+ model

ARTICLE IN PRESS
European Neuropsychopharmacology (2006) xx, xxx — xxx

www.elsevier.com/locate/euroneuro

REVIEW

Antipsychotic augmentation of serotonergic

antidepressants in treatment-resistant
obsessive—compulsive disorder: A meta-analysis of
the randomized controlled trials
Petros Skapinakis a,b,*, Tzeni Papatheodorou a, Venetsanos Mavreas a

a
Department of Psychiatry, University of Ioannina, School of Medicine, Ioannina 45110, Greece
b
Academic Unit of Psychiatry, University of Bristol, UK

Received 30 March 2006; received in revised form 29 June 2006; accepted 4 July 2006

KEYWORDS Abstract This study aimed to determine the effectiveness of antipsychotic augmentation of
Obsessive—compulsive serotonergic antidepressants in the management of treatment-resistant obsessive compulsive
disorder/drug therapy; disorder by carrying out a meta-analysis of all randomized controlled trials. Studies selected
Antipsychotic agents/ through a literature search conducted in March 2006. Ten trials comparing antipsychotic drugs
therapeutic use; versus placebo met inclusion criteria (haloperidol [n = 1], risperidone [n = 3], olanzapine [n = 2],
Antidepressive agents/ quetiapine [n = 4]). A total of 157 patients were randomized to study drug and 148 were
therapeutic use; randomized to placebo. Response occurred more often among patients randomized to
Serotonin uptake antipsychotic drugs. The weighted combined response rate ratio by random effects meta-
inhibitors/therapeutic analysis was 3.31 (95% CI 1.40—7.84). Significant between studies heterogeneity was partly
use; explained by the definition of refractoriness, the type and dose of the drug used and the
Controlled clinical inclusion or exclusion of patients with tic disorders. The study supports the use of antipsychotic
trials; drugs as an augmentation strategy but more and larger trials are needed.
Meta-analysis D 2006 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction

Obsessive—compulsive disorder (OCD) is a relatively com-

* Corresponding author. Department of Psychiatry, University of mon condition in the general population. Epidemiological
Ioannina, School of Medicine, Ioannina 45110, Greece. Tel.: +30 data from the UK have shown a prevalence of 1.2% in the
26510 97748; fax: +30 26510 97049. general population (Jenkins et al., 1997) and similar figures
E-mail address: pskapin@cc.uoi.gr (P. Skapinakis). have been reported from the US and elsewhere (Horwath

0924-977X/$ - see front matter D 2006 Elsevier B.V. and ECNP. All rights reserved.
doi:10.1016/j.euroneuro.2006.07.002

