REVIEW ARTICLE Are 5-HT 3 antagonists effective in obsessive–compulsive disorder? A systematic review of literature Daniele Serata 1,2 , Georgios D. Kotzalidis 1 *, Chiara Rapinesi 1,2 , Delfina Janiri 1 , Simone Di Pietro 1 , Gemma Callovini 1 , Daria Piacentino 1 , Carlotta Gasperoni 1 , Roberto Brugnoli 1 , Vittoria Rachele Ferri 1 , Nicoletta Girardi 1 , Roberto Tatarelli 1 , Stefano Ferracuti 1 , Gloria Angeletti 1 , Paolo Girardi 1,2 and Antonio Del Casale 1,3 1 Neurosciences, Mental Health, and Sensory Organs (NeSMOS) Department, School of Medicine and Psychology, Sapienza University of Rome, UOC Psychiatry, Sant’Andrea Hospital, Roma, Italy 2 Department of Neuropsychiatry, Villa Rosa Suore Ospedaliere of the Sacred Heart of Jesus, Viterbo, Italy 3 Department of Psychiatric Rehabilitation, P. Alberto Mileno Onlus Foundation, San Francesco Institute, Vasto, Chieti, Italy Objective The purpose of this literature database search-based review was to critically consider and evaluate the findings of literature fo- cusing on efficacy and safety of 5-HT 3 antagonists in the treatment of obsessive–compulsive disorder (OCD), so as to test whether preclinical data match clinical therapeutic trials. Design The PubMed database has been searched for papers on 5-HT 3 antagonists and OCD in humans and for animal models of OCD and 5-HT 3 receptors. Results Of the clinically tested 5-HT 3 receptor antagonists, ondansetron has been used to treat OCD in five therapeutic studies, whereas granisetron only in one recent trial. Both showed some efficacy in open studies and superiority to placebo in double-blind studies, along with fair safety. No animal OCD model directly implicated 5-HT 3 receptors. Conclusions Overall, results indicate some utility, but the available literature is too scanty to allow for valid conclusions to be drawn. The mismatch between animal models of obsessive–compulsive disorder and clinical data with 5-HT 3 antagonists needs more clinical data to en- sure that it is not an artefact. Copyright © 2015 John Wiley & Sons, Ltd. key words—clinical trials as topic; models; animal; obsessive–compulsive disorder; serotonin 5-HT 3 receptor antagonists; ondansetron; granisetron INTRODUCTION Obsessive–compulsive disorder (OCD) is severely dis- abling, with a 2–3% lifetime prevalence in the general population (Ruscio et al., 2010). There is evidence for short-term but not long-term (Fineberg et al., 2013) ef- ficacy of higher doses than those used for depressive and other anxiety disorders of clomipramine and selec- tive serotonin (5-HT) reuptake inhibitor (SSRI) antide- pressants (ADs) (Rabinowitz et al., 2008). Treatment resistance ranges from 30% to 57% (Katz et al., 1990; Ravizza et al., 1995; Newth and Rachman, 2001; Ferrão et al., 2007), stressing its pathophysiological complexity. The bulk of OCD treatment data points to drugs acting on serotonin (5-HT) bioavailability (American Psychiatric Association, 2007). The first studies involving 5-HT in OCD date back to the late 1960s, when clomipramine, the most specific 5-HT transporter inhibitor among tricyclic antidepres- sants (TCAs) (Fernández de Córdoba and López-Ibor Aliño, 1967; López-Ibor, 1969; Insel et al., 1983), showed symptom improvement. With the advent of the SSRIs, fluoxetine, fluvoxamine, paroxetine and ser- traline were tested and found to be effective in OCD (Goodman et al., 1989; Jenike et al., 1989). Studies of peripheral biomarkers of 5-HT metabolism in OCD (Hanna et al., 1991, 1995) and SSRI effectiveness support the involvement and dysfunction of 5-HT sys- tems in OCD patients. Despite conflicting results (Lucey et al., 1992; Norman et al., 1994), acute 5-HT stimulation might lead to OCD symptom worsening *Correspondence to: G. D. Kotzalidis, Sapienza University of Rome, Italy, School of Medicine and Psychology, Neurosciences, Mental Health and Sensory Organs (NeSMOS) Department Sant’Andrea Hospital, Via di Grottarossa 1035-1039, 00189 Rome, Italy. Tel. 06-33775951; Fax: 06- 33775342 E-mail: giorgio.kotzalidis@uniroma1.it Received 15 July 2014 Accepted 12 December 2014 Copyright © 2015 John Wiley & Sons, Ltd. human psychopharmacology Hum. Psychopharmacol Clin Exp 2015; 30: 70–84 Published online 10 February 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.2461