Review

Commonly asked questions in

the treatment of obsessive-
compulsive disorder
Expert Rev. Neurother. Early online, 1–13 (2014)
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Shyam Sundar Obsessive-compulsive disorder (OCD) is a common and often a highly disabling condition that
Arumugham* and was considered untreatable before the 1960s. The advent of serotonin reuptake inhibitors
YC Janardhan Reddy and exposure and response prevention revolutionized the treatment of OCD. Although they
are still the first line treatments for OCD, new treatments like augmentation strategies, brain
Department of Psychiatry, Obsessive-
Compulsive Disorder (OCD) Clinic,
stimulation techniques, psychosurgery, newer forms of psychotherapy (like cognitive therapy,
National Institute of Mental Health and acceptance and commitment therapy) have been added to the armamentarium. With the
NeuroSciences (NIMHANS), Bangalore, available treatment strategies, many patients can achieve at least partial remission of
India-560029 symptoms. Nevertheless, the plethora of information gives rise to many questions on their
*Author for correspondence:
Tel.: +91 802 699 5340 application for practicing clinicians. We provide evidence-based responses to these questions
a.shyamsundar@gmail.com and suggest a broad guideline for treatment of OCD.
shyamsundar.a@nimhans.kar.nic.in
For personal use only.

KEYWORDS: augmentation . behavior therapy . cognitive-behavior therapy . obsessive-compulsive disorder

. psychosurgery . repetitive transcranial magnetic stimulation . selective serotonin reuptake inhibitor . treatment

Obsessive-compulsive disorder (OCD) is a questions when discussing treatment of OCD

common and often a highly disabling condi- in academic fora and from well-informed
tion that was considered untreatable before the patients. Here, we provide evidence-based
1960s. Long-term studies show that many responses to these questions and suggest broad
patients have persistent symptoms up to guidelines for treatment of OCD. Recent sys-
40 years of follow-up [1]. Earlier psychological tematic reviews and guidelines have discussed
(e.g., psychodynamic therapy) and somatic extensively on treatment of OCD [4,9]. We
treatments (e.g., non-specific tricyclic antide- augment this valuable literature by providing
pressants [TCAs], electroconvulsive therapy evidence-based recommendations on specific
[ECT]) were ineffective in the treatment of aspects of implementation of various interven-
OCD [2–4]. In the later part of 20th century, it tions for OCD and the relative place of each
was recognized that OCD responds preferen- intervention. This review takes into considera-
tially to drugs that have powerful serotonin tion recent literature on a range of pharmaco-
reuptake inhibiting activity, namely, selective logical augmenting agents, evidence supporting
serotonin reuptake inhibitors (SSRIs) and clo- the use of cognitive behavior therapy (CBT)
mipramine [4]. Around the same time, behav- in partial responders and non-responders to
ior therapy (BT), in the form of exposure and SSRIs, brain stimulation techniques and neu-
response prevention (ERP), was also found to rosurgical interventions. Additionally, the
be effective [2]. New treatments like augmenta- review also briefly addresses management of
tion strategies [5], novel psychotherapies like OCD comorbid with schizophrenia and bipo-
acceptance and commitment therapy (ACT) [6], lar disorder (BPD).
novel brain stimulation techniques like repeti-
tive transcranial magnetic stimulation (rTMS) What is the first-line treatment of OCD?
[7] and neurosurgery [8] have been added to Randomized controlled trials (RCTs) and
the armamentarium. meta-analyses have consistently demonstrated
The plethora of information gives rise to the efficacy of SSRIs and clomipramine and
many questions on their application for prac- behaviorally oriented therapies (BT and CBT)
ticing clinicians. We encounter many such in the treatment of OCD [4,6,10,11]. Most

www.expert-reviews.com 10.1586/14737175.2014.874287
2014 Informa UK Ltd ISSN 1473-7175 1

 Review Arumugham & Reddy

treatment guidelines recommend either or both of them as 25% or greater reduction in Yale–Brown Obsessive Compulsive
first-line treatments in OCD [9,12]. Scale (Y-BOCS) [10]. It is generally recommended that people
Behavioral therapy using ERP has been consistently found to with OCD require a higher dose of SSRIs than that used in
be one of the most effective forms of treatment of OCD [11,13]. depression and other anxiety disorders [9,22]. Fixed-dose com-
Cognitive therapy with or without ERP has also been found to parison studies have shown a dose–response relationship for
be effective [6,13]. A recent meta-analysis has demonstrated an fluoxetine, paroxetine and escitalopram, but not for other
effect size of 1.35 for ERP (Hedge’s g, 95% CI: p < 0.001) SSRIs [4]. A recent meta-analysis of nine RCTs on SSRIs
compared with controls, which signifies a large effect size [14]. showed that high dose of SSRIs (60–80 mg fluoxetine equiva-
As there is widespread variability across different studies, it is lents) is more effective than low (20–30 mg fluoxetine equiva-
difficult to determine an adequate ‘dose’ of therapy [12]. Recent lents) or medium dose (40–50 mg fluoxetine equivalents) of
meta-analyses have found that intensity of treatment in the SSRIs [23]. High-dose SSRIs was associated with higher drop-
form of number and frequency of treatment sessions are unre- outs due to side effects, although the proportion of ‘all-cause’
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lated to treatment outcome [13,14]. Most of the studies in these dropouts did not differ based on SSRI dose [23]. There is some
meta-analyses carried out 10–15 sessions per patient. In the preliminary evidence to suggest that higher than recommended
meta-analysis by Olatunji et al., 11 of the 16 studies fall within dose of SSRIs (e.g., 250–400 mg/day of sertraline) may be use-
this range [14]. The lack of relationship could be due to insuffi- ful in non-responders to standard doses [24]. Improvement with
cient variability in these studies to allow a relationship to be SSRIs may start occurring at around 4–6 weeks, but there may
detected. In a more inclusive meta-analysis, treatment intensity be a delay in treatment onset up to 12 weeks, with increasing
in the form of number of therapist hours predicted treatment improvement observed up to 1 year after treatment initia-
efficacy [12]. The effect of number of therapist hours on treat- tion [9,12,22,25,26]. There is some recent evidence to suggest that
ment efficacy was stronger for interventions with less than early improvement in OC symptoms (at 4 weeks) predicts sub-
10 therapist hours per patient as compared with interventions sequent treatment response (at 12 week) [27]. In the above
with more than 10 therapist hours per patient [12], suggesting study, early improvement predicted subsequent treatment
some evidence of dose–response relationship. Recent large response with 76% sensitivity and 62% specificity [27]. In sum-
For personal use only.

