NUEVAS PERSPECTIVAS DE TRATAMIENTO SINTOMÁTICO EN ENFERMEDAD DE ALZHEIMER. Alcanzando dosis óptimas.
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Presentado en el curso Actualización de Demencias organizado por la Sociedad Peruana de Geriatría Auditorio de la Universidad Peruana Cayetano Heredia Setiembre 2011
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NUEVAS PERSPECTIVAS DE TRATAMIENTO SINTOMÁTICO EN ENFERMEDAD DE ALZHEIMER. Alcanzando dosis óptimas.
- 1. Nuevas perspectivas de tratamiento sintomático en Enfermedad de Alzheimer Alcanzando dosis óptimas
- 4. Estimado de pobladores con demencia a nivel mundial Ziegler-Graham K et al. Alzheimer’s Dement 2007;3(Suppl):S168–169
- 5. Predicción de incremento de prevalencia en enfermedad de Alzheimer para el 2050 285% 534% 476% 229% 497% 365% Basado en estimados de datos 2006 a 2050 Ziegler-Graham K et al. Alzheimer’s Dement 2007;3(Suppl):S168–9
- 6. Estudios basados en poblacion en LA Nitrini R. et al. International Psychogeriatrics 2009;21:622–630
- 7. Tasas de prevalencia de demencia según edad y género en LA y Europa Estudios Latino-americanos Estudios Europeos Mujer Hombre Mujer Hombre Edad Dem n Evalu n Media (%) (95% CI) Dem n Evalu n Media (%) (95% CI) Media (%) Media (%) 65-69 149 5620 2.65 (2.25-3.10) 79 3 479 2.27 (1.80-2.81) 1.0 1.6 70-74 196 4781 4.10 (3.55-4.69) 65 2 317 2.81 (2.17-3.57) 3.1 2.9 75-79 293 3802 7.71 (6.89-8.59) 112 1 888 5.93 (4.90-7.09) 6.0 5.6 80-84* 291 2326 12.51 (11.17-13.94) 162 1 489 10.88 (9.34-2.55) 12.6 11.0 85-89 281 1244 22.59 (20.30-24.97) 182 960 18.96 (16.49-21.55) 20.2 12.8 90+ 189 500 37.80 (33.56-42.28) 105 390 26.92 (22.54-31.67) 30.8 22.1
- 8. Causas de demencia en 103 casos: Cercado de Lima Custodio N, et al . An Fac Med 2008;69(4):233-238 Diagnóstico n % EA Probable 51 49.5 EA Posible 7 6.8 Demencia vascular 9 8.7 EA con EVC 16 15.5 DEP 3 2.9 DCL 2 1.9 DFT 2 1.9 No determinado 13 12.7
- 9. Severidad de EA en 37 casos: Cercado de Lima Custodio N, et al . An Fac Med 2008;69(4):233-238 Severidad n % ADAScog 16-20 6 16.2 ADAScog 21-30 18 48.6 ADAScog 31-45 8 21.6 ADAScog > 45 5 13.5
- 10. Prevalencia de demencia en relación a edad: Cercado de Lima X 2 = 221.17 ; p= 0.0000 Custodio N, et al . An Fac Med 2008;69(4):233-238 Grupo de edad n Demencia (n) Demencia (%) 65 – 69 582 6 1.1 70 – 74 428 9 2.1 75 – 79 252 21 8.3 80 – 84 179 26 14.5 85 – 96 91 41 45.1
- 11. Prevalencia de demencia según género y años de educación: Cercado de Lima * X 2 = 5.8 ; p= 0.001 ** X 2 = 32.37 ; p= 0.0000 Custodio N, et al . An Fac Med 2008;69(4):233-238 Género * n Demencia (n) Demencia (%) Masculino 636 29 4.6 Femenino 896 74 8.3 Años de educación ** Iletrados 269 41 15.2 1 a 3 312 25 8.1 4 a 7 417 17 4.1 Más de 8 534 20 3.7
- 12. Solo estamos sub-diagnosticando? < 50% recibe un diagnóstico 4.6 millones nuevos casos/año ~ 25% recibe tratamiento < 12% en terapia por más de 1 año En donde está tu paciente? Muchos permanecen en tratamiento recibiendo dosis sub-optimas Solomon PR & Murphy CA. Geriatrics 2005;60:26–31 Small G & Dubois B. Curr Med Res Opin 2007;23:2705–13 ?
