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Article history:
Received 30 June 2014
Received in revised form
26 November 2014
Accepted 4 December 2014
This narrative review gathers together a range of international experts to critically appraise the existing
trial-based evidence relating to the efcacy and tolerability of pharmacotherapy for obsessive
compulsive disorder in adults. We discuss the diagnostic evaluation and clinical characteristics followed
by treatment options suitable for the clinician working from primary through to specialist psychiatric
care. Robust data supports the effectiveness of treatment with selective serotonin reuptake inhibitors
(SSRIs) and clomipramine in the short-term and the longer-term treatment and for relapse prevention.
Owing to better tolerability, SSRIs are acknowledged as the rst-line pharmacological treatment of
choice. For those patients for whom rst line treatments have been ineffective, evidence supports the
use of adjunctive antipsychotic medication, and some evidence supports the use of high-dose SSRIs.
Novel compounds are also the subject of active investigation. Neurosurgical treatments, including
ablative lesion neurosurgery and deep brain stimulation, are reserved for severely symptomatic
individuals who have not experienced sustained response to both pharmacological and cognitive
behavior therapies.
& 2015 Published by Elsevier Ireland Ltd.
Keywords:
Obsessive
Compulsive
Pharmacotherapy
1. Introduction
http://dx.doi.org/10.1016/j.psychres.2014.12.003
0165-1781/& 2015 Published by Elsevier Ireland Ltd.
Please cite this article as: Fineberg, N.A., et al., Obsessivecompulsive disorder (OCD): Practical strategies for pharmacological and
somatic treatment in adults. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2014.12.003i
Please cite this article as: Fineberg, N.A., et al., Obsessivecompulsive disorder (OCD): Practical strategies for pharmacological and
somatic treatment in adults. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2014.12.003i
Please cite this article as: Fineberg, N.A., et al., Obsessivecompulsive disorder (OCD): Practical strategies for pharmacological and
somatic treatment in adults. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2014.12.003i
Please cite this article as: Fineberg, N.A., et al., Obsessivecompulsive disorder (OCD): Practical strategies for pharmacological and
somatic treatment in adults. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2014.12.003i
with placebo for relatively low xed clomipramine doses (75 mg/
day and 125 mg/day) (Montgomery et al., 1980). However, controlled studies also demonstrate efcacy and tolerability for doses
as high as 300 mg/day of clomipramine (DeVeaugh-Geiss et al.,
1989) and 80 mg/day uoxetine (Jenike et al., 1997; Liebowitz et
al., 2002). As clomipramine is associated with clinically relevant
cardiotoxicity and lowers the seizure-threshold, this compound
should usually be prescribed within the licensing dosage limits.
Doses of clomipramine exceeding 250 mg daily should be prescribed with caution and ECG/plasma level monitoring considered.
8.4. Dose titration
In randomized controlled OCD trials of SSRIs and clomipramine, improvements have been noted in obsessions and compulsions within 1 or 2 weeks after initiation (March et al., 1998;
Riddle et al., 2001; Hollander et al., 2003b; reviewed in Fineberg
et al. (2012)). Exacerbation of anxiety in the early stages of OCD
treatment is uncommon. However, irrespective of dose, improvement can take several weeks or months to develop. Although
studies may show small changes in symptom scores early in
treatment, these do not usually become clinically meaningful until
later in treatment; indeed it can be many weeks or several months
before gains are recognized by the patient. Therefore, the patient
should be advised to persevere with treatment, despite little immediate evidence of change. As observable benets may not appear
for several months, clinicians can feel pressured to change treatments or increase SRI doses prematurely. A balance is recommended between tolerability and the rate of dose increase.
There is no consensus on how quickly dose titration should be
attempted. The British Association for Psychopharmacology (Baldwin
et al., 2005, 2014) suggests initial treatment periods beyond 12
weeks may be needed to assess efcacy. The guidelines suggest starting with the lowest efcacious daily dosage of SSRIs, which may be
increased in the face of insufcient response at a lower dosage.
However, a drawback of a slow titration approach is that if a higher
dose is needed, it could take a long time to achieve a response, which
could be problematic, especially with more severely ill patients. In
contrast, the APA guidelines (Koran et al., 2007) recommend upward
titration of SSRI doses to maximum FDA-approved doses by 46
weeks, thereafter waiting another 6 weeks to evaluate effectiveness.
Attempts at pulse-loading, using either oral or intravenous clomipramine, did not produce a sustained advantage in a small number of
studies, although improvements may have been evident earlier compared to conventional dose titration (Koran et al., 1997).
8.5. Management of treatment response and early stages of
resistance
To date, we do not have reliable interim measures to predict,
early in the course of OCD treatment, which patient may or may
not go on to respond to treatment. As the treatment effect takes
considerable time to develop, it is important to ensure (a) that an
adequate trial of treatment has been achieved, so as to avoid
premature discontinuation of a treatment that could turn out to be
effective, and (b) that methods for evaluating the clinical response
are utilized. This usually entails at least 12 weeks of optimized
(maximally tolerated) SSRI dosages with evidence of good adherence. Regular clinic appointments have been shown to enhance
adherence (Santana et al., 2010).
Routine baseline assessment is recommended. Following the initial
treatment phase, reassessment allows differentiation into categories based on degree of responsee.g., full response (435% YBOCS
change), partial response (2535% YBOCS change), no response
(o25% YBOCS change) (Pallanti et al., 2002). In the event of a full
response, treatment may be continued into a maintenance phase (see
Please cite this article as: Fineberg, N.A., et al., Obsessivecompulsive disorder (OCD): Practical strategies for pharmacological and
somatic treatment in adults. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2014.12.003i
Please cite this article as: Fineberg, N.A., et al., Obsessivecompulsive disorder (OCD): Practical strategies for pharmacological and
somatic treatment in adults. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2014.12.003i
risperidone (Dold et al., 2013). However, a recent randomized pillplacebo controlled comparison of adjunctive risperidone and CBT
noted that those given CBT and SSRI performed better than those
given risperidone and SSRI (Simpson et al., 2013). In a single-blind
head-to-head comparison, adjunctive risperidone was associated
with relatively more sexual adverse effects, whereas olanzapine was
associated with metabolic effects and weight gain in OCD patients
(Maina et al., 2008).
