Catie

CATIE en la PRACTICA

Qu sabemos?Qu hay de nuevo?Qu aprendimos?Andrea Marquez de Lopez Matowww.ipbi.com.ar

ANDREA MARQUEZ LOPEZ MATO

Prof Psicofarmacologa CSMP. UBAPresidente CONCABAPresidente Electa CANPVicepresidente SAPNESecretaria Internacional AAPSecretaria GENBA LOPEZ MATOEXProf Psiconeuroinmunoendocrinologa Presidente AAPBSecretaria cientfica FLAPBDirectora Instituto Psiquiatra Biolgica Integral (ipbi)

OBJETIVO

Destacar algunos conceptos del CATIE sobre eficacia y seguridadde distintos antipsicticos ycompararlos con nuestras observaciones clnicas diarias en pacientes reales. Lopez Mato. 06

CATIE DISEO ESTUDIO1460 pacientescon esquizofreniaParticipants who discontinue phase 2 choose one of the following open-label treatments:AripiprazoleClozapineFluphenazine decanoateOlanzapinePerphenazineQuetiapineRisperidoneZiprasidone 2 of the antipsychotic abovePhase 3Phase 1*ROlanzapinaQuetiapinaRisperidoneZiprasidonePerphenazineDouble-blind, random treatment assignmentPhase 2Clozapine(open-label)Olanzapine, Quetiapine, or RisperidoneOlanzapine, Quetiapine, or RisperidoneZiprasidoneNo one assigned to same drug as in phase 1Participants who discontinue phase 1 choose either the clozapine or the ziprasidone randomization pathwaysStroup TS, et al. Schizophr Bull. 2003;29(1):15-31.

CARACTERISTICAS CLINICAS Y DEMOGRAFICAS. Lieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

Assessment Demographics

Total

(N=1460)

Age mean (SD)

40.6 (11.1)

Gender

Male

1080 (74%)

Race

White

Black/African-American

All other race groups

874 (60%)

513 (35%)

71 (5%)

Spanish/Hispanic/Latino ethnicity

170 (12%)

Education (years)

12.1 (2.3)

Marital status

Married

Previously married

Never married

167 (11%)

425 29%)

868 (59%)

Unemployed

1217 (85%)

Exacerbation in past 3 months

402 (28%)

PANSS total score (30-210)

75.7 (17.6)

Clinician-Rated CGI-Severity score (1-7)

CGI-S of 4=moderately ill

4.0 (0.9)

CATIE CRITERIOS INCLUSION Y EXCLUSIONEsquizofrnicos DSM-IV18-65 aosExcluidos Primer episodio y Refractarios Excluidos EPSIncluidos enfermedad medica comrbida, abuso de sustancias57 sitios con caractersticas distintas Stroup TS, et al. Schizophr Bull. 2003;29(1):15-31.

CATIE FASE I: DOBLE CIEGO Y RANDOMIZADO Personas con TD nt asignados a pefhenazina.Ziprasidona agregada despues de enrolamiento 40%.Olanzapina 7.5-30 mg/dayPerfenazina 8-32 mg/day*Quetiapina 200-800 mg/dayRisperidona 1.5-6 mg/dayZiprasidona 40-160 mg/dayStroup TS, et al. Schizophr Bull. 2003;29(1):15-31.

DISCONTINUACION POR CUALQUIER CAUSA (n 1432)

Cualquier causa 74.1%Falta de eficacia23.7%Intolerancia14.9%Decisin del paciente29.9%

CATIE I TIEMPO DE DICONTINUACION POR CUALQUIER CAUSAp

EFECTIVIDAD Lehman AF, et al. Am J Psychiatry 2004;161(suppl 2):1-56.Swartz MS, et al. Schizophr Bull 2003;29(1):33-43.

CATIEEficacia: mejora sintomtica y en escalas Discontinuacin por falta de respuesta

CATIE I TIEMPO DE DISCONTINUACION POR FALTA DE EFICACIA.P

PANSS TOTALInteraction of time treatment indicates significant variation in treatment effects over time. Improvement was initially greatest with olanzapine but its advantage diminished over time. The number of patients declines over assessment times. Least-square mean estimates are from a mixed model, which assumes that data are missing at random. Values at later timepoints are based on the observed data for continuing patients as well as estimated data for discontinued patients. p=.001 for time-by-treatment interactionp=.065 for ziprasidone cohort-12-10-8-6-4-200369121518OlanzapinePerphenazineQuetiapineRisperidoneZiprasidoneLeast-Square Mean Change in PANSS Total Score from BaselineMonthsLieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

PANSS NEGATIVOOlanzapinePerphenazineQuetiapineRisperidoneZiprasidoneThe number of patients declines over assessment times. Least-square mean estimates are from a mixed model, which assumes that data are missing at random. Values at later time points are based on the observed data for continuing patients as well as estimated data for discontinued patients. p=.177 for time-by-treatment interactionp=.019 for ziprasidone cohort-3-2.5-2-1.5-1-0.500.50369121518Least-Square Mean Change from BaselineMonthsLieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

NECESIDAD DE HOSPITALIZACION POR RECAIDA p

CATIE COGNICIONDatos no publicadosPresentados preliminarmente Lieberman APA 2006Perfenazina tan buena como olanzapina en disfuncion cognitiva

CONCLUSIONES CATIE IAlto % de discontinuacin (74%)Mayor que la hipotetizada de 60%Olanzapina es la droga ms efectivaPerfenazina es comparable a los ASGCognicin. Sntomas negativosDiferencias en perfil de efectos secundariosAumento de peso, EPSEficacia coincide con mediciones de subescalas Lieberman, APA, 06

CATIE FASE IIEFICACIATOLERABILIDADClozapinaabiertoOlanzapina, quetiapina, risperidona no tomados en fase IZiprasidonaRANDOMIZADOSRANDOMIZADOSStroup TS, et al. Schizophr Bull. 2003;29(1):15-31.