RCTs have employed at least 15–22 sessions of exposure [15–17]. mary, a high dose of SSRIs should be considered as the first-
Therefore, it seems reasonable to assume that 15–20 sessions line pharmacological treatment for OCD. Medications have to
over 8–12 weeks may be required for most patients. be continued for at least 12 weeks for adequate treatment
Despite its efficacy, BT is not widely practiced because of response.
lack of awareness, insufficient training and time intensive
nature of the treatment. Modifications have been made to BT Which is better – BT or SSRI?
to make it more accessible and cost-effective. The therapist As both BT and SSRI treatment have been found to be effective,
contact time can be decreased by administering patient- often the question arises which should be tried first in a given
controlled ERP with supervision by a therapist. Meta-analyses patient. There have been few head-to-head comparison trials com-
have found therapist-guided exposure superior to therapist- paring the relative efficacy of these treatments. Foa et al. com-
assisted self-exposure [13,18]. A recent study by van Oppen et al. pared the efficacy of clomipramine, ERP and their combination
showed that there was no significant difference in efficacy with a pill placebo [15] in a randomized multi-site study. ERP,
between patient-controlled and therapist-controlled ERP, con- either alone or in combination with clomipramine was superior to
ducted either by experienced behavior therapists or clinically clomipramine treatment. ERP was provided quite intensively in
inexperienced master’s students in clinical psychology [19]. But this study (daily 2-h therapist-guided exposure sessions 5 days a
the finding of this study may have to be interpreted in the con- week along with 2 h a day of ERP home work for initial 3 weeks
text of modest sample size. ERP has also been adapted to followed by 8 weekly maintenance sessions including 2 home vis-
group format, which has generally been found to be equally its by therapist in the 4th week), which may not be replicable in
effective to individual therapy [14]. A computer-guided BT self- many clinical settings. Less-intensive ERP (weekly sessions) has
help system (BT STEPS) was more effective than relaxation not been found to be superior to fluoxetine [28]. Meta-analyses
training, but less effective than therapist-guided exposure [20,21]. have usually revealed a larger effect-size for BT compared with
Such less intensive forms of BT may be tried in patients with pharmacotherapy [11,29], but the difference was not statistically sig-
mild-to-moderate OCD and intensive treatments with more nificant, after controlling for methodological variables [29].
therapist contact time can be reserved for severe and treatment- According to a recent meta-analysis, 62% of patients entering
resistant patients. ERP improve with treatment while 53% starting SSRIs improve
Among the pharmacotherapies, serotonin reuptake inhibitors with treatment [11]. The definition of improvement varied across
(SRIs) have the best evidence [11]. These include SSRIs and clo- studies included in this meta-analysis, limiting their comparabil-
mipramine. According to a recent meta-analysis, the relative ity. Foa et al. found a significantly higher response rate for ERP
risk of treatment response of SSRIs versus placebo is (Clinical Global Impression – Improvement scale £2) compared
1.84 (95% CI: 1.56–2.17) with a number needed to treat with clomipramine in treatment completers, but the difference
(NNT) of 6 [10]. In this meta-analysis, response was defined as was not significant in the treated group [15]. The percentage of

doi: 10.1586/14737175.2014.874287 Expert Rev. Neurother.

