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and Weissman, 2000; Karno et al., 1988). The course isusually chronic and the disorder may lead to considerabledisability without treatment (Karno et al., 1988; Skoog andSkoog, 1999; Steketee, 1997). Despite its prevalence, thedisorder is under-recognized and under-treated (Stein,2002; Steketee, 1997). Patients may be reluctant to reporttheir symptoms to doctors and depression, social phobiaand agoraphobia, with or without panic disorder, arecommonly diagnosed in patients with OCD (Bartz andHollander, 2006).

Pharmacological treatment of OCD is based on the use ofserotonergic antidepressants, mainly selective serotoninreuptake inhibitors (SSRIs) (Fineberg and Gale, 2005). Anadequate response is generally achieved by 40% to 60% ofpatients taking SSRIs and this leaves a lot of patients withpartial or poor response (Pallanti et al., 2002). A range ofaugmentation strategies have been proposed, both pharma-cological and non-pharmacological, for these patients(Fineberg and Gale, 2005). Regarding the former, the useof antipsychotic drugs has been suggested for at least tworeasons: a) the degree of insight into obsessions differs in

OCD. Some patients do not regard their symptoms assenseless or unreasonable and their obsessions resemblemore overvalued or delusional ideas than anxiety worries(Matsunaga et al., 2002); b) an involvement of the dopaminesystem has been postulated in the pathophysiology of OCD(Denys et al., 2005; Kim et al., 2003).

Early reports for the usefulness of typical antipsychot-ic drugs in treatment-resistant OCD (Delgado et al.,1990; McDougle et al., 1990) were followed by morerigorous randomized controlled trials of both typical andnewer antipsychotic drugs. At least five systematicreviews of the evidence behind the pharmacotherapy ofOCD have been published in the past three years, threeof them specifically reviewing the use of antipsychotic

drugs in treatment-resistant OCD (Fineberg et al., 2006;Fineberg and Gale, 2005; Kaplan and Hoolander, 2003;Keuneman et al., 2005; Sareen et al., 2004). Theirfindings support the use of these drugs, in combinationwith SSRIs, in OCD patients with poor or partial responseto SSRIs. These reviews, however, did not attempt tocombine the results of the available randomized con-trolled trials to give an estimate of the overall effect ofantipsychotic drugs in treatment-resistant OCD. Giventhat most of the studies were small and probablyunderpowered this is an important limitation that hasnot been addressed. In addition, during the past twoyears new randomized controlled trials on this issue were

published that were only included in a very recentsystematic review (Fineberg et al., 2006). For thesereasons, in the present paper we aimed to carry out ameta-analysis of all randomized controlled trials thatexamined the effectiveness of antipsychotic drugs asaugmenting agents in patients with OCD non-responsiveto monotherapy with antidepressants.

2. Experimental procedures

2.1. Search strategy

We searched PubMed for English and non-English medicalliterature published from 1966 to January 2006. We supplemented

this source by also searching EMBASE (19802005), the CochraneControlled Trials Register (2006, issue 1) and the PsiTri database(http://psitri.stakes.fi/). We manually checked the reference listsof prior reviews, systematic reviews and trials.

We used the following search string (string 1) in PubMed:(bObsessiveCompulsive DisorderQ[MeSH]) AND ((bClinical

TrialsQ[MeSH]) OR (bSingle-Blind MethodQ[MeSH]) OR (bDouble-BlindMethodQ[MeSH]) OR (bPlacebosQ[MeSH])) AND (bAntipsychotic

AgentsQ

[Pharmacological Action])Because the use of the MeSH terms does not return records thathave been supplied by the publishers or are in the process ofindexing, we also used the following sensitive string (string 2) toidentify new studies not yet officially indexed:

(Obsess* OR Compuls*) AND (Antipsychot* OR Haloperidol ORRisperidone OR Olanzapine OR Quetiapine OR Pimozide OR Chlor-promazine OR Sulpiride OR Amisulpride OR Clozapine OR Aripipra-zole OR Ziprasidone) AND ((publisher [sb]) OR (in process [sb])).

