NCT01931202

Mechanisms of Antidepressant Non-Response in Late-Life Depression

Completed NA Results posted Last updated 2 July 2020

What this trial tests

NA trial testing Escitalopram in Major Depressive Disorder in 138 participants. Completed in 17 January 2020.

Timeline

19 February 2014

Primary endpoint
17 January 2019

17 January 2020

Quick facts

Lead sponsor	New York State Psychiatric Institute
Phase	NA
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	138
Start date	19 February 2014
Primary completion	17 January 2019
Estimated completion	17 January 2020
Sites	1 location across United States

Drugs / interventions tested

• Escitalopram (escitalopram) — full drug profile →
• Placebo oral tablet — full drug profile →

Conditions studied

• Major Depressive Disorder — all drugs for Major Depressive Disorder →

Sponsor

New York State Psychiatric Institute

Who can join

Adults 60 to 90, any sex, with Major Depressive Disorder. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Hamilton Rating Scale for Depression (HRSD) Primary · Baseline

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.

Group	Value	95% CI
Double Blind-Placebo Group	22.8	± 4.9
Double Blind-Escitalopram Group	23.6	± 6.1
Open Treatment With Escitalopram	22.9	± 6.3

Hamilton Rating Scale for Depression (HRSD) Secondary · 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.

Group	Value	95% CI
Double Blind-Placebo Group	13.25	± 5.50
Double Blind-Escitalopram Group	14.39	± 8.13
Open Treatment With Escitalopram	11.67	± 7.58

Quick Inventory of Depressive Symptoms (QIDS-SR) Secondary · 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.

Group	Value	95% CI
Double Blind-Placebo Group	12.4	± 4.4
Double Blind-Escitalopram Group	13.5	± 4.5
Open Treatment With Escitalopram	13.0	± 4.7

Quick Inventory of Depressive Symptoms (QIDS-SR) Secondary · 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.

Group	Value	95% CI
Double Blind-Placebo Group	8.00	± 2.93
Double Blind-Escitalopram Group	6.93	± 5.14
Open Treatment With Escitalopram	6.34	± 5.31

Credibility and Expectancy Scale-Better (CES) Secondary · 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.

Group	Value	95% CI
Double Blind-Placebo Group	6	± 1.1
Double Blind-Escitalopram Group	5.5	± 1.2
Open Treatment With Escitalopram	5.3	± 1.3

Credibility and Expectancy Scale-Better (CES) Secondary · 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.

Group	Value	95% CI
Double Blind-Placebo Group	5.63	± 0.92
Double Blind-Escitalopram Group	5.00	± 1.36
Open Treatment With Escitalopram	5.67	± 1.40

Credibility and Expectancy Scale-Depression Secondary · 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.

Group	Value	95% CI
Double Blind-Placebo Group	6.3	± 1.2
Double Blind-Escitalopram Group	6.0	± 0.9
Open Treatment With Escitalopram	5.9	± 0.9

Credibility and Expectancy Scale-Depression Secondary · 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.

Group	Value	95% CI
Double Blind-Placebo Group	5.88	± 0.99
Double Blind-Escitalopram Group	5.40	± 1.09
Open Treatment With Escitalopram	6.06	± 0.84

Quick Inventory of Depression Scale (QIDS-SR): Expectancy Secondary · 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-

Group	Value	95% CI
Double Blind-Placebo Group	5.3	± 6.2
Double Blind-Escitalopram Group	4.8	± 3.7
Open Treatment With Escitalopram	5.8	± 4.5

Quick Inventory of Depression Scale (QIDS-SR): Expectancy Secondary · 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-

Group	Value	95% CI
Double Blind-Placebo Group	6.63	± 3.42
Double Blind-Escitalopram Group	6.20	± 4.83
Open Treatment With Escitalopram	4.92	± 3.83

Executive Dysfunction: Stroop Color Word Secondary · 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).

Group	Value	95% CI
Double Blind-Placebo Group	31.7	± 6.1
Double Blind-Escitalopram Group	31.0	± 9.0
Open Treatment With Escitalopram	32.6	± 11.0

Executive Dysfunction: Stroop Interference Secondary · 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.

Group	Value	95% CI
Double Blind-Placebo Group	42.2	± 6.8
Double Blind-Escitalopram Group	42.9	± 11.2
Open Treatment With Escitalopram	44.1	± 10.4

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were collected through the 8 week period of the study.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Double Blind-Placebo Group

Serious: 0/8 (0%)

Deaths: 0/8

Double Blind-Escitalopram Group

Serious: 2/51 (4%)

Deaths: 0/51

Open Treatment With Escitalopram

Serious: 1/49 (2%)

Deaths: 0/49

Serious adverse events (2 terms)

Reaction	System	Double Blind-Placebo Group	Double Blind-Escitalopram …	Open Treatment With Escita…
Fall	Nervous system disorders	—	—	—
Chest Pain	Respiratory, thoracic and mediastinal disorders	—	—	—

Most-reported serious reactions: Fall, Chest Pain.

Data from ClinicalTrials.gov NCT01931202 adverse events section.

Sponsor's own description

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.

Publications & conference data

6 peer-reviewed publications reference this trial (live from Europe PMC):

1. Frailty and Depression in Late Life: A High-Risk Comorbidity With Distinctive Clinical Presentation and Poor Antidepressant Response.
   Brown PJ, Ciarleglio A, Roose SP, Montes Garcia C, et al · · 2022 · cited 26× · PMID 34758065 · DOI 10.1093/gerona/glab338
2. Association of White Matter Integrity With Executive Function and Antidepressant Treatment Outcome in Patients With Late-Life Depression.
   He X, Pueraro E, Kim Y, Garcia CM, et al · · 2021 · cited 19× · PMID 33551234 · DOI 10.1016/j.jagp.2021.01.004
3. Association between neuromelanin-sensitive MRI signal and psychomotor slowing in late-life depression.
   Wengler K, Ashinoff BK, Pueraro E, Cassidy CM, et al · · 2021 · cited 17× · PMID 32919398 · DOI 10.1038/s41386-020-00860-z
4. Frailty Worsens Antidepressant Treatment Outcomes in Late Life Depression.
   Brown PJ, Ciarleglio A, Roose SP, Garcia CM, et al · · 2021 · cited 15× · PMID 33388223 · DOI 10.1016/j.jagp.2020.12.024
5. Slowed Processing Speed Disrupts Patient Expectancy in Late Life Depression.
   Rutherford BR, Choi CJ, Choi J, Mass B, et al · · 2021 · cited 11× · PMID 33250338 · DOI 10.1016/j.jagp.2020.11.001
6. Who benefits most from expectancy effects? A combined neuroimaging and antidepressant trial in depressed older adults.
   Zilcha-Mano S, Wallace ML, Brown PJ, Sneed J, et al · · 2021 · cited 5× · PMID 34526482 · DOI 10.1038/s41398-021-01606-1