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Treatment Of Refractory Obsessive Compulsive Disorder: What Can We Recommend?

Systematic Review of the Literature
Category: Literature and Topic Reviews

Treatment Of Refractory Obsessive Compulsive Disorder: What Can We
Recommend? A Systematic Review of the Literature

Howard Linder MD; Department of Psychiatry, Zucker Hillside Hospital

This paper reviews the current knowledge of different treatment modalities when the
conventional approach of Serotonin Reuptake Inhibitors (SRI) and Cognitive Behavioral
Therapy (CBT) fail to reduce symptoms of obsessive compulsive disorder (OCD). A
computerized search of the literature was conducted on Pubmed. Antipsychotic
augmentation in SRI-refractory OCD is indicated in patients who have been treated for at
least 3 months of maximal-tolerated therapy of an SRI. Patients with co-morbid tics are
likely to have a differential benefit to antipsychotic augmentation. A combination of an
SSRI and Clomipramine is also effective, whereas there have been mixed results when
switching to a serotonin norepinephrine reuptake inhibitor. The use of various
anxiolytics also have shown mixed results. Retrospective non randomized trials support
capsulatomy, however with significant adverse side effects. Trials using Deep Brain
Stimulators in patients with refractory symptoms have shown encouraging results.
Therefore, when conventional treatment of OCD fails, clinicians are often left with a
difficult treatment decision. Therefore, the risks and benefits of all treatment options
must be discussed with the patient, and informed decision must be made.
Obsessive compulsive Disorder (OCD) has a lifetime prevalence of
approximately 2-3%.
Although the pathophysiological characteristics of OCD are not
completely understood, abnormalities in the orbitofrontal cortex and caudate (a territory
of the striatum) have been demonstrated with patients with OCD. First line
pharmacotherapy treatments for OCD are the serotonin reuptake inhibitors (SRI) as well
as Clomipramine, a tricyclic antidepressant with a mechanism of action that primarily
involves serotonin reuptake inhibition. Although fewer controlled comparative trials of
SRI for the treatment of OCD have been conducted, it does not appear that any SRI is
more efficacious than another SRI for the treatment of OCD. Other than Clomipramine,
SRIs have been proven superior to tricyclic antidepressants.
A large growing number of randomized, double blind, placebo controlled trials
have demonstrated the efficacy of SRI, but the mean percentage of responders is reported
to be 40-60% of patients.
When patients do respond, usually a 20-40% mean decrease in
OCD symptoms are observed, which may make the patient feel better clinically, but a
significant amount of symptoms may still be present. Little practical advice is available
to clinicians on next step treatment strategies for patients who have shown either a partial
response or who have not responded to the gold standard of treatment. Before a clinician
can attempt to answer such questions such as, should I switch the patient to another
agent, augment, or perhaps recommend a somatic therapy such as Deep Brain
Stimulation, questions as to whether a patient had an adequate treatment trial should be
At the sixth International OCD Conference
, several experts postulated that an
adequate trial of an SRI, unlike for depression or anxiety, is at least 10-12 weeks long.
Treatment Of Refractory Obsessive Compulsive Disorder: What Can We Recommend? A
Systematic Review of the Literature
Category: Literature and Topic Reviews

Another important consideration was that the doses of SRI that are usually required to
achieve a response in OCD, are generally higher than the doses need to treat other
psychiatric disorders. They also defined treatment response as a rating of much or very
much improved on the Clinical Global Impressions Scale (CGI) and a more than 35%
reduction in the Yale Brown Obsessive Compulsive Scale (YBOCS) score. Treatment
resistance was defined as having failed 1 trial of a SRI, while treatment refractory as
having failed at least 2 adequate trials of SRI with no response. The purpose of this paper
is to provide an up to date review of the treatment options for patients with refractory
A computerized search of the literature was conducted on Pubmed using the words
refractory OCD, SRI augmentation and neuroleptics or second generation
antipsychotics (Aripipizole, Risperidone, Quetiapine, Olanzapine,
Ziprasidone), SNRI, Venlafaxine, Mirtazpine, Duloxetine, Anioxiolitics,
Buspirone, Trazodone,benzodiazepines Neurosurgical Approaches,
Capsulotomy, ECT, Transcranial Magnetic stimulation (TMS), and Deep Brain
Stimulator (DBS)
Augmentation Strategies
Pindolol: Pindolol is a serotonin beta adrenergic antagonist. Dannon et al.

