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

• PANSS Subscales Negative, Positive, General Psychopathology [ Time Frame: Weeks 0, 8, 16 ] [ Designated as safety issue: No ]
• GLOBAL ASSESSMENT OF FUNCTIONING- Split Version (S-GAF) [ Time Frame: Weeks 0, 8, 16 ] [ Designated as safety issue: No ]
  (S-GAF)Symptom Scale (S-GAF)Function Scale
• WONCA-COOP FUNCTIONAL HEALTH ASSESSMENT CHARTS [ Time Frame: Weeks 0, 8, 16 ] [ Designated as safety issue: No ]
  5 scales
• NIACIN SKIN FLUSH TEST [ Time Frame: Weeks 0, 8, 16 ] [ Designated as safety issue: No ]
  2 concentrations of niacin
• THE UKU SIDE EFFECT RATING SCALE (USERS) [ Time Frame: Weeks 0,4,8,12,16 ] [ Designated as safety issue: Yes ]
  1. Sum of scores
  2. Patients with side effects
• SERIOUS ADVERSE EVENTS [ Time Frame: Weeks 0,4,8,12,16 ] [ Designated as safety issue: Yes ]
• CONCOMITANT ANTIPSYCHOTIC MEDICATION [ Time Frame: Weeks 0,4,8,12,16 ] [ Designated as safety issue: No ]
  Defined Daily Doses (ATC/WHO)
• Kimura Recurring Recognition Figures Test [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: No ]
  A sub-sample of patients. For logistic reasons, only some study sites could participate.
• Hopkins Verbal Learning Test. [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: No ]
  A sub-sample of patients. For logistic reasons, only some study sites could participate.
• Continuous Performance Test [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: No ]
  A sub-sample of patients. For logistic reasons, only some study sites could participate.
• Hopkins Verbal Learning Test [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: No ]
  A sub-sample of patients. For logistic reasons, only some study sites could participate.
• Paced Auditory Serial Addition Test [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: No ]
  A sub-sample of patients. For logistic reasons, only some study sites could participate.
• Stroop Test [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: No ]
  A sub-sample of patients. For logistic reasons, only some study sites could participate.
• Digit Span [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: No ]
  A sub-sample of patients. For logistic reasons, only some study sites could participate.
• The Letter - Number Task [ Time Frame: Weeks 0,16 ] [ Designated as safety issue: No ]
  A sub-sample of patients. For logistic reasons, only some study sites could participate.
• Semantic and Category Fluency [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: No ]
  A sub-sample of patients. For logistic reasons, only some study sites could participate.
• Body Mass Index [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
• Blood pressure - systolic, diastolic [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
• Heart rate [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
• Albumin [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Serum
• Urate [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Serum
• Glucose [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Serum - fasting
• Cholesterol [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Serum - fasting
• Triglycerides [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Serum - fasting
• Fatty acids in red blood cells [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: No ]

  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.

• Alpha-tocopherol adjusted for [triglycerides]+[cholesterol]. [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: No ]
  Serum
• Total antioxidant status [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: No ]
  Serum
• Malondialdehyde [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Also called "TBARS". Serum
• F2-isoprostane (8-epiPGF2-alpha) [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Serum
• 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. [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: No ]
  Whole blood
• Mean Corpuscular Haemoglobin Concentration (MCHC) [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Whole blood
• Mean Corpuscular Volume (MCV) [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Whole blood
• C- Reactive Protein (CRP) [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Plasma
• Haemoglobin [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Whole blood
• Leukocytes [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Whole blood
• Calcium [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Serum
• Sodium [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Serum
• Potassium [ Time Frame: Weeks 0, 16 ]
  Serum
• Ferritin [ Time Frame: Weeks 0,16 ] [ Designated as safety issue: Yes ]
  Serum
• Free thyroxin (T4) [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Serum
• Thyroid Stimulating Hormone (TSH) [ Time Frame: Weeks 0, 16 ] [ Designated as safety issue: Yes ]
  Serum

• PANSS Subscales Negative, Positive, General Psychopathology (weeks 0, 8, 16)
• GLOBAL ASSESSMENT OF FUNCTIONING– Split Version (S-GAF)Symptom Scale, 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 (weeks 0,4,8,12,16)
• NEUROPSYCHOLOGICAL ASSESSMENT (weeks 0,16):
• Kimura Recurring Recognition Figures Test
• Hopkins Verbal Learning Test.
• Continuous Performance Test
• Hopkins Verbal Learning Test
• Paced Auditory Serial Addition Test
• Stroop Test
• Digit Span
• The Letter – Number Task
• Semantic and Category Fluency
• GENERAL MEDICAL EXAMINATION (weeks 0,16):
• Weight
• Blood pressure - systolic, diastolic
• Heart rate
• ORDINARY BIOCHEMICAL ANALYSES (Serum, blood)(weeks 0,16):
• Albumin
• Urate
• Glucose
• Cholesterol
• Triglycerides
• SPECIAL BIOCHEMICAL ANALYSES (Serum, blood)
• Fatty acids in red blood cells (DGLA, AA, EPA, DHA, total omega-3 PUFA, total omega-6 PUFA)
• Alpha-tocopherol adjusted for [triglycerides]+[cholesterol].
• Total antioxidant status
• Malondialdehyde
• F2-isoprostane (8-epiPGF2-alpha)
• Cytosolic PLA2 group IV in red blood cells(ELISA method)
• Gene expression of mRNA for PLA2 groups IVa and VIa in monocytes.

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.

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).

• Schizophrenia
• Schizophreniform Disorders
• Schizoaffective Disorder
• Psychotic Disorders

• Drug: Ethyl-eicosapentaenoic acid (EPA)
  Capsules, 2 g per day for 16 weeks
  Other Name: 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 Name: CellaVie (Ferrosan AS, Denmark)
• Other: Etyl EPA (placebo)
  Paraffin oil. Capsules, each 0.5 g.
  Other Name: Placebo EPA
• Other: Vitamins E+C (placebo)
  Tablets containing dicalciumphosphate
  Other Name: Placebo CellaVie, provided by Ferrosan AS, Denmark

• Experimental: Ethyl EPA (active) and Vitamins E + C (active)
  Interventions:

  • Drug: Ethyl-eicosapentaenoic acid (EPA)
  • Drug: Vitamins E + C
• Experimental: Ethyl EPA (active) and Vitamins E+C (placebo)
  Interventions:

  • Drug: Ethyl-eicosapentaenoic acid (EPA)
  • Other: Vitamins E+C (placebo)
• Experimental: Ethyl EPA (placebo) and Vitamins E+C (active)
  Interventions:

  • Drug: Vitamins E + C
  • Other: Etyl EPA (placebo)
• Placebo Comparator: Ethyl EPA (placebo) and Vitamins E+C (placebo)
  Intervention: Other: Vitamins E+C (placebo)

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)

• Diakonhjemmet Hospital
• Stanley Medical Research Institute
• Laxdale Ltd
• Scandinavian Society for Psychopharmacology
• Shipowner Emil Stray's legacy
• Johanne and Einar Eilertsen's research fund
• AstraZeneca
• Solveig and Johan P. Sommer's foundation
• Josef and Haldis Andresen's legacy
• University of Oslo
• Norwegian University of Science and Technology