Effects of haloperidol on antioxidant defense system enzymes in schizophrenia

Abstract

Dysregulation of free radical metabolism as reflected by abnormal erythrocyte activities of three critical enzymes of the antioxidant defense system (AODS), i.e. superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), has been reported in schizophrenic patients. The present study examined the effects of haloperidol, a standard antipsychotic agent, on the AODS enzymes, using a within-subject, repeated-measures, on–off haloperidol treatment design. The mean drug free period was 40 days. At baseline, there were no significant differences for all three enzymes between patients and age and sex-matched normal volunteers. During the drug-free condition, SOD activity, but not GSH-Px and CAT activities, was significantly higher relative to normal control subjects. However, within-subjects both SOD and GSH-Px activities, but not CAT activity, were higher in the drug-free condition compared to the treatment condition. No significant correlation was observed between SOD activity and plasma haloperidol (or daily haloperidol dose) levels. Smoking status, as assessed by the cotinine level, was unrelated to enzyme activities. In addition, none of the major AODS enzymes showed significant differences between relapsed and clinically stable patients. These findings suggest that haloperidol may not have direct regulatory effect on AODS enzyme activities and that SOD and GSH-Px activities may change in response to other factors such as change in symptom severity.

Introduction

Biological systems have evolved complex protective strategies against free radical toxicity. Free radicals, such as superoxide ion and hydroxyl radicals, are reactive chemical species generated during normal metabolic processes and, in excess, can damage lipids, proteins and DNA. Regions of high oxygen consumption, lipid content and transition metals are at particular risk. Hence, neuronal membranes are uniquely vulnerable to radical-mediated damage. Under physiological conditions the potential for free radical-mediated damage is kept in check by the antioxidant defense system, comprising a series of enzymatic and non-enzymatic components. The critical antioxidant enzymes include superoxide dismutase (SOD; E.C. 1.15.1.6), catalase (CAT; E.C. 1.11.1.6) and glutathione peroxidase (GSH-Px; E.C. 1.11.1.9). These enzymes act cooperatively at different sites in the metabolic pathway of free radicals.

SOD dismutates superoxide radicals to form hydrogen peroxide, which in turn is decomposed to water and oxygen by GSH-Px and CAT, thereby preventing the formation of hydroxyl radicals (see Fig. 1). Failure of this first line antioxidant defense may lead to an initiation of lipid peroxidation. Since SOD, CAT and GSH-Px are critical to different stages of free radical metabolism, altered activity of one enzyme without compensatory changes in other enzymes may leave membranes vulnerable to damage. Thus, the differential patterning of the antioxidant enzyme activities may provide important clues to the pathogenetic mechanisms of abnormal free radical metabolism (Reddy et al., 1991).

There is evidence that free radicals are involved in membrane pathology and may play a role in schizophrenia (Lohr and Cadet, 1987; Lohr, 1991; Reddy and Yao, 1996; Mahadik and Mukherjee, 1996; Smythies, 1997). This is suggested specifically by the findings of abnormal activities of critical antioxidant enzymes and other indices of lipid peroxidation in plasma, red blood cells (Michelson et al., 1977; Golse et al., 1978a; Golse et al., 1978b; Abdalla et al., 1986; Reddy et al., 1991) and cerebrospinal fluid (Lohr et al., 1990). Such abnormalities have been associated with tardive dyskinesia (Cadet et al., 1986; Lohr and Cadet, 1987; Cadet and Lohr, 1989), negative symptoms (Buckman et al., 1987; Buckman et al., 1990), neurological signs, poor premorbid function (Mukherjee et al., 1994) and CT scan abnormalities (Buckman et al., 1987; Buckman et al., 1990). A majority of these studies were conducted in patients being treated with neuroleptics, a methodological confound that merits examination. There is evidence from animal studies that short-term treatment with neuroleptics lead to variable changes of SOD, CAT and GSH-Px activities in brain and levels of lipid peroxidation (Reddy and Yao, 1996). If indeed neuroleptics have specific and direct effects on the antioxidant defense system, then the notion that free radicals have a pathophysiological role in schizophrenia will need to be reassessed.

To examine the specific effects of a commonly used antipsychotic, the present investigation was designed to assess the effects of haloperidol treatment on the antioxidant defense system (AODS) enzymes in chronic schizophrenic patients by using a within-subject, repeated-measures, on–off haloperidol treatment design.