Vortioxetine in Patients With Major Depressive Disorder and Coronary Artery Disease
Vortioxetine in Patients With Major Depressive Disorder and Coronary Artery Disease
This is a preliminary, open-label, clinical trial designed to assess the efficacy, safety,
 and tolerability of vortioxetine for the treatment of major depressive disorder in patients
 with coronary artery disease. In addition, the study will assess the effects of vortioxetine
 on heart rate variability in these patients.
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