Treatment of Schizophrenia With an Omega-3 Fatty Acid (EPA) and Antioxidants

Study Overview
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Brief Summary
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The purpose of this trial is to study the effect of adding the omega-3 fatty acid EPA and/or Vitamins E + C to antipsychotic drugs in younger patients with schizophrenia and related psychoses.

Detailed Description
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Objective: Study the effect of adding Ethyl-EPA and/or Vitamins E + C to antipsychotic drugs in younger patients with schizophrenia and related psychoses. Methods and material: Design: Multicentre, randomized, double-blind, placebo-controlled, fixed dose, 2x2 factorial, add-on clinical trial. Sample: Patients with schizophrenia, schizoaffective disorder or schizophreniform disorder (DSM-IV); aged 18-40 years; less than 15 years since first psychotic symptoms;admitted to a psychiatric department within the previous 21 days before screening; speaks fluently a Scandinavian language;treated with antipsychotics; written informed consent;no known allergy to trial agents;no substance dependence (DSM-IV);no warfarin currently or anamnestic indicators of impaired haemostasis. Planned: 200 patients. Actually included: 99 intent-to-treat patients. Healthy controls: aged 18-40 years;no mental disorder (DSM-IV). Included: 20 persons. Clinical assessments: Positive and Negative Syndrome Scale (PANSS) (main outcome variable). Self-report questionnaire. Adverse effects (UKURS). Neurocognitive assessment battery. Niacin skin flush test. General medical assessment. Blood samples: RBC fatty acids, S-α-tocopherol, F2-isoprostane (kits), monocyte mRNA Phospholipase A22 (PLA2) Gr4a and 6a (RT-PCR method), RBC Gr4a PLA2 concentration (ELISA technique), a range of other biochemical tests. Experimental treatment over 16 weeks: Ethyl-EPA 2 g/d or Placebo EPA and Vitamin E 364 mg/d + Vitamin C 1000 mg/d or Placebo Antioxidants Statistics: Linear Mixed Model for longitudinal analyses of effects; other uni- and multivariate methods (SPSS 12.0 - PASW Statistics 18).

Official Title
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A Multicentre, Placebo-controlled Trial of Eicosapentaenoic Acid (EPA) and Antioxidant Supplementation in the Treatment of Schizophrenia and Related Disorders

Conditions
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Schizophrenia, Schizophreniform Disorders, Schizoaffective Disorder, Psychotic Disorders