2.2. Inclusion and exclusion criteria

We selected studies that met all the following criteria:

a)study design: randomized controlled trial;

b) participants: adult patients with obsessivecompulsive disor-der non-responsive to previous antidepressant treatment;

c) experimental intervention: antipsychotic augmentation ofantidepressant monotherapy;

d) control intervention: placebo;e) outcome measurement: assessment of symptoms with the Yale-

Brown Obsessive Compulsive Scale (Y-BOCS) (Goodman et al.,1989) or general assessment of clinical response with theClinical Global Impressions-Improvement Scale (CGI-I) (Guy,1976).

We excluded studies from our analysis if they met at least one ofthe following criteria:

a) study design: crossover study;b) participants: patients with comorbid schizophrenia or other

psychotic disorder;

c) duration of study: less than 4 weeks.

2.3. Data extraction, outcome measurement and assess-

ment of methodological quality

Data extracted included information on:

a) patients (age, sex, diagnosis, comorbid conditions, type anddoses of antidepressant drugs);

b) methods (design, definition of treatment resistance, definition

of treatment response, duration of study, statistical analysis);c) interventions (type and doses of antipsychotic drugs used toaugment the antidepressant);

d) outcomes and results (number of patients entering andcompleting the study, number and reasons for dropouts andwithdrawals, baseline and end of study mean Y-BOCS scoresand standard deviations, mean change and standard deviationof change from baseline scores, number of patients respondingin active and control arms.

Our primary outcome measure was the number of patients whowere classified as responders based on pre-defined relative scoreimprovements on the Y-BOCS scale, the global improvement sub-scale of the CGI, or a combination of both. Since the duration of thestudies might differ, we recorded the number of respondents at the

P. Skapinakis et al.2
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time-point defined by the original investigators for the measure-ment of their primary outcome. We used improvement in OCDsymptoms measured as a dichotomous outcome (response vs. non-response) and not reduction in the severity of symptoms, measuredas a continuous outcome, because we think that results are morereadily interpretable from a clinical perspective. Although, thefocus of this review was the effectiveness of antipsychotic drugs,we also measured the total number of dropouts in each arm to

assess the safety of these drugs in patients with treatment-resistant OCD.We used the Jadad scale (Jadad et al., 1996) to assess study

quality but given that most studies were small, we additionallydeducted one point if losses to follow-up were greater than 20%.Studies were then classified into two categories as either of low (ascore of 2 or less on the modified Jadad scale) or acceptable quality(a score of 3 or more). The data were extracted onto hard copy datasheets. Data were extracted by one investigator (TP) and checkedby another investigator (PS). Quality assessment was made by twoinvestigators (PS and VM).

2.4. Statistical analysis

Data from the data sheets were entered into the Review Manager

4.2 software (The Cochrane Collaboration, 2003) by one investigator(PS). The number of respondents in each study was recordedaccording to the intention to treat principle. Using the ReviewManager software we calculated the response rate ratios (ratios ofthe number of patients who responded divided by the number ofpatients initially randomized to the respective group) and their 95%confidence intervals. Rate ratios greater than 1 indicate a betterresponse for the antipsychotic medication group. We combinedresults on the rate ratio using fixed or random effect models. Toinvestigate the degree of between-trial heterogeneity, the chisquared test was performed and I squared was calculated (Higginsand Thompson, 2002). In the presence of significant heterogeneity,a random effects model was used.

2.4.1. Subgroup analyses

Causes of heterogeneity were examined by the followingpredefined subgroup analyses:

a) the type of antipsychotic drug;b) the definition of refractoriness: studies were grouped into two

categories depending on whether they had used the 25% or the35% reduction in the Y-BOCS criterion for refractoriness;

c) the inclusion or exclusion of patients with comorbid ticdisorders: previous literature has suggested that antipsychoticdrugs may be more effective in treatment resistant OCD in thepresence of comorbid tic disorders (McDougle et al., 1994). Forthis reason we stratified studies into two categories, accordingto whether the authors had included or excluded patients withcomorbid tic disorders;