- 14. Estrategias terapéuticas en EA 55 50 45 40 35 30 25 20 15 10 5 0 Promedio en puntaje ADAS cog(DS) 23 puntos: Umbral para EA “MODERADA” 45 puntos: Umbral para EA “SEVERA” 33 puntos: Umbral para EA “MODERADAMENTE SEVERA” 60 TRATAMIENTO SINTOMATICO MODIFICACION ENFERMEDAD SIN TRATAMIENTO 26 52 78 104 130 156 182 208 234 260 Semanas
- 17. Puntaje MMSE Años 10 15 20 1 2 3 4 6 Progresión CDR1 a CDR2 5 Progresión CDR1 a CDR2 Modificación de EA: Retrasar progresión
- 18. Cual es el estadio clínico optimo para la modificación de la enfermedad en EA? EDAD TIEMPO SALUD CEREBRAL EA TCL PRECLINICO Escasa injuria neuronal/compromiso funcional
- 19. Necesidad del diagnostico precoz EDAD TIEMPO SALUD CEREBRAL EA TCL PRECLINICO
- 21. Prevalencia a 5 años de SNP en EA Steinberg M, et al. Int J Geriat Psychiatry 2008;23:170-177
- 22. Síntomas NP en EA según MMSE Craig D, et al. Am J Geriat Psychiatry 2005;13:460-468
- 24. Tratamiento de Síntomas NP en demencia Paciente con Demencia y problema conductual D/C delirio, dolor, causas ambientales Manejo no farmacológico Mejora problemas conductuales? Con s+s de depresión/ansiedad? Recibe un IChE? Inicie IChE c/s Memantina Mejora problemas conductuales? Mejora problemas conductuales? Inicie ISRS Mejora problemas conductuales? Considere CBZ/VPA Inicie ISRS Monitoree No Si No No No No Si Si Monitoree Si Monitoree Si Monitoree Si No Sink KM et al. JAMA 2005; 293:596-608 Gauthier S et al. Int Psychogeriatrics 2010;22:346-372 Inicie Tratamiento con Antipsicóticos Atípicos*
- 25. Mortalidad y Antipsicóticos en demencia Gill SS et al. Ann Intern Med 2007;146:775-786
- 26. Mortalidad y Antipsicóticos en demencia Ballard C. et al. Lancet Neurol 2009;8:151-157
- 27. Los Agentes atípicos son mejores que los típicos en manejo de demencia? Trifiro G. et al. Pharmacological Research 2009;59:1-12
- 28. Manejo de los síntomas conductuales en EA con inhibidores de colinesterasa (IChE)
- 29. IChE y memantina en el manejo de los síntomas conductuales Fuente Diseño N Tiempo Droga Reside Demencia McKeith, 2000 RCT 120 20 s R (9.4 mg/d) Com DCL MMSE 17.9 Feldman, 2000 RCT 290 24 s D (74%: 10 mg/d) Com EA MMSE 11.8 Tariot, 2001 RCT 208 24 s D (9.5 mg/d) NH EA MMSE 14.4 Erkinjuntti, 2002 RCT 592 24 s G (24 mg/d) Com DV MMSE 20.5 Olin, 2003 Meta-anal 2 RCT 1364 12-20 s G (16, 24, 32 mg/d) Com EA L-M Courtney, 2004 RCT 565 > 4 a D (5 ó 10 mg/d) Com EA MMSE 19 Holmes, 2004 RCT 96 12 s D (10 mg/d) Com EA MMSE 21 Reisberg, 2003 RCT 252 28 s M (20 mg/d) Com EA MMSE 7.9 Tariot, 2004 RCT 404 24 s M (20 mg/d) Com EA MMSE 10
- 30. IChE y memantina en el manejo de los síntomas conductuales Fuente Resultados Significancia Eventos Adversos McKeith, 2000 R vs Pla : No diferencia en NPI-4 No R > Pla Tasa retiro: 23% R, 19%Pla Feldman, 2000 D > Pla : 5.6 puntos NPI D > Pla: CIBIC-Plus Si D > Pla Tasa retiro: 8% D, 6% Pla Tariot, 2001 D vs Pla: No diferencia en NPI-NH No D> Pla Tasa retiro:18% D, 11% Pla Erkinjuntti, 2002 G > Pla : 2.2 puntos NPI D > Pla: CIBIC-Plus Si G> Pla Tasa retiro:20% G, 8% Pla Olin, 2003 G 16 mg > Pla: 2.1 puntos NPI Si Dependen de la dosis Courtney, 2004 D vs Pla: No diferencia en NPI No D > Pla Tasa retiro: 6% D, 1% Pla Holmes, 2004 D > Pla : 6.2 puntos NPI D > Pla: 2.8 puntos NPIc Si D > Pla Tasa retiro:18% D, 15% Pla Reisberg, 2003 M vs Pla : No diferencia en NPI y CIBIC-Plus No M > Pla Tasa retiro:17% M, 10% Pla Tariot, 2004 M > Pla : 3.7 puntos NPI M > Pla: CIBIC-Plus Si M > Pla Tasa retiro:25% M, 15% Pla
