Schizophrenia membrane phospholipid

Finally, an intriguing possible future therapy arises from a radical idea of Horrobin (2001) that schizophrenia is a nutritional disorder linked to a decreased intake of essential polyunsaturated fatty acids. Recent 31P-MRS studies have shown changes in plasma membrane phospholipids in the neocortex of unmedicated schizophrenics, which would have deleterious consequences on synaptic neurotransmission (Fukuzako, 2001). A clinical trial with the co6 fatty acid derivative ethyleicosa-pentaenoic acid (LAX-101) in patients who had been unresponsive to clozapine, reported that a daily dose of 2g LAX-101 gave a 26% improvement in symptoms over 12 weeks compared with 6% with placebo (Peet and Horrobin, 2001). Maybe in... 

Such imbalanced antioxidant systems in schizophrenia could lead to oxidative stress- and ROS-mediated injury as supported by increased lipid peroxidation products and reduced membrane polyunsaturated fatty acids (PUFAs). Decrease in membrane phospholipids in blood cells of psychotic patients (Keshavan et al., 1993 Reddy et al., 2004) and fibroblasts from drug-naive patients (Mahadik et al., 1994) as well as in postmortem brains (Horrobin et al., 1991) have indeed been reported. It has also been suggested that peripheral membrane anomalies correlate with abnormal central phospholipid metabolism in first-episode and chronic schizophrenia patients (Pettegrewet al., 1991 Yao et al., 2002). Recently, a microarray and proteomic study on postmortem brain showed anomalies of mitochondrial function and oxidative stress pathways in schizophrenia (Prabakaran et al., 2004). Mitochondrial dysfunction in schizophrenia has also been observed by Ben-Shachar (2002) and Altar et al. (2005). As main ROS producers, mitochondria are particularly susceptible to oxidative damage. Thus, a deficit in glutathione (GSH) or immobilization stress induce greater increase in lipid peroxidation and protein oxidation in mitochondrial rather than in cytosolic fractions of cerebral cortex (Liu et al., 1996). 

These results suggest that a GSH deficit significantly contributes to the oxidative stress-induced impairment of membrane phospholipid and mitochondrial function proposed to be involved in the pathophysiology of schizophrenia (Mahadik and Mukherjee, 1996 Mahadik et al., 1998 Yao et al., 1999 Herken et al., 2001 Evans et al., 2003 Marchbanks et al., 2003 Prabakaran et al., 2004). 

Horrobin DF. 1998. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res 30 193-208. 

Keshavan MS, Stanley JA, Montrose DM, Minshew NJ, Pettegrew JW. 2003. Prefrontal membrane phospholipid metabolism of child and adolescent offspring at risk for schizophrenia or schizoaffective disorder An in vivo (31)P... 

Early Studies of Phospholipid Changes in Schizophrenia and the Membrane Phospholipid... 

Jayakumar PN, Gangadhar BN, Subbakrishna DK, Janakira-maiah N, Srinivas JS, et al. 2003. Membrane phospholipid abnormalities of basal ganglia in never-treated schizophrenia A 31p magnetic resonance spectroscopy study. Biol Psychiatry 54 491-494. 

Puri BK, Richardson AJ, Horrobin DF, Easton T, Saeed N, Oatridge A, etal. Eicosapentaenoic acid treatment in schizophrenia associated with symptom remission, normalisation of blood fatty acids, reduced neuronal membrane phospholipid turnover and structural brain changes. Int J Clin Prac 2000 54( 1 ) 57—63. 

There are clear abnormalities of fatty acid concentrations in depression that are distinct from those in schizophrenia (Adams, Lawson, Sanigorski, Sinclair, 1996 Maes et al., 1996 Maes et al., 1999 Peet, Murphy, Shay, Horrobin, 1998 Edwards, Peet, Shay, Horrobin, 1998). Eirst, the abnormalities are present in both plasma and in red cells, raising the possibility that the problem may be in fatty acid metabolism in general, rather than membrane phospholipid metabolism in particular. Second, the abnormalities are specifically deficits in the omega-3 fatty acids EPA, DHA, and docosapentaenoic acid (DPA), and particularly in EPA. In contrast to the situation in schizophrenia, AA levels are either normal or elevated. 

In summary, existing drug treatments for schizophrenia are of limited efficacy and have substantial side effects. New treatment can arise only on the basis of a new hypothesis. The phospholipid hypothesis of schizophrenia provides the theoretical basis for treatment with PUPA supplementation. Pre vlous studies using n-6 supplementation have had mixed results. We now have evidence from a double-blind, placebo-controlled trial that EPA, but not DHA, is effective in reducing the symptoms of schizophrenia. It is possible that the response to EPA is impaired by concomitant treatment with antipsychotic drugs that damage membrane phospholipids. The best treatment effects of EPA have been seen in patients who are otherwise unmedicated or who are currently taking clozapine. This remains to be explored further. 

Mahadik, SP, Evans DR. Is schizophrenia a metabolic brain disorder Membrane phospholipid dysregulation and its therapeutic imphcations. Psychiatr Clin North Am 2003 26 41-63. 

Recent postmortem studies by Komoroski et al. utilized high-resolution P NMR spectroscopy such that GPC, GPE, PC, and PE signals could be quantified individually without contamination from the short T2 phospholipids.They found no significant differences in the membrane precursors PC and PE in schizophrenics compared to controls. GPC was foimd to be significantly increased among male schizophrenics relative to controls in extracts from the frontal, temporal, and occipital regions. While this finding is possibly attributable to schizophrenia, it is likely that... 

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