showed that when Pindolol was added to Paroxetine to patients that had previously failed
Paroxetine monotherapy, a significant improvement in the YBOCS was noted. This was
a small double blind placebo controlled study, and to date has not been replicated. This
study seems to suggest that Pindolol might be a good agent to augment a SRI, when an
SRI alone has failed.
Mirtazapine: Mirtazapine is an antagonist at alpha 2- adrenoreceptors which
disinhibits the norepinephrine activation of serotonin neurons, and thereby increases the
serotonin neurotransmission. Koran et al.
showed in an open trial followed by double
blind discontinuation, that Mirtazpine was an effective therapy for OCD as the mean
change in YBOCS score fell 2.6 points, while the placebo group mean score rose 9.1
points. This however, was a small trial consisting of only 13 patients. In a trial
conducted by Pallanti et al.
Mirtazapine was added to Citalopram which was compared
to treatment with Citalopram alone. The Citalopram plus Mirtazapine group achieved a
reduction of at least 35% in YBOCS score and a much improved or a very much
improved rating on the CGI scale from the 4th week, while the Citalopram plus placebo
group obtained these same results only from the 8
week on. The number of responders
was higher in the Citalopram plus Mirtazapine group at the 4
week of treatment, while
no difference between groups in the response rate was noted at the 8
and 12
weeks of
treatment. Thus, Mirtazapine may be an effective monotherapy for OCD symptoms and
if combined with an SRI, treatment recovery could take place faster. However, larger
randomized controlled studies are needed for further investigation.
SRI and Clomiprimine: There are no randomized controlled trials studying the
efficacy of combining an SRI with Clomipramine. However, clinicians have used this
approach for many years and there are some case reports showing that the combination of
medications was found to be more effective compared with either agent alone in children
Treatment Of Refractory Obsessive Compulsive Disorder: What Can We Recommend? A
Systematic Review of the Literature
Category: Literature and Topic Reviews

and adolescents.
5, 6
However, when using this combination clinicians must be aware of
the cardiovascular side effects, risks of serotonin syndrome, manic switch, insomnia,
extrapyramidal symptoms, and sexual dysfunction.
Lithium: Several open case reports suggested the efficacy of Lithium in OCD.

However, the only controlled trial of Lithium augmentation in Fluvoxamine treated
refractory patients failed to show a statistical or clinical improvement in OCD symptoms
during the 4 week treatment trial.

Tryptophan: L-Tryptophan, the amino acid precursor of serotonin was shown to
be effective in a case report at a dose of 2 to 10mg/day.
However, evidence from larger
randomized controlled trials are lacking.
Thyroid Hormone: Thyroid hormones have been shown to be effective adjunctive
agents for major depressive disorder
, but in the only controlled trial when given with
Clomipramine, refractory OCD patients failed to show a difference.

Buspirone: Buspirone is a serotonin 1a receptor partial agonist which was first
studied as an anti-OCD medication in 1991, when it was shown to be as efficacious as
However, several double blind studies that compared Buspirone to
placebo as an augmenting agent to either an SRI or Clomipramine did not show any
17, 18
In a small trial of patients that were partial responders to Clomipramine
treatment, the addition of Buspirone helped 29% of them to achieve a 25% reduction in
OCD symptoms.
Thus, there maybe a subgroup of patients who would benefit from
adjunct Buspirone.
Aripiprizole: One small 8 week open label trial showed a mean total YBOCS
score decrease from 23.9 to 17.6 at final visit.
More pronounced improvement was
observed in compulsive symptoms compared with obsessive symptoms. Two subjects
discontinued the medication because of side effects. There are also several open label
treatment studies that showed that patients with schizophrenia and comorbid OCD
improved when taking Aripiprazole.
These studies seem to suggest that Aripiprazole
monotherapy or as an adjunct to SRI may be effective for OCD; however larger
randomized controlled trials are needed.
Ziprasidone: When used as an adjunct to high dose SRI medications for patients
who were considered to have refractory OCD, the mean improvement on the CGI scale
was 44.4%.
In the same study Quetiapine was shown to have a mean improvement on
the CGI scale of 80%. In this study, Ziprasidone was found to be less effective than
Quetiapine in the treatment of refractory OCD.
Quetiapine: The use of Quetiapine in SRI treatment refractory OCD patients has
yielded mixed results. In a study done by Denys et al., 40 patients who failed to respond
to courses of treatment with at least 2 different SRI at maximal dose for 8 weeks showed
a mean decrease in YBOCS score of 9 points.
Also 8 out of 20 patients in the
Quetiapine group were responders. A later study showed similar conclusions where an
80% improvement in CGI was shown for refractory patients who were given Quetiapine
as an adjunct.
However, there has been 1 double blind randomized controlled study
done in which Quetiapine addition to SRI failed to show any difference. In Kordons et
al. study 40 patients were either randomized to Quetiapine plus SRI or SRI alone.

