PURPOSE: A link between poor sleep quality and Alzheimer's disease (AD) has recently been suggested. Since endogenous melatonin levels are already reduced at preclinical AD stages, it is important to ask whether replenishing the missing hormone would be beneficial in AD and whether any such effects would be related to the presence of sleep disorder in patients.
PATIENTS AND METHODS: The effects of add-on prolonged-release melatonin (PRM) (2 mg) to standard therapy on cognitive functioning and sleep were investigated in 80 patients (men [50.7%], women [49.3%], average age 75.3 years [range, 52-85 years]) diagnosed with mild to moderate AD, with and without insomnia comorbidity, and receiving standard therapy (acetylcholinesterase inhibitors with or without memantine). In this randomized, double-blind, parallel-group study, patients were treated for 2 weeks with placebo and then randomized (1:1) to receive 2 mg of PRM or placebo nightly for 24 weeks, followed by 2 weeks placebo. The AD Assessment Scale-Cognition (ADAS-Cog), Instrumental Activities of Daily Living (IADL), Mini-Mental State Examination (MMSE), sleep, as assessed by the Pittsburgh Sleep Quality Index (PSQI) and a daily sleep diary, and safety parameters were measured.
RESULTS: Patients treated with PRM (24 weeks) had significantly better cognitive performance than those treated with placebo, as measured by the IADL (P=0.004) and MMSE (P=0.044). Mean ADAS-Cog did not differ between the groups. Sleep efficiency, as measured by the PSQI, component 4, was also better with PRM (P=0.017). In the comorbid insomnia (PSQI ≥6) subgroup, PRM treatment resulted in significant and clinically meaningful effects versus the placebo, in mean IADL (P=0.032), MMSE score (+1.5 versus -3 points) (P=0.0177), and sleep efficiency (P=0.04). Median ADAS-Cog values (-3.5 versus +3 points) (P=0.045) were significantly better with PRM. Differences were more significant at longer treatment duration. PRM was well tolerated, with an adverse event profile similar to that of placebo.
CONCLUSION: Add-on PRM has positive effects on cognitive functioning and sleep maintenance in AD patients compared with placebo, particularly in those with insomnia comorbidity. The results suggest a possible causal link between poor sleep and cognitive decline.
OBJETIVOS: No existen ensayos clínicos aleatorizados respecto a la eficacia de la trazodona en el tratamiento de trastornos del sueño (SD) en pacientes con enfermedad de Alzheimer (EA). Pusimos a prueba la eficacia y seguridad de la trazodona para tratar la SD en pacientes con EA.
DISEÑO: Se realizó un ensayo clínico doble ciego, aleatorizado y controlado durante los períodos de 7-9 días al inicio del estudio y 2 semanas de tratamiento.
ESCENARIO: centro médico geriátrico del Hospital General de la Universidad.
PARTICIPANTES: Los individuos con probable EA y SD. El análisis completo compuesto por 30 pacientes asignados a ya sea el grupo activo de tratamiento (N = 15) o el grupo placebo (N = 15).
Intervención: Los pacientes recibieron 50 mg de trazodona una vez al día a las 10:00 PM o placebo en una proporción 1: 1 para 2 semanas.
Medidas: Los pacientes fueron evaluados utilizando actigrafía y escalas estructuradas antes y después de la intervención.
RESULTADOS: En comparación con el grupo placebo, los usuarios trazodona dormido 42.5 minutos más por noche y tenía su sueño nocturno por ciento aumentó 8,5 puntos porcentuales de acuerdo con el tratamiento posterior de datos actigráfico. Ni trazodona ni placebo inducidos somnolencia diurna significativa o siestas. Los tratamientos con trazodona o placebo no mostraron ningún efecto, ya sea en la cognición (Mini Examen del Estado Mental, tarea retención de dígitos hacia delante / atrás, letra y número secuenciación, aritmética, dígitos símbolo de la codificación y de búsqueda de símbolos) o funcionalidad (índice de Katz) . No hubo diferencias en la frecuencia o gravedad de calificación de eventos adversos entre los grupos.
