tropisetron and Schizophrenia

Double-blinded, randomized, placebo-control trials of selective serotonin 3 receptor antagonists (5-HT3R-ANTs) for schizophrenia have differed in outcome. This meta-analysis tests the hypothesis that 5-HT3R-ANTs are effective for the treatment for schizophrenia. We searched PubMed, the Cochrane Library database, and PsycINFO up to June 15, 2013. We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing 5-HT3R-ANTs add-on therapy with placebo. The risk ratio (RR), 95 % confidence intervals (CI), and standardized mean difference (SMD) were calculated. A random-effects model was used. Six studies (total n = 311) were identified. These included one granisetron plus risperidone study, one ondansetron plus risperidone study, one ondansetron plus haloperidol, and three tropisetron plus risperidone studies. The statistically significant effects of 5-HT3R-ANTs add-on therapy on Positive and Negative Syndrome Scale (PANSS) total scores were SMD = -1.03, CI = -1.70 to -0.36, p = 0.003 (I (2) = 82 %, 5 studies, n = 261); on negative scores were SMD = -1.10, CI = -1.82 to -0.39, p = 0.002 (I (2) = 84 %, 5 studies, n = 261); and on PANSS general scores were SMD = -0.70, CI = -1.23 to -0.17, p = 0.01 (I (2) = 73 %, 5 studies, n = 261). However, 5-HT3R-ANTs add-on therapy was not superior to placebo in PANSS positive scores (SMD = -0.12, p = 0.33). Dropout due to all cause (RR = 0.80, p = 0.50), inefficacy (RR = 0.76, p = 0.65), or adverse events (RR = 0.84, p = 0.75) was similar in both groups. Constipation occurred significantly more often with 5-HT3R-ANTs than placebo (RR = 2.05, CI = 1.07-3.91, p = 0.03, NNH = 11, p = 0.02). 5-HT3R-ANTs add-on therapy is more beneficial on the psychopathology (especially negative symptoms) than controls in patients with schizophrenia, and 5-HT3R-ANTs seem to be well-tolerated treatments.

Topics: Antipsychotic Agents; Constipation; Double-Blind Method; Drug Therapy, Combination; Granisetron; Haloperidol; Humans; Indoles; Nausea; Ondansetron; Randomized Controlled Trials as Topic; Receptors, Serotonin, 5-HT3; Risperidone; Schizophrenia; Serotonin 5-HT3 Receptor Antagonists; Severity of Illness Index; Symptom Assessment; Treatment Outcome; Tropisetron; Vomiting

The rate of smoking in patients with schizophrenia is higher than that in the general population. Nicotinic acetylcholine receptors (nAChR) are involved in the sensorimotor gating deficits in schizophrenia. We have revealed that nicotine ameliorates the disruption of the PPI, a model of sensorimotor gating, which is induced by apomorphine, a dopamine receptor agonist, but is not effective for the disruption of the PPI induced by phencyclidine, a glutamine NMDA receptor antagonist, in rats. Furthermore, the ameliorating effect of nicotine is antagonized by methyllycaconitine, a selective alpha7 nAChR antagonist. The effect of nocitine was also investigated in the stereotyped behavior induced by apomorphine, however, nicotine was found to have no significant effect. Considering these results, the ameliorating effect of the disruption of the PPI via alpha7 nAChR is therefore thought to be involved in dopaminergic systems. The dopaminergic systems involved in alpha7 nAChR may be different from the systems involved in stereotypy. In addition, this review describes the effects of the alpha7 nicotinic receptor agonists.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Antiemetics; Disease Models, Animal; Dopamine; Gait Disorders, Neurologic; Humans; Indoles; Neural Inhibition; Nicotine; Rats; Receptors, Nicotinic; Schizophrenia; Serotonin Antagonists; Stereotyped Behavior; Tropisetron