NEUPSY-09912; No of Pages 15
 ARTICLE IN PRESS
2 P. Skapinakis et al.
and Weissman, 2000; Karno et al., 1988). The course is
usually chronic and the disorder may lead to considerable
disability without treatment (Karno et al., 1988; Skoog and
Skoog, 1999; Steketee, 1997). Despite its prevalence, the
disorder is under-recognized and under-treated (Stein,
2002; Steketee, 1997). Patients may be reluctant to report
their symptoms to doctors and depression, social phobia
and agoraphobia, with or without panic disorder, are
commonly diagnosed in patients with OCD (Bartz and
Hollander, 2006).
Pharmacological treatment of OCD is based on the use of
serotonergic antidepressants, mainly selective serotonin
reuptake inhibitors (SSRIs) (Fineberg and Gale, 2005). An
adequate response is generally achieved by 40% to 60% of
patients taking SSRIs and this leaves a lot of patients with
partial or poor response (Pallanti et al., 2002). A range of
augmentation strategies have been proposed, both pharma-
cological and non-pharmacological, for these patients
(Fineberg and Gale, 2005). Regarding the former, the use
of antipsychotic drugs has been suggested for at least two
reasons: a) the degree of insight into obsessions differs in
OCD. Some patients do not regard their symptoms as
senseless or unreasonable and their obsessions resemble
more overvalued or delusional ideas than anxiety worries
(Matsunaga et al., 2002); b) an involvement of the dopamine
system 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 more
rigorous randomized controlled trials of both typical and
newer antipsychotic drugs. At least five systematic
reviews of the evidence behind the pharmacotherapy of
OCD have been published in the past three years, three
of 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). Their
findings support the use of these drugs, in combination
with SSRIs, in OCD patients with poor or partial response
to SSRIs. These reviews, however, did not attempt to
combine the results of the available randomized con-
trolled trials to give an estimate of the overall effect of
antipsychotic drugs in treatment-resistant OCD. Given
that most of the studies were small and probably
underpowered this is an important limitation that has
not been addressed. In addition, during the past two
years new randomized controlled trials on this issue were
published that were only included in a very recent
systematic review (Fineberg et al., 2006). For these
reasons, in the present paper we aimed to carry out a
meta-analysis of all randomized controlled trials that
examined the effectiveness of antipsychotic drugs as
augmenting agents in patients with OCD non-responsive
to monotherapy with antidepressants.
2. Experimental procedures
2.1. Search strategy
We searched PubMed for English and non-English medical
literature published from 1966 to January 2006. We supplemented
this source by also searching EMBASE (1980—2005), the Cochrane
Controlled Trials Register (2006, issue 1) and the PsiTri database
(http://psitri.stakes.fi/). We manually checked the reference lists
of prior reviews, systematic reviews and trials.
We used the following search string (string 1) in PubMed:
(bObsessive—Compulsive DisorderQ[MeSH]) AND ((bClinical
TrialsQ[MeSH]) OR (bSingle-Blind MethodQ[MeSH]) OR (bDouble-Blind
MethodQ[MeSH]) OR (bPlacebosQ[MeSH])) AND (bAntipsychotic
AgentsQ[Pharmacological Action])
Because the use of the MeSH terms does not return records that
have been supplied by the publishers or are in the process of
indexing, we also used the following sensitive string (string 2) to
identify new studies not yet officially indexed:
(Obsess* OR Compuls*) AND (Antipsychot* OR Haloperidol OR
Risperidone 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 obsessive—compulsive disor-
der non-responsive to previous antidepressant treatment;
c) experimental intervention: antipsychotic augmentation of
antidepressant 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 the
Clinical Global Impressions-Improvement Scale (CGI-I) (Guy,
1976).
We excluded studies from our analysis if they met at least one of
the 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 and
doses 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 to
augment the antidepressant);
d) outcomes and results (number of patients entering and
completing the study, number and reasons for dropouts and
withdrawals, baseline and end of study mean Y-BOCS scores
and standard deviations, mean change and standard deviation
of change from baseline scores, number of patients responding
in active and control arms.
Our primary outcome measure was the number of patients who
were classified as responders based on pre-defined relative score
improvements on the Y-BOCS scale, the global improvement sub-
scale of the CGI, or a combination of both. Since the duration of the
studies might differ, we recorded the number of respondents at the
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Antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD 3

time-point defined by the original investigators for the measure-
ment of their primary outcome. We used improvement in OCD
symptoms measured as a dichotomous outcome (response vs. non-
response) and not reduction in the severity of symptoms, measured
as a continuous outcome, because we think that results are more
readily interpretable from a clinical perspective. Although, the
focus 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 additionally
deducted one point if losses to follow-up were greater than 20%.
Studies were then classified into two categories as either of low (a
score 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 data
sheets. Data were extracted by one investigator (TP) and checked
by another investigator (PS). Quality assessment was made by two
investigators (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 recorded
according to the intention to treat principle. Using the Review
Manager software we calculated the response rate ratios (ratios of
the number of patients who responded divided by the number of
patients initially randomized to the respective group) and their 95%
confidence intervals. Rate ratios greater than 1 indicate a better
response for the antipsychotic medication group. We combined
results on the rate ratio using fixed or random effect models. To
investigate the degree of between-trial heterogeneity, the chi
squared test was performed and I squared was calculated (Higgins
and 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 following
predefined subgroup analyses:
may be more important for the antipsychotic effect. Based on
these measurements we classified studies into two categories
of low or standard/high dose if the mean dose reported was
below or above the cutoff to achieve adequate D2 occupancy
respectively;
e) the duration of the trial: studies were grouped into two
categories according to the duration of the randomized trial
(less than 8 weeks, 8 weeks or more).
Sensitivity analysis aimed to investigate the influence of study
quality as measured by the modified Jadad scale (2 or less was
recorded as low quality).
3. Results
3.1. Search flow
Our search strategy in Pubmed yielded 67 abstracts (49
abstracts from string 1 and 18 abstracts from string 2). A
total of 11 citations (10 out of 49 and 1 out of 18) were
retrieved as likely placebo-controlled trials, from which
10 (9 and 1 respectively) were retained after consider-
ation of the inclusion and exclusion criteria (Fig. 1). No
other trials were identified from other sources including
the reference lists of previous systematic reviews. The
study excluded was that of Li et al. (2005) which was a
crossover trial.
3.2. Studies and patients characteristics
Ten trials were included in the meta-analysis and their
characteristics are summarized in Table 1. These trials
included 1 haloperidol study (4-week duration) (McDougle
et al., 1994), 3 risperidone studies (6- to 8-week durations)

