Indication or mechanism of action? How should we best describe psychotropic drugs? Guy Goodwin University of Oxford, England President ECNP

Transcription

1 Indication or mechanism of action? How should we best describe psychotropic drugs? Guy Goodwin University of Oxford, England President ECNP

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3 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

4 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

5 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

6 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 properties Pharmacological properties Chemical properties 6

7 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 DDD, defined daily dose V Various 7

8 Current ATC classification of therapeutic drugs targeting the nervous system Analgesics Anti-epileptics Anti-Parkinson s disease drugs Anti-dementia drugs Antidepressants Non-selective monoamine reuptake inhibitors TCAs, eg imipramine, amitriptyline NRIs, eg desipramine, nortriptyline SSRIs eg zimelidine, fluvoxamine MAOIs, non-selective eg phenelzine, isocarboxazid Psycho-analeptics Psycholeptics Anaesthetics Other Psychostimulants Psycholeptics and psycho-analeptics in combinations 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; MT, melatonin MAO-AIs eg moclobemide, toloxatone Other antidepressants NRIs, eg reboxetine SNRIs, eg venlafaxine, milnacipran NDRIs, eg nomifensine, buproprion NaSSAs, eg mirtazapine SARIs, eg trazodone, nefazodone MT receptor agonist / 5-HT 2C antagonist, eg agomelatine 5-HT 1A partial agonist, eg gepirone WHO. Guidelines for ATC classification and DDD assignment. 2009, 12th ed 8

9 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

10 Current acronyms are random and confusing!!"#$%&'(')*+,'%&'-.*./+/% -'01*23'%+/4+5+*.- SSRI NAT &'()*+%,"-.-/0/+."1/%2-".," 10

11 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

12 SNRI =...selective noradrenaline reuptake inhibitor 3(4567 SNRI but on whose say so? 58)*+/-"19",/1:0/,+."1/%2-".," 12

13 Definitions in the current system confer no mechanistic information TCA = structural definition Many anti-psychotics and anti-histamines are also TCAs TCA DAT DAT, dopamine transporter 13

14 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

15 Vortioxetine: illustrating the problems Direct effects 5-HT 1A agonist Receptor activity 5-HT 1B partial agonist 5-HT 3 antagonist 5-HT 7 antagonist Lu AA21004 Reuptake inhibition Neurotransmitter enhancement SERT inhibitor Indirect effects Lserotonin Lnoradrenaline Lacetylcholine Ldopamine Lhistamine Bang-Andersen B et al. J Med Chem 2011;54:

16 How do we fit these compounds into the ATC system? Duloxetine Agomelatine OTHERS Vilazodone Lu AA21004 Nutt DJ. J Psychopharmacol 2009;23:

17 Current ATC classification of antidepressant drugs N Nervous system N06 Psycho-analeptics N06A Antidepressants N06AA Non-selective monoamine reuptake inhibitors N06AB SSRIs N06AF MAOIs, non-selective N06AG MAO-AIs N06AX Other antidepressants N06AA01 Desipramine N06AA02 Imipramine N06AA03 Imipramine oxide N06AA04 Clomipramine N06AA05 Opipramol N06AA06 Trimipramine N06AA07 Lofepramine N06AA08 Dibenzepin N06AA09 Amitriptyline N06AA10 Nortriptyline N06AA11 Protriptyline N06AA12 Doxepin N06AA13 Iprindole N06AA14 Melitracen N06AA15 Butriptyline N06AA16 Dosulepin N06AA17 Amoxapine N06AA18 Dimetacrine N06AA19 Amineptine N06AA21 Maprotiline N06AA23 Quinupramine N06AB02 Zimeldine N06AB03 Fluoxetine N06AB04 Citalopram N06AB05 Paroxetine N06AB06 Sertraline N06AB07 Alaproclate N06AB08 Fluvoxamine N06AB09 Etoperidone N06AB10 Escitalopram N06AF01 Isocarboxazid N06AF02 Nialamide N06AF03 Phenelzine N06AF04 Tranylcypromine N06AF05 Iproniazide N06AF06 Iproclozide N06AG02 Moclobemide N06AG03 Toloxatone N06AX01 Oxitriptan N06AX02 Tryptophan N06AX03 Mianserin N06AX04 Nomifensine N06AX05 Trazodone N06AX06 Nefazodone N06AX07 Minaprine N06AX08 Bifemelane N06AX09 Viloxazine N06AX10 Oxaflozane N06AX11 Mirtazapine N06AX12 Bupropion N06AX13 Medifoxamine N06AX14 Tianeptine N06AX15 Pivagabine N06AX16 Venlafaxine N06AX17 Milnacipran N06AX18 Reboxetine N06AX19 Gepirone N06AX21 Duloxetine N06AX22 Agomelatine N06AX23 Desvenlafaxine 17

18 Others is constantly growing 18

19 The opportunity to improve 19

20 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

21 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

22 ECNP, CINP, ACNP, AsCNP as lead organizations 22

23 The multiaxial system 23

24 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=455)

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27 Knowledge 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%).

