Indicated Prevention With Omega-3 Fatty Acids in Adolescents With 'At-Risk-Mental-State' for Psychosis
Indicated Prevention With Omega-3 Fatty Acids in Adolescents With 'At-Risk-Mental-State' for Psychosis
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.
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.
Inclusion Criteria:

 1. /written informed consent (for individuals under 18 written informed consent of at
 least one of the parents is required),

 2. /age between 13 and 25 years,

 3. /ARMS as classified by the PACE criteria (Yung et al., 1998)

 PACE criteria for ARMS include one or more of following characteristics which must have
 occurred within the last 12 months:

 -  Frank psychotic symptoms < 1 week (Transient psychosis group)

 -  Attenuated psychotic symptoms > 1 week, > 2 times per week

 -  Decline in global function (drop in GAF of > 30%) plus family history of psychosis or
 individual has schizotypal personality disorder To operationalize PACE criteria
 duration and severity ratings of psychotic symptoms will be performed using the
 Positive and Negative Syndromes of Schizophrenia Scale (PANSS) (Kay et al., 1987)
 applying following cut-off scores, following Morrison et al (2002): Ad 1) Transient
 psychosis is defined with the presence of symptoms that score 4 or more on
 hallucinations, 4 or more on delusions, or 5 or more on conceptual disorganizations,
 last less than one week and resolve without antipsychotic medication. Ad 2) Attenuated
 psychotic symptoms are defined by the presence of symptoms that score 3 on delusions,
 2-3 on hallucinations, 3-4 on suspiciousness or 3-4 on conceptual disorganization.

 Exclusion Criteria:

 1. /Acute suicidal behaviour, aggressive behaviour (PANSS hostility, suicidality = 7),

 2. /Drug abuse that contributed decisively to the presentation of the index episode,
 (dependency on morphine, cocaine, amphetamine, but not THC),

 3. /Alcohol abuse if considered as major problem,

 4. /Epilepsy,

 5. /Mental Retardation (IQ<80),

 6. /Pregnancy and lactation,

 7. /Structural changes in MRI or CT scan (e.g., tumours), expect for enlargement of
 ventricles or sulci,

 8. /Previous history of antipsychotic drug (>1 week) or mood stabilizer treatment,

 9. /Laboratory values more than 10% outside the normal range for transaminases, CRP or
 bleeding parameters,

 10. /Individuals with organic brain syndrome,

 11. /Individuals who are taking anticoagulants,

 12. /Individuals who are taking omega 3 supplements, currently or within 8 weeks of being
 included in the trial,

 13. /Individuals who have other, severe, intercurrent illness which in the opinion of the
 investigator may put them at risk or influence the results of the trial or affect
 ability to take part in the trial.