 Commonly asked questions in the treatment of OCD Review

excellent responders (Clinical Global Impression – Improvement and cognitive interventions. Most protocols that employ cogni-
scale = 1) was significantly higher in the ERP group in both the tive techniques also employ behavioral techniques in the form
treated group and the completer group [15]. Post-treatment Y- of ERP, often referred to as CBT. Cognitive interventions are
BOCS scores have been found to be lower in BT/CBT-treated often used to facilitate ERP and behavioral experiments used in
patients compared with SSRI-treated patients [11,15,30]. In a clinical cognitive therapy are similar to exposure strategies in that they
effectiveness trial mimicking ‘real-world’ scenario, patients receiv- provide opportunity to disconfirm distorted beliefs and also
ing group CBT and SSRI had similar post-treatment total Y- encourage habituation [37]. Most studies use the term CBT as it
BOCS scores and responder rates [31]. This study had broader often involves a combination of both techniques.
inclusion criteria compared with traditional RCTs, resulting in an Most of the head-to-head comparison studies and meta-
increased comorbidity profile in the sample. Hence, the superior- analyses have found similar efficacy for CBT and ERP [6,11,13,14].
ity of BT/CBT over SSRI seen in RCTs may not be apparent in CBT may be preferred in patients with pure obsessions [38,39].
the clinical setting. However, purely cognitive intervention without behavioral com-
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Patients treated with medications have a higher relapse rate ponent may be less effective [11,37]. The role of cognitive interven-
on treatment discontinuation compared with those treated with tions in poor-insight OCD has not been studied adequately. New
BT [32]. Although psychotherapies are considered to have no forms of cognitive interventions like Danger Ideation Reduction
adverse effects, ERP is associated with significant anxiety as a Therapy and cognitive coping therapy have been found to be
part of treatment, which leads to dropout rate as high as 30%. superior to BT/CBT in a few trials with methodological
In fact, the dropout rate has not been found to be different limitations [40–42]. But the findings have not been replicated by
between ERP and SRIs [15,29]. Patients with psychiatric comor- independent research groups. ACT and satiation therapy are other
bidity have a higher chance of dropout from either treat- new therapies that have been found effective in single trials [43,44].
ment [33]. Existing international guidelines recommend CBT in Psychodynamic therapy, stress management and other behavioral
mild illness and either CBT or SSRI or their combination in interventions like systematic desensitization, aversion therapy,
people with more severe illness considering factors like patient thought stopping techniques are of little use in OCD [2,6].
preference, comorbidity, previous treatment response, etc. [9,12]. Mindfulness has been demonstrated as an alternate way of
For personal use only.

Overall, it appears that CBT involving ERP may have some handling unwanted intrusions in a non-clinical student popula-
advantages compared with SSRIs in the form of greater symp- tion with OC symptoms [45]. In contrast to cognitive therapy
tom improvement and lower relapse rate. However, the choice which encourages patients to actively analyze the content of
of treatment is dictated by severity of illness, availability of obsessions to understand their irrationality, mindfulness
trained therapist, feasibility, ability to tolerate initial anxiety, encourages non-judgmental observation, awareness and accept-
motivation of the patient and patient preference. In most devel- ance of these intrusions to decrease their significance [45,46]. It
oping countries, there is severe shortage of mental health pro- has been suggested that mindfulness techniques may be less
fessionals, and in such situations SSRIs may become the anxiety provoking compared with ERP [46] and especially useful
preferred choice of treatment over CBT alone or a combination in managing thought-action fusion and thought suppression [47].
of SSRI and CBT. Despite the interesting premise, mindfulness has not been rig-
orously tested in controlled trials in OCD. Available evidence
What is the role of other psychotherapies like cognitive is in the form of case series and one non-RCT in a non-clinical
therapy or mindfulness-based techniques? population [45,47]. Further mindfulness is usually provided as a
Although ERP is considered ‘one of the success stories in behavior component of a package as in mindfulness-based cognitive ther-
therapy’ , it has its own limitations which include: refusal to apy and ACT [43,46]. Whether mindfulness is an active compo-
undergo BT; early dropout and poor response to BT; persis- nent in these treatments needs to be studied. A small RCT
tence of residual symptoms, which may need additional treat- (n = 22) found kundalini yoga meditation protocol superior to
ment; relapse in a sizable minority; doubtful efficacy in pure relaxation response plus mindfulness meditation technique in
obsessives without overt compulsions, hoarding, etc. and poor reducing OC symptoms [48]. Larger studies are needed to con-
motivation, non-compliance [34]. There was a need felt for firm the efficacy of these interventions.
innovations in psychotherapy for OCD. The primarily cogni- Overall, CBT is the only treatment that has been found to be
tive nature of obsessions makes cognitive therapy the obvious as effective as ERP. Cognitive strategy along with ERP may be
choice. It was hypothesized that cognitive interventions may tried in patients who do not cooperate or respond to ERP. The
also help people with poor insight to facilitate exposure [35]. role of new forms of therapy like mindfulness-based techniques,
Most cognitive therapies for OCD are variations of the original ACT and purely cognitive interventions has to be studied further.
Salkovskis model [36]. The cognitive model posits that obses-
sions arise because of faulty appraisal of normally occurring Is combination of psychotherapy & SSRI/clomipramine
innocuous mental intrusions as highly significant and poten- better than either treatment alone?
tially threatening [34]. The treatment consists of identification Given the efficacy of SSRIs and BT/CBT in OCD, it is natural
and correction of these misinterpretations and underlying to assume that a combination of these two treatments may
obsessive beliefs. There is a high degree of overlap between BT work better than either of them alone. Early controlled trials

