Jorge M Tamayo,MD,PharmS Propuesta Para una Clasificación Integrada de los Medicamentos “Antipsicóticos” (Más Allá del Concepto de Atipicidad) Jorge M Tamayo,MD,PharmS CRP-NS Lilly & co.

Evolución de los antipsicóticos

Atipicidad: Propuestas existentes Janicak PG y colaboradores (1997): Los antipsicóticos atípicos no producen síntomas extrapiramidales Disminuyen la tasa de disparo de dopamina en neuronas A-10 sin comprometer en mayor medida las neuronas A9. Aumentan la disponibilidad de noradrenalina y dopamina a nivel prefrontal Comparados con los antipsicóticos convencionales, los atípicos: Tienen menor afinidad por los receptores D2 Tienen mayor afinidad por los receptores D4 Actúan en forma selectiva sobre las neuronas dopaminérgicas mesocorticales Bloquean los receptores 5HT2 No producen síntomas extrapiramidales (SEP) Presentan menor incidencia de disfunción sexual o reproductiva No producen hiperprolactinemia In studies conducted on largely treatment naive patients in their first episode of psychosis, we have found that treatment outcome is quite good and that most patients recover or at least achieve a substantial degree of symptom remission. However, over the course of their illness and in the context of subsequent psychotic episodes, they may experience some decrease in their treatment response from illness progression. In addition, the heterogeneity of treatment outcome is associated with specific clinical (gender, primary negative symptoms of the deficit state, duration of psychosis) and biological variables (pHVA, ventricular volume). It is unclear whether these variables represent aspects of discrete subtypes of schizophrenia or dimensional measures of pathology within the broad context of a unitary disease entity. Lieberman et al., Neuropsychopharmacology 1996;14:13S-21S

Atipicidad: Propuestas existentes(2) Leonard BE (1998): Divide los atípicos en dos grupos : . Antagonistas selectivos D2: remoxipride . Con menor efecto D2 pero potente inhibición 5HT2A: clozapina, risperidona, zotepina, sertindole, olanzapina, ziprasidona, amperazida Comparado con los antipsicóticos convencionales, los atípicos : Disminuyen los síntomas positivos Disminuyen los síntomas negativos No producen SEP No elevan la prolactina Producen menor sedación Poseen menor actividad anti-muscarínica

Atipicidad: Propuestas existentes(3) American Psychiatric Association Compendium (2000): El compendium elaborado por un consenso de expertos de la Asociación Psiquiátrica Americana, divide los antipsicóticos en : Convencionales (neurolépticos) Clozapina, al cual llaman “atípico” por no producir SEP Risperidona, considerado “diferente a los convencionales” pero con la capacidad de producir SEP, elevación de la prolactina y disfunción sexual. No lo denominan atípico. Nuevos antipsicóticos: olanzapina, sertindole, quetiapina

Atipicidad: Propuestas existentes(4) Shiloh R y colaboradores (2000): Para estos autores los “nuevos antipsicóticos” son aquellos que comparten las siguientes características: Acción sobre los síntomas negativos Mínima capacidad de producir SEP Mínimos efectos sobre la prolactina sérica Antagonismo sobre los receptores 5HT2A post-sinápticos Mayor tasa en la relación de bloqueo serotonina/dopamina Acción sobre otros receptores: D4, 5HT6 y alfa-adrenoreceptores

Atipicidad: Propuestas existentes(5) Owens DGC (1999): Considera que un antipsicótico atípico no es sinónimo de un “nuevo” antipsicótico (clozapina fue lanzada al mercado a comienzos de los 70s) Los antipsicóticos se atípicos se caracterizan por: - su eficacia: en síntomas agudos de esquizofrenia mantenimiento a largo plazo acción sobre los síntomas negativos tratamiento en esquizofrenia resistente - tolerancia: pocos efectos adversos pocos efectos neurológicos adversos

Atipicidad: Propuestas existentes(6) Stahl & Dunitz (1999): Los antipsicóticos atípicos son llamados antagonistas dopamina-serotonina. No producen SEP, ni discinesia tardía No elevan la prolactina sérica Reducen los síntomas negativos

Evaluación de la “atipicidad” de los “nuevos” antipsicóticos Risperidona: Produce bloqueo dosis dependiente de receptores D2 a nivel de ganglios basales, comparable al observado con antipsicóticos convencionales (Nyberg et al. 1996). Se asocia a la producción de SEP y a la elevación de los niveles sanguíneos de prolactina (Casey, 1997), con una mayor incidencia de disfunción sexual versus otros antipsicóticos (Vallejo et al. 1998). Clozapina: Es la única que posee mayor afinidad por receptores D4 que por receptores D2 in vitro (Schotte et al. 1996). Olanzapina, Aripiprazol y Clozapina: Acción selectiva sobre el tracto dopaminérgico A10 con baja actividad inhibitoria sobre el tracto dopaminérgico A9 no observada con ziprasidona, quetiapina y risperidona (Skarsfeldt, 1995).