CATIE IICARACTERISTICAS DEMOGRAFICAS 161 pacientes elegibles, 136 randomizadosClozapina67Otros ASG69 (ola 30, quet 20, amis 9, risp 7)Edad promedio de 38 aos 68% hombres56% internados87% terminaron 52 semanas

CATIE II TIEMPO DE DISCONTINUACION POR CUALQUIER CAUSAOverall p-value=.028*00.20.40.60.810369121518Clozapine (n=45)Olanzapine (n=17)Quetiapine (n=14)Risperidone (n=14)Proportion of Patients Without EventTime to Discontinuation for Any Cause (Months)McEvoy JP, et al. Presented at: 44th ACNP Annual Meeting; Dec 11-15, 2005; Waikoloa, Hawaii.

CLO (n=45)

OLZ (n=17)

QUET (n=14)

RIS (n=14)

Number discontinued

25 (56%)

12 (71%)

13 (93%)

12 (86%)

Kaplan-Meier time to discontinuation (months)

10.5

[7.3,16.1]

2.7

[1.9, 11.9]

3.3

[1.0, 4.9]

2.8

[1.1, 4.0]

0.57

[0.29, 1.16]

0.121

CATIE II (I) TIEMPO DISCONTINUACION POR FALTA DE EFICACIATime to Discontinuation for Lack of Efficacy (Months)Overall p-value=.010*00.20.40.60.810369121518Clozapine (n=45)Olanzapine (n=17)Quetiapine (n=14)Risperidone (n=14)Proportion of Patients Without EventMcEvoy JP, et al. Presented at: 44th ACNP Annual Meeting; Dec 11-15, 2005; Waikoloa, Hawaii.

CLO (n=45)

OLZ (n=17)

QUET (n=14)

RIS (n=14)

Number discontinued

5 (11%)

6 (35%)

6 (43%)

6 (43%)

Hazard ratios for clozapine

0.24

[0.07, 0.78]

0.019*

0.16

[0.04, 0.54]

0.004*

0.16

[0.05, 0.54]

0.003*

Hazard ratios for olanzapine

0.66

[0.20, 2.22]

0.505

0.68

[0.21, 2.23]

0.528

Hazard ratios for quetiapine

1.03

[0.32, 3.28]

0.957

CATIE II (II) TIEMPO DISCONTINUACION POR CUALQUIER CAUSA

Overall P-value=0.004*McEvoy JP, et al. Presented at: 44th ACNP Annual Meeting; Dec 11-15, 2005; Waikoloa, Hawaii.

CONCLUSIONES CATIE IIEn pacientes esquizofrnicos no respondientes a primer tratamiento con una o ms drogas hay mejora sintomtica con clozapina ms que con otros ASGClozapina no di mejora esperada en calidad de vida (ms de 10 puntos sobre otros)Stroup, Mc Evoy, APA, 2006

CLINICA DIARIATenemos en nuestros pacientes un 74% de discontinuacin?Tenemos la misma eficacia ?Lopez Mato. 06

CATIE vs CLINICA DIARIANo se incluyeron pacientes de primer episodio

No se combinaron drogas

Dosis son suficientes?

Tpicos evaluadas son vlidos?Lopez Mato. 06

CATIE vs CLINICA DIARIA No se incluyeron pacientes de primer episodio




PRIMER EPISODIO- Si es menor de seis meses: psicosis reactiva breve o trastorno esquizofreniforme DSM IV- Sintomatologa florida Schooler 86, Lieberman 95- Generalmente hay prodromos de duracin variable Lieberman 95 - El grado de respuesta teraputica es mayor y ms rpida. Loebel 92- Requieren menos dosis antipsicticos Meltzer 92- Son ms sensibles a reacciones de extrapiramidalismo. Lieberman 95 Keks 96

RESPUESTA AL TRATAMIENTO DEL PRIMER EPISODIORemisin completa: 73%

Remisin parcial: 16%

Sin remisin: 11% Lieberman 98

CATIE vs CLINICA DIARIANo se incluyeron pacientes de primer episodio

No se combinaron drogas antipsicticas



CATIE I: MEDICACIONES CONCOMITANTES.Lieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

Assessment

OLZ(n=336)

QUET(n=337)

RIS(n=341)

PER(n=261)

ZIP(n=185)

p-Value

Lithium

CLINICA DIARIAQu porcentaje de nuestros pacientes esquizofrnicos estn solo con monoterapia de antipsicticos atpicos ?Lopez Mato. 06

CLINICA DIARIAAsociacin de antipsicticosAtpico ms tpico en bajas dosisAtpico ms atpicoAsociacin antipsictico ms antirrecurrencialAsociacin antipsictico ms antidepresivosAsociacin antipsictico ms BDZLopez Mato. 06

CATIE I DOSISLieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

OLZ(n=336)

QUET(n=337)

RIS

(n=341)

PER(n=261)

ZIP(n=185)

p-Value

Intent-to-treat patients

330

329

333

257

183

-

Average modal dose (mg)

20.1

543.4

3.9

20.8

112.8

-

Patients reaching maximal dose

40%

44%

40%

40%

48%

CATIE II (I) DOSIS EN FASEMcEvoy JP, et al. Presented at: 44th ACNP Annual Meeting; Dec 11-15, 2005; Waikoloa, Hawaii.

Assessment

CLO(n=45)

OLZ

(n=17)

QUET (n=14)

RIS

(n=14)

Mean modal dose (mg)

332.1

23.4

642.9

4.8

Number reaching maximum dose

N/A

10 (59%)

10 (71%)

8 (62%)

CATIE II (II) RANDOMIZACION Y TRATAMIENTOMcEvoy JP, et al. Presented at: 44th ACNP Annual Meeting; Dec 11-15, 2005; Waikoloa, Hawaii.