These patients had already failed 1 course of treat with SRI. Analysis of treatment effects
between the 2 groups showed no significant difference. In all trials Quetiapine was well
Treatment Of Refractory Obsessive Compulsive Disorder: What Can We Recommend? A
Systematic Review of the Literature
Category: Literature and Topic Reviews

tolerated, but side effects such as somnolence, dry mouth, weight gain, and dizziness
were reported.
Clozaril: One study in which Clozaril monotherapy was administered to 20
treatment resistant OCD patients for 10 weeks showed a lack of efficacy.
Also there are
several reports that have been published that showed a transient exacerbation of OCD
symptoms owing to Clozapine treatment.
Olanzapine: Several open trials, case reports, and case series reported efficacy of
Olanzapine addition to SRI in patients with refractory ocd.
Then in 2004, 2 separate
double blinded placebo controlled trials were published with somewhat different
conclusions. Shapira et al. added Olanzapine or a placebo to patients who had not
responded to 8 weeks of Fluoxetine.
Both the group that was given Olanzapine in
addition to Fluoxetine, and the group that continued to take Fluoxetine alone, improved
significantly over the additional 6 weeks of treatment. There was however, a numerical
advantage to the group that was given Olanzapine, but no statistical significance was
reported. The explanation for the lack of separation for the 2 groups was that patients
may continue to benefit when SRI treatment is continued past 6 weeks. Bystritsky et al.
also conducted a placebo controlled trial where Olanzapine was added to the treatment
regimen for patients who had failed to respond to 12 weeks of treatment with an SRI.

Subjects in the Olanzapine group had a mean decrease of 4.2 in YBOCS scores compared
with a mean increase in score of 0.54 for subjects in the placebo group. Forty six percent
in the Olanzapine group showed a 25% or greater improvement in YBOCS score
compared with zero from the placebo group. This data seems to suggest that Olanzapine
augmentation might be a good option for patients who have failed a longer term trial of a
Risperidone: Risperidone was found in 3 double blind studies and 3 open label
studies to be effective in alleviating obsessive compulsive symptoms in nonresponders.
In the biggest randomized placebo trial, Mcdougle et al. enrolled 36 patients who were
randomly assigned to receive 6 weeks of Risperidone treatment or placebo in addition to
a SRI.
Risperidone separated significantly from placebo at week 5 and continued its
separation through week 6. Fifty percent of the patients treated with Risperidone
responded, while none of the 15 patients given placebo responded. 17 patients given a
placebo during the double blind phase of the study received open label Risperidone after
its end; 50% of these patients responded to treatment. Even though bigger trials are
needed, Risperidone might prove to be an effective augmenting strategy in the treatment
of resistant OCD.
Haloperidol: Conventional neuroleptics have long been used for SRI
augmentation and one earlier controlled study demonstrated the efficacy of Haloperidol.

This study suggested that OCD patients who have comorbid tics were more likely to
respond to SRI augmentation with haloperidol than OCD patients who did not have
comorbid tics. However, in 2000 Mcdougle et al sowed that patients with comorbid tics
and patient without tics seemed o respond at an equal rate.

