Phospholipid Hypothesis of Depression: From Molecular Biology, Neuroimaging to Behaviour

Study Overview
=================
Brief Summary
-----------------
With the dissatisfaction of monoamine-based pharmacotherapy and the high comorbidity of physical illness in depression, the serotonin hypothesis seems to fail in approaching the etiology of depression. Based upon the evidence from epidemiological data, case-control studies of PUFAs compositions, and antidepressant effects in clinical trials, phospholipid polyunsaturated fatty acids (PUFAs) is enlightening a promising path to discover the unsolved of depression.

Detailed Description
-----------------
There are several important questions to answer regarding phospholipid polyunsaturated fatty acids (PUFAs) hypothesis of depression. Firstly, although case-control studies revealed that depressive patients had lower levels of omega-3 PUFAs, the abnormal findings in individual PUFA of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) or arachidonic acid (AA) are not consistent. Secondly, the deficits in n-3 PUFAs are related to their metabolic enzymes. However, the association study of polymorphisms of PUFA-metabolism related genes in depression is limited. Thirdly, the active component of antidepressant effect in n-3 PUFAs is still in debate. Fourthly, the molecular mechanisms of n-3 PUFAs' antidepressant effects have yet to be elucidated in human brain functional neuroimaging or in cellular models. This 3-year proposal is divided into 2 clinical studies. In study 1, the investigators aim to test the clinical and biological effects of n-3 PUFAs (EPA: 3.5 g/d and DHA: 1.75 g/d versus placebo: high oleic oil) for depressive symptoms in a 12-week, double-blind, placebo-controlled trial of patients with drug-free MDD. In study 2, the investigators will measure the biological and neuroimaging markers to investigate the biological mechanisms of EPA (3.5 g/d) versus DHA (1.75 g/d) in 12-week, double-blind, randomized-controlled trial with patients with drug-free major depression disorder (MDD).

Conditions
-----------------
Major Depressive Disorder

Intervention / Treatment
-----------------
* Dietary Supplement: EPA
* Dietary Supplement: DHA
* Dietary Supplement: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnostic and Statistical Manual (DSM)-IV criteria for major depressive disorder Age being age 18-65. Capacity and willingness to give written informed consent. Free from antidepressants, mood stabilizers, and antipsychotics for more than 4 weeks. Exclusion Criteria: Any major medical illnesses. A recent or past history of any Axis-I diagnoses besides major depressive disorder, including psychotic disorders; cognitively impaired mental disorders; impulse control disorders; substance use disorder or substance abuse (last 6 months prior to the studies); primary anxiety disorders, including post-traumatic stress disorder and panic disorder; and bipolar disorders; or Axis-II diagnoses, i.e. borderline and antisocial personality disorder.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EPA<br>3.5 g/day in Studies 1 & 2 | Dietary Supplement: EPA<br>* A daily treatment of 5 identical capsules of EPA (3.5 g/d) for Studies 1 & 2.<br>* Other names: Fish oil EPA;|
| Active Comparator: DHA<br>1.75 g/day in Studies 1 & 2 | Dietary Supplement: DHA<br>* A daily treatment of 5 identical capsules of DHA (1.75 g/d) for Studies 1 & 2.<br>* Other names: Fish oil DHA;|
| Placebo Comparator: Placebo capsules<br>oleic oil in Study 1 | Dietary Supplement: Placebo<br>* A daily treatment of 5 identical capsules of placebo (high oleic oil) in single or divided administration for Study 1.<br>* Other names: oleic oil;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from Baseline Hamilton Depression Rating Scale (HDRS) at 12 weeks |  | Week 12 | 
| Remission rate |  | Week 12 | 
| Response rate |  | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Beck Depression Inventory (BDI) |  | Week 12 | 
| Changes in Neurotoxicity Rating Scale (NRS) |  | Week 12 |