Major Depressive Disorder - Understanding The Link Between The Brain And The Heart
Major Depressive Disorder - Understanding The Link Between The Brain And The Heart
There is strong evidence that patients with major depressive disorder (MDD) have an increased
 risk of developing coronary heart disease (CHD). This elevated risk is independent of
 standard risk factors such as smoking, obesity, high cholesterol, diabetes, and high blood
 pressure. The relative risk of developing CHD is proportional to the severity of depression
 (the more severe the depression, the more likely the development of CHD).

 The sympathetic nervous system (the part of your nervous system that makes your heart beat
 harder and faster) is responsible for our "flight and fight" response to a threatening
 situation. It has been determined that increased sympathetic nervous system activation occurs
 in approximately one in three untreated patients with MDD (with no underlying CHD). There is
 growing evidence linking elevated sympathetic activity to early stages of kidney dysfunction
 and an increased incidence of cardiovascular (heart and blood vessel) disease development
 (eg, heart attacks). Sympathetic nervous system activation over a prolonged period of time
 may also be associated with abnormal blood pressure regulation and the development of insulin
 resistance (an important feature of type 2 diabetes).

 It has been suggested that a certain gene, known as the serotonin transporter (5-HTT) gene,
 may be involved. In particular, work from our group indicates that a particular type of this
 gene, the short form (or "short" allele) may be important in linking MDD, sympathetic nervous
 activation, and increased cardiac risk.

 This study aims to examine the role of the 5-HTT gene on cardiovascular risk factors
 associated with elevated sympathetic activity in patients with MDD. Additionally, the study
 will examine the effect of serotonin re-uptake inhibitor (SSRI) therapy on these parameters.

 A clearer understanding of these systems and processes will allow for identification of
 patients with increased cardiac risk and development of risk reduction strategies. Such
 information is clinically significant given the link between cardiovascular disease and MDD.

 Hypothesis 1: That MDD patients carrying the s allele of the 5-HTT transporter have higher
 sympathetic activity than homozygous ll patients.

 Hypothesis 2: that MDD patients with elevated sympathetic activity display early signs of
 left ventricular hypertrophy (LVH) and diastolic dysfunction.

 Hypothesis 3: That MDD patients with high sympathetic activity have greater morning surges in
 blood pressure than patients with normal sympathetic activity.

 Hypothesis 4: That MDD patients with elevated sympathetic activity display early signs of
 insulin resistance.

 Hypothesis 5: That SSRI therapy, in particular in those who carry the s allele of the 5-HTT,
 has a favourable effect on blood pressure variability and morning surge in blood pressure,
 sympathetic stress reactivity, and markers of insulin resistance.
Inclusion Criteria:

 -  Aged 18-70 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 > 70 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 the prescribed antidepressant or any of its
 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, 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.

 -  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 (amenorrhea for at least 12
 consecutive months) or surgically sterile are not considered to be WOCP.