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Cardiovascular Effects of Agomelatine and Escitalopram in Patients With Major Depressive Disorder (MDD)

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified December 2013 by Baker IDI Heart and Diabetes Institute
Sponsor:
Collaborators:
Servier Laboratories (Australia) Pty Ltd
The Alfred
Monash Medical Centre
Information provided by (Responsible Party):
Baker IDI Heart and Diabetes Institute
ClinicalTrials.gov Identifier:
NCT01483053
First received: November 27, 2011
Last updated: December 16, 2013
Last verified: December 2013
  Purpose

There is strong evidence that patients with major depressive disorder (MDD) are at increased risk of developing coronary heart disease (CHD). This elevated risk is independent of classical risk factors such as smoking, obesity, hypercholesterolemia, diabetes and hypertension. The risk of CHD is increased 1½-2 fold in those with minor depression and 3-4½ fold in subjects with MDD. Put simply, the relative risk of developing CHD is proportional to the severity of the depression. While the mechanism of increased cardiac risk attributable to MDD is not known disturbances in autonomic function most likely do play a part.

In untreated patients with MDD (with no underlying CHD) the investigators have identified that a marked sympathetic nervous activation and diminished heart rate variability (HRV) occurs in a proportion (approximately one third) of patients. Diminished HRV has been linked to increased incidence rates of acute cardiac events in conditions such as hypertension, diabetes and myocardial infarction. Importantly, whether treating depression actually improves the risk of: (1) CHD development or (2) recurrence of cardiac events in patients with existing CHD remains unknown.

The investigators, and others, have provided a growing body of evidence linking elevated sympathetic activity and exaggerated sympathetic responses to stress to early stages of end organ dysfunction and markers of disease development. Of particular note, in addition to possible effects on HRV is the association of chronic sympathetic nervous activation to: (a) abnormal blood pressure regulation and (b) the development of insulin resistance.

The investigators therefore plan to examine the cardiovascular effects of two different antidepressant medications, agomelatine and escitalopram, in patients with MDD. In addition, the investigators plan to investigate the effects these two medications have on sympathetic nervous system activity, blood pressure, HRV, endothelial function, metabolic and psychological effects.

Findings from this study will assist us to identify of biological correlates of sympathetic nervous activation which will enable us to: (1) identify those at potentially increased cardiac risk, and (2) potentially implement additional therapeutic strategies in order to reduce cardiac risk. Indeed, it is not known whether antidepressant treatment alone would be sufficient to reverse any adverse effects of sympathetic nervous activation. This study aims to answer this important clinical question.


Condition Intervention Phase
Major Depressive Disorder (MDD)
Drug: Agomelatine
Drug: Escitalopram
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomised Trial Investigating the Cardiovascular Effects of Agomelatine and Escitalopram in Patients With Major Depressive Disorder.

Resource links provided by NLM:


Further study details as provided by Baker IDI Heart and Diabetes Institute:

Primary Outcome Measures:
  • Change from baseline in markers of sympathetic nervous system activity. [ Time Frame: Baseline and following 12 weeks of antidepressant treatment. ] [ Designated as safety issue: No ]
    The investigators will measure sympathetic nervous system activity via whole body noradrenaline spillover and microneurography. Data will be used to examine the relationship between the degree of sympathetic nervous system activity and early signs of cardiac structure and function abnormalities, insulin resistance, and morning surge in blood pressure. This may help in identifying MDD patients who are at an increased risk.


Secondary Outcome Measures:
  • Change from baseline in the magnitude of morning surge in blood pressure. [ Time Frame: Baseline and following 12 weeks of antidepressant treatment. ] [ Designated as safety issue: No ]
    The investigators will explore the association between sympathetic nervous system activity and stress reactivity to the morning surge in blood pressure in patients with MDD. Blood pressure data will be used to test the hypothesis that MDD patients with high sympathetic activity have greater morning surges in blood pressure than patients with normal sympathetic activity.

  • To determine the association between sympathetic nervous system activity and left ventricular hypertrophy. [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The investigators will measure the relationship between sympathetic nervous system activity and left ventricular mass in patients with MDD. ECG, ECHO and blood pressure data will be used to test the hypothesis that MDD patients with elevated sympathetic activity display early signs of LVH and diastolic dysfunction.