Conclusiones: Este estudio muestra efectos terapéuticos significativos de trazodona 50 mg en pacientes con EA que viven en comunidad con SD.
IMPORTANCE: Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory.
OBJECTIVE: The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability.
DESIGN, SETTING, AND PARTICIPANTS: The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013.
INTERVENTIONS: Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability.
MAIN OUTCOMES AND MEASURES: Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events.
RESULTS: Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was -0.93 (95% CI, -1.80 to -0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (-1.05 points; 95% CI, -1.97 to -0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group.
CONCLUSIONS AND RELEVANCE: Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00898807.
OBJECTIVE: In a recent crossover trial, methylphenidate treatment decreased apathy in Alzheimer's disease. We further assessed this finding in the Apathy in Dementia Methylphenidate Trial (ADMET).
METHOD: Six-week, randomized, double-blind, placebo-controlled multicenter trial enrolling Alzheimer's disease participants (NINCDS-ADRDA criteria) with apathy assigned to methylphenidate 20 mg daily or placebo, conducted from June 2010 to December 2011. Primary outcomes were change in Apathy Evaluation Scale (AES) score and modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGI-C). Secondary outcomes included change in Neuropsychiatric Inventory (NPI) apathy score, Mini-Mental State Examination (MMSE) score, and safety.
RESULTS: 60 participants were randomly assigned (29 methylphenidate, 31 placebo). At baseline, mean (SD) age = 76 (8) years, MMSE score = 20 (5), AES score = 51 (12), NPI total score = 16 (8), and 62% of the participants (n = 37) were female. After 6 weeks' treatment, mean (SD) change in AES score was -1.9 (1.5) for methylphenidate and 0.6 (1.4) for placebo (P = .23). Odds ratio for improvement in ADCS-CGI-C was 3.7 (95% CI, 1.3 to 10.8) (P = .02), with 21% of methylphenidate versus 3% of placebo rated as moderately or markedly improved. NPI apathy score improvement was 1.8 points (95% CI, 0.3 to 3.4) greater on methylphenidate than on placebo (P = .02). MMSE trended toward improvement on methylphenidate (P = .06). There were trends toward greater anxiety and weight loss > 2% in the methylphenidate-treated group.
CONCLUSIONS: Methylphenidate treatment of apathy in Alzheimer's disease was associated with significant improvement in 2 of 3 efficacy outcomes and a trend toward improved global cognition with minimal adverse events, supporting the safety and efficacy of methylphenidate treatment for apathy in Alzheimer's disease.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01117181.
BACKGROUND: Mibampator, an amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor potentiator, was evaluated for treatment of agitation and aggression (A/A) in Alzheimer's disease (AD).
METHODS: Outpatients (n = 132) with probable AD and A/A randomized to 12 weeks of double-blind treatment with 3-mg po mibampator or placebo were assessed using the 4-domain A/A subscale of the Neuropsychiatric Inventory (NPI-4-A/A) derived from the Neuropsychiatric Inventory. Secondary measures included the Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia, Frontal Systems Behavior Inventory (FrSBe), and Alzheimer's Disease Assessment Scale-Cognitive. Efficacy was analyzed using mixed-effects model repeated measures from baseline to endpoint. Adverse events (AEs), labs, vital signs, and electrocardiograms were monitored.
RESULTS: Baseline characteristics were comparable between groups. Both groups improved on the NPI-4-A/A, but without group differences. Among secondaries, mibampator was significantly better (p = 0.007) than placebo only on the FrSBe. AEs were similar between groups. One death occurred in the placebo group.
CONCLUSION: Possible explanations for no significant group differences include caregiver, drug target engagement, and design issues. This trial is registered on ClinicalTrials.gov; ID: NCT00843518.
OBJETIVO: Este estudio examinó los efectos del modafinilo en sintomatología apática, el desempeño de las actividades de la vida diaria (AVD), y la carga del cuidador en individuos con enfermedad de Alzheimer (EA).