CLOZAPINA La única que posee mayor afinidad por receptores D4 que por receptores D2 in vitro Acción antimuscarínica superior a la observada con olanzapina Disminuye el umbral convulsivo Agranulocitosis (idiosincrasia) Empeoramiento de síntomas obsesivos en la esquizofrenia Control de la esquizofrenia refractaria

RISPERIDONA Bloqueo dosis dependiente de receptores D2 a nivel de ganglios basales, comparable a los antipsicóticos convencionales Mayor producción de SEP, incremento de PRL y disfunción sexual Sin estudios concluyentes sobre eficacia en síntomas negativos

OLANZAPINA Bloquea receptores 5-HT6 Eficacia en síntomas obsesivos de la esquizofrenia SEP más frecuente: acatisia

QUETIAPINA No bloquea receptores 5-HT2 a un nivel que constituya uno de sus principales mecanismos de acción Sin estudios concluyentes sobre su eficacia en síntomas negativos Eficaz en síntomas motores No existe literatura con evidencia clínica para relacionarla con cataratas

ZIPRASIDONA Síntomas afectivos en la esquizofrenia Efectos adversos más frecuentes: acatisia y rigidez Forma de administración más ventajosa: IM Los pacientes refieren experimentar una “relajación agradable” luego de su administración

ARIPIPRAZOL Actividad agonista parcial sobre receptores D2 y 5-HT1A con actividad antagonista receptores 5-HT2A La literatura muestra eficacia antipsicótica sostenida con un adecuado perfil de seguridad y tolerancia Considerado de tercera generación

CLOZAPINA, OLANZAPINA Y ARIPIPRAZOL Acción selectiva sobre el tracto dopaminérgico A10 con baja actividad inhibitoria sobre el tracto dopaminérgico A9 no observada con ziprasidona, quetiapina y risperidona

Evaluación de la “atipicidad” de los “nuevos” antipsicóticos (2) Quetiapina: No bloquea receptores 5-HT2 a un nivel que constituya uno de sus principales mecanismos de acción (Schotte et al. 1996). Risperidona y Quetiapina: Sin estudios concluyentes sobre su eficacia en síntomas negativos (Marder et al. 1997; Worrel et al. 2000). Clozapina: Acción antimuscarínica superior a la observada con olanzapina desde el punto de vista farmacológico y clínico (Chengappa et al. 2000). Olanzapina e Iloperidona: La acción bloqueadora de receptores 5-HT6 (Bymaster et al. 1996 ; Kongsamut et al. 1996). Clozapina: Control de la esquizofrenia refractaria (replicado) (Kane et al. 1988, Kane et al. 2001). Sin embargo disminuye en forma considerable el umbral convulsivo (Casey, 1997).

Spectrum vs. Atipicidad Se define, desde un punto de vista multidimensional, a un antipsicótico de amplio espectro como aquél que posee: - Accion biológica sobre múltiples receptores - Accion terapéutica sobre todos los cotejos sintomaticos de las esquizofrenias [síntomas positivos, negativos, afectivos, déficit cognoscitivo] - Accion terapéutica sobre algún otro trastorno psiquiátrico como trastorno bipolar, trastornos depresivos, tratornos de personalidad, drogodependencia, trastorno obsesivo-compulsivo, enfermedad de Parkinson, demencias… - Efectividad en resocializacion (calidad de vida, funcionamiento global) - Eficacia a largo plazo - Eficacia en pacientes refractarios - Seguridad con mínimos efectos extrapiramidales, hormonales y otros