  • Change from baseline in insulin resistance. [ Time Frame: Baseline and following 12 weeks of antidepressant treatment. ] [ Designated as safety issue: No ]
    The investigators will explore the association between sympathetic nervous system activity and stress reactivity to signs of insulin resistance in patients with MDD. Oral glucose tolerance data will be used to test the hypothesis that MDD patients with elevated sympathetic activity display early signs of insulin resistance.

  • Change from baseline on markers of cardiac risk. [ Time Frame: Baseline and following 12 weeks of antidepressant treatment. ] [ Designated as safety issue: No ]
    The investigators will explore the association between agomelatine/escitalopram treatment and markers of cardiac risk. They will test the hypothesis that agomelatine/escitalopram treatment has a favourable effect on blood pressure variability and morning surge in blood pressure, sympathetic stress reactivity and markers of insulin resistance.


Estimated Enrollment: 40
Study Start Date: January 2014
Estimated Study Completion Date: February 2015
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Agomelatine
Participants who are randomly assigned to the agomelatine group will be treated with agomelatine oral tablets for twelve weeks. Participants will begin their agomelatine treatment at 25mg/day dosage, increasing to 50mg/day as clinically indicated.
Drug: Agomelatine
Participants who are randomly assigned to the agomelatine group will be treated with agomelatine oral tablets for twelve weeks. Participants will begin their agomelatine treatment at 25mg/day dosage, increasing to 50mg/day as clinically indicated.
Other Name: Valdoxan
Active Comparator: Escitalopram
Participants who are randomly assigned to the escitalopram group will be treated with escitalopram oral tablets for twelve weeks. Participants will begin their escitalopram treatment at 10mg/day dosage, increasing to 20mg/day as clinically indicated.
Drug: Escitalopram
Participants who are randomly assigned to the escitalopram group will be treated with escitalopram oral tablets for twelve weeks. Participants will begin their escitalopram treatment at 10mg/day dosage, increasing to 20mg/day as clinically indicated.
Other Names:
  • Lexapro
  • Various generics, for example:
  • Esitalo
  • Esipram
  • Escicor
  • Lexam
  • Loxalate

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Aged 18-65 years.
  • Capable of understanding and willing to provide signed and dated written, voluntary informed consent in advance of any protocol-specific procedures.
  • MDD or MDD with melancholia according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Patients with comorbid panic or anxiety disorders will be included if MDD is the primary diagnosis.
  • Hamilton Depression (HAM D) > 18.
  • Beck Depression Inventory (BDI-II) >18.

Exclusion Criteria:

  • Aged < 18 or > 65 years.
  • Current antidepressant treatment.
  • Previous failed response to SSRI treatment at the maximum tolerated dose for at least 4 weeks.
  • Known or suspected hypersensitivity to either escitalopram or agomelatine or any of their ingredients.
  • Current high suicide risk.
  • Comorbid panic or anxiety disorders as the primary diagnosis.
  • Pre-existing and/or current diagnosed heart disease.
  • Comorbid medical conditions including type 1 diabetes, hepatic impairment (cirrhosis or active liver disease), medicated hypertension, epilepsy, bleeding disorders, alcohol/drug dependence, infectious blood diseases, psychotic disorders, personality disorders, eating disorders, mental retardation, dementia (ie, Mini Mental State Examination [MMSE] < 23), or gastrointestinal illness or previous bariatric (weight loss) surgery that may impair antidepressant absorption.
  • Participants on betablockers (for example, metoprolol).
  • Participants currently taking the following contraindicated medications for agomelatine and/or escitalopram:

    • Cytochrome (CYP) P450 1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin)
    • Monoamine Oxidase Inhibitors;

      • Irreversible non-selective monoamine oxidase inhibitors (MAOIs)
      • Reversible, selective MAO-A inhibitor (e.g. moclobemide)
      • Reversible, non-selective MAOI (e.g. linezolid)
    • Pimozide

Participants who are eligible to take part in the study are prohibited to take the contraindicated medications listed above for the entire duration of the study.

  • Clinically significant abnormalities on examination or laboratory testing and clinically significant medical conditions not listed above that are serious and/or unstable.
  • Pregnant or breastfeeding women.
  • Women of childbearing potential (WOCP) who are not using medically accepted contraception (ie, intrauterine devices [IUDs], hormonal contraceptives [oral, depot, patch or injectable], and double barrier methods such as condoms or diaphragms with spermicidal gel or foam). Women who are postmenopausal (ie, amenorrhea for at least 12 consecutive months) or surgically sterile are not considered to be WOCP.
  • Sexually active men with WOCP partners who are not using medically accepted contraception.

