1. ENFERMEDAD BIPOLAR Y ANTIPSICOTICOS ATIPICOS Dr. José Bitrán Instituto Neuropsiquiátrico de Chile Santiago, Mayo de 2004

8. Tratamientos Anti Manía I.- Litio II.- Anti Convulsivantes III.-Neurolépticos Atípicos IV.-Neurolépticos Típicos V .-TEC

11. Positivos Negativos Litio Lamotrigina Valproato Gabapentina Olanzapina Topiramato Risperidona Quetiapina Ziprasidona Aripiprazol Tratamientos de la Manía Ensayos de Monoterapia (placebo-controlados)

12. Tratamientos de la Manía Ensayos de Combinación (placebo-controlados) Positivos Litio (Litemia 0.8-1.2) Valproato(1,25g-3g) Olanzapina (10-30mg) Risperidona (1-4 mg) Quetiapina (0.3-0.9g) Ziprasidona Aripiprazol Negativos Lamotrigina Gabapentina Topiramato

14. Estudios Randomiz ados, Doble ciego, de eficacia de Monoterapia con Olanzapina en Manía Study Study Duration Sample Size Total=1452 Efficacy p-Value 1. Tohen M et al. Am J Psychiatry . 1999;156(5):702-709. 2. Tohen M et al. Arch Gen Psychiatry . 2000;57(9):841-849. 3. Berk M et al. Int Clin Psychopharmacol . 1999;14(6):339-343. 4. Tohen M et al. Presented at: WPA International Congress; Sept 30-Oct 4, 2001; Madrid, Spain. 5. Tohen M et al. Am J Psychiatry. 2002;159(6):1011-1017. 6. Zajecka JM et al. Presented at: 39th ACNP Annual Meeting; Dec 10-14, 2000; San Juan, Puerto Rico. 7. Tohen M et al. Arch Gen Psychiatry. 2002;59(1):62-69. 4 weeks 115 OLZ vs PBO 2 <.001 251 3 weeks OLZ vs DVPX 5 .028 OLZ vs HAL 4 6 weeks 453 .152 OLZ + Li + or VPA vs Li + or VPA 7 6 weeks 344 .003 OLZ vs DVPX (Abbott study) 6 3 weeks .210 120 4 weeks 30 OLZ vs Li + ( Berk et al) 3 .44

15. Eficacia de Olanzapina vs Valproato en pacientes con Manía No Psicótica -16 -14 -12 -10 -8 -6 -4 -2 0 *p<.001 25.7 26.1 Among psychotic patients, improvement comparable between olanzapine and divalproex groups, p=.93. T ohen M et al. Am J Psychiatry. 2002;159(6):1011-1017. Olanzapine (n=63) Divalproex (n=72 ) Mean YMRS Change (LOCF) Baseline to Endpoint (Week 3) Improvement * Baseline

16. Mejoría en Síntomas Depresivos Comorbidos con Manía Comparaciones Olanzapina-Valproato -4,9 -3,5 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 Olanzapine (n=123) Divalproex (n=123) Mean Change in HAM-D (LOCF) Baseline to Endpoint (Week 3) -6,9 -6,3 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 Olanzapine (n=53) Divalproex (n=56) 13.4 14.8 Baseline: p=NS Tohen M et al. Am J Psychiatry. 2002;159(6):1011-1107. p=NS Improvement Mean Change in HAM-D (LOCF) Baseline to Endpoint Improvement 14.9 15.1 Zajecka JM et al. Presented at: 39th ACNP Annual Meeting; Dec 10-14, 2000; San Juan, Puerto Rico.

17. Mejoría en síntomas depresivos Comorbidos con Manía, durante el tratamiento con O lanzapin a -11,5 -6,8 -15 -10 -5 0 25.0 25.4 Baseline: Pooled 3-week efficacy findings in manic or mixed patients with baseline depression defined as HAMD-21. Total score  20 at baseline. Baker RW et al. J Clin Psychopharmacol . In press. * Olanzapine (n=33) Placebo (n=35) Mean Change in HAMD-21 Total After 3 Weeks of Treatment (LOCF) *p=.038 Olanzapine (5-20 mg/day) Compared to Placebo

18. -16 -14 -12 -10 -8 -6 -4 -2 0 0 1 2 3 4 5 6 7 14 21 Days Divalproex (n=123) Olanzapine (n=125) Only significant p-values are shown. Mean modal dose was 17 mg/day for olanzapine and 1400 mg/day for divalproex. Tohen M et al. Am J Psychiatry. 2002;159(6):1011-1017. Visitwise Improvement from Baseline in YMRS Total Score (LOCF) Control Rápido de la Man í a : Olanzapin a vs V alpro ato

