Subscribe to RSS
DOI: 10.1055/s-2005-871240
Serum Concentrations of Haloperidol Pyridinium Metabolites and the Relationship with Tardive Dyskinesia and Parkinsonism: A Cross-Section Study in Psychiatric Patients
This publication is dedicated to Ines GärtnerPublication History
Received: 8.10.2004
Revised: 13.1.2005
Accepted: 2.3.2005
Publication Date:
18 July 2005 (online)
Introduction: The objective of this study was to provide more clinical data of the potential neurotoxic metabolite haloperidol pyridinium (HP+) in psychiatric patients during long-term treatment with haloperidol and to investigate a possible relationship with extrapyramidal adverse effects. Methods: Serum concentrations of HP+, reduced haloperidol pyridinium (RHP+), haloperidol (H), and reduced haloperidol (RH) were measured for 41 psychiatric patients of a nursing residence (27 females, 14 males, 34-79 years of age). Severity of tardive dyskinesia (TD) and parkinsonism were rated with the Tardive Dyskinesia Rating Scale (TDRS) and Extrapyramidal Symptom Rating Scale (EPS), respectively. In addition, several patient- and treatment-related variables were investigated, for example cumulative dose (Dcum) of haloperidol. Results: Serum concentration were 0.69 μg/L (0-1.53) for HP+ and 0.41 μg/L (0-1.50) for RHP+ with ratios HP+/H of 0.072 (0.017-0.18) and RHP+/RH of 0.094 (0-0.36) at doses of 10.6 mg/day (3.6-30) [mean (range) in each case]. Multiple regression revealed decreased clearance of HP+ with age. One third of patients with more severe TD (TDRS ≥ 10, n = 14) had an increased relative body burden of HP+ and H, as calculated by HP+/H * Dcum of haloperidol than patients with less severe or no TD (TDRS < 10, n = 27), i. e. 5.8 g (2.0-11.9) and 3.3 g (0-9.5), respectively [mean (range), p = 0.005, U test]. Patients with mild to severe parkinsonism (EPS > 0.3, n = 16) had a significantly higher aromatization ratio HP+/H than patients with no or minimal parkinsonism (EPS ≤ 0.3, n = 25), i. e. 0.14 (0.04-0.36) and 0.06 (0-0.16), respectively [mean (range), p = 0.003, U test]. Conclusion: In psychiatric patients treated with haloperidol for the long-term, the severity of TD and parkinsonism is associated with an increased ratio HP+/H. This is explained by the neurotoxicity of HP+ according to the pyridinium hypothesis.
References
- 1 Andreassen O A, Jorgensen H A. Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats: Implications for tardive dyskinesia. Progr Neurobiol. 2000; 61 525-541
- 2 Avent K M, Usuki E, Eyles D W. et al . Haloperidol and its tetrahydropyridine derivative (HPTP) are metabolized to potentially neurotoxic pyridinium species in the baboon. Life Sci. 1996; 59 1473-1482
- 3 Barret D H, Morris R D, Akhtar F Z. et al . Serum dioxin and cognitive functioning among veterans of Operation Ranch Hand. Neurotoxicology. 2001; 22 491-502
- 4 Blanchet P J, Konitsiotis S, Hyland K. et al . Chronic exposure to MPTP as a primate model of progressive parkinsonism: a pilot study with a free radical scavanger. Exp Neurol. 1998; 153 214-222
- 5 Bloomquist J, King E, Wright A. et al . 1-Methyl-4-phenylpyridinium-like neurotoxicity of a pyridinium metabolite derived from haloperidol: cell culture and neurotransmitter uptake studies. J Pharmacol Exp Ther. 1994; 270 822-830
- 6 Brockmöller J, Kirchheiner J, Schmider J. et al . The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment. Clin Pharmacol Ther. 2002; 72 438-452
- 7 Burkhardt C, Kelly J P, Lim Y H. et al . Neuroleptic medications inhibit complex I of the electron transport chain. Ann Neurol. 1993; 33 512-517
-
8 Casey D E. Tardive Dyskinesia: Pathophysiology. In: Bloom FE, Kupfer DJ, editors
