Escitalopram Effects on CSF Amyloid Beta

Escitalopram Effects on CSF Amyloid Beta Total Concentrations

Alzheimers disease (AD) is a devastating illness, estimated to affect 5 million patients in the United States alone and projected to increase dramatically over the next decades as the population ages unless preventive measures can be developed. The investigators have preliminary evidence that selective serotonin reuptake inhibitor (SSRI) antidepressants lower the amount of amyloid plaques in the human brain. The interventions now propose to study the effects of an SSRI (escitalopram) on levels of amyloid beta peptide (the major constituent of the plaques) in the cerebrospinal fluid (CSF) of cognitively normal older adults.

Study Overview

• Status: Completed
• Conditions: Amyloid Beta Protein
• Intervention / Treatment: Drug: Escitalopram 20mg for 2 weeks; Drug: Placebo; Drug: Escitalopram 30mg for 8 weeks; Drug: Escitalopram 20mg for 8 weeks

Detailed Description

The investigators will measure CSF Amyloid Beta levels before and after two weeks or eight weeks of treatment with escitalopram using a double blind placebo-controlled study design with approximately 30 cognitively normal participants, age 60-85, with a MOCA of 23 or higher. They will be recruited from the community. Participants will be randomized (approximately 30 per group).

Participants in the 2 week arm will have 3 study visits:

1. Screening Visit: Consent and screening procedures will be complete. Participants will be randomized 1:1 to receive escitalopram or placebo.
2. Study Visit 1: This visit will take approximately 45 minutes - 1 hour; participants will have a lumbar puncture (LP) in order to obtain cerebrospinal fluid (CSF), a blood draw, and will receive study medication.
3. Study Visit 2: This visit will take approximately 45 minutes - 1 hour; participants will have a lumbar puncture (LP) in order to obtain cerebrospinal fluid (CSF), a blood draw, will receive taper-down study medication, and will complete an end-of-study questionnaire.

Participants in the 8-week arm(s) will have 4 study visits:

1. Screening Visit: Consent and screening procedures will be complete. Participants will be randomized 1:1 to receive escitalopram or placebo.
2. Study Visit 1: This visit will take approximately 45 minutes - 1 hour; participants will have a lumbar puncture (LP) in order to obtain cerebrospinal fluid (CSF), a blood draw, and will receive 4 weeks of study medication.
3. Study Visit 2: Researchers will check in with participants and participants will receive another 4 weeks of study medication.
4. Study Visit 3:This visit will take approximately 45 minutes - 1 hour; participants will have a lumbar puncture (LP) in order to obtain cerebrospinal fluid (CSF), a blood draw, will receive taper-down study medication, and will complete an end-of-study questionnaire.

The current proposal will test whether clinically relevant doses of an SSRI reduce CSF levels of Amyloid Beta in healthy older human participants. The investigators hypothesize that compared to placebo, participants receiving escitalopram will show significantly lower Amyloid Beta levels in the second CSF sample.

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1) Age 60-85 (inclusive), male and female, any race.
• 2) Capacity to give informed consent and follow study procedures.
• 3) English speaking.
• 4) MOCA = 23 or greater

Exclusion Criteria:

