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A Double-blind, Placebo-Controlled Study
of Risperidone Addition in Serotonin Reuptake
Inhibitor–Refractory Obsessive-compulsive Disorder
Christopher J. McDougle, MD; C. Neill Epperson, MD; Gregory H. Pelton, MD;Suzanne Wasylink, RNC; Lawrence H. Price, MD Background: To date, only 1 controlled study has found
Results: For study completers, 9 (50%) of 18 risperidone-
a drug (haloperidol) to be efficacious in augmenting re- treated patients were responders (mean daily dose, 2.2±0.7 sponse in patients with obsessive-compulsive disorder mg/d) compared with 0 of 15 in the placebo addition (OCD) refractory to serotonin reuptake inhibitor (SRI) group (PϽ.005). Seven (50%) of 14 patients who re- monotherapy; patients with comorbid chronic tic disor- ceived open-label risperidone addition responded. Ris- ders showed a preferential response. This report de- peridone addition was superior to placebo in reducing scribes the first controlled study of risperidone addition OCD (PϽ.001), depressive (PϽ.001), and anxiety in patients with OCD refractory to treatment with SRI (P = .003) symptoms. There was no difference in re- sponse between OCD patients with and without comor-bid diagnoses of chronic tic disorder or schizotypal per- Methods: Seventy adult patients with a primary
sonalty disorder. Other than mild, transient sedation, DSM-IV diagnosis of OCD received 12 weeks of treat- ment with an SRI. Thirty-six patients were refractory tothe SRI and were randomized in a double-blind manner Conclusion: These results suggest that OCD patients
to 6 weeks of risperidone (n = 20) or placebo (n = 16) with and without comorbid chronic tic disorders or addition. Behavioral ratings, including the Yale-Brown schizotypal personality disorder may respond to the Obsessive Compulsive Scale, were obtained at baseline addition of low-dose risperidone to ongoing SRI and throughout the trial. Placebo-treated patients sub- sequently received an identical open-label trial of ris-peridone addition.
Arch Gen Psychiatry. 2000;57:794-801 From the Department ofPsychiatry, Section of Child andAdolescent Psychiatry, IndianaUniversity School of Medicine,Indianapolis (Dr McDougle);Department of Psychiatry, YaleUniversity School of Medicine, SEROTONINREUPTAKEinhibi- verseeffectswithconventionaldopamine
logical treatments for the SRI-refractory [5-HT]) function, such as lithium,2 buspi- NY (Dr Pelton); and theDepartment of Psychiatry and rone,3 and clonazepam,4 have yielded dis- patients refractory to SRIs alone. It was peridol,6 to the treatment of SRI-refractory patients. This strategy has been shown to speakers’ bureau for Eli Lilly and bid chronic tic disorder, such as Tourette’s for Pfizer Inc, New York, NY;Janssen Pharmaceutica, disorder (SPD).5 Because of the potential (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, AUG 2000 2000 American Medical Association. All rights reserved.
PATIENTS AND METHODS
mg/d (clomipramine, fluvoxamine, sertraline) or 20 mg/d(fluoxetine, paroxetine) and increased to a maximum toler-ated daily dose of clomipramine (250 mg/d), fluvoxamine (300 PATIENTS
mg/d), sertraline (200 mg/d), fluoxetine (80 mg/d), and par-oxetine (60 mg/d). Clomipramine and fluvoxamine were in- Seventy patients gave written informed consent for partici- creased by 50 mg every 4 to 5 days; sertraline was increased pation in this study, which had been approved by the Hu- by 50 mg/d each week and fluoxetine and paroxetine were man Investigation Committee of Yale University School of increased by 20 mg/d each week. Thus, patients received the Medicine, New Haven, Conn. A semistructured interview maximum tolerated dose of the SRI for at least 8 weeks be- modeled after the Schedule for Affective Disorders and Schizo- fore being considered for the risperidone-addition phase.
