working memory capacity in ADHD. HYPOTHESIS The actions of dopaminergic vs noradrenergic agents, currently available for the treatment of ADHD have overlapping, but different actions in the prefrontal cortex (PFC) and subcortical centers. While stimulants act on D1 receptors in the dorsolateral prefrontal cortex, they also have effects on D2 receptors in the corpus striatum and may also have serotonergic effects at orbitofrontal areas. At therapeutic levels, dopamine (DA) stimulation (through DAT transporter inhibition) decreases noise level acting on subcortical D2 receptors, while NE stimulation (through alpha-2A agonists) increases signal by acting preferentially in the PFC possibly on DAD1 receptors. On the other hand, alpha-2A noradrenergic transmission is more limited to the prefrontal cortex (PFC), and thus less likely to have motor or stereotypic side effects, while alpha-2B and alpha-2C agonists may have wider cortical effects. The data suggest a possible hierarchy of specificity in the current medications used in the treatment of ADHD, with guanfacine likely to be most specific for the treatment of prefrontal attentional and working memory deficits. Stimulants may have broader effects on both vigilance and motor impulsivity, depending on dose levels, while atomoxetine may have effects on attention, anxiety, social affect, and sedation via noradrenergic transmission. TESTS OF THE HYPOTHESIS At a theoretical level, the advent of possible specific alpha-2A noradrenergic therapies has posed the question of the role of working memory in ADHD. Head to head comparisons of stimulant and noradrenergic alpha-2A, alpha-2B and alpha-2C agonists, utilizing vigilance and affective measures should help to clarify pharmacological and therapeutic differences.
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Affiliation(s)
- Florence Levy
- School of Psychiatry, University of New South Wales, Prince of Wales Hospital, Sydney, NSW 2031, Australia.
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Pohlmann A, Barjat H, Tilling LC, James MF. Pharmacological fMRI - Challenges in Analysing Drug-Induced Single-Event BOLD Responses. ACTA ACUST UNITED AC 2007; 2007:3411-6. [DOI: 10.1109/iembs.2007.4353064] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Easton N, Marshall F, Fone KCF, Marsden CA. Differential effects of the D- and L- isomers of amphetamine on pharmacological MRI BOLD contrast in the rat. Psychopharmacology (Berl) 2007; 193:11-30. [PMID: 17387459 DOI: 10.1007/s00213-007-0756-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2006] [Accepted: 02/19/2007] [Indexed: 01/24/2023]
Abstract
RATIONALE The D - and L-amphetamine sulphate isomers are used in the formulation of Adderall XR(R), which is effective in the treatment of attention-deficit hyperactivity disorder (ADHD). The effects of these isomers on brain activity has not been examined using neuroimaging. OBJECTIVES This study determines the pharmacological magnetic resonance imaging blood-oxygenation-level-dependent (BOLD) response in rat brain regions after administration of each isomer. MATERIALS AND METHODS Rats were individually placed into a 2.35 T Bruker magnet for 60 min to achieve basal recording of variation in signal intensity. Either saline (n = 9), D-amphetamine sulphate (2 mg/kg, i.p.; n = 9) or L: -amphetamine sulphate (4 mg/kg, i.p.; n = 9) were administered, and recording continued for a further 90 min. Data were analysed for BOLD effects using statistical parametric maps. Blood pressure, blood gases and respiratory rate were monitored during scanning. RESULTS The isomers show overlapping effects on the BOLD responses in areas including nucleus accumbens, medial entorhinal cortex, colliculi, field CA1 of hippocampus and thalamic nuclei. The L-isomer produced greater global changes in the positive BOLD response than the D-isomer, including the somatosensory and motor cortices and frontal brain regions such as the orbitofrontal cortices, prelimbic and infralimbic cortex which were not observed with the D-isomer. CONCLUSIONS The amphetamine isomers produce different BOLD responses in brain areas related to cognition, pleasure, pain processing and motor control probably because of variations on brain amine systems such as dopamine and noradrenaline. The isomers may, therefore, have distinct actions on brain regions affected in ADHD patients.
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Affiliation(s)
- Neil Easton
- School of Biomedical Sciences, Medical School, Institute of Neuroscience, University of Nottingham, Queens Medical Centre, Nottingham, NG7 2UH, UK
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Easton N, Marshall F, Fone K, Marsden C. Atomoxetine produces changes in cortico-basal thalamic loop circuits: assessed by phMRI BOLD contrast. Neuropharmacology 2006; 52:812-26. [PMID: 17140608 DOI: 10.1016/j.neuropharm.2006.09.024] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2006] [Revised: 09/21/2006] [Accepted: 09/29/2006] [Indexed: 10/23/2022]
Abstract
Atomoxetine is a selective noradrenaline reuptake inhibitor used in the treatment of attention deficit hyperactivity disorder (ADHD) which has not yet been assessed using pharmacological neuroimaging for its effects on rat brain activity. The pharmacological magnetic resonance imaging (phMRI) blood oxygenation level dependent (BOLD) response was determined in rat brain regions following administration of atomoxetine. Rats were individually placed into a 2.35T Bruker magnet for 60min to achieve basal recording of changes in signal intensity. Either saline (n=9) or atomoxetine hydrochloride (2mg/kg; i.p.; n=10) was then administered and recording continued for a further 90min. Data were analysed for BOLD random effects using statistical parametric maps and time course analysis. The main changes observed were widespread negative BOLD responses in the caudate putamen and changes in brain regions associated with the cortico-basal thalamic loop circuits. BOLD changes in the basal ganglia help explain its efficacy in reducing hyperactivity observed in ADHD patients. Although positive BOLD changes in the prefrontal cortex were limited to the ventral orbital cortex this is an area associated with behavioral control and may be of relevance to the use of the drug in ADHD.
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Affiliation(s)
- Neil Easton
- School of Biomedical Sciences, Medical School, Institute of Neuroscience, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, UK.
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