- 31. Rivastigmina y síntomas conductuales tras 6 meses de tratamiento Gauthier S et al. Int J Clin Pract 2007;61:886-895
- 32. Reporte de cuidadores y cambios en dosis de psicotrópicos tras 6 meses con Rivastigmina Gauthier S et al. Int J Clin Pract 2007;61:886-895
- 36. Progresión de disfunción en EA EDAD TCL EA L-M EA-S Pre-Sintomático Sintomático “ Funcionalidad” Función cognitiva Carga patológica
- 38. Lo que se pierde, no se recupera! Definiciones de Global Deterioration Scale Reisberg B et al. Am J Psychiatry 1982;139:1136–9 INCREMENTO SEVERIDAD INCREMENTO CARGA Estadio 7 – Muy severo Estadio 6 – Severo Estadio 6 – Severo Estadio 5 – Moderad. severo Estadio 4 – Moderado Estadio 3 – Leve Estadio 2 – Muy leve Estadio 1 – Aparent. normal Años después del inicio 0 5 10 15 20 Pierde el lenguaje, marcha, conciencia; muerte Necesita cuidados todo el tiempo; institucionalizado No puede cuidarse por si mismo; incontinente, deprimido Nopuede pasar mucho tiempo sin asistencia personal; agitado, necesita cuidados Familia y amigos notan ciertos problemas Normal Declinación cognitiva no evidente Deficit funcional leve – ‘olvidadizo’
- 39. Rountree SD et al. Alzheimer’s Research and Therapy 2009;1-7
- 40. Qué pasa cuando se retrasa el inicio del tratamiento con algún IChE? -4 -2 0 +2 +4 +6 +8 +10 MEJORÍA DETERIORO Cambios en ADAScog desde el basal 12 26 38 44 52 * ** ** ** * p<0,001 vs placebo ** p<0,001 vs placebo proyectado Farlow M et al. Eur Neurol 2000;44:236-241 Doble Ciego Abierto 9-12 mg/día 3-6mg/día Placebo Todos los pacientes con Rivastigmina
- 41. Efectos de la descontinuación de los IChE en pacientes con demencia Daiello LA et al. Am J Geriatr Pharmacother 2009;7:74-83 Continuad:116 / Descontinuad: 62 Cambio/mes 95% CI p Conductual: Escala agresividad Descontinuadores IChE 0.08 0.01-0.16 0.03 Continuadores IChE -0.01 -0.06-0.04 0.66 Diferencia entre grupos 0.09 0.01-0.18 0.03 Cognicion: Escala de performance cognitiva Descontinuadores IChE 0.06 -0.013-0.13 0.10 Continuadores IChE 0.02 -0.006-0.05 0.12 Diferencia entre grupos 0.04 -0.044-0.12 0.38 Funcionabilidad: Escala actividades de vida diaria Descontinuadores IChE 0.10 0.02-0.17 0.01 Continuadores IChE 0.03 0.01-0.06 0.02 Diferencia entre grupos 0.07 -0.01-0.14 0.10 Funcionabilidad: Tiempo empleado en actividades placenteras Descontinuadores IChE 0.11 0-0.23 0.04 Continuadores IChE -0.26 -0.50 - -0.02 0.03 Diferencia entre grupos 0.37 0.10-0.65 0.01
- 43. Todos los IChE han demostrado que retrasan la declinación Gauthier S. Brain Aging 2002;2:9–22 Linea Basal Cambio desde la Linea de Base Tratados No Tratados
- 44. En lugar de usar toda la eficacia desde el inicio, qué pasa si reservamos algo para después? Cambio desde la Linea de Base Tratado No Tratado Aumento de la Dosis Nosotros debemos ser capaz de Retrasar otra vez ….
