Clinical trial NCT02161458
Conditions: Amyloid Beta Protein
Keywords: Escitalopram Amyloid Beta Cerebrospinal Fluid
Sponsor: University of Pennsylvania
Start date: 2014-06-01; Completion date: 2019-01-01
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

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.

Arms: arm 1: 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. arm 2: 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. arm 3: 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. arm 4: 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.
Interventions: intervention 1: Escitalopram 20mg for 2 weeks intervention 2: Escitalopram 20mg for 8 weeks intervention 3: Escitalopram 30mg for 8 weeks intervention 4: Placebo
Intervention descriptions: intervention 1: 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. intervention 2: 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. intervention 3: 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. intervention 4: 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.

Protocol documents:
Prot_SAP_001.pdf: 
Cover Page 
Study Title: Escitalopram Effects on CSF Amyloid Beta Total Concentrations 
NCT02161458 
October 31, 2018


 
Escitalopram Effects on CSF Amyloid Beta Total Concentrations 
Principal Investigator: Yvette Sheline, MD 
 
Protocol 
Abstract 
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. We have preliminary evidence that selective serotonin reuptake inhibitor (SSRI) 
antidepressants lower the amount of amyloid plaques in the human brain.  
We 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. We will measure 
CSF Amyloid Beta levels before and after treatment with escitalopram.  We will use a double blind, placebo-
controlled study design with approximately 120 cognitively-normal participants across two sites. Participants 
will be age 60-85, with a Montreal Cognitive Assessment (MOCA) of 26 or higher. They will be recruited from 
the community. Participants will be randomized (approximately 30 per drug group and 30 in the placebo 
group).  
 
 
Objectives 
Overall objectives 
To assess the effect of exposure to escitalopram on levels of amyloid beta peptide in the cerebrospinal fluid 
(CSF) of cognitively-normal older adults and to determine the ideal dose of escitalopram for reducing levels of 
amyloid beta. To assess whether there is a differential response to: escitalopram 20 mg for 2 weeks, 
escitalopram 20 mg for 8 weeks, or escitalopram 30 mg for 8 weeks. 
 
Primary outcome variable(s) 
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 2 weeks or 8 weeks of exposure with escitalopram 20 
vs. 30 mg/day. 
 
Secondary outcome variable(s) 
CSF and blood will be stored for subsequent analysis of additional yet to be discovered  biomarkers. 
 
 
Background 
Results from our R21 proposal "PET Amyloid Plaque Imaging in Late-life Depression" showed that those 
participants who had received any antidepressant medication for 12 months or more had significantly lower 
Amyloid Plaque mean Mean Cortical Binding Potential by PET imaging with the amyloid tracer Pittsburgh 
Compound B (PiB) than those who had received medication for less than 12 months. Following up on these 
results, a subsequent study was conducted using an APP transgenic mouse model of AD. Compared to vehicle-
treated mice, both citalopram and fluoxetine reduced levels of A in brain interstitial fluid (ISF) almost 
immediately following drug administration with a significant decrease observed after 10-14 hours of 
treatment. We conducted a study of Amyloid Beta synthesis in healthy young adults. In this study, participants 
had an indwelling lumbar catheter placed so that CSF could be collected hourly. We now have data indicating 
a significant difference in total concentrations between participants who had received placebo vs. those who 
received citalopram. In the current protocol, we will extend these studies to healthy older adults who will be 
treated with escitalopram for two weeks or 8 weeks at 20 or 30mg. This study will measure steady state CSF 


 
Amyloid Beta levels rather than Amyloid Beta synthesis as the primary endpoint. It is important to understand   
the effects of escitalopram/fluoxetine on Amyloid Beta levels after a short duration of treatment before 
proceeding to more long-term dosing studies as a prevention strategy. We  chose escitalopram for this study 
because, among available SSRIs, it is among the most selective for serotonin, has excellent bioavailability, and 
excellent safety, tolerability and efficacy, with the fewest side effects (DeVane, 1999; DeVane and Boulton, 
2002; Cipriani et al., 2009). We chose the dose of 20 mg, because it is commonly used as the upper end of 
usual doses in antidepressant treatment trials (DeVane, 1999; DeVane and Boulton, 2002). We have added the 
additional 30 mg dose because our initial study data was not showing quite the effect we hoped for based on 
trails in mice and younger humans (Sheline et al., 2014). Though the antidepressant effect has not been shown 
to increase after 20 mg/day, we are investigating a different mechanism, the effect on CSF levels of amyloid 
beta. Previous concerns about the QTc interval increase in escitalopram have been revised (Keller, 2013). 
Consequently this enables a dosing strategy that would achieve similar doses to those used in our rodent 
studies (Cirrito et al., 2011) which is equivalent to a human dose of 66mg/day. We  are added a 3rd arm of the 
study with 30 mg of escitalopram because our preliminary data  from our LP study show approximately a 10% 
decrease in Abeta on 20 mg , whereas in our animal studies there was a 25% decrease. Further, the human 
equivalent of the doses we used in the animal studies is approximately 25-30 mg and so we feel it is important 
to achieve the same equivalent doses for a greater effect size. We conducted a study of Amyloid Beta 
synthesis in healthy young adults. In this study, participants had an indwelling lumbar catheter placed so that 
CSF could be collected hourly.  
 
