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Med Hypotheses. 2005;65(6):1076-81. Epub 2005 Aug 25.
Impaired neuronal glucose uptake in pathogenesis of schizophrenia - can GLUT 1 and GLUT 3 deficits explain imaging, post-mortem and pharmacological findings?
, Leeds University, United Kingdom. Tees and North East Yorkshire NHS Trust, The Anchorage, 11 Byland Road, Whitby YO21 1JH, United KingdomHelen.Clarke@tney.northy.nhs.uk
The largely empirical dopamine theory has limited value in clarifying the pathogenesis of schizophrenia, due to its inability to explain consistent imaging findings, such as cortical grey matter loss, reduced frontal and thalamic activity, and, reduced D1 receptor load.
Furthermore, the most effective drug for treating positive and negative symptoms - clozapine - has minimal dopaminergic activity whilst olanzapine often has substantial HYPERglycemia activity. An alternative HYPO-thesis, therefore, is proposed ... centring on presumed deficits in membrane bound glucose transporter proteins GLUT 1 and GLUT 3, either in absolute numbers or functional capacity.
In situations of high demand, intracellular HYPOglycemia in neurones and astrocytes will produce acute symptoms of misperceptions, misinterpretations, anxiety and irritability - the usual features of prodromal and first onset schizophrenia.
Furthermore, reduced glucose uptake will disrupt production of glutamate--functionally similar to the schizophrenia-like syndrome produced by PCP, a glutamate antagonist.
In the longer term, reduced neuronal growth and poor synaptic contacts will produce chronic cognitive difficulties and perpetuate acute symptoms. A backlog effect due to reduced brain uptake of glucose would produce systemic HYPERglycemia observed in drug naive subjects.
Rat studies have shown that clozapine and similar compounds block GLUT proteins in the brain and peripherally, more so than selective dopamine blockers. By blocking GLUT proteins, clozapine would break malfunctioning circuits, resulting in the disappearance of cognitive and perceptual symptoms.
Unfortunately, these drugs would also raise systemic glucose levels, increasing the risk of diabetes, as observed in longer term studies of clozapine in particular.
This HYPO-thesis summarizes potentially useful research strategies, including studying the genotype of GLUT proteins with respect to schizophrenia phenotypes, activation studies involving fMRI using deoxyglucose as a substrate, and investigating clinical features of Schizophrenic Patients prior to and following treatment for co-existing diabetes.
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