Por Qué Amplio Espectro? - Necesidad de englobar la eficacia no sólo en las esquizofrenias sino también en otros espectros sintomáticos o trastornos, teniendo en cuenta el perfil de seguridad - El concepto de amplio espectro refleja el tropismo del medicamento sobre diferentes áreas cerebrales (sistema límbico; lóbulo frontal; conexiones límbico-frontales; conexiones hipocampo-corticales). - Igualmente refleja un mecanismo de acción que va más allá de la interacción con estructuras dopaminérgicas e incluye perfiles de afinidad por otros receptores: D1 (clozapina y olanzapina), 5-HT1A (clozapina y ziprasidona), 5-HT2C (sertindol, clozapina, olanzapina y ziprasidona), 5HT6 (clozapina, olanzapina y sertindol), 5HT7 (clozapina y risperidona), 2 (risperidona), H1 (clozapina, olanzapina, risperidona y quetiapina) o M4 (clozapina y olanzapina). (Arnt & Skarsfeldt, 1998).

Tamayo JM et al., 2001 Rev Latinoamericana de Psiquiatria. In press

Broad Receptor Activity Results in a Wide Range of Effectiveness Olanzapine Clozapine Quetiapine D1 D4.2 D2 5-HT2A 5-HT2C 5-HT1A 5-HT6 1 2 Musc H1 Risperidone Ziprasidone Haloperidol Aripiprazole 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. Bymaster 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.

Pharmacodynamic Hypothesis in Antipsychotics HAL – ARI – ? + CLO + – +/– OLZ + – QUET + ? – +/– RIS – ? +/– ZIP – ? + A10 selective1 (low EPS, TD) Blocks NMDA antagonists2 e.g., PCP (improves psychosis, negative symptoms, cognition) Increases acetylcholine3,4 (improves cognition) Increases 5-HT & DA in PFC5 (improves cognition,depression) Increases c-fos expression6-8 in prefrontal cortex (improves depression, cognition) 5-HT & NA reuptake inhibitor9 (improves depression) D2 Partial agonism10 (low EPS) 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 1999:377–393. 10. Lieberman JA. Presented at APA 2002

Perfil De Afinidad Por Receptores De Los Antipsicóticos Tamayo JM et al., 2001 En este esquema el tamaño de las áreas no está relacionado con la Ki para cada grupo de receptores

Poder 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 placebo 4. Estudios controlados con otro medicamento, aleatorizados (DCM) 5. Estudios aleatorizados 6. Estudios abiertos (EA) 7. Series de pacientes con controles retrospectivos (R) 8. Series de pacientes con controles en la literatura 9. Casos obtenidos de una base de datos computadorizada 10. Series de pacientes sin controles (S) 11. Reportes de caso 12. Observaciones anecdóticas B. Spilker. Guide to Clinical Trials. Chapter 73, 1993

Rango probable de calificación final Amisulprida Quetiapina Clozapina Ziprasidona Aripiprazol (*) Iloperidona (*) Olanzapina Risperidona Haloperidol Tioridazina Sertindol ANTIPSICÓTICO DE AMPLIO ESPECTRO ANTIPSICOTICO PURO * Medicamento en fase III. Se requiere tener información de estudios a largo plazo y resocialización para dar una ubicación definitiva en la escala. Rango probable de calificación final

