The purpose of this study is to evaluate the safety and efficacy of escitalopram for agitation in Alzheimer's dementia.

This study is designed to examine the efficacy and safety of escitalopram as treatment for agitation in Alzheimer's dementia (AD) patients. Participants with clinically significant agitation, and their caregiver(s), will receive a structured psychosocial intervention. Participants not showing a response three weeks later will be randomized 1:1 to escitalopram (up to 15 mg/day) or a matching placebo. Participants will receive study drug or placebo for 12 weeks, with in-person and remote (phone/video) visits at weeks 3, 6, 9, and 12, and with telephone contacts between in-person and remote visits. Participants who do show a response to the psychosocial intervention will not be randomized to study drug but will be followed remotely.

Inclusion criteria

1. Alzheimer's dementia diagnosed clinically by the National Institute on Aging (NIA) and the Alzheimer's Association (AA) (2011 NIA/AA criteria)

2. Mini-Mental State Examination Telephone (MMSET) score of 3-20 inclusive

3. Meets the International Psychogeriatric Association (IPA) provisional criteria for agitation in cognitive disorders

4. Clinically significant agitation/aggression as assessed by the Neuropsychiatric Inventory (NPI) for which either:

   • The frequency is 'Very frequently,' or
   • The frequency is 'Frequently' AND the severity is 'Moderate' or 'Marked'

5. Provision of informed consent for participation in the study by both caregiver and participant (or, if participant is unable to provide informed consent, with surrogate consent and participant assent)

6. Availability of a caregiver who spends at least several hours per week with the participant, supervises his/her care, is willing to accompany the participant to study visits, and is willing to participate in the study

7. Stable (for ≥ 7 days) dosing of antipsychotics for agitation or psychosis, if being used at all

8. A medication for agitation is appropriate, in the opinion of the study physician

Exclusion criteria

1. Has major depression, as indicated by major depressive episode (MDE) in the past 90 days (meeting the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) criteria)

2. Presence of another brain disease that fully explains the dementia, (e.g., extensive brain vascular disease, Parkinson's disease, dementia with Lewy bodies, traumatic brain injury, or multiple sclerosis)

3. Residence in a skilled nursing or Long-Term Acute Care (LTAC) facility

4. Contraindication to treatment with escitalopram as determined by a study physician, such as recent (30 days) use of monoamine oxidase inhibitors (MAOIs) or potential participant is hypersensitive to escitalopram or citalopram or any inactive ingredients

5. Prior failed treatment attempt with citalopram or escitalopram for agitation after adequate trial, at minimally accepted dose

6. Indication for psychiatric hospitalization or acute suicidality, in the opinion of the study physician

7. Recent (< 7 days) changes in antipsychotics, anticonvulsants, or psychosis (delusions or hallucinations) requiring a new or change in antipsychotic treatment (in the opinion of the study physician)

8. Abnormal corrected QT interval using Bazett's formula (QTcB)** as determined on enrollment ECG (defined as > 450 ms for men and > 470 ms for women)

9. Recent (30 days) presence of severely reduced renal function (as identified by a Glomerular filtration rate (GFR) clearance < 30 mL/min) or reduced hepatic function

10. Current treatment (within 7 days) with any of the following:

    • antidepressants (other than trazodone, ≤ 100 mg per day at bedtime)
    • benzodiazepines (other than lorazepam), or
    • psychostimulants

11. Recent (< 14 days) changes in Dextromethorphan/quinidine, prazosin, and pimavanserin

12. Recent (< 14 days) use of medical marijuana

13. Current participation in a clinical trial or in any study that may add a significant burden or affect neuropsychological or other study outcomes

14. Significant communicative impairments that would affect participation in a clinical trial

15. Any condition that, in the opinion of the study physician, makes it medically inappropriate or risky for the potential participant to enroll in the trial

    • if the QTcB is determined while the rhythm is paced, 50 ms is subtracted from the calculated value. The study cardiologist must confirm eligibility in this scenario.

Over-encapsulation