Worsening of motor function in Parkinson’s disease

Neuroleptic medications, which block dopamine receptors, are effective antipsychotic agents. They have, however, been fraught with adverse effects, particularly extrapyramidal syndromes (EPS). The new generation of antipsychotics are referred to as “atypical” antipsychotics because their antipsychotic actions are rarely associated with acute or subacute EPS in psychiatric populations.1

Psychosis occurs in approximately 20% of patients with PD who are treated with antiparkinsonian agents, and is the number one cause of nursing home placement.2 Patients with PD are, however, extremely sensitive to antidopaminergic actions of drugs. Until fairly recently, clinicians attempting to treat drug-induced psychosis in PD were in a quandary. Potential treatment strategies were limited to the equally unsatisfactory options of reducing the antiparkinsonian medications or using a neuroleptic, both of which generally worsened motor function.

Recently, the “atypical” antipsychotic clozapine was found to be an effective and well-tolerated treatment for drug-induced psychosis in PD, based on a multicenter, double-blind, placebo-controlled trial.3 Clozapine, in dosages dramatically lower than those generally used in primary psychiatric patients, not only failed to worsen motor function, it actually reduced tremor. The major problem with clozapine is the risk for fatal agranulocytosis that necessitates rigorous monitoring of the white blood cell count. None the less, the ability to reduce disabling psychosis without worsening motor function has been, for many, a reason to use clozapine.

Several newer antipsychotics have been developed with the hope that they too would be “atypical” antipsychotics, in that they would have efficacy without EPS, but that unlike clozapine, they would not carry the risk of agranulocytosis or other serious adverse

effects. The first “atypical” antipsychotic to be widely used was risperidone. However, it was quickly recognized to worsen parkinsonian motor function.4 This observation suggested that motor response to new antipsychotic medications in patients with PD may be a very sensitive indicator of potential EPS. Other promising “atypical” antipsychotics include olanzapine and quetiapine. Uncontrolled studies have suggested that they may improve psychosis in PD without worsening motor function.5-8⇓⇓⇓

However, two studies in this issue have cast doubt on the appropriateness of olanzapine for the treatment of psychosis in PD. Goetz et al.9 conducted a double-blind comparison of clozapine and olanzapine for the treatment of drug-induced psychosis in PD. They concluded that olanzapine, as opposed to clozapine, aggravated parkinsonism and was not as efficacious as clozapine against psychosis. This is a small but well-designed study. Despite randomization, there is a difference in baseline motor impairment between the two treatment groups, with the clozapine group being worse. The relevance of this when interpreting the results is not clear. The study, which was powered to detect antipsychotic efficacy, was cut short due to worsening of motor function in the olanzapine treated group.

In an effort to determine whether or not olanzapine could be used to control dyskinesias, Manson et al.10 conducted a small, randomized, placebo-controlled, double blind crossover trial in which patients with PD received 2-week courses of olanzapine or placebo with 1-week washout between phases. Low-dose olanzapine reduced dyskinesias but increased parkinsonism and “off” time. These results not only indicate the potential hazards of using olanzapine in PD, but raise questions about the pharmacological feasibility of eliciting an antidyskinetic effect without increasing parkinsonism.

The studies involving olanzapine that are reported in this issue are important because they contradict the conclusion based on uncontrolled studies; that olanzapine is an effective and well-tolerated antipsychotic in PD.7,8⇓ This highlights the larger issue of the need for controlled clinical trials to guide clinicians. It is impressive that these two small controlled trials found a prominent worsening of parkinsonism when some open trials missed the effect. The search for the ideal antipsychotic agent continues and we eagerly await controlled trials of other “atypical” agents (e.g., quetiapine) for the treatment of psychosis in PD. For now, clozapine in low doses is the only antipsychotic medication proven to treat drug-induced psychosis without worsening motor function in PD.