- 45. Y ………otra vez………….. Aumento de la Dosis Cambio de la Linea de Base Tratado No Tratado
- 48. Efectos adversos colinérgicos de los IChE son Dosis-relacionados Imbimbo BP. CNS Drugs 2001;15:375–90 Relationship between AChE inhibition and incidences of adverse events (differences vs. placebo) in Alzheimer’s disease patients participating in 6-month RCTs. Includes data from trials with tacrine, donepezil, rivastigmine, metrifonate, physostigmine and eptastigmine 70 60 50 40 30 20 10 0 Incidencia nausea (%) r = 0.0683 p < 0.01 0 10 5 15 20 Incidencia diarrea (%) r = 0.817 p < 0.001
- 51. Diagnostico Temprano Rivastigmina oral 3 mg/día Rivastigmina patch 4.6 mg/24 h Donepecilo tabletas 5 mg/día Galantamina ER tabletas 8 mg/día ‘ Tratamiento Óptimo’ Lo mejor para después
- 52. Diagnostico Temprano Rivastigmina oral 3 mg/día Rivastigmina patch 4.6 mg/24 h Donepecilo tabletas 5 mg/día Galantamina ER tabletas 8 mg/día Aumentar la Dosis! Rivastigmina oral 12 mg/día Rivastigmina patch 9.5 mg/24 h Donepecilo tabletas 10 mg/día Galantamina ER tableta16 mg/día ‘ Tratamiento Óptimo’ Lo mejor para después
- 53. Diagnostico Temprano Rivastigmina oral 3 mg/día Rivastigmina parche 4.6 mg/24 h Donepecilo tabletas 5 mg/día Galantamina ER tabletas 8 mg/día Aumentar la Dosis! Rivastigmina oral 12 mg/día Rivastigmina patch 9.5 mg/24 h Donepecilo tabletas 10 mg/día Galantamina ER tableta16 mg/día Si hay una dosis mayor disponible, AUMENTARLA! ‘ Tratamiento Óptimo’ Lo mejor para después Aumentar la Dosis? Rivastigmina patch 13.3 mg/24 h Galantamina ER tableta 24 mg/día
- 54. Y sí realizamos los maximos esfuerzos para iniciar el tratamiento más efectivo que tenemos, lo más temprano posible? Tiempo Funcion Cognitiva Tratamiento Tardio Prediciendo los resultados del Tratamiento Temprano Tratamiento Temprano Sin Tratamiento
- 55. Qué pasa cuando se retrasa el inicio del tratamiento con algún IChE? -4 -2 0 +2 +4 +6 +8 +10 MEJORÍA DETERIORO Cambios en ADAScog desde el basal 12 26 38 44 52 * ** ** ** * p<0,001 vs placebo ** p<0,001 vs placebo proyectado Farlow M et al. Eur Neurol 2000;44:236-241 Doble Ciego Abierto 9-12 mg/día 3-6mg/día Placebo Todos los pacientes con Rivastigmina
- 56. Altas dosis de IChE brindan mejores efectos clínicos Mejoria Anand R et al. Int J Geriatr Psychopharmacol 2000;2:68–72 Media de Cambio desde el Basal del ADAS-cog -1 0 1 2 3 4 Ultima dosis prescripta de rivastigmina oral (mg/dia) n = 2,791 Rivastigmina data (26 semanas) 0 2 4 6 8 10 12 95% Interv.Confianza Respuesta Predecida
- 57. Altas dosis de IChE brindan mejores efectos clínicos Burns A et al. Dement Geriatr Cogn Disord 1999;10:237–44 Media de Cambio del Basal delADAS- cog n = 544 Donepecilo data (24 semanas) Mejoria -3 -2.5 -2 -1.5 -1 -0.5 0 5 mg/dia 10 mg/dia
- 58. n : 1998 1832 1490 1219 1003 810 611 399 279 166 75 semana: 0 26 52 78 104 130 156 182 208 234 260 55 50 45 40 35 30 25 20 15 10 5 0 Pacientes tratados con Rivastigmina Proyección basada en Modelos de deterioro de pacientes no tratados Proyección basada en Modelos de deterioro en pacientes no tratados (ajustada según el estado al ingreso de los pacientes que permanecen en el estudio) Small GM, et al. Int J Clin Pract 2005;59:473-477 Promedio en puntaje ADAS cog(DS) 23 puntos: Umbral para EA “MODERADA” 45 puntos: Umbral para EA “SEVERA” 33 puntos: Umbral para EA “MODERADAMENTE SEVERA” BENEFICIO DE LOS IChE EN EL LARGO PLAZO Variación ADAScog con Rivastigmina a 5 años
