Vortioxetine Monotherapy for Major Depressive Disorder in Type 2 Diabetes

This will be a 9-week, open-label, single-arm, pilot investigation for Type 2 Diabetes (T2D)
patients with Major Depressive Disorder (MDD). The study includes a screening visit, a 1-week
washout phase (or 30-day washout phase for serotonergic agents), and an 8-week flexible dose
phase that includes the baseline and post-treatment follow-up visits. A minimum of N=70
participants will be enrolled in the treatment.

At the screening visit, the study will be explained and the informed consent process will
take place. Patients who sign the IRB-approved consent form will undergo a psychiatric
interview. The diagnosis of MDD will be established in this examination using the psychiatric
interview and Hamilton Depression Rating Scale (HAM-D) by the study PI.

Eligible participants will be instructed how to taper the antidepressant they have been
taking (if relevant) over the course of the one-week (or 30-days for serotonergic agents).

After these tapers, all participants will return for a baseline visit where they will be
re-assessed to ensure persistent depressive symptoms. If patients continue to score ≥18 on
the HAM-D, they will complete the psychosocial questionnaires; patients scoring below <18 on
the HAM-D at this visit will be terminated from the study and offered conventional, standard
of care treatment within LUMC Department of Psychiatry. Once participants are given the
psychosocial questionnaires as part of the baseline visit, a blood draw will be conducted by
the Study Nurse/Coordinator, and MRI scans will be completed.

At the end of the baseline session, participants will receive Vortioxetine for the remaining
8-week flexible dosing period (i.e., 10 mg to 20 mg dosing). In the instance a patient is
unable to tolerate either 10 mg to 20 mg of Vortioextine (as reported in the medication
packet insert), the patient will be allowed to reduce their dosage to 5 mg, which will be
done in consultation with the PI and sub-investigator.

Following the 8-week intervention, participants will be scheduled for the post visit, which
will include the following: another clinical interview and HAM-D conducted by the PI,
completion of post visit-related psychosocial questionnaires, a second blood draw conducted
by the Study Nurse/Coordinator, and then post visit-MRI scans will be completed. Should any
patients continue to score >18 on the HAM-D at study conclusion, resources and referrals will
be provided for further psychological/psychiatric interventions, as needed.

Inclusion Criteria:

- Adults 40 to 65 years of age at time of screening visit.

- Women only: Must be post-menopausal at time of screening visit (i.e., defined by NO
menstruation for at least the past 12-months).

- Diagnosis of T2D, as defined by a diagnosis of T2D (for at least 12 months) in the
medical record made by a physician (i.e., denoted as 250.XX according to ICD-9/ICD-10
billing codes) OR

- current use of oral hypoglycemic medications or insulin OR

- having a fasting plasma glucose ≥126 mg/dL in the medical record OR

- having a 2-hour oral glucose tolerance test ≥200 mg/dL in the medical record

- Patients who meet criteria for current MDD without significant co-morbid psychiatric
diagnoses, as determined by study PI from screening visit:

- Clinical Psychiatric Interview to determine DSM-V criteria for current MDD AND

- A minimum score of 18 on the Hamilton Depression Scale (HAM-D)

- Patients with T2D and current MDD that would benefit from antidepressant therapy,
which may include:

- Patients with current MDD who were NOT prescribed an antidepressant medication in the
past;

- Patients with current MDD who are NOT responding to their current prescribed
antidepressant;

- Patients with current MDD who are experiencing breakthrough depressive symptoms
despite being maintained on another antidepressant.

- Must have the ability to provide informed consent to participate in the study.

Exclusion Criteria:

- Patients with any form of contraindication to Vortioxetine treatment, as outlined in
the medication packet insert, (e.g., presence of a known hypersensitivity to the study
drug or hypersensitivity to MAO-I use, etc.).

MRI-Related Exclusion Criteria

- Participants weighing >550 lbs (per MRI weight restrictions set by Loyola University
Medical Center);

- Patients with a pacemaker, AICD, ossicular prosthesis, nerve stimulator, or another
contraindication to MRI;

- Pregnant patients;

- Patients with an inability to tolerate being in enclosed places/spaces such as MRI;

- Patients with a history of neurosurgery, brain irradiation, or cerebral endovascular
treatment.;

- Patients with history of epilepsy, stroke, neurodegenerative disorder, severe
traumatic brain injury, hydrocephalus or demyelinating disorder;

- Patients with a history of malignant neoplasm

Exclusion Criteria to Reduce False Positive Rates of Inflammation

- Specific pre-existing chronic pain conditions such as rheumatoid arthritis or
fibromyalgia. However, this will NOT include more localized pain-related conditions
such as low-back pain or complications associated with T2D (e.g., diabetic
neuropathy).

- History of peptic ulcer complicated by perforation, hemorrhage, or obstruction;
symptoms of peptic ulcer within 4 weeks of enrollment date that has not been treated.

- Current diagnosis of substance abuse/dependence during the 6 months prior to study
enrollment.

- Current diagnosis of uncontrolled hypertension, anemia, liver disease, kidney disease,
stroke, and autoimmune disease. Based on the clinical judgment of the study PI, a risk
assessment will be conducted if a participant endorses any of these diagnoses but
would be otherwise a suitable participant to enroll in the study.

- Current acute infection/infectious disease (i.e., a cold or the flu). Based on the
clinical judgement of the study PI, a risk assessment will be conducted if a
participant endorses some acute infection/infectious disease, but would be otherwise
suitable to enroll in the study following a brief wait period for full symptom
remission.

- Pre- and peri-menopausal women (i.e., defined as the presence of ANY menstruation
within the past 12 months).

- Certain steroids (e.g., use of hormonal birth control) and any systemic
corticosteroids. Please note that hormone replacement therapy will be allowed along
with any topical corticosteroid creams.

- Patients currently enrolled in any other clinical trial for treatment of MDD (e.g.,
patients receiving experimental vitamin D supplementation).