Efficacy of ondansetron and simvastatin on cognition and negative symptoms in established schizophrenia.

Background: Despite initial excitement in the psychiatric possibilities of new 5HT3 receptor antagonists such as ondansetron in the 1980s, few if any clinical trials were carried out. The drugs are now mainly used as anti-emetics. However, a re-purposing study funded by the Stanley Medical Research Institute (SMRI) in China reported a 10- point benefit over placebo on Positive and Negative Syndrome Scale (PANSS) scores in treatment resistant schizophrenia (PMID: 16959472). We, together with the SMRI, have shown that atypical anti-inflammatory drugs such as minocycline could be of benefit in schizophrenia (PMID: 22526685). Since ondansetron has anti-inflammatory actions we designed a definitive and mechanistic study in stable but symptomatic patients. We included tests of cognitive performance. We compared ondansetron with simvastatin, identified by the SMRI as another drug with off-target anti-inflammatory actions but untested in psychosis. We tested the hypothesis that the 2 drugs might potentiate each other's actions in improving negative symptoms of schizophrenia. Methods: The protocol and feasibility study have been published (PMID:23782463; 25057343). The study was carried out in three centres in Pakistan supervised by PIs at the University of Manchester in collaboration with the Dow University of Health Sciences, Karachi. Patients aged 18-65 under stable treatment with a schizophrenia-related DSM IV diagnoses were recruited. They were randomly allocated to receive 8mg ondansetron daily (O) or matching placebo capsules (P) and to 40mg simvastatin (S) or matching placebo (P). Thus each patient received 2 different capsules. Treatment allocation was by a randomized permuted blocks algorithm within centres, controlled by the trial statistician in the UK via the local trial pharmacist. Power calculations resulted in an intended sample size of 54 in each of the 4 treatment groups. The primary outcome variable was the PANSS negative syndrome score rated after 3 and 6 months of treatment. Clinical Global Impression and Social and Occupational Functioning Scales were completed. Cognitive tasks included Stroop, verbal fluency and Coughlan verbal and visual list learning. Pre-planned analysis was by mixed model analysis of variance of the 3 and 6 month follow-up (within subjects) data of the intention to treat sample with factors for ondansetron, simvastatin and centre and covariation for baseline scores. Results: The four cells of the 2x2 design over-recruited to 74-78 each. There were 7-9 drop outs from each of the 3 active treatment groups and 12 from the P+P group with none due to side effects. There were 3 deaths from natural causes and one suicide. Group mean total PANSS scores ranged from 72-78 and negative subscale scores from 17-18. The groups did not differ significantly on age or sex. Adjusted mean (95% CI) post-treatment negative PANSS scores were P+P=15.4 (14.6-16.2); O+P=13.5 (12.7- 14.3); S+P=13.7 (12.9-14.4); O+S=14.1 (13.3-14.8), there being no significant effects of follow-up (3 vs 6 months). The interaction between ondansetron and simvastatin (OxS) was significant at p=.006 (F=7.7; df 1/492) reflecting the lower scores in the 3 active treatment groups than in the P+P group. The OxS interaction was also significant for total PANSS but not for positive symptoms. Calgary Depression, Clinical Global Impression and EQ50 quality life scores also showed significant OxS interactions respectively p=.001; p=.04 and p=.02. There was no evidence for positive interaction between the drugs. Ondansetron improved both Coughlan verbal and visual list learning (respective main effects p=.007 and p=.02) but there were no treatment effects on verbal fluency, Stroop or block designs. There were no group differences in side-effect ratings or withdrawals. Conclusions: Both drugs tended to improve negative symptoms at 3 and 6 months resulting in a OxS interaction but their effects were not additive. The hypothesis that the 2 drug's actions on immune function would synergise in improving negative symptoms was clearly not borne out. Verbal learning impairment has been associated with negative symptoms and poor social outcome in schizophrenia (PMID:8610818). The substantial main effect of ondansetron (16% improvement vs 2% on S or P) on verbal list learning suggests cognitive enhancement may contribute to benefits on symptoms and functioning. Other main effects of ondansetron occurred only in the presence of OxS interaction. There were no main effects of simvastatin. Further statistical analysis is in progress to model discontinuations and possible influences of sex and centre to formally determine relative effect sizes of the 2 drugs. Our results corroborate the earlier SMRI finding and recent reports of benefits on negative symptoms with ondansetron and granisetron (PMID:18789844). The benefit of ondansetron observed on cognition suggests it could prove useful in augmenting cognitive remediation.