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Mechanisms of Antidepressant Non-Response in Late-Life Depression

30 de junio de 2020 actualizado por: Bret Rutherford, New York State Psychiatric Institute
This project seeks to elucidate the mechanisms by which antidepressant medications have limited efficacy in Late Life Depression (LLD) in order to develop new treatment interventions for this prevalent and disabling illness. Investigators hypothesize that the presence of executive dysfunction (ED),which is common in depressed adults over 60, impairs the ability to form appropriate expectancies of improvement with antidepressant treatment. Greater expectancy has been shown to improve antidepressant treatment outcome and is hypothesized to be a primary mechanism of placebo effects. Moreover, white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) are more prevalent in patients with LLD compared to healthy controls. It has been argued that WMH contribute to the pathogenesis of LLD with ED and decrease the efficacy of antidepressant medications by disrupting connections between prefrontal cortical (PFC) and subcortical structures. Vascular lesions to white matter tracts may also compromise the pathway by which expectancy-based placebo effects influence depressive symptoms. Expectancies reflect activation in PFC areas that may improve depressive symptoms by modulating the activity of subcortical regions subserving negative affective systems (i.e., amygdala) as well as those important in reward and hedonic capacity (nucleus accumbens and ventral striatum). Thus, LLD patients with ED and WMH may sustain a "double-hit" to their ability to experience placebo effects in antidepressant treatments: ED diminishes the ability to generate appropriate treatment expectancies, while WMH disrupt the physiologic pathways by which expectancies lead to improvement in depressive symptoms.

Descripción general del estudio

Estado

Terminado

Condiciones

Intervención / Tratamiento

Descripción detallada

To determine whether decreased antidepressant medication response in LLD patients with ED and WMH is caused by a loss of expectancy effects, Investigators will evaluate 130 outpatients with LLD at baseline to determine their degree of ED (interference score on Stroop Color-Word Test), WMH burden (severity score on Fazekas modified Coffey Rating Scale derived from anatomical MRI), and white matter tract integrity (using diffusion tensor imaging [DTI]). Building on work from the investigators K23 Award, the investigator will manipulate participants' expectancy of improvement in an 8-week duration antidepressant trial by randomizing patients between open administration of escitalopram (i.e., high expectancy) and placebo-controlled administration of escitalopram (i.e., low expectancy). The difference in antidepressant response observed between open and placebo-controlled medication treatment is a measure of the expectancy contribution to outcome, which is substantial in younger depressed adults but investigators hypothesize this will be diminished in LLD patients with ED and WMH.

Tipo de estudio

Intervencionista

Inscripción (Actual)

138

Fase

  • No aplica

Contactos y Ubicaciones

Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.

Ubicaciones de estudio

  • Estados Unidos
    • New York
      • New York, New York, Estados Unidos, 10032
        • New York State Psychiatric Institute

Criterios de participación

Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.

Criterio de elegibilidad

Edades elegibles para estudiar

60 años a 90 años (Adulto, Adulto Mayor)

Acepta Voluntarios Saludables

No

Géneros elegibles para el estudio

Todos

Descripción

Inclusion Criteria:

  • Men and women aged 60-90 years
  • Diagnosis with nonpsychotic Diagnostic and Statistical Manual (DSM) IV MDD
  • 24-item Hamilton Rating Scale for Depression (HRSD) score ≥ 16
  • Willing to and capable of providing informed consent and complying with study procedures

Exclusion Criteria:

  • Current comorbid Axis I DSM IV disorder other than Nicotine Dependence, Adjustment Disorder, or Anxiety Disorder
  • diagnosis of substance abuse or dependence (excluding Nicotine Dependence) within the past 12 months
  • History of psychosis, psychotic disorder, mania, or bipolar disorder
  • Diagnosis of probable Alzheimer's Disease, Vascular Dementia, or Parkinson's Disease
  • MMSE < 24
  • HRSD suicide item > 2 or Clinical Global Impressions (CGI)-Severity score of 7 at baseline
  • history of allergic or adverse reaction to escitalopram, or non-response to adequate trial of escitalopram (at least 4 weeks at dose of 20mg) during the current episode
  • current treatment with psychotherapy, antidepressants, antipsychotics, or mood stabilizers
  • having contraindication to MRI scanning (such as metal in body) or unable to tolerate the scanning procedures (i.e., severe obesity, claustrophobia)
  • acute, severe, or unstable medical or neurological illness

Plan de estudios

Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.

¿Cómo está diseñado el estudio?

