Serum Concentrations of Haloperidol Pyridinium Metabolites and the Relationship with Tardive Dyskinesia and Parkinsonism: A Cross-Section Study in Psychiatric Patients

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 (D_cum) 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 * D_cum 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.

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