Omega-3 Supplementation and Depression Clinical Trial

Study Overview
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Brief Summary
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Fish oil omega-3 supplements provide essential nutrients for brain health and functioning. These nutrients have been proven to be effective in reducing depressive symptoms. They have also been found to be effective and well tolerated in reducing the bad fat accumulation among patients infected with human immunodeficiency virus (HIV)and are using highly active antiretroviral treatment. The role of this nutritional supplement in combating depression among pregnant women who are living with HIV infection has however not been established. Yet, currently, more than 2 million pregnant women are estimated to be living with HIV infection globally. In Kenya, about 9.0% of pregnant women are HIV-seropositive. In this study, it is hypothesized that there is no difference in the levels of depressive symptoms among HIV infected pregnant women who are taking omega-3 fish oil supplements and those taking a placebo. The study will therefore seek to ascertain that taking omega-3 fish oil nutritional supplement has a significant positive effect on depressive symptoms among HIV infected pregnant women, compared to a placebo.

Detailed Description
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Background to the study: Fatty acids are the key building blocks of most fats and oils, both those in the body and in foods. Among the essential fatty acids that are required to maintain health, but must come from the diet, is omega-3. These omega-3 fatty acids are important constituents of all cell membranes and are involved in the movement of substances in and out of the cells. They also produce hormone-like substances which regulate many functions of the body. The omega-3 fatty acids occur naturally, and consist of shorter long-chain alphalinolenic acid (ALA) and the longer chain, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The ALA is naturally found in green leafy vegetables, flax seed, soybean oil and walnuts. The long chain EPA and DHA are naturally found in dark muscles of sea fish such as salmon, mackerel and tuna. These nutrients must be consumed in the diet because they cannot be synthesized by humans[1]. Research on the health benefits of omega-3 fatty acids dates back to 1929 when it was found to promote growth and prevent inflammation of the skin in rats [2, 3]. The essentiality of long-chain fatty acids for human health however emerged in 1970's when the first total parenteral nutrition which was fat-free was found to induce the essential fatty acid deficiencies among infants with volvulus, a bowel obstruction, at birth[4]. Further research in the 1970s on the health status of modern-hunter-gatherer Inuit Eskimos was also found to be related to their staple diet of fatty sea fish and fish eating marine mammals rich in long chain omega-3 fatty acids, EPA and DHA [5]. It has been proven that omega-3 long chain fatty acids, EPA and DHA improve depressive symptoms [6, 7]. As a mood disorder, depression is characterized by feelings of unhappiness and hopelessness, and generally marked by altered mood. It is not a single disease, but a syndrome encompassing a spectrum of symptoms with multiple causes [8, 9]. Women experience at least one episode of minor or major depression during pregnancy and after childbirth. This is however often under-diagnosed, undetected and missed out due to lack of screening. Although screening for depression may not be a routine activity in antenatal care, studies that have screened for depression in pregnancy indicate that 20-30% of pregnant women are depressed [10, 11]. The prevalence of depression is high during the second and third trimesters of pregnancy [12] when maternal level of omega-3 fatty acids is depleted. Adequate intake of long chain omega-3 fatty acids is also essential, during pregnancy to support normal growth and maturation of many fetal organ systems, particularly the brain and eyes [13, 14]. Moreover, long chain omega-3 fatty acids are critical for the development and function of many different organ systems of the fetus, including the structure of the brain and retina of the eye [15]. Premature birth and its potential neurological complications may result from omega-3 deficiency [16]. Documented research findings on omega-3 fatty acids and human immune-deficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS) are mainly two-fold: one, on plasma triglycerides levels, and two, on the immune response parameters. Studies have shown that use of omega-3 fatty acids among HIV infected patients receiving highly active antiretroviral therapy is well tolerated and effective in reducing the plasma triglyceride levels [17-19]. The fish oil has therefore been recommended as second-line therapy for HIV patients with hypertriglyceridemia [12]. One of the metabolic end products of long chain fatty acids of omega-3 and omega-6, once eaten and absorbed by the body, are prostaglandin hormones which are responsible for the inflammation response. Research shows that omega-3 fatty acids produce less prostaglandin than omega-6 fatty acids, decreasing the inflammatory process [5]. Earlier research reported that omega-3 fish oil is immuno-suppressive as it significantly decreased various parameters of the immune response [20]. However, more recent studies have shown that dietary intake of omega-3 fatty acids increased the cluster of differentiation 4 (CD4) cell count [21] The role of long chain omega-3 fatty acids in combating depression among HIV-seropositive pregnant women has however not been established. The specific symptoms which may be more responsive to omega-3 supplementation have also not been established. Currently, more than 2 million pregnant women are estimated to be living with HIV infection globally. In Kenya, about 9.0% of pregnant women are HIV-seropositive [22] and their health conditions as well as that of their unborn babies silently