The Pathophysiology of Psychosis May Be Nonspecific

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The Pathophysiology of Psychosis May Be Nonspecific

Years after Kraepelin differentiated between dementia praecox and manic-depressive insanity, he could no longer tell them apart with certainty. In postmortem brain studies of 15 patients with schizophrenia, 15 with bipolar disorder (11 psychotic), 15 with nonpsychotic unipolar depression, and 15 controls, researchers measured messenger RNA and proteins associated with reelin, glutamic acid decarboxylase₆₇ (GAD₆₇), GAD₆₅, and disabled-1 gene product (DAB-1). The glycoprotein reelin acts via intracellular DAB-1 to promote synaptic spine maturation and plasticity associated with learning. GAD₆₇ regulates the activity of GABAergic neurons, which downregulate reelin expression in cortical areas implicated in schizophrenia.

Compared with controls, patients with schizophrenia or psychotic bipolar disorder, but not nonpsychotic bipolar disorder or unipolar depression, had 50 percent reductions of reelin messenger RNA and GAD₆₇ protein in the prefrontal cortex. Cell loss did not cause these reductions because other neuronal markers such as GAD₆₅ and DAB-1 messenger RNA and protein were not altered in the psychotic patients. The degree of reduction did not correlate with lifetime dose of antipsychotic drugs; psychotic patients who had never received antipsychotic medications had the same changes.

Comment: Because reelin is involved in learning and early development of neuronal architecture, loss of reelin could lead to abnormal synaptic structure and function in the prefrontal cortex and other areas found to be abnormal in schizophrenia. Reelin loss also could account for indicators of abnormal information processing, such as the sensory-gating deficit found in patients with schizophrenia and bipolar disorder. The findings of this study suggest that the interactions among risk factors for psychosis, defective social interaction, and mood regulation, all of which may have entirely different etiologies, determine whether someone will develop schizophrenia, psychotic mood disorder, or another psychotic illness.

— S Dubovsky

Published in Journal Watch Psychiatry January 9, 2001

Citation(s):

Guidotti A et al. Decrease in reelin and glutamic acid decarboxylase₆₇ (GAD₆₇) expression in schizophrenia and bipolar disorder: A postmortem brain study. Arch Gen Psychiatry 2000 Nov 57 1061-1069.

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