Other Monotherapy Options
Serotonin Norepinephrine reuptake inhibitors (SNRI): Another strategy for
patients who have not responded to treatment with an SRI is to switch them to a SNRI
Treatment Of Refractory Obsessive Compulsive Disorder: What Can We Recommend? A
Systematic Review of the Literature
Category: Literature and Topic Reviews

because some patients may respond better to agents that target multiple systems. One
double blind placebo controlled study of Venlafaxine demonstrated no significant clinical
However, another double blind, head-to-head study comparing
Venlafaxine to Paroxetine found that the 2 agents were equally efficacious.
A 12 week
single blind study of Venlafaxine versus Clomipramine showed no statistical significance
between the 2 drugs with the Venlafaxine group reporting fewer side effects.
response rates of Venlafaxine for both trials were 40% and 36 % respectively. In another
study Hollander et al. demonstrated the efficacy of Venlafaxine in patients who were
resistant to prior treatment with SRIs.
Of the 29 patients who had not responded to 1
or more trials of an SRI, 18 (81.8%) responded to treatment with Venlafaxine. However,
since this trial was not a prospective double blind placebo controlled trial more studies
are needed to confirm the results.
There is also a case series of patients with comorbid mood and anxiety disorders,
who showed partial or no response o SRI, who were switched to Duloxetine (another
Three out of 4 patients showed at least a 35% reduction in their YBOCS scores.
This is evidence that Duloxetine may be beneficial for patients with treatment resistant
OCD, but larger controlled studies are needed to confirm this.
Intravenous (IV) Medications: Currently there are 2 intravenous antidepressants
available, Clomipramime and Citalopram. In 2002 Pallanti et al. tested IV Citalopram in
39 patients who had failed at least 2 adequate trials of a SRI.
This was an open trial
where a flexible dose of IV Citalopram was given for a total of 3 weeks. This was
followed by a 9 week continuation phase of oral Citalopram. At day 21, patients showed
a significant decrease in YBOCS scores. At day 21, 23 (59%) of 39 patients had a more
than 25 point decrease in YBOCS scores. At endpoint, 25 out of 27 responders who
responded to initial 3 weeks of IV Citalopram, had more than a 35% decrease in Y-BOC
scores from baseline. IV Citalopram was well tolerated as only 1 participant dropped out
because of side effects (nausea) in the IV phase.
The earliest reports of the successful use of IV Clomipramine for the treatment of
resistant obsessional states were from Europe in the 1970s
42, 43
followed by 5 case
reports by Warneke (1984) in North America.
Some postulated theories of why IV
Clomipramine might be more effective than oral Clomipramine, include making the
medication more bioavailable, thus establishing an earlier steady state by eliminating first
pass metabolism in the liver. Also by eliminating the first pass effect the molecule tends
to stay in its original form instead of being converted to its primary metabolite which is
less serontenergic. The largest randomized double blind study was done by Fallon et al.
in 1998, when 54 patients who were poorly responsive to oral Clomipramine were
randomized to IV gradually dosed Clomiprimine versus IV placebo for 2 weeks.
placebo group then received 2 weeks of open label IV Clomipramine. After 14 infusions
the IV Clomipramine group showed significant improvement on the National Institute of
mental health Obsessive compulsive scale and CGI compared with placebo. At 1 week
post infusions, Clomiprimine responders initially randomized to IV Clomipramine versus
initially randomized to IV placebo were 43% and 0%. At 1 month post infusions, 18/31
patients were deemed Clomipramine responders. In 2008 Ross and Fallon et al.,
provided long term follow up to the patients that were involved in their 1998 study.
the 44 patients interviewed at follow up, 13 had subthreshold OCD (29.5%) and 31 met
Treatment Of Refractory Obsessive Compulsive Disorder: What Can We Recommend? A
Systematic Review of the Literature
Category: Literature and Topic Reviews