d) the dose of antipsychotic medication used: antipsychotic drugsare given in OCD for their effect on the dopaminergic system,mainly the direct dopamine-D2 blockade (Ramasubbu et al.,2000; Sareen et al., 2004). It has been suggested that thesedrugs can exert their antipsychotic effect only if they haveblocked more than 60% to 65% of the dopamine D2 receptors(Kapur et al., 2000a,b; Nordstrom et al., 1993). Previous PETstudies have shown that the dose needed to achieve this D2occupancy is for Haloperidol 24 mg/day (Kapur et al., 1996),Risperidone 2 mg/day (Kapur et al., 1999, Remington et al.,1998), Olanzapine 10 mg/day (Kapur et al., 1998; Kapur et al.,1999) and Quetiapine 400 mg/day (Kapur et al., 2000a,b). Itshould be noted that the figure for Quetiapine is estimated attwo hours after administration and not at twelve hours, but theauthors have suggested that for this drug the transient effect

may be more important for the antipsychotic effect. Based onthese measurements we classified studies into two categoriesof low or standard/high dose if the mean dose reported wasbelow or above the cutoff to achieve adequate D2 occupancyrespectively;

e) the duration of the trial: studies were grouped into twocategories according to the duration of the randomized trial(less than 8 weeks, 8 weeks or more).

Sensitivity analysis aimed to investigate the influence of studyquality as measured by the modified Jadad scale (2 or less wasrecorded as low quality).

3. Results

3.1. Search flow

Our search strategy in Pubmed yielded 67 abstracts (49abstracts from string 1 and 18 abstracts from string 2). Atotal of 11 citations (10 out of 49 and 1 out of 18) wereretrieved as likely placebo-controlled trials, from which10 (9 and 1 respectively) were retained after consider-ation of the inclusion and exclusion criteria (Fig. 1). Noother trials were identified from other sources includingthe reference lists of previous systematic reviews. Thestudy excluded was that of Li et al. (2005) which was acrossover trial.

3.2. Studies and patients characteristics

Ten trials were included in the meta-analysis and theircharacteristics are summarized in Table 1. These trialsincluded 1 haloperidol study (4-week duration) (McDougleet al., 1994), 3 risperidone studies (6- to 8-week durations)

Figure 1 Trials identification and selection.

Antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD 3


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Table 1 Characteristics of ten trials of antipsychotic augmentation in treatment-resistant obsessivecompulsive disorder included in the meta-analysis

Study/country N (% male) Duration

(weeks)

Antidepressanta Antipsychotic Mean age (SDb)

(A=antipsychotic

P=placebo)

Mean daily

dose mg (SDb)

Duration of

pre-randomization

antidepressanttreatment

McDougle et al.

(1994)/USA

34 4 1 Haloperidol 35 (12) 6.2 (3.0)

(76%)

McDougle et al.

(2000)/USA

36 6 1,2,3,4,5 Risperidone A: 39.8 (10.2) 2.2 (0.7) 12 weeks (8 at maximum

dose)

(58%) P: 34.5 (10.3)

Hollander et al.

(2003)/USA

16 8 1,2,3,4,5,6,7 Risperidone A: 36.8 (10.4) 2.2 (0.9) 12 weeks (most on

maximum dose)

(56%) P: 43.2 (15.8)

Erzegovesi et al.

(2005)/Italy

20 6 1 Risperidone A: 38 (13.4) 0.5 12 weeks (mostly at

maximum dose)

(53%) P: 31.8 (7.8)

Bystritsky et al.

(2004)/USA

26 6 2,3,4,5 Olanzapine A: 44.5 (17.3) 11.2 (6.5) 12 weeks (most at

maximum dose)

(50%) P: 38.3 (9.1)

Shapira et al.(2004)/USA

44 6 2 Olanzapine 36.9 (11.1) 6.1 (2.1) 8 weeks (at moderatedoses)

(41%)

Atmaca et al.

(2002)/Turkey

27 8 1,2,3 Quetiapine A: 28.6 (8.5) 91.1 (41.1) 12 weeks

(52%) P: 28.1 (8.7)

Denys et al.

(2004a,b)/

Netherlands

40 8 1,2,3,5,6,7,8 Quetiapine A: 36 (14) 300 16 weeks (2 SRIs

8 weeks each)

(25%) P: 34 (12)

Carey et al.

