DOCSLIB.ORG

Reboxetine: a Randomized Controlled Open-Label Study in Children and Adolescents with Major Depression

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Reboxetine: a Randomized Controlled Open-Label Study in Children and Adolescents with Major Depression IsrIsr JJ PsychiatryPsychiatry -- Vol. 56 - No 1 (2019) Reboxetine: A Randomized Controlled Open-label Study in Children and Adolescents with Major Depression Paz Toren, MD,1,2 Guy Goldstein, MA,1,3 Galit Ben-Amitay, MD,1,2 Joseph Ben-Sheetrit, MD,1,4 and Michelle Slone, PhD3 1 Tel Aviv Brüll Community Mental Health Center, Clalit Health Services, Tel Aviv, Israel 2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel 4 Geha Mental Health Center, Petah Tikva, Israel INTRODUCTION ABSTRACT Objective: This study is the first to examine the efficacy General rates of adolescents diagnosed as having major of reboxetine in the treatment of children and adolescents depressive disorder (MDD) or dysthymia are approxi- with depression. mately 10% (1), with an annual prevalence of 8%-20% for adolescents and 5% for children (2, 3). Youth depres- Method: In this open-label randomized controlled study, 14 sion may lead to impairment in social and educational youths (aged 9-18 years) with major depression received functioning and can impact mental health through to either reboxetine (4mg/day) or fluoxetine (20mg/day) adulthood (4, 5). Individuals who suffered from depres- in a 2:1 ratio. Primary outcome measures included the sion in their youth are twice or three times more likely to Children’s Depression Rating Scale-Revised (CDRS-R), develop major depression as young adults compared to the Clinical Global Impression-Improvement scale (CGI-I), children and adolescents who did not suffer from depres- and the Children’s Depression Inventory (CDI). Response sion (6, 7). Children and adolescents with MDD are also at was defined by either a 20% reduction in CDRS-R or a increased risk for suicidality compared to non-depressed 2-point reduction in CGI-I. youth (8). Reboxetine is an antidepressant of the selective norepi- Results: Improvement in depression with reboxetine nephrine reuptake inhibitors (NaRIs). Reboxetine’s main was noted within 4 weeks. A further non-significant action is in raising the synaptic levels of norepinephrine improvement was noted after 8 weeks, proceeding through by binding to the norepinephrine transporter and block- week 12. Response was achieved by six subjects (66.7%) ing its reuptake (9). Reboxetine’s selectivity was found by week 4 and eight subjects (88.9%) by week 12. Both to be equal or superior to desipramine and superior to reboxetine and fluoxetine were safe with tolerable adverse imipramine (10). Reboxetine was found to be effective effects, although several non-significant differences in for treating adult depression compared to placebo and efficacy and overall frequency of side effects were found other antidepressants. Reboxetine as effective as imipra- in favor of fluoxetine. mine and fluoxetine, and at least as effective as desipra- Conclusions: Reboxetine was safe and effective in mine (11-14). Recent meta-analyses have addressed the treating youth with major depressive disorder. Further question of the efficacy of reboxetine compared to the studies with long-term follow up are needed in order to selective serotonin reuptake inhibitors (SSRIs) in adults. replicate our findings and determine the relative efficacy Eyding et al. (15) concluded that reboxetine showed no of reboxetine compared to fluoxetine. differences from placebo and was inferior to SSRIs on both response and remission rates, whereas Papakostas et al. (16) concluded that the efficacy of the SSRIs and Address for Correspondence: Joseph Ben-Sheetrit, MD, Tel Aviv Brüll Community Mental Health Center, 9 Hatzvi St., Tel Aviv 6719709, Israel [email protected] 26 PAZ TOREN ET AL. reboxetine were similar, and that the major differences or fluoxetine (20 mg/day) treatment. All participants between them were only in their adverse effects profiles. were intended to receive concomitant dynamic psycho- Reboxetine has a high safety profile (10). Adverse therapy. By the end of the 8th week, the medication dosage effects were found to subside spontaneously with no was gradually reduced until termination. When clinical cardiotoxic potential (13). No differences were found in improvement was noted, the pharmacological treatment the rates of adverse effects of fluoxetine and reboxetine could be continued beyond the 8th week, depending on (15). A previous study reported that the adverse effects clinical considerations. of the NaRIs, including reboxetine are as tolerable as Assessments were made at baseline, after 2 and 4 weeks those of the SSRIs (17). on drug treatment, and every 4 weeks thereafter, and In a previous 6-week open-label study in the Tel Aviv included: Community Mental Health Center clinic (18), we assessed a. A DSM-IV-based psychiatric interview of the child the efficacy of reboxetine (4 mg/day) in the treatment of 31 and an interview with his or her parents, by a senior children and adolescents