full criteria for OCD (70.5%). Moreover, of the 44 patients, 20 (45.5%) reported an
overall subjective clinical improvement based on the patient rated CGI improvement
scale. Another randomized controlled study showed a significant decrease from baseline
in YBOCS scores of IV Clomipramine, but no difference in scores when compared with
oral Clomipramine.
Side effects of IV Clomipramine were hypotension, cardiac
arrhythmias, bradycardia, tremor, headache, and sexual dysfunction. The treatment
should be in a monitored setting because of fear of sudden death.
These studies seem to suggest that there is evidence to suggest that patients could
benefit from intravenous medications. However, because of the risks they are not
approve for use in the United States and should be done in a monitored setting.
Monoamine Oxidase inhibitors (MAOI): Three out of four controlled trials of
MAOIs, including a trial of Fluoxetine versus Phenelzine done by J enike et al., showed
little benefit for most patients with OCD except possibly for a small subgroup of patients
with symmetry related obsessions.
One small controlled study that compared
Phenelzine and Clomipramine suggested that Phenelzine maybe effective, but there was
no significant difference in efficacy when comparing the 2 agents.
Therefore, the use of
MAOIs in treatment of OCD is unfounded.
Trazodone: This nontricyclic antidepressant possess serotonin reuptake inhibiting
properties and was shown to be efficacious in OCD in open trials and case reports.
50, 51

However in the only double blind placebo controlled trial, there was no significant
difference in OCD or depressive symptoms in the 17 patients who completed the 10
weeks of Trazodone administration.

Clonazepam: This serotonergic benzodiazepine has been shown in several case
reports to be an effective treatment as either a monotherapy or as an augmentation
53, 54
However, the only double blind controlled study failed to show a
significant difference between Clonazepam and placebo.

Novel approaches: There have been mixed results when Inositol or Antiandrogen
therapy have been used in the treatment of ocd.
In each of these cases, there have
been one controlled trial that was positive, but attempts at replication of the original
studies failed. Case reports and open label trials have also shown that oral morphine can
also help alleviate symptoms of OCD. One small placebo controlled study showed that
the mean reduction in the YBOCS score was statistically significant compared to
However, longer term follow up is needed to determine whether the early
responses persist over time, and whether morphine is a tolerable treatment approach.
Medications that also affect glutamatergic neurotransmission, such as Memantine and
Riluzole, have also been studied in open trials to treat resistant OCD. In two separate
studies (one from each medications) these medications were shown to significantly
improve the Y-BOCS score and 7/10 patients responded to Memantine, while 7/13
responded to Riluzole.
60, 61

Somatic Therapies
Electroconvulsive Therapy (ECT): There are no controlled data regarding the
efficacy of ECT for OCD. ECT should probably be reserved for symptomatic treatment
of severely depressed and or suicidal OCD patients.

Treatment Of Refractory Obsessive Compulsive Disorder: What Can We Recommend? A
Systematic Review of the Literature
Category: Literature and Topic Reviews

Vagal Nerve Stimulation (VNS): VNS which is currently approved for the
treatment of affective disorders has been tested for the treatment of OCD. Thus far there
is no compelling evidence for its use in OCD.

