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Goodwin Nomenclature Indication or mechanism of action? How should we best describe psychotropic drugs ? Guy Goodwin University of Oxford, England President ECNP !"#$%&#'() ! "#$%&' ()#*+)#,-./*+&$0 ! 12%2#$#+$ 3'&#$4)%)5$,-67(,- 8+'$+,-9:%;<)5=,-()#*+)# ! (>$#)' ./*+&$0 ! .$+;-?2'+&+2%' @%+*)#'+&A-2B-CDB2#; ! 3;*+'2#A-<2$#;'-- 3'&#$4)%)5$,-62)>#+%E)#- F%E)0>)+G,-67(,-H)?>$02%,- 9:%;<)5=,-./I+&$0,-J25>),- ()#*+)# ! 8D?)#&-K+&%)'' 9+00A,-()#*+)# Objectives •The existing nomenclature –Its origins, it limitations, its contradictions •The opportunity to improve –ECNP, CINP, ACNP, AsCNP, IUPHAR as lead organizations –The DSM5 controversy – does nomenclature impede understanding •The multiaxial system we propose •Why it matters 3 Pharmacological Nomenclature: the Status Quo • Current nomenclature began in the early 1950’s by the WHO and was based on their clinical use at the time • Predates neuroscientific understanding of psychopharmacology • Some classes of drugs have not been updated with current knowledge Rationale for WHO drug classification system (1) • WHO symposium in Oslo in 1969 agreed a consensus that an international system of drug classification was needed: the Drug Utilisation Research Group (DURG) was established • DURG created the WHO ATC (Anatomical Therapeutic Chemical) classification system • Controlled by the WHO Collaborating Centre for Drug Statistics Methodology (WHOCC) • The ATC system was 1st published in 1976 and is used to present drug utilisation data – National and international comparisons of drug utilisation – Evaluation of long-term trends in drug use – Assessing the impact of certain events on drug use – Providing denominator data in investigations of drug safety 5 Rationale for WHO drug classification system (2) • The classification system divides drugs into different groups according to the organ or system on which they act and / or their therapeutic and chemical characteristics !"#$% Organ /system Therapeutic Pharmacological Chemical properties properties properties 6 WHO guidelines for ATC classification and DDD assignment ATC SYSTEM MAIN GROUPS The main groups of the ATC classification system are listed below. A survey of each main group is given in the beginning of each of the following chapters A Alimentary tract and metabolism B Blood and blood-forming organs C Cardiovascular system D Dermatologicals G Genitourinary system and sex hormones H Systemic hormonal preparations, excl. sex hormones and insulins J Anti-infectives for systemic use L Anti-neoplastic and immunomodulating agents M Musculo-skeletal system N Nervous system P Anti-parasitic products, insecticides and repellents R Respiratory system S Sensory organs V Various DDD, defined daily dose 7 Current ATC classification of therapeutic drugs targeting the nervous system Non-selective monoamine reuptake inhibitors TCAs, eg imipramine, amitriptyline NRIs, eg desipramine, nortriptyline Analgesics Anti-dementia drugs SSRIs eg zimelidine, fluvoxamine Anti-epileptics Anti-Parkinsons Antidepressants MAOIs, non-selective disease drugs eg phenelzine, isocarboxazid Psycho-analeptics MAO-AIs eg moclobemide, toloxatone Psycho- stimulants Psycholeptics Other antidepressants NRIs, eg reboxetine SNRIs, eg venlafaxine, milnacipran Anaesthetics NDRIs, eg nomifensine, buproprion Psycholeptics and NaSSAs, eg mirtazapine psycho-analeptics SARIs, eg trazodone, nefazodone Other in combinations MT receptor agonist / 5-HT2C antagonist, eg agomelatine 5-HT1A partial agonist, eg gepirone TCA, tricyclic antidepressant; NRI, noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; MAOI, monoamine oxidase inhibitor; MAO-AI, monoamine oxidase A inhibitor; SNRI, serotonin–noradrenaline reuptake inhibitor; NDRI, noradrenaline–dopamine reuptake inhibitor; NaSSA, noradrenergic and specific serotonergic antidepressant; SARI, serotonin-2 antagonist / reuptake inhibitor; WHO. Guidelines for ATC classification and MT, melatonin DDD assignment. 2009, 12th ed 8 Obvious problems with current ATC classification system Current acronyms are random and confusing eg SSRI –v– SNRI –v– NaSSA –v– TCA Some acronyms confer no mechanistic information Others as a class is meaningless 9 Current acronyms are random and confusing NAT !!"#$%&'(')*+,'%&'-.*./+/% SSRI -'01*23'%+/4+5+*.- &'()*+%,"-.-/0/+."1/%2-".," 10 Question !"#$$%&#'#()*)+,!-)#()./,/0!0#.)12,34)# !05!6!,/.#753,#(5/1*8##$9%&#:)30; $)*)+,!-)#0/.38.)03*!0)#.)12,34)# !05!6!,/. $)./,/0!0#0/0<()*)+,!-)#.)12,34)# !05!6!,/. $)./,/0!0#0/.38.)03*!0)#.)12,34)# !05!6!,/.