Atypical Antipsychotics: An Independent Review of Efficacy in Schizophrenia Positive Symptoms Negative Symptoms Vs. Placebo Vs. Hal. Vs. Placebo Vs. Hal. Olanzapine + + + + Clozapine + + + + Risperidone + +* + 0** Quetiapine +*** 0 + 0 + Study results are not consistent (Dose dependency) "Sometimes findings for one agent in the atypical class are extrapolated to the other agents in the class without supportive data." * Most studies used 20mg fixed haldol. But vs. lower / adjusted dose haldol no sig. difference between risperidone and ANY measure of efficacy. ** Marder et al 1997 conducted post-Hoc analysis of 2 Ris vs. PLC or fixed dose Haldol 20mg/day and stated statistical improvement on negative sx. But, neither study found this independently. Refs: Marder J Clin Psychiatry 1997;58(12):538-46; Chouinard. J Clin Psychopharm 1993;13:25-40; Marder. Am J Psych 1994;151:825-835. ***Quetiapine vs. Placebo inconsistent findings from study to study. The pharmacology, efficacy, and adverse effects of atypical antipsychotic agents when used to treat schizophrenia and other disorders are reviewed. Atypical antipsychotic agents were developed in response to problems with typical agents, including lack of efficacy in some patients, lack of improvement in negative symptoms, and troublesome adverse effects, especially extrapyramidal symptoms (EPSs) and tardive dyskinesia CTD). Atypical antipsychotics differ from typical psychotics in their "limbic-specific" dopamine type 2 (D2)-receptor binding and high ratio of serotonin type 2 (5-HT2)-receptor binding to D2 binding. In clinical trials in patients with non-treatment-resistant schizophrenia, risperidone and olanzapine were superior to placebo for positive and negative symptoms. Risperidone and olanzapine were superior to haloperidol on some measures. Quetiapine was better than placebo but was not better than typical antipsychotics. Head-to-head comparisons of atypical antipsychotics in non-treatment-resistant schizophrenia have been inconclusive. Clozapine remains the standard agent for treatment- resistant schizophrenia. Atypical agents are substantially more expensive than their typical antipsychotic counterparts. To fully determine the overall efficiency of these drugs, other potential benefits, such as improved quality of life, need to be factored in. Atypical antipsychotics are associated with a decreased capacity to cause EPSs, TD, neuroleptic malignant syndrome, and hyperprolactinemia. Clozapine carries a risk of agranulocytosis; the white blood cell count must be monitored. Atypical antipsychotics are increasingly being used for indications other than schizophrenia, such as the management of aggression, mania, and depression. Atypical antipsychotics are often considered first-line agents for treating schizophrenia and are promising treatment alternatives for other psychiatric and neurologic conditions. Worrel J, et al Am J Health Syst Pharm 2000;57:238-55

El Continuum del tratamiento EFICACIA Alivio de síntomas negativos Mejoría de síntomas afectivos Mejoría cognitiva Prevención del suicidio Alivio de Síntomas positivos,hostilidad, agresividad, síntomas afectivos y maniformes Control Agitación Prevención de recaída 1-3 días 7-14 días 6+ meses Disquinesia Tardía Hiperprolactinemia Aumento de peso Hiperglucemia Hipertrigliceridemia Prolongación QTc Distonia Aguda Sedación Ortostatismo Prolongación QTc EPS Interacciones medicamentosas Prolongación QTc SEGURIDAD

IMPACTO DE LOS SÍNTOMAS DE LA ESQUIZOFRENIA EN EL FUNCIONAMIENTO GENERAL Síntomas negativos Síntomas positivos : Social Ideal delirantes Ocupacional aplanamiento afectivo alucinaciones alogia lenguaje desorganizado avolición catatonia anhedonia Síntomas cognitivos Interpersonal Laboral Síntomas Afectivos Atención Memoria disforia Funciones ejecutivas suicidio abstracción Autocuidado desesperanza B395 Gorman 14

SÍNTOMAS POSITIVOS CLOZAPINA HALOPERIDOL OLANZAPINA RISPERIDONA QUETIAPINA ARIPIPRAZOL ZIPRASIDONA

SINTOMAS NEGATIVOS CLOZAPINA ARIPIPRAZOL ZIPRASIDONA OLANZAPINA

SÍNTOMAS AFECTIVOS CLOZAPINA ZIPRASIDONA ARIPIPRAZOL QUETIAPINA OLANZAPINA

EFECTOS ADVERSOS

AUMENTO DE PESO Mayor incidencia en mujeres Mayor incidencia en bipolares Mayor aumento cuanto menor BMI No dosis dependiente Historia personal o familiar de obesidad Metabolismo genético-dependiente: polimorfismo CYP2D6 El aumento de peso correlaciona con la mejoría sintomática (resocialización) (Ellingrod. Psychiatr Genetics, marzo 2002)

AUMENTO DE PESO CLOZAPINA OLANZAPINA RISPERIDONA HALOPERIDOL QUETIAPINA ARIPIPRAZOL ZIPRASIDONA

AUMENTO DE TRIGLICÉRIDOS CLOZAPINA OLANZAPINA RISPERIDONA ARIPIPRAZOL QUETIAPINA ZIPRASIDONA

HISTORIA NATURAL de la ESQUIZOFRENIA Bueno Función Psicopatológica Premorbido Prodromo Progresión Recaída Pobre 10 20 30 40 50 60 Edad (años) Data of J. A. Lieberman.

