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

NCT01483053 | Unknown Phase 4

• 1 other identifier: 498/11
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 3

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.

Conditions

Major Depressive Disorder (MDD)

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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.

  Baseline and following 12 weeks of antidepressant treatment.

Secondary Outcomes (4)

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

  Baseline and following 12 weeks of antidepressant treatment.

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

  Baseline

• Change from baseline in insulin resistance.

  Baseline and following 12 weeks of antidepressant treatment.

• Change from baseline on markers of cardiac risk.

  Baseline and following 12 weeks of antidepressant treatment.

Study Arms (2)

Agomelatine

ACTIVE COMPARATOR

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

Escitalopram

ACTIVE COMPARATOR

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

Interventions

Agomelatine DRUG

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.

Also known as: Valdoxan

Agomelatine

Escitalopram DRUG

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.

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

Escitalopram

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Baker Heart and Diabetes Institute: lead
• Servier Laboratories (Australia) Pty Ltd: collaborator
• The Alfred: collaborator
• Monash Medical Centre: collaborator

Study Sites (3)

Monash Medical Centre - Monash Health

Clayton, Victoria, 3168, Australia

Location

Alfred and Baker Medical Unit - Alfred Hospital

Melbourne, Victoria, 3004, Australia

Location

Baker IDI Heart & Diabetes Institute

Melbourne, Victoria, 3004, Australia

Location

MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

agomelatine; Escitalopram

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Gavin Lambert

  Baker IDI Heart & Diabetes Institute

  STUDY DIRECTOR

• David Barton

  Monash Medical Centre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sarah Tremethick

CONTACT

+61 3 8532 1145; sarah.tremethick@bakeridi.edu.au

Jennifer Grigo

CONTACT

+61 3 8531 1166; jennifer.grigo@bakeridi.edu.au

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 27, 2011
• First Posted: December 1, 2011
• Study Start: January 1, 2014
• Primary Completion: February 1, 2015
• Study Completion: February 1, 2015
• Last Updated: December 18, 2013

Record last verified: 2013-12

Locations

AU (3)