(2005)/

South Africa

and Canada

41 6 1,2,3,4,5,6 Quetiapine A: 33.8 (9.6) 168.7 (120.8) 12 weeks (at least 6

at maximum dose)

(46%) P: 31.8 (12.1)

Fineberg and

Gale (2005)/

UK

21 16 4,5,6 Quetiapine A: 37.4 (11.4) 215 (124) 12 weeks (mostly at

maximum dose)

(57%) P: 37.9 (10.7)

a 1 fluvoxamine; 2 fluoxetine; 3 clomipramine; 4 sertraline; 5 paroxetine; 6 citalopram; 7 venlafaxine; 8 imipramine.b SD: standard deviation.c 1 b35% improvement in Y-BOCS; 2 b25% improvement in Y-BOCS; 3 CGI-I b2; 4 consensus of the authors.d Y-BOCS: Yale-Brown Obsessive Compulsive Scale.e Numbers extracted approximately from a graph; standard deviation of mean change from baseline reported.f Definition of response was identical to the definition of refractoriness.


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(Erzegovesi et al., 2005; Hollander et al., 2003; McDougle etal., 2000), 2 olanzapine studies (6-week durations)(Bystritsky et al., 2004; Shapira et al., 2004), and 4quetiapine studies (6- to 16-week durations) (Atmaca etal., 2002; Carey et al., 2005; Denys et al., 2004a,b; Fineberget al., 2005).

The mean age of the participants was below 40 years oldfor the majority of the studies. Only three studies had morefemale than male patients. Five studies included patientswith comorbid tic disorders (Carey et al., 2005; Fineberg etal., 2005; McDougle et al., 1994; McDougle et al., 2000;Shapira et al., 2004).

The duration of antidepressant treatment before ran-domization was generally 12 weeks but there was somevariation on the duration of use of the maximum tolerateddose. Only one study had a duration of 8 weeks and usedmoderate only doses of antidepressants in the pre-randomization phase (Shapira et al., 2004). This studyalso differed in that the patients randomized had lesssevere OCD symptoms at the point of randomization (Y-BOCS score was 19 or 20 for placebo or antipsychotic

respectively). The studies used a variety of antidepressantdrugs but most often fluvoxamine, fluoxetine and clomi-pramine (Table 1).

The mean dose of the antipsychotic drugs was generallylower than the dose normally used for treating schizophre-nia. According to our definitions, 4 studies were classifiedinto the standard or high dose group that could inducehigher than 60% to 65% D2 occupancy: one haloperidol study(McDougle et al., 1994), two risperidone studies (Hollanderet al., 2003; McDougle et al., 2000) and one olanzapinestudy (Bystritsky et al., 2004). Six studies were classifiedinto the low dose category: all four quetiapine studies(Atmaca et al., 2002; Carey et al., 2005; Denys et al.,2004a,b; Fineberg et al., 2005), one risperidone study

(Erzegovesi et al., 2005) and one olanzapine study (Shapiraet al., 2004).

Definition of refractoriness and definition of responsewas not uniform across studies, and some studies appliedstricter criteria for refractoriness or response. However, inall studies there was consistency between definition ofrefractoriness and response. Using the percentage reductionin the Y-BOCS criterion, 5 studies were classified into the35% reduction group (Atmaca et al., 2002; Bystritsky et al.,2004; Erzegovesi et al., 2005; McDougle et al., 1994;McDougle et al., 2000) and the remaining 5 into the 25%reduction group.

Overall, 157 patients were randomized to antipsychotic

drug (17 were randomized to haloperidol, 40 to risper-idone, 35 to olanzapine and 65 to quetiapine) and 148patients were randomized to placebo. There were 73responses in the antipsychotic group (response rate 46%)and 24 responses in the placebo group (response rate16%).

3.3. Meta-analysis outcome

For the 10 trials included in the meta-analysis response rateratios were heterogeneous (X2=26.45, p =0.002, I2=66%).The combined response rate ratio for the 10 studies was 3.31(95% confidence interval 1.407.84) using a random effectsmodel (Fig. 2).