Prodromal Study-Effects on PANSS Positive Symptoms (Observed Cases)  

OLZ vs HAL – 1st Episode Time to Discontinuation for Any Reason Cumulative Prob. Remaining in Study P=.058 Double-blind, 262 patients treated with olanzapine (5-20 mg/day) or haloperidol (2-20 mg/day) Lieberman et al. HGDH Study Group. In Press

MRI: Frontal Cortical Volume p=.028 p=.002 p=.023 Lieberman et al. HGDH Study Group. In Press

Neurocognitive Composite Score Composite = sum of Z scores of CPTIPSEN, CVLTRECL, WIASTRAW, .5 LNCORRES, -0.5 VWMDIST, MOTORSP, VERBFSUM

Overall Improvement After One Year At endpoint, p-values from logit model: Therapy (p<.001) and Episode (p<.001). Tollefson et al AJP 1997

Time to Clinical Response Within group Comparison P-value (log-rank) Hal First vs Multiple Episode <.001 Olz First Episode Hal vs Olz .308 Multiple Episode Tollefson et al AJP 1997

Results: Positive Symptom Survival Distribution (BPRS pos subgroup) P = NS Positive Sx Remission defined as not having a BPRS POSITIVE sx score for any one positive symptom domain that met the inclusion criteria (4moderate, or 7 severe) Prmz = Promazine A short acting sedating typical antipsychotic used as adjunctive treatment to manage aggressive and positive symptoms. Bottom Line: In this small sample of 1st episode schizophrenia patients, with substantial augmentation using typical antipsychotics (and lorazapam), Positive symptoms are significantly improved with low doses of risperidone and no significant difference between strengths were observed. Important Discussion Point: “Meaningful clinical Improvement” Was defined as a 50% reduction in BPRS score. At end point 80.8% and 65.2% of the 4mg and 2mg groups achieved a meaningful clin. Improvement. While not statistically significant, one would wonder if it would have been given a more reasonable sample size. Merlo M, et al. J Clin Psychiatry 2002; 63(10): 885-891

AP in global symptoms

BPRS Total Score. Mean Change from Baseline # Mean Change from Baseline * initial dose = 5 mg/day; # p < .05 Keck Paul et al., Psychopharm. (Berl.) 1998; David Daniel et al., Neuropsychopharm. 1999; Simpson et al APA 2001; NDA 20-825, FDA; Beasley et al., Psychopharmacology 1996; Tran et al., Abstract - NCDEU, 1996; Arvanitis ACNP 1998

BPRS Total Score: Mean Change from Baseline By Week (LOCF) * * * * * * * * * Mean Change from Baseline Mean change from baseline * * Basline PANSS scores where similar for each of studies. Bring attention to the 4 week timpoint with OLZ data. PBO arm acted same in both studies. We can look up the N of HGAD and #s pts in each arm * * * * p=< 0.05; OLZ 15mg vs. OLZ 5mg * Statistically different from placebo p=<0.05 Anutosh S, et al. Eur Psychiatry. 2002 May;17 Suppl 1:103. Beasley et al., Psychopharmacology 1996

Olanzapine versus haloperidol: short term- continuous outcomes Croker et al. Presented at: CINP Meeting 2002

Olanzapine versus haloperidol: longer term- continuous outcomes Croker et al. Presented at: CINP Meeting 2002

Response (> 40% improvement on BPRS Total) % of Patients % of Patients In looking at response as measured by a > 40% improvement, less than 30% of patients on quetiapine reached this protocol-defined endpoint at any dose. Once again a flat dose-response relationship is seen with quetiapine. This can present difficulties when trying to predict a target dose for dosing to efficacy. Olanzapine appears to show a more robust and dose-related treatment effect, with 33% subjects on 5 mg having at least a 40% improvement, increasing to almost 50% of patients receiving 15 mg. A clear dose response relationship enables clinicians to dose appropriately and effectively, allowing patients to achieve maximal improvement. Arvanitis ACNP 1998; Beasley et al., Psychopharmacology 1996

Percent of Patients Responding Response Rates: Percentage of Improvement in PANSS Total Score by Week 28 (LOCF) 70 Olanzapine Risperidone 60 *p=.049 **p=.020 50 40 * Percent of Patients Responding 30 ** 20 A significantly (p=.049) greater proportion of olanzapine-treated patients achieved a response of at least 40% improvement in PANSS Total score by Week 28 compared to baseline than risperidone-treated patients. Moreover, nearly twice as many patients in the olanzapine treatment group as in the risperidone group achieved an improvement from baseline of at least 50% or more in PANSS Total score. Although both drugs are able to demonstrate equivalent efficacy when compared by the standard metric of antipsychotic response (20%), olanzapine patients were more likely to achieve a high bar of response associated with favorable response in multiple symptom domains, which may optimize the chance for functional improvements. 10 20 30 40 50 Percent Improvement Tran PV, et al. J Clin Psychopharmacol. 1997;17(5):407-418.

