Title: Schizophrenia And Depression
Key words: Horrobin hypothesis, HUFA, PUFA, arachidonic acid, phospholipids, membrane proteins, neurotransmitter function, dietary EPA and DHA, serotonin uptake, neuronal membrane, cerebral atrophy, dietary supplementation with HUFA
Date: Sept 2000
Category: The Mind
Author: Dr Van Rhijn
Schizophrenia And Depression
The Possible Role of Phospholipid Metabolism
Evidence from different fields (biochemical, nutritional, molecular genetics, neuroimaging, and magnetic resonance spectroscopy) increasingly supports the Horrobin hypothesis. This states that abnormal neuronal membrane phospholipid and related highly unsaturated fatty acid (HUFA) metabolism1 contribute to neuropsychiatric disorders2,3,4. Theoretically, treatment with various fatty acids (FAs) could reverse fundamental phospholipid abnormalities in cell membranes, leading to improvement in psychiatric conditions. Red blood cell (RBC) membranes are an easily available tool as a measure of membrane FA composition in both schizophrenia and depression. This measure correlates well with brain n-3 FA composition, confirmed by a study on post-mortem schizophrenic brains, identifying strong reductions in total PUFAs, especially arachidonic acid5.
Phospholipids make up approximately 60% of the brain's dry weight. They are mainly present in neuronal membranes. Phospholipid bilayers form the matrix within which membrane proteins, such as receptors and ion channels are embedded and to which membrane-associated proteins are attached. Membrane composition (fluidity) can affect the structures of membrane-bound receptors associated with neurotransmitter functioning. FAs can influence key aspects of cell functioning as most secondary messenger systems depend on FAs, leucotrienes and prostaglandins6. Arachidonic acid (AA) and dihomogamma linoleic acid (DGLA) from the n-6 series and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from the n-3 series are the four most important brain poly-unsaturated fatty acids (PUFAs), and precursors of biological eicosanoids7. They influence many aspects of brain development including neuronal migration, axonal and dendritic growth, remodelling8 and pruning9 of synaptic connections. Deficiencies can permanently disrupt neuronal integrity during foetal development and signal transduction10. Phospholipid studies on RBC membranes and brain 31P magnetic resonance spectroscopy11 reported deficiencies in both depressed and schizophrenic patients, raising the question about specificity.
RBC membrane phospholipids in schizophrenia show increased depletion of HUFAs (bimodal distribution)12, especially DGLA, EPA13, AA14 and DHA15. Several mechanisms (enzymatic and non-enzymatic) could explain this depletion such as abnormalities in over activity of cytosolic phospholipase A2 (PLA2)16,17,18,19 (a phospholipid-catabolising enzyme that increases dopamine activity), under activity of fatty acid coenzyme-A ligases (FACL) and abnormal antioxidant defence mechanisms20. EPA inhibits PLA2 and activates FACL explaining its efficacy in the treatment of schizophrenia as both is required to inactivate the PLA2 cycle. Reduced availability of AA can be detected by a reduced flushing response to topical niacin21, a potential screening and diagnostic test (impaired phospholipid-dependent signal transduction22). A strong inverse relationship exists between a lifetime severity score for schizophrenia and the ratio of EFA to other dietary fats23, and positive symptoms are inversely related to dietary EPA & DHA24. Magnetic resonance spectroscopy studies confirmed that altered membrane phospholipid metabolism in the left temporal lobe is associated with neuroleptic-resistant positive symptoms in schizophrenic patients25, that can be partially normalised with neuroleptics26.
Significant depletion of n-3 PUFAs, especially (DHA)27, and an increased ratio of AA:EPA in RBC, correlated with the severity of depression28, but the disorders may persist despite successful antidepressant treatment29. There is also evidence of oxidative damage30 and these findings may primarily be clinically significant in the etiology of depression31. Increased membrane levels of n-3 FAs increase membrane fluidity, thereby increasing serotonin uptake by endothelial cells 32. Acute episodes of major depression in drug naοve patients are associated with an increased sensitivity of the inositol-phospholipid (IPL) signal transduction system33.
EPA (n-3) administration to drug-naοve schizophrenic patients, led to dramatic and sustained clinical improvement in both positive and negative symptoms, accompanied by a correction of both n-3 & n-6 HUFA in RBC membranes. There was reduced neuronal membrane phospholipid turnover and cerebral atrophy reversal34 (31-phosphorus cerebral magnetic resonance spectroscopy), thereby correcting a left over right hemispheric imbalance35.
Depression, bipolar disorders and schizophrenia are very common disorders and only 60-70% of patients respond to the modern psychotropic drug regimes. New treatments are needed, and with substantial evidence in support of the membrane phospholipid model, dietary supplementation with HUFA may improve the long-term outcome of these conditions.
1. Horrobin, D.F. et al. Essential fatty acids in plasma phospholipids in schizophrenics. Biol. Psychiatry. 1989; 25(5): 562 568.
2. Horrobin, D.F. & Bennett, C.N. New gene targets related to schizophrenia and other psychiatric disorders: enzymes, binding proteins and transport proteins involved in phospholipid and fatty acid metabolism. Prostaglandins Leukot. Essent. Fatty Acids. 1999; 60(3): 141 167.
3. Fenton, W.S. et al. Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia. Biol. Psychiatry. 2000; 47(1): 8 21.
4. Horrobin, D.F. et al. The membrane hypothesis of schizophrenia. Schizophr. Res. 1994; 13(3): 195 207.
5. Yao, J.K. et al. Membrane phospholipid abnormalities in post-mortem brains from schizophrenic patients. Schizophr. Res. 2000; 42(1): 7 17.
6. Uauy, R. et al. Essential fatty acids in early life: structural and functional role. Proc. Nutr. Soc. 2000; 59: 3 15.
7. Uauy, R. et al. Essential fatty acid metabolism in the micropremie. Clin. Perinatol. 2000; 27(1): 71 93.
8. Smalheiser, N.R. et al. Rapid regulation of neurite outgrowth and retraction by phospholipase A2-derived arachidonic acid and its metabolites. Brain res. 1996; 721: 39 48.
9. de Kok, M. et al. The induction of apoptosis in human cervical carcinoma (HeLa) cells by gamma-linolenic acid. Prostaglandins Leukot. Essent. Fatty Acids. 1996; 55: 403 411.
10. Keshavan, M.S. et al. Erythrocyte membrane phospholipids in psychotic patients. Psychiatry Res. 1993; 49(1): 89 95.
11. Williamson, P.C. et al. 31P magnetic resonance spectroscopy studies in schizophrenia. Prostaglandins Leukot. Essent. Fatty Acids. 1996; 55(1-2): 115 118.
12. Glen, A.I.M. et al. A red cell membrane abnormality in a subgroup of schizophrenic patients: Evidence for two diseases. Schizophr. Res. 1994; 12(1): 53 61.
13. Kaiya, H. et al. Essential and other fatty acids in plasma in schizophrenics and normal individuals from Japan. Biol. Psychiatry. 1991; 30(4): 357 362.
14. Horrobin, D.F. et al. Possible relevance of phospholipid abnormalities and genetic interactions in psychiatric disorders: the relationship between dyslexia and schizophrenia. Med. Hypotheses. 1995; 45(6): 605 613.
15. Peet, M. et al. Essential fatty acid deficiency in erythrocyte membranes from chronic schizophrenic patients, and the clinical effects of dietary supplementation. Prostaglandins Leukot. Essent. Fatty Acids. 1996; 55(1-2): 71 75.
16. Gattaz, W.F. et al. Increased platelet phospholipase A2 in schizophrenia. Schizophr. Res. 1995; 16: 1 6.
17. Horrobin, D.F. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr. Res. 1998; 30(3): 193 208.
18. Gattaz, W.F. et al. Increased serum phospholipase A2 activity in schizophrenia: a replication study. Biol. Psychiatry. 1990; 28(6): 495 501.
19. Ross, B.M. et al. Increased phospholipid breakdown in schizophrenia. Evidence for the involvement of a calcium-independent phospholipase A2. Arch. Gen. Psychiatry. 1997; 54(5): 487 494.
20. Reddy, R.D. & Yao, J.K. Free radical pathology in schizophrenia: A review. Prostaglandins Leukot. Essent. Fatty Acids. 1996; 55: 33 43.
21. Ward, P. et al. Skin flushing in response to graded doses of topical niacin: a new test, which distinguishes schizophrenics from controls. Schizophr, res. 1997a; 24: 70.
22. Hudson, C.J. et al. The niacin challenge test: clinical manifestation of altered transmembrane signal transduction in schizophrenia? Biol. Psychiatry. 1997; 41(5): 507 513.
23. Horrobin, D.F. The relationship between schizophrenia and essential fatty acid and eicosanoids metabolism. Prostaglandins Leukot. Essent. Fatty Acids. 1992b; 46: 71 77.
24. Peet, M. et al. Fatty acid supplementation in schizophrenic patients. Schizophr. Res. 1997a; 24; 209.
25. Fukuzako, H. et al. Phosphorus magnetic resonance spectroscopy in schizophrenia: correlation between membrane phospholipid metabolism in the temporal lobe and positive symptoms. Prog. Neuropsychopharmacol. Biol. Psychiatry. 1996; 20(4): 629 640.
26. Fukuzako, H. et al. Haloperidol improves membrane phospholipid abnormalities in temporal lobes of schizophrenic patients. Neuropsychopharmacology. 1999; 21(4): 542 549.
27. Maes, M. et al. fatty acid composition in major depression: Decreased w3 fractions in cholesteryl esters and increased c20:4w6/c20:5w3 ratio in cholesteryl esters and phospholipids. J. Affect. Discord. 1996: 38: 35 46.
28. Adams, P.B. et al. Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids. 1996; 31(Suppl): S157 S161.
29. Maes, M. et al. Lowered omega3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Res. 1999; 85(3): 275 291.
30. Peet, M. et al. Depletion of Omega-3 Fatty Acid Levels in Red Blood Cell Membranes of Depressive Patients. Biol. Psych. 1998; 43: 315 319.
31. Horribin, D.F. & Bennett, C.N. Depression and bipolar disorder: relationships to impaired fatty acid and phospholipids metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Prostaglandins Leukot. Essent. Fatty Acids. 1999; 60(4): 217 234.
32. Block, E.R. & Edwards, D. Effect of plasma membrane fluidity on serotonin transport by
endothelial cells. Am. J. Physiol. 1987; 253: C672 C678.
33. Bohus, M. et al. Increased sensitivity of the inositol-phospholipid system in neutrophils from patients with acute major depressive episodes. Psychiatry Res. 1996; 65(1): 45 51.
34. Puri, B.K. et al. 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. Pract. 2000; 54(1): 57 63.
35. Richardson, A.J. et al. Laterality changes accompanying symptom remission in schizophrenia following treatment with eicosapentaenoic acid. Int. J. Psychophysiol. 1999; 34(3): 333 339.