continue to deteriorate partly due to depression related comorbidities. This research will seek to ascertain that taking omega-3 fish oil supplement with higher EPA in relation to DHA can have a significant positive effect on depressive symptoms among HIV-seropositive pregnant women compared to a placebo. It will also monitor and identify those depressive symptoms that are more responsive to this nutrient among the HIV-seropositive pregnant women, and can be managed through nutrition supplementation. Conceptual Framework: The major risk factors for depression are genetic predisposition, hormonal imbalance and stressful events which could be of environmental, social or psychological origin as well as nutrition-related factors [11, 23-25]. Stressful events could however also cause hormonal imbalance, which, in the process can increase the stress hormone, cortisol, causing depression [23]. Both pregnancy and HIV infection status are also accompanied by high nutrient demand, in the presence of inadequate and inappropriate dietary intake as well as a high intake of saturated fats in fried food. This is likely to contribute to nutrient deficiencies, which also determines the neurotransmitter function and hormonal balance in mental health. Problem statement: This study seeks to ascertain that taking omega-3 fish oil supplement with higher EPA in relation to DHA have a significant positive effect on depressive symptoms among HIV-seropositive pregnant women. The level of omega-3 fatty acids rapidly declines during pregnancy as some of it is transferred to the fetus for the rapid formation of the fetal brain cells [13]. The resultant depletion in omega-3 might precipitate the occurrence of depression in pregnant women unless the nutrient deficit is met through dietary intake of omega-3 rich foods or supplementation. The modern diet is however inadequate in long chain omega-3 fatty acids [5]. About 40% of HIV-seropositive pregnant women are reportedly depressed [26, 27]. The depression in HIV-seropositive pregnant women is a significant public health problem due to its negative effects on both maternal and child health. It may adversely affect the quality of life and adherence to HIV/AIDS medication regimens [27, 28] which may subsequently affect disease progression and health outcome [29] of the women. Currently, more than 2 million pregnant women are estimated to be living with HIV infection globally [9]. In Kenya, about 9.0% of pregnant women are HIV-seropositive [22]. Justification of the study: This study will contribute to the debate on nutritional support and management of depressive symptoms and related health complications in HIV infected pregnant women and other vulnerable populations, to improve their mental health, hence improve the quality of life. A reduction in the prevalence of depression could therefore influence nutrition and health agencies as well as policy makers to make omega-3 fatty acid nutritional supplement accessible to HIV positive pregnant women and other vulnerable populations. Overall aim: To ascertain that taking omega-3 fish oil supplement with higher EPA in relation to DHA have a significant positive effect on depressive symptoms compared to a placebo among HIV-seropositive pregnant women. Research questions: 1.Does taking omega-3 fish oil supplement with higher EPA in relation to DHA have a significant positive effect on depressive symptoms among HIV-seropositive pregnant women, compared to a placebo? 2. Is the change in depressive symptom levels among study participants related to the change in their omega-3 fatty acid status after intervention with omega-3 fish oil supplement and placebo? 3. Which depressive symptoms are more responsive to omega-3 fish oil supplement intervention? Study setting: The study will be conducted at health facilities in Nairobi, Kenya. According to the latest Kenya national population and housing census results of 2009, [30], Nairobi, which is the capital city of Kenya, is the most populated city in the country with about 3.1 million people (about 1.6 million males and 1.5 million females) and an annual growth rate of about 4.1%[16]. The available sentinel survey data indicate that the prevalence of HIV/AIDS among pregnant women in Nairobi was 10.1% [31] in 2006. Methodology: This will be a double-blind, parallel randomized control trial (RCT) using omega-3 fish oil supplements and placebo. Both the study participants and the research administrators, including the principle investigator, will not know the difference between omega-3 supplement and placebo which will be of similar physical characteristics. Participants will be recruited from purposely sampled health facilities with highest attendance at the Prevention-of Mother-to-Child-Transmission (PMTCT) of HIV AIDS programs. The sampling frame will consist of pregnant women with known HIV-seropositive status and enrolled in PMTCT program at these health facilities. A total of 200 women who meet the study inclusion and exclusion criteria will be enrolled to participate in the study. Data Collection: Quantitative methods will be used to collect socio-demographic information, dietary intake data, and depressive symptoms, biological specimens of cheek cells, maternal weight, CD4 count, blood pressure and compliance with routine medication and study intervention. The primary measurement tool for efficacy of omega-3 fish oil will be the Beck Depression Inventory, Second Edition (BDI-II) scoring scale with a cut-off score for depression of 14 or more. Further understanding of depression in pregnancy and HIV/AIDS condition will be gained through qualitative methods. Cheek cell samples will be collected through mouth wash method for laboratory extraction of lipids for omega-3 analysis. The lipids will be extracted from the cheek cells using Bligh and Dyer methodology [32]. Gas-liquid chromatography by the method of Gibson and Kneebone [33] will be used to determine per cent (%) levels of omega-3 fatty acids in the lipids before, during and after the intervention.

