Granisetron as an add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: Randomized double-blind placebo-controlled study

https://doi.org/10.1016/j.jpsychires.2013.01.011Get rights and content

Abstract

Some 5-HT3 antagonists such as ondansetron have shown beneficial effects on negative symptoms of patients with schizophrenia. We aimed to evaluate the efficacy of granisetron (another 5-HT3 antagonist) add-on therapy in the treatment of negative symptoms of patients with stable schizophrenia. In a randomized, double-blind, and placebo-controlled study, forty stable patients with schizophrenia (DSM-IV-TR), were randomized to either granisetron (1 mg twice daily) or placebo (twice daily) in addition to risperidone up to 6 mg/day for eight weeks. The patients were assessed using positive and negative syndrome scale (PANSS) and extrapyramidal symptom rating scale (ESRS) at baseline, week 4 and 8. Hamilton depression rating scale (HDRS) was used to assess depression at baseline and week 8. Thirty-eight patients completed the trial. Granisetron group showed a significantly greater improvement on negative subscale than the placebo group at endpoint [t(38) = 6.046, mean difference (±95% CI) = 3.2(1.8–3.7), P < 0.001]. The same effect was observed for total score [t(38) = 4.168, mean difference (95% CI) = 3.2(1.6–4.7), P < 0.001]. However the placebo and granisetron groups did not differ in their reduction of positive and general psychopathology symptoms scores. HDRS scores and its changes did not differ between the two groups. The ESRS score at week 4 was significantly lower in the granisetron than the placebo group while the two groups showed similar ESRS score at week 8. Frequency of other side effects was similar between the two groups. In summary, granisetron add-on can safely and effectively reduce the primary negative symptoms of patients with schizophrenia.

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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