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 the
35% reduction in the Y-BOCS criterion for refractoriness;
c) the inclusion or exclusion of patients with comorbid tic
disorders: previous literature has suggested that antipsychotic
drugs may be more effective in treatment resistant OCD in the
presence of comorbid tic disorders (McDougle et al., 1994). For
this reason we stratified studies into two categories, according
to whether the authors had included or excluded patients with
comorbid tic disorders;
d) the dose of antipsychotic medication used: antipsychotic drugs
are 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 these
drugs can exert their antipsychotic effect only if they have
blocked more than 60% to 65% of the dopamine D2 receptors
(Kapur et al., 2000a,b; Nordstrom et al., 1993). Previous PET
studies have shown that the dose needed to achieve this D2
occupancy is for Haloperidol 2—4 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). It
should be noted that the figure for Quetiapine is estimated at
two hours after administration and not at twelve hours, but the
authors have suggested that for this drug the transient effect Figure 1 Trials identification and selection.
 4
Table 1 Characteristics of ten trials of antipsychotic augmentation in treatment-resistant obsessive—compulsive disorder included in the meta-analysis
Study/country N (% male) Duration Antidepressanta Antipsychotic Mean age (SDb) Mean daily Duration of Definition of Mean baseline Response
(weeks) (A= antipsychotic dose mg (SDb) pre-randomization refractorinessc Y-BOCSd ratef
P = placebo) antidepressanttreatment
McDougle et al. 34 4 1 Haloperidol 35 (12) 6.2 (3.0) 1 and 3 and 4 A: 25.4 (5.0) A: 65%
(1994)/USA (76%) P: 24.9 (4.0) P: 0%
McDougle et al. 36 6 1,2,3,4,5 Risperidone A: 39.8 (10.2) 2.2 (0.7) 12 weeks (8 at maximum 1 and 3 and 4 A: 27.4 (5.4) A: 50%
(2000)/USA dose)
(58%) P: 34.5 (10.3) P: 27.6 (3.7) P: 0%
Hollander et al. 16 8 1,2,3,4,5,6,7 Risperidone A: 36.8 (10.4) 2.2 (0.9) 12 weeks (most on 2 and 3 A: 29.2 (5.7) A: 40%
(2003)/USA maximum dose)

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(56%) P: 43.2 (15.8) P: 29.3 (2.8) P: 0%
Erzegovesi et al. 20 6 1 Risperidone A: 38 (13.4) 0.5 12 weeks (mostly at 1 and 3 A: 30.9 (4.7) A: 50%
(2005)/Italy maximum dose)
(53%) P: 31.8 (7.8) P: 26.4 (4.8) P: 20%
Bystritsky et al. 26 6 2,3,4,5 Olanzapine A: 44.5 (17.3) 11.2 (6.5) 12 weeks (most at 2 A: 24.2 (4.8) A: 46%
(2004)/USA maximum dose)
(50%) P: 38.3 (9.1) P: 25.2 (4.2) P: 0%
Shapira et al. 44 6 2 Olanzapine 36.9 (11.1) 6.1 (2.1) 8 weeks (at moderate 2 A: 20.3 (4.9)e A: 41%
(2004)/USA doses)
(41%) P: 19.1 (3.8)e P: 41%
Atmaca et al. 27 8 1,2,3 Quetiapine A: 28.6 (8.5) 91.1 (41.1) 12 weeks 1 and 4 A: 24.1 (4.9) A: 71.4%
(2002)/Turkey (52%) P: 28.1 (8.7) P: 23.8 (4.1) P: 0%
Denys et al. 40 8 1,2,3,5,6,7,8 Quetiapine A: 36 (14) 300 16 weeks (2 SRIs 1 and 3 A: 28.2 (4.3) A: 31%
(2004a,b)/ 8 weeks each)
Netherlands (25%) P: 34 (12) P: 26.4 (6.3) P: 6%
Carey et al. 41 6 1,2,3,4,5,6 Quetiapine A: 33.8 (9.6) 168.7 (120.8) 12 weeks (at least 6 2 and 3 A: 26.4 (4.6) A: 40%
(2005)/ at maximum dose)
South Africa (46%) P: 31.8 (12.1) P: 27.7 (8.4) P: 47.6%
and Canada
Fineberg and 21 16 4,5,6 Quetiapine A: 37.4 (11.4) 215 (124) 12 weeks (mostly at 2 A: 24.5 (4.6) A: 27%
Gale (2005)/ maximum dose)
UK (57%) P: 37.9 (10.7) P: 24.1 (4.3) P: 10%
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