OLZ (n=66)

RIS (n=69)

QUET (n=63)

ZIP (n=135)

p-Value

Average modal dose (mg)

21.0

4.3

573.8

115.9

Patients reaching maximal dose

48%

49%

46%

52%

0.114

CLINICA DIARIALos neurolpticos de mayor potencia son iguales?Perfenazina es igual a haloperidol?

Dosis de perfenazina elejida por diseo de protocolo en CATIE es la habitual?Es perfenazina de primera eleccin en nuestra prctica?Lopez Mato. 06

CLINICA DIARIAQu dosis son suficientes y habituales en la clnica? Dosis CATIE son ms altas que las habituales (para todos salvo ziprasidone) comparados con el VERISPAN (internados) Lieberman, APA 2006Qu dosis usamos nosotros?Lopez Mato. 06

CATIE OTRO MODO DE VERLONNT: cuanto menor, mejor es la drogaCLOZA VS RISP O ZIPRAS : 2.7 A 3CLOZA VS OLA: 7

NNH: cuanto mayor, mejor la drogaOLA: AUMENTO DE PESO1/12-18 ABANDONARON POR ESTOCitrome Stroup, julio 2006

.Ninguna pldora puede ayudarme a lidiar con el problema de no querer tomarlas Godwin and Jamison, 90

El punto ms difcil no es que respondan al tratamiento; sino que continen tomando la medicacin Lieberman, 90

CATIE Discontinuacin por intolerancia

Efectos colaterales

CATIE

Discontinuacin por intolerancia

Efectos colaterales

CATIE I TIEMPO DE DISCONTINUACION POR INTOLERANCIA

Overall p-value=.05400.20.40.60.81.00369121518OlanzapinePerphenazineQuetiapineRisperidoneZiprasidoneProportion of Patients Without EventTime to Discontinuation Owing to Intolerability (Months)Lieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

OLZ (n=330)

QUET (n=329)

RIS (n=333)

PER (n=257)

ZIP (n=183)

Discontinued

62 (19%)

49 (15%)

34 (10%)

40 (16%)

28 (15%)

Hazard ratios for risperidone

0.620.027

0.65 0.051

---

0.600.043

0.790.41

RAZONES DE DISCONTINUACION POR INTOLERANCIA.Lieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

Assessment

Statistic

OLZ (n=336)

QUET(n=337)

RIS (n=341)

PER(n=261)

ZIP (n=185)

p-Value

Discontinued for intolerability

Discontinued for intolerability

n (%)

62 (18%)

49 (15%)

34 (10%)

40 (15%)

28 (15%)

.04

Tolerability discontinuations: most problematic side effect

Weight/metabolic

n (%)

31(9%)

12(4%)

6 (2%)

3 (1%)

6 (3%)

Discontinuacin por intolerancia

Efectos colaterales

CATIE EFECTOS ADVERSOS Lieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

Assessment

OLZ(n=336)

QUET(n=337)

RISP(n=341)

PER(n=261)

ZIP(n=185)

p-Value

Any serious AE

10%

9%

10%

11%

10%

.47

Suicide attempt

1%

1%

CATIE ESCALA DE MOVIMIENTOS ANORMALES Not significantLieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

CATIE: SIMPSON-ANGUS (SEP)

Not significantLieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

CATIE BARNES AKATHISIA RATING SCALE

Not significantLieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

CRITERIOS de EXCLUSINEs esto un bias?

En CATIE se excluyeron para perfenazina pacientes con antecedentes de SEPNo se excluyeron para olanzapina o cloza antecedentes de desorden metablicoNo se excluyeron para risperidona antecedentes de SEPNo se excluyeron para ziprasidona antecedentes de cardiopata. Lopez Mato. 06

CLINICA DIARIAMOVIMIENTOS ANORMALES POR AP:BUTIROFENONASSULPIRIDAAMISULPRIDERISPERIDONAPROMAZINICOSARIPRIPAZOLOLANZAPINAZIPRASIDONACLOZAPINA

Lopez Mato A., 2003

PARKINSONISMOParkinsonismo MotorEPSDistonaDiskinesia tarda

Parkinsonismo CognitivoPensamiento enlentecido y pobreSentimiento de vacoDificultades de concentracin

Gerlach 98

PARKINSONISMOParkinsonismo SocialFalta de iniciativaDisminucin de las energasPobreza de contactos sociales

Parkinsonismo EmocionalIndiferencia emocionalAnhedoniaFalta de placer en las actividadesGerlach 98

CATIE I: CAMBIOS DESDE BASAL HASTA 2 ENTREVISTAS POSTERIORESLieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

Assessment

Statistic

OLZ(n=336)

QUET(n=337)

RIS(n=341)

PER(n=261)

ZIP(n=185)

p-Value

Blood glucose (mg/dL)

Mean (SE) MedianExposure-adjusted. Mean (SE)

15.0 (2.8)7.013.7 (2.5)

6.8 (2.5)4.37.5 (2.5)

6.7 (2.0)5.56.6 (2.5)

5.2 (2.0)1.55.4 (2.8)

2.3 (3.9)2.52.9 (3.4)

.59

Hemoglobin A1C (%)


0.41 (0.09)0.200.40 (0.07)

0.05 (0.05) 0.100.04 (0.08)

0.08 (0.04)0.050.07 (0.08)

0.10 (0.06)0.050.09 (0.09)

-0.10 (0.14)0.100.11(0.09)

.01

Cholesterol (mg/dL)

Mean (SE) MedianExposure-adjusted Mean (SE)

9.7 (2.1)8.59.4 (2.4)

