Title: Phospholipid metabolism in schizophrenia and depression.
Key words: Horrobin model, phospholipase A, schizophrenia, DGLA, EPA, AA, DHA, clozapine, prostaglandins, AMP, depression, Omega-3, electro-retinogram, niacin flush, ethane
Date: Jan 2001
Category: 7. The Mind
Author: Kate Neil (NS3)
Phospholipid metabolism in schizophrenia and depression.
Horrobin proposed a neuronal membrane phospholipid model of neuropsychiatric disorders in the late 1970’s. Since then, increasing evidence from biochemical studies, nutritional studies, neurochemistry, molecular genetics, structural neuroimaging and magnetic resonance spectroscopy has been accumulating that supports the Horrobin model, in disorders as diverse as schizophrenia, depression, ADHD, dyslexia, dyspraxia and Huntingdon’s disease.
There are increased circulating levels of phospholipase A2 (PLA2) activity in the blood in schizophrenia. (PLA2) removes essential fatty acids EFAs from the Sn2 position of phospholipids. Overactivity could result in an increased rate of loss of dihomogammalinoleic acid (DGLA), eicosapentaenoic acid (EPA), arachidonic acid (AA), and docosahexaenoic acid (DHA) from the Sn2 position. In some schizophrenics, red cell membranes are depleted of AA and DHA. AA and DHA are predominately found in the Sn2 position. Genes control the enzymes involved in the synthesis and breakdown of phospholipids, but the key EFA’s must come from the diet. Environment/gene interactions will determine final phospholipid structures.
A dramatic rise in red cell membrane concentrations of AA and DHA in schizophrenics, in response to clozapine treatment has been demonstrated. The success of this medication may be a result of it being a prostaglandin E analogue. E prostaglandins are potent stimulators of cyclic AMP formation, which in turn inhibits PLA2 activity.
Depressive patients show significant depletion of total omega-3 fatty acids and particularly DHA. Incubation of red blood cells from controls with hydrogen peroxide abolished all significant differences between patients and controls. Cardiovascular disease is strongly correlated with depression. Omega-3 fatty acids have frequently been shown to be beneficial in the management of cardiovascular disease.
Two different genetic abnormalities have been found in the vicinity of the gene for PLA2 on chromosome 1. There is overactivity of PLA2, which is breaking down phospholipids and an underactivity of fatty acid coenzyme-A ligases (FACLs), which enable phospholipids to be reconstructed.
Schizophrenia and manic depression run in the same families. Researchers postulate that there is an overactivity of PLA2 in bipolar disorder whereas schizophrenia manifests as overactivity of PLA2 combined with underactivity of FACL.
Magnetic Resonance Imaging MRI
MRI shows evidence of an increased rate of phospholipid breadown as might be produced by increased PLA2 activity in the cerebral cortex of schizophrenics.
A reduced maximal ERG response to a light stimulus is an indicator for insufficient DHA availability. The retina is rich in DHA and the maximum ERG depends on its availability for cell signalling. Schizophrenics show a significantly reduced ERG response.
Niacin stimulates the conversion of AA to prostaglandin E2, a potent vasodilator. Schizophrenics show a reduced flushing response to oral or topical niacin indicating a lack of availability of AA for cell signalling. This is a useful marker for AA availability.
Ethane is a metabolite of AA. In normal individuals there is between 1 and 10 ng of ethane per litre of breath. In schizophrenics, there is between 50 and 100 ng/l in breath. This simple breath test, analysed by mass spectrometry, could prove very valuable for psychiatric and (neurological – Alzheimers) disorders.
The ELISA assay is specific to cytosolic PLA2 in human red cells and reflects what is in the brain. It has no cross-reactivity with a wide range of other PLA2s. About 50% of schizophrenics show a clear abnormality in PLA2, in as much as there is over-expression of a normal PLA2.
Clinical Observations in Schizophrenia
Resistance to inflammatory disorders, resistance to pain, relief of psychosis by fever, increased risk of viral infections, increased risk associated with poor maternal nutrition in pregnancy, reduced female risk and increased risk post-menopausally, better outcomes in countries with a high ratio of unsaturated to saturated fat intake, precipitation by stress and reduced flushing in response to niacin can all be readily explained by the phospholipid hypothesis.
Appropriate omega-3 supplementation in schizophrenia and depression is showing itself to be of clinical benefit.