a.denayer@hopitaux-gilly.be 22 novembre2007 Le Modèle de Montigny: un indice therapeutique,aide au bon usage des neuroleptiques ? a.denayer@hopitaux-gilly.be 22 novembre2007 ADN 2007

Natural History of Schizophrenia Stages of illness Premorbid Prodromal Onset / deterioration Chronic / residual Healthy   Worsening severity of signs and symptoms Deterioration Margin of prevention Sensitisation by dopamine Excitatory neurotoxicity of glutamate Abnormal brain development Neurochemical dysregulation Neurodegenerative? Gestation / birth 10 Puberty 20 30 40 50 Years ADN 2007 Lieberman et al 2001

ADN 2007

Schizophrenia Remission mode(single episode) Symptom Severity Diagnostic symptoms Other symptoms “Normalcy” Diagnostic level Remission ADN 2007 Time

Longitudinal course: schizophrenia Relapse Diverse Disease States Remission Recovery Function Threshold Symptom severity Functioning Note: This is a key slide: ahw voorstel van een nieuw model : nb. Na remissie – recovery, waarbij de functioning weer belangrijk wordt en toe moet nemen !! Cognition : hoe dit er moet inpassen is nog steeds niet duidelijk – In dit model worden Functioning/& Cognition duidelijk ondergebracht in de fase van recovery – Remissie: tijdsfactor is belangrijk Diverse symptoms Unity of key symptoms 6 months Time ? Cognition ? ADN 2007

ADN 2007

Quelques Données supplémentaires 40% de rechutes durant la premiere année 20% sous médication 66% sous placebo ADN 2007

Remission 1/3 des cas ADN 2007

Remission: Au fil du temps JOURS 1 Episode Rémission 40 2 Episode 60 120 3 Episode ADN 2007

LORS DES RECHUTES Quid de la compliance ??? 10% Adaptation des posologies selon le stade.Modèle du Parkinson Durées du TTT-Drug holidays ? La nouvelle notion de Rémission ADN 2007

Facteurs de Rechutes non Biologiques E.E (X 2,5) Attitudes familiales critiques ou surprotectives Life events Stress ADN 2007

Facteurs Protecteurs non Biologiques Ressources personnelles prémorbides Un réseau social compétent ADN 2007

Caractéristiques des patients a faibles risques de Rechutes Femmes Age > 40 ans ADN 2007

Caractéristiques des patients a risques élevés de Rechutes Antécédents suicidaires Religiosités Intenses Diagnostic de Psychose Schizo Affective ADN 2007

PARADOXES et DIFFICULTES du TRAITEMENT PHARMACOLOGIQUE des DIFFERENTES PHASES de la (des ) SCHIZOPHRENIE (S) ADN 2007

Un Aphorisme trop occulté L’ADMISSION EN URGENCE EST LE PLUS SOUVENT CONDITIONNEE PAR L’ARGUMENT SOCIAL ET L’AGITATION INDUITE QUE PAR LA PSYCHOSE EN TANT QUE TELLE ADN 2003 ADN 2007

CONSEQUENCE LA NEUROLEPTISATION DE PAR SON MODE D’ACTION ANTIPSYCHOTIQUE EST DONC NI FORCEMENT TOUJOURS REQUISE,NI TOUJOURS ADEQUATE ADN 2003 ADN 2007

BIENFONDE D’UNE INTERVENTION RAPIDE DANS LES ETATS PSYCHOTIQUES PROPRIETE DESTRUCTURANTE DU DELIRE ADN 2007

Receptor Binding Characteristic of Antipsychotics Goldstein,2000 ADN 2007

Histamine Type 1 Receptor H1 Antagonism Sedation, sleepiness, Together with 5-HT2C and D2 antagonism contributes to substantial weight gain Some new antipsychotics are primary H1 antagonists and highly sedative, which together with 5-HT2C antagonism contribute to substantial weight gain. ADN 2007

LES ANTAGONISTES H1 DISPONIBLES CLOZAPINE MAIS….Agranulocytose OLANZAPINE MAIS… Syndrome Metabolique. QUETIAPINE MAIS… A posologie élevée.Titration. RISPERIDONE MAIS …EPS a posologie utile ADN 2007

