Low-dose risperidone augmentation of fluvoxamine treatment in obsessive-compulsive disorder: a double-blind, placebo-controlled study

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Abstract

According to previous data, the addition of risperidone in obsessive-compulsive patients refractory to serotonin reuptake inhibitors (SRIs) is shown to be a safe and effective treatment strategy. The aims of our study were to evaluate the efficacy of risperidone addition, in comparison to placebo, in fluvoxamine-refractory obsessive-compulsive patients and to investigate whether risperidone could boost the efficacy of fluvoxamine in fluvoxamine-responder patients. Subjects were 45 obsessive-compulsive inpatients, consecutively recruited at the Department of Neurosciences at the San Raffaele Hospital, Milan. Thirty-nine patients completed the study. All patients received 12 weeks of a standardized open-label fluvoxamine monotherapy and then continued for 6 weeks with placebo or risperidone in a double-blind design. Results showed a significant effect of risperidone addition, at the end of the double-blind phase (18th week), only for fluvoxamine-refractory patients. Five patients on risperidone (50%) and two (20%) on placebo became responders, with a Yale–Brown Obsessive-Compulsive Scale (Y–BOCS) decrease ≥35%. Risperidone was generally well tolerated, except for a mild transient sedation and a mild increase in appetite. This preliminary study suggests that even very low (0.5 mg) risperidone doses are effective in OC patients who were nonresponders to a standardized treatment with fluvoxamine.

Introduction

Although the effectiveness of serotonin reuptake inhibitors (SRIs) in the treatment of obsessive-compulsive disorder (OCD) has been well established Thoren et al., 1980, Jenike et al., 1990, Smeraldi et al., 1992, Fineberg et al., 1992, Tollefson et al., 1994, Greist et al., 1995, Zohar et al., 1996, Mundo et al., 1997, Todorov et al., 2000, Montgomery et al., 2001, Bogetto et al., 2002, Liebowitz et al., 2002, a significant percentage of OCD patients (40–60%) seems to be refractory to SRI monotherapy Alarcon et al., 1993, Ravizza et al., 1995, Erzegovesi et al., 2001. SRI-refractory OCD patients should be considered for adjunctive pharmacological treatments (Hollander et al., 2002).

According to the serotonin hypothesis of OCD Zohar et al., 1987, Barr et al., 1992, the addition of serotonin-enhancing drugs to an ongoing SRI treatment could be a possible option. In fact, double-blind studies of 5-HT-enhancing strategies such as lithium McDougle et al., 1991, Pigott et al., 1991, tryptophan (Mattes, 1986), and buspirone (Pigott et al., 1992) failed to show a significant improvement in OCD symptoms. Another approach could be pindolol, a 5-HT1A blocker, which was successfully employed in major depression to increase the response rates (Artigas et al., 1994). Pindolol addition to fluvoxamine in a double-blind controlled study in OCD (Mundo et al., 1998) did not increase the response rate to fluvoxamine.

Another approach could be the addition of a dopamine (DA) receptor antagonist to SRIs, according to the hypothesis of a biological heterogeneity, involving both 5-HT and DA, in the pathogenesis of OCD (McDougle et al., 1994). Two studies showed significant efficacy of neuroleptic addition in SRI-refractory OCD patients: an open-label trial with pimozide (McDougle et al., 1990) and a double-blind, placebo-controlled trial with haloperidol (McDougle et al., 1994). Such augmentation strategy was particularly effective in patients with a comorbid schizotypal personality disorder (McDougle et al., 1990) or chronic tic disorder (McDougle et al., 1994).

Recent studies have tested atypical antipsychotics in OCD. Open-label administration of risperidone in SRI-refractory OCD patients Giakas, 1995, Jacobsen, 1995, Lombroso et al., 1995, McDougle et al., 1995, Stein et al., 1997 significantly increased the antiobsessional response. In a double-blind placebo controlled study, McDougle et al. (2000) confirmed the open-label results.

The aim of our study was to evaluate the efficacy and tolerability of a low-dose risperidone addition to an ongoing fluvoxamine treatment in OCD patients, both responders and nonresponders, to a fluvoxamine standardized treatment.

Section snippets

Patients

Forty-five patients (24 men and 21 women) were consecutively recruited from the Department of Neuropsychiatric Sciences at the San Raffaele Hospital, Milan, Italy, from September 2000 to September 2001. All patients gave oral and written informed consents for pharmacological treatment and for the participation in the study.

Inclusion criteria were the following: age between 18 and 65 years, diagnosis of OCD according to DSM-IV criteria (American Psychiatric Association, 1994), at least a 1-year

Results

Demographic and clinical variables divided into four groups: placebo addition/responders to fluvoxamine, placebo addition/nonresponders to fluvoxamine, risperidone addition/responders to fluvoxamine, and risperidone addition/nonresponders to fluvoxamine (see Table 1). There were no significant differences among the four groups for the variables considered: age (F=0.85; df=3; p=0.47), age at onset of OCD (F=0.22; df=3; p=0.88), duration of OCD (F=0.71; df=3; p=0.55), baseline Y–BOCS scores (F

Discussion

At the present time, a major concern in the clinical psychopharmacology of OCD is the number of nonresponders to drug therapy. As many as 40–60% of patients treated with SRIs at adequate dosages did not show a significant improvement in OC symptoms. The significant rate of nonresponders in OCD can explain the growing interest in add-on therapies.

Several reports showed a significant effect of dopamine antagonists in SRI-resistant patients, either for typical (e.g., haloperidol, pimozide;

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