Bipolar Disorder, Coronary Artery Disease, Major Depression, Schizoaffective Disorder, Schizophrenia
Conditions
Keywords
Omega-3 fatty acids, Statins, Antipsychotic drug, Antidepressant drug, Antimanic drug, Placebos, Double-blind method, Bipolar (depressed phase)
Brief summary
The purpose of this study is to determine whether the administration of omega-3 polyunsaturated fatty acids, particularly eicosapentaenoic acid (EPA), can be useful both to reduce coronary artery disease (CAD) risk and illness severity in clinically-stable patients with schizophrenia (or schizoaffective disorder), major depression or bipolar disorder (depressed phase) being treated with lipid lowering drugs (e.g., statins).
Detailed description
We propose to study the effects of EPA (2 g of EPA in 4 x 500 mg capsules daily) compared to placebo supplementation in clinically-stable schizophrenic patients being treated with statins (n=30 each) for 4 months using a randomized, double-blind design. The National Cholesterol Education Program Adult Treatment Panel III guidelines will be used to select those patients with CAD risk to participate. Clinical assessments and comprehensive assessment of the risk for CAD, including plasma total, high-density lipoprotein (HDL)- (HDL2- and HDL3-), low-density lipoprotein (LDL)- (LDL-Real-, Lp(a)-, and IDL-), and VLDL- (VLDL1,2- and VLDL3-) cholesterol, plasma triglycerides, as well as plasma homocysteine and high sensitivity C-reactive protein, will be conducted at baseline, 1 month, 2 months and 4 months after supplementation. It is anticipated that patients who receive EPA supplementation will have significantly greater reduction in plasma triglycerides and LDL4-cholesterol, and increases in HDL2-cholesterol measures, as well as improvements in psychopathology severity than those patients receiving placebo. If indeed EPA is effective in decreasing the risk of CAD, any psychiatric benefits from EPA supplementation will be a further boon to the patients and the treatment team. A tremendous advantage to the clinical use of EPA includes low cost, no significant side effects, and ease of use.
Interventions
2 g of Eicosapentaenoic acid in 4 x 500 mg capsules daily for baseline, 1 month, 2 months and 4 months
DRUGPlacebo
2 g of Placebo (soy bean oil) in 4 x 500 mg capsules daily for baseline, 1 month, 2 months and 4 months
Sponsors
American Heart Association
VA Pittsburgh Healthcare System
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients meeting Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) criteria for schizophrenia (or schizoaffective disorder), major depression, or bipolar (depressed phase) disorder who are treated with antipsychotic, antidepressant or antimanic drugs and a lipid-lowering drug (statin) for 2 months or longer will be screened to participate in the proposed project. * Based upon the CAD risk determinants (see below) and the National Cholesterol Education Program (NCEP) recommendation of goals for LDL-lowering therapy, the investigators will only enroll schizophrenic patients with baseline (before statin treatment) LDL-cholesterol exceeding: * 70 mg/dL having CAD and CAD risk equivalents, e.g., peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease, and diabetes, as well as multiple risk factors that confer a 10-year risk for CAD \> 20% * 130 mg/dL having 2 or more risk factors; and * 160 mg/dL having less than 2 risk factors to participate in the EPA trial. In addition, these CAD-risk patients have not reached the NCEP goal level within the past year following statin treatment. * Risk factors for CAD. The NCEP Expert Panel (NIH Publication No. 01-3670, May 2001) on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III or ATPIII) recognizes the following CAD risk factors: * being male, 45 years or older, or being female 55 years or older; * family history of premature CAD; * current cigarette smoking; * hypertension with 140/90 mmHg or greater; and * low HDL-cholesterol (less than 40 mg/dL).
Exclusion criteria
* Patients with history of bleeding disorders, current drug or alcohol abuse (within one month), neurological disorders (including head injury with loss of consciousness for greater than 10 minutes), antisocial personality disorder, borderline personality disorder, or mental retardation as indicated in medical records * Patients who are pregnant (as determined by urine pregnancy test) * Patients who have already achieved their NCEP goal in terms of their lipid profile (as indicated in laboratory tests) will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Levels of Triglycerides and Lipoprotein Cholesterol | 4 months | Biochemical measures: Plasma levels of triglycerides, small dense LDL (LDL3- and LDL4-) cholesterol, large buoyant LDL (LDL1- and LDL2-) cholesterol, and HDL2-cholesterol. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Cholesterol Levels in Various Lipoprotein Fractions | 4 months | Biochemical Measures: Plasma levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, VLDL-cholesterol, Lp(a) cholesterol, IDL-cholesterol, HDL3-cholesterol, VLDL1,2-cholesterol, and VLDL3-cholesterol. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Omega-3 Fatty Acid Eicosapentaenoic acid (omega-3 fatty acid, 2 g in 4x500 mg softgels daily) + Antipsychotic drug (doctor's choice) treatment for baseline, 1 month, 2 months and 4 months duration.
Eicosapentaenoic acid (omega-3 fatty acid): 2 g of Eicosapentaenoic acid in 4 x 500 mg capsules daily for baseline, 1 month, 2 months and 4 months | 28 |
| Placebo Placebo (soy bean oil, 2 g in 4x500 mg softgels daily) + Antipsychotic drug (doctor's choice) treatment for baseline, 1 month, 2 months and 4 months duration.