3.4. Sensitivity analysis

Only one study scored 2 or less on the modified Jadad scale(Atmaca et al., 2002). Omitting this study from the analysisslightly reduced the combined response rate ratio (2.78[1.216.37]).

3.5. Sub-group analysis

3.5.1. Type of antipsychotic drug used

Fig. 2 also shows the analysis of different classes ofantipsychotic drugs. Although the number of studies islimited within each class, it is worth noting that the resultsfor risperidone are more consistent and there is nostatistical heterogeneity. There is only one study withHaloperidol so conclusions cannot be made for this drug.The combined rate ratios for the other drugs were notsignificantly different from unity.

3.5.2. Definition of refractoriness/response

Fig. 3 shows the results for the studies stratified according

to the definition used for refractoriness. Studies that usedthe 25% reduction in Y-BOCS scores criterion were notsignificantly different from placebo in the combined anal-ysis, with small between studies heterogeneity.

3.5.3. Low versus standard/high dose

Fig. 4 shows the stratification of studies according to thedosing scheme used. The combined response rate ratio forthe studies using higher doses was 12.75 (95% CI 3.2050.85). The combined rate ratio for the lower dose studieswas 1.82 (0.853.91). This stratification reduced consider-ably the heterogeneity. In the low dose group, the onlyoutlier was the study of Atmaca et al. (2002).

3.5.4. Stratification by tic disordersContrary to what would have been expected based on theprevious literature inclusion of tic disorders was associat-ed with a smaller and non-significant response rate ratio(Fig. 5). Since this result was in the opposite direction ofwhat we had hypothesized, we also examined the possibilityof an interaction between the dose used and the inclusion orexclusion of patients with tic disorders. For this reason weclassified the studies into four categories:

a) standard/high dose plus tics: one haloperidol study(McDougle et al., 1994) and one risperidone study(McDougle et al., 2000),

b) standard/high dose minus tics: one olanzapine(Bystritsky et al., 2004) and one risperidone study(Hollander et al., 2003),

c) low dose minus tics: one risperidone (Erzegovesi et al.,2005) and two quetiapine studies (Atmaca et al., 2002;Denys et al., 2004a,b), and

d) low dose plus tics: one olanzapine (Shapira et al., 2004)and two quetiapine studies (Carey et al., 2005; Fineberget al., 2005).

Results are shown in Fig. 6. This stratification signifi-cantly reduced the heterogeneity between studies. Gener-ally, higher doses were associated with a higher responserate but this was more pronounced in studies that included



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Figure 2 Response rate ratios of antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD, by type of


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Figure 3 Response rate ratios of antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD, by defin

procedures), compared with Placebo.


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Figure 4 Response rate ratios of antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD, by dose of drug

with Placebo.


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Figure 5 Response rate ratios of antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD, by inclusion o



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Figure 6 Response rate ratios of antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD, by inclusion



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Figure 7 Response rate ratios of antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD, by dura


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patients with tic disorders. The combined response rateratio for the three studies that used a low dose andincluded patients with tics was not significantly differentfrom unity.

3.5.5. Stratification by duration of the trial

Results of this subgroup analysis are shown in Fig. 7. Studieswith a (post-randomization) duration of at least 8 weeksshowed a statistically significant result while this was notevident in the group of studies with less duration. This grouphowever was quite heterogeneneous.

3.6. Dropouts

Although the primary aim of this analysis was to report onthe efficacy, we also report on the safety and tolerability ofthe use of antipsychotic drugs in OCD patients. No studyreported any serious adverse events. However, most of thepatients treated with antipsychotic drugs reported mild sideeffects typical of the drug used (akathisia in haloperidol,sedation and dry mouth in risperidone, sedation and weight

gain in olanzapine and quetiapine). There were 24 dropouts(out of 130 patients) in the antipsychotic group compared to12 (out of 121) in the placebo group, a combined weightedrelative risk for dropouts of 1.43 (95% CI 0.52, 3.98). In thiscalculation we have excluded two studies either becausethey did not report dropouts in each group (Erzegovesi etal., 2005) or because there were no dropouts in either group(McDougle et al., 1994). Most common reason for dropout inthe drug group was a side effect and for the placebo groupwas lack of effect.