with attention deficit/hyperactivity child and adolescent psychiatrist (baseline only). disorder (ADHD). A significant improvement was shown b. Clinician-rated (see Study Tools 1-3) and self-report in ADHD symptoms, as well as a decrease in comorbid (see Study Tools 4-6) questionnaires. depressive symptoms, but not in anxiety symptoms. Adverse c. Monitoring of adverse events. effects were generally mild and tolerable, appearing within the first days of treatment and subsiding spontaneously SamPLE SIZE within a few days. The most common adverse effects were Considering a strict criterion of being able to demonstrate drowsiness or sedation and gastrointestinal complaints a significant difference for depression of mild baseline (18). The reduction in depression symptoms and the safety severity (e.g., CDRS-R=55)(20) and assuming an expected profile of the drug suggested that reboxetine may be an standard deviation of SD=9.9 (based on a previous study appropriate antidepressant treatment for this age group. (21)), in order to detect a 20% difference in CDRS-R scores Surprisingly, no data have yet been published regarding (considering α=.05 and 1-β=.80), a total sample size of the efficacy of reboxetine in the treatment of depression N=30 would be required in a 2:1 ratio (i.e., n=20 for the in youth. The present randomized controlled open-label reboxetine group and n=10 for the fluoxetine group), study aimed to assess the efficacy of reboxetine as an anti- which would then yield an effect size of d=1.1. depressant in children and adolescents, and the tolerability of reboxetine compared to fluoxetine as antidepressants SUBJECTS in children and adolescents. Seventeen subjects (11 girls and 5 boys, aged 15.6±2.24 years, range 9-18 years) gave their consent to participate in the study and matched the enrollment criteria. Two METHODS subjects (11.8%, a 15.5-year-old male and a 17-year-old INCLUSION & EXCLUSION CRITERIA female) did not receive the study medication due to All subjects met the Diagnostic and Statistical Manual of baseline ECG abnormalities. Ten participants were ran- Mental Disorders, 4th edition, text revision (DSM-IV-TR) domized to receive reboxetine treatment and 5 to receive (19) criteria for major depressive disorder. The diagnosis fluoxetine treatment. One subject in the reboxetine group was made by a senior child and adolescent psychiatrist. (a 17-year-old male) dropped out before the 2nd week of All participants were drug-naïve or without any medi- treatment due to noncompliance. In the fluoxetine group, cation for at least one month. Exclusion criteria were no dropouts occurred before the 2nd week of the study. a diagnosis of autistic spectrum disorder, psychosis or Fourteen of the 17 (82.3%) subjects who initially signed bipolar disorder. Other mental disorders were allowed to up for the study completed at least 4 weeks of treatment. be documented and included in the study. Children with A full treatment period of 12 weeks was completed by 6 intellectual disability, substance use or chronic medical (66%) subjects of the reboxetine and 5 (100%) of the fluox- illnesses were excluded. etine group. Two subjects (22%) in the reboxetine group completed only 4 weeks of treatment: non-compliance DESIGN & INTERVENTION attributed to symptom improvement (1 subject) and Following baseline assessment, participants were ran- non-compliance due to mild side effects, i.e., mild loss domly assigned to receive either reboxetine (4 mg/day) of appetite and mild insomnia (1 subject). 27 REBOXETINE IN CHILDREN There were no significant differences in the CDRS-R gastrointestinal complaints, headaches and dizziness). baseline scores between of subjects who completed the Weight and height, heart rate, blood pressure and elec- entire treatment period, subjects who completed more trocardiograms (ECGs) were also assessed. Complete than two weeks of treatment, and those who did not have blood counts (CBCs) and liver and kidney functions a minimum of 2 weeks of treatment (F2=0.13, ns). Further, were assessed at baseline and after 4 weeks of treatment, no significant correlations were found between treatment and according to clinical judgement thereafter. length and baseline CDRS-R scores for either of the study groups. The analysis of dropout subjects was made accord- ETHICAL APPROVAL ing to the intention-to-treat method. Two subjects (22%) The study (Clinicaltrials.gov NCT00426946) was approved from the reboxetine group continued to receive reboxetine by the Institutional and the Ministry of Health Review treatment after study termination. One was treated for 6 Boards. All children gave their assent to participate in the months and the other was treated for a year. study and their parents signed an informed consent form. MEASURES DaTA ANALYSIS MAIN OUTCOMES Data analysis was made according to the “intention to 1. The Children’s Depression Rating Scale-Revised treat” principle. Baseline age and gender distribution (CDRS-R) (22) is a semi-structured clinician-rated were analyzed by the two tailed independent sample interview for the assessment of youth depression.