- 59. Pueden las dosis iniciales determinar los resultados a largo plazo? Cambio de la Linea Basal Dosis Baja Temprana No Tratado Dosis Alta Temprana
- 61. Liberación de droga lenta y contínua Mercier F et al. Curr Med Res Opin 2007;23:3199–204 Concentración en Plasma (ng/mL) Rivastigmina 6 mg BID capsula Rivastigmina 9.5 mg/24 h parche 0 5 10 15 20 0 6 12 18 24 Tiempo (horas)
- 62. Eficacia en ADAS cog Rivastigmina capsulas vs parches Análisis ITT-LOCF * p < 0.05 and ** p < 0.001 versus placebo Cambio a las 24 semanas desde basal en puntos ADAS-cog Rivastigmina 9.5 mg/24 h (10 cm 2 ) n = 248 Rivastigmina 12 mg/d cápsulas n = 253 Rivastigmina 17.4 mg/24 h (20 cm 2 ) n = 262 Placebo n = 281 ** * * Winblad B, et al. Int J Geriatr Psychiatry 2007;22:456–67 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 Empeoramiento Mejoría
- 63. EFECTOS ADVERSOS A ALTAS DOSIS Náuseas y vómitos Winblad B, et al. Int J Geriatr Psychiatry 2007;22:456–67 Pacientes que reportaron eventos adversos (%) rivastigmina 12 mg/d cápsulas rivastigmina parche 9.5 mg/24 h (10 cm 2 ) Placebo 25 20 15 10 5 0 Náuseas Vómitos 23.1% 7.2% 5.0% 17.0% 6.2% 3.3%
- 64. Lo que suponemos, será demostrado? Farlow M, et al. Current Medical Research Opinion 2010;26:2441–2247
- 65. Diagnostico Temprano Rivastigmina oral 3 mg/dia Rivastigmina patch 4.6 mg/24 h Donepecilo tabletas 5 mg/dia Galantamina tabletas 8 mg/dia ‘ Tratamiento Óptimo’ Lo mejor desde el inicio
- 66. Diagnostico Temprano Rivastigmina oral 3 mg/dia Rivastigmina patch 4.6 mg/24 h Donepecilo tabletas 5 mg/dia Galantamina tabletas 8 mg/dia Rivastigmina oral 12 mg/dia Rivastigmina patch 9.5-13.3 mg/24 h Donepecilo tabletas 10 mg/dia Galantamina tabletas 24 mg/dia ‘ Tratamiento Óptimo’ Lo mejor desde el inicio
- 67. Diagnostico Temprano Rivastigmina oral 3 mg/dia Rivastigmina patch 4.6 mg/24 h Donepecilo tabletas 5 mg/dia Galantamina tabletas 8 mg/dia Rivastigmina oral 12 mg/dia Rivastigmina patch 9.5-13.3 mg/24 h Donepecilo tabletas 10 mg/dia Galantamina tabletas 24 mg/dia ‘ Tratamiento Óptimo’ Lo mejor desde el inicio
- 68. Diagnostico Temprano Rivastigmina oral 3 mg/dia Rivastigmina patch 4.6 mg/24 h Donepecilo tabletas 5 mg/dia Galantamina tabletas 8 mg/dia Rivastigmina oral 12 mg/dia Rivastigmina patch 9.5-13.3 mg/24 h Donepecilo tabletas 10 mg/dia Galantamina tabletas 24 mg/dia Explicar sobre las expectativas y beneficios del tratamiento Permanecer bajo tratamiento tanto tiempo como sea posible Agregar memantina en los casos moderados/severos ‘ Tratamiento Óptimo’ Lo mejor desde el inicio
- 70. IChE en EA: Después o desde el inicio? Cambios desde el basal rescate rescate Cambios desde el Basal Bajas dosis iniciales Altas dosis iniciales
- 74. Nilton Custodio [email_address] www.neuroconsultas.com Twitter.com/neuroconsultas n euroconsultas.blogspot.com neuroconsultas
Notas do Editor
- shows the progression of a standard course of AD, as well as progression from CDR 1 at the start of the trial to CDR 2. A placebo group reaches CDR 2 in ~3 years, whereas the group receiving a trial drug reaches CDR at ~6 years after onset of therapy. Slide 3 shows increasing drug-placebo difference over time, in which the trial drug is associated with a drug-placebo difference of ~2 points on the MMSE at 18 months after the introduction of therapy. This would be a drug-placebo difference of ~4 points on the MMSE after 36 months of therapy.