4. Discussion

4.1. Main findings

In this meta-analysis we found that the use of antipsychoticdrugs, as augmenting agents of serotonergic antidepres-sants, was associated with a short-term higher response ratein adults with treatment resistant OCD compared withplacebo. We also found considerable heterogeneity betweenstudies. Predefined subgroup analyses showed reducedheterogeneity and positive outcome for risperidone (amongthe three drugs with 2 or more studies) and for usingstandard/high doses of antipsychotic drugs. Use of lowerdoses was not associated with a better outcome comparedto placebo but further stratification by inclusion or exclusionof patients with tic disorders showed that this could be dueto the studies that used a low dose in the presence ofcomorbid tic disorders. A duration of trials of at least8 weeks was generally associated with a better outcome.

4.2. Limitations of the study

Our results should be interpreted in the context of thefollowing limitations:

First, studies were generally small and only half of themhad a total sample of more than 30 patients. The resultsshould therefore be interpreted with caution. Although intheory the advantage of randomization is that it can beassumed that all potential confounding variables have been

controlled, an imbalance in the two arms cannot beexcluded given the small number of patients randomized.Second, the total number of trials included in the analysis(ten) was small and this makes the interpretation ofsubgroup analyses difficult. There were few studies withineach class of antipsychotic drugs and future publication ofmore and larger trials may influence the results in eitherdirection. The same applies for our stratification of studiesby dose and inclusion of tic disorders. It should also be notedthat the variable binclusion of patients with tic disordersQ isat the study level, and therefore it should not be assumedthat the association reported refers to individual patients, inwhich case an ecological bias could take place. Even thoughwe carried out subgroup analyses based on predefinedsubgroups and also we made specific hypotheses afterreviewing the previous literature, it is likely that some ofthe results would be different if more and larger trials hadbeen published. Although Type II errors would be more likelygiven the small number of trials, we cannot exclude thepossibility of Type I errors for the reported positive results.Third, definition of refractoriness and response differed

between studies and this was found to be associated withthe outcome. However, one of the advantages of the meta-analysis is that it can take into account these differencesthrough sub-group analyses or meta-regression techniques.Issues of response (or non-response) have not been stan-dardized in OCD research and it is likely that otherdefinitions might yield slightly different results in eitherthe combined or subgroup analysis.

4.3. Interpretation of the main finding clinical

implications

All antipsychotic drugs influence the dopaminergic pathwaysin areas of the brain that have been linked to th e

pathophysiology of OCD, such as the basal ganglia (Kim etal., 2003). Dopamine D2 receptor blockade is considered asa sufficient and necessary condition for antipsychotic action(Kapur and Seeman, 2001), although the effect to otherdopamine or serotonin receptors may also be importantespecially for extrapyramidal symptoms or other side effects(Kapur et al., 1999). Even though antipsychotic drugs differin their D2 blockade potency, most are capable of blockingmore than 65% of the D2 receptors if given in sufficientdoses. Only quetiapine and clozapine show consistentlylower D2 occupancy rates (Seeman and Tallerico, 1999),but it has been suggested that these two drugs have a veryfast dissociation from the D2 receptor and if their occupancy

is measured in two hours after administration, and not intwelve hours as is normally done, their D2 occupancy rate isquite high at therapeutic doses (Kapur and Seeman, 2001).

There is now evidence that a dopamine dysfunction maybe involved in the pathophysiology of OCD (Denys et al.,2004b; Stein, 2002). Neuroimaging studies have shown thatpatients with OCD have higher dopamine transporterdensities and lower dopamine D2 binding ratios comparedto controls (Kim et al., 2003) and this has been considered asindirect evidence of an increased dopaminergic activity inOCD. The results of this meta-analysis show that the use ofantipsychotic drugs is associated with a higher response inpatients who had not responded previously to a serotonergicantidepressant. Moreover we found that lower doses had a