 
Study Design 
Phase* 
Phase IV 
 
Design 
This is a double-blind, placebo-controlled, parallel-assigned design.    Participants will be randomly assigned to 
one of four arms: 
• 
Arm 1 – Escitlopram 20mg 2 weeks 
• 
Arm 2 – Escitalopram 20 mg 8 weeks 
• 
Arm 3 – Escitalopram 30 mg 8 weeks 
• 
Arm 4 – Placebo 2 or 8 weeks 
 
Participants and investigators will be blinded to drug status. Participants will undergo lumbar puncture (LP) for 
CSF analysis and determination of amyloid status pre- and post- treatment.   Blood will be used for genetic 
testing for APOE and also to determine drug levels in plasma.  
 
 
Characteristics of the Study Population 
Target population 
Approximately 120 cognitively-normal research participants aged 60-85 who have a MOCA score ≥ 26 will be 
recruited from the community.  
 
Key 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) Montreal Cognitive Assessment (MOCA) of 26 or higher. 
 
Key exclusion criteria 
1) Known history of relevant severe drug allergy or hypersensitivity (e.g. to Citalopram, Escitalopram, or 
Fluoxetine)  
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 (not including short-acting 
anti-coagulants that are okay for surgery after 24 hours off medication) 
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 this facility) 
 
 
Study Procedures 
Procedures 
• 
Participant Selection and Recruitment: This study will be made known to the community through 
flyers, brochures, online, print, and radio advertisements.  Interested participants will contact study 
personnel.  Personnel will explain the study, including the time commitment required for 
participation, the basic procedures to be done, and will review the inclusion and exclusion criteria. 
This initial screening will be pre study consent and will take place as a phone interview, as a self-report 
measure on RedCap, or as a combination of these 2 methods. Following the initial screening, the study 
coordinator will contact interested participants and will schedule an in- person visit (Visit 1).  
 
• 
Consent: All interested participants, meeting the basic eligibility criteria and willing to consider 
participating, will have the opportunity to review the Informed Consent Form (ICF) in detail with a 
member of the study team.  Participants will be given the opportunity to read the consent in full, ask 
any questions they have, and have their questions answered before being asked to sign the ICF.  


 
Individuals may choose not to sign the ICF at the time of the consent conversation and may take it 
home with them to review further and may share with their physician to assist them in making an 
informed decision about participation.  No study procedures will be conducted until the ICF has been 
signed by the participant. The participant will receive a copy of their signed ICF. 
 
• 
Visit 1 - Screening:  After informed consent is obtained, eligibility criteria are reviewed.  This will 
include a review of current and recent medications, medical and psychiatric history, and the 
administration of the Montreal Cognitive Assessment (MOCA).  Participants meeting eligibility criteria 
will be scheduled for Visit 2 – Baseline Assessment. 
 
• 
Visit 2 – Baseline/Pre-treatment Assessment: This visit will include a blood draw, lumbar puncture, and 
administration of study drug.  Participants will be asked to fast overnight (no food after midnight) the 
evening before this visit. Participants may drink water and may take medications.  Participants will 
arrive at the study site at in the morning. The following study procedures will take place:  
o Blood Draw: About 1 ½ tablespoons of blood will be tested for APoE 4 genotype as well as any 
other factors in the future that are determined to be related to the biology of Alzheimer's 
disease. Some blood will be retained and banked for future research.  
o Lumbar puncture (LP): LP will be performed by one of the study physicians; LP will be at the 
L3-4 interspace with a 22 g Sprotte (atraumatic) needle. The area around the site of the LP will 
be numbed with a small injection of Lidocaine prior to the start   of the procedure. Once the 
area is numb, a small amount (~ 4 teaspoons) of cerebrospinal fluid (CSF), a fluid found in the 
brain and spinal column, will be drawn through a needle inserted into your back. An LP is the 
most common and safest method of obtaining CSF samples. The CSF will be stored for future 
research.  
o Participants will be randomized into one of the 4 study arms: escitalopram 20 mg 2 weeks, 
escitalopram 20 mg 8 weeks, escitalopram 30 mg 8 weeks or placebo (2 weeks or 8 weeks).  
Participants and study physicians will be blinded as to the treatment arm.  Participants will be 
given the study drug in capsules and will be provided written and oral instruction on how to 
take the study drug, including details regarding the titration schedule. Titration Schedule: 
 
escitalopram 20 mg 2 weeks: 10mg (1 cap) qd for 5 days; 20mg (2 caps) qd for 9 days. 
 
