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International Clinical Psychopharmacology 2002, 17:115–119 Quetiapine augmentation in patients withtreatment resistant obsessive^compulsivedisorder: a single-blind, placebo-controlled study M. Atmaca, M. Kuloglu, E. Tez can and O. Gecici Firat University, Medical Faculty Hospital, Department of Psychiatry, Elazig, Turkey Correspondence to Murad Atmaca, Firat (Euphrates) Universitesi, Firat T|p Merkezi, PsikiyatriAnabilim Dali, 23119 Elazig,TurkeyTel: +90 424 233 3555/2282 2300; fax: +90 424 2388096; e-mail: matmaca _ [email protected] Received 19 September 2001; accepted 21 February 2002 Recently, atypical antipsychotics have been used for the management of the patients with refractory obsessive–compulsive disorder(OCD). The aim of the present study was to evaluate the results of quetiapine augmentation to a serotonin reuptake inhibitor (SRI)in the patients with refractory OCD. Fifty-two patients with OCD according to DSM-IV entered 3 months of an open-label phasetreatment with a SRI with or without concomitant adjunctive treatment regimen. Of them, 27 patients were refractory OCD. Thesepatients were randomly divided into two groups, SRI plus quetiapine and SRI plus placebo, for an 8-week single-blind phase. Thecourse of OCD was evaluated by Yale–Brown Obsession–Compulsion (Y-BOCS) and Clinical Global Impression–Severity ofIllness and Improvement (CGI-SI and I) Scales every other week for 8 weeks. Of the 14 patients in group I, nine (64.4%) showedsignificant improvement with 60% or greater improvement on the Y-BOCS and one (7.1%) partial improvement with 30% orgreater improvement on the Y-BOCS, whereas no improvement was observed in group II. The addition of quetiapine to ongoing SRItherapy has been found to be effective and well-tolerated approach in patients with refractory OCD. Int Clin Psychopharmacol 17:115–119r 2002 Lippincott Williams & Wilkins Keywords: augmentation,OCD,quetiapine,refractory,SRI Young et al.,1994). The addition of risperidone orolanzapine to SRI has been shown to be considerably Serotonin reuptake inhibitors (SRI) are used in the beneficial (Saxena et al.,1996; Weiss et al.,1999). On treatment of the patients with obsessive–compulsive the one hand,to the best of our knowledge,there is no disorder (OCD) as the first choice. However,approxi- available information about using quetiapine (alone or mately 40–60% of patients do not response to this with a SRI),a new atypical antipsychotic derived treatment and obsessive–compulsive symptoms persist dibenzothiazepine,in the treatment of OCD. On the (Goodman et al.,1989b). One of the approaches in other hand,although they differ in some pharmacolo- treatment of refractory OCD is to add to another gic properties [e.g. quetiapine has high affinity for a1 group of drug to SRIs. Addition of central serotonin adrenergic and histamine H1 receptors,lower affinity (5-HT) enhancers such as lithium (McDougle et al., for a2 adrenergic and dopamine D1 receptors and no 1991) and buspirone (McDougle et al.,1993) plus SRI muscarinic M1 activity (Saller and Salama,1993), has not been found effective,whereas adding dopamine olanzapine has high affinity for a1 adrenergic,hista- receptor antagonists,such as pimozide and haloper- mine H1,dopamine D1 receptors and muscarinic M1 idol,has been shown to be effective in the treatment of activity (Bymaster et al.,1996) and risperidone’s refractory OCD with comorbid schizotypal personality pharmacologic profile demonstrates a somewhat lower disorder or chronic tic disorder (McDougle et al.,1990; affinity for a1 and a2 adrenergic and histamine H1 receptors (Leysen et al.,1988)],quetiapine has some Atypical antipsychotics have also been tried in the similarities with risperidone and olanzapine in regard patients with treatment resistant OCD (Patil,1992; to receptor binding profile,such as greater affinity for 0268-1315 r 2002 Lippincott Williams & Wilkins International Clinical Psychopharmacology 2002,Vol 17 No 3 serotonin-2 (5-HT2) receptors than dopamine D2 of three of the authors (M.A.,M.K. and E.T.) that the receptors. Therefore,we decided to evaluate the results of quetiapine augmentation to SRI in the patients withtreatment resistant OCD.
