The major findings of this double-blind, placebo-controlled study are that administration of tropisetron, but not placebo, significantly improved auditory sensory gating P50 deficits in patients with schizophrenia, and that tropisetron had a significant impact on the sustained visual attention measured with the RVP subtest of CANTAB in non-smoking patients. Previously, we reported that the effect of a single administration of tropisetron (10 mg) on P50 deficits in patients with schizophrenia was significant only for the non-smokers [23
], indicating that smoking status can affect P50 deficits in schizophrenia. In the present study, we also found that administration of tropisetron (10 mg/day for 8 weeks), but not placebo, significantly improved P50 deficits in non-smoking patients with schizophrenia, suggesting that chronic as well as acute administration of tropisetron (10 mg) can improve P50 deficits in non-smoking patients with schizophrenia. Interestingly, we found that sustained visual attention as measured with the RVP subtest of CANTAB in non-smoking patients was significantly improved by tropisetron treatment, but not by placebo treatment. It has been reported that the α7 nAChR agonist 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) had effects on auditory P50 deficits, attention/vigilance and working memory Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) [36
] domains in stable and non-smoking patients with schizophrenia [13
]. Auditory sensory P50 deficits have also been shown to be associated with attentional deficits in schizophrenia [24
]. Unexpectedly, we did not observe any significant correlation between P50 changes and RVP subtest changes in the non-smoking patients because of the small sample size. A further study using a large sample size will be necessary. Taken together, it is likely that the improvement of P50 deficits by tropisetron is involved in the beneficial effects of this drug on attention. Furthermore, the results of this trial suggest that stimulation at α7 nAChRs by α7 nAChR agonists can lead to improvement in auditory P50 deficits and aspects of cognitive performance such as attention.
Several studies strongly suggest that cognitive deficits have a major impact on QOL in patients with schizophrenia [1
]. A recent review of longitudinal studies demonstrated that cognition deficits are associated with functional outcomes in schizophrenia, and that cognitive assessment predicts later functional outcomes in patients, suggesting a rationale for psychopharmacological interventions for cognitive deficits [4
]. It is thus significant that, in the present study, an 8-week treatment with tropisetron could improve the QOL in total patients with schizophrenia although this is not significant in the non-smoking patients. In addition, we did not observe any significant correlation between P50 changes and QLS score change in the non-smoking patients because of small sample size. A further study using a large sample size will be necessary. Freedman et al.
] reported that treatment with DMXB-A significantly improved two subscales (for example, alogia and anhedonia) of the Scale for the Assessment of Negative Symptoms (SANS), but not the total score of the Brief Psychiatric Rating Scale (BPRS). The effects of DMXB-A on negative symptoms are also noteworthy, as these negative symptoms are generally resistant to antipsychotic drugs. However, in this trial, we did not observe any effect of tropisetron on the positive symptoms or negative symptoms scores of PANSS. Further detailed studies regarding the effects of tropisetron on psychotic symptoms such as negative symptoms will therefore be necessary.
Tropisetron is also a potent antagonist at 5-HT3
receptors. At present, it is unclear whether improvement of P50 deficits by tropisetron is mediated via direct agonist effects on α7 nAChRs or via direct antagonist effects on 5-HT3
receptors. Previously, we reported that tropisetron, but not the selective 5-HT3
receptor antagonist ondansetron, attenuated PCP-induced cognitive deficits in mice, and that this effect of tropisetron was blocked by coadministration of the selective α7 nAChR antagonist MLA [21
]. These results suggest that activation of α7 nicotinic receptors by tropisetron is likely to play a role in the mechanism of action of tropisetron [17
]. In contrast, the selective 5-HT3
receptor antagonist ondansetron was reported to improve deficient auditory gating in DBA/2 mice [40
]. In addition, ondansetron was shown to be effective in auditory P50 deficits, negative symptoms and cognitive symptoms in patients with schizophrenia [41
]. These results suggest that 5-HT3
receptor antagonism may contribute to the action of tropisetron. Therefore, a clinical/feasibility study comparing tropisetron versus ondansetron with or without placebo will help to determine whether the addition of the α7 nAChR partial agonism of tropisetron has enhanced effects versus simply adding a 5-HT3
receptor antagonist. In contrast, it seems that DMXB-A addition to an atypical antipsychotic or versus placebo has the advantage of specificity of action. Nonetheless, in order to confirm the role of α7 nAChRs in the treatment of schizophrenia, a randomised double-blind, placebo-controlled study of the selective α7 nAChR agonists in patients with schizophrenia would be necessary.
There were no adverse side effects associated with the tropisetron trial. Tropisetron, which is already approved for human use outside the USA, is widely used in the treatment of patients with chemotherapy-induced or postoperative nausea and vomiting [18
]. Thus, it was not surprising that tropisetron (10 mg) was well tolerated in this trial. Freedman et al.