Detalles de diseño

  • Propósito principal: Tratamiento
  • Asignación: Aleatorizado
  • Modelo Intervencionista: Asignación paralela
  • Enmascaramiento: Cuadruplicar

Armas e Intervenciones

Grupo de participantes/brazo
Intervención / Tratamiento
Comparador de placebos: Double Blind-Placebo
Blinded treatment with placebo, one pill a day. If after the 4 weeks, the patient has not remitted, they will be increased to 2 pills a day.
Droga: Placebo oral tablet
Inert substance or treatment which is designed to have no therapeutic value but resemble the active medication in this study
Otros nombres:
  • placebo
Comparador activo: Double Blind-Escitalopram
Blinded treatment with either escitalopram 10mg, increased to escitalopram 20mg at week 4 if depression has not remitted.
Droga: Escitalopram
Escitalopram is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is FDA approved for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD) in adults and children over 12 years of age.
Otros nombres:
  • Lexapro
Comparador activo: Open Treatment with Escitalopram
Open treatment with 10mg of escitalopram, increased to 20mg if depression has not remitted at week 4.
Droga: Escitalopram
Escitalopram is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is FDA approved for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD) in adults and children over 12 years of age.
Otros nombres:
  • Lexapro

¿Qué mide el estudio?

Medidas de resultado primarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Escala de calificación de Hamilton para la depresión (HRSD)
Periodo de tiempo: Base
Nuestro objetivo es la sintomatología depresiva medida por la escala de calificación de Hamilton para la depresión (HRSD). El HRSD es un cuestionario de 24 ítems que se utiliza como indicador de depresión y como guía para evaluar la recuperación. Las puntuaciones totales oscilan entre 0 y 74, sin incluir la subescala de síntomas atípicos. Por lo general, se considera que una puntuación de 16 o más indica la presencia de síntomas depresivos. Las puntuaciones más altas indican una mayor gravedad.
Base

