Vortioxetine for MDD, Cognition, and Systemic Inflammatory Biomarkers

Major depression is an independent risk factor for incident cancer, recurrence and
mortality. Women with chronic major depression exhibit a four-fold increased rate of
incident breast cancer and a 39% higher mortality rate compared to non-depressed women with
breast cancer. Although the precise biological mechanism linking depression with cancer
progression remains unclear, elevated concentrations of systemic inflammatory biomarkers
(e.g., pro-inflammatory cytokine interleukin-6 (IL-6) and associated cytokine proteins) have
been independently associated with depression and cancer progression. In the context of
breast cancer, secretion of tumor-derived cytokines is a known mechanism by which epithelial
tumors are able to recruit immune cells (MDSCs). The presence of MDSCs at the primary tumor
site favors tumor pathogenesis and correlates with more aggressive breast cancer subtypes.
At the systemic level, increased levels of interleukin-6, circulating MDSCs, circulating
tumor cells (CTCs) and inflammatory markers in the bloodstream of breast cancer patients are
found to strongly correlate with poor prognosis.

Medical conditions such as major depression are associated with increased levels of systemic
pro-inflammatory cytokines, thereby creating a host environment that promotes cancer
progression. Indeed, innate immune activation and chronic inflammation have been implicated
in the pathogenesis of major depression and may account for the biological mechanism linking
depression and cancer progression. Several studies have shown antidepressant treatment
response attenuates and normalizes pro-inflammatory cytokine plasma levels in
medically-healthy patients with depression. To date, only three randomized controlled
antidepressant studies have been conducted in depressed women with breast cancer. Two
studies found mainserin to be effective and superior to placebo, whereas paroxetine and
desipramine were comparable to placebo. Notably, several randomized controlled trials in
depressed breast cancer patients found psychotherapy to be an effective depression
treatment. Moreover, these studies found psychotherapy significantly lengthened survival
time in depressed breast cancer patients with metastatic disease. Remarkably, no randomized
controlled trials have examined the impact of antidepressant medications on cancer survival.

To date, there have been no randomized, placebo-controlled antidepressant studies in
depressed women with breast cancer to investigate the impact of depression treatment on
cognition and the inflammatory mediators that promote cancer progression. This study will
explore the efficacy of vortioxetine on depression and cognition in women with breast
cancer, and determine whether successful treatment of depression alters circulating
cytokines, immune mediators, and circulating tumor cells, thus elucidating a possible
mechanism to explain improved cancer outcome with effective antidepressant treatment. Given
the disproportionately high rate of depression in women with breast cancer and its negative
impact on cancer outcome, understanding the biological mechanism that drives this
relationship is critical. This study may uncover novel immune-mediated mechanisms by which
vortioxetine treatment ameliorates depression, enhances cognition, and influences cancer
outcome.

Primary Objective - To assess antidepressant efficacy of vortioxetine (VTX) treatment in
women with major depressive disorder (MDD) who have completed curative treatment of Stage I,
II or III breast cancer.

Primary Endpoint Antidepressant efficacy will be assessed by the Hamilton Depression Rating
Scale-21 (HDRS-21) total score administered at specified time points. Antidepressant
response is defined as a 50% reduction in baseline HDRS-21 total score, and treatment
remission is defined as an HDRS-21 total score ≤7. Antidepressants will be deemed effective
if the patient's depression does not worsen. A participant's depression will be classified
as "worse" if a) the participant becomes suicidal or psychotic, b) their HAM-D score
increases > 18, or over a four-week period of time: c) the HAM-D score increases, and d) the
CGI Improvement Rating has increased by at least one point. The definitions of
antidepressant efficacy and worsening depression remain the same during Cycle 2.

- Cognitive function will be assessed by Brief Assessment of Cognition in Affective
Disorders (BAC-A) test battery with measures in: (1) list learning, (2) digit sequencing
task, (3) token motor task, (4) verbal fluency, (5) tower of London test, (6) symbol coding,
and (7) affective processing subtest. All BAC-A measures will be administered at specified
time points, and the total composite z-scores will be compared to baseline total composite
z-scores.

Inclusion Criteria:

1. Female patients 18 to 75 years of age

2. Confirmed diagnosis of Stage I, II, or III breast cancer

3. Completed curative cancer treatment (surgery, chemotherapy, and/or radiotherapy) at
least four weeks (≥ 4 weeks) prior to study entry no more than 5 years.

4. Unipolar major depression confirmed by the mood disorder module in Structured
Clinical interview for DSM-V (SCID)

5. Baseline depression severity total score ≥18 by Hamilton Depression Rating Scale-21
(HDRS-21)

6. Negative urine pregnancy test in women of child-bearing potential (WOCBP).

7. Use of medically-established contraceptive method (e.g., contraceptive hormone
therapy or intrauterine device) in women of child-bearing potential (WOCBP) or
abstinence from heterosexual intercourse from the time of signing informed consent
through 14 days after the last dose of study drug.

8. Ability to understand and the willingness to sign a written informed consent and
HIPAA document/s

Exclusion Criteria:

- 1. Other active cancers [EXCEPTION: cured skin cancer]. 2. Actively suicidal, as
determined by certified mental health provider. 3. Comorbid bipolar disorder or
psychosis, as diagnosed by psychiatric clinical interview conducted by a certified
mental health provider.

4. Mini-mental state exam (MMSE) score <24 at baseline assessment 5. Current use of
stimulant and/or amphetamine for cancer-related fatigue or cognitive impairment.

6. Use of current and effective antidepressants during study period. [NOTE: Patients
who have not responded to current antidepressant may be tapered off medication prior
to study entry.] 7. Uncontrolled hypothyroidism. Must be biochemically (TSH, T3, T4)
and clinically euthyroid at baseline assessment.

8. Use of monoamine oxidase inhibitors (MAOIs) in past 14 days. 9. Concomitant use of
mood stabilizer including lithium, lamictal and atypical antipsychotics 10. Failed
prior therapy with vortioxetine (VTX) 11. Positive urine toxicology screen for
cocaine, opiates, marijuana, amphetamines.

12. Comorbid alcohol and/or substance use disorder within the prior 12 months of
screening, as diagnosed by psychiatric clinical interview conducted by a certified
mental health provider.