Official Title
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Role of Omega-3 Fish Oil Fatty Acids on Depression Among HIV-seropositive Pregnant Pregnant Women in Nairobi: A Randomized Double-blind Controlled Trial

Conditions
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Depressive Symptoms

Intervention / Treatment
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* Dietary Supplement: Soybean oil soft gels
* Dietary Supplement: Fish oil omega-3 EPA-rich soft gels


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All pregnant HIV seropositive women with known CD4 cell count less than 500 Pregnant women who are in their 2nd trimester of pregnancy (Week 13-27). Normal nutritional status pregnancy with mid-upper arm circumference (MUAC of 22 cm - 33 cm)at entry into the study; Beck Depression Inventory Second Edition (BDI-II) Scale scores at entry into the study of 14 or more; Pregnant HIV positive women who will give consent to participate in the study Exclusion Criteria: Underweight with MUAC less than 22 cm and overweight with MUAC more than 33 cm at entry into the study; Pregnant women taking antidepressant medications; Those on anti-clotting medication (those with liver disease, varicose veins, peptic ulcers); or Vitamin K supplement. Omega-3 supplements may increase their effects; Those on diabetic medication since Omega-3 may increase their blood sugar. Incomplete depression screening form (more than 5 items unanswered) Those whose BDI-II screening scores are less than 14; Those women currently taking omega-3 nutritional supplement Pregnant HIV-seropositive women without consent to participate in the study.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Soybean oil soft gels<br>Participants on this arm will receive a dietary supplement of OmegaVia soybean oil soft gels as a placebo for 8 weeks with bi-weekly follow-up visits to monitor side effects and compliance. | Dietary Supplement: Soybean oil soft gels<br>* Each participant will receive OmegaVia soybean oil soft gels to take orally, one soft gel taken three times per day in the morning, mid-day and in the evening after meals for a period of 8 weeks<br>* Other names: OmegaVia Soybean oil soft gels;|
| Experimental: Fish oil omega-3 EPA-rich soft gels<br>Participants will receive OmegaVia fish oil omega-3 EPA-rich soft gels to take orally for eight (8) weeks with bi-weekly follow-up visits for monitoring of side effects and compliance and data collection. | Dietary Supplement: Fish oil omega-3 EPA-rich soft gels<br>* A total of 3.0g of OmegaVia fish oil omega-3 EPA-rich soft gels will be taken orally per day as one soft gel in the morning, mid-day and evening after meals for 8 weeks with bi-weekly follow-up visits.<br>* Other names: OmegaVia fish oil omega-3 EPA-rich soft gels;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in BDI-II Depressive Symptom Scores | Depressive symptoms were assessed by Beck Depression Inventory Second Edition (BDI-II) Scoring scale at Baseline and end of study during the 8- week study period. The BDI-II Scale is a 21-item scoring tool which measures the existence and severity of symptoms of depression. Each of the 21 items on BDI-II tool represent a depressive symptom. The symptoms are each scored on a 4-point Likert scale of 0 to 3 (0=symptom is absent; 3=symptom is severe).Scores for each symptom are added up to obtain the total scores for all 21 items, which are interpreted as follows: Scores of 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression and 29-63: severe depression. The change in BDI-II scores were computed from post-intervention scores at week 8 and baseline BDI-II scores at week 0. | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EPA, Omega-3, Depression, HIV infected, Pregnant women