The core features of schizophrenia (SCZ) include cognitive deficits and impaired sensory gating represented by P50 inhibition deficits, which appear to be related to the α7 nicotinic acetylcholine receptor (nAChR). An agonist of nAChR receptor may improve these defects. This study aimed to investigate how administering multiple doses of tropisetron, a partial agonist of nAChR, for 1 day would affect cognitive deficits and P50 inhibition deficits in SCZ patients. We randomized 40 SCZ non-smokers into a double-blind clinical trial with four groups: placebo, 5 mg/d, 10 mg/d, and 20 mg/d of oral tropisetron. Their P50 ratios were all more than 0.5 and they took risperidone at 3-6 mg/day for at least a month before participating in the experiment. We measured the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and P50 inhibition before and one day after treatment. After one day of treatment, the total RBANS scores of the 20 mg and 5 mg tropisetron groups, and the immediate memory of the 10 mg group were significantly higher than placebo group. The P50 ratio was smaller in the 5 mg and 10 mg groups than in the placebo group (both p < 0.05) after treatment. Furthermore, the improvement in RBANS total score was correlated with increased S1 latency (p < 0.05), and the increase in immediate memory score was correlated with decreased S2 amplitude. One day of treatment with tropisetron improved both cognitive and P50 inhibition deficits, suggesting that longer term treatment with α7 nAChR agonists for these deficits in SCZ may be promising.

Topics: Cognition; Cognition Disorders; Humans; Schizophrenia; Sensory Gating; Tropisetron

A growing body of evidence illustrates that 5-HT3 receptor antagonist drugs may be of benefit in the treatment of negative symptoms in schizophrenia.. The objective of this study was to assess the efficacy and tolerability of tropisetron add-on to risperidone on negative symptoms in patients with chronic stable schizophrenia.. In a double-blind, placebo-controlled 8-week trial, 40 patients with chronic schizophrenia who were stabilized on risperidone were randomized into tropisetron or placebo add-on groups. Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) every 2 weeks. Furthermore, extrapyramidal and depressive symptoms as well as side effects were assessed. The primary outcome measure was the difference in change from baseline of negative subscale scores between the two groups at week 8.. Tropisetron resulted in greater improvement of the total PANSS scores [F(1.860,70.699) = 37.366, p < 0.001] as well as negative scores [F(2.439,92.675) = 16.623, p < 0.001] and general psychopathology [F(1.767,67.158) = 4.602, p = 0.017], but not positive subscale scores [F(1.348, 51.218) = 0.048, p = 0.893] compared to placebo. In a multiple regression analysis controlling for positive, extrapyramidal, and depressive symptoms, treatment group (standardized β = -0.640) significantly predicted changes in primary negative symptoms. The side effect profile did not differ significantly between the two groups.. Tropisetron add-on to risperidone improves the primary negative symptoms of patients with chronic stable schizophrenia.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indoles; Male; Regression Analysis; Risperidone; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists; Severity of Illness Index; Treatment Outcome; Tropisetron

The α7 nicotinic acetylcholine receptor (nAChR) is associated with cognitive and P50 auditory gating deficits in schizophrenia, and α7 nAChR agonists can potentially reverse these deficits. The authors examined multiple dosages of tropisetron, a partial agonist at the nAChR, for short-term effects on cognition and P50 deficits in schizophrenia.. In a randomized double-blind design, 40 nonsmoking patients with schizophrenia who had P50 ratios greater than 0.5 and were stabilized on 3-6 mg/day of risperidone were randomly assigned to receive placebo (N=10) or oral tropisetron at 5 mg/day (N=10), 10 mg/day (N=10), or 20 mg/day (N=10). The authors measured P50 inhibitory gating and administered the Chinese-language version of the Repeatable Battery for the Assessment of Neuropsychological Status at baseline and after 10 days of treatment.. After 10 days of treatment, all three daily doses of tropisetron significantly improved overall cognitive deficits, with 10 mg showing the greatest improvement for the immediate memory index score and 20 mg for the delayed memory index score on the cognitive battery. The P50 deficits were also improved, and that improvement was significantly correlated with cognitive improvement. Two patients in the 20 mg/day group dropped out because of adverse effects, but the other dosages were well tolerated.. The improvement of cognition with tropisetron appeared to be associated with normalization in P50 deficits. Thus, α7 nAChR agonists appear to be a promising therapeutic approach for the treatment of cognitive deficits that are related to abnormal P50 suppression in schizophrenia.

