Clozapine for the treatment of levodopa-induced dyskinesias

Abstract

1 recently investigated the efficacy and safety of clozapine, an atypical neuroleptic, for the treatment of LID in patients with PD. This is the first randomised, parallel-group, placebo-controlled study showing that low dose clozapine is effective in reducing LID in patients with advanced PD. Previous studies were open-label in design and involved small groups of patients. Duriff and colleagues 1 randomly assigned 50 patients to receive suggest that the ability of clozapine to reduce LID in PD could be related to its D1 receptor antagonist activity. Selective D1 receptor antago- nists have not yet been tested in patients with PD; however, in MPTP-treated monkeys, selective D1 receptor antago- nists improve LID but worsen parkinsonism. 3 In Duriff's study, low dose clozapine did not compromise the relief of parkinsonian symptoms, which suggests that the antidyskinetic effect of this drug does not rely on a direct dopaminergic mechanism. There is now strong evidence that pulsatile, rather than continuous, stimulation of striatal dopamine receptors by dopamine (derived from exogenous levodopa) induces plastic changes in striatal medium spiny neurons in the presence of dopamin- ergic neuron loss and the loss of their storage capacity. 4 Alterations in the function of medium spiny neurons can disregulate information flow into and through the ouput nuclei of the basal ganglia. Experimental data have provided valuable evidence that non- physiological, intermittent stimulation of striatal dopamine receptors can lead to aberrant activation of intracellular protein kinase signalling cascades in medium spiny neurons; in turn this causes hyperphosphorylation and upregulation of glutamatergic receptor (NMDA and AMPA) subunits. Indeed, the pharmacological blockade of these receptors with amantadine and other NMDA receptor antagonists decreases LID in patients with PD. Activation of adenosine A2A receptors, which are expressed on striatal medium spiny neurons, may also contribute to the hyperphosphorylation of glutamatergic subunits via a similar mechanism. Recently, istradefylline (KW6002), an adenosine A2A receptor antagonist, was shown to reduce off time without increasing severity of dyskinesias in patients with fluctuating PD in a randomised controlled trial. 5