Results: Change in PANSS Total Score at Week 14 (LOCF) Baseline: 97.6 91.0 89.5 90.4 -2 -1.7 -3.1* -4 Mean Change from Baseline (LOCF): PANSS Total Score, Week 14 -6 -6.7* † -8 * p.05 reduction from baseline † p.05 vs haloperidol The efficacy of a series of atypical antipsychotic drugs compared with haloperidol was further examined in this NIMH-sponsored 14-week study of severely ill patients (N=157) with schizophrenia or schizoaffective disorder who met rigorous criteria for treatment resistance. Statistically significant within-treatment improvement on total score for all of the atypical antipsychotic drugs was demonstrated. The improvement of olanzapine- and clozapine-treated patients on the PANSS Total was superior to the improvement of haloperidol-treated patients, whereas improvement of patients on risperidone did not significantly separate from that of the patients on haloperidol. The target dose of the first 8-week period of this study was as follows. target mean clozapine 500 mg/day 402 mg/day olanzapine 20 mg/day 20 mg/day risperidone 8 mg/day 8 mg/day haloperidol 20 mg/day 19 mg/day The final 6-week period of the study allowed for higher dosing if adequate improvement was not achieved. target mean clozapine 200-800 mg/day 527 mg/day olanzapine 10-40 mg/day 30 mg/day risperidone 4-16 mg/day 12 mg/day haloperidol 10-30 mg/day 26 mg/day -9.1* † -10 Clozapine (n=40) Olanzapine (n=39) Risperidone (n=41) Haloperidol (n=37) Volavka J, et al. Am J Psychiatry. 2002;159(2):255-262.

PANSS Total Scores: Change from Baseline to 8 and 14 Weeks 100 8 weeks** 95 14 weeks** † ‡ † 90 † † † 85 † ‡ 80 75 70 Clozapine Olanzapine Risperidone Haloperidol (n=40) (n=39) (n=41) (n=37) *Significant baseline differences; **Last observation carried forward; †Significant reduction from baseline (P.05); ‡ Significant superiority from haloperidol (P .05).

AP in negative symptoms

Results: Change in PANSS Negative Score at Week 14 (LOCF) -2.0 -1.6 -1.2 -0.8 -0.4 Baseline: -1.6* † 25.1 Clozapine (n=40) 21.7 Olanzapine (n=39) -0.2 † 23.1 Risperidone (n=41) 0.7 21.9 Haloperidol (n=37) * p.05 reduction from baseline † p.05 vs haloperidol Mean Change from Baseline 0.4 0.8 Volavka J, et al. Am J Psychiatry. 2002;159(2):255-262.

PANSS Negative Sub-scale: Change from Baseline to 8 and 14 Weeks 100 8 weeks** † ‡ † 14 weeks** 95 ‡ ‡ † † ‡ 20 15 10 5 Clozapine Olanzapine Risperidone Haloperidol (n=40) (n=39) (n=41) (n=37) *Significant baseline differences; **Last observation carried forward; †Significant reduction from baseline (P.05); ‡ Significant superiority from haloperidol (P .05).

SANS Total Score. Relative Efficacy vs Placebo # Estimated Treatment Effect # p < .05 NDA 20-825, FDA; Beasley et al., Psychopharmacology 1996; Small et al., 1997

AP in cognitive deficit

General Cognitive Factor Change Scores (± SE) Group effect, N = 99: F(3, 94) = 4.46, p<.006 Post-hoc: OLZ > HAL (p<.02); RIS > HAL (p<.024) Volavka J, et al. Am J Psychiatry 2002; 159:255–262

Percentage of Patients in Each Treatment Group Showing Improvement of at Least 1.0 SD on the Global Neurocognitive Scale % Improved (>1.0 SD) Bilder et al. Eur Neuropsychopharm. 2001;11(suppl 3):S256

AP in affective symptoms

MADRS Total Depression Scores in Schizophrenia # # Mean Change from Baseline # p < .05 Tollefson GD, et al. Am J Psychiatry. 1997; 154: 457-465; NDA 20-825, FDA; Kane JM. APA May 2002.

