The first-line pharmacological therapy for OCD (SSRIs) has been shown to decrease resting-state activity of the anterior insula in depression [103], suggesting that this form of treatment could be modulating circuitry related to SP. Single high doses of ondansetron, a 5-HT3 receptor antagonist FDA approved for severe nausea and vomiting [104], reduce activation in the insula, precentral and postcentral gyri, and cingulate cortex [105]. Interestingly, several smaller pilot trials showed that repeated dosing of ondansetron over multiple weeks reduced overall symptom severity in OCD [106–107] and TS [108], with potential utility as an augmentation strategy in SSRI-resistant OCD [106]. However, a larger Phase 2 trial using adjunctive very low dose ondansetron in 168 OCD patients failed to find a significant Y-BOCS reduction at the end of 12 weeks [109]. These discrepant findings might indicate that the low dose in the Phase 2 trial was not sufficient to engage relevant neural circuitry; alternatively, perhaps ondansetron is effective only for sensory phenomena, but their prevalence was not reported in this or prior trials. Addressing this issue, a double-blind placebo-controlled mechanistic trial testing the effects of repeated high-dose ondansetron on SP and neural circuitry is currently underway in OCD (NCT03239210).