Dose and procedureThe subjects were randomly assigned to two groups:SRI plus quetiapine (group I) (n ¼ 14,seven femalesand seven males) and SRI plus placebo (group II) (n ¼ 13,six females and seven males). The randomassignment was single-blind. Quetiapine (50 mg/day) or placebo was added to SRI at the beginning of the Of the patients who had applied to Firat University study. Quetiapine was increased to a dose of 25 mg/day Medical Faculty Department of Psychiatry,and who in each 2-week period,if the Y-BOCS score did not were diagnosed with OCD without psychotic features decrease by 2 or more. Placebo remained stable according to DSM-IV (APA,1994) between September throughout the study period. SRI doses were stabilized and December 2000,52 gave their written informed (fluoxetine 40 mg/day in five patients in both group I consent to take part after receiving a complete and II; fluvoxamine 200 mg/day in five patients in description of the study. The study protocol was group I and in four patients in group II; and approved by the Firat University School of Medicine clomipramine 150 mg/day in four patients in group I and in four patients in group II). No other drugs and First,52 patients entered 3 months of an open-label formal behaviour therapy were given. The course of screening phase. All patients received at least one OCD was evaluated by Y-BOCS and CGI every other adequate SRI trial before this phase. The SRI week for 8 weeks. The instruments were administered treatment was started at the dose of 37.5 mg/day for by the same rater (M.A.) throughout the study.
clomipramine,50 mg/day for fluvoxamine or 20 mg/day for fluoxetine,and titrated up to 300 mg/day forclomipramine,300 mg/day for fluvoxamine and 80 mg/ day for fluoxetine according to clinical response and Data were evaluated by the SPSS Statistical Package, experienced side-effects [fluoxetine (maximum 80 mg/ version 9.05. (SPSS,Chicago,IL,USA). Comparisons day,mean 46.6 mg),fluvoxamine (maximum 300 mg/ were performed using the chi-square test and Student’s day,mean 140.8 mg) and clomipramine (maximum 300 mg/day,mean 185.5 mg)]. In some patients,eithera combination of SRI and anxiolytic (clonazepam intwo patients and alprazolam in one patient),pimozide (in one patient) or lithium carbonate (in two patients)was given. Nineteen patients responded to this treat- Fourteen patients were randomized to quetiapine and ment regimen. Four patients dropped out of the study 13 patients to placebo administered group. The mean due to treatment incompliance and two were excluded age of the patients was 28.6 years (SD 8.5; range 18– from the study due to intolerance. Therefore,27 44 years) and 28.1 years (SD 8.7; range 20–49 years) in patients entered the 8-week,single-blind and placebo- groups I and II,respectively (P40.05). The mean age at onset was 21.3 years (SD 5.2) and 22.1 years (SD Refractoriness to treatment were accepted when all 4.7) in groups I and II,respectively (P40.05). The following criteria were met: (i) still having a Yale– mean previous failed adequate SRI trial was 1.9 (SD 0.7; range 1–3) in group I and 2.1 (SD 0.6; range 1–3) (Goodman et al.,1989a) score of 18 or greater in group II before starting open-label phase (P40.05).
(Goodman et al.,1989b); (ii) the agreement of three Eight patients from group I and six from group II had of the authors (M.A.,M.K. and E.T.) that the patient failed trials of behaviour therapy. The most frequent was not enough improved; and (iii) minimal improve- obsession and compulsion were dirt contamination ment on Clinical Global Impression–Improvement (n ¼ 13) and washing (n ¼ 12) for entire sample.
Of the patients,14(51.9%) had comorbid axis I In order to determine the response to 8-week disorder. These comorbid disorders were major de- treatment,the following criteria were used: (i) 60% pressive disorder (n ¼ 8),social phobia (n ¼ 2),hypo- or greater improvement on the Y-BOCS (significant chondriasis (n ¼ 2) and panic disorder (n ¼ 2). There is improvement); (ii) 30% or greater improvement on Y- no statistically significant difference between treatment BOCS (partial improvement); and (iii) the agreement groups with respect to the distribution of comorbid 116 International Clinical Psychopharmacology 2002,Vol 17 No 3 Table1. Comparison of scale scores (mean7SD) both at baseline and endpoint of the quetiapine or placebo addition phaseand that of responders at endpoint aStudent’s t-test. bChi-square test. Y-BOCS, Yale^Brown Obsession^Compulsion Scale; CGI-I, Clinical Global Impression^ diagnoses (P40.05). No patient had comorbid tic ence between treatment groups with respect to treatment response (Po0.0001) (Table 1).