phrenia was administered to ascertain that all patients met Thirty-four of the 70 patients did not enter the ris- Diagnostic and Statistical Manual of Mental Disorders, Fourth peridone-addition phase. Of these, 23 responded to SRI Edition (DSM-IV)12 criteria for OCD. Only patients with OCD alone, 7 had treatment-limiting adverse effects to the SRI, symptoms of at least 1 year’s duration and of at least mod- and 4 were noncompliant with treatment.
erate severity on the Clinical Global Impression Scale (CGI)13 Thirty-six patients were refractory to SRI monotherapy were included. Patients were categorized as “depressed” (sec- and entered the 6-week controlled risperidone-addition phase.
ondary to OCD) if they met DSM-IV criteria for major Criteria for refractoriness to the SRI included (1) less than depressive disorder or received a baseline score on the 35% improvement on the Yale-Brown Obsessive Compul- modified 19-item Hamilton Rating Scale for Depression sive Scale (Y-BOCS)18,19 or a Y-BOCS score of greater than (HAM-D)14 of greater than 20. Relevant portions of the Sched- 16, (2) no better than “minimally improved” on the CGI global ule for Tourette’s Syndrome and Other Behavioral Syn- improvement item, and (3) consensus of the treating clini- dromes15 modified for DSM-IV were used to diagnose tic dis- cian and 2 of the authors (C.J.M. and C.N.E.) that the pa- orders. Patients with chronic tics (motor and/or vocal) were tient’s condition was unimproved (based on direct clinical included, provided that OCD symptoms, rather than tics, interview and review of behavioral ratings). Only patients who constituted the chief complaint. The Schedule for Schizo- met all 3 criteria were considered refractory.
typal Personalities16 and DSM-IV criteria were used to make The SRI dose was maintained during the risperidone- diagnoses of SPD. Each subject and each subject’s available addition phase. Assignment to risperidone (1 mg per first-degree relatives were also asked to report on each of their capsule) or placebo was done randomly from a computer- first-degree relatives’ psychiatric symptoms using a semi- generated list, with patients, treating staff (including structured format. All diagnostic instruments were admin- prescribing physicians), and the rater blind to assign- istered by the same experienced clinician (S.W.) who had ment. Patients were given risperidone, 1 mg/d for 7 days, attained satisfactory interrater reliability with other diagnos- with the dosage then increased by 1 mg every week, to a ticians within our research group. Final diagnoses for pa- maximum of 6 mg/d, as tolerated. No other drugs were ad- tients were made independently following the best-estimate ministered and patients were not instructed in formal be- diagnostic procedures developed by Leckman et al.17 havior therapy techniques. The clinical characteristics of Patients were healthy based on results of physical ex- each treatment group are summarized in Table 1.
amination, electrocardiogram, and screening tests of blood After completing the controlled phase of the study, and urine. Females had negative results on serum human placebo-treated patients received open-label risperidone chorionic gonadotropin testing. Patients were free of psy- chotropic medications for at least 4 weeks before startingthe study.
STUDY DESIGN
Patients were assessed weekly by the same trained blind rater(S.W.). Obsessive-compulsive symptoms were measured with Seventy patients received 12 weeks of open-label SRI mono- the Y-BOCS. Depression was rated with a 19-item version of therapy. The choice of SRI was based on each patient’s priorSRI treatment. The SRI therapy was started at a dose of 50 2. There was no significant difference in dosage be-tween patients randomized to risperidone (2.2 ± 0.7 mg/d) CLINICAL CHARACTERISTICS
and placebo (2.6 ± 0.8 mg/d) (Table 2).