AP in maintenance phase

Time to Relapse Olanzapine vs. Placebo 5.54%* p=3.61x10-13 vs. placebo % of Patients 55.19% Compared to placebo, olanzapine-treated patients demonstrated significantly greater improvement in mean Y-MRS scores by the end of week one. This effect was maintained throughout all four weeks of the clinical trial. Further studies are needed to determine whether a treatment effect may be seen earlier than this seven day post-baseline assessment captured. Olanzapine (N=224) Placebo (N=102) Days of Double-blind Therapy Breier et al. submitted Data on File, Lilly & Co.

Proportion Relapse Free (LOCF) Relapse Prevention With Ziprasidone 1-Year Kaplan–Meier Estimate Ziprasidone 40 mg/day (n=71) Ziprasidone 80 mg/day (n=68) Ziprasidone 160 mg/day (n=67) Placebo (n=71) ** *** Weeks 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 3 6 16 28 40 52 Proportion Relapse Free (LOCF) These results show that in chronically ill patients with stable schizophrenia, ziprasidone is significantly effective in preventing relapse over 1 year. The relapse rate, based on a survival analysis of time to relapse, was statistically significantly lower in all ziprasidone groups compared with placebo. References: Arató M, O’Connor R, Meltzer H and the ZEUS Study Group. The Ziprasidone Extended Use in Schizophrenia (ZEUS) study: A prospective, double-blind, placebo-controlled, 1-year clinical trial. Submitted. Data on file, Pfizer Inc. ** P<0.01; *** P<0.001 vs placebo Arató et al. submitted Data on File, Pfizer Inc.

Proportion Relapse Free Aripiprazole Relapse Prevention Trial: Time to IMPENDING* Relapse 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Aripiprazole 15 mg Placebo 0 20 40 60 80 100 120 140 160 180 Days Proportion Relapse Free P<0.001 IMPENDING: CGI-I > 5 (minimally worse) OR PANSS > 4 (moderately severe) on hostility or uncooperativeness (2 consecutive days) OR PANSS Total > 20% increase Weiden PJ. APA May 2002.

Incidence of Psychotropic Monotherapy in Schizophrenia Infoscriber Corporation, March 1, 2001 (www.infoscriber.com)

Olanzapine vs Clozapine in Treatment Resistant Schizophrenic Patients 0.0 -1.1 -0.9 -5.0 -6.4 -5.6 -6.8 -7.1 -10.0 -14.0 Cambio Promedio desde la línea de base -15.0 -15.2 -20.0 Olanzapina -22.1 Clozapina -25.0 -25.6 PANSS Total PANSS Positivo PANSS Negativo BPRS Total CGI- Severity Beuzen et al, 1998

Dosing in Double-Blind Study in Treatment -Resistant Schizophrenic Patients Escalation and fixed dose Clinical titration 10-30 mg/day Haloperidol 20 mg/day 200-800 mg/day Clozapine 500 mg/day 4-16 mg/day Risperidone 8 mg/day 10-40 mg/day Previous medication Olanzapine 20 mg/day -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Weeks Volavka J, et al. Am J Psychiatry 2002; 159:255–262

Probability of Remaining in the Study During Treatment With Haloperidol, Olanzapine, or Risperidone (Kaplan-Meier Estimates) Probability of Remaining in Study Weeks Volavka J, et al. Am J Psychiatry 2002; 159:255–262

AJP Editorial Comments About Volavka's Study When compared with haloperidol treatment (with conservative corrections for the performance of multiple statistical tests), only clozapine and olanzapine demonstrated statistically significant improvement in negative symptoms. In addition, none of the three atypical antipsychotics produced a statistically significant improvement in positive symptoms or general psychopathology compared with haloperidol. In contrast to investigations that are initiated and controlled by industry, the authors had complete independence in the design, conduct, analysis, and interpretation of the study. In some ways, this study may represent a model approach for the support of clinical trials; that is, the study was designed and conducted by independent investigators, principally funded by the federal government, and supplemented by contributions from, but without undue influence by, the pharmaceutical industry. Indeed, such government/private collaborations for investigator-initiated research have been encouraged by NIMH. DAVID A. LEWIS, M.D. Am J Psychiatry 2002; 159