Aβ Dynamics in LLMD

Depression Treatment and Aβ Dynamics: A Study of Alzheimer's Disease Risk (ABD Study)

This study will examine the biological factors that may modulate the relationship between depression and the development of Alzheimer's disease (AD). Since the direction of causation between depression and the biological factors associated with AD is unknown, the only way to understand cause and associated risk is to treat the depressive symptoms and examine the effects on AD biomarkers. The study involves an FDA-approved treatment for major depressive disorder. It will compare the SSRI antidepressant escitalopram with placebo. The hypothesis is that a reduction in depressive symptoms will be associated with a normalization of CSF AD biomarkers as well as peripheral inflammatory markers. This research would contribute to fundamental knowledge about potentially modifiable risks of Alzheimer's disease (AD).

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease; Major Depressive Disorder
• Intervention / Treatment: Drug: Escitalopram Oxalate; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Antero Sarreal, MD; Phone Number: 845-398-6532; Email: Antero.sarreal@nki.rfmh.org
• Study Contact Backup: Name: Chelsea Reichert Plaska, PhD; Phone Number: 845-398-5583; Email: Chelsea.reichert@nki.rfmh.org

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • Recruiting
      • NYU Langone Health
      • Principal Investigator: Nunzio Pomara, MD
    • Orangeburg, New York, United States, 10962
      • Recruiting
      • Nathan S. Kline Institute for Psychiatric Research
      • Contact: Antero Sarreal, MD; Phone Number: 845-398-6532; Email: Antero.sarreal@nki.rfmh.org
      • Principal Investigator: Nunzio Pomara, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male and female subjects, age 60+ years inclusive, at the time of signing the informed consent.
2. Meeting Structured Clinical Interview (SCID-5-RV) for DSM-5 criteria for Major depressive disorder.
3. Montgomery-Åsberg Depression Rating Scale (MADRS) ≥18.
4. Have results of a physical examination, neurological examination, vitals, and EKG within normal limits at screening.
5. Cognitively unimpaired at screening visit as defined by Mini-Mental State Examination (MMSE) >27.
6. Clinical Dementia Rating Scale (CDR) Global of 0.
7. A score of 85 or greater on the RBANS delayed memory index score.
8. Fluent in English, because some of the instruments used in this study have not been translated and validated in other languages, and are able to read at a 6th grade level or equivalent, as determined by the PI.
9. Medically stable with no significant cerebrovascular, neurological, or systemic disease expected to interfere with the study.
10. Adequate auditory acuity and normal-to-corrected vision.
11. Willing to undergo brain MRI, urine drug screen and blood sampling for routine laboratory testing, lumbar puncture, APOE genotyping and plasma drug levels.
12. Only individuals with normal hepatic and renal function including normal creatinine clearance will be included.

Exclusion Criteria:

1. History of brain tumor, MRI evidence of brain damage or brain disease including significant trauma, hydrocephalus, seizures, or confluent (or more extensive) white matter hyperintensities.
2. Mental retardation, or other serious neurological disorder (e.g. Parkinson's disease or other movement disorders).
3. Subjects with a Fazekas scale >2.
4. Significant history of alcoholism or drug abuse in the past 2 years. Fulfilling SCID-5-RV/DSM-5 criteria for current or past diagnosis of any psychiatric disorder (e.g., schizophrenia, bipolar disorder, or any psychotic disorder) other than recurrent MDD or anxiety disorders (e.g., panic disorder, agoraphobia, etc.).
5. A current significant risk for suicidality based on the Columbia-Suicide-Severity Rating Scale (C-SSRS).
6. Insulin dependent diabetes.
7. Evidence of clinically relevant or unstable cardiac, pulmonary, endocrine or hematological conditions.
8. Any prosthetic devices (e.g., pacemaker or surgical clips) that constitutes a hazard for MRI imaging.
9. Positive urine drug screen for illicit drugs.
10. History of poor tolerance to, poor response to, or ongoing treatment with escitalopram.
11. If taking antidepressants, currently taking fluoxetine, due to the length of time required to washout.

12. Treatment with following medications will not be permitted. In some cases, medications will be allowed if medically prescribed and dose regimen stable. Note: Some medications (e.g., amphetamines, opiates) may appear on the routine urine drug test in the screening period but can be allowed as per protocol.

    • For subjects taking prescribed psychoactive medications and supplements (i.e., opioids, amphetamines, amphetamine-like substances, and cannabinoids), must be on a stable dose for 1 month prior to randomization.
    • Anti-Parkinsonian medications (carbidopa/levodopa, amantadine, bromocriptine, pergolide, selegiline).
    • Cholinesterase inhibitors and memantine
    • Continuous aspirin (any dosage) use which can affect platelet function is prohibited. Exception: If participant is on low dose aspirin for prophylaxis and is willing to temporarily discontinue prior to research blood draw (i.e., 2 days before).
    • Continuous use of other medications which are also known to affect platelet function, including nonsteroidal anti-inflammatory drugs (NSAIDs), anti-histamines. Exception: If participant is taking medication continuously and is willing to temporarily discontinue prior to research blood draw (i.e., 2 days before)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo (PBO)	Drug: Placebo; Daily dose of placebo will mimic that of ESC.; Other Names: PBO
Active Comparator: Escitalopram (ESC)	Drug: Escitalopram Oxalate; The daily dose of ESC/PBO will be 10 mg for the first 2 weeks, then increase to 20 mg as tolerated, with an option to reduce back to 10 mg if necessary.; Other Names: Lexapro; ESC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cerebrospinal Fluid (CSF) Aβ40 Biomarker Levels		Baseline, Week 8
Change in Cerebrospinal Fluid (CSF) Aβ42 Biomarker Levels		Baseline, Week 8
Change in Vascular Dysfunction (VD) Biomarker Levels		Baseline, Week 8
Change in Scores on Montgomery-Asberg Depression Ration Scale (MADRS)	MADRS consists of 10 items evaluating core symptoms of depression (e.g, apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thought, and suicidal thoughts). Each symptom is rated on a 0-6 scale (0=no abnormality, 6=severe). The total score ranges from 0 to 60; the higher the score, the more severe the symptoms.	Baseline, Week 8

Other Outcome Measures

Outcome Measure	Time Frame
Change in Plasma Aβ Biomarker Levels	Baseline, Week 8
Change in Cerebrospinal Fluid (CSF) P-tau Biomarker Levels	Baseline, Week 8
Change in Cerebrospinal Fluid (CSF) T-tau Biomarker Levels	Baseline, Week 8

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Nunzio Pomara, MD, NYU Langone Health

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2022
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: August 12, 2021
• First Submitted That Met QC Criteria: August 12, 2021
• First Posted (Actual): August 13, 2021

Study Record Updates

• Last Update Posted (Actual): November 1, 2023
• Last Update Submitted That Met QC Criteria: October 31, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mood Disorders; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Depressive Disorder; Alzheimer Disease; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Antidepressive Agents, Second-Generation; Antiparkinson Agents; Anti-Dyskinesia Agents; Selective Serotonin Reuptake Inhibitors; Citalopram; Dexetimide; Escitalopram
• Other Study ID Numbers: 21-00535

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be shared upon reasonable request.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• IPD Sharing Access Criteria: The investigator who proposed to use the data will have access to the data upon reasonable request. Requests should be directed to nunzio.pomara@nki.rfmh.org. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes