Vortioxetine in Patients With Major Depressive Disorder and Coronary Artery Disease

Comorbid Major Depressive Disorder (MDD) and Coronary Artery Disease (CAD) are common:

Major depressive disorder is a highly prevalent disorder that is serious, and in some cases
life-threatening, condition. The 12-month prevalence of major depressive disorder in the
United States is 6.6% (Kessler et al., 2003). Coronary artery disease (CAD) is also a large
and growing problem in the United States. According to the 2014 American Heart Association
(AHA) report on heart disease and stroke statistics, an estimated 15.4 million Americans ≥20
years of age have coronary artery disease. The total prevalence of coronary artery disease
in this population is estimated to be 6.4%, with a prevalence of 7.9% in men and 5.1% in
women. By the year 2030, the prevalence of coronary artery disease is projected to increase
approximately 18% from 2013 estimates (Go et al., 2014). Thus, patients with major
depressive disorder and comorbid CAD represent a large population of patients.

Depression in patients with CAD is clinically important:

Depression frequently accompanies coronary artery disease and has been linked more somatic
symptoms, hospitalizations, increased financial burden, and poorer quality of life, as well
as being a predictor of worse outcomes of cardiac disease. Reduction of cardiac risk factors
is less likely to be successful in depressed patients. Depression may also interfere with
medication adherence, as depressed patients are three times as likely to be noncompliant
with their medication regimens. In addition, depression is associated with decreased rates
of participation in cardiac rehabilitation, higher healthcare utilization and costs, and
greatly reduced quality of life (Lichtman et al., 2009). Due to these effects of depression
on coronary artery disease, there is increasing recognition that depression should be
formally considered a risk factor for adverse medical outcomes in patients with acute
coronary syndrome (Lichtman et al., 2014).

Thus, there is a great, unmet clinical need to treat patients with major depressive disorder
and coronary artery disease.

In addition to the older tricyclic antidepressants, the newer serotonin-norepinephrine
reuptake inhibitors are also associated with cardiovascular risks like hypertension,
orthostatic hypotension, and perhaps QTc prolongation (Mago et al., 2014). Vortioxetine is a
newly approved antidepressant thought to work by combining modulation of 5-HT receptor
subtypes and inhibition of the serotonin transporter (Citrome, 2014). Early data suggests
that this multimodal mechanism of action results in increased brain levels of serotonin,
dopamine, and noradrenaline in the prefrontal cortex (Pehrson et al., 2013). Clinical trials
of vortioxetine for major depressive disorder have not shown any cardiovascular adverse
effects (Mago et al., 2014).

Heart Rate Variability (HRV) Heart Rate Variability is a measure is based on the changes in
the interval between consecutive heart beats and between consecutive instantaneous heart
rates. It has become the conventionally accepted term to describe variations of both
instantaneous heart rate and RR intervals. Long term reduced heart rate variability can lead
to immune dysfunction and inflammation, cardiovascular disease and mortality (Newhouse,
2014). Several studies in depressive patients have shown reduced heart rate variability that
suggests an increased sympathetic activity and/or reduced vagal activity (Carney et al.,
2009). Thus, treating depression effectively may reduce heart rate variability, which is a
surrogate marker for better cardiovascular outcomes.

The proposed study has been planned as a pilot, open-label study of the use, for the first
time, of vortioxetine in patients with documented coronary disease. Therefore, the sample
size is not based on a formal sample size calculation but on feasibility of a small study
that, if positive, can lead to a future larger, adequately powered study. A sample size of
25 patients is appropriate for the present purpose. The results of this proposed study would
inform sample size calculation for a future, larger study.

Inclusion Criteria:

1. DSM-5 diagnosis of a major depressive disorder based on clinical evaluation by the
study psychiatrist

2. At least moderate severity of depression as indicated by a Montgomery-Asberg
Depression Rating Scale (MADRS) score of 22 or greater

3. History of coronary artery disease as defined by:

- History of coronary stenosis in one or more vessels that is greater ≥ 70% by
coronary angiography or CT angiogram, OR

- History of abnormal stress test (at least medium-sized, moderate, reversible
defect), OR

- History of documented myocardial infarction including ST elevation myocardial
infarction or non-ST elevation myocardial infarction (with elevated troponins),
OR

4. Evidence of adequate treatment of the coronary artery disease as defined by at least
one of the following that was done at least six months prior to the Screening visit,
AND was followed by the patient being clinically stable in the opinion of a
cardiologist who has evaluated the case:

- Coronary artery bypass grafting (CABG)

- Percutaneous coronary intervention (PCI)/ stenting

- Adequate management with optimal medical treatment (such as one or more of the
following medications: aspirin, beta blockers, a statin (e.g., atorvastatin),
and either an ACE inhibitor or an angiotensin-receptor blocker.)

Key Exclusion Criteria:

Psychiatric Exclusion Criteria:

1. Patients who in the past have failed to respond to a trial of vortioxetine at the
minimum recommended dose (10 mg/day) or greater taken for at least six weeks, or had
unacceptable adverse effects while taking vortioxetine.

2. Patients must not have failed treatment with more than one antidepressant (taken at
an adequate dose and for at least six weeks) in the current episode of major
depressive disorder (i.e., did not have > 50% reduction in severity of depression
based on patient history)

3. Patients with a current primary DSM-5 diagnosis of:

i) Delirium, dementia, amnestic, or other cognitive disorder; ii) Eating Disorder
(including Anorexia Nervosa or Bulimia); iii) Obsessive Compulsive Disorder; iv)
Panic Disorder; v) Post-Traumatic Stress Disorder (PTSD);

4. Current or past (lifetime) DSM-5 diagnosis of:

i) Bipolar I or II disorder; ii) Hypomanic episode iii) Substance-induced manic or
hypomanic episode iii) Schizophrenia or other psychotic disorder

Cardiovascular Exclusion Criteria:

1. Patients who have had a myocardial infarction within 30 days of the screening visit

2. Any cardiovascular condition that is unstable or decompensated

3. In the opinion of the Investigators, the patient is at significant risk of
cardiovascular adverse events

4. Coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI)/
stenting within three months of the screening visit

5. Admission to a hospital for any cardiac condition within three months of the
screening visit

6. Decompensated heart failure within 6 months of the screening visit

7. QTc prolongation (screening ECG with QTc ≥ 450 msec for men or QTc ≥ 470 msec for
women) using QTc Fridericia correction

8. Second-degree (if Mobitz II) or third-degree atrioventricular block

9. Heart rate on ECG of ≤ 50 bpm or ≥ 120 bpm or any heart rate that is clinically
symptomatic

10. Premature Ventricular Contractions (PVCs) associated with clinical symptoms and/or
any complex premature ventricular contractions (ie, PVCs that are frequent [> 30/hr]
or ≥ 2 beats if multifocal, or show bigeminy, trigeminy, quadrigeminy, couplets,
triplets [salvos], or the R on T phenomenon)

11. Atrial fibrillation or flutter

12. Supine (after patient has been supine for 5 minutes) systolic BP > 160 mm Hg or < 90
mm Hg or diastolic BP > 100 mm Hg or any systolic or diastolic BP that is symptomatic
or clinically significant based on the opinion of the Principal Investigator

13. Patients who are receiving warfarin