Ignite Creation Date:
2024-05-05 @ 5:08 PM
Last Modification Date:
2024-10-26 @ 9:28 AM
Study NCT ID:
NCT00396643
Status:
COMPLETED
Last Update Posted:
2007-12-27
First Post:
2006-11-06
Brief Title:
Indicated Prevention With Omega-3 Fatty Acids in Adolescents With At-Risk-Mental-State for Psychosis
Sponsor:
Medical University of Vienna
Organization:
Medical University of Vienna
Study Overview
Official Title:
Indicated Prevention With Omega-3 Fatty Acids in Adolescents With At-Risk-Mental-State for Psychosis A Randomised Double Blind Placebo-Controlled Treatment Trial
Status:
COMPLETED
Status Verified Date:
2007-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 12 gramm per day eicosapentaenoic aciddocosahexaenoic acidEPADHA 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 12 gday EPADHA 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 EPADHA 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 prepost treatment by 1analyzing bioactive lipid composition of red-blood cell membranes 2measuring 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 3the 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 EPADHA 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 EPADHA 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 eg 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 -45 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 andor 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 2gday 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 EPAday significantly more effective in reducing symptom scores on psychiatric rating scales than 1g and 4g EPAday Peet et al 2002
On the other hand Fenton et al 2002 investigated augmentation of neuroleptics with 3 gday of EPA on symptoms and cognition in patients with schizophrenia or schizoaffective disorder and reported a negative finding The patients in Fenton et als 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 12 gramm per day EPADHA or placebo for 12 weeks Follow-up assessments will be conducted at 123481226and 52 weeks All patients will receive standard treatment which includes management by a psychiatrist or resident psychiatrist and non-neuroleptic pharmacotherapy as clinically indicated
Specifically we propose to investigate
The clinical effects of EPADHA 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 prepost treatment by 1analyzing bioactive lipid composition of red-blood cell membranes 2measuring 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 3the 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 EPADHA 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 EPADHA 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 eg 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 -45 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 andor 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 2gday 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 EPAday significantly more effective in reducing symptom scores on psychiatric rating scales than 1g and 4g EPAday Peet et al 2002
On the other hand Fenton et al 2002 investigated augmentation of neuroleptics with 3 gday of EPA on symptoms and cognition in patients with schizophrenia or schizoaffective disorder and reported a negative finding The patients in Fenton et als 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 12 gramm per day EPADHA or placebo for 12 weeks Follow-up assessments will be conducted at 123481226and 52 weeks All patients will receive standard treatment which includes management by a psychiatrist or resident psychiatrist and non-neuroleptic pharmacotherapy as clinically indicated
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| FA765Z0003 | None | None | None |
| EK Nr 4152002 | None | None | None |