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