Intervention / Treatment
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* Drug: Ethyl-eicosapentaenoic acid (EPA)
* Drug: Vitamins E + C
* Other: Etyl EPA (placebo)
* Other: Vitamins E+C (placebo)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with schizophrenia, schizophreniform disorder or schizoaffective disorder (DSM-IV) Admitted to a psychiatric hospital/department within the previous twenty-one days before screening Less than fifteen years, in retrospect, since first psychotic symptoms (DSM-IV 295, criteria A,1-4) Age 18-40 years Speaks fluently a Scandinavian language A written informed consent must be obtained before any trial-related activities Exclusion Criteria: A diagnosis of substance dependence (DSM-IV) Known allergy to study medication Currently taking warfarin or having anamnestic indicators of impaired haemostasis (profuse bleeding, except epistaxis)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ethyl EPA (active) and Vitamins E + C (active)<br> | Drug: Ethyl-eicosapentaenoic acid (EPA)<br>* Capsules, 2 g per day for 16 weeks<br>* Other names: Provided by Laxdale Ltd., Scotland, UK;Drug: Vitamins E + C<br>* RRR-alpha-tocopherol 392 mg + slow-release ascorbic acid 1000 mg per day, for 16 weeks<br>* Other names: CellaVie (Ferrosan AS, Denmark);|
| Experimental: Ethyl EPA (active) and Vitamins E+C (placebo)<br> | Drug: Ethyl-eicosapentaenoic acid (EPA)<br>* Capsules, 2 g per day for 16 weeks<br>* Other names: Provided by Laxdale Ltd., Scotland, UK;Other: Vitamins E+C (placebo)<br>* Tablets containing dicalciumphosphate<br>* Other names: Placebo CellaVie, provided by Ferrosan AS, Denmark;|
| Experimental: Ethyl EPA (placebo) and Vitamins E+C (active)<br> | Drug: Vitamins E + C<br>* RRR-alpha-tocopherol 392 mg + slow-release ascorbic acid 1000 mg per day, for 16 weeks<br>* Other names: CellaVie (Ferrosan AS, Denmark);Other: Etyl EPA (placebo)<br>* Paraffin oil. Capsules, each 0.5 g.<br>* Other names: Placebo EPA;|
| Placebo Comparator: Ethyl EPA (placebo) and Vitamins E+C (placebo)<br> | Other: Vitamins E+C (placebo)<br>* Tablets containing dicalciumphosphate<br>* Other names: Placebo CellaVie, provided by Ferrosan AS, Denmark;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive and Negative Syndrome Scale (PANSS)- Total |  | Baseline - 8 weeks - 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PANSS Subscales Negative, Positive, General Psychopathology |  | Weeks 0, 8, 16 | 
| GLOBAL ASSESSMENT OF FUNCTIONING- Split Version (S-GAF) | (S-GAF)Symptom Scale (S-GAF)Function Scale | Weeks 0, 8, 16 | 
| WONCA-COOP FUNCTIONAL HEALTH ASSESSMENT CHARTS | 5 scales | Weeks 0, 8, 16 | 
| NIACIN SKIN FLUSH TEST | 2 concentrations of niacin | Weeks 0, 8, 16 | 
| THE UKU SIDE EFFECT RATING SCALE (USERS) | Sum of scores Patients with side effects | Weeks 0,4,8,12,16 | 
| SERIOUS ADVERSE EVENTS |  | Weeks 0,4,8,12,16 | 
| CONCOMITANT ANTIPSYCHOTIC MEDICATION | Defined Daily Doses (ATC/WHO) | Weeks 0,4,8,12,16 | 
| Kimura Recurring Recognition Figures Test | A sub-sample of patients. For logistic reasons, only some study sites could participate. | Weeks 0, 16 | 
| Hopkins Verbal Learning Test. | A sub-sample of patients. For logistic reasons, only some study sites could participate. | Weeks 0, 16 | 
| Continuous Performance Test | A sub-sample of patients. For logistic reasons, only some study sites could participate. | Weeks 0, 16 | 
| Hopkins Verbal Learning Test | A sub-sample of patients. For logistic reasons, only some study sites could participate. | Weeks 0, 16 | 
| Paced Auditory Serial Addition Test | A sub-sample of patients. For logistic reasons, only some study sites could participate. | Weeks 0, 16 | 
| Stroop Test | A sub-sample of patients. For logistic reasons, only some study sites could participate. | Weeks 0, 16 | 
| Digit Span | A sub-sample of patients. For logistic reasons, only some study sites could participate. | Weeks 0, 16 | 
| The Letter - Number Task | A sub-sample of patients. For logistic reasons, only some study sites could participate. | Weeks 0,16 | 
| Semantic and Category Fluency | A sub-sample of patients. For logistic reasons, only some study sites could participate. | Weeks 0, 16 | 
| Body Mass Index |  | Weeks 0, 16 | 
| Blood pressure - systolic, diastolic |  | Weeks 0, 16 | 
| Heart rate |  | Weeks 0, 16 | 
| Albumin | Serum | Weeks 0, 16 | 
| Urate | Serum | Weeks 0, 16 | 
| Glucose | Serum - fasting | Weeks 0, 16 | 
| Cholesterol | Serum - fasting | Weeks 0, 16 | 
| Triglycerides | Serum - fasting | Weeks 0, 16 | 
| Fatty acids in red blood cells | The concentrations of long-chain (C14-18) and very long-chain (C20-24)fatty acids in erythrocytes were measured. Fasting condition. We selected DGLA, AA, EPA, DHA, total omega-3 Polyunsaturated Fatty Acids (PUFA), total omega-6 PUFA, PUFA and LCPUFA (long-chain PUFA) as outcome measures. | Weeks 0, 16 | 
| Alpha-tocopherol adjusted for [triglycerides]+[cholesterol]. | Serum | Weeks 0, 16 | 
| Total antioxidant status | Serum | Weeks 0, 16 | 
| Malondialdehyde | Also called TBARS. Serum | Weeks 0, 16 | 
| F2-isoprostane (8-epiPGF2-alpha) | Serum | Weeks 0, 16 | 
| Cytosolic PLA2 group IV in red blood cells(ELISA method) | Omitted from stastical analyses because of problems with the pre-analytic procedure (treatment the of blood) |  | 
| Gene expression of mRNA for Phospholipase A2 (PLA2) groups IVa and VIa in monocytes. | Whole blood | Weeks 0, 16 | 
| Mean Corpuscular Haemoglobin Concentration (MCHC) | Whole blood | Weeks 0, 16 | 
| Mean Corpuscular Volume (MCV) | Whole blood | Weeks 0, 16 | 
| C- Reactive Protein (CRP) | Plasma | Weeks 0, 16 | 
| Haemoglobin | Whole blood | Weeks 0, 16 | 
| Leukocytes | Whole blood | Weeks 0, 16 | 
| Calcium | Serum | Weeks 0, 16 | 
| Sodium | Serum | Weeks 0, 16 | 
| Potassium | Serum | Weeks 0, 16 | 
| Ferritin | Serum | Weeks 0,16 | 
| Free thyroxin (T4) | Serum | Weeks 0, 16 | 
| Thyroid Stimulating Hormone (TSH) | Serum | Weeks 0, 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Niacin, Schizophrenia, Schizophreniform disorders, Schizoaffective disorder, Psychotic disorders, Randomized Controlled Trials, Longitudinal Studies, Fatty Acids, Omega-3, Eicosapentaenoic Acid, Vitamins, Antioxidants, Ascorbic Acid, Alpha-Tocopherol, Placebos, Antipsychotic Agents, Oxidative Stress, Fatty Acids, Unsaturated, Phospholipases, Adverse effects, Delusions, Hallucinations, Neuropsychological Tests, Attention, Memory, Hypertriglyceridemia, Models, Statistical