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 Review Arumugham & Reddy

were not able to find any advantage of combination of drugs and compared with paroxetine (40 mg/day), but there was no dif-
CBT over either of them alone [49]. Combination treatment was ference at end point [60]. No significant difference in efficacy
found to be helpful only in people with comorbid severe depres- was found in two other small head-to-head comparison stud-
sion [50,51]. However, three recent multi-center RCTs have shown ies [61,62]. Meta-analyses of RCTs in adults and children could
that combination of SSRI/clomipramine and CBT may be supe- not find any significant difference in efficacy between the indi-
rior to the medications alone [15,52,53]. In the Pediatric OCD vidual SSRIs [10,63]. Overall, there is little evidence to support
Treatment Study trial, combination of sertraline and CBT was the use of any particular SSRI over the other in OCD. The
found to be superior to either treatment alone in children [52]. choice of SSRI will ultimately depend upon previous response,
A subsequent study, Pediatric OCD Treatment Study II too drug interactions and adverse-effect profile.
demonstrated that a combination of medication and CBT was Meta-analyses of RCTs in adults and children comparing clo-
superior to medication alone in children with partial response to mipramine and SSRIs have shown that clomipramine may be
SRI [53]. A study in adults demonstrated that a combination of superior in terms of efficacy [11,63]. A systematic analysis of pub-
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ERP + clomipramine and ERP alone were superior to clomipr- lished and unpublished data by the UK National Institute for
amine, but there was no significant difference between ERP alone Health and Clinical Excellence has negated this finding [12].
and ERP plus clomipramine [15]. Head-to-head trials have consistently shown that clomipramine
The studies on augmentation strategy have been more con- has similar efficacy to comparator drugs (fluoxetine, sertraline, flu-
sistent. Many RCTs have shown that adding BT/CBT voxamine, citalopram and paroxetine), but poor tolerability [64–67].
improves the treatment outcome in partial/poor responders to Given the questionable superiority and poor tolerability of clo-
SSRI/clomipramine treatment [16,53–55]. In a recent SSRI aug- mipramine, SSRIs should be considered the first choice of medi-
mentation study, CBT was superior to risperidone and risperi- cations in OCD and clomipramine should be tried if patients do
done was no better than pill placebo [17]. The effectiveness of not show satisfactory response to initial trials of SSRIs [12,22].
CBT augmentation in partial responders to SRIs has been
demonstrated in a naturalistic setting in a multi-center trial [56]. What is the optimum duration of pharmacotherapy?
There is also some evidence that the effect of CBT may persist The question often arises on how long to continue treatment
For personal use only.

up to 1 year post-treatment in well-characterized SSRI non- after a successful SSRI trial. Treatment guidelines recommend
responders [57]. Albert et al. recently reviewed the efficacy of continuation of medications for at least 1–2 years to prevent
combination treatments and found that combination is consis- relapse and to allow further improvement [9,12]. Ongoing
tently effective as augmentation strategy for SSRIs, while it has improvement with SSRIs has been observed both over short term
yielded conflicting results when started together [49]. (20–24 weeks) and long term (1 year) in treatment continuation
studies [25,26,59,60,68]. A meta-analysis of the RCTs found a statisti-
Which SSRI to choose? cally significant superior efficacy of SSRIs compared with placebo
Clomipramine was the first pharmacological agent found to be in relapse prevention (relative risk of relapse: 0.52; 95% CI:
efficacious in OCD. The strong serotonin reuptake inhibiting 0.41–0.66; p < 0.00001) [69]. Patients who improve with phar-
property of clomipramine is hypothesized to be responsible for macotherapy have a higher chance of relapse on treatment dis-
its anti-obsessive action [4]. Other non-selective TCAs have continuation [70]. In most studies, SSRIs were continued in the
been found to be ineffective in OCD [11,58]. Clomipramine also same therapeutic dose. A small study (n = 30) with a relatively
acts on other neurotransmitter systems (like acetylcholine, hista- brief follow-up duration (102 days) showed that dose reduction
mine and norepinephrine), which leads to unwanted side does not affect the efficacy in the relapse prevention phase [71].
effects. It can also cause some serious adverse events like seiz- Without replication from larger studies with longer follow-up
ures and prolongation of QT interval. SSRIs are selectively duration, this strategy may not be advisable. Taken together, the
serotonergic with negligible effects on other neurotransmitters available evidence suggests that SSRIs should be continued for
and have less severe adverse effects. Over the years, evidence relapse prevention for at least 1–2 years after remission. Treat-
has accumulated for the efficacy of all available SSRIs in OCD ment discontinuation should be decided considering various fac-
including fluoxetine, fluvoxamine, sertraline, paroxetine, citalo- tors such as severity and duration of the illness, number of
pram and escitalopram [4]. previous episodes, history of relapse upon discontinuation, pres-
There have been a few head-to-head comparison studies ence of residual symptoms and concurrent psychosocial difficul-
comparing different SSRIs. In a double-blinded RCT compar- ties [12]. It should be emphasized that discontinuation of SSRIs
ing fluoxetine (n = 73) and sertraline (n = 77), patients on ser- should be carefully considered and in most patients continued
traline showed a significantly greater improvement at earlier treatment may be necessary in view of high rates of relapse upon
assessments (up to 12 weeks), which disappeared at the end of discontinuation [69].
the study (24 weeks). The apparent difference in early response
was not significant in Kaplan–Meier analysis. Further, the study What is the role of other antidepressants in OCD?
was not powered to detect between-group differences in early Venlafaxine has been found to be effective in one double-
treatment response [59]. In a study by Stein et al., escitalopram blinded [72] and one single-blinded active comparator study [73].
(20 mg/day) was associated with earlier treatment response Other serotonin norepinephrine reuptake inhibitors like

doi: 10.1586/14737175.2014.874287 Expert Rev. Neurother.

