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Indication or mechanism of action? How should we best describe psychotropic ?

Guy Goodwin University of Oxford, England President ECNP !"#$%&#'()

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•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 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

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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 , NRIs, eg , Analgesics Anti-dementia drugs SSRIs eg , Anti-epileptics

Anti-Parkinsons MAOIs, non-selective disease drugs eg ,

Psycho-analeptics MAO-AIs eg , Psycho- Psycholeptics Other antidepressants NRIs, eg SNRIs, eg , Anaesthetics NDRIs, eg , buproprion Psycholeptics and NaSSAs, eg psycho-analeptics SARIs, eg , Other in combinations MT receptor / 5-HT2C antagonist, eg

5-HT1A partial agonist, eg TCA, ; NRI, noradrenaline ; SSRI, selective reuptake inhibitor; MAOI, monoamine oxidase inhibitor; MAO-AI, monoamine oxidase A inhibitor; SNRI, serotonin–noradrenaline reuptake inhibitor; NDRI, noradrenaline– reuptake inhibitor; NaSSA, noradrenergic and specific 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+*.-

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10 Question

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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, 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 : 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 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 N06AF02 N06AG03 Toloxatone N06AX02 N06AA03 Imipramine oxide N06AB04 N06AF03 Phenelzine N06AX03 N06AA04 N06AB05 N06AF04 N06AX04 Nomifensine N06AA05 N06AB06 N06AF05 Iproniazide N06AX05 Trazodone N06AA06 N06AB07 N06AF06 N06AX06 Nefazodone N06AA07 N06AB08 Fluvoxamine N06AX07 N06AA08 N06AB09 N06AX08 N06AA09 Amitriptyline N06AB10 N06AX09 N06AA10 Nortriptyline N06AX10 N06AA11 N06AX11 Mirtazapine N06AA12 N06AX12 N06AA13 N06AX13 N06AA14 N06AX14 N06AA15 N06AX15 N06AA16 N06AX16 Venlafaxine N06AA17 N06AX17 Milnacipran N06AA18 N06AX18 Reboxetine N06AA19 N06AX19 Gepirone N06AA21 N06AX21 N06AA23 N06AX22 Agomelatine N06AX23

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=455) "'&1./&' CGHD% CDE% =!%>'5? 6.*2(% 7/8IJK< 7/8F:< &0-,'@% 7/89:;< 7/8ABB< D&@)4+2*-+&* JJM JALNM BBM ;BL9M

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•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 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 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 );,+'<5=+8<5=+<>5=+8%<5=+>?=@8(+=(4A'<)+

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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 Clinical observations (including major adverse effects) Axis 5 Indications

34 B1C-."0$0/,

Axis 1 Class glutamate • Relevant mechanism ion

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 • 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 ; aggressive or self mutilating behaviour (Europe).

Committee notes • Mechanism of action unclear, inositol involved in dopamine receptor signalling? • 36 D0%#1:0%0/$+=%EF;01."0F+G,90F1.0-/

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41 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 This is a work in progress

HELP US TO MAKE IT BETTER

43