Aβ Dynamics in LLMD

Inclusion criteria

• Male and female subjects, age 60+ years inclusive, at the time of signing the informed consent.
• Meeting Structured Clinical Interview (SCID-5-RV) for DSM-5 criteria for Major depressive disorder.
• Montgomery-Åsberg Depression Rating Scale (MADRS) ≥18.
• Have results of a physical examination, neurological examination, vitals, and EKG within normal limits at screening.
• Cognitively unimpaired at screening visit as defined by Mini-Mental State Examination (MMSE) >27.
• Clinical Dementia Rating Scale (CDR) Global of 0*.
• A score of 85 or greater on the RBANS delayed memory index score.
• 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.
• Medically stable with no significant cerebrovascular, neurological, or systemic disease expected to interfere with the study.
• Adequate auditory acuity and normal-to-corrected vision.
• Willing to undergo brain MRI, urine drug screen and blood sampling for routine laboratory testing, lumbar puncture, APOE genotyping and plasma drug levels.
• Only individuals with normal or non-clinically significant abnormalities on routine laboratory tests, will be included.

• If study partner is not available, the CDR will be skipped.

Exclusion criteria

• 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.
• Mental retardation, or other serious neurological disorder (e.g. Parkinson's disease or other movement disorders).
• Subjects with a Fazekas scale >2.
• 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.).
• A current significant risk for suicidality based on the Columbia-Suicide-Severity Rating Scale (C-SSRS).
• Insulin dependent diabetes.
• Evidence of clinically relevant or unstable cardiac, pulmonary, endocrine or hematological conditions.
• Any prosthetic devices (e.g., pacemaker or surgical clips) that constitutes a hazard for MRI imaging.
• Positive urine drug screen for illicit drugs.
• History of poor tolerance to, poor response to, or ongoing treatment with escitalopram.
• If taking antidepressants, currently taking fluoxetine, due to the length of time required to washout.
• 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)