# 11 SNRI = ...selective noradrenaline reuptake inhibitor SNRI 3(4567 …but on whose say so? 58)*+/-"19",/1:0/,+."1/%2-".," 12 Definitions in the current system confer no mechanistic information • TCA = structural definition TCA DAT • Many anti-psychotics and anti-histamines are also TCAs DAT, dopamine transporter 13 Others as a class is meaningless Current system is random and confusing SSRI –v– SNRI –v– NaSSA –v– TCA In WHO system, most antidepressant drugs are others 14 Vortioxetine: illustrating the problems Direct effects 5-HT1A agonist 5-HT1B partial agonist Receptor activity 5-HT3 antagonist 5-HT7 antagonist Reuptake inhibition SERT inhibitor Lu AA21004 Indirect effects Lserotonin Lnoradrenaline Neurotransmitter Lacetylcholine enhancement Ldopamine Lhistamine Bang-Andersen B et al. J Med Chem 2011;54:3206-21 15 How do we fit these compounds into the ATC system? Duloxetine Agomelatine OTHERS Lu Vilazodone AA21004 Nutt DJ. J Psychopharmacol 2009;23:343-5 16 Current ATC classification of antidepressant drugs N Nervous system N06 Psycho-analeptics N06A Antidepressants N06AA N06AF N06AX Non-selective N06AB N06AG MAOIs, Other monoamine SSRIs MAO-AIs non-selective antidepressants reuptake inhibitors N06AA01 Desipramine N06AB02 Zimeldine N06AF01 Isocarboxazid N06AG02 Moclobemide N06AX01 Oxitriptan N06AA02 Imipramine N06AB03 Fluoxetine N06AF02 Nialamide N06AG03 Toloxatone N06AX02 Tryptophan N06AA03 Imipramine oxide N06AB04 Citalopram N06AF03 Phenelzine N06AX03 Mianserin N06AA04 Clomipramine N06AB05 Paroxetine N06AF04 Tranylcypromine N06AX04 Nomifensine N06AA05 Opipramol N06AB06 Sertraline N06AF05 Iproniazide N06AX05 Trazodone N06AA06 Trimipramine N06AB07 Alaproclate N06AF06 Iproclozide N06AX06 Nefazodone N06AA07 Lofepramine N06AB08 Fluvoxamine N06AX07 Minaprine N06AA08 Dibenzepin N06AB09 Etoperidone N06AX08 Bifemelane N06AA09 Amitriptyline N06AB10 Escitalopram N06AX09 Viloxazine N06AA10 Nortriptyline N06AX10 Oxaflozane N06AA11 Protriptyline N06AX11 Mirtazapine N06AA12 Doxepin N06AX12 Bupropion N06AA13 Iprindole N06AX13 Medifoxamine N06AA14 Melitracen N06AX14 Tianeptine N06AA15 Butriptyline N06AX15 Pivagabine N06AA16 Dosulepin N06AX16 Venlafaxine N06AA17 Amoxapine N06AX17 Milnacipran N06AA18 Dimetacrine N06AX18 Reboxetine N06AA19 Amineptine N06AX19 Gepirone N06AA21 Maprotiline N06AX21 Duloxetine N06AA23 Quinupramine N06AX22 Agomelatine N06AX23 Desvenlafaxine 17 Others is constantly growing 18 The opportunity to improve 19 The DSM5 controversy – does nomenclature impede understanding • DSM5 is very little changed from DSM-IV • Widespread feeling that there needs to be a more neuroscientific approach to classification • The Research Domain Criteria project (RDoC)– by NIMH •new ways of classifying psychopathology based on dimensions of observable behavior and neurobiological measures. 20 • define basic dimensions of functioning (such as fear circuitry or working memory) to be studied across multiple units of analysis, from genes to neural circuits to behaviors, cutting across disorders as traditionally defined. • The intent is to translate rapid progress in basic neurobiological and behavioral research to an improved integrative understanding of psychopathology and the development of new and/or optimally matched treatments for mental disorders. 21 ECNP, CINP, ACNP, AsCNP as lead organizations 22 The multiaxial system 23 Testing the Multi-axial Template •September 2011, Paris – at an educational track session in the ECNP Annual Congress (n=371) •March 2012, Prague – at an educational session in the EPA Annual Congress (n=80) •February 2012 – an online survey completed by US practitioners and researchers (n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nowledge of current system •602 (66.4%) had not heard of the WHO drug classes •Only 274 (30.2%) knew antidepressants were categorized as "thymoleptics". •754 respondents (83.2%) acknowledged that the classifications of SSRI and SNRI affected their prescribing decisions. •Most (62.3%) claimed that pharmacology was the main factor in choosing an antidepressant, with adverse events the second most popular consideration (25.1%). Knowledge of current system •if SSRI is Selective Serotonin Reuptake Inhibitor….. – 583 (64.3%) claimed that the actual meaning – Serotonin-Noradrenaline Reuptake Inhibitor – is an obvious choice –293 (32.3%) conceded that the meaning of SNRI should logically be presumed to be Selective Noradrenaline Reuptake Inhibitor. How should nomenclature in neuropsychopharmacology
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