Repetitive Transcranial Magnetic Stimulation (rTMS): Greenberg et al
administered rTMS to the right lateral prefrontal, left lateral prefrontal, and midoccipital
(as a control site) lobes.
In this blinded trial compulsive urges decreased significantly
for 8 hours after right lateral prefrontal rTMS. Subsequently, in an open trial with 12
OCD individuals Sachdev et al. showed that right or left prefrontal fast rTMS resulted in
reduction in some YBOCS subscales although not in total scores.
However, a recent
study by Mansur et al. investigated the effects of rTMS by studying 12 outpatients with
resistant OCD (had at least 3 trials of SRI previously) who were maintained on stable
treatment regimens for at least 8 weeks and, and then submitted to 6 weeks of either
active or sham rTMS delivered to the right dorsolateral prefrontal cortex.
In this study,
there was no significant difference between groups on any evaluation scale. A similar
study by Sachdev yielded the same outcome.
Thus, it appears that rTMS has little
benefit for the treatment of OCD, but further questions as to the exact placement of the
stimulator should be explored before completely ruling this out as an ineffective
Deep Bain Stimulator (DBS):After Benabid et al. showed that electrical
stimulation of the brain resulted in clinical benefits comparable to those of surgical
ablation, stereotactic interventions such as DBS was used to treat refractory OCD.
idea behind this was to disrupt the neuronal circuits that pass through the anterior limb of
the internal capsule that connect the frontal lobe and basal ganglia which lead to OCD.
In 1999 Nuttin et al. reported 4 cases of patient with severe OCD that were treated with
DBS in the anterior limbs of the internal capsules.
Three patients were followed for up
to 39 months and two patients had sustained improvement of symptoms as measured by
YBOCS. No side effects and no deleterious impact on neuropsychological measures
were noted. Anderson and Ahmed reported one case of successful DBS on the anterior
limbs of the internal capsule for refractory OCD.
Further suggestion of the efficacy of
DBS in OCD came from blinded randomized crossover studies from Nuttin et al. in
and then again from Mallet et al. 2008.
In the latter study researchers from
France randomized 16 patients with severe refractory OCD to 3 months of active or sham
DBS in the subthalamic nucleus, with subsequent crossover. Compared with sham
treatment DBS significantly improved OCD scores (by 32% on YBOCS) and rating
functioning (by 30% on CGI scores) without altering cognition or mood. Serious adverse
effects included an intracerebral hemorrhage and 2 infections. Thus DBS is a possible
treatment approach for OCD and was recently approved by the FDA for use in refractory
Neurosurgery: OCD is associated with hyperactivity of the right caudate and
cortico-striatal-pallidal thalamic-cortical loop associated with overgeneration or
inadequate inhibition of mental and physical behavior. Cingulatomy, capsulotomy, and
subcaudate tractotomy disrupt this pathway. In a recent study Lui et al. showed that
20/35 (57%) patients became symptom free after MRI guided stereotactic bilateral
anterior capsulotomy, 10/35 (29%) experienced significant improvement, and 5/35 (14%)
experienced no significant improvement.
There was also a significant decrease in
Treatment Of Refractory Obsessive Compulsive Disorder: What Can We Recommend? A
Systematic Review of the Literature
Category: Literature and Topic Reviews

YBOCS scores. In another study J ung et al. showed a mean improvement rate of 48%
from baseline on the Y-BOCS score of 17, with 8 patients becoming symptom free after
stereotactic bilateral anterior cingulotomies.
The literature also suggests that serious
long term adverse events have occurred such as seizures, behavioral and cognitive
distortions, intracerebral bleeds, and even death and this must balanced with the possible
benefits that a patient would receive from such a procedure.
OCD is a common, disabling treatment and provides a challenge for even the
most experienced clinician to treat. While SRI and Clomipramine with or without
cognitive behavioral therapy remains the gold standard treatment, many patients either
respond partially or not all. New double blind treatment trials have emerged lately
testing out more treatment options for these patients. Most of them are small studies and
are unreplicated. With many conflicting trials, no follow up studies to previous treatment
trials what is a clinician to recommend to their patients who have symptoms of OCD?
J udging by the review done above, all patients should have at least 1 trial of
Clomipramine and at least 2 trials of high dosed SRI for at least 10-12 weeks. If
treatment fails, cognitive behavioral therapy should be added prior to further
augmentation or switch strategies. If this fails, augmentation should be recommended
next. Since several augmentation strategies have shown to be effective, a clinician
should individualize the treatment to a particular patient. If patient has no cardiac
problems, has little risk for serotonin syndrome, and can tolerate the use of an SRI and
Clomipramine, then the combination of the two can be used. Haldol has been shown to
be an effective augmentation medication when a patient has comorbid tics. Risperidone
and Olanzapine were shown to have favorable results in about 1/3 of patients, but the risk
of extrapyramidal side effects, tardive dyskinesia, and the metabolic syndrome must be
considered. Pindolol and Mirtazapine should also be considered. If none of these
augmentation strategies work, a clinician should choose to switch from an SRI to another
medication. Venlafaxine has some positive data in the treatment of OCD, while
Duloxetine still needs to be tested further. Even though the use of intravenous
medications has been shown to be effective, because of their potential side effects their
use is limited. If any of these trials fail for a particular patient the least invasive surgical
procedure, i.e. DBS should be attempted, provided that the patient is a good surgical
candidate. More invasive surgeries, such as cingulotomy could also be recommended.
Bigger studies are needed to fully answer this question in the future, but the best a
clinician can do at this point is to explain the risks and benefits of all options and then
help the patient make an informed decision.

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Systematic Review of the Literature
Category: Literature and Topic Reviews

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