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

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

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.

Study Overview

• Status: Completed
• Conditions: Psychotic Disorders; Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorders
• Intervention / Treatment: Drug: Ethyl-eicosapentaenoic acid (EPA); Drug: Vitamins E + C; Other: Vitamins E+C (placebo); Other: Etyl EPA (placebo)

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0320
    • Aker University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 36 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University Hospital, Aker
• Collaborators: University of Oslo; AstraZeneca; Norwegian University of Science and Technology; Diakonhjemmet Hospital; Stanley Medical Research Institute; Laxdale Ltd; Scandinavian Society for Psychopharmacology; Shipowner Emil Stray's legacy; Johanne and Einar Eilertsen's research fund; Solveig and Johan P. Sommer's foundation; Josef and Haldis Andresen's legacy
• Investigators: Study Director: Håvard Bentsen, MD PhD, Aker University Hospital (-2004), Diakonhjemmet Hospital (2004-); Study Chair: Odd Lingjærde, MD PhD, University Hospital, Aker

Study record dates

Study Major Dates

• Study Start: September 1, 2001
• Primary Completion (Actual): April 1, 2004
• Study Completion (Actual): April 1, 2004

Study Registration Dates

• First Submitted: January 5, 2007
• First Submitted That Met QC Criteria: January 5, 2007
• First Posted (Estimate): January 8, 2007

Study Record Updates

• Last Update Posted (Estimate): January 4, 2011
• Last Update Submitted That Met QC Criteria: January 3, 2011
• Last Verified: August 1, 2010

More Information

Terms related to this study

• Keywords: Antioxidants; Schizophrenia; Longitudinal Studies; Randomized Controlled Trials; Attention; Alpha-Tocopherol; Oxidative Stress; Ascorbic Acid; Memory; Placebos; Neuropsychological Tests; Antipsychotic Agents; Niacin; Psychotic disorders; Delusions; Schizoaffective disorder; Hallucinations; Adverse effects; Eicosapentaenoic Acid; Hypertriglyceridemia; Vitamins; Fatty Acids, Omega-3; Schizophreniform disorders; Fatty Acids, Unsaturated; Phospholipases; Models, Statistical
• Additional Relevant MeSH Terms: Pathologic Processes; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Disease; Psychotic Disorders; Mental Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Protective Agents; Micronutrients; Lipid Regulating Agents; Antioxidants; Vitamin E; Tocopherols; alpha-Tocopherol; Vitamins; Tocotrienols; Eicosapentaenoic acid ethyl ester
• Other Study ID Numbers: LA.01.07.0001; 01T-106 (Stanley M.R.I.,USA)