Indication or mechanism of action? How should we best describe … · 2019-09-21 · Psycho-analeptics Anti-dementia drugs Antidepressants Psycho-stimulants Psycholeptics and psycho-analeptics

Indication or mechanism of action? How should we best

describe psychotropic drugs ?

Guy GoodwinUniversity of Oxford, England

President ECNP

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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

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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

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• 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

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Therapeutic properties

Pharmacological properties

Chemical properties

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Rationale for WHO drug classification system (2)

WHO guidelines for ATC classification andDDD assignment

ATC SYSTEM MAIN GROUPSThe main groups of the ATC classification system arelisted below. A survey of each main group is given inthe 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 Various7DDD, defined daily dose

Current ATC classification of therapeutic drugs targeting the nervous system

WHO. Guidelines for ATC classification and DDD assignment. 2009, 12th ed

Psycho-analeptics

Anti-dementia drugs

Antidepressants

Psycho-stimulants

Psycholeptics and psycho-analeptics in combinations

Non-selective monoamine reuptake inhibitorsTCAs, eg imipramine, amitriptyline NRIs, eg desipramine, nortriptyline

SSRIseg zimelidine, fluvoxamine

MAOIs, non-selectiveeg phenelzine, isocarboxazid

MAO-AIseg moclobemide, toloxatone

Other antidepressantsNRIs, eg reboxetineSNRIs, eg venlafaxine, milnacipranNDRIs, eg nomifensine, buproprionNaSSAs, eg mirtazapineSARIs, eg trazodone, nefazodoneMT receptor agonist / 5-HT2Cantagonist, eg agomelatine5-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; MT, melatonin

Analgesics

Anti-epileptics

Anti-Parkinson s disease drugs

Psycholeptics

Anaesthetics

Other

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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

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Current acronyms are random and confusing

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SSRI NAT

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Question

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SNRI =

3(4567 SNRI

...selective noradrenaline reuptakeinhibitor

…but on whose say so?

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DATTCA

Definitions in the current system confer no mechanistic information

• TCA = structural definition

• 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

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Receptor activity

Reuptake inhibition

Neurotransmitter enhancement

5-HT1B partial agonist

5-HT3 antagonist

Direct effects

Indirect effects

5-HT1A agonist

5-HT7 antagonist

SERT inhibitor

Lserotonin

Lnoradrenaline

Lacetylcholine

Ldopamine

Lhistamine

Vortioxetine: illustrating the problems

Bang-Andersen B et al. J Med Chem 2011;54:3206-21 15

Vilazodone

OTHERS

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How do we fit these compounds into the ATC system?

Nutt DJ. J Psychopharmacol 2009;23:343-5

Agomelatine

Duloxetine

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Current ATC classification ofantidepressant drugs

N Nervous system

N06 Psycho-analeptics

N06A Antidepressants

N06AANon-selectivemonoamine

reuptake inhibitors

N06AB SSRIs

N06AF MAOIs,

non-selective

N06AG MAO-AIs

N06AX Other

antidepressants

N06AA01 DesipramineN06AA02 Imipramine

N06AA03 Imipramine oxideN06AA04 Clomipramine

N06AA05 OpipramolN06AA06 TrimipramineN06AA07 LofepramineN06AA08 Dibenzepin

N06AA09 AmitriptylineN06AA10 NortriptylineN06AA11 Protriptyline

N06AA12 DoxepinN06AA13 IprindoleN06AA14 Melitracen

N06AA15 ButriptylineN06AA16 Dosulepin

N06AA17 AmoxapineN06AA18 DimetacrineN06AA19 AmineptineN06AA21 Maprotiline

N06AA23 Quinupramine

N06AB02 ZimeldineN06AB03 FluoxetineN06AB04 Citalopram N06AB05 ParoxetineN06AB06 SertralineN06AB07 Alaproclate

N06AB08 FluvoxamineN06AB09 EtoperidoneN06AB10 Escitalopram

N06AF01 IsocarboxazidN06AF02 NialamideN06AF03 Phenelzine

N06AF04 TranylcypromineN06AF05 IproniazideN06AF06 Iproclozide

N06AG02 MoclobemideN06AG03 Toloxatone

N06AX01 OxitriptanN06AX02 TryptophanN06AX03 Mianserin

N06AX04 NomifensineN06AX05 Trazodone

N06AX06 NefazodoneN06AX07 Minaprine

N06AX08 BifemelaneN06AX09 ViloxazineN06AX10 OxaflozaneN06AX11 MirtazapineN06AX12 Bupropion

N06AX13 MedifoxamineN06AX14 TianeptineN06AX15 PivagabineN06AX16 VenlafaxineN06AX17 MilnacipranN06AX18 ReboxetineN06AX19 Gepirone

N06AX21 DuloxetineN06AX22 Agomelatine

N06AX23 Desvenlafaxine

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Others is constantly growing

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The opportunity to improve

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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.

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•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.

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ECNP, CINP, ACNP, AsCNP as lead organizations

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The multiaxial system

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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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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%).

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 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.

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.

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

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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The new multi-axial classification system

Axis 1ClassSubtype

Axis 2Name (primary pharmacological targets)

Axis 3Neurobiological activity

Animal and HumanNeurotransmitter effects/Phenotypes/Brain circuits/Gene expression/PhysiologicalAxis 4

Clinical observations (including major adverse effects)

Axis 5Indications

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Axis 1 Class glutamate • Relevant mechanism 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

B0.;0#C

• Axis 1 Class Cation• Relevant mechanism cation, enzyme inhibitor • Axis 2 Subclass lithium • Axis 3 Efficacy 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? •

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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

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This is a work in progress

HELP US TO MAKE IT BETTER

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