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

Primary Purpose

Major Depressive Disorder (MDD)

Status

Unknown status

Phase

Phase 4

Locations

Australia

Study Type

Interventional

Intervention

Agomelatine

Escitalopram

About this trial

This is an interventional treatment trial for Major Depressive Disorder (MDD) focused on measuring Major depressive disorder, Sympathetic nervous system activation, Cardiovascular risk factors, Agomelatine, Escitalopram

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Monash Medical Centre - Monash Health
Alfred and Baker Medical Unit - Alfred Hospital
Baker IDI Heart & Diabetes Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Agomelatine

Escitalopram

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Change from baseline in markers of sympathetic nervous system activity.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT01483053

First Posted

November 27, 2011

Last Updated

December 16, 2013

Sponsor

Baker Heart and Diabetes Institute

Collaborators

Servier Laboratories (Australia) Pty Ltd, The Alfred, Monash Medical Centre

1. Study Identification

Unique Protocol Identification Number

NCT01483053

Brief Title

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

Official Title

A Randomised Trial Investigating the Cardiovascular Effects of Agomelatine and Escitalopram in Patients With Major Depressive Disorder.

Study Type

Interventional

2. Study Status

Record Verification Date

December 2013

Overall Recruitment Status

Unknown status

Study Start Date

January 2014 (undefined)

Primary Completion Date

February 2015 (Anticipated)

Study Completion Date

February 2015 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Baker Heart and Diabetes Institute

Collaborators

Servier Laboratories (Australia) Pty Ltd, The Alfred, Monash Medical Centre

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Major Depressive Disorder (MDD)

Keywords

Major depressive disorder, Sympathetic nervous system activation, Cardiovascular risk factors, Agomelatine, Escitalopram

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Agomelatine

Arm Type

Active Comparator

Arm Description

Arm Title

Escitalopram

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Agomelatine

Other Intervention Name(s)

Valdoxan

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Escitalopram

Other Intervention Name(s)

Lexapro, Various generics, for example:, Esitalo, Esipram, Escicor, Lexam, Loxalate

Intervention Description

Primary Outcome Measure Information:

Title

Change from baseline in markers of sympathetic nervous system activity.

Description

Time Frame

Baseline and following 12 weeks of antidepressant treatment.

Secondary Outcome Measure Information:

Title

Change from baseline in the magnitude of morning surge in blood pressure.

Description

Time Frame

Baseline and following 12 weeks of antidepressant treatment.

Title

To determine the association between sympathetic nervous system activity and left ventricular hypertrophy.

Description

Time Frame

Baseline

Title

Change from baseline in insulin resistance.

Description

Time Frame

Baseline and following 12 weeks of antidepressant treatment.

Title

Change from baseline on markers of cardiac risk.

Description

Time Frame

Baseline and following 12 weeks of antidepressant treatment.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Sarah Tremethick

Phone

+61 3 8532 1145

sarah.tremethick@bakeridi.edu.au

First Name & Middle Initial & Last Name or Official Title & Degree

Jennifer Grigo

Phone

+61 3 8531 1166

jennifer.grigo@bakeridi.edu.au

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Gavin Lambert

Organizational Affiliation

Baker IDI Heart & Diabetes Institute

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

David Barton

Organizational Affiliation

Monash Medical Centre

Official's Role

Principal Investigator

Facility Information:

Facility Name

Monash Medical Centre - Monash Health

City

Clayton

State/Province

Victoria

ZIP/Postal Code

3168

Country

Australia

Facility Contact:

First Name & Middle Initial & Last Name & Degree

David Barton

First Name & Middle Initial & Last Name & Degree

Arup Dhar

First Name & Middle Initial & Last Name & Degree

Sarah Tremethick

First Name & Middle Initial & Last Name & Degree

Jennifer Grigo

First Name & Middle Initial & Last Name & Degree

Krishna Vaddadi

Facility Name

Alfred and Baker Medical Unit - Alfred Hospital

City

Melbourne

State/Province

Victoria

ZIP/Postal Code

3004

Country

Australia

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Gavin Lambert

First Name & Middle Initial & Last Name & Degree

Arup Dhar

First Name & Middle Initial & Last Name & Degree

Sarah Tremethick

First Name & Middle Initial & Last Name & Degree

Jennifer Grigo

First Name & Middle Initial & Last Name & Degree

Markus Schlaich

First Name & Middle Initial & Last Name & Degree

Elisabeth Lambert

First Name & Middle Initial & Last Name & Degree

Murray Esler

First Name & Middle Initial & Last Name & Degree

Geoff Head

First Name & Middle Initial & Last Name & Degree

Nina Eikelis

First Name & Middle Initial & Last Name & Degree

Carolina Ika Sari

First Name & Middle Initial & Last Name & Degree

Petra Marusic

First Name & Middle Initial & Last Name & Degree

Toni Rice

First Name & Middle Initial & Last Name & Degree

Mariee Grima

First Name & Middle Initial & Last Name & Degree

Donna Vizi

First Name & Middle Initial & Last Name & Degree

Louise Hammond

First Name & Middle Initial & Last Name & Degree

David Barton

First Name & Middle Initial & Last Name & Degree

Dagmara Hering

Facility Name

Baker IDI Heart & Diabetes Institute

City

Melbourne

State/Province

Victoria

ZIP/Postal Code

3004

Country

Australia

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Gavin Lambert

First Name & Middle Initial & Last Name & Degree

Arup Dhar

First Name & Middle Initial & Last Name & Degree

Sarah Tremethick

First Name & Middle Initial & Last Name & Degree

Jennifer Grigo

First Name & Middle Initial & Last Name & Degree

Markus Schlaich

First Name & Middle Initial & Last Name & Degree

Elisabeth Lambert

First Name & Middle Initial & Last Name & Degree

Murray Esler

First Name & Middle Initial & Last Name & Degree

Geoff Head

First Name & Middle Initial & Last Name & Degree

Nina Eikelis

First Name & Middle Initial & Last Name & Degree

Carolina Ika Sari

First Name & Middle Initial & Last Name & Degree

Petra Marusic

First Name & Middle Initial & Last Name & Degree

Toni Rice

First Name & Middle Initial & Last Name & Degree

Mariee Grima

First Name & Middle Initial & Last Name & Degree

Donna Vizi

First Name & Middle Initial & Last Name & Degree

Louise Hammond

First Name & Middle Initial & Last Name & Degree

David Barton

First Name & Middle Initial & Last Name & Degree

Dagmara Hering

12. IPD Sharing Statement

Learn more about this trial

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

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