] reported that nausea occurred in 45% of a group of patients receiving a high dose of the α7 nAChR agonist DMXB-A, and this was suggested to be due to the known effects of nicotinic agonists on gastrointestinal mobility. Considering the high incidence of nausea among patients treated with α7 nAChR agonists (for example, DMXB-A), it is likely that α7 nAChR agonists (for example, tropisetron) with 5-HT3
receptor antagonism will be suitable therapeutic drugs for schizophrenia, since 5-HT3
receptor antagonists are therapeutic drugs for nausea [45
It has been reported that varenicline, a partial agonist at α4β2 nAChRs as well as a full agonist at α7 nAChR agonists, was not effective in the auditory P50 deficits in patients with schizophrenia [46
]. The precise reasons underlying the lack of varenicline on P50 deficits is currently unknown. One possibility is that the receptor desensitisation may occur by the time measurement because varenicline is a full agonist at the α7 nAChRs. A further detailed study using a selective partial agonist and a selective full agonist will be necessary. Another possibility is that there was incomplete absorption of a single dose of varenicline, leading to insufficient levels of the drug in the brain [46
]. Furthermore, Freedman [47
] reported the case of a patient with schizophrenia who received varenicline and experienced an activated psychotic relapse. The US Food and Drug Administration (FDA) and the Institute for Safe Medication Practices stated that serious neuropsychiatric symptoms including changes in behaviour, agitation, depressed mood, suicidal ideation and attempted and completed suicide have occurred in patients with taking varenicline [48
]. Therefore, close monitoring of patients prescribed this drug will be warranted. In contrast, tropisetron and DMXB-A have not been reported to induce psychosis in patients with schizophrenia (this study, and [14
]). Therefore, it is likely that tropisetron and DMXB-A have lower risk of inducing psychosis than varenicline although the reasons underlying this difference are currently unknown.
Inhibitory interneurons with α7 nAChRs are possible candidates for medication to ameliorate the habituation of auditory responses in the hippocampus, because activation of the interneurons via α7 nAChRs would increase the inhibitory synaptic input to pyramidal neurons and thereby diminish the responsiveness of these pyramidal neurons to sensory stimulation [49
]. This parallels a study of postmortem human tissue that documented a decreased expression of hippocampal α7 nAChRs in schizophrenic patients [49
]. Furthermore, it has been reported that [125
I]α-bungarotoxin binding to α7 nAChRs is reduced in the thalamic reticular nucleus of schizophrenic subjects [50
], and that α7 nAChR protein levels are reduced in the frontal cortex in patients with schizophrenia [51
]. Thus, it seems that schizophrenic patients have fewer α7 nAChRs in the hippocampus, a condition which may lead to failure of cholinergic activation of inhibitory interneurons, clinically manifested as decreased gating of the response to sensory stimulation [17
]. Therefore, it is of great interest to study whether the density of α7 nAChRs is altered in the intact brain of patients with schizophrenia. A positron emission tomography (PET) study using the selective α7 nAChR ligand [11
] in the intact brains of patients with schizophrenia is currently underway.
Finally, several limitations of this study should be mentioned. One of the main limitations of this trial was its small sample size (total n = 40) and the use of only one dose (10 mg) of tropisetron. The dose (10 mg) of tropisetron used in this study was well tolerated and resulted in significant effects on P50 deficits, and aspects of cognitive performance such as attention. However, it is currently unclear if other dosing approaches would be more efficacious. Very recently, using [11
C]CHIBA-1001 and PET, we found that a single oral administration of tropisetron (5, 10 or 20 mg), but not ondansetron, could bind to α7 nAChRs in the intact human brain in a dose-dependent manner (Ishikawa M, Ishii K, Wu J, Toyohara J, Sakata M, Oda K, Kimura Y, Iyo M, Ishiwata K, Hashimoto K. unpublished results
). Therefore, a randomised double-blind, placebo-controlled study of higher doses (for example, 20 mg) of tropisetron in patients with schizophrenia using a larger sample will be needed. In addition, the duration of treatment in this trial (8 weeks) was fairly short. A double-blind, placebo-controlled study with a longer duration (for example, 48 weeks) of tropisetron treatment would also be of use. Another limitation was the possible presence of practice effects for CANTAB [31
], which may have been responsible for the improvement of cognitive performance in the placebo group of this study. In this study, sustained visual attention measured with the RVP subtest was significantly improved by tropisetron, but not by placebo, in non-smokers, suggesting that the effects of tropisetron on RVP might not be due to practice effects. Furthermore, Freedman et al.
] also observed practice effects in a study using the MATRICS Consensus Cognitive Battery to investigate the efficacy of DMXB-A. Therefore, further detailed studies to validate the use of other cognitive batteries in patients taking tropisetron, such as MATRICS, Brief Assessment of Cognition in Schizophrenia (BACS) [54
], and the CogState Schizophrenia Battery [55
], would be of interest.
In conclusion, the results of the present feasibility study investigating adjunctive tropisetron as a treatment strategy for cognitive deficits in schizophrenia are promising. Similar to ondansetron and DMXB-A, tropisetron was well tolerated in this trial, and was associated with no untoward effects. If these initial pilot findings are confirmed in larger randomised controlled trials, tropisetron will be a potential therapeutic drug for the treatment of cognitive deficits and QOL in patients with schizophrenia.