Elsevier

Schizophrenia Research

Volume 88, Issues 1–3, December 2006, Pages 102-110
Schizophrenia Research

Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: A double-blind, randomized, placebo-controlled study

https://doi.org/10.1016/j.schres.2006.07.010Get rights and content

Abstract

Background

Previous studies suggest that the serotonin-3 (5-HT3) receptor antagonist ondansetron possesses the therapeutic potential for schizophrenia. This study was designed to determine whether ondansetron as an adjunct to haloperidol could enhance the clinical efficacy and reduce the adverse side effects in chronic treatment-resistant schizophrenia.

Methods

Under double-blind, randomized conditions, 121 treatment-resistant inpatients with chronic DSM-IV-diagnosed schizophrenia received haloperidol (4–30 mg/day) combined with either placebo (N = 63) or a fixed dose of 8 mg/day of ondansetron (N = 58) for 12 weeks. Efficacy was defined as the change from baseline to endpoint in score on overall scale and subscales of the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). Side effects were evaluated using the Treatment Emergent Symptom Scale and Extrapyramidal Symptom Rating Scale.

Results

Ondansetron combined with haloperidol produced a significantly greater improvement on PANSS overall scale and subscales for negative symptoms, general psychopathology, and cognition at endpoint compared to placebo with haloperidol, but no between-treatment group difference was observed on the subscale for positive symptoms and CGI-S. The ondansetron-treated group had a significantly higher proportion of patients with a 30% or greater baseline-to-endpoint reduction in PANSS total score than placebo. Patients in adjunctive ondansetron therapy also experienced significantly lower incidence and severity of parkinsonism and akathisia as well as fewer behavioral hyperactivity, cardiac, and gastrointestinal side effects.

Conclusions

Ondansetron is an effective adjunctive agent in enhancing the effectiveness and reducing some adverse side effects of antipsychotic therapy for chronic, treatment-resistant schizophrenia, particularly for negative and cognitive symptoms.

Introduction

A prominent clinical feature of chronic schizophrenia is persistent negative symptoms that mainly include blunted emotions, social withdrawal, loss of drive, and poverty of thought (Goff and Evins, 1998). The majority of chronic individuals, to a variable degree, also experienced a range of cognitive impairments, such as deficits in attention, problem solving, learning, and memory (Elvevag and Goldberg, 2000). These lingering manifestations have posed an obstacle to patients' reintegration into society due to poor functional outcomes (Sharma and Antonova, 2003). Numerous studies have shown that the currently available antipsychotic therapies, conventional and atypical, are ineffective or less effective in treating both clusters of symptoms (Chakos et al., 2001, Peuskens et al., 2005, Javitt, 2001). In addition, long-term use of some conventional neuroleptics may themselves reduce and even damage cognitive function (Sharma, 2002). Poor outcomes in chronic individuals have also been demonstrated to be associated with high medication noncompliance, largely resulting from the intolerance to neuroleptic-induced movement and cardiovascular adverse effects (Krausz, 2002). These shortcomings have led to a search of alternatives that produce improvements in particular for negative symptoms, cognitive dysfunctions, and reduce the major adverse effects associated with antipsychotic therapy.

It is well documented that central 5-HT3 receptors are involved in the pathogenesis of psychotic disorders and cognitive disturbance (Costall and Naylor, 1991, Costall and Naylor, 2004). Antagonism of the 5-HT3 receptor is thought to be a contributing factor in the therapeutic advantages of atypical antipsychotic agents (Meltzer, 1995, Potvin et al., 2003). This therefore has led to the hypothesis that 5-HT3 receptor antagonist may be a class of effective agents in improving treatment-resistant negative symptoms and cognitive impairment in schizophrenic patients. Indeed, ondansetron and other 5-HT3 antagonists have been shown to have a broad spectrum of psychotropic effects in animal models, including correcting psychotic-like behavior, alleviating cognitive disturbances, and antagonizing locomotor hyperactivity induced by dopamine stimulants (Costall and Naylor, 1991, Costall and Naylor, 2004). Several case reports and open-label, small-scale trials have found that ondansetron is an effective add-on therapy in controlling psychotic symptoms and adverse motor adverse effects associated with neuroleptics, although its effectiveness for cognitive impairment remains inconclusive (Briskin and Curtis, 1997, Broocks et al., 1998, Levkovitz et al., 2005, Sirota et al., 2000, White et al., 1991, Zoldan et al., 1995). These observations have established the need for a rigorous study evaluating the therapeutic values of this drug in schizophrenia.

Haloperidol is a conventional antipsychotic agent widely used for the treatment of various psychotic disorders. Although it has been shown to robustly suppress acute psychotic episodes, its effectiveness against negative symptoms and cognitive dysfunction is limited (Tandon and Fleischhacker, 2005). Moreover, haloperidol therapy frequently causes various adverse side effects, most commonly neurological motor and cardiac symptoms (Tandon and Fleischhacker, 2005).

The purpose of this study was to determine whether ondansetron as an adjunct to haloperidol could yield beneficial effects in enhancing the clinical efficacy and reducing adverse effects compared with haloperidol alone in patients with treatment-resistant chronic schizophrenia using a double-blind, randomized, placebo-controlled protocol.

Section snippets

Study funding and setting

The project (04T-580) was funded by the Stanley Medical Research Institute, Bethesda, Maryland, USA, and conducted in six psychiatric institutions in northern China from September 2004 to October 2005. The study protocol was approved by the Medical Ethical Committee of the First Affiliated Hospital of Xi'an Jiaotong University College of Medicine in conformity with the Declaration of Helsinki and its subsequent amendment. Each participant and/or his/her guardian were required to sign an

Subject disposition and characteristics

A total of 121 patients entered the study and were randomly assigned to receive a combination treatment of haloperidol with placebo (N = 63) or ondansetron (N = 58). Nearly 84% of them (102/121) completed 12-week treatment and evaluations. The number of subjects who discontinued treatment for each reason is summarized in Table 1. No differences in the discontinuation rate were observed between the two treatment groups for any reason. Three patients who failed to complete post-baseline evaluation

Discussion

This study represents the first double-blind, placebo-controlled investigation of the therapeutic value of the 5-HT3 receptor antagonist ondansetron in the treatment of psychotic disorders. The study results confirm that ondansetron, as an adjunct to conventional therapy, has positive effects against chronic treatment-resistant schizophrenia, particularly in controlling negative symptoms, cognition dysfunction, and certain adverse side effects associated with conventional agents.

Consistent with

Acknowledgments

This project (04T-580) was supported by the Stanley Medical Research Institute, Bethesda, Maryland, U.S.A. The authors acknowledge the following investigators participating in the study: Xiang-Dong Yang, M.D., Shi-Zhong Wang, M.D.,Yong-Ping Ma, M.D., Xiu-Yue Zhu, M.D., Yu-Xiang Su, M.D., Huai-Lin Ju, M.D., Cui-Ling Zhang, M.D., Jing-Yu Chen, M.D., and Ming-Jie Han, M.D., at Huaying Psychiatric Hospital, Huaxian, Shaanxi; Li Zhang, M.D., Yu Wu, M.D., and Juan Guo, M.D., at Xi'an Mental Health

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