- It shows the evolution of behavioral changes, in terms of Neuropsychiatric Inventory (NPI) symptoms, as found in the Cache County Study (five-year period prevalence; Steinberg et al., 2008). Latent class and factor analytic studies suggest the existence of several overlapping behavioral syndromes or factors (Frisoni et al., 1999; Lyketsos et al., 2001; Moran et al., 2004). Frisoni et al. (1999) grouped these into three syndromes: “psychotic” (agitation, hallucinations, delusions, irritability), “mood” (anxiety, depression), and “frontal” (disinhibition, euphoria). Lyketsos et al. (2001) identified three groupings: “no neuropsychiatric symptoms”, “affective” and “psychotic” symptoms. The most frequently occurring of the NPS are apathy, depression, and anxiety (Robert et al., 2005; Steinberg et al., 2008)
- Apathy can be present in all stages of the disease, but increases in prevalence with severity of disease. Apathy appears to be an independent syndrome, whereas agitation may occur in combination with many different symptoms. Senanarong et al. (2004) found significant correlations between agitation and all other NPI subscale scores, with the strongest correlations existing with irritability, disinhibition, delusions, and aberrant motor activity (p <0.001 in all cases) (Senanarong et al., 2004). Aberrant motor behavior (wandering, pacing, rummaging, purposeless hyperactivity) is observable in more than one-quarter of patients with dementia (Aalten et al., 2007), and falls into the behavioral category of “hyperactivity”, which also comprises agitation, disinhibition and irritability (Aalten et al., 2007). Agitation and aggression are among the most troublesome of the NPS for caregivers and, along with depression and psychosis, are leading predictors of institutionalization (Yaffe et al., 2002; Gauthier et al., 2008; Gaugler et al., 2009) . Within care facilities, 40–60% of AD patients have aggression and agitation (Margallo-Lana et al., 2001; Ballard and Howard, 2006). Irritability is common and can be troublesome to the caregiver; it occurs with a prevalence of ∼40% of patients with mild and moderate AD, increasing to ∼50% of patients in the more severe stages of the disease (Cummings and Back, 1998; Robert et al., 2002). Psychotic disorders (delusions and hallucinations) can affect 27–45% of AD patients (Leroi et al., 2003; Jost and Grossberg, 1996), and has been associated with accelerated cognitive decline, earlier institutionalization, and caregiver burnout (Drevets and Rubin 1989; Yaffe et al., 2002; Lesser and Hughes, 2006). Delusions most often present in the form of beliefs of theft and infidelity, and hallucinations (most often visual) are usually visions of people from the past, or of intruders. Prospective studies show that hallucinations often resolve over a few months, but delusions and agitation are more persistent (Ballard and Howard, 2006). The prevalence of depression in AD patients, as estimated in both population and clinical studies, is between 20% (Lyketsos et al., 2000; 2003) and 50% (Lyketsos and Olin, 2002). Regular screening for depression in AD is recommended: preliminary studies suggest that antidepressant treatment instigated on the basis of screening for the condition improves outcomes for patients (in terms of depression symptom scores) (Cohen et al., 2003), and may decrease the strain on the caregiver. Sleep problems, which are estimated to occur in 25–54% of AD patients (Chen et al., 2000; Hart et al., 2003; Moran et al., 2005), can impact greatly on the quality of sleep of caregivers. It is well established that sleep disturbance, and the accompanying caregiver stress, are very common precipitants of institutionalization in dementia (Vitiello and Borson, 2001).