Load more

Recommended publications
  • Lega Italiana Per La Lotta Contro La Malattia Di Parkinson Le Sindromi Extrapiramidali E Le Demenze
    LIMPE lega italiana per la lotta contro la malattia di parkinson le sindromi extrapiramidali e le demenze Web site: http://www.parkinson-limpe.it/ XXIX National Congress Lecce 23–25 October 2002 Parkinson Parkinsonism Dementia: from Biotechnology to Medical Management SELECTED SHORT PAPERS Scientific Committee Bruno Bergamasco, Giovanni U. Corsini, Mario Manfredi, Stefano Ruggieri, Pierfranco Spano Secretariat LIMPE Viale dell’Università 30, 00185 Roma Tel. and Fax: +39-06-4455618 E-mail: [email protected] Neurol Sci (2003) 24:149–150 DOI 10.1007/s10072-003-0103-5 123I-Ioflupane/SPECT binding to to the dopamine transporter (DAT) may be better suited and provide more-accurate estimation of degeneration. Several striatal dopamine transporter (DAT) tracers that bind to DAT and utilize SPECT are available; uptake in patients with Parkinson’s they are all cocaine derivatives. The most widely used are disease, multiple system atrophy, and [123I]β-CIT and 123I-Ioflupane ([123I]FP-CIT) [3, 4]. The main advantage of 123I-Ioflupane is that a steady state allow- progressive supranuclear palsy ing SPECT imaging is reached 3 h after a single bolus injec- 1 2 1 tion of the radioligand, compared with the 18–24 h required A. Antonini (౧) • R. Benti • R. De Notaris 1 1 1 for [123I]β-CIT. Therefore DAT imaging with 123I-Ioflupane S. Tesei • A. Zecchinelli • G. Sacilotto 1 1 1 1 can be completed the same day. N. Meucci • M. Canesi • C. Mariani • G. Pezzoli 123 P. Gerundini2 Several studies have demonstrated the usefulness of I- 1 Centro per la malattia di Parkinson, Dipartimento di Ioflupane SPECT imaging in the diagnosis of parkinsonism.
    [Show full text]
  • Selective Knockdown of TASK3 Potassium Channel in Monoamine
    Manuscript Click here to download Manuscript Fullana et al - TASK3.docx 1 Research Article – Molecular Neurobiology 2 3 Selective Knockdown of TASK3 Potassium Channel in Monoamine 4 Neurons: A New Therapeutic Approach for Depression 5 M Neus Fullana1,2,3*, Albert Ferrés-Coy1,2,3*, Jorge E Ortega3,4, Esther Ruiz-Bronchal1,2,3, Verónica 6 Paz1,2,3, J Javier Meana3,4, Francesc Artigas1,2,3 and Analia Bortolozzi1,2,3 7 8 1Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain 9 2Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (Consejo Superior de 10 Investigaciones Científicas), Barcelona, Spain. 11 3Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain. 12 4Department of Pharmacology, University of Basque Country UPV/EHU and BioCruces Health 13 Research Institute, Bizkaia, Spain 14 15 NF* and AF-C* contributed equally to this work. 16 For correspondence: Analia Bortolozzi, Department of Neurochemistry and Neuropharmacology 17 (IIBB-CSIC), Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Rosello 161, 18 Barcelona 08036, Spain. Tel: +34 93638313 Fax: +34 933638301 E-mail: 19 [email protected] 20 21 22 23 Running title: Intranasal delivery of conjugated TASK3-siRNA 24 25 26 1 Abstract 2 Current pharmacological treatments for major depressive disorder (MDD) are severely compromised 3 by both slow action and limited efficacy. RNAi strategies have been used to evoke antidepressant-like 4 effects faster than classical drugs. Using small interfering RNA (siRNA), we herein show that TASK3 5 potassium channel knockdown in monoamine neurons induces antidepressant-like responses in mice.
