Multiple neurotoxic effects of haloperidol resulting in neuronal death.

Several published studies have reported an association between antipsychotic medications, especially first-generation agents, and a decline in gray matter volume. This prompted us to review the possible neurotoxic mechanisms of first-generation antipsychotics (FGAs), especially haloperidol, which has been widely used over the past several decades.A PubMed search was conducted using the keywords haloperidol, antipsychotic, neurotoxicity, apoptosis, oxidative stress, and neuroplasticity. No restrictions were placed on the date of the articles or language. Studies with a clearly described methodology were included.Animal, cell culture, and human tissue studies were identified. Thirty reports met the criteria for the search. All studies included haloperidol; a few also included other FGAs (fluphenazine and perphenazine) and/or second-generation agents (SGAs) (aripiprazole, paliperidone, and risperidone). A neurotoxic effect of haloperidol and other FGAs was a common theme across all studies. Minimal (mainly at high doses) or no neurotoxic effects were noted in SGAs.A review of the literature suggests that haloperidol exerts measurable neurotoxic effects at all doses via many molecular mechanisms that lead to neuronal death. A similar effect was observed in 2 other FGAs, but the effect in SGAs was much smaller and occurred mainly at high doses. A stronger binding to serotonin 5HT-2A receptors than to dopamine D2 receptors may have a neuroprotective effect among SGAs. Further studies are warranted to confirm these findings.