Haloperidol Cytotoxicity and Its Relation to Oxidative Stress

Abstract

Haloperidol (HP) is used for the symptomatic treatment of psychosis, manic phases, hyperactivity, aggressiveness, and acute delirium. Long-term use leads to various adverse side effects, especially to severe impairment of extrapyramidal nerve tracts and in particular, altered QT interval and increased incidence of arrhytmias. It is believed that cytotoxicity of HP and its metabolites is responsible for both neurotoxicity and cardiotoxicity. Extrapyramidal and cardiac adverse side effects may be explained by the HP-induced oxidative stress, as implicated by many studies. HP was reported to induce lipid peroxidation with subsequent membrane changes, responsible for cell death. Vice versa, cells resistant to oxidative stress are also resistant to the toxic effects of HP. Similarly, high percentage of patients suffering from extrapyramidal symptoms treated by vitamin E and other lipid-soluble antioxidants demonstrates diminishing of these adverse side effects. HP's ability to induce oxidative stress by multi-modal action (increased metabolism of dopamine, decrease of glutathione content, induction of NF-κB transcription factor, and inhibition of complex I of respiratory chain) has been established just recently. This review brings summarizing view on the cytotoxicity of haloperidol and involvement of reactive oxygen species and oxidative stress HP-induced cytotoxicity.

The Effect of Antipsychotic Treatment on Cortical Gray Matter Changes in Schizophrenia: Does the Class Matter? A Meta-analysis and Meta-regression of Longitudinal Magnetic Resonance Imaging Studies

“…It has been hypothesized that SGAs may have a neuroprotective effect, either increasing the expression of neurotrophic factors (41) or stimulating neurogenesis (42) or interacting with and increasing the activity of N-methyl-D-aspartate glutamate receptors (43). Conversely, the excessive reduction in cortical GM observed in patients treated with FGAs may be attributable to a direct neurotoxic effect secondary to oxidative stress and/or excitotoxic phenomena, which have been well documented in animals treated with haloperidol (44)(45)(46)(47)(48). It may also indicate a hypothetical lower capacity of FGAs to interfere with the natural pathophysiologic trajectory of the disease, which may also be reflected in the different impact on cerebral blood flow and metabolism of FGAs versus SGAs (49-55).…”

Alleviation of haloperidol induced oxidative stress in rats: Effects of sucrose vs grape seed extract

“…13 HP is cytotoxic to primary hippocampal neurons. 14 It was demonstrated that it causes necrotic death rather than apoptotic.…”

Risk of Mortality Among Patients Treated With Antipsychotic Medications

“…19 Because of the high acceptance rate and low price, haloperidol became one of the most widely used antipsychotic medications, particularly for managing acute conditions. 20 Therefore, whether haloperidol increases the risk of mortality is a serious public health concern. Most pharmacoepidemiological studies have involved a specific patient group, such as elderly adults, dementia patients, 21,22 and schizophrenic patients.…”