MÉTODO: 23 participantes con un diagnóstico de leve a moderada AD probable según el Instituto Nacional de Neurológica y trastorno comunicativa y la enfermedad de Stroke-Alzheimer y criterios Trastornos Relacionados fueron aleatorizados en el experimental (modafinilo 200 mg al día) o grupos de control (placebo) . Todos los participantes también recibieron dosis estables de un medicamento inhibidor de la colinesterasa. Los participantes completaron evaluaciones al inicio del estudio y después de 8 semanas de tratamiento. Las medidas de resultado incluyeron medidas de informes de familia de la apatía, el rendimiento ADL y la carga del cuidador, así como la evaluación directa de la actuación ADL. El estudio se realizó en un hospital psiquiátrico privado en Rhode Island desde septiembre de 2005 hasta septiembre de 2007.
RESULTADOS Ambos: los grupos experimentales y de control mostraron reducciones en la apatía en la escala de comportamiento frontal Sistemas entre el inicio y evaluaciones finales (F1,20 = 18,017, p <0,001, η2 = 0,474), y no hubo reducción adicional significativa en la apatía con modafinilo (F1,20 = 0,008, P = 0,932, η2 = 0,000). Los grupos no mostraron cambios significativos en el informe médico del desempeño ADL en el tiempo (F1,19 = 0,268, P = 0,611). La correlación entre el cambio en el apatía y el cambio en la carga del cuidador no fue significativa (r = 0,355; p = 0,053), pero no hubo una tendencia hacia la mejora de los niveles de apatía que se relaciona con disminución de los niveles de carga del cuidador.
CONCLUSIONES: La adición de modafinilo para el tratamiento estándar (medicación inhibidor de la colinesterasa) no dio lugar a reducciones adicionales significativas en la apatía o mejoras en el funcionamiento ADL. La reducción de la apatía informado observado en ambos grupos entre las evaluaciones iniciales y finales probablemente debido al efecto placebo. Sin embargo, la reducción de la sintomatología percibida apáticos se correlacionaron con reducciones en reportado malestar del cuidador y la carga. Se necesitan estudios más grandes con mayor poder estadístico para confirmar la ausencia de efectos significativos.
REGISTRO DE PRUEBA: Identificador ClinicalTrials.gov: NCT01172145.
ANTECEDENTES: La agitación en la enfermedad de Alzheimer (EA) es frecuente y se asocia con una mala calidad de vida en el paciente y la angustia cuidador. Los mejores tratamientos farmacológicos basados en la evidencia son los antipsicóticos que tienen beneficios limitados con aumento de la morbilidad y la mortalidad. No existen ensayos memantina en agitación clínicamente significativo, pero los análisis post-hoc en otras poblaciones encontraron agitación reducida. Pusimos a prueba la hipótesis principal, la memantina es superior al placebo para la agitación clínicamente significativa, en los pacientes con EA de moderada a grave.
MÉTODOS Y RESULTADOS: Se reclutaron 153 participantes con Alzheimer y agitación clínicamente significativa del cuidado de casas u hospitales para un ensayo doble ciego aleatorizado controlado y 149 personas empezamos el juicio de la memantina frente a placebo. El resultado primario fue 6 semanas mezclados análisis autorregresivo modelo de Cohen-Mansfield Inventario Agitación (CMAI). Los resultados secundarios fueron: 12 semanas CMAI; 6 y 12 semanas los síntomas neuropsiquiátricos (NPI), la Impresión Clínica Global de Cambio (CGI-C), estandarizada Mini Examen del Estado Mental, batería Deterioro severo. El uso de un modelo de efectos mixtos no se encontraron diferencias significativas en el resultado primario, 6 semanas CMAI, entre memantina y placebo (memantina menor -3,0; -8,3 a 2,2; p = 0,26); ó 12 semanas CMAI; o CGI-C o eventos adversos a los 6 o 12 semanas. NPI diferencia media memantina favorecida en las semanas 6 (-6,9; -12,2 a -1,6; p = 0,012) y 12 (-9,6; -15,0 a -4,3 p = 0,0005). La memantina fue significativamente mejor que el placebo para la cognición. La principal limitación del estudio es que todavía queda por determinar si la memantina tiene un papel en la agitación suave en la EA.
CONCLUSIONES: La memantina no mejoraron la agitación significativa en personas con en el año de moderada a severa. Los estudios futuros se necesitan con urgencia para poner a prueba otros candidatos farmacológicos de este grupo y la memantina para los síntomas neuropsiquiátricos.
