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Background: Accumulating data support the involvement of the serotonin (5-hydroxytryptamine [5-HT]) system in the pathophysiology of chronic fatigue syndrome. Neuropharmacologic studies point to a hyperactive 5-HT system, and open-label treatment studies with 5-HT3 receptor antagonists have shown promising results. In this randomized controlled clinical trial, the effect of ondansetron, a 5-HT3 receptor antagonist, was assessed on fatigue severity and functional impairment in adult patients with chronic fatigue syndrome.

Method: A randomized, placebo-controlled, double-blind clinical trial was conducted at Radboud University Nijmegen Medical Centre, The Netherlands. Sixty-seven adult patients who fulfilled the US Centers for Disease Control and Prevention (CDC) criteria for chronic fatigue syndrome and who were free from current psychiatric comorbidity participated in the clinical trial. Participants received either ondansetron 16 mg per day or placebo for 10 weeks. The primary outcome variables were fatigue severity (Checklist Individual Strength fatigue severity subscale [CIS-fatigue]) and functional impairment (Sickness Impact Profile-8 [SIP-8]). The effect of ondansetron was assessed by analysis of covariance. Data were analyzed on an intention-to-treat basis. All patients were recruited between June 2003 and March 2006.

Results: Thirty-three patients were allocated to the ondansetron condition, 34 to the placebo condition. The 2 groups were well matched in terms of age, sex, fatigue severity, functional impairment, and CDC symptoms. Analysis of covariance showed no significant differences between the ondansetron- and placebo-treated groups during the 10-week treatment period in fatigue severity and functional impairment.

Conclusions: This clinical trial demonstrates no benefit of ondansetron compared to placebo in the treatment of chronic fatigue syndrome.

Trial Registration: www.trialregister.nl: ISRCTN02536681

Submitted: September 16, 2008; accepted February 2, 2009.

Online ahead of print: January 26, 2010.

Corresponding author: Gerard K. H. The, MD, Radboud University Nijmegen Medical Centre, Department of Psychiatry, 966, Reinier Postlaan 10, 6525 GC Nijmegen, The Netherlands (g.the@aig.umcn.nl).