Indicated Prevention With Omega-3 Fatty Acids in Adolescents With 'At-Risk-Mental-State' for Psychosis
Condition: Schizophrenia; Prodrome
MeSH terms: Schizophrenia; Psychotic Disorders; Mental Disorders
Study type: Interventional
Phase: Phase 4

Summary: 
      Early intervention in psychosis might be associated with better outcomes. However,
      intervention in the pre-psychotic phase has been questioned as, using current criteria, only
      20-50% of individuals classified as prodromal develop a psychotic disorder within a 1-2 years
      period. Treatment agents investigated in the pre-psychotic phase of schizophrenia and other
      psychotic disorders should, therefore, not have major side effects. This proposal
      investigates omega-3 fatty acids (1.2 gramm per day eicosapentaenoic acid/docosahexaenoic
      acid;EPA/DHA) as a beneficial and possible preventive therapeutic agent in young people at
      ultra high-risk for developing a psychotic disorder.
    

Detailed description: 
      1. Aims of the study The principal aim is to test if 1.2 g/day EPA/DHA can prevent
           transition to first-episode psychosis in 13-25 year old ultra-high risk individuals.

           Specifically we propose to investigate:

             -  The clinical effects of EPA/DHA supplementation as an adjunct to standard therapy
                in individuals with 'At-Risk Mental State' (ARMS) for psychosis as defined by the
                PACE criteria (Yung et al., 1998).

             -  Lipid metabolism in peripheral tissue pre/post treatment by 1./analyzing bioactive
                lipid composition of red-blood cell membranes, 2./measuring phospholipase A2
                (cPLA2) activity in serum (the enzyme responsible for the cleavage of arachidonic
                acid (AA) and other precursors of bioactive lipids from glycerophospholipids (GPL)
                and 3./the topical niacin flush test (a clinical test of the AA-prostaglandin D2
                cascade).

        2. Background and evidence that bioactive lipids are altered in schizophrenia and can be
           influenced by EPA/DHA supplementation

           There is suggestion that early intervention in psychosis might be associated with better
           outcomes (Norman & Malla, 2001). However, intervention in the pre-psychotic phase has
           been questioned as, using current criteria, only 20-50% of individuals classified as
           prodromal develop a psychotic disorder within a 1-2 years period (McGlashan et al.,
           2001). Treatment agents investigated in the pre-psychotic phase of schizophrenia and
           other psychotic disorders should, therefore, not have major side effects. This proposal
           introduces EPA/DHA, two omega-3 essential fatty acids (EFA), as a beneficial and
           possible preventative therapeutic agent in young people at ultra high-risk for
           developing a psychotic disorder.

           Bioactive lipids and their role in the brain Bioactive lipids are molecules that have
           both intra- and intercellular roles, including mediation, modulation and control of
           neurobiological processes, such as ion channel and receptor activity, neurotransmitter
           release, synaptic plasticity, second messenger pathways and neuronal gene expression
           (Agranoff et al., 1998). Emphasis has been placed on AA and its metabolites, known
           collectively as eicosanoids. A major proportion of lipids in the brain consist of
           bioactive lipids such as AA and its metabolites, also referred to as EFA, which are
           mainly bound to GPL. Bioactive lipids are released through direct and indirect enzymatic
           pathways (e.g., phospholipases) from membrane GPL. AA is a precursor of prostaglandins,
           thromboxanes, leukotriens (5-HpETE) and prostacyclins. Animal studies and preliminary
           studies in humans have shown an association between bioactive lipid metabolism,
           behaviour and cognition (Zimmer et al., 2000).

           Reduced membrane EFA in schizophrenia Abnormal membrane GPL EFA metabolism has been
           suggested to contribute to the aetiopathophysiology of schizophrenia. A recent review of
           15 published studies confirmed a depletion of bioactive lipids in cell membranes of
           patients with schizophrenia (Fenton et al., 2000). The most consistent findings were
           reductions in AA and its precursors, and these were independent of drug treatment (Yao
           et al., 1996). Reductions in AA and its precursors have also been found in post mortem
           brains of patients with schizophrenia, relative to normal control brains [Yao et al.,
           2000]. Yao and van Kammen (1996) suggested that defective uptake of AA into membrane GPL
           was a possible aetiopathological mechanism in schizophrenia, whereas Peet et al. (1996),
           who reported an additional increase of EFA peroxidation products, suggested there was
           increased breakdown of membrane GPL.