Psychopharmacology: The fourth generation of progress . New York; Raven 1995: 1497-1502 - 9 Casey D E. Tardive dyskinesia: Pathophysiology and animal models. J Clin Psychiatry. 2000; 61 (4 Suppl.) 5S -9S
- 10 Davis G C, Williams A C, Markey S P. et al . Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res. 1979; 13 249 - 254
- 11 Eyles D W, Avent K M, Stedman T J. et al . Two pyridinium metabolites of haloperidol are present in the brain of patients at post-mortem. Life Sci. 1997; 60 529-534
- 12 Eyles D W, McGrath J J, Pond S M. Formation of pyridinium species of haloperidol in human liver and brain. Psychopharmacology. 1996; 125 214-219
- 13 Eyles D W, McLennan H R, Jones A. et al . Quantitative analysis of two pyridinium metabolites of haloperidol in patients with schizophrenia. Clin Pharmacol Ther. 1994; 56 512-520
- 14 Eyles D W, Pond S M, Van der Schyf C J. et al . Mitochondrial ultrastructure and density in a primate model of persistent tardive dyskinesia. Life Sci. 2000; 66 1345-1350
- 15 Fang J. Hyperactive behavioural effects induced by intranigral infusion of a pyridinium metabolite of haloperidol in rats. Can J Physiol Pharmacol. 1996; 74 1359-1361
- 16 Fang J, Yu P H. Effects of a quarternary pyridinium metabolite of haloperidol (HP+) on viability and catecholamine levels of cultured PC12 cells. Can J Physiol Pharmacol. 1997; 75 996-1000
- 17 Fang J, Zuo D, Yu P H. Comparison of cytotoxicity of a quaternary pyridinium metabolite of haloperidol (HP+) with neurotoxin N-methyl-4-phenylpyridinium (MPP+) towards cultured dopaminergic neuroblastoma cells. Psychopharmacology (Berl). 1995; 121 373-378
- 18 Halliday G M, Pond S M, Cartwright H. et al . Clinical and neuropathological abnormalities in baboons treated with HPTP, the tetrahydropyridine analog of haloperidol. Exp Neurol. 1999; 158 155-163
- 19 Haskel Y, Udassin R, Chevion M. Mechanistic aspects of 1-methyl-4-phenyl pyridinium iodide toxicity in E. coli: the role of oxygen and hydrogen peroxide. Israel J Med Sci. 1991; 27 207-212
- 20 Hertzman C, Wiens M, Bowering D. et al . Parkinson’s disease: a case-control study of occupational and environmental risk factors. Am J Ind Med. 1990; 17 349-355
- 21 Igarashi K, Castagnoli N J r. Determination of the pyridinium metabolite derived from haloperidol in brain tissue, plasma and urine by high-performance liquid chromatography with fluorescence detection. J Chromatogr B. 1992; 579 277-283
- 22 Iwahashi K, Anemo K, Nakamura K. et al . Analysis of the metabolism of haloperidol and its neurotoxic pyridinium metabolite in patients with drug-induced parkinsonism. Neuropsychobiology. 2001; 44 126-128
- 23 Johannessen J N. A model of chronic neurotoxicity: long-term retention of the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) within catecholaminergic neurons. Neurotoxicology. 1991; 12 285-302
-
24 Kane J M. Tardive dyskinesia: epidemiological and clinical presentation. In: Bloom FE, Kupfer DJ, editors
Psychopharmacology: The fourth generation of progress . New York; Raven 1995: 1485-1495 - 25 Kawashima H, Iida Y, Kitamura Y. et al . Brain extraction of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium ion (HPP+), a neurotoxic metabolite of haloperidol: studies using [3H]HPP+ . Jpn J Pharmacol. 2002; 89 426-428
- 26 Langston J W. The etiology of Parkinson’s disease with emphasis on the MPTP story. Neurology. 1996; 47 153S-160S
- 27 Lerer B, Segman R H, Fangerau H. et al . Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism. Neuropsychopharmacology. 2002; 27 105-119
- 28 Liou H H, Tsai M C, Chen C J. et al . Environmental risk factors and Parkinson’s disease: a case control study in Taiwan. Neurology. 1997; 48 1583-1588
- 29 McCormack A L, Thiruchelvam M, Manning-Bog A B. et al . Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis. 2002; 10 119-127
