Fatty acids schizophrenia

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... 

In view of these factors, it has been suggested that a deficiency of omega-3 fatty acid in the diet will decrease the concentration of these fatty acids available for synthesis of the required phospholipids in the body, including the brain. If this was a chronic deficiency it could increase the risk of development of some disorders, including depression, schizophrenia and attention deficit syndrome. There is some evidence that this is the case. 

The three disorders depression, schizophrenia and dementia are discussed in relation to the possible involvement of omega-3 fatty acids in these diseases, that is a deficiency may be involved in the aetiology of these diseases. 

The amonnts of both omega-3 and omega-6 fatty acids are low in erythrocytes from patients snffering from schizophrenia. As with depression, snpplementation of the diet of snch patients with omega-3 fatty acids has been claimed to improve the condition. 

There are reports of an association between low fish consumption and increased prevalence of depression (Hibbelin, 1998). Some studies have found a reduced level of omega-3 fatty acids in depressed patients. It has also been speculated that EFAs have a role in the causation of schizophrenia and, more recently, ADHD and behavioral problems (Stevens et ah, 1996 Burgess et ah, 2000). 

Fenton, W.S., Hibbeln, J., and Knable, M. (2000) Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia Bio Psychiatry 47 8-21. 

R. Reddy and M. S. Keshavan, Phosphorus magnetic resonance spectroscopy its utility in examining the membrane hypothesis of schizophrenia. Prostaglandins Leukot. Essent. Fatty Acids, 2003,69,401-405. 

In addition, many different psychiatric conditions such as schizophrenia, depression and post-traumatic stress syndrome have been associated with changes in the essential fatty acid levels that can easily be measured in erythrocytes or plasma [2, 3]. 

The co-3 fatty acids have numerous important functions, especially in the brain. Accordingly, a deficiency of DHA and EPA may cause dysfunction of the central nervous system and probably also the retina, thereby resulting in impaired vision. In addition, there is a variety of neurological and psychiatric disorders that have been associated with decreased levels of especially DHA and AA, such as, for example, schizophrenia and depression [3], post-traumatic stress syndrome, autism and attention deficit hyperactivity disorder. Since no primary inherited defect of essential fatty acid interconversion has yet been described, no specific explanations for the essential fatty acid concentration changes are readily available. 

Mahadik S. P. and Scheffer R. E. (1996). Oxidative injury and potential use of antioxidants in schizophrenia. Prostaglandins Leukot. Essent. Fatty Acids 55 45-54. 

Horrobin D. F. (2003b). Omega-3 fatty acid for schizophrenia. Am. J. Psychiat. 160 188-189. 

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). 

Reddy RD, Keshavan MS, Yao JK. 2004. Reduced red blood cell membrane essential polyunsaturated fatty acids in first episode schizophrenia at neuroleptic-naive baseline. Schi-zophr Bull 30 901-911. 

Das UN. Can perinatal supplementation of long-chain polyunsaturated fatty acids prevents schizophrenia in adult life Med. Sci. Monit. 2004 10 HY33-HY37. 

Ranjekar PK, Hinge A, Hegde MV, Ghate M, Kale A, Sitasawad S, et al. Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenia and bipolar mood disorder patients. Psychiatry Res. 2003 121 109-122. 

Arvindakshan M, Ghate M, Ranjekar PK, Evans DR, Mahadik SP. Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia. Schizophr. Res. 2003 62 195-204. 

Horrobin, D.F. (1996) Schizophrenia as a membrane lipid disorder which is expressed throughout the body. Prostaglandins Leukot. Essent. Fatty Acids. 55 3-7. 

Warner, R., Laughame, J., Peet, M., Brown, L. and Rogers, N. (1999) Retinal function as a marker for cell membrane omega-3 fatty acid depletion in schizophrenia a pilot study. Biol. Psychiatry. 45 1138-1142. 

Yao JK. van Kammen DP, Gurklis J. Red blood cellmembrane dynamics in schizophrenia. IB. Correlation of fatty acid abnormalities with clinical measures. Schizophr Res 1994 13 227-232. 

The use of omega-3 fatty acids also seems promising for some symptoms of schizophrenia see Fenton et al., 2000, for a review). A series of case reports by Rudin (1981 1982) described significant reductions of psychosis after treatment with flax seed oil. More recent open trials have also indicated possible efficacy (Mellor et al., 1995 Puri and Richardson, 1998 Puri et al. 2000). Three double-blind, placebo-controlled trials (Peet and Mellor, 1998 Peet et al., 2000a Peet et al., 2000b) have reported clinical improvements among schizophrenics treated with EPA alone, while one study found no clinical improvements (Fenton, et al., unpublished data). Unfortunately, results in the form of full publications are not yet available for any of the double-blind trials. Of these studies, the most striking report is that when treated with 3 g/d of EPA alone, 10 of 30 unmedicated... 

Peet M, Mellor J. Double blind placebo controlled trial of n-3 polyunsaturated fatty acids as an adjunct to neuroleptics. 9th Schizophrenia Winter Workshop, Davos Switzerland, 1998. 

Peet M, Mellor J, Ramchand CN, Shah S, Vankar GK. Eicosapentaenoic acid (EPA) in the treatment of schizophrenia. 4th Congress of the International Society for the Study of Lipids and Fatty Acids, 2000, p. 108. 

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. 

---