CONFUSION DES ATTENTES!!! Difficultés du TTT en fonction de la Symptomatologie CONFUSION DES ATTENTES!!! BLOCAGE D2 OU SEDATION? ADN 2007

Un prescripteurs pieds et poings liés D2 et HI structurellement dans un rapport fixe non modifié par la posologie. Toutes modifications désirées de l ’une entraîne celles de l ’autre rarement souhaitées . Conséquence: manque de liberté du prescripteurs ADN 2007

Difficultés du TTT en fonction de la Symptomatologie Positifs: Exces de la fonction normale: -Hallucinations,Délires.Exitation, Négatifs: Réduction ou Disparition de la fonction normale -Anhédonie,Retrait social,Aboulie,Emoussement ,Alogie, Troubles Cognitifs. SEDATION ACTIVATION ADN 2007

Les Difficultés de l ’Adaptation Posologique 1/Posologie d ’attaque élevée : en vue d ’une nécessaire Sédation 2/Posologie de Maintenance trop élevée La Sédation n’étant plus nécessaire et Pour favoriser la Resocialisation 3/Baisse Posologique : D’où risques de rechute ADN 2007

Comment obtenir l’occupation optimale des D2 ? Doses faibles de neuroleptiques classiques Action sur les 5-HT2A (neuroleptiques atypiques) Antagonisme partiel (aripiprazole) Dissociation rapide (quetiapine) Atténuation du passage de la BBB (sulpiride) ADN 2007

Transient D2 Receptor Occupancy with Quetiapine 57% D2 occupancy 20% D2 occupancy 400mg Seroquel 3 hours 9 hours PRL 19 ng/mL ELEVATED PRL 4 ng/mL NORMAL C-11 raclopride 0% D2 occupancy 64% D2 occupancy 450mg Seroquel 2 hours 24 hours PRL 27 ng/mL ELEVATED PRL 2 ng/mL BELOW NORMAL ADN 2007 From Kapur, 1999 (presentation)

Une constante le contrôle D2 Quid des variables 1/ Contrôle de l’agitation 2/ La maintenance 3/ La socialisation ADN 2007

Maintenance Acute Acute Attaque ADN 2007

1 4 2 3 5 (6) 6 6 2 5 7 4 1 ( 2 ) 3 ADN 2007

Affinity for receptors: Ki values (nM) D2 5-HT2A D2/5HT 3.30 O.16 20 4.00 36.0 0,1 4.79 0.42 11 11.0 4.00 2,7 160 294  0,5 180 1.60 112 DRUGS Risperidone` Haloperidol Ziprasidone Olanzapine Quietiapine Clozapine ADN 2007

Data are average from Roth et all 1995 Seeger et al 1996 Richelson 1999/2000 ADN 2007

D2/H1 D2 H1 D2/H1 1/Sertindole 0,45 500 0,0009 Haloperidol 4 1890 0,002 2/Ziprasidone 0,42 47 0,009 3/Risperidone 3,30 59 0,056 4/Aripiprazol 3,40 61 5/Olanzapine 11 7,14 1,54 6/Quetiapine 160 14,5 7/Clozapine 180 2,75 65,45 ADN 2007

H1/D2 D2 H1 H1/D2 Clozapine 180 2,75 0,015 Quetiapine 160 11 0,07 Olanzapine 7,14 0,65 Aripiprazol 3,40 61 18 Risperidone 3,30 59 Ziprasidone 0,42 47 112 Haloperidol 4 1890 472,5 Sertindole 0,45 500 1111 ADN 2007

H1 sedation D2 incisivité 1/CLOZ 2/OLAZ 3/QUET 4/RISP 5/SERT 6/ZIPR 7/AMI 8/ARIP 1/ARIP 2/SERT 3/RISP 4/AMI 5/ZIP 6/OLA 7/CLO 8/QUE ADN 2007

Schmidt eur j pharmacology 2001 H1 D2/H1 cloz 130 1,8 72,2 OLZ 20 2,8 7,14 QUET 180 8,7 20,68 zIP 3,1 47 0,06 hALD 1,4 44 0,031 ADN 2007