JUICIO DE INSCRIPCIÓN: ClinicalTrials.gov NCT00371059.
REGISTRO DE PRUEBA: Norma internacional aleatorizado Trial 24953404 controlada.
OBJECTIVES: To test the effects of walking, light exposure, and a combination intervention (walking, light, and sleep education) on the sleep of persons with Alzheimer's disease (AD).
DESIGN: Randomized, controlled trial with blinded assessors.
SETTING: Independent community living.
PARTICIPANTS: One hundred thirty-two people with AD and their in-home caregivers.
INTERVENTIONS: Participants were randomly assigned to one of three active treatments (walking, light, combination treatment) or contact control and received three or six in-home visits.
MEASUREMENTS: Primary outcomes were participant total wake time based on wrist actigraphy and caregiver ratings of participant sleep quality on the Sleep Disorders Inventory (SDI). Secondary sleep outcomes included additional actigraphic measurements of sleep percentage, number of awakenings, and total sleep time.
RESULTS: Participants in walking (P=.05), light (P=.04), and combination treatment (P=.01) had significantly greater improvements in total wake time at posttest (effect size 0.51-0.63) than controls but no significant improvement on the SDI. Moderate effect size improvements in actigraphic sleep percentage were also observed in active treatment participants. There were no significant differences between the active treatment groups and no group differences for any sleep outcomes at 6 months. Participants with better adherence (4 d/wk) to walking and light exposure recommendations had significantly less total wake time (P=.006) and better sleep efficiency (P=.005) at posttest than those with poorer adherence.
CONCLUSION: Walking, light exposure, and their combination are potentially effective treatments for improving sleep in community-dwelling persons with AD, but consistent adherence to treatment recommendations is required.
A link between poor sleep quality and Alzheimer's disease (AD) has recently been suggested. Since endogenous melatonin levels are already reduced at preclinical AD stages, it is important to ask whether replenishing the missing hormone would be beneficial in AD and whether any such effects would be related to the presence of sleep disorder in patients.
PATIENTS AND METHODS:
The effects of add-on prolonged-release melatonin (PRM) (2 mg) to standard therapy on cognitive functioning and sleep were investigated in 80 patients (men [50.7%], women [49.3%], average age 75.3 years [range, 52-85 years]) diagnosed with mild to moderate AD, with and without insomnia comorbidity, and receiving standard therapy (acetylcholinesterase inhibitors with or without memantine). In this randomized, double-blind, parallel-group study, patients were treated for 2 weeks with placebo and then randomized (1:1) to receive 2 mg of PRM or placebo nightly for 24 weeks, followed by 2 weeks placebo. The AD Assessment Scale-Cognition (ADAS-Cog), Instrumental Activities of Daily Living (IADL), Mini-Mental State Examination (MMSE), sleep, as assessed by the Pittsburgh Sleep Quality Index (PSQI) and a daily sleep diary, and safety parameters were measured.
RESULTS:
Patients treated with PRM (24 weeks) had significantly better cognitive performance than those treated with placebo, as measured by the IADL (P=0.004) and MMSE (P=0.044). Mean ADAS-Cog did not differ between the groups. Sleep efficiency, as measured by the PSQI, component 4, was also better with PRM (P=0.017). In the comorbid insomnia (PSQI ≥6) subgroup, PRM treatment resulted in significant and clinically meaningful effects versus the placebo, in mean IADL (P=0.032), MMSE score (+1.5 versus -3 points) (P=0.0177), and sleep efficiency (P=0.04). Median ADAS-Cog values (-3.5 versus +3 points) (P=0.045) were significantly better with PRM. Differences were more significant at longer treatment duration. PRM was well tolerated, with an adverse event profile similar to that of placebo.
CONCLUSION:
Add-on PRM has positive effects on cognitive functioning and sleep maintenance in AD patients compared with placebo, particularly in those with insomnia comorbidity. The results suggest a possible causal link between poor sleep and cognitive decline.
Diseño del estudio»Ensayo controlado aleatorizado (ECA)