5.3 (2.1)3.56.6 (2.4)

-2.1 (1.9)-3.0-1.3 (2.4)

0.5 (2.3)0.51.5 (2.7)

-9.2 (5.2) -1.0-8.2 (3.2)

PROLACTINA (NG/ML) EN ENSAYOS CONTROLADOS CON OLANZAPINAHGAJHGBGP022Prolactina en plasma (ng/mL)1200204060801000102030405060Semana relativa de tratamiento01020304050600102030405060OlanzapinaHaloperidolRisperidona

LA PROLACTINA ES MAS QUEUNA HORMONA DE MATERNAJE Funcin sexual y maternal Funcin en coping (afrontamiento) al stress Funcin metablica (hormona anablica) Funcin sobre SNC (crecimiento neuronal, sinaptognesis y poda dendrtica) Funcin sobre inmunomodulacinLopez Mato PNIE Polemos 2002.

CLINICA DIARIAAUMENTO PROLACTINA POR AP:BUTIROFENONASSULPIRIDAAMISULPRIDERISPERIDONAPROMAZINICOSOLANZAPINA ARIPRIPAZOL CLOZAPINAZIPRASIDONA

Lopez Mato A., 2003

CLINICA DIARIAOTROS EFECTOS ENDOCRINOSDisminucin de LH y FSH

Osteoporosis

Intolerancia a la glucosa

Sndrome metablico

Lopez Mato A., Presented at International Meeting in Schizophrenia. Buenos Aires. 2004

CATIE I: PACIENTES QUE GANARON MAS DEL 7 % DEL PESO CORPORAL.p

CATIE OTRO MODO DE VERLONNT: cuanto menor, mejor es la drogaCLOZA VS RISP O ZIPRAS : 2.7 A 3CLOZA VS OLA: 7

NNH: cuanto mayor, mejor la drogaOLA: AUMENTO DE PESO1/12-18 ABANDONARON POR ESTO

CATIE I: CAMBIOS DESDE BASAL HASTA 2 ENTREVISTAS POSTERIORESLieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

Assessment

Statistic

OLZ(n=336)

QUET(n=337)

RIS(n=341)

PER(n=261)

ZIP(n=185)

p-Value

Blood glucose (mg/dL)


15.0 (2.8)7.013.7 (2.5)

6.8 (2.5)4.37.5 (2.5)

6.7 (2.0)5.56.6 (2.5)

5.2 (2.0)1.55.4 (2.8)

2.3 (3.9)2.52.9 (3.4)

.59

Hemoglobin A1C (%)


0.41 (0.09)0.200.40 (0.07)

0.05 (0.05) 0.100.04 (0.08)

0.08 (0.04)0.050.07 (0.08)

0.10 (0.06)0.050.09 (0.09)

-0.10 (0.14)0.100.11(0.09)

.01

Cholesterol (mg/dL)

Mean (SE) MedianExposure-adjusted Mean (SE)

9.7 (2.1)8.59.4 (2.4)

5.3 (2.1)3.56.6 (2.4)

-2.1 (1.9)-3.0-1.3 (2.4)

0.5 (2.3)0.51.5 (2.7)

-9.2 (5.2) -1.0-8.2 (3.2)

CAMBIO EN PESO CON ANTIPSICOTICOS.Marder SR, et al. Schizophr Res. 2003;61:123-36. Adapted from: Allison DB, et al. Am J Psychiatry. 1999;156(11):1686-1696.Cambio de peso estimado a las 10 semanas con dsis estandarHaloperidolPolypharmacyRisperidoneChlorpromazineOlanzapineClozapineQuetiapineThioridazine/Mesoridazine6Weight Change (kg)543210-1-2-3PlaceboMolindoneFluphenazineZiprasidone13.2Weight Change (lb)11.08.86.64.42.20-2.2-4.4-6.6**Aripiprazole*

CAMBIO DE PESO EN LA ERA PREANTIPSICOTICAThe taking of food fluctuates from complete refusal to the greatest voracity. The body weight usually falls at first, often to a considerable degree, even to extreme emaciation, in spite of the most abundant nourishment. Later, on the contrary, we see the weight not infrequently rise quickly in the most extraordinary way, so that patients in short time acquire an uncommonly well-nourished turgid appearanceKraepelin, E. Dementia Praecox and Paraphrenia, Munich 1919

POR QUE LOS PACIENTES GANAN PESO CON ANTIPSICOTICOS?1 Baptista T. Acta Psychiatr Scand. 1999;100(1):3-16. 2 Cohen S, et al. J Clin Psychiatry. 2001;62(2):114-116. 3 Heiman ML, et al. Presented at: 154th APA Annual Meeting; May 5-10, 2001; New Orleans, La. 4 Mercer LP, et al. J Nutr. 1994;124(7):1029-1036. 5 Reynolds GP, et al. Lancet. 2002;359(9323):2086-2087. 6 Simansky KJ. Behav Brain Res. 1996;73(1-2):37-42. 7 Stanton JM. Schizophr Bull. 1995;21(3):463-472. 8 Tecott LH, et al. Nature. 1995;374(6522):542-546. 9 Virkkunen M, Pharmacopsychiatry. 2002;35(3):124-126. 10 Lopez Mato el al, VerteX .2003 Accin en Hipotlamo lateral y ventromedialCambios en la Sensibilidad a la Leptina

INTERVENCIONES CONDUCTUALES PARA LA PERDIDA DE PESO012345678Aumento de peso mximoAumento de peso final Aumento de peso por antipsicticos Wirshing DA, et al. J Clin Psychiatry. 1999;60(6):358-363.*

