The Use of Duloxetine for Cognition Improvement in Individuals With Mild Cognitive Impairment

The goal of this study is to conduct a proof of concept clinical trial using antidepressant
therapy to improve cognition. This study will utilize a randomized, double blinded, placebo -
controlled trial design. The investigators will recruit up to 100 patients. Patients will be
screened multiple times to determine eligibility. Patients will be randomized into one of two
study groups (placebo control group and Duloxetine group). Patients in the Duloxetine group
will receive up to 60 mg of an FDA approved antidepressant, Duloxetine. Patients in the
control group will receive a placebo that is the exact shape and size of the study drug. The
patients, primary investigators, and research personnel will be blinded to the study
condition. The investigators will designate one on-site personnel to serve as data and safety
monitor. This person will not be blinded and will randomize patients to condition, work with
the pharmacy, and can un-blind condition if necessary.

Potential patients will be invited to a screening visit. This visit is designed to ensure
that the patients meet study criteria and that it is safe for them to participate in the
study. The screening visit will consist of physical examinations, medical and psychological
history, cognitive and functional testing, interviews, questionnaires, research/clinical
venipuncture, and a meeting with the study doctor. If a patient is accepted to the trial,
he/she will be expected to stay in the study for a minimum of 6 months.

After the screening visit, the study team will meet to determine if the patient will continue
to remain in the study. If a patient does remain in the study, he/she will be invited to a
randomization visit. Patients will be randomized into either the Duloxetine group or the
placebo control group. The data and safety monitor will use a randomization software. This
program allows the researcher to enter in the number of subject, and condition, and will
generate a table of randomly assigned patients to condition. The patients and study personnel
will be blinded to the condition. The data safety monitor will randomly assign patients to
condition and work with the pharmacy to properly label the study drugs. Only the data
monitoring personnel will be un-blinded and will generate the table of random numbers. After
randomization, patients will undergo vitals, interviews, testing, and the study drug will be
dispensed to them. First dosage will consist of 30 mg of Duloxetine or placebo, and the
participant will be asked to take the first dose at this visit.

Patients will be invited to a 2 week post randomization visit that will consist of a meeting
with the study doctor to discuss concerns or side effects. Medication dosage will be raised
to 60 mg of Duloxetine or placebo.

Patients will be seen monthly for the next three months. During these visits the patients
will receive their study drugs, have their vital signs measured, and be questioned about
adverse events or any health changes.

One month later, patients will have a follow up visit. This visit will consist of follow up
interview and neuropsychological testing, clinical/research blood draw, and study doctor
visit. This will be the final data collection study visit. The investigators will reduce the
dosage of the study drug to 30 mg at this visit. The patients will be instructed that the
investigators will be weaning off the study drug at this time.

The last study visit will be 2 weeks after the follow-up visit. This visit will consist of a
study debriefing with the patient. At this visit the investigators will discontinue the study
drug. The investigators will also arrange for the data monitoring personnel to un-blind the
study at this time. No data will be collected at this visit. The participants will be
informed of whether or not they were on the study drug or placebo. If a patient in the study
drug group wishes to remain on Duloxetine, the patients will be advised to discuss it with
their personal healthcare provider.

Research data will be stored and managed in a secure manner following NIH guidelines and
according to state and institutional policies. Only authorized key personnel shall have
access to research related documents. All personnel will be properly trained and supervised
regarding the management and handling of confidential materials. The Principal Investigator
assumes full responsibility for such training, supervision, and conduct.

All data will be stored in locked file cabinets behind locked doors in the PIs research
laboratory until entered into the research database. Computer-based data entry will not
require hard copy storage. All data collected via paper-pencil will be double entered into
the research database by independent research assistants and results checked for quality
control (QC). Once all hard copies have been entered, they will be scanned into PDF files for
storage; all hard copies will be shredded. We will maintain the original signed consent forms
for our records (these documents will not be shredded and will be kept in a locked file
cabinet). Electronic scanned files will be stored in password protected files for security
purposes. All discrepancies will be validated by chart review before the data are merged into
the larger database. The database will contain item-level data to avoid the need for
subsequent data entry processes as potential data analyses arise. Periodic QC checks will be
conducted by our IT personnel and provided to the PI. All electronic records will be
maintained on password protected computers behind locked doors in the PI's office space. All
files will be backed up weekly on an independent external hard drive, which is also password
protected.

Inclusion Criteria:

- Male or female, age 50 and up.

- Female participants must be post-menopausal for at least two consecutive years.

- Health and Aging Brain Study participant, who provided consent for re-contact

- Diagnosis of MCI (by Health and Aging Brain Study Consensus Review).

- Has an elevated DepE score (2 or more). This is calculated by summing scores for five
items (Items 14, 16, 17,25 &26) on the Geriatric Depression Scale.

Exclusion Criteria:

- Inability to provide informed consent by self or by proxy.

- Pregnant or breast feeding women

- Uncontrolled narrow angle glaucoma

- Known hypersensitivity to duloxetine.

- Participation in a Clinical Trial in the last three months.

- Other psychiatric disorder like bipolar disorder, schizophrenia, or dementia.

- Use of antidepressants, anti-psychotics, and mood stabilizers.

- History of stroke.