19. Olanzapin a vs V alpro ato : Mejoría en escala de Man í a Olanzapine-treated patients had a significantly greater mean improvement on the primary efficacy measure (YMRS Total score) than divalproex-treated patients. Tohen M et al. Presented at: 13th Congress of the ECNP; Sep 9-13, 2000; Munich, Germany. -16 -14 -12 -10 -8 -6 -4 -2 0 Baseline: 27.4 27.9 -13.4 * -10.4 Mean Change from Baseline to Endpoint (Week 3) for YMRS Total Score *p=.028 Olanzapine (n=125) Divalproex (n=123)

20. Mejoría en pacientes con manía leve moderada: Olanzapin a vs Valproato Less severely manic patients defined as those with baseline YMRS Total score below the median baseline of 27. Data on file, Eli Lilly and Company. -10,72 -6,81 -15 -10 -5 0 Olanzapine (n=60) Divalproex (n=63 ) Baseline to Endpoint Change in YMRS Total Score (LOCF) *p=.011 * Improvement Baseline: 22.89 22.98

21. Coterapia con Olanzapin a Mejora Síntomas Maniacos (breakthrough) e n Pa c ient e s en Lit io o Valproat o Olanzapine 5-20 mg/day or placebo added to ongoing open treatmentwith lithium or divalproex.Tohen M et al. Arch Gen Psychiatry. 2002;59(1):62-69. -14 -12 -10 -8 -6 -4 -2 0 Mean Change from Baseline to Endpoint (Week 6) for YMRS Total Score OLZ + Li + /VPA (n=220 ) PBO + Li + /VPA (n=114 ) -13.11 -9.10 * Baseline: 22.31 22.67 *p=.003

23. PANSS-EC ratings during 47-week mania study. Data on file, Eli Lilly and Company. Mejoría de síntomas de agitación en Man í a:Olanzapin a Compar a d a a V alpro ato -4,0 -3,5 -3,0 -2,5 -2,0 -1,5 -1,0 -0,5 0,0 Olanzapine (n=123) Divalproex (n=123 ) Mean Change from Baseline to Endpoint in PANSS-EC Score (LOCF) Improvement Hostility Poor Impulse Control Excitement Uncooperativeness Tension Overall PANSS- EC Score

24. Mejoría de Síntomas específicos de Manía Coterap ia con Olanzapin a vs Lit io/ Valproat o en Monoterap ia Olanzapine cotherapy demonstrated a statistically significant improvement compared to monotherapy on the YMRS items of (5) irritability, (6) speech, (7) language/thought disorder, and (9) disruptive/aggressive behavior. Tohen M et al. Arch Gen Psychiatry. 2002;59(1):62-69. Scale Legend: 1. Elevated mood 5. Irritability 9. Disruptive/aggressive behavior 2. Increased motor activity/energy 6. Speech 10. Appearance 3. Sexual interest 7. Language/thought disorder 11. Insight 4. Sleep 8. Content YMRS Item Change from Baseline to Endpoint (LOCF, Week 6) -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 3 4 5 6 7 8 9 10 11 1 2 OLZ cotherapy (n=220) Li + /VPA monotherapy (n=114) * * * ** *p<.025 **p=.002

25. Cot erapia con Olanzapin a mejora lo depresivo comorbido con Mania Tohen M et al. Arch Gen Psychiatry. 2002;59(1):62-69. Mean Change in HAM-D from Baseline to Endpoint (Week 6) 6-Week Trial of Olanzapine or Placebo Added to Lithium or Valproate for Mixed or Manic Episodes -6 -5 -4 -3 -2 -1 0 OLZ + Li + /VPA (n=220 ) PBO + Li + /VPA (n=114) -4.98 -0.89 * Baseline: 14.52 13.54 * p<.001

26. -1 0 OLZ (n=220) PBO (n=114) Mejoría de lo depresivo en la Manía : Coterapia con Olanzapin a Compar ado a Monoterapia con Lit io o Valproat o Mean HAM-D Item Change (LOCF) Baseline to Endpoint (Week 6) Improvemen t 1. Depressed mood 2. Feelings of guilt *p<.001 3. Suicide **p=.029 4. Early insomnia † p=.028 * * ** † ‡ || Tohen M et al. Arch Gen Psychiatry. 2002;59(1):62-69 . 10. Psychic anxiety ‡ p=.003 20. Paranoia || p=.001 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

27. Tolera ncia a la Olanzapin a e n Mania Results are from short-term (3- and 4-week) placebo-controlled trials of olanzapine 5-20 mg/day in acute bipolar mania. Difference between olanzapine and placebo was not statistically significant. Tohen M et al. Am J Psychiatry. 1999;156(5):702-709. Tohen M et al. Arch Gen Psychiatry. 2000;57(9):841-849. % of Patients Discontinuing Due to Treatment-Emergent Adverse Events in Placebo-Controlled Registration Trials 0 10 20 2.3% 1.6% Olanzapine (n=125) Placebo (n=129 ) 100 % of Patients

28. Quetiapina en Manía Juvenil: Porcentaje de Respondedores DVP DVP + QUET Manic Mixed Psych NPsych 90 80 70 60 50 40 30 20 10 0 % DeBello et al. J Am Acad Child Adolesc Pysichiatry- 2002