 Commonly asked questions in the treatment of OCD Review

duloxetine and milnacipran have not been studied adequately. clomipramine [91] have been shown to be useful in treatment-
Mirtazapine was found to be effective in an open-label trial fol- resistant patients, but one study demonstrated equal efficacy
lowed by double-blinded discontinuation [74]. Mirtazapine has for oral and intravenous pulse loading clomipramine regi-
also been found to accelerate the response to citalopram in a mens [92]. High-dose and intravenous SSRI treatment have not
single-blinded placebo-controlled trial, although there was no been studied adequately and should be tried only when other
difference in the response rate at the end of treatment [75]. measures fail.
TCAs (except clomipramine), monoamine oxidase inhibitors
and benzodiazepines have not been found to be effective [5,11]. How to boost the efficacy of CBT?
Venlafaxine may be tried if SSRIs/clomipramine are not toler- Augmentation strategies have also been tried to boost the effi-
ated or are found ineffective. cacy of CBT. One interesting strategy is augmentation of BT
sessions with D-cycloserine, a NMDA partial agonist, which has
What are the options in a person who has shown par- been shown to promote extinction of conditioned fear and con-
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tial or poor response to a SSRI trial? solidation of learning associated with extinction training. Small
Non-response and partial response are quite common with placebo-controlled trials have demonstrated the efficacy of add-
SSRI treatment. A significant proportion of patients continue ing D-cycloserine 1–2 h before therapy sessions [93–95]. How-
to have clinically significant symptoms despite improving with ever, in a study by Storch et al., D-cycloserine was not superior
treatment. A meta-analysis showed that average post-treatment to placebo when given 4 h before the exposure session [96].
Y-BOCS score was 17.9, suggesting significant residual symp- Large well-controlled trials are needed to confirm the efficacy
toms [11]. The initial SSRI should be tried for at least 12 weeks of this strategy. Adding motivational interviewing to improve
for assessing treatment response. Delayed response has been patient adherence to CBT has yielded mixed results [97–99].
seen, especially in trials with fluoxetine [59,76]. Switching over to Strategies for BT non-responders have not been studied
a different SSRI is recommended for people with non-response, adequately. van Balkom et al. found fluvoxamine to be superior
while augmentation strategies are generally recommended for to cognitive therapy in non-responders to BT [100]. Although
people with partial response. In people with non-response controlled trials show that a combination of SRIs and BT may
For personal use only.

to initial SSRI, switching to a different SSRI has been found to not be superior to BT alone [15], the strategy of augmenting
be useful in around 40% of patients [77]. Switching over to BT/CBT with SSRIs in those who are not responding to BT/
venlafaxine and clomipramine are other options [22,78,79]. CBT has not been studied systematically. As SSRIs are one of
Augmentation refers to the process of adding medications the effective treatments for OCD and probably have a different
with a different mechanism of action to the primary drug to mechanism of action, it may be worthwhile trying them in
boost its therapeutic efficacy. BT/CBT and rTMS are also used BT/CBT non-responders.
as augmentation strategies. We recently reviewed augmentation
strategies in OCD and found that antipsychotic and CBT aug- How to manage a drug-induced manic switch or
mentation have the best evidence for efficacy [5]. Among anti- comorbid BPD?
psychotics, risperidone has the best evidence followed by Recent epidemiological studies show that the prevalence rate of
aripiprazole and haloperidol [5,80]. A recent multi-center BPD in OCD is markedly higher than expected [101]. SSRIs,
randomized controlled study found augmentation of SSRIs the drugs of choice in OCD, can induce switch to mania/
with CBT to be much superior to augmentation with risperi- hypomania in BPD patients and may cause cycle acceleration
done and risperidone was no better than placebo [17]. In view and suicidal behavior [102]. Clinicians often face the dilemma of
of this important observation, it is recommended that CBT treating this rather complex but common comorbidity. The saf-
should be considered as a first-line augmenting strategy in est option would be to treat BPD with mood stabilizers and/or
those who do not show satisfactory response to SSRIs. Other atypical antipsychotics and OCD with BT/CBT. But this is
promising augmentation strategies include clomipramine, not always a viable option when SSRIs are indicated or
5HT-3 antagonists like ondansetron and granisetron, meman- unavoidable for various reasons. Some case series have demon-
tine, lamotrigine and topiramate [25,81–87]. The evidence for strated that treatment of patients with comorbid BPD and
these augmenting agents is based on few RCTs involving small OCD with standard mood stabilizers like lithium or antipsy-
sample sizes; therefore, larger studies are required to confirm chotics lead to improvement in both OC and mood symptoms,
their efficacy. Preliminary evidence exists for psychostimulants, without the need for SSRIs [103–105]. This is in keeping with
pregabalin and glutamatergic agents [5]. N-Acetyl cysteine, a other lines of evidence which suggest that OCD in people with
N-methyl-D-aspartate (NMDA) modulator has shown positive BPD share many features with primary mood disorders than
result in a recent RCT [88]. OCD including episodic course of illness, and high family
Other innovative strategies have been tried in treatment loading of mood disorders [101,106]. Hence, some recommend
non-responders. Few studies suggest that higher than recom- withholding SSRIs and suggest mood stabilization as the first
mended dose of SSRIs (e.g., 250–400 mg of sertraline) priority [103]. There are no controlled studies to support this
may be efficacious and tolerated well in people not responding strategy. The need for SSRI has to be assessed on a case-by-
to usual doses [24,89]. Intravenous citalopram [90] and case basis. SSRIs can be used in patients with persistent OC

