Added ondansetron for stable schizophrenia: A double blind, placebo controlled trial
Introduction
Schizophrenia is a devastating neurobiologic disorder that typically strikes the brain function of adolescents and young adults, occurring in about 1 of every 100 people worldwide (Akhondzadeh, 2006). The pathophysiology of schizophrenia remains puzzling. Although the introduction of conventional antipsychotic agents almost 50 years ago heralded a major advance in the treatment of schizophrenia and other psychotic disorders, these compounds have serious limitations in terms of both efficacy and tolerability. Patients treated with these agents often have persistent psychotic symptoms, have frequent relapses, develop prominent functional impairment and experience distressing and disabling adverse effects (Mohammadi and Akhondzadeh, 2001). Patients with schizophrenia characteristically exhibit cognitive deficits. The level of cognitive impairment is found to predict the functional outcome of the illness more strongly than the severity of positive or negative symptoms (Akhondzadeh et al., 2005, Bowie and Harvey, 2005).
Cognitive impairment is estimated to occur in 75%–85% of patients with schizophrenia and often precedes the onset of other symptoms. The treatment of cognitive impairments may be essential for improving the quality of life of patients with schizophrenia (Bowie and Harvey, 2005, Keefe et al., 2007). The main cognitive domains affected include verbal and working memory, executive functioning, sustained attention, visual–spatial performance, and processing speed (Bowie and Harvey, 2005, Keefe et al., 2007). Despite appropriate treatment with either typical antipsychotics or atypical antipsychotics, patients with schizophrenia continue to exhibit cognitive impairments. The lack of marked cognitive benefit of antipsychotics has led to the investigation of alternative agents or polypharmacy for the treatment of cognitive deficit (Jann, 2004, Peuskens et al., 2005, Harvey, 2006, Jones et al., 2006, McGurk et al., 2007).
5-HT3 (5-hydroxytryptamine3) receptors are prime candidates due to their functional diversity to treat cognition impairments in patients with schizophrenia (Akhondzadeh, 2001, Costall and Naylor, 2004). 5-HT3 receptor antagonists have been reported to be a novel agent for cognition improvement in patients with schizophrenia (Costall and Naylor, 2004). Among the receptors for serotonin, the 5-HT3 receptor is the only ligand-gated ion Channel (Arnsten et al., 1997, Akhondzadeh, 2001, Costall and Naylor, 2004). In pre-clinical studies, the injection or infusion of dopamine, amphetamine or 2-methyl-5-HT into limbic brain areas enhanced locomotor behavior in the rat and this was blocked by ondansetron a 5-HT3 receptor antagonist (Costall and Naylor, 2004). It has also been shown that ondansetron, at a low dose of 0.01 mg/kg, blocked the amphetamine induced disruption of latent inhibition in the rat. Ondansetron was found to have dose-related beneficial effects on learning and memory (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 effects associated with neuroleptics, although its effectiveness for cognitive impairment remains inconclusive (Briskin and Curtis, 1997, Broocks et al., 1998, Sirota et al., 2000, Levkovitz et al., 2005). A recent study showed that short-term administration of ondansetron, was associated with significantly improved visuo-spatial memory as measured by the Rey–Osterich Complex Figure Test in patients with schizophrenia (Levkovitz et al., 2005). In addition, another study presented that ondansetron enhances the effectiveness of haloperidol for chronic, treatment-resistant schizophrenia, particularly for negative and cognitive symptoms (Zhang et al., 2006). To the best of our knowledge, the study of Levkovitz et al. (2005) is the only published study that has used a cognitive battery consisting major domains of cognition (including attention, working memory, executive function, verbal memory, visual memory and construction), to assess the efficacy of ondansetron for cognition improvement in schizophrenia. These studies suggest the need for further rigorous, double blind and placebo controlled trial, to evaluate the therapeutic effect of ondansetron on different domains of cognition schizophrenia. The purpose of the present investigation was to assess the efficacy of ondansetron adjunctive treatment to risperidone for cognitive impairments in chronic schizophrenia. We also examined the effect of ondansetron on psychosis and general psychopathology.
Section snippets
Setting
This investigation was a 12-week, double blind study of parallel groups of patients with chronic schizophrenia and was undertaken in Roozbeh Psychiatric Hospital (Tehran, Iran) and Dr. Beheshti Hospital (Zanjan, Iran) from January 2006 to January 2008.
Patients
Thirty patients were recruited from both inpatient and outpatient departments, although most patients were outpatients (28), and some had brief periods of hospitalization during the study (11 women and 19 men) age ranging from 22 to 44 years. All
Patients disposition and characteristics
Eighty six patients were screened for the study and 30 were randomized to trial medication (15 patients in each group) (Fig. 1). No significant differences were identified between patients randomly assigned to the group 1 or 2 condition with regard to basic demographic data including age, gender, marital status, level of education, mean duration of illness and number of life-time hospitalization (Table 1). All 30 patients completed the trial.
Positive symptoms
There were no significant differences between the two
Discussion
Studies to improve the cognition impairments of community-based patients with schizophrenia are particularly important to facilitate their continued remission. It has been reported that central 5-HT3 receptors are involved in the pathogenesis of psychotic disorders and cognition impairments (Costall and Naylor, 2004). Antagonism of the 5-HT3 receptor is thought to have therapeutic effect in treatment of patients with schizophrenia (Levkovitz et al., 2005, Zhang et al., 2006). This therefore has
Conclusion
Generally, the present study indicates ondansetron as a potential adjunctive treatment strategy for chronic schizophrenia particularly for negative symptoms, cognitive impairments, and reduced adverse side effects associated with risperidone.
Role of the funding source
This study was supported by a grant from Tehran University of Medical Sciences to Prof. Shahin Akhondzadeh (Grant No: 2727).
Contributors
Shahin Akhondzadeh: principal investigator and statistical support, clinical neuropsychopharmacologist from Jan. 2006 to Jan. 2008. Neyousha Mohammadi: resident of psychiatry, trialist from Jan. 2006 to Jan. 2008. Maryam Noroozian: clinical coordinator, neurologist from Jan. 2006 to Jan. 2008. Narges Karamghadiri: clinical psychologist, from Jan. 2006 to Jan. 2008. Aboulfazl Ghoreishi: clinical coordinator, psychiatrist from Jan. 2006 to Jan. 2008. Amir-Hossein Jamshidi: Pharmacist, from Jan.
Conflict of interest statement
We declare that we have no conflict of interest.
Acknowledgments
This study was Dr. Neyousha Mohammadi's postgraduate thesis. This study was supported by a grant from Tehran University of Medical Sciences to Prof. Shahin Akhondzadeh (Grant No: 2727).
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