OF TREATMENT GROUPS
GLOBAL TREATMENT RESPONSE
Twenty patients were randomized to risperidone and 16to placebo. The 2 groups did not differ significantly in Ratings on the CGI global improvement item showed treatment setting, age, sex distribution (although the risperidone addition superior to placebo (F1,31= 7.65, power may be too low for this particular ␹2 test), age at PϽ.001) (Figure 1). The ANCOVA demonstrated
onset of OCD, duration of OCD, comorbid secondary ma- that risperidone had significant superiority beginning jor depression, chronic tic disorders, or SPD, number of at week 3 and continuing at weeks 4, 5, and 6 (Figure previous medication trials, number of previous SRI tri- 1). The ANOVA demonstrated a significant degree of als, previous behavior therapy, or baseline Y-BOCS, global improvement over time in the risperidone HAM-D, and HAM-A scores (Table 1 and Table 2). The
group (F1,17= 12.86, PϽ.001) but not in the placebo particular SRI used to treat each patient appears in Table (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, AUG 2000 2000 American Medical Association. All rights reserved.
the HAM-D, which excludes an item for rating OCD symp- pattern changes [females], muscle stiffness, nausea, palpi- toms. Anxiety was measured with the Hamilton Rating Scale tations, restlessness, rhinitis, sedation, sialorrhea, tinni- for Anxiety (HAM-A).20 The frequency dimension of the tus, urinary urgency, and vomiting) at baseline and at the Yale Global Tic Severity Scale21 (rated from 0=none to 5=al- end of weeks 1 through 6 of the controlled study.
ways) was used to measure change in tic frequency for thosepatients with comorbid tics. A clinician rating of global im- STATISTICAL ANALYSIS
provement was made with the CGI (7=“very much worse,”4=“no change,” 1=“very much improved”), compared with Thirty-three of the 36 refractory patients completed the study and were included in the efficacy analyses. One patient (ris-peridone group) dropped out prior to completing the first TREATMENT RESPONSE
week of treatment owing to intolerable insomnia. Two oth-ers (1 receiving risperidone, 1 receiving placebo) were non- Criteria for response to the SRI-risperidone combination compliant with the protocol and dropped out prior to com- included (1) 35% or greater improvement on the Y-BOCS pleting the first week of treatment. Only baseline ratings from the beginning of the risperidone-addition trial and a were recorded for these 3 patients. Baseline ratings were final Y-BOCS score of 16 or less, (2) a final CGI rating of obtained after 12 weeks of SRI treatment. Student t tests “much improved” or “very much improved,” and (3) con- were calculated to determine baseline differences in rat- sensus of the treating clinician and 2 of the primary inves- ing scale measures, age, age of onset and duration of OCD, tigators (C.J.M. and C.N.E.) that the patient’s condition was and number of prior adequate medication and SRI trials.
improved (based on direct clinical interview and behav- The ␹2 test with Yates correction was used to determine dif- ioral ratings). Patients who met all 3 criteria were classi- ferences in sex distribution, treatment setting, and previ- fied as “marked” responders, those who met two thirds of ous behavior therapy between groups.
the criteria were “partial” responders, and those who met Testing with the Shapiro-Wilks statistic showed that less than 2 of the criteria were nonresponders.
Y-BOCS scores could be approximated by the normal distri-bution at all assessment time points in both the risperidone DETERMINATION OF SRI BLOOD LEVELS
and placebo groups. Two-way analysis of variance (ANOVA)with repeated measures was calculated for the 6 weeks of ris- Blood samples were collected before and after the 6-week peridone or placebo addition to assess the main effects of drug, double-blind trial to determine SRI blood levels. Blood lev- time, and drugϫtime interactions for the behavioral ratings.
els of SRIs were determined by high-performance liquid Analysis of covariance (ANCOVA), using baseline score as a chromatography with fluorescence detection by a com- covariate, was used to determine when significant risperidone- mercial laboratory. A commercially available assay for flu- placebo differences took place on the CGI and Y-BOCS.
voxamine was not available at the time of the study.