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 Review Arumugham & Reddy

symptoms only under the cover of mood stabilizers after the evidence in the form of case reports and case series has shown
acute control of manic symptoms. mixed results [3]. The improvement observed in some reports
has been attributed to comorbid illnesses like depression, schiz-
How to treat OC symptoms in patients with psychotic ophrenia, etc. [3]. The available evidence does not support the
disorders? use of ECT targeting OCD alone, but may be tried for a
Obsessive-compulsive symptoms (OCS) are frequently comorbid comorbid illness like depression or schizophrenia.
with schizophrenia. The term schizo-obsessive disorder is some- rTMS involves application of rapidly changing electromag-
times used to denote this comorbidity [107]. Epidemiological stud- netic fields over the scalp to modulate activity in specific brain
ies show that around 8–26% of patients of schizophrenia suffer regions. Application of high-frequency rTMS (‡5 Hz) increases
from OCD and 10–60% have comorbid OC symptoms [108]. cortical excitability in specific regions, while low-frequency
This is much higher than the prevalence of 2–2.5% seen in the rTMS (£1 Hz) decreases cortical excitability [7]. rTMS using
general population [109]. OC symptoms occur in schizophrenia in standard coils can modulate cortical excitability up to a maxi-
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different contexts. OC symptoms precede the onset of schizophre- mum depth of 1.5–2.5 cm from the scalp [123]. The neural
nia in 49–76% of patients and succeed schizophrenia onset in regions implicated in OCD consist of deeper structures (orbito-
23–25% of patients [108]. Atypical antipsychotics may also induce frontal cortex, thalamus, basal ganglia), which are difficult to
de novo OC symptoms in people with psychosis [110]. Hence, OC access directly using standard TMS coils. Other easily accessible
symptoms in schizophrenia have been variably conceptualized as a regions which have connections with these structures are usually
manifestation of the disease process or as a comorbid illness or as targeted in the treatment of OCD. Despite some encouraging
an adverse effect of medication. Different strategies have been results from open-label trials, RCTs have shown that rTMS
tried depending on the conceptualization [111]. applied to the right or left dorsolateral prefrontal cortex is not
Very few studies have examined the treatment strategies for effective in OCD [7]. Two double-blind RCTs have demon-
OC symptoms in schizophrenia. There is some evidence to strated the efficacy of low-frequency rTMS over bilateral sup-
suggest that continuing antipsychotics alone may decrease OC plementary motor area (SMA) in resistant OCD [124,125]. The
symptoms in a subset of patients [111,112]. This strategy has been extensive connections of SMA with other deeper brain regions
For personal use only.

recommended when OC symptoms appear to be secondary to like thalamus and basal ganglia may explain the efficacy of this
the psychotic process [111]. It has been seen that OC symptoms target [125]. However, sequential administration of low-
in schizophrenia are phenomenologically similar to that seen in frequency rTMS over right dorsolateral prefrontal cortex and
‘pure OCD’ and hence may share similar pathogenic mecha- bilateral SMA was not effective in a sham controlled trial [126].
nisms [113]. Therefore, treatment strategies used in routine care A single-blind RCT demonstrated the efficacy of low-frequency
of OCD has been recommended by some authors [114]. Few rTMS applied over orbitofrontal cortex in drug-resistant OCD
open-label trials [115–117] support the efficacy of SSRIs in the patients [127]. An earlier meta-analysis of three RCTs did not
treatment of OCS in schizophrenia. The SSRIs with less drug find rTMS effective in OCD [128]. A recent meta-analysis
interactions like citalopram, escitalopram and sertraline are gen- including 10 sham-controlled RCTs found a medium effect
erally recommended [118]. There is some evidence to support size of 0.59 (z = 2.73; p = 0.006) for active rTMS [129]. Sub-
the use of CBT in this population [119,120]. For patients with group analysis revealed promising results for low-frequency
antipsychotic-induced OC symptoms, either a dose reduc- rTMS and rTMS over SMA and OFC [129]. Current evidence
tion [111] or shifting to a drug with less antiserotinergic action suggests that low-frequency rTMS over SMA or OFC may
like amisulpride may be helpful [121]. Lamotrigine augmenta- have a role in OCD, but the evidence is not convincing
tion to an antipsychotic regimen has been found to be effective enough to recommend rTMS in the routine management of
decreasing OC symptoms in an open-label trial [122]. OCD. Larger sham-controlled RCTs are required to establish
There is insufficient evidence to definitively guide treatment of the efficacy of rTMS in OCD.
OC symptoms in schizophrenia. A trial with an antipsychotic
alone can be tried as an initial strategy for people who have OC What is the role of neurosurgery in OCD?
symptoms only during the course of psychosis, particularly in There has been a resurgence of interest in neurosurgical proce-
acute psychotic conditions. OC symptoms may be persistent in dures for treatment refractory psychiatric disorders, especially
many patients with schizophrenia. In such patients, SSRIs and depression and OCD [130]. With the help of modern-day neu-
CBT may be indicated. Dosage reduction or shift to a different rosurgical procedures using MRI, stereotactic instruments,
antipsychotic can be tried in people with clear history of radiosurgery, etc., reliable lesions can be produced non-
antipsychotic-induced OC symptoms. More stringent and larger invasively in specific brain regions. Deep brain stimulation
studies are needed test these recommendations. (DBS) allows us to place electrodes in specific brain regions
and alter functioning of the regions in a flexible and reversible
What is the role of brain stimulation techniques like manner [8].
ECT and rTMS? It has been estimated that around 20% of patients are refrac-
ECT is a well-established treatment for severe depression. The tory to available pharmacological and psychological treat-
efficacy of ECT in OCD is still unproven and the available ments [8]. Converging evidence suggest the involvement of

doi: 10.1586/14737175.2014.874287 Expert Rev. Neurother.