P. Skapinakis et al.
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.
 ARTICLE IN PRESS
Antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD
(Erzegovesi et al., 2005; Hollander et al., 2003; McDougle et
al., 2000), 2 olanzapine studies (6-week durations)
(Bystritsky et al., 2004; Shapira et al., 2004), and 4
quetiapine studies (6- to 16-week durations) (Atmaca et
al., 2002; Carey et al., 2005; Denys et al., 2004a,b; Fineberg
et al., 2005).
The mean age of the participants was below 40 years old
for the majority of the studies. Only three studies had more
female than male patients. Five studies included patients
with comorbid tic disorders (Carey et al., 2005; Fineberg et
al., 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 some
variation on the duration of use of the maximum tolerated
dose. Only one study had a duration of 8 weeks and used
moderate only doses of antidepressants in the pre-
randomization phase (Shapira et al., 2004). This study
also differed in that the patients randomized had less
severe 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 antidepressant
drugs but most often fluvoxamine, fluoxetine and clomi-
pramine (Table 1).
The mean dose of the antipsychotic drugs was generally
lower than the dose normally used for treating schizophre-
nia. According to our definitions, 4 studies were classified
into the standard or high dose group that could induce
higher than 60% to 65% D2 occupancy: one haloperidol study
(McDougle et al., 1994), two risperidone studies (Hollander
et al., 2003; McDougle et al., 2000) and one olanzapine
study (Bystritsky et al., 2004). Six studies were classified
into 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 (Shapira
et al., 2004).
Definition of refractoriness and definition of response
was not uniform across studies, and some studies applied
stricter criteria for refractoriness or response. However, in
all studies there was consistency between definition of
refractoriness and response. Using the percentage reduction
in the Y-BOCS criterion, 5 studies were classified into the
35% 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 148
patients were randomized to placebo. There were 73
responses in the antipsychotic group (response rate 46%)
and 24 responses in the placebo group (response rate
16%).
3.3. Meta-analysis outcome
For the 10 trials included in the meta-analysis response rate
ratios were heterogeneous (X 2 = 26.45, p = 0.002, I 2 = 66%).
The combined response rate ratio for the 10 studies was 3.31
(95% confidence interval 1.40—7.84) using a random effects
model (Fig. 2).
5
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 analysis
slightly reduced the combined response rate ratio (2.78
[1.21—6.37]).
3.5. Sub-group analysis
3.5.1. Type of antipsychotic drug used
Fig. 2 also shows the analysis of different classes of
antipsychotic drugs. Although the number of studies is
limited within each class, it is worth noting that the results
for risperidone are more consistent and there is no
statistical heterogeneity. There is only one study with
Haloperidol so conclusions cannot be made for this drug.
The combined rate ratios for the other drugs were not
significantly 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 used
the 25% reduction in Y-BOCS scores criterion were not
significantly 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 the
dosing scheme used. The combined response rate ratio for
the studies using higher doses was 12.75 (95% CI 3.20—
50.85). The combined rate ratio for the lower dose studies
was 1.82 (0.85—3.91). This stratification reduced consider-
ably the heterogeneity. In the low dose group, the only
outlier was the study of Atmaca et al. (2002).
3.5.4. Stratification by tic disorders
Contrary to what would have been expected based on the
previous 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 of
what we had hypothesized, we also examined the possibility
of an interaction between the dose used and the inclusion or
exclusion of patients with tic disorders. For this reason we
classified 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; Fineberg
et 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 response
rate but this was more pronounced in studies that included
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P. Skapinakis et al.
Figure 2 Response rate ratios of antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD, by type of drug and overall compared with Placebo.
 Antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD
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Figure 3 Response rate ratios of antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD, by definition of refractoriness (see Experimental
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 (see Experimental procedures), compared

P. Skapinakis et al.
with Placebo.
 Antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD
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Figure 5 Response rate ratios of antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD, by inclusion of comorbid tic disorders (see Experimental
procedures), compared with Placebo.