    [Show full text]
  • Monoamine Reuptake Inhibitors in Parkinson's Disease
    Hindawi Publishing Corporation Parkinson’s Disease Volume 2015, Article ID 609428, 71 pages http://dx.doi.org/10.1155/2015/609428 Review Article Monoamine Reuptake Inhibitors in Parkinson’s Disease Philippe Huot,1,2,3 Susan H. Fox,1,2 and Jonathan M. Brotchie1 1 Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8 2Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, University of Toronto, 399BathurstStreet,Toronto,ON,CanadaM5T2S8 3Department of Pharmacology and Division of Neurology, Faculty of Medicine, UniversitedeMontr´ eal´ and Centre Hospitalier de l’UniversitedeMontr´ eal,´ Montreal,´ QC, Canada Correspondence should be addressed to Jonathan M. Brotchie; [email protected] Received 19 September 2014; Accepted 26 December 2014 Academic Editor: Maral M. Mouradian Copyright © 2015 Philippe Huot et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The motor manifestations of Parkinson’s disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters.
    [Show full text]
  • Male Anorgasmia: from “No” to “Go!”
    Male Anorgasmia: From “No” to “Go!” Alexander W. Pastuszak, MD, PhD Assistant Professor Center for Reproductive Medicine Division of Male Reproductive Medicine and Surgery Scott Department of Urology Baylor College of Medicine Disclosures • Endo – speaker, consultant, advisor • Boston Scientific / AMS – consultant • Woven Health – founder, CMO Objectives • Understand what delayed ejaculation (DE) and anorgasmia are • Review the anatomy and physiology relevant to these conditions • Review what is known about the causes of DE and anorgasmia • Discuss management of DE and anorgasmia Definitions Delayed Ejaculation (DE) / Anorgasmia • The persistent or recurrent delay, difficulty, or absence of orgasm after sufficient sexual stimulation that causes personal distress Intravaginal Ejaculatory Latency Time (IELT) • Normal (median) à 5.4 minutes (0.55-44.1 minutes) • DE à mean IELT + 2 SD = 25 minutes • Incidence à 2-11% • Depends in part on definition used J Sex Med. 2005; 2: 492. Int J Impot Res. 2012; 24: 131. Ejaculation • Separate event from erection! • Thus, can occur in the ABSENCE of erection! Periurethral muscle Sensory input - glans (S2-4) contraction Emission Vas deferens contraction Sympathetic input (T12-L1) SV, prostate contraction Bladder neck contraction Expulsion Bulbocavernosus / Somatic input (S1-3) spongiosus contraction Projectile ejaculation J Sex Med. 2011; 8 (Suppl 4): 310. Neurochemistry Sexual Response Areas of the Brain • Pons • Nucleus paragigantocellularis Neurochemicals • Norepinephrine, serotonin: • Inhibit libido,
    [Show full text]
  • Pharmaceuticals As Environmental Contaminants
    PharmaceuticalsPharmaceuticals asas EnvironmentalEnvironmental Contaminants:Contaminants: anan OverviewOverview ofof thethe ScienceScience Christian G. Daughton, Ph.D. Chief, Environmental Chemistry Branch Environmental Sciences Division National Exposure Research Laboratory Office of Research and Development Environmental Protection Agency Las Vegas, Nevada 89119 [email protected] Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada Why and how do drugs contaminate the environment? What might it all mean? How do we prevent it? Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada This talk presents only a cursory overview of some of the many science issues surrounding the topic of pharmaceuticals as environmental contaminants Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada A Clarification We sometimes loosely (but incorrectly) refer to drugs, medicines, medications, or pharmaceuticals as being the substances that contaminant the environment. The actual environmental contaminants, however, are the active pharmaceutical ingredients – APIs. These terms are all often used interchangeably Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada Office of Research and Development Available: http://www.epa.gov/nerlesd1/chemistry/pharma/image/drawing.pdfNational
    [Show full text]
  • Lobelane Analogs with Various Methylene Linker Lengths and Acyclic Lobelane Analogs As Potential Pharmacotherapies to Treat Methamphetamine Abuse
    University of Kentucky UKnowledge Theses and Dissertations--Pharmacy College of Pharmacy 2014 LOBELANE ANALOGS WITH VARIOUS METHYLENE LINKER LENGTHS AND ACYCLIC LOBELANE ANALOGS AS POTENTIAL PHARMACOTHERAPIES TO TREAT METHAMPHETAMINE ABUSE Zheng Cao University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Cao, Zheng, "LOBELANE ANALOGS WITH VARIOUS METHYLENE LINKER LENGTHS AND ACYCLIC LOBELANE ANALOGS AS POTENTIAL PHARMACOTHERAPIES TO TREAT METHAMPHETAMINE ABUSE" (2014). Theses and Dissertations--Pharmacy. 32. https://uknowledge.uky.edu/pharmacy_etds/32 This Doctoral Dissertation is brought to you for free and open access by the College of Pharmacy at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Pharmacy by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known.