- Despite the growing number of elderly patients who will be affected by cognitive deterioration and BPSD in the future, critical aspects of the management remain unsolved. Drugs should be used only when non-pharmacological approaches have failed to adequately control behavioral disruption. Despite there are substantial differences in the pharmacological properties between the two classes of antipsychotics, the most updated scientific evidence reviewed in this article seems to suggest that when used in elderly demented patients, there are no significant differences between atypical and conventional antipsychotics. This is now officially recognized by regulatory agencies. The findings related to antipsychotics safety should be taken seriously by physicians in assessing the potential risk and benefits of treatment in a elderly, frail population. Clinicians should continue to consider individual safety profile of different antipsychotics whenever they decide to start a treatment. The lowest dosage and the shortest duration of use are recommended for agents of both classes. Other classes of medications have shown some evidence of efficacy on distinct items of BPSD, including cholinesterase inhibitors, NMDA modulators, anticonvulsants, some antidepressants, and benzodiazepines. The evidence base for the use of these pharmacological agents is poor, there is no clear standard of care, and none of them could be considered as a safer alternative to antipsychotics. As for antipsychotics, clinicians considering using these medications should discuss the potential risks and benefits of treatment with patients and their surrogate decision makers, and must ensure a balance between side effects and tolerability compared with clinical benefit and quality of life.
- In summary, most double-blind, placebo-controlled trials and open-label assessments that have included behavioral outcome measures indicate a behavioral benefit with treatment with antidementia agents. Not all studies have demonstrated a drug-placebo difference, and further investigation of the behavioral benefits of these therapies is warranted. A variety of factors must be considered when constructing trials to explore the psychotropic effects of antidementia agents including profile of behavioral symptoms at baseline, baseline behavioral symptom severity, baseline dementia severity, residential status, linguistic and cultural diversity of study sites, and whether psychotropic drugs are allowed at baseline. Attention to these elements in clinical trials will allow more definitive conclusions to be drawn regarding the behavioral benefits of antidementia treatments.
- Proportion of patients experiencing improvement, no change or worsening of attention difficulties, anxiety, apathy and agitation at 6 months (observed cases)
- Proportion of caregivers reporting improvement, no change or worsening of caregiver burden at 6 months (observed cases). Changes in regimens at 6 months among patients receiving psychotropic medications at baseline (observed cases).