31. QUETIAPINA EN MANIA AGUDA JonesM Huizar K paper presented at Annual Meeting of the American Psychiatric Assoation, May 17-22-2003 San Francisco California

32. Ziprasidona vs Placebo: Reducción en YMRS (Manía) Cambio de línea de Base 0 2 4 7 14 21 Study Day 0 -2 -4 -6 -8 -10 -12 -14 Mean Change from Baseline (LOCF) Placebo (n=66) Ziprasidone (n=131) P<0.001 vs placebo Keck PE Jr et al Am J Psychiatry 2003;160:741-748

33. Aripiprazole en Mania Aguda: Tasa de Respuesta 45 40 35 30 25 20 15 10 50 0 Day 4 Week 3 Response defined as > 50% reduction in YMRS P< 0.01 LOCF analysis Jody et al. Int J Neuropsychopharmol. 2002:5 (suppl 1):S57 Placebo Aripiprazole * * %

34. Aripiprazol en Manía Aguda Keck PeJr.,et alAm J Psychiatry, 2003:160:1651.1658

35. Mejoría en escala CGI-1 en 2 Estudios Doble Ciego Placebo + MS Risperidone +MS Haloperidol +MS Placebo +Ms Risperidone +MS 60 50 40 30 20 10 0 26 16 22 36 Very Much Improved (%) Much Improved (%) US Study International Study MS = mood stabilizer Data from Sachs GS. Int J Neuropsychopharmacol 2000;3(suppl1): S143 Data from Yatham LN J Clin Psychiatry 2002;63 (suppl3):10-14 P< 0.1 risperidone vs placebo; P<0.5 Patients with CGI Improvements at Endpoint (%)

37. Algori t m o para el Tratamiento de Manía en el Trast. Bipolar Report e del Panel de Consenso de Texas Etapa 1 Litio, Divalproex , o Olanzapina Manía/Hipomanía Eufórica/ Manía/Hipomanía Disfórica/Mixta Manía Psicótica Divalproex o Olanzapina Litio, Divalproex , o Olanzapina Monoterap ia Respuesta Respuesta Tratamiento combinado CONT Etapas 2-7 Parcial o Sin respuesta CONT Adapted from: Suppes T et al. J Clin Psychiatry. 2002;63(4):288-299.

38. Compar ación por 1 año de Olanzapin a y Liti o en Preven c i ó n de Recaídas e n Trastorno Bipolar Tohen M et al. Presented at: Stanley Bipolar Meeting; September 11-14, 2002; Freiberg, Germany . Acute bipolar I mania Lithium level 0.5-1.0 mEq/L n=214 Open-label treatment Stable euthymic patients randomized 1-year double-blind monotherapy for relapse prevention n=431 Olanzapine 5-20 mg/day n=217 n=543

39. Re caída a l a Man í a o Depresi ó n: Resultados (escalas) e n 1 año de comparación Olanzapine-Lithium 0 10 20 30 40 50 14.3% 28.0% p=.055 p=.895 *p<.001 Overall Relapse % of Patients Depressive Relapse Manic Relapse 15.4% 16.1% 38.8% 30.0% Olanzapine (n=217) Lithium (n=214) Relapse defined by YMRS  15 and/or HAM-D  15. Tohen M et al. Presented at: Stanley Bipolar Meeting; September 11-14, 2002; Freiberg, Germany . * *

40. Tiempo para recaida a Manía o Depresión Basado en Hospitalización y/o Criterio Sintomático Tohen, MF, et al. APA Meeting.2003. San Francisco, CA

41. Tiempo para Recidiva Sintomática de Manía o Depresión luego de Remisión de Manía y Depresión Tohen MF et at Presented at: Annual Meeting of the American Psychiatric Association: May 17, 22 2003 san Francisco California

46. Eficacia de los NA. En el Trastorno Bipolar *Antimanic effects are seen in pure and mixed or dysphoric mania Key:+:probably effective.-:+/:possibly effective.?:untested. ? ? + Aripiprazole ? ? + Ziprasidone ? ? + Quetiapine ? +/- + Risperidone +/- +/- + Olanzapine +/- +/- + Clozapine +/- - + Neurolépticos Típicos ANTIDEPRESIVO ESTABILIZANTE ANTIMANIACO AGENTE

47. Tolerancia de los NA. en el Trastorno Bipolar 0=none known (placebo rate):+=minimal or rare,++=moderate or occasional,+++=severe or common Strakowski SM,et al CNS Drugs 2001:1.5,701-718Strakowski SM,et al.Expert Cpn Pharmacother.2003;4-751-760. ++ ++ + + Ariprazole + + ++ ++ Quetiapine + ++ + + Ziprasidone + ++ + ++ Risperidone + + ++ +++ Olanzapine GI EPS Sedación Aumen. Peso Agente

57. Olanzapina y Fluoxetina en Depresión Resistente Puntaje MADRS:Cambio Medio desde la Linea de Base Shelton RC et al. Am J Psychiatry.2001;158:131-134