Clozapine in Parkinsonian Rest Tremor: A Review of Outcomes, Adverse Reactions, and Possible Mechanisms of Action

Background: The pathogenesis of rest tremor in Parkinson's disease (PD) is incompletely understood. This symptom can be resistant to typical anti-PD medications. Therefore, new treatments are needed given the concern that this symptom causes to patients and family. Limited experience suggests that clozapine can have an important antitremor effect in PD. The mechanism(s) underlying this effect is not well understood, but could provide insight and impetus to the development of more-effective and safer antitremor therapies. Methods and Results: Exemplifying the antitremor effects of clozapine, we describe a patient with tremor-predominant PD who obtained prominent reduction of rest tremor with clozapine treatment. We review the responses to this treatment in another 7 of our PD patients with treatment-resistant rest tremor. We also review the published literature on clozapine for tremor in PD and discuss its potential mechanisms of action and possible adverse effects. In our case series, there was a 64% reduction of tremor score after clozapine was initiated. The mechanism of tremor reduction remains unclear with possible involvement of anticholinergic, serotonergic, antihistaminergic, antiadrenergic, and antidopaminergic effects. Clozapine does have potential serious adverse effects. Conclusions: Clozapine may be effective in controlling rest tremor in PD. Given the potential fatal side effects, if clozapine is to be initiated in PD patients, it has to be used cautiously with proper monitoring, preferably in specialized centers. We acknowledge that the number of patients in this case series is small. Further studies are needed to understand clozapine's mechanism of action in reducing tremor.