The ␹2 test with Yates correction was used to com- pare the 2 groups for rate of responders (marked or par- PHYSIOLOGICAL MEASURES AND ADVERSE
tial) vs nonresponders, and to determine if response was EFFECTS ASSESSMENT
related to sex or treatment setting. The relationship be-tween response vs nonresponse to risperidone and the pres- Sitting and standing blood pressure and pulse, tempera- ence or absence of a comorbid chronic tic disorder or SPD ture, and respiratory rate were recorded at baseline and at was determined by the Fisher exact test. Paired t tests were the end of weeks 1 through 6 of the controlled trial. Each used to determine change in behavioral ratings (baseline patient was examined for extrapyramidal (abnormal gait, to end of week 6) for patients given open-label risperi- ataxia, dystonia, hyperkinesia, hypertonia, hypokinesia, in- done. Fourteen of these 16 patients completed the 6-week voluntary muscle contractions, oculogyric crisis, and tremor) open-label risperidone phase. One patient was noncom- and other adverse effects (agitation, blurry vision, consti- pliant and the other moved to another country prior to en- pation, coughing, diaphoresis, diarrhea, dizziness, dry tering this phase of the study. Data are presented as mean mouth, dyspepsia, enuresis, gynecomastia, headache, in- ± SD unless otherwise indicated, and are reported as sig- creased appetite, insomnia, lightheadedness, menstrual nificant when PϽ.05 (2 tailed).
Nine (50%) of 18 risperidone-treated patients The ANOVA revealed significant interaction effects of responded (4 marked response, 5 partial response) drug ϫtime (F1,31=6.59, PϽ.001) for the risperidone- vs (Figure 2). None of 15 placebo-treated patients
placebo-addition phase. In comparing the effects of ris- were categorized as responders (␹2= 8.0, PϽ.005) peridone and placebo on OCD symptoms, ANCOVA showed that risperidone was significantly better than Seven (50%) of 14 patients who received 6 weeks placebo beginning at week 5 and continuing at week 6 of open-label risperidone addition following the double- (Figure 3). The ANOVA showed a highly significant blind placebo phase were categorized as responders (4 decrease in total Y-BOCS scores from baseline in the marked response, 3 partial response).
risperidone group (31.8%; 27.4 ± 5.4 to 18.7 ± 8.3)(F1,17= 14.61, PϽ.001). In responders, Y-BOCS scores RESPONSE OF OCD, DEPRESSIVE,
decreased by 51.6%, from a baseline score of 27.5 ± 3.8 AND ANXIETY SYMPTOMS
to a final score of 13.3 ± 6.0, following 6 weeks of risperi-done. In contrast, ANOVA showed no significant change As measured by reduction in total Y-BOCS scores, ris- in Y-BOCS scores for any week following baseline in peridone addition was superior to placebo (Figure 3).
the placebo group (27.6 ± 3.7 to 25.0 ± 4.4) (Figure 3).
(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, AUG 2000 2000 American Medical Association. All rights reserved.
Table 1. Clinical Characteristics of Patients With OCD Treated With Risperidone or Placebo Addition to SRI*
Patient No./
Age, y/Sex/
Duration
Ethnicity
OCD Symptoms‡
Comorbid Diagnoses§
Family History
Risperidone Group
Placebo Group
Sister: anorexia nervosa; father: bipolar Major depression, Tourette’s disorder (3) Major depression, Tourette’s disorder (4) *OCD indicates obsessive-compulsive disorder; SRI, serotonin reuptake inhibitor; M, male; W, white; F, female; OCPD, obsessive-compulsive personality disorder; H, Hispanic; ADHD, attention-deficit/hyperactivity disorder; AA, African American; and AS, Asian American.
†Treated as inpatient.
‡Primary obsessions precede semicolon and primary compulsions follow it. Agg indicates aggressive; sym/ext, symmetry/exactness; chk, checking; ntk, need to know; rpt, repeating; ord/arr, ordering/arranging; ctm, contamination; cln/wsh; cleaning/washing; som, somatic; rel, religious; hrd, hoarding; cnt, counting; ntr, need totouch, tap, or rub; and sex, sexual.
§Numbers in parentheses indicate baseline Yale Global Tic Severity Scale score (0 = none to 5 = always).
(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, AUG 2000 2000 American Medical Association. All rights reserved.
