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Effects of zonisamide on tardive dyskinesia: A preliminary open-label trial

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Abstract

Once developed, tardive dyskinesia (TD) is a challenging condition to treat. The recent evidence has indicated that zonisamide, an antiepileptic drug indicated for partial-onset seizures, may also have beneficial effects for ameliorating dyskinesia in Parkinson's disease. However, this finding has not systematically been tested in psychiatric patients with TD associated with antipsychotic treatment. The objective of this study was to examine the efficacy, tolerability, and safety of zonisamide against TD in these patients. In this 4-week open-label study, subjects who suffered TD were given 50–100 mg/day of add-on zonisamide. Severity of TD was evaluated at the baseline and endpoint, using the Abnormal Involuntary Movement Scale (AIMS). Eleven subjects (6 females; mean ± SD age, 75.5 ± 4.7 years; schizophrenia [N = 6], bipolar affective disorder [N = 2], schizoaffective disorder [N = 1], mental retardation [N = 1], mental retardation with epilepsy [N = 1]; 6 were antipsychotic free at baseline) participated in this study. The AIMS total score (mean ± SD) was significantly decreased from 24.1 ± 5.5 to 19.5 ± 5.9, with 36.4% of the subjects (N = 4) demonstrating 20% or more decrease in the AIMS total score. Treatment with zonisamide was well-tolerated and no participants dropped out prematurely. In conclusion, zonisamide may be safe and effective for the treatment of TD associated with antipsychotic treatment. These preliminary findings need to be further explored by larger well-designed trials.

Introduction

Second-generation antipsychotics (SGAs) may result in a lower likelihood of development of tardive dyskinesia (TD) than first-generation antipsychotics (FGAs). Studies on the prevalence/incidence of TD are challenging since the study duration should be sufficiently long and the ascertainment of TD be ideally made with a standardized definition. This is important since TD typically develops after long-term (i.e., decades of) use of antipsychotics. Additionally, as SGAs have been in the market for a relatively short period of time, it may be premature to unequivocally say that SGAs yield a lower incidence of TD.

In recent years, some articles indeed showed that TD incidence was higher with a usage of SGAs than previously thought [1]. Naturalistic study by De Leon indicated that, in 516 severely mentally ill patients, there were no significant differences in the prevalence of TD between patients treated with SGAs versus FGAs [2]. Another prospective cohort study on 352 patients also found no significant difference in the incidence of TD between patients treated with FGAs and SGAs. According to the data from this study, the incidence and the prevalence were similar to previous findings at the same site two decades earlier [3], challenging a notion that SGAs are more favorable in this respect.

Taken together, it is not yet completely clear if SGAs result in a lower incidence of TD and it is at this moment fair to say that they could still be associated with TD. A lack of thorough understanding on pathophysiology of TD renders various treatment interventions generally disappointing; in fact, although many potentially effective strategies have been suggested, no single treatment has proven specifically useful for TD [4], making prevention a priority.

Zonisamide is a sulfonamide antiepileptic drug indicated for partial-onset seizures, infantile spasm, mixed seizure types of Lennox–Gastaut syndrome, myoclonic, and generalized tonic clonic seizures [5]. Interestingly, recent double-blind trials showed that low doses of zonisamide improved Parkinsonism and wearing-off phenomena in patients with Parkinson's disease [6]. Furthermore, a decrease in dyskinesia severity was observed in patients who were receiving 50 mg of zonisamide [6], which suggests a potential clinical utility of this agent for the treatment of TD. Furthermore, one case series demonstrated the effectiveness of zonisamide for TD in patients with schizophrenia (n = 5) and vascular dementia (n = 4) [7]. However, a lack of systematic trials limits interpretation of the data. As such, this preliminary open-label study investigated the usefulness of this medication for TD associated with antipsychotic treatment in psychiatric patients.

Section snippets

Participants

In- and outpatients were included if they fulfilled the following inclusion criteria: (1) age 18 years or older, (2) diagnosis of any psychiatric disorder according to the International Classification of Diseases and Related Health Problems, the 10th version (ICD-10) [8], and (3) meeting the research diagnostic criteria for TD proposed by Schooler and Kane [9]. For safety reasons, subjects with clinically unstable psychopathology or medical conditions were excluded.

This study was conducted at

Clinical characteristics of study participants

A total of 11 (6 females; mean ± SD age, 75.5 ± 4.7 year-old, range 65 to 82 years-old) participated in this study; all subjects successfully completed the entire study. Clinical and demographic characteristics are summarized in Table 1. The mean ± SD duration of antipsychotic treatment was 39.4 ± 18.1 years.

5 patients were taking antipsychotic drug. Details and chlorpromazine equivalent doses [12] are summarized in Table 1. The chlorpromazine equivalent dose was 311 ± 152.8 mg/day (mean ± SD). 4 patients were

Discussion

To the best of our knowledge, this is the first study that systematically examined the effectiveness of zonisamide in treating TD that was thought to stem from long-term treatment with antipsychotic medications. The results showed that zonisamide appears to be effective for TD without causing any significant adverse effects, suggesting a clinical utility of this agent for this difficult-to-treat motor side effect.

Despite many years of research and various theories regarding the development of

Conflict of interest

Dr. Uchida has received grants, speaker's honoraria, or manuscript fees from Pfizer Health Research Foundation, GlaxoSmithKline, Otsuka Pharmaceutical, Dainippon Sumitomo Pharma, Janssen Pharmaceutical, and Pfizer within the past 5 years. Dr. Suzuki has received fellowship grants from the Japanese Society of Clinical Psychopharmacology, Government of Canada Post-Doctoral Research Fellowships, Foundation and Mochida Memorial Foundation, and manuscript fees from Dainippon Sumitomo Pharma and Kyowa

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