Is free radical pathology of any consequence in schizophrenia and its treatment

Abstract

There is growing evidence that toxic free radicals may contribute to the pathology of many neuropsychiatric disorders e.g., (Science 262:689, 1993; Arch Gen Psychiatry, 48:1097,1991). Whether increased oxidative stress contributes to the development of these disorders or alters their phenotype remains to be determined. However, that free radicals can produce pathological alterations in cellular constituents is indisputable. Specific targets of fTee radical-induced damage include membranes and their constituents, mitochondria, chromosomes, and cytosolic enzymes. Although free radicals are ubiquitous and normally of little threat, damage can occur due to generation of excess free radicals, deficient antioxidant mechanisms or both processes. The possibility that free radicals may contribute to schizophrenic pathophysiology was first proposed by Hoffer et al. (1954). Subsequently an increasing number of studies have found alterations in various indices of free radical metabolism (e.g., Biol Psychiatry 30:409,1991). The findings from these studies converge to suggest that altered free radical metabolism may be associated with specific domains of pathology (CT scan abnormalities, negative symptoms, tardive dyski. nesia). There also is accumulating evidence from animal and human studies of neuroleptic-indueed free radical damaf~¢, and that antioxidants (e.g., ct.tocopherol) decrease the severity of tardive dyskinesia and psychopathology. Taken together, there Is to date sufficient evidence to make worthwhile the examination of free radical-mediated pathology in schizophrenia. A review of the findings from human, animal, and in vitro studies will be presented, with the aim of developing testable hypotheses, future research directions and therapeutic strategies.