Pharmacopsychiatry 2005; 38 - 90
DOI: 10.1055/s-2005-862703

Haloperidol Pyridinium Serum Levels and Tardive Dyskinesia

S Ulrich 1, U Sandmann 1, 2, A Genz 2
  • 1Institute of Clinical Pharmacology, University Hospital Magdeburg, Germany
  • 2 Psychiatric Clinic Haldensleben, Germany

The potential neurotoxic metabolite haloperidol pyridinium (HP+) has been investigated mainly in pre-clinical studies as an analogue of the established neurotoxin 1-methyl-4-phenylpyridinium (MPP+) for about 10 years. According to the pharmacokinetic approach, it is expected that high serum concentrations of HP+ are related to tardive dyskinesia (TD) in psychiatric patients treated with haloperidol.

Serum concentrations of HP+, reduced haloperidol pyridinium (RHP+), haloperidol (H) and reduced haloperidol (RH) were measured in 41 psychiatric patients of a nursing residence (27 female, 14 male, 34–79 years of age) who were treated with haloperidol for many years. Severity of 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.

Serum concentration were 0.69µg/L (0–1.53) for HP+ and 0.41µg/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 10.6mg/day (3.6–30) (mean (range)). Multiple regression revealed decreased clearance of HP+ with age. Patients with serious TD (TDRS ≥ 10, n=14) had an increased relative body burden HP+/H * Dcum of haloperidol in comparison with patients with less serious or no TD (TDRS <10, n=27), i.e. 5.8g (2.0–11.9) and 3.3g (0–9.5), respectively (mean (range), p=0.005, U test). Patients with mild to serious 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).

In conclusion, serious TD and parkinsonism are associated with an increased ratio HP+/H in psychiatric patients treated with haloperidol for the long-term. This may be explained by the neurotoxicity of HP+ according to the pyridinium hypothesis.