Increased hexosaminidase activity in antipsychotic-induced extrapyramidal side effects: Possible association with higher occurrence in bipolar disorder patients

Abstract

Dystonic movements and Parkinsonism are frequently seen in gangliosidoses and these conditions have been reported to modify dopaminergic plasticity. We investigated whether the activity of hexosaminidase, a type-two ganglioside (GM2) degrading enzyme, correlates with drug-induced extrapyramidal system (EPS) side effects in psychiatric patients. We compared hexosaminidase activity in the lymphocytes of 29 EPS-positive patients, 13 EPS-negative patients, and 30 healthy volunteers. The activities of A and B isoforms of hexosaminidase were higher in EPS-positive patients than EPS-negative patients and healthy controls. Multivariate analysis suggested an interaction with increased B isoform activity and EPS side effects in female bipolar disorder patients. Higher levels of hexosaminidase enzyme activity may explain the frequent occurrence of antipsychotic-induced extrapyramidal side effects in mood disorder patients.

Introduction

Although antipsychotic-induced extrapyramidal system (EPS) side effects are related to dopamine blockade, the full pathophysiology of drug-related Parkinsonism, acute dystonia and tardive dyskinesia is not completely understood (Casey, 2004). Gangliosides are sialic acid-containing phospholipids whose synthesis begins with the formation of ceramide, a very long chain fatty acid (Marinetti, 1990). These sialic acid-containing phospholipids affect dopaminergic plasticity (Agnati et al., 1983) and, subsequently, neuroleptic-induced dopaminergic supersensitivity (Vital et al., 1995). Type-two gangliosides (GM2) accumulate particularly in the caudate nucleus (Siegel and Walkley, 1994), and are degraded by hexosaminidase (β-N-acetylhexosaminidase), a lysosomal enzyme with two isoforms, A and B (O'Brien, 1987). Deficiency of isoform A has been reported to be associated with neuroleptic malignant syndrome (NMS) (Manor et al., 1997, Rosebush et al., 1995), Parkinsonian symptoms, as well as severe dystonia in Tay-Sachs disease (Hurowitz et al., 1993, Rosebush et al., 1995, Streifler et al., 1989). On the other hand, increased hexosaminidase activity has been reported in torticollis and writer's cramp diseases (Costanzi et al., 1999).

Antipsychotic drugs appear to be unsuccessful in treating patients with isoform A hexoaminidase deficiency, and such medications may even worsen the underlying pathology by depleting cellular hexosaminidase (Hurowitz et al., 1993, Ovsiew, 1993, Shapiro et al., 2006, Zelnik et al., 2000). However, type 1 gangliosides (GM1) have been found to be effective treatments for Parkinson disease and tardive dyskinesia (Schneider et al., 1992, Sommer et al., 1994).

In order to examine the relationship between ganglioside metabolism and EPS side effects, we investigated the activity of A and B isoforms of beta-hexosaminidase in groups of patients with and without antipsychotic drug-induced EPS side effects. Our hypothesis was that EPS-positive patients would have lower activity of the A isoform of beta-hexosaminidase than EPS-negative patients.