28 Knowledge of current system if SSRI is Selective Serotonin Reuptake Inhibitor (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.

29 How should nomenclature in neuropsychopharmacology be formulated? Should new antipsychotics be called second generation (28.3%), atypical (32.6%), serotonin dopamine antagonists (23.8%) or some other term (15.4%). However, after considering that some "antipsychotics" are also approved as "antimanics" and "antidepressants", 591 (71.5%) agreed that these terminologies were inadequate or confusing. 288 (34.9%) preferred that antipsychotics be classified according to their principal shared mechanism of action, although 322 (39%) preferred that they be classified by several characteristics if possible - clinical use, functional neurobiological effect and symptom improvement profile.

30 Solutions for specific dilemmas arising in classification of drugs For drugs with multiple targets of action, opinion was split between multifunctional (26.3%), multimodal (42.8%) and mixed action (25.3%). For agents that improve psychosis along with other clinical actions, the preference was for a pharmacologically driven term (52.9%), rather than a clinical-based term (24.8%) or any other option (18.5%). If more than one term applies to a single molecule, respondents felt that placing the molecule in more than one class, or giving it more than one name would be helpful (74.4%). If a drug improves negative symptoms in schizophrenia, but does not block D2 receptors, 572 (63.1%) of the participants felt that it should be primarily categorized by its pharmacological action.

31 The Taskforce Five international neuropsychopharmacological organizations joined forces to create a new nomenclature ECNP: European College of Neuropsychopharmacology ACNP: American College of Neuropsychopharmacology AsCNP: Asian College of Neuropsychopharmacology CINP: International College of Neuropsychopharmacology IUPHAR: International Union of Basic and Clinical Pharmacology

32 The Taskforce Chair: Joseph Zohar, European College of Neuropsychopharmacology Stephen Stahl, International College of Neuropsychopharmacology Hans-Jürgen Möller, International College of Neuropsychopharmacology Pierre Blier, American College of Neuropsychopharmacology David Kupfer, American College of Neuropsychopharmacology Shigeto Yamawaki, Asian College of Neuropsychopharmacology Hiroyuki Uchida, Asian College of Neuropsychopharmacology Michael Spedding, International Union of Basic and Clinical Pharmacology Guy Goodwin, European College of Neuropsychopharmacology David Nutt, European College of Neuropsychopharmacology Coordinator: Sue Wilson, Imperial College of London

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34 The new multi-axial classification system Axis 1 Class Subtype Axis 2 Name (primary pharmacological targets) Axis 3 Neurobiological activity Animal and Human Neurotransmitter effects/phenotypes/brain circuits/gene expression/physiological Axis 4 Axis 5 Clinical observations (including major adverse effects) Indications 34

35 B1C-."0$0/, Axis 1 Class Relevant mechanism glutamate ion channel blocker Axis 2 Subclass lamotrigine Axis 3 Efficacy anti-epilepsy; prevention of depressive episodes in bipolar disorder Side effects Skin rash, dizziness Axis 4 Indications (FDA or EMA approved, or as stated) Prevention of mood episodes in patients with bipolar disorder predominantly by preventing depressive episodes; epilepsy See next page for more detailed neurobiological description, referen 35

36 B0.;0#C Axis 1 Class Relevant mechanism Axis 2 Subclass Axis 3 Efficacy Cation lithium cation, enzyme inhibitor Anti-manic, mood-stabilizing; used to augment antidepressants Side effects Weight gain, tremor, thyroid dysfunction, renal dysfunction Axis 4 Indications (FDA or EMA approved, or as stated) Bipolar disorder; mania; (US and Europe); recurrent depression; aggressive or self mutilating behaviour (Europe). Committee notes Mechanism of action unclear, inositol involved in dopamine receptor signalling? 36

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42 Conclusions The existing nomenclature Is embarrasssing The opportunity to improve ECNP, CINP, ACNP, AsCNP as lead organizations The multiaxial system we propose Why it matters More words, means deeper understanding, better practice 42

43 This is a work in progress HELP US TO MAKE IT BETTER 43