• 1) Known history of relevant severe drug allergy or hypersensitivity (e.g. to Citalopram or Escitalopram)
• 2) Does not speak English
• 3) Cannot give informed consent
• 4) Diagnosis of Major Depression
• 5) Previous history of neurological disorders, such as Parkinson's disease, Alzheimer's disease or traumatic brain injury, cognitive impairment or dementia.
• 6) Diagnosis of a chronic psychiatric illness
• 7) Significant hearing or visual impairment
• 8) Bleeding diathesis
• 9) Clinically significant hepatic, renal, pulmonary, metabolic or endocrine disturbances as indicated by history, which in the opinion of the investigator might pose a potential safety risk to the subject.
• 10) Current clinically significant cardiovascular disease. Clinically significant cardiovascular disease usually includes one or more of the following: cardiac surgery or myocardial infarction within the last 4 weeks; unstable angina; acute decompensated congestive heart failure or class IV heart failure; current significant cardiac arrhythmia or conduction disturbance, particularly those resulting in ventricular fibrillation, or causing syncope or near syncope; uncontrolled high blood pressure; QTc greater than 450msec (by history for subjects with cardiac disease); documented prior stroke.
• 11) Clinically significant abnormalities on EKG. Primary AV block or Right bundle branch block are not necessarily exclusionary.
• 12) History of drug or alcohol abuse within the last year or prior prolonged history of abuse
• 13) Use of an Investigational medicine within the past 30 days 14) Use of Coumadin, Warfarin or other blood thinners within the past 6 months
• 15) Use of antipsychotic medication or antidepressant medication (e.g. MAOIs, SSRIs, SNRIs).
• 16) Use of the following drug/drug classes: Pimozide, Triptans, Tricyclics, Lithium, Tramadol
• 17) Use of over-the-counter supplements such as tryptophan or St. Johns Wort 18) Any other factor that in the investigator's judgment may affect patient safety or compliance (e.g. distance greater than 100 miles from the research institution)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Escitalopram 20mg for 2 weeks; 30 cognitively normal adults aged 60-85 will receive escitalopram 20mg for 2 weeks (upward titration as: 10mg for 5 days, then 20mg for 9 days); and amyloid beta levels in the CSF will be measured at baseline (before drug administration) and after 2 weeks of study drug (active or placebo). Participants will taper off medication following the 2nd CSF measurement.	Drug: Escitalopram 20mg for 2 weeks; 30 cognitively normal adults aged 60-85 will receive escitalopram 20 mg for 2 weeks; amyloid beta levels in the CSF will be measured at baseline (before drug administration) and following the full study drug (i.e., active drug) administration.
Placebo Comparator: Placebo (sugar pill); 30 cognitively normal adults aged 60-85 will receive placebo for 2 weeks (upward titration as: 10mg for 5 days, then 20mg for 9 days) or 8 weeks (upward titration as: 10mg for 5 days, then 20mg for 51 days); and amyloid beta levels in the CSF will be measured at baseline (before drug administration) and after 2 or 8 weeks of study drug (active or placebo). Participants will taper off medication following the 2nd CSF measurement.	Drug: Placebo; Additionally, 30 cognitively normal adults aged 60-85 will receive a placebo; amyloid beta levels in the CSF will be measured at baseline (before drug administration) and following the full study drug (i.e., placebo) administration.
Experimental: Escitalopram 30mg for 8 weeks; 30 cognitively normal adults aged 60-85 will receive escitalopram 30 mg for 8 weeks (upward titration as: 10mg for 5 days, then 20mg for 5 days; then 30 mg for 46 days); and amyloid beta levels in the CSF will be measured at baseline (before drug administration) and after 8 weeks of study drug (active or placebo). Participants will taper off medication following the 2nd CSF measurement.	Drug: Escitalopram 30mg for 8 weeks; 30 cognitively normal adults aged 60-85 will receive escitalopram 30 mg for 8 weeks; amyloid beta levels in the CSF will be measured at baseline (before drug administration) and following the full study drug (i.e., active drug) administration.
Experimental: Escitalopram 20mg for 8 weeks; 30 cognitively normal adults aged 60-85 will receive escitalopram 20mg for 8 weeks (upward titration as: 10mg for 5 days, then 20mg for 51 days); and amyloid beta levels in the CSF will be measured at baseline (before drug administration) and after 8 weeks of study drug (active or placebo). Participants will taper off medication following the 2nd CSF measurement.	Drug: Escitalopram 20mg for 8 weeks; 30 cognitively normal adults aged 60-85 will receive escitalopram 20 mg for 8 weeks; amyloid beta levels in the CSF will be measured at baseline (before drug administration) and following the full study drug (i.e., active drug) administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amyloid Beta Levels in CSF	Change in the level of Amyloid Beta peptides (Amyloid Beta 42 and Amyloid Beta 40) in the CSF between the measurement at baseline and the measurement after exposure with escitalopram.	2 - 8 Weeks (we used week 8 minus baseline and week 2 minus baseline)

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Washington University School of Medicine
• Investigators: Principal Investigator: Yvette Sheline, M.D., University of Pennsylvania

Publications and helpful links

General Publications

• Sheline YI, Snider BJ, Beer JC, Seok D, Fagan AM, Suckow RF, Lee JM, Waligorska T, Korecka M, Aselcioglu I, Morris JC, Shaw LM, Cirrito JR. Effect of escitalopram dose and treatment duration on CSF Abeta levels in healthy older adults: A controlled clinical trial. Neurology. 2020 Nov 10;95(19):e2658-e2665. doi: 10.1212/WNL.0000000000010725. Epub 2020 Sep 10.

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): January 1, 2019

Study Registration Dates

• First Submitted: June 5, 2014
• First Submitted That Met QC Criteria: June 10, 2014
• First Posted (Estimate): June 11, 2014

Study Record Updates

• Last Update Posted (Actual): April 9, 2020
• Last Update Submitted That Met QC Criteria: April 6, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Escitalopram; Cerebrospinal Fluid; Amyloid Beta
• Additional Relevant MeSH Terms: Metabolic Diseases; Proteostasis Deficiencies; Amyloidosis; 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; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Antidepressive Agents, Second-Generation; Antiparkinson Agents; Anti-Dyskinesia Agents; Citalopram; Dexetimide
• Other Study ID Numbers: R01AG041502 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No