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

Type: Article

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.


Phospholipid Metabolism

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.


Outcome studies

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.



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