Receptor binding (Ki values, nM) Ser Ris Olz Clz Que D2 0.45 0.44 2.1 36 69 H1 440 88 5.6 17 21 D2/H1 0,001 0,005 0,375 2,1 3,28 Serdolect® has been tested in a number of in vitro binding assays and compared with various other antipsychotics (see slide). Serdolect® has a high affinity for serotonin 5-HT2A, 5-HT2C, dopamine D2 and 1-adrenergic receptors, and a low affinity for serotonin 5-HT1A, muscarinic cholinergic, histamine H1 and -adrenergic receptors. The in vitro rank order of receptor affinity of Serdolect® is serotonin 5-HT2A dopamine D2 > 1-adrenergic. However, in ex vivo binding studies the affinity ranking is serotonin 5-HT2 > 1-adrenergic > dopamine D2. Arnt & Skarsfeldt. Neuropsychopharmacology 1998; 18: 63–101. Hyttel J, Nielsen JB, Nowak G. J Neural Transm [GenSect] 1992; 89: 61–69. ADN 2007 Arnt & Skarsfeldt 1998

Receptor binding (Ki values, nM) Que Clz Olz Ris Ser D2 69 36 2.1 0.44 0.45 H1 21 17 5.6 88 440 H1/D2 0,30 0,47 2,66 200 978 Serdolect® has been tested in a number of in vitro binding assays and compared with various other antipsychotics (see slide). Serdolect® has a high affinity for serotonin 5-HT2A, 5-HT2C, dopamine D2 and 1-adrenergic receptors, and a low affinity for serotonin 5-HT1A, muscarinic cholinergic, histamine H1 and -adrenergic receptors. The in vitro rank order of receptor affinity of Serdolect® is serotonin 5-HT2A dopamine D2 > 1-adrenergic. However, in ex vivo binding studies the affinity ranking is serotonin 5-HT2 > 1-adrenergic > dopamine D2. Arnt & Skarsfeldt. Neuropsychopharmacology 1998; 18: 63–101. Hyttel J, Nielsen JB, Nowak G. J Neural Transm [GenSect] 1992; 89: 61–69. ADN 2007 Arnt & Skarsfeldt 1998

Quotient D2 /H1(INC/SED) CLOZ :72,2 QUET: 20,68 OLAZ:7,14 _________________Seuil_d’équivalence RISP:0,115 ZIP:0,065 AMI:0,00046 ARIP:  Le seuil d’action antipsychotique N’est atteint qu’au prix de la sédation ADN 2007

Quotient D2 /H1(INC/SED) INCISIVITE CLOZ :72,2 QUET: 20,68 OLAZ:7,14 Seuil_d’Equivalence RISP:0,115 TTT de Phases de Maintenance ZIP:0,065 AMI:0,00046 ARIP: TTT de phases initiales …. SEDATION ADN 2007

Quotient D2 /H1(INC/SED) CLOZ :72,2 QUET: 20,68 OLAZ:7,14 Seuil_d’Equivalence RISP:0,115 TTT de Phases de maintenance ZIP:0,065 AMI:0,00046 ARIP:  TTT de phases initiales ….avec risques d’inéfficacité lors d’une diminution en vue d’eviter l’excès de sédation lors de la phase de maintenance Nécéssité d’une coprescrition lors d’utilisation en phase Initiale( non nécéssairement anti-D2…Ex:BZD) ADN 2007

La coprescription :une solution? ADN 2007

BZD AVANTAGES: ACTION RAPIDE ,SURE ,EFFICACE, PAS D’INFLUENCE D2 DESAVANTAGE :CONFUSION REPONSE ET REMISSION REPONSE « SYMPTÔMATOLOGIQUE » TROUBLE MNESIQUE ADN 2007

Quotient D2 /H1(INC/SED) CLOZ :72,2 QUET: 20,68 OLAZ:7,14 Seuil_d’Equivalence RISP:0,115 ZIP:0,065 AMI:0,00046 ARIP: ASSOCIATION : Possible Entre les 2 catégories, Mais a Posologie Moindre (Effet anti-D2 cumulatif ) Ensuite OBLIGATION D’arrêt de la molécule sédative Et D’augmentation de la molecule incisive pour garder un blocage D2 suffisant ADN 2007