Medidas de resultado secundarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Hamilton Rating Scale for Depression (HRSD)
Periodo de tiempo: Week 8
Our target is depressive symptomatology as measured by the Hamilton Rating Scale for Depression (HRSD). The HRSD is a 24-item questionnaire used as an indication of depression and a guide to evaluate recovery. Total scores range from 0-74, not including atypical symptoms sub-scale. A score of 16 or above is typically considered to indicate the presence of depressive symptoms. Higher scores indicate greater severity.
Week 8
Quick Inventory of Depressive Symptoms (QIDS-SR)
Periodo de tiempo: Baseline
QIDS-SR is a 16 item scale self-report form that was used to measure depression outcomes. This self-report is valuable in this study, because it is less susceptible to clinician and rater bias. The QIDS-SR has been increasingly used in antidepressant studies due to its equivalent weightings for each symptom item, clearly understandable anchor points, and inclusion of all DSM criteria for depression. The scores range from 0-27 with 27 being worse depressive symptoms.
Baseline
Quick Inventory of Depressive Symptoms (QIDS-SR)
Periodo de tiempo: Week 8
QIDS-SR is a 16 item scale self-report form that was used to measure depression outcomes. This self-report is valuable in this study, because it is less susceptible to clinician and rater bias. The QIDS-SR has been increasingly used in antidepressant studies due to its equivalent weightings for each symptom item, clearly understandable anchor points, and inclusion of all DSM criteria for depression. The scores range from 0-27 with 27 being worse depressive symptoms.
Week 8
Credibility and Expectancy Scale-Better (CES)
Periodo de tiempo: Pre-Baseline
CES is an 8 item scale in which subjects rate their impression of the credibility of the treatment and how they estimate their expectation of improvement. The CES is the most widely used measure of expectancy and has demonstrated good psychometric properties in multiple studies. Question 2 ('Better') asks the patient the chances of their depression being completely better at the end of this study, from 1 = very poor to 7 = very good. The higher the number, the higher the expectancy that they will be better.
Pre-Baseline
Credibility and Expectancy Scale-Better (CES)
Periodo de tiempo: Week 0
CES is an 8 item scale in which subjects rate their impression of the credibility of the treatment and how they estimate their expectation of improvement. The CES is the most widely used measure of expectancy and has demonstrated good psychometric properties in multiple studies. Question 2 ('Better') asks the patient the chances of their depression being completely better at the end of this study, from 1 = very poor to 7 = very good. The higher the number, the higher the expectancy that they will be better.
Week 0
Credibility and Expectancy Scale-Depression
Periodo de tiempo: Pre-baseline
CES is an 8 item scale in which subjects rate their impression of the credibility of the treatment and how they estimate their expectation of improvement. The CES is the most widely used measure of expectancy and has demonstrated good psychometric properties in multiple studies. CES question 3 ('Depression') asks how the patient's depression will be at the end of the study, compared with now, from 1 = much worse to 7= much better. The higher the number, the higher the expectancy that their depression will be much better.
Pre-baseline
Credibility and Expectancy Scale-Depression
Periodo de tiempo: Week 0
CES is an 8 item scale in which subjects rate their impression of the credibility of the treatment and how they estimate their expectation of improvement. The CES is the most widely used measure of expectancy and has demonstrated good psychometric properties in multiple studies. CES question 3 ('Depression') asks how the patient's depression will be at the end of the study, compared with now, from 1 = much worse to 7= much better. The higher the number, the higher the expectancy that their depression will be much better.
Week 0
Quick Inventory of Depression Scale (QIDS-SR): Expectancy
Periodo de tiempo: Pre-Baseline
This 16-items assessment is used to rate the 9 criterion symptom domains of a major depressive episode: 4 items are used to rate sleep disturbance (early, middle, and late insomnia plus hypersomnia); 2 items are used to rate psychomotor disturbance (agitation and retardation); 4 items are used to rate appetite/weight disturbance (appetite increase or decrease and weight increase or decrease). Only 1 item is used to rate the remaining 6 domains (depressed mood, decreased interest, decreased energy, worthlessness/guilt, concentration/decision making, and suicidal ideation). Each item is rated 0-3. For symptom domains that require more than 1 item, the highest score of the item relevant for each domain is taken. The total score ranges from 0-27. A lower rating indicates higher expectancy of improvement and lower expectation of depressive symptomatology, and a higher rating indicates lower expectancy of improvement, higher expectation of depression.
Pre-Baseline
Quick Inventory of Depression Scale (QIDS-SR): Expectancy
Periodo de tiempo: Week 0
This 16-items assessment is used to rate the 9 criterion symptom domains of a major depressive episode: 4 items are used to rate sleep disturbance (early, middle, and late insomnia plus hypersomnia); 2 items are used to rate psychomotor disturbance (agitation and retardation); 4 items are used to rate appetite/weight disturbance (appetite increase or decrease and weight increase or decrease). Only 1 item is used to rate the remaining 6 domains (depressed mood, decreased interest, decreased energy, worthlessness/guilt, concentration/decision making, and suicidal ideation). Each item is rated 0-3. For symptom domains that require more than 1 item, the highest score of the item relevant for each domain is taken. The total score ranges from 0-27. A lower rating indicates higher expectancy of improvement and lower expectation of depressive symptomatology, and a higher rating indicates lower expectancy of improvement, higher expectation of depression.
Week 0
Executive Dysfunction: Stroop Color Word
Periodo de tiempo: Pre-Baseline
Stroop Color Word test asks patients to name the color of a word rather than reading the word. Stroop Color Word is how many colors they can name in 45 sec (higher is better, e.g., less executive dysfunction).
Pre-Baseline
Executive Dysfunction: Stroop Interference
Periodo de tiempo: Pre-Baseline
The Stroop is a measure of inhibition under distracting conditions that is sensitive to frontal lobe dysfunction. in Stroop Color Word test patients are to name the color of a word rather than reading the word. Stroop Color Word is how many colors they can name in 45 sec (higher is better, e.g., less executive dysfunction). Stroop Interference is this score adjusted for age and education.
Pre-Baseline
White Matter Hyperintensity (WMH) Outcome- Total WMH
Periodo de tiempo: Pre-Baseline
Magnetic Resonance Imaging (MRI) of the Brain was acquired. We rated the severity of WMH on axial T2 FLAIR images using the Fazekas modified Coffey Rating Scale. Deep WMH are scored as 0 (absent), 1 (punctate foci), 2 (beginning confluence of foci), and 3 (large confluent areas); subcortical gray matter HIs (basal ganglia) are scored as 0 (absent), 1 (punctate), 2 (multipunctate), and 3 (diffuse); periventricular HIs are scored as 0 (absent), 1 (caps), 2 (smooth halo), and 3 (irregular and extending into the deep white matter). Our primary measure of WMH burden will be DWMH score, which has been used to establish the only empirically validated diagnostic criteria for vascular depression, where scores of 0-1 were normal, but 2-3 indicated WHM.
Pre-Baseline

Colaboradores e Investigadores

Aquí es donde encontrará personas y organizaciones involucradas en este estudio.

Patrocinador

New York State Psychiatric Institute

Publicaciones y enlaces útiles

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Publicaciones Generales

Enlaces Útiles

Fechas de registro del estudio

Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados ​​por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.

Fechas importantes del estudio

Inicio del estudio (Actual)

19 de febrero de 2014

Finalización primaria (Actual)

17 de enero de 2019

Finalización del estudio (Actual)

17 de enero de 2020

Fechas de registro del estudio

Enviado por primera vez

26 de agosto de 2013

Primero enviado que cumplió con los criterios de control de calidad

26 de agosto de 2013

Publicado por primera vez (Estimar)

29 de agosto de 2013

Actualizaciones de registros de estudio

Última actualización publicada (Actual)

2 de julio de 2020

Última actualización enviada que cumplió con los criterios de control de calidad

30 de junio de 2020

Última verificación

1 de junio de 2020

Más información

Términos relacionados con este estudio

Términos MeSH relevantes adicionales

Otros números de identificación del estudio

  • 6836 (Sponsor ref)

Plan de datos de participantes individuales (IPD)

¿Planea compartir datos de participantes individuales (IPD)?

NO

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