ESTRATEGIAS PARA PREVENIR AUMENTO DE PESO

EstrgenosMetformina (Glucophage )Sibutramina (Ipomex Aderan )Fluoxetina (Prozac )Amantadina (Symmetrel)Quetiapina (Seroquel)Topiramato (Topamax) OrlistatAntagonistas H2 ; Nizatadine (Axid) , Ranitidina(Taural) Cimetidina (Tagamet) Lopez Mato A., Vertex 2003

CLINICA DIARIAAUMENTO DE PESO POR AP:CLOZAPINAOLANZAPINARISPERIDONAQUETIAPINAZIPRASIDONAHALOPERIDOLARIPIRAZOL

Nashraldam H, Korn M, Metabolic Disorders in Schizophrenic. Relation to AA Treatment. Schizophrenia Medscape Expert Columm, 28-7-04

CATIE I ELECTROCARDIOGRAMA Y CATARATASLieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

Assessment

Statistic

OLZ(n=336)

QUET(n=337)

RIS(n=341)

PER(n=261)

ZIP(n=185)

p-Value

Electrocardiogram

Change in QTc (msec) to last observation

Mean (SE)

1.2 (1.8)

5.9 (1.9)

0.2 (1.8)

1.4 (2.0)

1.3 (2.2)

.25

Treatment-emergent prolongated QTc

n (%)

0

6 (3%)

7 (3%)

2 (1%)

2 (1%)

.03

Cataracts

New cataracts

n (%)

3 (1%)

1 (

CLINICA DIARIARIESGO DE EVENTOS CARDIOLOGICOS POR AP:TIORIDAZINA ZIPRASIDONAPROMAZINICOS

RIESGO DE EVENTOS OFTALMOLOGICOS POR AP:

QUETIAPINAPROMAZINICOSLopez Mato A., 2003

CLINICA DIARIARIESGO DE EVENTOS HEMATOLOGICOS POR APCLOZAPINA

PROMAZINICOSCARBAMACEPINALITIO

Lopez Mato A., 2003

1 DE 49 EN CATIE0,8 A 2 EN OTROS ESTUDIOS

EFECTOS ADVERSOS NEUROCOGNITIVOS

SedacinConfusinDeterioro de memoriaEnlentecimiento psicomotorDeliriumDescenso del umbral convulsivoLopez Mato, PNIE Polemos, 2002

CLINICA DIARIA RIESGO DE EVENTOS NEUROCOGNITIVO POR AP:ANTICOLINERGICOS BUTIROFENONASPROMAZINICOSCLOZAPINAARIPRIPAZOLZIPRASIDONARISPERIDONAOLANZAPINA

Lopez Mato A., 2003

CLINICA DIARIA RIESGO DE SIADH POR AP:PROMAZINICOS

ZIPRASIDONACLOZAPINAOLANZAPINAOTROS ANTIPSICOTICOSBUTIROFENONAS

Lopez Mato A, 2003

RIESGO DE AUMENTO DE DESORDEN INMUNITARIO POR ANTIPSICOTICOS ?Lopez Mato A., 2003

FDA RIESGO DE EVENTOS TERATOGENICOS POR AP:ANTICOLINRGICOS CBUTIROFENONAS CPROMAZNICOS CARIPRIPAZOL CZIPRASIDONA CRISPERIDONA COLANZAPINA CBCLOZAPINA B

Lopez Mato. 03

CONCLUSIONES CATIE ORIGINALESTodos los antipsicticos pueden ser efectivos y tienen limitaciones por discontinuacin, efectos colaterales e inadecuado control de sntomasEn pacientes no refractarios olanzapina es la ms efectivaLos neurolpticos de mediana potencia en dosis moderadas son efectivas y tienen pocos efectos colaterales (???????) Perfenazina no es menos eficaz que ASG (tolerancia?)

Lieberman, APA, 06

CONCLUSIONES CATIE ORIGINALESLos efectos colaterales deben ser individualizadosClozapina y olanzapina produjeron los mayores efectos metablicos por aumento de peso (prevencion solo para olanzapina ) Clozapina y luego olanzapina de cerca son las ms efectivas en falta de respuesta efectiva a otro tratamientoPara discontinuacin por intolerancia evaluar cambio de droga segn efecto colateral indeseable

Lieberman, APA, 06

CONCLUSIONES CATIE ORIGINALESSIEMPRE EVALUAR RIESGO-BENEFICIO EN CADA CASO INDIVIDUAL Lieberman, APA, 06

Las conclusiones del CATIE son la nueva Biblia sobre tratamiento de esquizofrenia?Son suficientes para extrapolar a cada subtipo?Son suficientes para extrapolar a cada momento evolutivo?Lopez Mato. 06

EL CONTINUUM DEL TRATAMIENTOEFICACIASEGURIDAD1-3 das7-14 das 6+ meses ControlAgitacin Alivio de sntomas negativos Mejora de sntomas afectivos Mejora cognitiva Prevencin del suicidio Prevencin de recadaAlivio de Sntomas positivos,hostilidad, agresividad, sntomas afectivos y maniformesDistona AgudaSedacinOrtostatismoProlongacin QTcEPSInteracciones medicamentosasProlongacin QTc Disquinesia TardaHiperprolactinemiaAumento de pesoHiperglucemiaHipertrigliceridemiaProlongacin QTc

AA EFICACIA EN:ESQUIZOFRENIATRASTORNO BIPOLARTRASTORNO UNIPOLAR REFRACTARIOTRASTORNOS DE PERSONALIDADTRASTORNO DE CONDUCTADEMENCIASTRASTORNOS DE ALIMENTACINTRASTORNOS DE ANSIEDAD (TAG,PTSD)??????????Lopez Mato. 06

AA Y FUNCIN RECEPTORIALOlanzapineClozapine RisperidoneQuetiapineZiprasidoneHaloperidolBymaster FP, et al. Neuropsychopharmacology. 1996;14(2):87-96. Schotte A, et al. Psychopharmacology (Berl). 1996;124(1-2):57-73.Lawler, C, et al. Neuropsychopharmacology. 1999;20(6):612-27.Corbett, R, et al. CNS Drug Reviews. 1997;3(2):120-47.