    [Show full text]
  • Neurotransmission Product Guide | Edition 1
    Neurotransmission Product Guide | Edition 1 Delphinium Delphinium A source of Methyllycaconitine Contents by Research Area: • Dopaminergic Transmission • Glutamatergic Transmission • Opioid Peptide Transmission • Serotonergic Transmission • Chemogenetics Tocris Product Guide Series Neurotransmission Research Contents Page Principles of Neurotransmission 3 Dopaminergic Transmission 5 Glutamatergic Transmission 6 Opioid Peptide Transmission 8 Serotonergic Transmission 10 Chemogenetics in Neurotransmission Research 12 Depression 14 Addiction 18 Epilepsy 20 List of Acronyms 22 Neurotransmission Research Products 23 Featured Publications and Further Reading 34 Introduction Neurotransmission, or synaptic transmission, refers to the passage of signals from one neuron to another, allowing the spread of information via the propagation of action potentials. This process is the basis of communication between neurons within, and between, the peripheral and central nervous systems, and is vital for memory and cognition, muscle contraction and co-ordination of organ function. The following guide outlines the principles of dopaminergic, opioid, glutamatergic and serotonergic transmission, as well as providing a brief outline of how neurotransmission can be investigated in a range of neurological disorders. Included in this guide are key products for the study of neurotransmission, targeting different neurotransmitter systems. The use of small molecules to interrogate neuronal circuits has led to a better understanding of the under- lying mechanisms of disease states associated with neurotransmission, and has highlighted new avenues for treat- ment. Tocris provides an innovative range of high performance life science reagents for use in neurotransmission research, equipping researchers with the latest tools to investigate neuronal network signaling in health and disease. A selection of relevant products can be found on pages 23-33.
    [Show full text]
  • Treatment of Problem Cocaine Use a Review of the Literature the of Review a Literature
    TREATMENT OF PROBLEM COCAINE USE COCAINE PROBLEM OF TREATMENT A REVIEW OF THE LITERATURE LITERATURE REVIEW ISBN 92-9168-274-8 ISBN EMCDDA literature reviews Treatment of problem cocaine use: a review of the literature EMCDDA literature reviews — Treatment of problem cocaine use Acknowledgements This literature review is based on a consultant report by Christian Haasen and Katja Thane, Institut für Interdisziplinäre Sucht- und Drogenforschung (ISD), Hamburg, at the Zentrum für Interdisziplinäre Suchtforschung (ZIS) of the University of Hamburg (Service Contract CT.06.RES.144.1.0). EMCDDA project managers: Dagmar Hedrich and Alessandro Pirona. Other contributors to this project included Prepress Projects, Rosemary de Sousa and Peter Thomas. Cataloguing data European Monitoring Centre for Drugs and Drug Addiction, 2007 EMCDDA Literature reviews — Treatment of problem cocaine use: a review of the literature Lisbon: European Monitoring Centre for Drugs and Drug Addiction 2007 — 50 pp. — 21 x 29.7 cm Language: EN Catalogue Number: TD-XB-06-001-EN-N ISBN: 92-9168-274-8 ISSN: 1725-0579 © European Monitoring Centre for Drugs and Drug Addiction, 2007. Reproduction is authorised provided the source is acknowledged. Rua da Cruz de Santa Apolónia 23-25, PT-1149-045 Lisbon, Portugal Tel: (+351) 21 811 3000 Fax: (+351) 21 813 1711 [email protected] http://www.emcdda.europa.eu 3 EMCDDA literature reviews — Treatment of problem cocaine use List of abbreviations ADHD attention deficit hyperactivity disorder BBD blood-borne disease CA Cocaine Anonymous
    [Show full text]
  • Cholinergic Regulation of Mood: from Basic and Clinical Studies to Emerging Therapeutics