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P. Skapinakis et al.
Figure 6 Response rate ratios of antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD, by inclusion of tics and dose of drug (see Experimental
procedures), compared with Placebo.
 Antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD
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Figure 7 Response rate ratios of antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD, by duration of trial, compared with Placebo.

11
 ARTICLE IN PRESS
12
patients with tic disorders. The combined response rate
ratio for the three studies that used a low dose and
included patients with tics was not significantly different
from unity.
3.5.5. Stratification by duration of the trial
Results of this subgroup analysis are shown in Fig. 7. Studies
with a (post-randomization) duration of at least 8 weeks
showed a statistically significant result while this was not
evident in the group of studies with less duration. This group
however was quite heterogeneneous.
3.6. Dropouts
Although the primary aim of this analysis was to report on
the efficacy, we also report on the safety and tolerability of
the use of antipsychotic drugs in OCD patients. No study
reported any serious adverse events. However, most of the
patients treated with antipsychotic drugs reported mild side
effects 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 to
12 (out of 121) in the placebo group, a combined weighted
relative risk for dropouts of 1.43 (95% CI 0.52, 3.98). In this
calculation we have excluded two studies either because
they did not report dropouts in each group (Erzegovesi et
al., 2005) or because there were no dropouts in either group
(McDougle et al., 1994). Most common reason for dropout in
the drug group was a side effect and for the placebo group
was lack of effect.
4. Discussion
4.1. Main findings
In this meta-analysis we found that the use of antipsychotic
drugs, as augmenting agents of serotonergic antidepres-
sants, was associated with a short-term higher response rate
in adults with treatment resistant OCD compared with
placebo. We also found considerable heterogeneity between
studies. Predefined subgroup analyses showed reduced
heterogeneity and positive outcome for risperidone (among
the three drugs with 2 or more studies) and for using
standard/high doses of antipsychotic drugs. Use of lower
doses was not associated with a better outcome compared
to placebo but further stratification by inclusion or exclusion
of patients with tic disorders showed that this could be due
to the studies that used a low dose in the presence of
comorbid tic disorders. A duration of trials of at least
8 weeks was generally associated with a better outcome.
4.2. Limitations of the study
Our results should be interpreted in the context of the
following limitations:
First, studies were generally small and only half of them
had a total sample of more than 30 patients. The results
should therefore be interpreted with caution. Although in
theory the advantage of randomization is that it can be
assumed that all potential confounding variables have been
P. Skapinakis et al.
controlled, an imbalance in the two arms cannot be
excluded 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 of
subgroup analyses difficult. There were few studies within
each class of antipsychotic drugs and future publication of
more and larger trials may influence the results in either
direction. The same applies for our stratification of studies
by dose and inclusion of tic disorders. It should also be noted
that the variable binclusion of patients with tic disordersQ is
at the study level, and therefore it should not be assumed
that the association reported refers to individual patients, in
which case an ecological bias could take place. Even though
we carried out subgroup analyses based on predefined
subgroups and also we made specific hypotheses after
reviewing the previous literature, it is likely that some of
the results would be different if more and larger trials had
been published. Although Type II errors would be more likely
given the small number of trials, we cannot exclude the
possibility 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 with
the outcome. However, one of the advantages of the meta-
analysis is that it can take into account these differences
through 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 other
definitions might yield slightly different results in either
the combined or subgroup analysis.
4.3. Interpretation of the main finding — clinical
implications
All antipsychotic drugs influence the dopaminergic pathways
in areas of the brain that have been linked to the
pathophysiology of OCD, such as the basal ganglia (Kim et
al., 2003). Dopamine D2 receptor blockade is considered as
a sufficient and necessary condition for antipsychotic action
(Kapur and Seeman, 2001), although the effect to other
dopamine or serotonin receptors may also be important
especially for extrapyramidal symptoms or other side effects
(Kapur et al., 1999). Even though antipsychotic drugs differ
in their D2 blockade potency, most are capable of blocking
more than 65% of the D2 receptors if given in sufficient
doses. Only quetiapine and clozapine show consistently
lower D2 occupancy rates (Seeman and Tallerico, 1999),
but it has been suggested that these two drugs have a very
fast dissociation from the D2 receptor and if their occupancy
is measured in two hours after administration, and not in
twelve hours as is normally done, their D2 occupancy rate is
quite high at therapeutic doses (Kapur and Seeman, 2001).