Aripiprazole

PERFIL DE AFINIDAD POR RECEPTORES DE LOS ANTIPSICTICOS Tamayo JM et al., 2001En este esquema el tamao de las reas no est relacionado con la Ki para cada grupo de receptores

FARMACODINAMIA DE AAA10 selective1 (low EPS, TD)Increases 5-HT & DA in PFC5 (improves cognition,depression)Increases c-fos expression6-8 in prefrontal cortex (improves depression, cognition)Blocks NMDA antagonists2 e.g., PCP (improves psychosis, negative symptoms, cognition)Increases acetylcholine3,4 (improves cognition)1.Skarsfeldt T. Eur J Pharmacol. 1995;281(3):289-294. 2.Corbett R, et al. Psychopharmacology (Berl). 1995;120(1):67-74. 3.Meltzer HY, O'Laughlin IA. Presented at: 29th SFN Annual Meeting; Oct 23-28, 1999; Miami Beach, Fla. 4.Corbett R, et al. Psychopharmacology (Berl). 1995;120(1):67-74. 5. Li et al., Psychopharmacology 136:153-161, 1998. 6.Robertson GS, Fibiger HC. Neuropsychopharmacology. 1996;14(2):105-110. 7.Sebens JB, et al. Eur J Pharmacol. 1998;353(1):13-21. 8.Robertson GS, et al. J Pharmacol Exp Ther. 1994;271(2):1058-1066. 9. Zorn et al. Interactive Monoaminergic Brain Disorders 1999:377393. 10. Lieberman JA. Presented at APA 2002 5-HT & NA reuptake inhibitor9 (improves depression)D2 Partial agonism10 (low EPS)

ATIPICOS. EFICACIA Y SEGURIDADConsenso internacional sobre el uso y la utilizacin de antipsicticos de segunda generacin WPA 1999 (Presidente: Prof. Norman Sartorius)

Validacin Argentina(Presidente: Dra Andrea Lopez Mato) AAP 2000Experiencia en hospitales neuropsiquitricos argentinos 2002Actualizacin 2006 Lopez Mato

AMISULPRIDEAntagonista D2/D3Vida media: 12 hs.Dosis: 400/800 mg daClara mejora de los sntomas afectivosBuena mejora de los sntomas negativosEPS dosis dependiente, menos TDHIPERPROLACTINEMIA Y AUMENTO DE PESO DOSIS DEPENDIENTEGeneralmente usado como activador en asociacin

ARIPRIPAZOLEAccin D2, 5-HT2No EPS ni hiperprolactinemia a pesar de accin D2Mejora de los sntomas positivos y negativosEficaz en mana. Dosis?Titulacin hacia abajo

CLOZAPINAAccin 5-HT 6-7-2, 1-2, D 4-5-2, H 1Mejora de los sntomas negativos y afectivos Mejora de los sntomas positivos en dosis altasMejora sntomas cognitivos (no disfuncin frontal)Espectacular para esquizofrenia resistente pero esperarlo hasta seis mesesUnico en Prevencin de suicidioDosis en USA doble que Europa (200- 300mg/da)Dosis: 100-600 De eleccin en hostilidad y agresividad

CLOZAPINANo EPSSirve para tratar distona aguda y disquinesia tardaAGRANULOCITOSIS (8 %) generalmente dentro de seis meses (0.5 a 2 %) idiosincrticaAumento de pesoDisfuncin sexualConvulsiones dosis dependientes (espigas EEG)SialorreaExacerbacin sntomas OCD

OLANZAPINAAccin 5-HT 6-2, D 2-4 M, H1, 1Vida media 30 hs.Dosis 5 a 10 mg sntomas afectivos y negativos Dosis 12,5 a 20 mg sntomas productivos No efecto probado en estados residualesLa mejor en snt.cognitivos por 5HT6- NMDANo exacerba OCDNeuroproteccin dosis?Esquizofrenia refractaria?

OLANZAPINANo EPS (acatisia que cede con BDZ)Menor riesgo de TDAUMENTO DE PESOHiperglucemia? Hipertrigliceridemia?Aumento fugaz y transitorio de enzimas hepticas y prolactina

QUETIAPINAAccin H1, 5-HT 2, 1-2, D 2-3-4 MVida media 4 a 6,9 hs. Administracin 2 a 3 por daDosis 150 a 750 mg daMenos efectos sobre los sntomas negativosEficaz en ancianos y en ParkinsonDe eleccin en paciente neurolgicoEficacia a largo tiempoEficaz en catatona

QUETIAPINAAumento transitorio de enzimas hepticasHIPOTENSIN ORTOSTTICA Y VRTIGO, primeros das (con dosis altas, no solo al principio)CATARATAS? (riesgo ancianos y diabticos)No aumento de prolactinaNo aumento de peso, disminucin?Exacerbacin sntomas OCD

RISPERIDONAAntipsictico atpico Bloqueante 5HT2A, 1 y 2, H1, 5HT1A y 5HT7. Muy alta afinidad por D2, (en altas dosis produce SEP)Absorcin oral sin interferencia con los alimentosFcil posologa y administracinBien tolerada en nios y ancianos Efecto adversos: hiperprolactinemia y SEP

RISPERIDONAEPS en dosis mayores idiosincrticoMayor EPS en primer episodioMayor EPS en afectivos y bipolaresHIPERPROLACTINEMIAInsomnio en ancianosSedacin en dementes

ZIPRASIDONAAccin 5-HT 2A, D 2-3-4, 1-2, 5-HT1AInhibe la recaptura de serotonina y noradrenalinaVida media: 3,2 a 10 hs.Dosis: 80 a 160 mg (O MAS)Mejora de los sntomas afectivos, negativos, cognitivos y positivos?Previene recadasMejora cognitiva?