Medically accepted contraception for women and sexually active men with WOCP partners will be continued throughout the study and for 30 days after the last antidepressant dose.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01483053

Contacts
Contact: Sarah Tremethick +61 3 8532 1145 sarah.tremethick@bakeridi.edu.au
Contact: Jennifer Grigo +61 3 8531 1166 jennifer.grigo@bakeridi.edu.au

Locations
Australia, Victoria
Monash Medical Centre - Monash Health Not yet recruiting
Clayton, Victoria, Australia, 3168
Principal Investigator: David Barton         
Sub-Investigator: Arup Dhar         
Sub-Investigator: Sarah Tremethick         
Sub-Investigator: Jennifer Grigo         
Sub-Investigator: Krishna Vaddadi         
Alfred and Baker Medical Unit - Alfred Hospital Not yet recruiting
Melbourne, Victoria, Australia, 3004
Principal Investigator: Gavin Lambert         
Sub-Investigator: Arup Dhar         
Sub-Investigator: Sarah Tremethick         
Sub-Investigator: Jennifer Grigo         
Sub-Investigator: Markus Schlaich         
Sub-Investigator: Elisabeth Lambert         
Sub-Investigator: Murray Esler         
Sub-Investigator: Geoff Head         
Sub-Investigator: Nina Eikelis         
Sub-Investigator: Carolina Ika Sari         
Sub-Investigator: Petra Marusic         
Sub-Investigator: Toni Rice         
Sub-Investigator: Mariee Grima         
Sub-Investigator: Donna Vizi         
Sub-Investigator: Louise Hammond         
Sub-Investigator: David Barton         
Sub-Investigator: Dagmara Hering         
Baker IDI Heart & Diabetes Institute Not yet recruiting
Melbourne, Victoria, Australia, 3004
Principal Investigator: Gavin Lambert         
Sub-Investigator: Arup Dhar         
Sub-Investigator: Sarah Tremethick         
Sub-Investigator: Jennifer Grigo         
Sub-Investigator: Markus Schlaich         
Sub-Investigator: Elisabeth Lambert         
Sub-Investigator: Murray Esler         
Sub-Investigator: Geoff Head         
Sub-Investigator: Nina Eikelis         
Sub-Investigator: Carolina Ika Sari         
Sub-Investigator: Petra Marusic         
Sub-Investigator: Toni Rice         
Sub-Investigator: Mariee Grima         
Sub-Investigator: Donna Vizi         
Sub-Investigator: Louise Hammond         
Sub-Investigator: David Barton         
Sub-Investigator: Dagmara Hering         
Sponsors and Collaborators
Baker IDI Heart and Diabetes Institute
Servier Laboratories (Australia) Pty Ltd
The Alfred
Monash Medical Centre
Investigators
Study Director: Gavin Lambert Baker IDI Heart & Diabetes Institute
Principal Investigator: David Barton Monash Medical Centre
  More Information

No publications provided

Responsible Party: Baker IDI Heart and Diabetes Institute
ClinicalTrials.gov Identifier: NCT01483053     History of Changes
Other Study ID Numbers: 498/11
Study First Received: November 27, 2011
Last Updated: December 16, 2013
Health Authority: Australia: Human Research Ethics Committee
Australia: Department of Health and Ageing Therapeutic Goods Administration
Australia: National Health and Medical Research Council

Keywords provided by Baker IDI Heart and Diabetes Institute:
Major depressive disorder
Sympathetic nervous system activation
Cardiovascular risk factors
Agomelatine
Escitalopram

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Major
Disease
Behavioral Symptoms
Mental Disorders
Mood Disorders
Pathologic Processes
Citalopram
Dexetimide
S 20098
Anti-Dyskinesia Agents
Antidepressive Agents
Antidepressive Agents, Second-Generation
Antiparkinson Agents
Autonomic Agents
Central Nervous System Agents
Central Nervous System Depressants
Cholinergic Agents
Cholinergic Antagonists
Hypnotics and Sedatives
Molecular Mechanisms of Pharmacological Action
Muscarinic Antagonists
Neurotransmitter Agents
Neurotransmitter Uptake Inhibitors
Parasympatholytics
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs

ClinicalTrials.gov processed this record on November 25, 2014