- If in line with treatment indications and disease severity, ChEI therapy will be initiated at the time of AD diagnosis; behavioral changes may or may not be present at this stage. Early initiation of ChEI treatment may defer the emergence of behavioral changes as the disease progresses (Cummings et al., 2004a). In the presence of NPS, therapy with a ChEI, with or without memantine, should be implemented prior to the use of psychotropic agents, since both cognitive and behavioral benefit may ensue, and the use of psychotropic agents may be avoided in some patients. Similarly, the use of ChEI therapy may make it possible to use lower doses of psychotropic agents (Bergman et al., 2003), or to minimize duration of psychotropic treatment periods, thereby minimizing risks associated with these agents. It may be possible to discontinue therapy with psychotropic medications if patients are being treated with these agents when ChEIs are introduced. The withdrawal of ChEIs has been associated with behavioral deterioration and, therefore, patients should be closely monitored for the emergence of new behavioral changes if ChEIs are withdrawn (Holmes et al., 2004). The appearance of new or worsening behavioral disturbances in the course of withdrawal indicates that the patient is deriving behavioral benefit from treatment, and the ChEI should be continued. ChEIs reduce behavioral changes in AD as well as improving or delaying decline in cognition and function. Behavioral improvement associated with ChEI treatment has been documented primarily in patients with mild to moderate AD (Matthews et al., 2000; Cummings et al., 2004a; Holmes et al., 2004; Herrmann et al., 2005). The greatest effects have been on depression, apathy and aberrantmotor behavior (e.g.Matthews et al., 2000; Aupperle et al., 2004; Cummings et al., 2004a; Holmes et al., 2004; Feldman et al., 2005). In some studies, total NPI scores have also been reduced (Aupperle et al., 2004; Cummings et al., 2005). The observed variation is not necessarily an indication of differential efficacy of the ChEIs used, but may indicate the spectrum of positive and negative behavioral changes reported in clinical studies of ChEIs. The behavioral symptoms most likely to improve with ChEI treatment appear to be apathy, depression, and aberrant motor behavior (e.g. Feldman et al., 2005; Holmes et al., 2004; Matthews et al., 2000; Aupperle et al., 2004; Cummings et al., 2004a). There are few predictors of response to ChEIs. Patients with more severe behavioral changes at baseline tend to have more robust responses to therapy. The presence of visual hallucinations also appears to predict a better cognitive response to treatment with ChEIs (Emre et al., 2007). Cognitive and behavioral responses to ChEI therapy are only weakly correlated, and patients may exhibit behavioral improvement while experiencing only limited or no cognitive improvement (Spalleta et al., 2004).
- The final matched sample (N = 178) included 62 CHEl-DC cases and 116 CHEI-CONT controls. More than half of the cohort was aged ~85 years, and the sample was predominantly female. A diagnosis of Alzheimer's disease was documented in 40 .3%of the CHEI-DC patients and in 46.5% of the CHEI-CONT patients. Behavioral worsening, indicated by an increase in the estimated mean monthly point change in ABS score, occurred in the CHEI-DC group (0.08; 95%CI, 0.01 to 0.16 ) but not in the CHE1-CONT group (- 0.0 1; 95%CI, -0.06 to 0.04 ), and the between-group difference was significant (0.09; 95%CI, 0.01 to 0.18 ). There were no significant between group differences in the mean monthly point change in mood symptoms on the DRS (0.04; 95%C1,-0.03 to 0.12). For the secondary outcomes, the mean monthly MDS point change for frequency of repetitive verbal behaviors indicated that CHEl -DC patients exhibited significantly more episodes of repetitive questioning (0. 17; 95%CI, 0.05 to 0.29 ) and repetitive health complaints (0.16; 95% CI, 0.04 to 0.27) compared with CHEI-CONT residents. Continued use of CHE1s was associated with more time spent in leisure-related activities over the study period (- 0.26; 95%C1, -0.50 to - 0.02), with the CHEl-DC group spending less time in activities (0.11; 95%CI, 0 to 0.23 ); the between- group difference was also significant (0.37; 95%C1, 0.10 to 0.65 ).