           Khan et al. (2002) reported on erythrocyte membrane EFA levels and levels of plasma
           lipid peroxides, products of damaged EFAs, in drug-naive patients within +/-4.5 days of
           onset of psychosis. The levels of EFAs, particularly AA and docosahexaenoic acid (DHA)
           were significantly lower in drug-naive patients at the onset of psychosis compared to
           matched normal controls. These lower EFA levels were associated with significantly
           higher levels of lipid peroxides in patients. The levels of AA and DHA were also lower
           and lipid peroxides higher in chronic medicated patients than normal controls.
           Interestingly in context with this proposal, EFA levels were higher in chronic medicated
           patients than drug-naive first-episode patients. Khan et al. concluded that these
           findings could indicate that lower membrane AA and DHA most likely predate the illness
           and probably contribute to the onset of illness. The lipid peroxidation data suggest
           that possible increased oxidative stress may be one of the mechanisms of reduced
           membrane EFAs. The findings also imply that supplementation of EFAs and/or antioxidants
           might provide effective treatments for early psychosis. This view is supported by
           Horrobin et al. (2002) who showed that increase in red cell AA levels resulted from
           treatment with the optimal levels of EPA and that, clinical improvement was highly
           significantly positively correlated with rises in red cell membrane AA in individuals
           with schizophrenia.

           Treatment studies in schizophrenia Three randomized controlled treatment studies
           conducted over 12 weeks found 2g/day EPA significantly more effective than placebo in
           reducing psychopathological symptoms in individuals with schizophrenia (Peet et al.,
           2001; Emsley et al., 2002). Symptom improvements in those studies were both, clinically
           relevant and statistically significant. A dose-ranging exploratory study of the effects
           of EPA in individuals with schizophrenia who experienced persistent symptoms found 2 g
           EPA/day significantly more effective in reducing symptom scores on psychiatric rating
           scales than 1g and 4g EPA/day (Peet et al., 2002).

           On the other hand, Fenton et al. (2002) investigated augmentation of neuroleptics with 3
           g/day of EPA on symptoms and cognition in patients with schizophrenia or schizoaffective
           disorder and reported a negative finding. The patients in Fenton et al.s' study had,
           however, been ill for two decades and had substantial symptoms, despite treatment with
           newer neuroleptics, including clozapine. The patients described as benefiting from EPA
           in the other studies were younger and had a shorter duration of illness.

           It must be emphasized that in all EPA treatment studies, no treatment-related side
           effects or adverse biochemical or haematological effects have been observed. EPA proved
           safe to administer to schizophrenic patients as an adjunct therapy. EPA did not cause
           side effects other than mild gastrointestinal symptoms by itself, nor did it enhance the
           side effects of existing drugs. Patients found EPA highly tolerable. The proportion of
           patients who completed 12 weeks (89%) compares favourably with mean withdrawal rates of
           54% in the novel neuroleptic groups and 67% in the placebo groups in trials in the FDA
           database (Peet et al., 2002). Acceptance of a substance which is normally found in the
           human body without significant side effects, with a potency potentially similar to the
           antipsychotic drugs in the early phase of psychotic disorders could contribute to reduce
           the duration of untreated psychosis and to increase compliance.

        3. Study design We will use a prospective, randomized, double-blind, placebo-controlled,
           single-centre study design. Eighty one individuals aged 13-25 will be randomly assigned
           in two treatment conditions at the University Clinic for Child and Adolescent
           Neuropsychiatry, Vienna, Austria. Randomization codes will be generated and stored off
           site. The treatment groups will receive 1.2 gramm per day EPA/DHA or placebo for 12
           weeks. Follow-up assessments will be conducted at 1,2,3,4,8,12,26,and 52 weeks. All
           patients will receive standard treatment, which includes management by a psychiatrist or
           resident psychiatrist and non-neuroleptic pharmacotherapy as clinically indicated.
    

Intervention name(s): Omega 3 fatty acids
Intervention type(s): Drug
Intervention description(s): The active treatment is a supplement of yellow gelatin 0.5 g fish oil capsules. The daily dose of 4 (2x2) capsules provides 700 mg of eicosapentaenoic acid and 500 mg of docosahexaenoic acid, and 10 mg of Vitamin E. Placebo treatment comprises coconut oil capsules, carefully matched with the active treatment with respect to both appearance and flavor, also containing 10 mg Vitamin E, and 10 mg of fish oil to mimic taste. Coconut oil was chosen as placebo because it does not contain polyunsaturated fatty acids and has no impact on n-3 fatty acid metabolism. The intervention period is 12 weeks.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Ultra-High Risk; Psychosis; Schizophrenia; Omega-3 fatty acids; RCT