 Commonly asked questions in the treatment of OCD Review

medial and orbital frontal–basal ganglia–thalamic circuits in Table 1. Recommended dose of anti-obsessive
the pathogenesis of OCD [8]. Lesioning procedures (also agents.
known as ablative neurosurgery) targeting various regions in
Drug Anti-obsessive dosage/day (mg)
this circuit have been tried in refractory OCD. The common
ablative procedures practiced include anterior cingulotomy, Fluoxetine 40–80
capsulotomy, subcaudate tractotomy and limbic leucotomy. Sertraline 150–200
There are no controlled studies on the efficacy of ablative pro-
Fluoxamine 200–300
cedures. Uncontrolled studies suggest that 45–65% of patients
improve with these procedures [131]. The improvement is usu- Paroxetine 40–60
ally observed after 6 months to 2 years post-surgery. A recent Escitalopram 20–40
review suggests that capsulotomy may be a more effective pro-
cedure for OCD [132]. Stereotactic surgery is associated with Clomipramine 150–250
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minimal adverse effects. There are reports of isolated post- Venlafaxine 225–300
operative convulsions. Occasional cases of intra-cerebral hemor-
rhage and infection have been reported with traditional open major neurological/medical illness, significant abnormalities in
surgeries [133]. Such complications can be prevented by the use MRI and other physical contraindications for surgery are
of radiosurgery. Gamma knife surgeries may lead to radiation- excluded [131,135,138]. Ideally, an independent review committee
induced edema and delayed cyst formation. Late cyst formation consisting of independent psychiatrists, neurosurgeons and neu-
has been observed in 1.6–3.6% of patients after radiosurgery rologists should assess each patient regarding suitability
for arterio-venous malformations [134]. Long-lasting personality for surgery.
alterations, weight gain, incontinence and cognitive disturban-
ces have been reported in less than 10% of patients [133]. Expert commentary
The most common target for DBS in OCD is the ventral Current evidence suggests that either SSRI or BT/CBT is the
capsule/ventral striatum, which includes the nucleus accumbens. first-line treatment of OCD. There is not enough evidence to
For personal use only.

Other targets include bed nucleus of the stria terminalis, infe- support the use of combination of BT/CBT and SSRI at the
rior thalamic peduncle and subthalamic nucleus. A few double- beginning of treatment, especially in adults. However, this
blind crossover studies have been conducted. A review of the treatment strategy is effective in non-responders. Both treat-
90 patients who received DBS in internal capsule/ventral stria- ments seem to be equally effective, though BT may have some
tum showed around 50% improvement occurs in OCD, advantages in the form of greater reduction of symptoms and
depressive and anxiety symptoms [135]. It has been suggested better relapse prevention. Guidelines recommend use of CBT
that DBS over this region enhances extinction of conditioned alone in mild to moderately ill patients. Nevertheless, due to
fear [136]. Hence, DBS could augment the effectiveness of BT pragmatic considerations, pharmacotherapy is more widely
for OCD. In 2009, the US FDA approved a humanitarian practiced. If pharmacotherapy is the chosen modality, SSRIs
device exemption for DBS for severe and treatment-resistant are the drugs of choice. All SSRIs are equally effective and the
OCD [137]. choice is made based on adverse effects, drug interactions and
previous treatment response. SSRIs should be given at a higher
How to select patients for surgery? dose (TABLE 1) and continued for at least 12 weeks to assess treat-
Despite the availability of safe procedures, psychosurgery ment response. Patients with partial response may continue to
remains a contentious area. This is partly fallout of overzealous improve on extending the treatment further. If psychotherapy
use of procedures of doubtful efficacy in the past. Further, pro- is the chosen modality, BT using ERP has the best evidence.
ducing irreversible changes in the brain without knowing the Cognitive interventions in combination with behavioral techni-
exact mechanism of action raises ethical concerns. Nevertheless, ques are also effective. In people who respond to SSRI treat-
neurosurgical procedures have a role in contemporary psychiat- ment, medications should be continued for at least 1–2 years
ric practice, provided patients are carefully selected based on after remission of symptoms. Many patients need longer treat-
predetermined criteria. ment. The duration of treatment should be decided on individ-
Most centers use similar criteria for selecting OCD patients ual case basis considering chance of relapse, severity of illness
for surgery. The criteria includes patients with a primary diag- and adverse effects. For non-responders to one SSRI, another
nosis of OCD, with a duration of ‡5 years, with severe symp- SSRI may be tried in an adequate dose for adequate duration.
toms (Y-BOCS ‡28) causing functional impairment. Clomipramine may be tried if a person does not respond to
Treatment resistance is usually defined as insufficient improve- two SSRIs. For partial responders and non-responders, aug-
ment with at least 3 SRIs (one of which should be clomipr- mentation strategies may be tried. Low dose of atypical antipsy-
amine), 1–2 augmentation strategies and at least 20 h of BT/ chotics, especially ripseridone are the preferred augmenting
CBT. Patients with clearly documented intolerance to BT/CBT agents. They should be tried for at least 4–8 weeks to assess
and clomipramine are also included. Patients with comorbid their effectiveness [5]. CBT augmentation of a SSRI is also a
psychosis, recent manic episode, current substance dependence, highly effective intervention and should be tried early on, if