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smaller (non-significant) effect compared to standard/highdoses. These empirical data support the hypothesis of anincreased dopaminergic activity in treatment-resistant OCDpatients. An alternative mechanism could be that the lowerdoses are sufficient to block the serotonin 5HT2 but not thedopamine D2 receptors and thus worsen OCD symptoms(Lykouras et al., 2003; Ramasubbu et al., 2000). In addition,previous research has shown that the co-administration ofatypical antipsychotics and SSRIs may increase synergisti-cally extracellular dopamine and/or noradrenaline, espe-cially in the prefrontal cortex (Dennys et al., 2004; Zhang etal., 2000). These cortical dopaminergic pathways areimportant in regulating the mesolimbic dopaminergic path-ways that may be affected in OCD (Denys et al., 2004b).Finally, one cannot exclude the possibility that higher dosesare associated with a greater non-specific anxiolytic effectwhich is reflected in patients measurements of OCDsymptoms.

It is very difficult, given the small number of trials, tocomment on the relative efficacy of specific antipsychoticdrugs. We noted previously that in the case of risperidone

there was low between studies heterogeneity. Results forother drugs do not seem to be sensitive to additional trialsthat may be published in the future. For example, in thecase of quetiapine we calculated that in order to achieve acombined response rate ratio similar to that of risperidone atrial of 70 patients (35 in each arm) would be needed with25 responses in the quetiapine arm and 5 responses in theplacebo arm (71% versus 14% response rate). This wouldresult in a marginally significant combined response rateratio. In the case of olanzapine, even a study of 200 patientswith a 60% response rate in the active arm versus 10%response rate in the placebo arm would not be capable ofyielding a significant combined rate ratio for olanzapine.However, we cannot exclude this possibility for both drugs,

especially if higher doses are given in the future. The onehaloperidol study seems promising but it is difficult to makerecommendations based on a single study. Notwithstandingthese limitations, the results of this meta-analysis supportthe use of risperidone as a first choice and haloperidol as asecond choice in the short-term management of treatment-resistant OCD. Risperidone is more likely effective in dosescloser to 2 mg/day. Haloperidol was effective at a meandose of 6 mg/day but it may also be effective in doses of 2 to3 mg/day that are capable of blocking more than 65% of D2receptors (Kapur et al., 1996). It should also be noted that inpatients without tics smaller doses may be tried.

Our analysis showed an association between the defini-

tion of refractoriness and the response rate ratio. Studiesthat used the 25% reduction on the Y-BOCS scale criterion forrefractoriness/response were associated with a non-signif-icant combined rate ratio. However, one should take intoaccount that most of these studies also used low doses.Therefore, it is likely that this has resulted in the negativeresult. It has also been suggested by others (Fineberg et al.,2006), that two of these studies (Carey et al., 2005; Shapiraet al., 2004) had an unusually high response rate forplacebo. This may be an indirect indication of a previouslyinadequate treatment with the serotonergic antidepressant.

Trials that have included patients with tic disordersgenerally report that the antipsychotic drugs were notbetter in the subgroup of patients with tic disorders. Only

the first haloperidol study reported that the drug waseffective in the tics subgroup, while there was no effect inOCD patients without tics (McDougle et al., 1994). In ourcombined analysis we noted that studies that includedpatients with tic disorders were associated with smallerresponse rates not significantly different from placebo.Patients with tic disorders may constitute a difficultsubgroup of OCD patients. Alternatively, as we suggest,these patients may need larger doses of antipsychotic drugs.The haloperidol study largely confirms that but we needmore studies to make a recommendation.

The duration of the trial was found to be significantlyassociated with a better outcome. This finding emphasizesthe need for extending the period of observation for at least8 weeks before one can conclude that the augmenting agentis or is not effective in reducing OCD symptoms.

4.4. Implications for research

Future trials on antipsychotic drugs in treatment-resistantOCD should try to avoid using low doses of antipsychotic

drugs. In addition, there should be careful evaluation of thepresence of comorbid tic disorders. Alternative dosingschemes within a trial are also of interest, for examplecomparing low doses versus standard doses with placebo.The use of more selective D2 antagonists could offer usefuldata. Finally, there is a need for larger trials of longerduration in order to evaluate both efficacy and safety in thelong-term.

Acknowledgements

The authors would like to thank Dr. Thomas A. Trikalinos,Department of Hygiene and Epidemiology of the University

of Ioannina, for his comments on an earlier draft of themanuscript.

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