At the beginning of the 3-month period before the The quetiapine doses received in group I were: addition of quetiapine or placebo,the mean Y-BOCS 50 mg/day in three patients (21.5%); 75 mg/day in five score for total patients in groups I and II was 28.475.2 patients (35.7%); 100 mg/day in four patients (28.6%); whereas it was 23.974.6 at the end of this period,with 150 mg/day in one patient (7.1%) and 200 mg/day in a mean Y-BOCS score of 24.174.9 in group I and 23.874.1 in group II (P40.05). The comparisons of Nine of the patients (64.4%) in group I complained Y-BOCS and Clinical Global Impression–Severity of of side-effects. The most frequent side-effect was Illness (CGI-SI) scores both at baseline and endpoint is nausea (n ¼ 6),followed by sedation (n ¼ 3) and summarized in Table 1. In addition,the mean Y-BOCS dizziness (n ¼ 1). In group I,the mean weight gain scores at each evaluation point are presented in Fig. 1.
from baseline to endpoint in the 8-week phase was Of the group I patients,nine (64.3%) exhibited significant improvement and one (7.1%) partial Four of the patients (30.7%) in group II reported improvement. In the patients with significant improve- side-effects,including sedation (n ¼ 2),headache (n ¼ 1) ment,the mean Y-BOCS score was 24.2(SD 5.3) and and nervousness (n ¼ 1). The mean weight gain was 12.2 (SD 4.8) before and after the addition of quetiapine,respectively. Of them,five were considered No patient dropped out of the study in the 8-week as very much improved and four much improved by quetiapine or placebo addition phase.
CGI-I. In the patient with ‘partial’ improvement,themean Y-BOCS score was 22 and 14 before and afterquetiapine addition,respectively. This patient was evaluated as much improved by CGI-I. None of thegroup II patients showed partial or significant im- Our results reveal that quetiapine augmentation is provement. There was a statistically significant differ- effective and well-tolerated in the treatment of patientswith refractory OCD. Of the patients,71.4% (64.3%significant and 7.1% partial) demonstrated improve-ment. Antipsychotic drugs at low doses have been usedin the treatment of refractory OCD as adjunctivetreatment (McDougle et al.,1990). Therefore,atypicalantipsychotics such as clozapine,risperidone andolanzapine,have recently been tried in the patientswith refractory OCD. In a case reported by Younget al. (1994),the patient with primary OCD,unrespon-siveness to multiple drugs,ECT and psychosurgery,showed partial response to clozapine treatment. How-ever,it has been reported that patients with schizo-phrenia obsessive–compulsive symptoms (Baker et al.,1992; (Y-BOCS) Scores at 2, 4, 6 and 8 weeks in groups I and Patil,1992; Patel and Tandon,1993). In addition,it II. aP40.05, bP40.05, cPo0.05, dPo0.05.
has been reported that risperidone,when used alone, International Clinical Psychopharmacology 2002,Vol 17 No 3 exacerbated obsessive and compulsive symptoms in the In conclusion,the results of the present study patient with comorbid bipolar disorder and OCD suggest that quetiapine augmentation to a SRI may (Remington and Adams,1994) or with comorbid OCD be effective and well-tolerated in patients with treat- and schizophrenia (Kopala and Honer,1994). When ment resistant OCD. However,further double-blind risperidone was combined with a SRI,the complaints studies involving a large group of patients are needed.
considerably improved in the latter case. As can beseen,the descriptions of exacerbation in obsessive–compulsive symptoms occurred in patients with primary psychotic disorder or comorbid OCD andpsychotic or bipolar disorder rather than primary American Psychiatric Association (1994) Diagnostic and OCD. Weiss et al. (1999) added olanzapine to SSRI in Statistical Manual of Mental Disorders,4th edn. Wa-shington,DC: American Psychiatric Association Press.
10 patients with refractory OCD. Of these,70% of Baker RW,Chengappa KNR,Baird JW,Steingard S, patients (40% almost full responder) responded to this Christ MA,Schooler NR (1992) Emergence of obsessive treatment regimen. In another study performed by compulsive symptoms during treatment with clozapine. J Saxena et al. (1996),87% of the patients with SRI refractory OCD showed clinically significant improve- Bymaster FP,Calligaro DO,Falcone JF,Marsh RD, ment after risperidone augmentation to SRI treatment.
binding profile of the atypical antipsychotic olanzapine.
