Serum concentrations of haloperidol pyridinium metabolites and the relationship with tardive dyskinesia and parkinsonism: a cross-section study in psychiatric patients.
BACKGROUND
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 microg/L (0-1.53) for HP+ and 0.41 microg/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 > or = 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 < or = 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].


CONCLUSIONS
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.
Ulrich
S
S
Institute of Clinical Pharmacology, University Hospital, Otto-von-Guericke University, Magdeburg, Germany. SUlrichMagdeburg@aol.com
Sandmann
U
U
Genz
A
A
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D014150:Antipsychotic Agents / Q000097:blood* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000097:blood* / Q000453:epidemiology; D005260:Female; D006220:Haloperidol / Q000097:blood* / Q000627:therapeutic use; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010302:Parkinson Disease, Secondary / Q000097:blood* / Q000453:epidemiology; D011618:Psychotic Disorders / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D011726:Pyridinium Compounds / Q000097:blood*; D012189:Retrospective Studies; D013050:Spectrometry, Fluorescence
D014150:Antipsychotic Agents; D011726:Pyridinium Compounds; D006220:Haloperidol