Table 2. Treatment Data of Patients With OCD Who Received Risperidone or Placebo Addition to SRI*
Previous
Previous
Y-BOCS Score,
Medication
Behavior
Daily SRI
Risperidone
Treatment
Pre/Post
Previous SRI Trials
Current SRI
Response
Intervention
Risperidone Group
Placebo Group
*OCD indicates obsessive-compulsive disorder; SRI, serotonin reuptake inhibitor; CGI, Clinical Global Impression Scale global improvement item (7 = “very much worse,” 6 = “much worse,” 5 = “minimally worse,” 4 = “no change,” 3 = “minimally improved,” 2 = “much improved,” 1 = “very much improved)”; Y-BOCS,Yale-Brown Obsessive Compulsive Scale (0 = “no symptoms,” 40 = “maximal symptoms”); and ellipses, not applicable.
As measured by reduction in total HAM-D scores, As determined by reduction in total HAM-A scores, risperidone addition was superior to placebo for risperidone addition was also significantly better than reducing depressive symptoms. The ANOVA revealed placebo for reducing symptoms of anxiety. The ANOVA s i g n i f i c a n t i n t e r a c t i o n e f f e c t s o f d r u g ϫ time revealed significant interaction effects of drug ϫ time (F1,31= 5.29, PϽ.001) for the risperidone- vs placebo- (F1,31=3.78, P=.003) for the controlled addition phase.
addition phase. The ANOVA showed a significant The ANOVA demonstrated a significant decrease in decrease in HAM-D scores from baseline (11.7 ± 7.8 to HAM-A scores from baseline (13.2±5.4 to 9.1±4.3) with 7.6 ± 4.9) with risperidone (F1,17= 4.16, P = .002). No risperidone (F1,17=3.52, P=.007) but not placebo (13.5± significant change in HAM-D scores occurred for any week following baseline in the placebo group (12.2 ± For the 14 patients who received 6 weeks of open- label risperidone addition, the drug resulted in signifi- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, AUG 2000 2000 American Medical Association. All rights reserved.
Figure 1. Global improvement in patients with obsessive-compulsive
Figure 2. Change in total Yale-Brown Obsessive Compulsive Scale (Y-BOCS)
disorder given risperidone (n = 18) or placebo (n = 15) for 6 weeks in addition scores for patients with obsessive-compulsive disorder categorized as to ongoing serotonin reuptake inhibitor treatment, as measured by the responders (solid lines) or nonresponders (dashed lines) to risperidone Clinical Global Impression Scale (CGI) global improvement item (7 = “very (n = 18) or placebo (n = 15) for 6 weeks in addition to ongoing serotonin much worse,” 4 = “no change,” 1 = “very much improved”). The baseline score of 4.0 ± 0.0 is not actually a measured score, but rather the inferredstarting point of reference to the later change scores. Asterisk and doubleasterisk, F1,31=11.55, P=.002; dagger, F1,31=8.82, P=.006; double dagger, F1,31=17.34, PϽ.001, change from beginning of double-blind addition phase,risperidone vs placebo, analysis of covariance. Error bars represent SE.
cant reductions in total Y-BOCS (24.8±4.5 to 18.3 ± 6.2, t=3.2, P=.007) and HAM-A (15.4±7.9 to 11.4±6.3, t=2.3, P = .04) scores, but not HAM-D (13.4 ± 6.3 to 10.9 ± 7.1) TREATMENT RESPONSE AND COMORBID
CHRONIC TIC DISORDER AND/OR SPD
Three of 5 patients with a comorbid chronic tic disorder (Tourette’s disorder, n = 2; chronic motor tic disorder, n = 1) were responders (1 marked response, 2 partial re- sponse) to the double-blind addition of risperidone, whereas 6 of 13 patients without tics (no known familyhistory of tics) responded (Fisher exact test, P=1.0). Three Figure 3. Change in severity of obsessive-compulsive symptoms in patients
of 5 patients with comorbid SPD were responders (1 with obsessive-compulsive disorder given risperidone (n = 18) or placebo(n = 15) for 6 weeks in addition to ongoing serotonin reuptake inhibitor marked response, 2 partial response) to risperidone, treatment, as measured by the Yale-Brown Obsessive Compulsive Scale whereas 6 of 13 patients without SPD responded (Fisher (Y-BOCS) total scores (0 = “no symptoms,” 40 = “maximal symptoms”).