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Mol Psychiatry Manuscript Author . Author Manuscript Author manuscript; available in PMC 2020 April 30. Published in final edited form as: Mol Psychiatry. 2019 May ; 24(5): 694–709. doi:10.1038/s41380-018-0219-x. Cholinergic Regulation of Mood: From Basic and Clinical Studies to Emerging Therapeutics Stephanie C. Dulawa, Ph.D.1,*, David S. Janowsky, M.D.1 1Department of Psychiatry, University of California at San Diego Abstract Mood disorders are highly prevalent and are the leading cause of disability worldwide. The neurobiological mechanisms underlying depression remain poorly understood, although theories regarding dysfunction within various neurotransmitter systems have been postulated. Over 50 years ago, clinical studies suggested that increases in central acetylcholine could lead to depressed mood. Evidence has continued to accumulate suggesting that the cholinergic system plays a important role in mood regulation. In particular, the finding that the antimuscarinic agent, scopolamine, exerts fast-onset and sustained antidepressant effects in depressed humans has led to a renewal of interest in the cholinergic system as an important player in the neurochemistry of major depression and bipolar disorder. Here, we synthesize current knowledge regarding the modulation of mood by the central cholinergic system, drawing upon studies from human postmortem brain, neuroimaging, and drug challenge investigations, as well as animal model studies. First, we describe an illustrative series of early discoveries which suggest a role for acetylcholine in the pathophysiology of mood disorders. Then, we discuss more recent studies conducted in humans and/or animals which have identified roles for both acetylcholinergic muscarinic and nicotinic receptors in different mood states, and as targets for novel therapies.
    [Show full text]
  • Neurochemical Features of Rem Sleep Behaviour Disorder
    Journal of Personalized Medicine Review Neurochemical Features of Rem Sleep Behaviour Disorder Félix Javier Jiménez-Jiménez 1,* , Hortensia Alonso-Navarro 1, Elena García-Martín 2 and José A. G. Agúndez 2 1 Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, C/Marroquina 14, 3 B, E28030 Madrid, Spain; [email protected] 2 UNEx, ARADyAL, Instituto de Salud Carlos III, University Institute of Molecular Pathology, E10071 Cáceres, Spain; [email protected] (E.G.-M.); [email protected] (J.A.G.A.) * Correspondence: [email protected] or [email protected]; Tel.: +34-636968395; Fax: +34-913280704 Abstract: Dopaminergic deficiency, shown by many studies using functional neuroimaging with Sin- gle Photon Emission Computerized Tomography (SPECT) and Positron Emission Tomography (PET), is the most consistent neurochemical feature of rapid eye movement (REM) sleep behaviour disorder (RBD) and, together with transcranial ultrasonography, and determination of alpha-synuclein in certain tissues, should be considered as a reliable marker for the phenoconversion of idiopathic RBD (iRBD) to a synucleopathy (Parkinson’s disease –PD- or Lewy body dementia -LBD). The possible role in the pathogenesis of RBD of other neurotransmitters such as noradrenaline, acetylcholine, and excitatory and inhibitory neurotransmitters; hormones such as melatonin, and proinflammatory factors have also been suggested by recent reports. In general, brain perfusion and brain glucose metabolism studies have shown patterns resembling partially those of PD and LBD. Finally, the results of structural and functional MRI suggest the presence of structural changes in deep gray matter nuclei, cortical gray matter atrophy, and alterations in the functional connectivity within the basal ganglia, the cortico-striatal, and the cortico-cortical networks, but they should be considered as preliminary.
