Granisetron as an add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: Randomized double-blind placebo-controlled study
Introduction
Primary negative symptoms of schizophrenia are associated with poor functional outcome and long-term disability (Fenton and McGlashan, 1991). Due to unsatisfactory response to antipsychotic drugs, negative symptoms are one of the most challenging aspects of schizophrenia (Kirkpatrick et al., 2006; Murphy et al., 2006). Typical and atypical antipsychotics have been inconsistently effective in the treatment of primary negative symptoms (Murphy et al., 2006). Food and Drug Administration (FDA) now considers negative symptoms of schizophrenia as a specific target for drug development (Laughren and Levin, 2006). This is because of possible differences between the mechanisms underlying negative symptoms and mechanisms underlying other symptoms of schizophrenia, which translates to differential responsiveness of these symptoms to antipsychotic drugs (Buchanan, 2007). In the recent decade, increasing effort has been devoted to development of agents that specifically target the negative symptoms (Akhondzadeh et al., 2011; Amiri et al., 2008; Ghaleiha et al., 2010; Murphy et al., 2006). Drug development has generally targeted serotoninergic, cholinergic, glutamatergic, and other recently proposed mechanisms of negative symptoms (Abbasi et al., 2010; Akhondzadeh, 2001; Akhondzadeh et al., 2008a; Kucinski et al., 2011; Murphy et al., 2006).
There is an emerging role for the serotoninergic system in the pathogenesis of cognitive and negative symptoms of schizophrenia (Akhondzadeh, 2001; Bennett and Vila, 2010). Several animal and human studies have suggested that serotonin (5HT2 and 5-HT3) receptors antagonists might be of benefit in the treatment of negative and cognitive symptoms (Akhondzadeh et al., 2008b, 2009; Bennett and Vila, 2010; Briskin and Curtis, 1997; Den Boer et al., 2000; Duinkerke et al., 1993; Levkovitz et al., 2005; Wildeboer et al., 2009; Zhang et al., 2006). Studies in animal models have shown a wide variety of psychotropic and cognitive effects for 5-HT3 receptors (Broocks et al., 1998; Ramamoorthy et al., 2008). The evidence of beneficial effect of 5-HT3 antagonists on negative symptoms however, primarily comes from human studies. Ondansetron is the most widely studied 5-HT3 antagonist in the setting of psychiatric disorders (Bennett and Vila, 2010). Several observational studies and randomized trials have shown that ondansetron can significantly improve negative symptoms as well as some aspects of cognitive symptoms, extrapyramidal symptoms, and tardive dyskinesia in patients with schizophrenia (Akhondzadeh et al., 2009; Sirota et al., 2000; White et al., 1991; Zhang et al., 2006). Zacopride, another 5-HT3 antagonist, has shown beneficial effect in the treatment of several symptoms of schizophrenia (Newcomer et al., 1992). Importantly, both tropisetron and ondansetron are capable of improving auditory sensory gating deficit which is a well-known deficit in patients with schizophrenia (Koike et al., 2005; Shiina et al., 2010; Wildeboer et al., 2009). Granisetron is another 5-HT3 antagonist which is as potent and safe as ondansetron in treatment of chemotherapy-induced emesis, while causing minimal alteration in cytochrome p450 activity (Bloomer et al., 1994). Compared with other 5-HT3 antagonists, granisetron may have longer duration of action, better tolerability profile, and lower risk of drug interactions (Blower, 2003). To our knowledge, no study has evaluated the efficacy of granisetron in symptoms of patients with schizophrenia.
We hypothesized that granisetron could improve the negative symptoms of schizophrenia. To address the primary negative symptoms, we had to minimize the effect of acute schizophrenia on negative symptoms by stabilizing the patients. Thus, in the present study, we aimed to evaluate the efficacy and tolerability of granisetron in the treatment of negative symptoms of schizophrenia patients.
Section snippets
Trial design
This study was a double-center, 8-week, randomized, double-blind, placebo-controlled, parallel-group study of patients with chronic schizophrenia. The study was conducted in outpatient clinics of Roozbeh psychiatric hospital (Tehran University of Medical Sciences, Tehran, Iran) and Psychiatric Teaching Hospital (Kurdistan University of Medical Sciences, Sanandaj, Iran) from July 2010 to December 2011. The study participants were randomized to risperidone plus granisetron or risperidone plus
Participants
A total of eighty two patients were screened for the trial and 40 were randomly allocated to risperidone plus granisetron or risperidone plus placebo (Fig. 1). Thirty-eight patients (19 in each group) completed the trial. Only four patients were on other antipsychotic drugs prior to stabilization by risperidone (Granisetron group, 2 on olanzapine/placebo group, 1 haloperidol, 1 olanzapine). All patients had been stabilized on risperidone at least eight weeks prior to starting add-on treatment.
Discussion
In line with our hypothesis we showed that granisetron add-on to risperidone was effective in the treatment of negative symptoms in patients with stable schizophrenia. Clinical trials addressing the negative symptoms are generally challenging because these symptoms might be affected by severity of positive symptoms, extrapyramidal symptoms, and depressive symptoms (Buchanan, 2007; Kirkpatrick et al., 2006; Murphy et al., 2006). Therefore, in an unstable patient with acute schizophrenia,
Authors contribution
Shahin Akhondzadeh was the principal investigator and provided statistical support. He was also the clinical neuropsychopharmacologist from July 2010 to December 2011. Sahar Seddighi and Maryam Mohammad-Karimi were the residents of psychiatry and trialist from July 2010 to December 2011. Mohammad-Reza Khodaie-Ardakani, Farzin Rezaei, Bahman Salehi, Narges Shams-Alizadeh and Gholam-Reza Esfandiari were the clinical coordinators and psychiatrists from July 2010 to December 2011. Amirhossein
Conflict of interests
No conflict of interest exists for any of the authors associated with the manuscript and there was no source of extra-institutional commercial funding.
Funding
This study was supported by a grant from Tehran University of Medical Sciences to Professor Shahin Akhondzadeh (Grant number: 9740).
Acknowledgment
This was the postgraduate thesis of Dr. Sahar Seddighi toward the Iranian Board of Psychiatry under supervision of Professor Shahin Akhondzadeh. This study was registered in the Iranian Registry of Clinical Trials (IRCT IRCT138902241556N14, www.irct.ir)
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