- 30 Miennie L J, Bergh J J, Van Staden E. et al . Metabolic defects caused by treatment with the tetrahydropyridine analog of haloperidol (HPTP), in baboons. Life Sci. 1997; 61 265-272
- 31 Pinto S S, Enterline P E, Henderson V. et al . Mortality experience in relation to a measured arsenic trioxide exposure. Environ Health Perspect. 1977; 19 127-130
- 32 Rollema H, Skolnik M, D'Engelbronner J. et al . MPP+-like neurotoxicity of a pyridinium metabolite derived from haloperidol: in vivo microdialysis and in vitro mitochondrial studies. J Pharmacol Exp Ther. 1994; 268 380-387
- 33 Russ H, Hihatsch W, Gerlach M. et al . Neurochemical and behavioural features induced by chronic low dose treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset: implications for Parkinson’s disease?. Neurosci Lett. 1991; 123 115-118
- 34 Sachdev P S. The current status of tardive dyskinesia. Aust N Z J Psychiatry. 2000; 34 355-369
- 35 Salvan A, Thomaseth K, Bortot P. et al . Use of a toxicokinetic model in the analysis of cancer mortality in relation to the estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD). Sci Total Environ. 2001; 274 21-35
- 36 Simpson G M, Angus J WS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand. 1970; 212 11S-119S
- 37 Simpson G M, Lee J H, Zoubok B. et al . A rating scale for tardive dyskinesia. Psychopharmacol (Berl). 1979; 64 171-179
- 38 Steuerwald U, Weihe P, Jorgensen P J. et al . Maternal seafood diet, methylmercury exposure, and neonatal neurologic function. J Pediatr. 2000; 136 599-605
- 39 Stübner S, Rustenbeck E, Grohmann R. et al . Severe and uncommon involuntary movement disorders due to psychotropic drugs. Pharmacopsychiatry. 2004; 37 (S1) 54-64
- 40 Subramanyam B, Pond S M, Eyles D W. et al . Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol. Biochem Biophys Res Commun. 1991a; 181 573-578
- 41 Subramanyam B, Rollema H, Woolf T. et al . Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats. Biochem Biophys Res Commun. 1990; 166 238-244
- 42 Tsang M W, Shader R I, Greenblatt D J. Metabolism of haloperidol: clinical implications and unanswered questions. J Clin Psychopharmacol. 1994; 14 159-162
- 43 Ulrich S, Neuhof S, Braun V. et al . Therapeutic window of serum haloperidol concentration in acute schizophrenia and schizoaffective disorder. Pharmacopsychiatry. 1998; 31 163-169
- 44 Ulrich S Neuhof S, Braun V. et al . Reduced haloperidol does not interfere with the antipsychotic activity of haloperidol in the treatment of acute schizophrenia. Int Clin Psychopharmacol. 1999; 14 219-228
- 45 Ulrich S, Neuhof P, Braun V. et al . Disposition of haloperidol pyridinium and reduced haloperidol pyridinium in schizophrenic patients: no relationship with clinical variables during short-term treatment. J Clin Psychopharmacol. 2000; 20 210-219
- 46 Van der Schyf C J, Dormehl I C, Oliver D. et al . Long-term treatment with the tetrahydro-pyridine analog (HPTP) of haloperidol influences dopamine ligand binding in baboon brain. An [123I]iodobenzamide (IBZM) SPECT study. Brain Res Mol Brain Res. 1996; 43 251-258
- 47 Weiss B, Clarkson T W, Simon W. Silent latency in methylmercery poisoning and in neurodegenerative disease. Environ Health Perspect. 2002; 110 (5 Suppl.) 851S-854S
- 48 Wright A M, Bempong J J, Kirby M L. et al . Effects of haloperidol metabolites on neuro-transmitter uptake and release: possible role in neurotoxicity and tardive dyskinesia. Brain Res. 1998; 788 215-222
- 49 Yassa R, Dimitry R. Single phenothiazines and tardive dyskinesia. J Clin Psychiatry. 1983; 44 233-234
Dr. PD Sven Ulrich
Institute of Clinical Pharmacology
University Hospital Magdeburg
Leipziger Strasse 44
39120 Magdeburg
Germany
Phone: +49 391 6713060
Fax: +49 391 6713062
Email: SUlrichMagdeburg@aol.com