Indicated Prevention With Omega-3 Fatty Acids in Adolescents With 'At-Risk-Mental-State' for Psychosis: A Randomised, Double Blind, Placebo-Controlled Treatment Trial

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.