Escitalopram prevents relapse of obsessive-compulsive disorder
Introduction
Obsessive-compulsive disorder (OCD) is a prevalent and disabling lifespan disorder. Wide-ranging epidemiological surveys repeatedly demonstrated high lifetime prevalence, amounting to 2–3% of the population worldwide, under DSM-III and DSM-III-R criteria (Robins et al., 1984, Weissman et al., 1994), although a recent analysis (Kessler et al., 2005a, Kessler et al., 2005b) suggested a lower estimate (12-month prevalence, 1.0%: lifetime estimate 1.6%). Untreated OCD usually runs a chronic course, fluctuating in intensity but rarely disappearing. In a seminal follow-up study spanning several decades, Skoog and Skoog (1999) reported only a minority of patients had become symptom-free. Convincing evidence from large-scale placebo-referenced randomised controlled trials supports efficacy for the serotonin reuptake inhibitors (SRIs) clomipramine and selective serotonin reuptake inhibitors (SSRIs) fluvoxamine, fluoxetine, paroxetine, sertraline and citalopram in the acute treatment of OCD. Response is characteristically partial with few patients achieving remission [defined as a Y-BOCS (Goodman et al., 1989) score ≤ 10]. Fixed-dose comparator studies provide evidence of a dose-response relationship with SSRIs (reviewed in Fineberg and Gale, 2005).
There have been fewer studies of long-term treatment and it remains less conclusively understood as to how well treatments that have been shown to be effective in short-term studies maintain their efficacy over the longer term. Studies of clomipramine (Katz et al., 1990), fluoxetine (Tollefson et al., 1994) and sertraline (Greist et al., 1995) investigated ‘responders’ from the acute treatment period and continued their previous treatment for up to 12 months including placebo. In all three trials, the authors concluded that the response to SRI was sustained, with no evidence of tolerance developing. In contrast, studies that have examined the discontinuation of active treatment and randomised patients to placebo have, in the main, demonstrated re-emergence of symptoms in the placebo-treated cohort. (Pato et al., 1988); (reviewed in Fineberg and Gale, 2005). Some, but not all relapse prevention studies investigating acute treatment-responders revealed a significant advantage for remaining on active medication. In the case of paroxetine, one published study of adult OCD (Hollander et al., 2003b) showed evidence supporting continuing the active drug compared with placebo, but a study on childhood OCD (Geller et al., 2003) and a small adulthood study (Bailer et al., 2005 — not peer reviewed) did not. In the fluoxetine relapse prevention trial, a significant advantage was restricted to the 60 mg fixed dose-level (Romano et al., 2001), whereas in the sertraline trial, efficacy was not established on the primary efficacy criterion but there was subsidiary evidence that sertraline reduced the occurrence of acute exacerbations of OCD and numbers of patients withdrawing prematurely from treatment due to relapse (Koran et al., 2002). There is some evidence to suggest that relapse after drug discontinuation is associated with increased resistance to resumed pharmacotherapy (Maina et al., 2001).
Escitalopram, an antidepressant that binds to both the primary site on the serotonin transporter as well as to the allosteric site, which has been shown to augment the efficiency of the inhibition of serotonin reuptake (Sánchez et al., 2004), is a new treatment for OCD. A recent placebo and reference controlled study of fixed doses of 10 mg and 20 mg escitalopram or 40 mg paroxetine showed efficacy for the 20 mg escitalopram dose-level compared with placebo at week 12, and efficacy for all active treatments at week 24 (Stein et al., 2006 — submitted for publication).
The primary objective of the current study was to compare the efficacy of escitalopram 10 mg or 20 mg/day with that of placebo in preventing relapse during 24 weeks in outpatients with OCD who had responded to 16 weeks prior open label treatment with escitalopram. The secondary objectives were to assess long-term efficacy and tolerability of escitalopram (10 and 20 mg/day) in outpatients with OCD during sustained treatment with escitalopram.
Section snippets
Experimental procedures
The study was conducted at 62 centres in 14 countries, in accordance with the principles of Good Clinical Practice (ICH, 1996) and the Declaration of Helsinki (1964, and its amendments in force at the initiation of the study) (WMA, 1964). The study was approved by local ethics committees and all patients gave written, informed consent.
Patient characteristics at inclusion and at randomisation
Of the 468 patients entering the open label period, 320 patients (69%) were randomised to double-blind treatment: 163 patients to escitalopram and 157 patients to placebo. The ITT population comprised 320 patients due to the exclusion of two patients that were randomised without having met the Y-BOCS response criterion during the open label period (Fig. 2). Although the majority of patients were Caucasian, there was a broad mixture of other ethnicities in the study population (Table 1). At
Discussion
In this relapse prevention study, escitalopram was found to be effective, safe, and generally well tolerated for long-term treatment for OCD. Although most studies that have looked at continuation treatment have found an advantage for remaining on effective anti-OCD medication beyond the acute treatment phase (Tollefson et al., 1994, Greist et al., 1995, Katz et al., 1990), the number of such studies is still rather few (Fineberg and Gale, 2005). The balance between efficacy and tolerability in
Conclusions
This study shows that escitalopram at a dose of 10 mg or 20 mg/day significantly reduced the risk of relapse in the patients with OCD who met the inclusion criteria. Escitalopram at a dose of 10 mg or 20 mg/day was well tolerated by patients with OCD and had an anti-OCD effect during 16 weeks of open label treatment and a significant relapse preventing effect during continued treatment up to 24 weeks.
Acknowledgments
The authors gratefully acknowledge the contribution of the investigators in each of the centres in this study: Australia (48 patients): Mike Theodoros, Isaac Schweitzer, David Barton, Graham Burrows, Kevin McNamara, Austria (55 patients): Siegfried Kasper, Margot Schmitz, Hartmann Hinterhuber, Georg Schönbeck, Canada (38 patients): Martin Tremblay, Guy Debonnel, Angelo Fallu, Jacques Plamondon, John Pecknold, Satpal Girgla, Martin Katzman, Hungary (100 patients): Gabriella Agoston, Katalin
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