Quotient D2 /H1(INC/SED) CLOZ :72,2 QUET: 20,68 OLAZ:7,14 Seuil_d’Equivalence RISP:0,115 ZIP:0,065 AMI:0,00046 ARIP: Ensuite DIMINUTION ou D’arrêt de la molécule sédative Et D’augmentation de la molecule incisive pour garder un blocage D2 suffisant ADN 2007

POUR ATTEINDRE LE BUT FINAL :LA REMISSION La sédation n’a plus de raison Elle devient obstacle et non solution….. ADN 2007

Maintenance Acute Acute Maintenance Attaque ADN 2007

ZONE THERAPEUTIQUE BLOCAGE D2 SEDATION/HI ADN 2007

COPRESCRIPTION TYPIQUES ATYPIQUES 1/PERTE DE L’AVANTAGE :CUMUL DES ANTAGONISMES DES RECEPTEURS D2 avec priorité aux affinités élevée Sait- on in fine lequel prescrit- on? Cumul des actions dirty drug et donc des AE ADN 2003 ADN 2007

.QUELLE MOLECULE? QUELLE POSOLOGIE? ADN 2007

STRATEGIES POSSIBLES (1) LA MOLECULE INITIALE est maintenue Double tâche paradoxale:passage obligé de la sédation a l’’activation, du contrôle de la symptomatologie positive a celui de la symptomatologie négative / ADN 2007

STRATEGIES POSSIBLES (1) Pour atteindre ce but généralement le clinicien réduit la posologie avec le risque subséquent de ne plus bloquer suffisamment les D2 Et donc de quitter la zone thérapeutique / ADN 2007

STRATEGIES POSSIBLES (2) Soit une molecule initiale sédative suivie d’une molécule incisive qui ne l’est moins …..D’ou le problème du SWITCH ADN 2007

Cross-tapering Target dose (%) Time (days) Switching to Seroquel improves Parkinsonian symptoms in schizophrenia irrespective of previous antipsychotic (02050410) Switching to Seroquel significantly improves Parkinsonian symptoms in schizophrenia patients with suboptimal outcomes on olanzapine, risperidone, typical monotherapy, combination antipsychotics and low-dose haloperidol[1] SPECTRUM (Seroquel Patient Evaluation on Changing Treatment Relative to Usual Medication) was a 12-week, open-label, non-comparative trial examining clinical benefit to patients with schizophrenia switched to Seroquel following inadequate response to or intolerance of previous antipsychotics[1] Patients (n=509) were switched over a 7-day period and then treated with 300-750 mg/day Seroquel for 11 weeks[1] This slide presents an analysis of the Simpson-Angus Scale (SAS) score according to the antipsychotic drug patients were switched from. The mean modal dose of Seroquel in each of these groups was as follows: 470 mg/day in patients switched from olanzapine monotherapy; 483 mg/day in patients previously receiving risperidone monotherapy; 502 mg/day in patients switched from any typical antipsychotic monotherapy; 537 mg/day in patients previously receiving any combination of antipsychotics; and 501 mg/day in patients switched from low-dose haloperidol (</=10 mg/day). It should be noted that the low-dose haloperidol group of patients is a subpopulation of the typical antipsychotic monotherapy group[1] At Week 12 (last value carried forward [LVCF]) the least square mean (LSM) change from baseline in SAS score was statistically significant (p<0.001), irrespective of previous antipsychotic medication[2] References 1.Data on file (S174) – AstraZeneca. 2.Larmo I, Jones AM, Whiteford JL et al. Switching to quetiapine reduces EPS in patients with schizophrenia. Poster presented at the 23rd Congress of the Collegium Internationale Neuro-Psychopharmacologicum, Montreal, Canada, 2002. Poster number P.3.W.024. Time (days) ADN 2007 Initial target maintenance dose for ‘Seroquel’ : 400 mg by Day 5

