HPP+ may contribute to the development ofextrapyramidal symptoms (EPS) in patients undergoing long-term haloperidol therapy.[2] An alternative theory posits that these symptoms result from long-termdopamine receptorsupersensitivity, rather than direct neurotoxicity.[2]
HPP+ was first identified as a neurotoxic metabolite of haloperidol in 1990 and 1991, many years after haloperidol was introduced clinically and following the discovery of MPTP.[2][5][6][7]
No relationships were found for serum concentrations of HPP+ or the ratio of serum concentrations of HPP+ and haloperidol with clinical variables (changes of Brief Psychiatric Rating Scale, Extrapyramidal Symptom Rating Scale) during the treatment of acute exacerbations of schizophrenic patients for 6 weeks.[9] In a cross section study of chronic schizophrenic patients treated with haloperidol, the patients with more severe tardive dyskinesia had an increased relative body burden of HPP+ as calculated by the ratio of HPP+ and haloperidol serum concentrations multiplied by the cumulative dose of haloperidol.[10]
^abcdKostrzewa RM (2022). "Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons".Handbook of Neurotoxicity. Cham: Springer International Publishing. pp. 159–198.doi:10.1007/978-3-031-15080-7_53.ISBN978-3-031-15079-1.
^abcdefghiIgarashi K (1998). "The Possible Role of an Active Metabolite Derived from the Neuroleptic Agent Haloperidol in Drug-Induced Parkinsonism".Journal of Toxicology: Toxin Reviews.17 (1):27–38.doi:10.3109/15569549809006488.ISSN0731-3837.
^Górska A, Marszałł M, Sloderbach A (October 2015). "[The neurotoxicity of pyridinium metabolites of haloperidol]" [The neurotoxicity of pyridinium metabolites of haloperidol].Postepy Higieny I Medycyny Doswiadczalnej (in Polish).69:1169–1175.doi:10.5604/17322693.1175009 (inactive 12 July 2025).PMID26561842.{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link)
^Castagnoli N, Castagnoli KP, Van der Schyf CJ, Usuki E, Igarashi K, Steyn SJ, et al. (1999). "Enzyme-catalyzed bioactivation of cyclic tertiary amines to form potential neurotoxins".Polish Journal of Pharmacology.51 (1):31–38.PMID10389142.
^Subramanyam B, Rollema H, Woolf T, Castagnoli N (January 1990). "Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats".Biochemical and Biophysical Research Communications.166 (1):238–244.doi:10.1016/0006-291x(90)91936-m.PMID2302206.
^Subramanyam B, Woolf T, Castagnoli N (1991). "Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite".Chemical Research in Toxicology.4 (1):123–128.doi:10.1021/tx00019a017.PMID1912294.
^Subramanyam B, Pond SM, Eyles DW, Whiteford HA, Fouda HG, Castagnoli N (December 1991). "Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol".Biochemical and Biophysical Research Communications.181 (2):573–578.doi:10.1016/0006-291x(91)91228-5.PMID1755839.
^Avent KM, DeVoss JJ, Gillam EM (July 2006). "Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites".Chem Res Toxicol.19 (7):914–920.doi:10.1021/tx0600090.PMID16841959.
^Ulrich S, Neuhof S, Braun V, Danos P, Pester U, Hoy L (April 2000). "Disposition of haloperidol pyridinium and reduced haloperidol pyridinium in schizophrenic patients: no relationship with clinical variables during short-term treatment".J Clin Psychopharmacology.20 (2):210–219.doi:10.1097/00004714-200004000-00014.PMID10770460.
^Ulrich S, Sandmann U, Genz A (July 2005). "Serum concentrations of haloperidol pyridinium metabolites and the relationship with tardive dyskinesia and parkinsonism: a cross-section study in psychiatric patients".Pharmacopsychiatry.38 (4):171–177.doi:10.1055/s-2005-871240.PMID16025420.