Asterisk, F1,31=7.66, P=.01; double asterisk, F1,31=9.30, P=.005, change For the 14 patients treated with 6 weeks of open- from beginning of double-blind addition phase, risperidone vs placebo,analysis of covariance. Error bars represent SE.
label risperidone addition, 2 of 4 patients with a comor-bid chronic tic disorder (Tourette’s disorder, n = 2) wereresponders (both marked response), whereas 5 of 10 pa- done-treated patients experienced at least 1 adverse ef- tients without tics (no known family history of tics) re- fect. These included constipation (n = 1), diaphoresis sponded (Fisher exact test, P = 1.0). The 1 patient with (n = 1), dry mouth (n = 5), increased appetite (n = 6), in- somnia (n=1), lightheadedness (n=1), restlessness (n=6), For the 5 patients with comorbid chronic tics who sedation (n = 17), tinnitus (n = 2), and urinary urgency completed the double-blind risperidone addition phase, (n = 1). No clinically significant changes in blood pres- a significant reduction in tic frequency was determined sure, heart rate, respiratory rate, or temperature were re- (1.8 ± 0.4 to 1.0 ± 1.2, t = 4.0, P = .02) with the Yale Global corded, and no acute extrapyramidal effects, seizures, or cardiac events occurred. Anticholinergic agents or ␤-blockers were not required for any patient for risperi- TOLERABILITY OF
done-related extrapyramidal symptoms. The most promi- SRI/RISPERIDONE TREATMENT
nent adverse effect was initial, mild transient sedation.
Fifteen of 16 patients experienced at least 1 adverse ef- The SRI/risperidone treatment was generally well- fect while receiving placebo. These included blurry vi- tolerated. During the controlled phase, 18 of 20 risperi- sion (n=2), diaphoresis (n=4), diarrhea (n=1), dry mouth (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, AUG 2000 2000 American Medical Association. All rights reserved.
(n = 5), headache (n = 5), increased appetite (n = 3), in- patients diagnosed with a psychotic disorder, rather than somnia (n = 1), lightheadedness (n = 4), muscle stiffness (n = 1), palpitations (n = 1), restlessness (n = 6), sedation That treatment response was due to a longer dura- tion of SRI administration is unlikely, as none of the 15placebo-treated patients responded. Although the sample SRI BLOOD LEVEL RESULTS
sizes were small, no significant differences in SRI bloodlevels were found between the risperidone- and placebo- Complete SRI blood level data were available for 4 ris- treated groups. Also, blood levels did not seem to be peridone-treated patients (clomipramine [n = 2], fluox- related to treatment response. Thus, it is unlikely that etine [n = 2]) and 7 placebo-treated patients (clomipra- risperidone exerted a therapeutic effect through a phar- mine [n = 4], fluoxetine [n = 2], sertraline [n = 1]). In the risperidone group, clomipramine plus desmethylclomip- A balance of full 5-HT2A receptor occupancy and par- ramine levels changed from 450 ng/mL to 348 ng/mL and tial D2 receptor occupancy has been hypothesized to un- 514 ng/mL to 333 ng/mL, respectively; and fluoxetine plus derlie risperidone’s lower tendency to cause extrapyra- norfluoxetine levels changed from 880 µg/L to 1049 µg/L midal effects compared with typical neuroleptics.23 In the and 841 µg/L to 845 µg/L, respectively. In the placebo present study, risperidone was generally well-tolerated, group, clomipramine plus desmethylclomipramine lev- with no evidence that acute extrapyramidal effects dif- els changed from 461 ng/mL to 434 ng/mL, 558 ng/mL fered between drug and placebo. The most common ad- to 514 ng/mL, 424 ng/mL to 496 ng/mL, and 484 ng/mL verse effect was mild, transient sedation, which re- to 297 ng/mL, respectively; fluoxetine plus norfluox- solved early in the treatment course. This adverse effects etine levels changed from 293 µg/L to 408 µg/L and 799 profile is in contrast to our experience with haloperidol µg/L to 805 µg/L, respectively; and sertraline levels addition in fluvoxamine-refractory OCD.6 In that study, changed from 150 ng/mL to 308 ng/mL.