Placebo: 2 g of Placebo (soy bean oil) in 4 x 500 mg capsules daily for baseline, 1 month, 2 months and 4 months | 24 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 5 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 7 |
Baseline characteristics
| Characteristic | Omega-3 Fatty Acid | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 8 | 54 years STANDARD_DEVIATION 8 | 55 years STANDARD_DEVIATION 8 |
| Body Mass Index | 31 kg/m^2 STANDARD_DEVIATION 7 | 31 kg/m^2 STANDARD_DEVIATION 6 | 31 kg/m^2 STANDARD_DEVIATION 6 |
| Region of Enrollment United States | 28 participants | 24 participants | 52 participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 26 Participants | 24 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 28 | 1 / 24 |
| serious Total, serious adverse events | 0 / 28 | 0 / 24 |
Outcome results
Primary
Plasma Levels of Triglycerides and Lipoprotein Cholesterol
Biochemical measures: Plasma levels of triglycerides, small dense LDL (LDL3- and LDL4-) cholesterol, large buoyant LDL (LDL1- and LDL2-) cholesterol, and HDL2-cholesterol.
Time frame: 4 months
Population: Plasma triglyceride levels
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Omega-3 Fatty Acid | Plasma Levels of Triglycerides and Lipoprotein Cholesterol | Plasma triglyceride | 155 mg/dL | Standard Deviation 78 |
| Omega-3 Fatty Acid | Plasma Levels of Triglycerides and Lipoprotein Cholesterol | Plasma LDL-1 cholesterol | 12.68 mg/dL | Standard Deviation 4.93 |
| Omega-3 Fatty Acid | Plasma Levels of Triglycerides and Lipoprotein Cholesterol | Plasma LDL-2 cholesterol | 14.62 mg/dL | Standard Deviation 11.36 |
| Omega-3 Fatty Acid | Plasma Levels of Triglycerides and Lipoprotein Cholesterol | Plasma LDL-3 cholesterol | 40.93 mg/dL | Standard Deviation 14.69 |
| Omega-3 Fatty Acid | Plasma Levels of Triglycerides and Lipoprotein Cholesterol | Plasma LDL-4 cholesterol | 15.61 mg/dL | Standard Deviation 10.47 |
| Omega-3 Fatty Acid | Plasma Levels of Triglycerides and Lipoprotein Cholesterol | Plasma HDL-2 cholesterol | 8.00 mg/dL | Standard Deviation 3.96 |
| Placebo | Plasma Levels of Triglycerides and Lipoprotein Cholesterol | Plasma LDL-4 cholesterol | 17.66 mg/dL | Standard Deviation 12.5 |
| Placebo | Plasma Levels of Triglycerides and Lipoprotein Cholesterol | Plasma triglyceride | 182 mg/dL | Standard Deviation 67 |
| Placebo | Plasma Levels of Triglycerides and Lipoprotein Cholesterol | Plasma LDL-3 cholesterol | 43.47 mg/dL | Standard Deviation 23.44 |
| Placebo | Plasma Levels of Triglycerides and Lipoprotein Cholesterol | Plasma LDL-1 cholesterol | 16.92 mg/dL | Standard Deviation 7.1 |
| Placebo | Plasma Levels of Triglycerides and Lipoprotein Cholesterol | Plasma HDL-2 cholesterol | 8.56 mg/dL | Standard Deviation 2.41 |
| Placebo | Plasma Levels of Triglycerides and Lipoprotein Cholesterol | Plasma LDL-2 cholesterol | 15.79 mg/dL | Standard Deviation 12.37 |
Secondary
Plasma Cholesterol Levels in Various Lipoprotein Fractions
Biochemical Measures: Plasma levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, VLDL-cholesterol, Lp(a) cholesterol, IDL-cholesterol, HDL3-cholesterol, VLDL1,2-cholesterol, and VLDL3-cholesterol.
Time frame: 4 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Omega-3 Fatty Acid | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma LDL cholesterol | 98.14 mg/dL | Standard Deviation 30.5 |
| Omega-3 Fatty Acid | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma IDL cholesterol | 8.24 mg/dL | Standard Deviation 5.7 |
| Omega-3 Fatty Acid | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma VLDL cholesterol | 21.24 mg/dL | Standard Deviation 5.27 |
| Omega-3 Fatty Acid | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma HDL3 cholesterol | 31.00 mg/dL | Standard Deviation 8.26 |
| Omega-3 Fatty Acid | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma HDL cholesterol | 38.95 mg/dL | Standard Deviation 11.79 |
| Omega-3 Fatty Acid | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma VLDL1 + VLDL2 cholesterol | 9.62 mg/dL | Standard Deviation 2.85 |
| Omega-3 Fatty Acid | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma Lp(a) cholesterol | 6.10 mg/dL | Standard Deviation 4.06 |
| Omega-3 Fatty Acid | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma VLDL3 cholesterol | 11.67 mg/dL | Standard Deviation 2.82 |
| Omega-3 Fatty Acid | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma total cholesterol | 158 mg/dL | Standard Deviation 38 |
| Placebo | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma VLDL3 cholesterol | 13.39 mg/dL | Standard Deviation 3.09 |
| Placebo | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma total cholesterol | 175 mg/dL | Standard Deviation 45 |
| Placebo | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma LDL cholesterol | 109.83 mg/dL | Standard Deviation 37.55 |
| Placebo | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma HDL cholesterol | 40.22 mg/dL | Standard Deviation 8.61 |
| Placebo | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma VLDL cholesterol | 24.67 mg/dL | Standard Deviation 6.06 |
| Placebo | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma Lp(a) cholesterol | 4.83 mg/dL | Standard Deviation 2.71 |
| Placebo | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma IDL cholesterol | 11.17 mg/dL | Standard Deviation 6.14 |
| Placebo | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma HDL3 cholesterol | 31.61 mg/dL | Standard Deviation 7.28 |
| Placebo | Plasma Cholesterol Levels in Various Lipoprotein Fractions | Plasma VLDL1 + VLDL2 cholesterol | 11.45 mg/dL | Standard Deviation 3.26 |