ZIPRASIDONAMenor aumento de pesoSedacin con dosis altaActivacin con dosis bajasNo EPS, disquinesia tarda?AUMENTO DE INTERVALO QTcAbsorcin solo con comida

POR QU SEGUIR LLAMNDOLOS ANTIPSICTICOS?

POR QU SEGUIR LLAMANDLOS ATPICOS?

ANTIPSICOTICOS DE SEGUNDA GENERACION

Tamayo,J; Lpez-Mato,A; Tllez,J; Calil,HM; Fernndez,ARevista Latinoamericana de Psiquiatra, v.3, n.1, p. 5-36, 2003.

PROPOSAL FOR A BROAD AND INTEGRATED CLASSIFICATION OF ANTIPSYCHOTIC DRUGS (BEYOND THE ATYPICALITY CONCEPT)

Se define, multidimensionalmente, a un antipsictico de amplio espectro como aqul que posee:

Accin biolgica sobre mltiples receptores

Accin teraputica sobre todos los cotejos sintomticos de las esquizofrenias (sntomas positivos, negativos, afectivos, dficit cognoscitivo)

SPECTRUM ITamayo JM, Lopez Mato A et al., 2003

SPECTRUM IIAccin teraputica sobre algn otro trastorno psiquitrico como trastorno bipolar, trastornos depresivos, tratornos de personalidad, drogodependencia, trastorno obsesivo-compulsivo, enfermedad de Parkinson, demencias

Tamayo JM, Lopez Mato A et al., 2003

SPECTRUM IIIEfectividad en resocializacion (calidad de vida, funcionamiento global)

Eficacia a largo plazo

Eficacia en pacientes refractarios Seguridad con mnimos efectos extrapiramidales, hormonales y otros

Tamayo JM, Lopez Mato A et al., 2003

B. Spilker. Guide to Clinical Trials. Chapter 73, 1993PODER RELATIVO DE EVIDENCIA 1. Estudios confirmatorios de un trabajo previo clasificado en 2 o 3 abajo.2. Estudios placebo-controlados aleatorizados doble ciego (DCP)3. Estudios controlados con placebo4. Estudios controlados con otro medicamento, aleatorizados (DCM)5. Estudios aleatorizados6. Estudios abiertos (EA)7. Series de pacientes con controles retrospectivos (R)8. Series de pacientes con controles en la literatura9. Casos obtenidos de una base de datos computadorizada10. Series de pacientes sin controles (S)11. Reportes de caso12. Observaciones anecdticas

* Medicamento en fase III. Se requiere tener informacin de estudios a largo plazo y resocializacin para dar una ubicacin definitiva en la escala.Rango probable de calificacin finalTamayo JM, Lopez Mato A et al., 2003

QUE ANTIPSICOTICO ELEGIRIA UN PSIQUIATRA PARA EL Y SUS FAMILIARES?Steinert T., European Psychiatry, 18, 2003; 40 - 41

LA CLINICA ES SOBERANA...Y MUCHO MAS DIVERTIDA MUCHAS GRACIAS POR ATENDER...PACIENTESANDREA M. LOPEZ MATOwww.aapb.com.ar

Insert Edited Table 1In order to enroll a broad array of patients representing those who are actually seen in clinics, we developed minimal inclusion and exclusion criteria:

The Kaplan Meier median is the time by which half of the patients have discontinuedThe hazard ratio for olanzapine vs. quetiapine is 0.63: at any given time, patients on olanzapine are 63% less likely to discontinue treatment compared to patients on quetiapine.The Hazard ratio is from Cox proportional hazards regression, and is the ratio of the probability of discontinuing the phase at any timepoint for one treatment group vs. another.Key Points: The concept of treatment effectiveness considers the impact of the medication on controlling the various symptoms of the illness, as well as the safety and tolerability of the medication.1 Despite the established need for a patient to continue on their prescribed treatment, many patients with schizophrenia fail to adhere to their medication. Interruption of antipsychotic treatment in patients with schizophrenia, through treatment discontinuation or inconsistent adherence, is associated with increases in rates of relapse, hospitalization, and treatment costs.2-5Background: Poor adherence to treatment of chronic diseases is a worldwide problem of striking magnitude. Adherence to long-term therapy for chronic illnesses in developing countries averages 50%.6References:1.Swartz MS, Perkins DO, Stroup TS, et al. Assessing clinical and functional outcomes in the clinical antipsychotic trials of intervention effectiveness (CATIE) schizophrenia trial. Schizophr Bull 2003;29(1):33-43.2.Herz MI, et al. Intermittent vs. maintenance medication in schizophrenia: two-year results. Arch Gen Psychiatry 1991;48:333-339.3.Svarstad BL, Shireman TI, Sweeney JK. Using drug claims data to assess the relationship of medication adherence with hospitalization and costs. Psychiatr Serv 2001;52:805-811.4.Ascher-Svanum H, Zhu B, Faries D, et al. A comparison of olanzapine and risperidone on the risk of psychiatric hospitalization in the naturalistic treatment of patients with schizophrenia. Ann Gen Hosp Psychiatry 2004;3(1):11.5.Gilmer TP, Dolder CR, Lacro JP, et al. Adherence to treatment with antipsychotic medication and health care costs among Medicaid beneficiaries with schizophrenia. Am J Psychiatry 2004;161(4):692-699. 6.Haynes RB. Interventions for helping patients to follow prescriptions for medications. Cochrane Database of Systematic Reviews 2001;1.7.Lehman AF, Lieberman JA, Dixon LB, et al. APA practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry 2004;161(suppl 2):1-56.The Kaplan Meier 25th %ile is the time by which 25% of the patients have discontinued. The median can not be estimated due to low event rates.The hazard ratio for olanzapine vs. quetiapine is 0.41: at any given time, patients on olanzapine are 41% less likely to discontinue treatment for lack of efficacy compared to patients on quetiapine.The Hazard ratio is from Cox proportional hazards regression, and is the ratio of the probability of discontinuing the phase at any timepoint for one treatment group vs. another.Intent-to-treat (ITT) patients received at least one dose of study medication.Dose and efficacy assessments are reported for the ITT patients. Safety assessments are reported for all randomized patients.Intent-to-treat (ITT) patients received at least one dose of study medication.Dose and efficacy assessments are reported for the ITT patients. Safety assessments are reported for all randomized patients.Intent-to-treat (ITT) patients received at least one dose of study medication.Dose and efficacy assessments are reported for the ITT patients. Safety assessments are reported for all randomized patients.Key Points: The concept of treatment effectiveness considers the impact of the medication on controlling the various symptoms of the illness, as well as the safety and tolerability of the medication.1 Despite the established need for a patient to continue on their prescribed treatment, many patients with schizophrenia fail to adhere to their medication. Interruption of antipsychotic treatment in patients with schizophrenia, through treatment discontinuation or inconsistent adherence, is associated with increases in rates of relapse, hospitalization, and treatment costs.2-5Background: Poor adherence to treatment of chronic diseases is a worldwide problem of striking magnitude. Adherence to long-term therapy for chronic illnesses in developing countries averages 50%.6References:1.Swartz MS, Perkins DO, Stroup TS, et al. Assessing clinical and functional outcomes in the clinical antipsychotic trials of intervention effectiveness (CATIE) schizophrenia trial. Schizophr Bull 2003;29(1):33-43.2.Herz MI, et al. Intermittent vs. maintenance medication in schizophrenia: two-year results. Arch Gen Psychiatry 1991;48:333-339.3.Svarstad BL, Shireman TI, Sweeney JK. Using drug claims data to assess the relationship of medication adherence with hospitalization and costs. Psychiatr Serv 2001;52:805-811.4.Ascher-Svanum H, Zhu B, Faries D, et al. A comparison of olanzapine and risperidone on the risk of psychiatric hospitalization in the naturalistic treatment of patients with schizophrenia. Ann Gen Hosp Psychiatry 2004;3(1):11.5.Gilmer TP, Dolder CR, Lacro JP, et al. Adherence to treatment with antipsychotic medication and health care costs among Medicaid beneficiaries with schizophrenia. Am J Psychiatry 2004;161(4):692-699. 6.Haynes RB. Interventions for helping patients to follow prescriptions for medications. Cochrane Database of Systematic Reviews 2001;1.7.Lehman AF, Lieberman JA, Dixon LB, et al. APA practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry 2004;161(suppl 2):1-56.Kaplan Meier medians and 25th %ile can not be estimated due to low event ratesThe hazard ratio for risperidone vs. olanzapine is 0.62: at any given time, patients on risperidone are 62% less likely to discontinue treatment for intolerability compared to patients on olanzapine. This difference is not significant since the overall p-value was not less than 0.05.The Hazard ratio is from Cox proportional hazards regression, and is the ratio of the probability of discontinuing the phase at any timepoint for one treatment group vs. another.FYI: the percentages of patients discontinued for intolerability differ slightly between this slide and the previous one because this slide is based on all randomized patients, and the previous slide is limited to ITT patients who took at least one dose of study medication.patients were instructed to fast, nonfasting results were not excluded Exposure-adjusted means are the estimated mean values that we would see at the average treatment duration across all groups (8.3 months). They are least squares means from an ANCOVA model adjusting for treatment duration.patients were instructed to fast, nonfasting results were not excluded Exposure-adjusted means are the estimated mean values that we would see at the average treatment duration across all groups (8.3 months). They are least squares means from an ANCOVA model adjusting for treatment duration.[Keywords] 530, Maguire, Justice, CME, Optima Q, Optima, 6/18/2001, neuroscience, schizophrenia, psychosis, Zyprexa, Olanzapine, critical, breakthroughs, psychiatric, treatment, redefining, standard, care, Lilly, Echo Swinford, Angela Sisson, choices, results , weight, change ###

[Narration] Behavioral interventions in patients on atypical antipsychotics have been studied as to effectiveness. In a study by Wirshing et al (1), a stepwise approach was taken such that patients were subject to increasingly intensive interventions (self-weighing, food diary, nutrition consult, education, group support, exercise classes) depending on their ability to control their weight. ###[Narration] The maximum weight gained during therapy and final weight gain after interventions is depicted in this graph for different drugs. Only clozapine showed a sustained increase in weight unresponsive to intervention.###[Narration] It is important to note that these patients were not enrolled in one large, comparative trial but were rather enrolled in multiple controlled trials at Dr. Wirshing's site. Thus, they should be taken as pilot data but nonetheless suggest that behavioral interventions may be successful in moderating olanzapine-associated weight gain.###

[Narration] Average Duration of Treatment:###[Narration] Clozapine, 27.2 wks###[Narration] Olanzapine, 73.1 wks###[Narration] Risperidone 25.8 wks###[Narration] Haloperidol, 24.7 wks###[Narration] Sertindole, 42.5 wks###[Narration] 1 "Novel Antipsychotics: Comparison of Weight Gain Liabilities" by Wirshing DA et al. J Clin Psych 1999; 60(6):358-3###

This slide is a simplistic way to discuss the differences between the antipsychotics from a mechanistic point of view. It is important to point out the broad receptor binding affinity of olanzapine and how this relates to improvement in a wide range of psychiatric symptoms.

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