29% of haloperidol-treated patients required adjunctivepropranolol for akathisia despite being prophylactically treated with benztropine. No patient required proprano-lol or anticholinergic agents in the current investiga- These results demonstrate that the addition of risperi- tion. While this study does not address the potential long- done to the treatment of OCD patients refractory to SRI term adverse effects of risperidone, only 2 (0.2%) of 882 alone is significantly more effective than placebo for re- patients with schizophrenia exposed to more than 12 ducing OCD, depressive, and anxiety symptoms. Con- weeks of risperidone have developed tardive dyskinesia sistent with a previous study,22 risperidone was also ef- (written communication, Martin Brecher, MD, 1999).
fective for reducing tics in patients with comorbid tics.
Nonetheless, because of reports of possible tardive dys- Contrary to our hypothesis and results from previous stud- kinesia with risperidone,31 continued close monitoring ies of haloperidol6 and pimozide5 addition in fluvoxamine- of the drug and longer-term follow-up studies are war- refractory OCD, no significant difference in treatment re- ranted. Additional research is necessary to replicate these sponse was found between OCD patients with and without findings and to investigate this treatment strategy in chil- comorbid chronic tic disorder or SPD. The ability to de- dren and adolescents with SRI-refractory OCD.
tect significant differences between these groups, how-ever, may have been limited by the relatively small sample Accepted for publication March 24, 2000. sizes of patients with such comorbidity. The broader ef- This work was supported in part by grant PO1 fects of risperidone across these diagnostic subtypes of MH49351 (J. F. Leckman, MD) from the US Public Health OCD, compared with haloperidol and pimozide, may be Service, Bethesda, Md; Young Investigator Awards from the National Alliance for Research in Schizophrenia and Depression, Chicago, Ill (Drs McDougle, Epperson, and Pel- 2 blockade, which is particularly relevant at the rela- tively low dosages required in this study.23 Risperi- ton); Theodore and Vada Stanley Foundation Research done’s affinity in vitro is 20 times higher for 5-HT Awards Program, Arlington, Va (Drs McDougle and Price); and the State of Connecticut, Department of Mental Health 2 receptors; in vivo it occupies 5-HT2A receptors at over, unlike haloperidol, risperidone has been shown to Elizabeth Kyle, AS, prepared the manuscript, Sally J. dose-dependently increase extracellular concentrations Vegso, MS, performed the statistical analyses, and Elizabeth M. Ruff and Krista Guenin, BA, constructed the graphics. The design of this study does not exclude the pos- Reprints: Christopher J. McDougle, MD, Indiana Uni- sibility that treatment response was due to risperidone versity School of Medicine, Section of Child and Adolescent alone. Based on a review of the literature on atypical an- Psychiatry, James Whitcomb Riley Hospital for Children, tipsychotics,25 and on our previous investigation of cloza- 702 Barnhill Dr, Room 3701, Indianapolis, IN 46202- pine monotherapy in refractory OCD,26 this would not 5200 (e-mail: cmcdougl@iupui.edu). be anticipated. Considering prior reports, one might havehypothesized that an atypical antipsychotic (eg, cloza- pine,27 risperidone,28 olanzapine29) would induce or ex-acerbate OCD symptoms. However, as we have previ- 1. Greist JH, Jefferson JW, Kobak KA, Katzelnick DJ, Serlin RC. Efficacy and toler- ously commented,30 all of these descriptions of clinical ability of serotonin transport inhibitors in obsessive-compulsive disorder: a meta- induction or worsening of OCD symptoms occurred in analysis. Arch Gen Psychiatry. 1995;52:53-60.
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(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, AUG 2000 2000 American Medical Association. All rights reserved.

Source: http://www.homepage.psy.utexas.edu/HomePage/Class/Psy394Q/Behavior%20Therapy%20Class/Assigned%20Readings/OCD/McDougal00.pdf