Topics: Adult; alpha7 Nicotinic Acetylcholine Receptor; Auditory Perceptual Disorders; Cognition Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Evoked Potentials, Auditory; Female; Humans; Indoles; Male; Middle Aged; Neuropsychological Tests; Nicotinic Agonists; Receptors, Nicotinic; Schizophrenia; Schizophrenic Psychology; Sensory Gating; Tropisetron

Cognitive deficits in schizophrenia are the core symptoms of this disorder, and are strongly correlated with decreased QOL in patients. Antipsychotic drugs have been used therapeutically for positive symptoms, including hallucinations and delusions. However, many patients treated with antipsychotic drugs fail to recover from cognitive deficits. Therefore, a number of new therapeutic drugs for cognitive deficits in schizophrenia are currently being developed around the world. A number of studies suggest that nicotine, a major component of cigarettes, could improve cognitive deficits in patients with schizophrenia. Accumulating evidence suggests that the alpha7 subtype of nicotinic receptors (alpha7 nAchRs) play a role in the pathophysiology of schizophrenia, as well as deficits in auditory evoked potential P50 in patients with schizophrenia. We have reported that the antiemetic drug tropisetron (alpha7 nAchR agonist and 5-HT3 receptor antagonist) improved auditory P20-N40 deficits in DBA/2 mice, and cognitive deficits after administration of the NMDA receptor antagonist phencyclidine. Furthermore, a single administration of tropisetron was associated with improved auditory P50 deficits in non-smoking patients with schizophrenia. Moreover, a randomized, double-blind, placebo-controlled study demonstrated that tropisetron significantly improved auditory P50 deficits and attention deficits in patients with schizophrenia. In this paper, the author will discuss the therapeutic potential of alpha7 nAChR agonists for cognitive deficits in patients with schizophrenia.

Topics: Animals; Antiemetics; Cognition; Double-Blind Method; Evoked Potentials, Auditory; Humans; Indoles; Mice; Schizophrenia; Serotonin Antagonists; Tropisetron

Physiological deficits in inhibition of the P50 auditory evoked potential in schizophrenia have been related to diminished expression of alpha7 nicotinic acetylcholine receptors. Diminished P50 inhibition is correlated with neuropsychological deficits in attention, one of the principal neurocognitive disturbances in schizophrenia. Nicotine administration improves P50 inhibition, presumably by achieving additional activation of these diminished receptors, but its toxicity and marked tachyphylaxis make it an ineffective therapeutic. Nicotine also has weak positive effects on several neurocognitive deficits in schizophrenia, which raises the possibility that the alpha7 nicotinic receptor is a clinically relevant therapeutic target that should be addressed by less toxic agents. Tropisetron, a drug already approved for clinical use outside the United States as an anti-emetic, is a partial agonist at alpha7 nicotinic receptors and an antagonist at 5-HT(3) receptors. As an initial proof-of-principle study, we determined that a single administration of tropisetron significantly improves P50 inhibition in schizophrenia. These data are consistent with biological activity at a pathophysiological mechanism in schizophrenia and support further trials of this drug as a possible therapeutic for neurocognitive deficits in schizophrenia.

Topics: Adult; alpha7 Nicotinic Acetylcholine Receptor; Antipsychotic Agents; Drug Therapy, Combination; Electroencephalography; Evoked Potentials; Evoked Potentials, Auditory; Female; Habituation, Psychophysiologic; Humans; Indoles; Male; Middle Aged; Neural Inhibition; Receptors, Nicotinic; Reference Values; Schizophrenia; Schizophrenic Psychology; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Tropisetron