www.expert-reviews.com doi: 10.1586/14737175.2014.874287

 Review Arumugham & Reddy

facilities are available. Other potentially effective augmenting From the traditional serotonin hypothesis, there has been a
agents include ondansetron, clomipramine, memantine, rilu- shift to other neurobiological mechanisms. Several lines of evi-
zole, N-acetyl cysteine, lamotrigine and topiramate. Patients dence including genetic studies, magnetic resonance spectroscopy
may respond to a particular SSRI despite poor response to studies, CSF analysis and animal studies, point to a glutamatergic
others. In patients who do not respond to initial trials of dysfunction in OCD [139]. Current evidence of drugs acting on
SSRIs, clomipramine or standard augmenting strategies, other glutamatergic system (e.g., memantine, riluzole, N-acetyl cysteine)
SRIs including venlafaxine may be tried in tandem. High-dose have focused on NMDA receptors and have shown promising
SSRIs or intravenous SRIs may be tried if the first-line treat- results as augmenting agents. Their role as stand-alone interven-
ments and augmenting strategies fail, but evidence supporting tions has to be studied. Drugs acting on other glutamate receptors
their efficacy is limited. ECT does not have any role unless the like the metabotropic receptors are currently being patented and
patient has comorbid severe depression that interferes with tested [139]. Agents targeting 5HT-1D and 5HT-2A/2C receptors
treatment. rTMS over SMA may be tried if facilities are avail- which are currently implicated in the pathogenesis of OCD have
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by 117.202.18.81 on 12/27/13

able, but more evidence is required to recommend it as a rou- to be studied [140]. In this regard, there have been open-label stud-
tine treatment. A substantial minority of patients do not ies on agomelatine and mirtazapine [74,141]. Well-designed con-
respond to all available pharmacotherapy and psychotherapy. If trolled trials on these and other serotonergic agents have to be
such patients are highly dysfunctional for long periods, surgery conducted. The other need is to decrease the time lag in therapeu-
may be considered in the form of gamma ventral capsulotomy tic response for SSRIs. Mirtazapine has shown some promise in
or anterior cingulotomy or DBS. this regard [75], but it has to be replicated.
Current treatment algorithms are based on trial-and-error basis
Five-year view and there are no clear indicators on choosing treatment for a par-
There have been hardly any paradigm shifts in the treatment of ticular patient. OCD is a heterogeneous condition. Many differ-
OCD after the introduction of SSRIs and CBT. The other ent subtypes have been proposed based on symptom dimensions,
interventions studied till date, are useful as augmentation strat- age of onset and comorbidity pattern [142]. Efficacy of treatments
egies, but have not been consistently found to be effective as on different subtypes of illness has seldom been studied. These
For personal use only.

stand-alone treatments. A considerable proportion of patients may help in individualizing the treatment process.
do not respond adequately to both BT and SSRIs, including There is likely to be changes in other biological treatments
clomipramine. Hence, there is a need for alternate first-line too. Development of deep rTMS coils for rTMS may help in
treatments. targeting areas particularly involved in OCD. The targets for
Cognitive interventions have been hailed as a major innova- DBS and ablative surgeries are currently being refined. These
tion in OCD treatment. However, clinical trials have not have to be to be studied more extensively, particularly regard-
found it to be superior to ERP. Cognitive therapy may be ing their long-term safety and benefits.
more effective in a subset of patients where ERP is less effective
like compulsive hoarders, primary obsessive slowness, people Financial & competing interests disclosure
with pure obsessions without compulsions and people with The authors have no relevant affiliations or financial involvement with
poor insight OCD [34]. This has to be studied systematically. any organization or entity with a financial interest in or financial conflict
New age therapies like those using mindfulness techniques with the subject matter or materials discussed in the manuscript. This
(e.g., ACT) have a different way of handling intrusive thoughts includes employment, consultancies, honoraria, stock ownership or options,
compared with traditional CBT. Their efficacy in comparison expert testimony, grants or patents received or pending or royalties.
with CBT should be studied. No writing assistance was utilized in the production of this manuscript.

Key issues
. The first-line treatment of obsessive-compulsive disorder (OCD) is either selective serotonin reuptake inhibitors (SSRI) or behavior
therapy/cognitive behavior therapy (CBT).
. Combination of SSRI and CBT is recommended for severely ill and SSRI non-responsive patients.
. Both behavioral and cognitive interventions are effective and can complement each other.
. A second SSRI can be tried in those who do not show response to first trial. Clomipramine can be tried in patients not responding to
‡2 SSRIs.
. Augmentation with CBT or atypical antipsychotics has the best evidence base and therefore is recommended in partial responders and
non-responders to SSRIs.
. Other potential augmentation strategies include N-methyl-D-aspartate antagonists, 5HT-3 antagonists, clomipramine, lamotrigine and
topiramate.
. Ablative neurosurgery or deep brain stimulation may be tried in carefully selected treatment refractory patients.

doi: 10.1586/14737175.2014.874287 Expert Rev. Neurother.

 Commonly asked questions in the treatment of OCD Review

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