There is now evidence that a dopamine dysfunction may
be involved in the pathophysiology of OCD (Denys et al.,
2004b; Stein, 2002). Neuroimaging studies have shown that
patients with OCD have higher dopamine transporter
densities and lower dopamine D2 binding ratios compared
to controls (Kim et al., 2003) and this has been considered as
indirect evidence of an increased dopaminergic activity in
OCD. The results of this meta-analysis show that the use of
antipsychotic drugs is associated with a higher response in
patients who had not responded previously to a serotonergic
antidepressant. Moreover we found that lower doses had a
 ARTICLE IN PRESS
Antipsychotic augmentation of serotonergic antidepressants in treatment-resistant OCD
smaller (non-significant) effect compared to standard/high
doses. These empirical data support the hypothesis of an
increased dopaminergic activity in treatment-resistant OCD
patients. An alternative mechanism could be that the lower
doses are sufficient to block the serotonin 5HT2 but not the
dopamine 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 of
atypical antipsychotics and SSRIs may increase synergisti-
cally extracellular dopamine and/or noradrenaline, espe-
cially in the prefrontal cortex (Dennys et al., 2004; Zhang et
al., 2000). These cortical dopaminergic pathways are
important 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 doses
are associated with a greater non-specific anxiolytic effect
which is reflected in patients’ measurements of OCD
symptoms.
It is very difficult, given the small number of trials, to
comment on the relative efficacy of specific antipsychotic
drugs. We noted previously that in the case of risperidone
there was low between studies heterogeneity. Results for
other drugs do not seem to be sensitive to additional trials
that may be published in the future. For example, in the
case of quetiapine we calculated that in order to achieve a
combined response rate ratio similar to that of risperidone a
trial of 70 patients (35 in each arm) would be needed with
25 responses in the quetiapine arm and 5 responses in the
placebo arm (71% versus 14% response rate). This would
result in a marginally significant combined response rate
ratio. In the case of olanzapine, even a study of 200 patients
with a 60% response rate in the active arm versus 10%
response rate in the placebo arm would not be capable of
yielding 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 one
haloperidol study seems promising but it is difficult to make
recommendations based on a single study. Notwithstanding
these limitations, the results of this meta-analysis support
the use of risperidone as a first choice and haloperidol as a
second choice in the short-term management of treatment-
resistant OCD. Risperidone is more likely effective in doses
closer to 2 mg/day. Haloperidol was effective at a mean
dose of 6 mg/day but it may also be effective in doses of 2 to
3 mg/day that are capable of blocking more than 65% of D2
receptors (Kapur et al., 1996). It should also be noted that in
patients without tics smaller doses may be tried.
Our analysis showed an association between the defini-
tion of refractoriness and the response rate ratio. Studies
that used the 25% reduction on the Y-BOCS scale criterion for
refractoriness/response were associated with a non-signif-
icant combined rate ratio. However, one should take into
account that most of these studies also used low doses.
Therefore, it is likely that this has resulted in the negative
result. It has also been suggested by others (Fineberg et al.,
2006), that two of these studies (Carey et al., 2005; Shapira
et al., 2004) had an unusually high response rate for
placebo. This may be an indirect indication of a previously
inadequate treatment with the serotonergic antidepressant.
Trials that have included patients with tic disorders
generally report that the antipsychotic drugs were not
better in the subgroup of patients with tic disorders. Only
13
the first haloperidol study reported that the drug was
effective in the tics subgroup, while there was no effect in
OCD patients without tics (McDougle et al., 1994). In our
combined analysis we noted that studies that included
patients with tic disorders were associated with smaller
response rates not significantly different from placebo.
Patients with tic disorders may constitute a difficult
subgroup of OCD patients. Alternatively, as we suggest,
these patients may need larger doses of antipsychotic drugs.
The haloperidol study largely confirms that but we need
more studies to make a recommendation.
The duration of the trial was found to be significantly
associated with a better outcome. This finding emphasizes
the need for extending the period of observation for at least
8 weeks before one can conclude that the augmenting agent
is or is not effective in reducing OCD symptoms.
4.4. Implications for research
Future trials on antipsychotic drugs in treatment-resistant
OCD should try to avoid using low doses of antipsychotic
drugs. In addition, there should be careful evaluation of the
presence of comorbid tic disorders. Alternative dosing
schemes within a trial are also of interest, for example
comparing low doses versus standard doses with placebo.
The use of more selective D2 antagonists could offer useful
data. Finally, there is a need for larger trials of longer
duration in order to evaluate both efficacy and safety in the
long-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 the
manuscript.
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