escitalopram 20 mg 8 weeks: 10mg (1 cap) qd for 5 days; 20mg (2 caps) qd for 
remainder of 8 weeks 
 
escitalopram 30 mg 8 weeks: 10mg (1 cap) qd for 5 days; 20mg (2 caps) qd for 5 days; 
30mg (3 caps) qd for remainder of 8 weeks 
 
Placebo (2 weeks or 8 weeks): 1 cap qd for 5 days; 2 caps qd for remainder of 2 or 8 
weeks 
 
• 
Phone Call: The study coordinator will call participants after their visit to check on their status 
following the procedures (e.g., side effects from the LP, study medication) and to make sure that 
participants are comfortable with the instructions. Participants will be contacted by research staff to 
inquire about their experience with the drug/placebo and to assess for tolerance and side effects (e.g., 
nausea) from the drug/placebo. These calls will occur approximately every 3 days until day 10 and 
then once per week after.  If participants experience side effects from the higher dosage, they may be 
instructed to reduce the dose down to the last tolerable dose for the remainder of their participation.  
 
• 
Visit Three – Post-treatment Assessment: This visit will include a lumbar puncture, drug accountability, 
self-report questionnaire, and administration of study drug for taper off. Participants will be asked to 
fast overnight (no food after midnight) the evening before this visit. Participants may drink water and 


 
may take medications.  Participants will arrive at the study site at in the morning. The following study 
procedures will take place:  
o Lumbar puncture (LP): LP will be performed by one of the study physicians; LP will be at the 
L3-4 interspace with a 22 g Sprotte (atraumatic) needle. The area around the site of the LP will 
be numbed with a small injection of Lidocaine prior to the start   of the procedure. Once the 
area is numb, a small amount (~ 4 teaspoons) of cerebrospinal fluid (CSF), a fluid found in the 
brain and spinal column, will be drawn through a needle inserted into your back. An LP is the 
most common and safest method of obtaining CSF samples. The CSF will be stored for future 
research.  
o Participants will be provided the study drug in capsules and will be provided written and oral 
instruction on how to taper off of the study drug. Taper Down Schedule: 
 
escitalopram 20 mg 2 weeks: 10mg (1 cap) qd for 3 days 
 
escitalopram 20 mg 8 weeks: 10mg (1 cap) qd for 3 days 
 
escitalopram 30 mg 8 weeks: 20mg (2 caps) qd for 3 days; 10mg (1 cap) qd for 3 days; 
 
Placebo (2 weeks or 8 weeks): 1 cap qd for 3 days 
o To address drug accountability, participants will be asked to bring their pill bottles to Visit 3 so 
that the number of pills consumed and the number of pills remaining can be recorded. 
o Participants will be asked to complete a self-report questionnaire regarding their experience in 
study.  
 
• 
Phone Call: The study coordinator will call participants the day after Visit 3 to inquire about side 
effects from the LP, study medication or other study procedures.    
 
There will be no additional follow up with study participants.  However, study participants are encouraged to 
contact the study personnel regarding any potential Adverse Events that may occur following in the days 
following the lumbar puncture procedure and in the days following the termination of the study drug. 
 
Deception 
Does your project use deception? No 
 
 
Analysis Plan 
We will conduct standard demographic comparisons to ensure that the groups are matched in age, gender 
and race. We will then conduct paired t-tests to compare CSF values for each participant before and after 
drug/placebo administration (within participant comparison) and will conduct an unpaired t- test to compare 
CSF values between groups (placebo and escitalopram) at baseline and at the end of the study. Based on our 
results in young people we expect that 30 subjects per drug arm and 45 in the placebo group (acquired across 
two sites) will provide sufficient power to detect a difference between placebo and treated groups and to 
detect a change between baseline and the end of participation for those treated with escitalopram. The effect 
size was estimated based on preliminary data collected over a 36 hour period in 24 young healthy cognitively-
normal adults (15 treated with citalopram and 9 with placebo). The mean and SD for the groups was 30.0 
(15.8) and 42.3 (11.0), respectively. This provides an effect size of 0.77, which is larger than the effect size 
(0.73) necessary to detect a significant difference with n of 30 per group at a power of 0.80 and an alpha of 
0.05. The additional numbers of subjects will protect against potentially greater variability in an older age 
group and the smaller number of samples (2 versus 24).