McDougle et al. (2000) reported that 50% of patients Goodman WK,Price LH,Rasmussen SA,Mazure C, with refractory OCD who were given risperidone plus Fleischmann RL,Hill CL,et al. (1989a) The Yale– SRI,and none of the patients given placebo plus SRI, Brown Obsessive Compulsive Scale I: development,useand reliability. Arch Gen Psychiatry 46:1006.
responded. In general,the response rate of our study is Goodman WK,Price LH,Rasmussen SA,Delgado PL, comparable with open-label studies (Saxena et al., Heninger GR,Charney D (1989b) Efficacy of fluvox- 1996; Weiss et al.,1999) but higher than double-blind amine in obsessive-compulsive disorder: a double-blind design studies (McDougle et al.,1994,2000). This comparison with placebo. Arch Gen Psychiatry 46:36–43.
situation suggests that the study design itself may affect obsessive-compulsive symptoms (OCS): a case report and review of atypical antipsychotic induced OCS. J Psy- We have only been able to identify one case report regarding the relation between quetiapine and obses- Kopala L,Honer WG (1994) Risperidone,serotonergic sive–compulsive symptoms in the literature. Khullar et mechanisms,and obsessive-compulsive symptoms in al. (2001) reported quetiapine to exacerbate obsessive schizophrenia (letter). Am J Psychiatry 151:1714–1715.
Leysen JE (1992) 5-HT2 receptors: location,pharmacolo- and compulsive symptoms in a case who had OCD and gical,pathological,and physiological role. In: Serotonin comorbid delusional disorder. Quetiapine,similar to Receptors: Pharmacologic Significance and Clinical Im- risperidone,has strong antagonist effects on 5-HT1C plication. (Lanser SZ,Brunello N,Racagni G,et al., 2 receptors. Therefore,it might be expected to increase obsessions and compulsions. However,the courcelles D,Stoof JC,Janssen PAJ (1988) Biochemical existence of a complex relationship between obsessive– profile of risperidone,a new antipsychotic. J Pharmacol compulsive symptoms and atypical antipsychotics has been noted (Kopala and Honer,1994). Moreover,the McDougle CJ,Goodman WK,Price LH,Delgado PL, fact that atypical antipsychotics,including quetiapine addition to an SRI,are effective in patients refractory Neuroleptic addition in fluvoxamine-refractory obses-sive-compulsive disorder. Am J Psychiatry 147:652–654.
to a combination of SRI and typical neuroleptics might McDougle CJ,Prive LH,Goodman WK,Charney DS, be explained by their strong antagonistic effects on many serotonin receptor subtypes (5-HT2A,5-HT2C, augmentation in fluvoxamine-refractory obsessive com- pulsive disorder: lack of efficacy. J Clin Psychopharmacol 1A,5-HT1D and 5-HT7). These receptors are down- regulated by chronic SRI use and,consequently,the McDougle CJ,Goodman WK,Leckman JF,Holzer JC, blockade of serotonin receptors by atypical antipsycho- tics,including quetiapine,can result in increased action therapeutic effect of addition of buspirone in fluvox- of an SRI (Leysen,1992; Richelson,1994).
amine-refractory obsessive-compulsive disorder. Am J Several limitations should be taken into considera- tion when interpreting our results. The main limitation McDougle CJ,Goodman WK,Leckman JF,Lee NC, Heninger GR,Price LH (1994) Haloperidol addition in of our study was the single-blind design. In addition, fluvoxamine-refractory obsessive compulsive disorder: a because of the small sample size,our results could be double-blind,placebo-controlled study in patients with and without tics. Arch Gen Psychiatry 51:302–308.
118 International Clinical Psychopharmacology 2002,Vol 17 No 3 McDougle CJ,Epperson CN,Pelton GH,Wasylink S, LH (2000) A double-blind,placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive compulsive disorder. Arch Saxena S,Wang D,Bystritsky A,Baxter LRJ (1996) Risperidone augmentation of SRI treatment for refrac- tory obsessive-compulsive disorder. J Clin Psychiatry compulsive symptoms during clozapine treatment (let- Weiss EL,Potenza MN,McDougle CJ,Epperson CN VJ (1992) Development of transient obsessive- (1999) Olanzapine addition in obsessive-compulsive compulsive symptoms during the treatment with cloza- disorder refractory to selective serotonin reuptake pine (letter). Am J Psychiatry 149:272.
inhibitors. J Clin Psychiatry 60:524–527.
Young CR,Bostic JQ,McDonald CL (1994) Clozapine and refractory obsessive-compulsive disorder: a case report (letter). J Clin Psychopharmacol 14:209–210.
Richelson E (1994) Preclinical pharmacology of antipsy- chotic drugs: relationship to efficacy and side effects. JClin Psychiatry Monograph 12:13–17.
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