Overlap & taper Dose Time (weeks) ADN 2007 Switching to Seroquel improves Parkinsonian symptoms in schizophrenia irrespective of previous antipsychotic (02050410) Switching to Seroquel significantly improves Parkinsonian symptoms in schizophrenia patients with suboptimal outcomes on olanzapine, risperidone, typical monotherapy, combination antipsychotics and low-dose haloperidol[1] SPECTRUM (Seroquel Patient Evaluation on Changing Treatment Relative to Usual Medication) was a 12-week, open-label, non-comparative trial examining clinical benefit to patients with schizophrenia switched to Seroquel following inadequate response to or intolerance of previous antipsychotics[1] Patients (n=509) were switched over a 7-day period and then treated with 300-750 mg/day Seroquel for 11 weeks[1] This slide presents an analysis of the Simpson-Angus Scale (SAS) score according to the antipsychotic drug patients were switched from. The mean modal dose of Seroquel in each of these groups was as follows: 470 mg/day in patients switched from olanzapine monotherapy; 483 mg/day in patients previously receiving risperidone monotherapy; 502 mg/day in patients switched from any typical antipsychotic monotherapy; 537 mg/day in patients previously receiving any combination of antipsychotics; and 501 mg/day in patients switched from low-dose haloperidol (</=10 mg/day). It should be noted that the low-dose haloperidol group of patients is a subpopulation of the typical antipsychotic monotherapy group[1] At Week 12 (last value carried forward [LVCF]) the least square mean (LSM) change from baseline in SAS score was statistically significant (p<0.001), irrespective of previous antipsychotic medication[2] References 1.Data on file (S174) – AstraZeneca. 2.Larmo I, Jones AM, Whiteford JL et al. Switching to quetiapine reduces EPS in patients with schizophrenia. Poster presented at the 23rd Congress of the Collegium Internationale Neuro-Psychopharmacologicum, Montreal, Canada, 2002. Poster number P.3.W.024. Time (weeks) ADN 2007

Abrupt discontinuation (2) Dose Switching to Seroquel improves Parkinsonian symptoms in schizophrenia irrespective of previous antipsychotic (02050410) Switching to Seroquel significantly improves Parkinsonian symptoms in schizophrenia patients with suboptimal outcomes on olanzapine, risperidone, typical monotherapy, combination antipsychotics and low-dose haloperidol[1] SPECTRUM (Seroquel Patient Evaluation on Changing Treatment Relative to Usual Medication) was a 12-week, open-label, non-comparative trial examining clinical benefit to patients with schizophrenia switched to Seroquel following inadequate response to or intolerance of previous antipsychotics[1] Patients (n=509) were switched over a 7-day period and then treated with 300-750 mg/day Seroquel for 11 weeks[1] This slide presents an analysis of the Simpson-Angus Scale (SAS) score according to the antipsychotic drug patients were switched from. The mean modal dose of Seroquel in each of these groups was as follows: 470 mg/day in patients switched from olanzapine monotherapy; 483 mg/day in patients previously receiving risperidone monotherapy; 502 mg/day in patients switched from any typical antipsychotic monotherapy; 537 mg/day in patients previously receiving any combination of antipsychotics; and 501 mg/day in patients switched from low-dose haloperidol (</=10 mg/day). It should be noted that the low-dose haloperidol group of patients is a subpopulation of the typical antipsychotic monotherapy group[1] At Week 12 (last value carried forward [LVCF]) the least square mean (LSM) change from baseline in SAS score was statistically significant (p<0.001), irrespective of previous antipsychotic medication[2] References 1.Data on file (S174) – AstraZeneca. 2.Larmo I, Jones AM, Whiteford JL et al. Switching to quetiapine reduces EPS in patients with schizophrenia. Poster presented at the 23rd Congress of the Collegium Internationale Neuro-Psychopharmacologicum, Montreal, Canada, 2002. Poster number P.3.W.024. Time (days) ADN 2007