    [Show full text]
  • Monoacylglycerol Lipase Inhibitors Produce Pro- Or Antidepressant Responses Via Hippocampal CA1 Gabaergic Synapses
    OPEN Molecular Psychiatry (2017) 22, 215–226 www.nature.com/mp ORIGINAL ARTICLE Monoacylglycerol lipase inhibitors produce pro- or antidepressant responses via hippocampal CA1 GABAergic synapses Y Wang1,2,9,NGu1,9, T Duan1,9, P Kesner1, F Blaskovits1, J Liu3,YLu4, L Tong1, F Gao1, C Harris5, K Mackie6,JLi4,QTan2, MN Hill7, Z Yuan8 and X Zhang1,2 The probability of suffering the mood disorder depression is up to 30% in women and 15% in men during their life span. Pharmacological options for depression are limited: conventional antidepressants have low efficacy and a delayed onset of action (several weeks). Here we investigate the antidepressant actions of inhibitors of monoacylglycerol lipase (MAGL), the major degradative enzyme of the endocannabinoid 2-arachidonoylglycerol. A low-dose of MAGL inhibitors produces antidepressant effects on acute stress-exposed mice, through glutamatergic synaptic long-term depression (LTD), without significant effects on chronic corticosterone-exposed mice. In contrast, a high-dose of MAGL inhibitors produces pro- or antidepressant effects on acute stress- or chronic corticosterone-exposed mice, respectively, through GABAergic synaptic disinhibition. In the hippocampus, in vivo inhibition of MAGL induces a CB1 cannabinoid receptor (CB1R)-dependent suppression of inhibitory GABAergic synapses and an in vivo LTD of excitatory glutamatergic synapses. LTD induction requires CB1R in astroglial cells (but not in GABAergic or glutamatergic neurons) and postsynaptic glutamate receptors. The conventional antidepressant fluoxetine produces rapid or delayed antidepressant effects in acute stress- or chronic corticosterone-exposed mice, respectively. We propose that depression- like behavior of animals in response to acute stress is the normal behavioral response, and thus, MAGL inhibitors, which produce antidepressant effects in chronic corticosterone-exposed animals through GABAergic synaptic disinhibition, represent a new class of rapidly-acting and long-lasting antidepressants.
    [Show full text]
  • New Pharmacological Agents to Aid Smoking Cessation and Tobacco Harm Reduction: What Has Been Investigated and What Is
    New Pharmacological Agents to Aid Smoking Cessation and Tobacco Harm Reduction: What has been Investigated and What is in the Pipeline? Emma Beard1,2, Lion Shahab1, Damian M. Cummings3, Susan Michie2 & Robert West1 1 University College London, Department of Epidemiology and Public Health, London, UK 2 University College London, Department of Clinical, Educational and Health Psychology, London, UK 3 University college London, Department of Neuroscience, Physiology & Pharmacology, London, UK Running header: New Agents for smoking cessation and tobacco harm reduction Word count: 12,739 Journal: Invited by CNS drugs Correspondence: Emma Beard, Cancer Research UK Health Behaviour Research Centre, University College London, WC1E 6BP, UK. Email: [email protected]. Tel: 0203 108 3179 Abstract A wide range of support is available to help smokers to quit and aid attempts at harm reduction, including three first-line smoking cessation medications: nicotine replacement therapy, varenicline and bupropion. Despite the efficacy of these, there is a continual need to diversify the range of medications so that the needs of tobacco users are met. This paper compares the first-line smoking cessation medications to: 1) two variants of these existing products: new galenic formulations of varenicline and novel nicotine delivery devices; and 2) twenty-four alternative products: cytisine (novel outside of central and eastern Europe), nortriptyline, other tricyclic antidepressants, electronic cigarettes, clonidine (an anxiolytic), other anxiolytics (e.g. buspirone), selective 5-hydroxytryptamine (5-HT) reuptake inhibitors, supplements (e.g. St John’s wort), silver acetate, nicobrevin, modafinil, venlafaxine, monoamine oxidase inhibitors (MAOI), opioid antagonist, nicotinic acetylcholine receptors (nAChR) antagonists, glucose tablets, selective cannabinoid type 1 receptor antagonists, nicotine vaccines, drugs that affect gamma-aminobutyric acid (GABA) transmission, drugs that affect N-methyl-D-aspartate receptors (NMDA), dopamine agonists (e.g.
    [Show full text]