CARBOHYDRATE METABOLISM IN MOOD AND PSYCHOTIC DISORDERS: LINKING PATHWAY FLUX TO
PROTEONIMICS IN POSTMORTEM BRAIN
T. Regenold, M.D.C.M. and Pornima Phatak, Ph.D.
University of Maryland Department of Psychiatry, Geriatric Psychiatry Division
University of Maryland Medical Center, Baltimore, MD
Background: Measurement of fluxes through metabolic pathways can provide data
that link genomic and proteonomic data to pathophysiology and eventually
pharmacotherapy. A vulnerability to abnormal carbohydrate metabolism, evidenced
by increased rates of glucose intolerance or diabetes mellitus, has been
reported in patients with schizophrenia, bipolar disorder and major depression;
however, its relevance to the pathophysiology of these illnesses is unclear.
This study investigated the polyol pathway—by which glucose is converted by
aldose reductase to sorbitol—in these illnesses, because it has been linked to
nervous system disease in diabetes.
Using a gas chromatography-mass spectrometry (GC-MS) method, sorbitol, fructose,
and myoinositol concentrations were measured in 60 blocks of postmortem,
parietal lobe tissue—15 blocks from individuals with schizophrenia, bipolar
disorder, and nonpsychotic unipolar depression and 15 blocks from individuals
with no history of psychiatric illness or treatment—obtained from the Stanley
Foundation Brain Bank.
Median sorbitol concentrations (nmol/g wet tissue) of the three psychiatric
brain groups were significantly (p<0.05) greater than normal controls: schizophrenia (116); bipolar disorder (88); nonpsychotic unipolar depression (114); normal controls (45), (χ2=13.6, df=3, p=0.004). These
differences persisted after adjusting for the effect of postmortem interval and
brain pH as well as after excluding three diabetic brains from the analysis.
Furthermore, concentrations of fructose and sorbitol—the polyol pathway
metabolites of glucose—correlated positively and significantly with previously
reported elevated levels of fructose-1,6-bisphosphatase protein using a 2-D gel
technique with the same brains (Johnston-Wilson et al. Molecular Psychiatry
Conclusions: These results suggest that increased glucose flux through the
brain polyol pathway occurs in some individuals with schizophrenia, bipolar
disorder, and unipolar major depression. Correlation with proteonomic findings
related to carbohydrate metabolism suggests further that increased polyol
pathway activity may be part of a larger disturbance in brain carbohydrate
metabolism. Further studies investigating the relationship of polyol pathway
activity to indices of brain disease are needed to determine whether increased
polyol pathway activity is involved in the pathophysiology of mood and psychotic