Abrupt discontinuation (1) Dose Switching to Seroquel improves Parkinsonian symptoms in schizophrenia irrespective of previous antipsychotic (02050410) Switching to Seroquel significantly improves Parkinsonian symptoms in schizophrenia patients with suboptimal outcomes on olanzapine, risperidone, typical monotherapy, combination antipsychotics and low-dose haloperidol[1] SPECTRUM (Seroquel Patient Evaluation on Changing Treatment Relative to Usual Medication) was a 12-week, open-label, non-comparative trial examining clinical benefit to patients with schizophrenia switched to Seroquel following inadequate response to or intolerance of previous antipsychotics[1] Patients (n=509) were switched over a 7-day period and then treated with 300-750 mg/day Seroquel for 11 weeks[1] This slide presents an analysis of the Simpson-Angus Scale (SAS) score according to the antipsychotic drug patients were switched from. The mean modal dose of Seroquel in each of these groups was as follows: 470 mg/day in patients switched from olanzapine monotherapy; 483 mg/day in patients previously receiving risperidone monotherapy; 502 mg/day in patients switched from any typical antipsychotic monotherapy; 537 mg/day in patients previously receiving any combination of antipsychotics; and 501 mg/day in patients switched from low-dose haloperidol (</=10 mg/day). It should be noted that the low-dose haloperidol group of patients is a subpopulation of the typical antipsychotic monotherapy group[1] At Week 12 (last value carried forward [LVCF]) the least square mean (LSM) change from baseline in SAS score was statistically significant (p<0.001), irrespective of previous antipsychotic medication[2] References 1.Data on file (S174) – AstraZeneca. 2.Larmo I, Jones AM, Whiteford JL et al. Switching to quetiapine reduces EPS in patients with schizophrenia. Poster presented at the 23rd Congress of the Collegium Internationale Neuro-Psychopharmacologicum, Montreal, Canada, 2002. Poster number P.3.W.024. Time (days) ADN 2007

No Tapering For Amisulpride: 600 mg Olanzapine:20 mg Quetiapine: 600 mg Risperidone: 6 mg ADN 2003 ADN 2007

POSOLOGIES EQUIVALENCES SEROQUEL 100MG= 0,75 MG RISPERDAL 100 MG SOLIAN 75 MG LEPONEX 2,5 MG ZYPREXA 2,5 MG SERDOLECT ADN 2003 ADN 2007

POSOLOGIES EQUIVALENCES 0,75 MG RISPERDAL =100MG SEROQUEL 100 MG SOLIAN 75 MG LEPONEX 2,5 MG ZYPREXA 2,5 MG SERDOLECT ADN 2003 ADN 2007

ADN 2006 ADN 2007

ADN 2006 ADN 2007

Différents modes d’action Bloca % Occupat D2 Blocage D2 Action Post Syn Classiques +EP 100 100 -100 Classique correct 80 100 -80 Atypiques 70 100 -70 Aripiprazole 100 30 -70 ADN 2007

Evolution sous atypiques : prédominance initiale de la sédation ADN 2007

Evolution sous Aripiprazole: prédominance de l’effet antipsychotique ADN 2007

QUETIAPINE New Titration STRATEGIE 1 QUETIAPINE New Titration Day 1: 400mg Day 2: if necessary 600mg Day 3: if necessary 800mg One daily evening dose ADN 2003 ADN 2007

Brusque amplification de l’action dopaminergique (amphetamine like) due au déblocage? Non Confera tur l’ancien concept des drugs holiday ADN 2007

NOUVELLE DENOMINATION D2 Partial Blocker D2PB ACRONYME PARADIGMATIQUE ADN 2007

TAKE HOME MESSAGE ADN 2007

Facteurs favorisants la rémission d’un processus neuro dégénératif LE MODELE DE MONTIGNIES Facteurs favorisants la rémission d’un processus neuro dégénératif Précocité de la prise en charge -Détection précoce (! Diagnostic) -Jeune âge - Limitation de la Déstructuration Posologie efficace mais adaptée aux phases Maintenance assurée par le suivi ADN 2007

Pourquoi moins de rechute? LE MODELE DE MONTIGNIES Pourquoi moins de rechute? Filière unique Orientée patient : Un patient Un même psy ambulatoire et hosp Une équipe hospitalière Familiale petite unité et Subunité Pas d’unité mono- diagnostic (clivages d’un continuum ?) Absence de lit T régionaux Entretiens Familiaux systématisés Absence de modules fragmentaires ADN 2007

LE MODELE DE MONTIGNIES L’absence de structure ,de leadership ,d’organisation formelle Autrefois considérée comme une faiblesse est devenue un atout majeur. Des groupes apparemment chaotiques ont défié et vaincus les institutions . Les règles du jeu ont changé.Les organisations de l’ère du net ne sont plus des araignées que l’on peut tuer en tranchant la tête Mais des étoiles de mer : elles n’ont pas de tête et coupées en deux Elles se dedoublent sans mourir ADN 2007

Q & R ADN 2007