The choice of adjunctive antipsychotic agent may depend on
the SSRI being used. For example, uoxetine/clomipramine may
interact pharmacokinetically with risperidone. Dose-nding studies of antipsychotic in OCD have not so far been performed. However, the studies that investigated these compounds according to
the authors' judgment, tended to use low or moderate antipsychotic doses. The antipsychotic dose range noted to be effective includes; haloperidol (24 mg/day), risperidone (12 mg/day),
quetiapine (150600 mg/day), olanzapine (510 mg/day) and aripiprazole (1530 mg/day) (reviewed in Fineberg et al. (2012)).
At present it is uncertain how long adjunctive antipsychotic
treatment is required. Some evidence, including from naturalistic
follow-up data (Marazziti et al., 2005; Matsunaga et al., 2009),
suggests that if the patient has responded there may be benet in
continuing the antipsychotic for at least 1 year. A small retrospective study (Maina et al., 2003) showed that the majority of
patients (15 of 18), who had responded to the addition of an
antipsychotic to their SRI, subsequently relapsed when the antipsychotic was withdrawn. Following 12 months of successful
antipsychotic treatment, individualized collaborative care-planning, taking account of treatment-tolerability, symptom prole
(e.g., the presence of tic), and history of relapse, may help
determine whether discontinuation of the antipsychotic is appropriate. For those opting for long-term adjunctive antipsychotic
with a second-generation agent, metabolic monitoring may be
advisable. Evidence is accruing for metabolic complications associated with the long term use of second generation antipsychotic
(Pramyothin and Khaodhiar, 2010).In addition, there are reports
of de novo production or exacerbation of obsessive compulsive
symptoms with second generation antipsychotic in patients with
schizophrenia (Schirmbeck and Zink 2012). However it is unclear
whether the same applies to patients with OCD in the presence of
concomitant SRI treatment.
8.8.5. Parenteral SSRI or clomipramine
The intravenous administration of a compound increases its
bioavailability by by-passing rst pass hepato-enteric metabolism.
Options include slow infusion of intravenous clomipramine or
citalopram in normal saline. While some positive results have
been noted for up to 14 days of daily treatment (Fallon et al., 1998),
intravenous treatment is generally inconvenient and difcult to set
up on a routine basis in mental health clinics. There is also a need
for continual monitoring of cardiac activity and vital signs during
and shortly after the infusion.
8.8.6. Combining SSRI and clomipramine
This strategy should be approached cautiously; ECG and plasma
level monitoring are advisable, given the potential for pharmacokinetic interactions on the hepatic cytochrome P450 isoenzymes
that could lead to a dangerous build-up of clomipramine, especially with co-administered uoxetine and paroxetine as well as
the risk for serotonin syndrome. Citalopram, escitalopram and to a
lesser extent sertraline are theoretically less likely to interact
pharmacokinetically with clomipramine than other SSRIs. Small,
uncontrolled case series have shown positive results for combining
an SSRI and clomipramine (Pallanti et al., 1999), although ECG
changes have been reported in cases involving the combination of
Please cite this article as: Fineberg, N.A., et al., Obsessivecompulsive disorder (OCD): Practical strategies for pharmacological and
somatic treatment in adults. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2014.12.003i
clomipramine with uvoxamine (Szegedi et al., 1996). In a randomised open-label trial, nine pharmacotherapy-refractory patients
were given citalopram with clomipramine, and seven were treated with citalopram alone. Signicantly larger improvements in
YBOCS ratings were reported for those given the combination, all
of whom experienced decreases of Z35% from baseline. This
combination was well tolerated and did not alter the metabolism
of clomipramine (Pallanti et al., 1999). The recent demonstration of
prolongation of the ECG QT interval associated with higher doselevels of citalopram (and to a lesser extent escitalopram) (FDA
Drug Safety Communication, 2011) argues for a degree of caution
in using citalopram and clomipramine in combination. In another
study, combining uoxetine with clomipramine was no more
effective than uoxetine and placebo in SSRI non-responders
(Diniz et al., 2011). No controlled studies of the co-administration of different SSRIs have been published.
Please cite this article as: Fineberg, N.A., et al., Obsessivecompulsive disorder (OCD): Practical strategies for pharmacological and
somatic treatment in adults. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2014.12.003i
Acknowledgments
9.4. Ablative neurosurgery
Modern ablative neurosurgical procedures are stereotactically
guided, resulting in small and accurately placed lesions. This is most
commonly achieved using thermal stimuli, although there is ongoing research into the use of radiosurgical techniques such as the
gamma knife. There are two procedures that are offered by the international centers involved in the provision of such therapies. Anterior cingulotomy, involving lesions placed in the dorsal anterior
cingulate cortex (Sheth et al., 2013) and anterior capsulotomy,
involving lesions placed within the inferior fronto-thalamic connections within the anterior limb of the internal capsule (Ruck et al.,
2003), are the most common procedures. Both procedures are
believed to modulate functioning within the corticostriatalthalamic circuitry. Overall the available evidence suggests that such
procedures offer signicant therapeutic benets to 3060% of patients with otherwise highly refractory OCD. Serious adverse effects
are uncommon, but have been reported with both procedures (e.g.
intracranial hemorrhage, recurrent seizures). Anterior cingulotomy
appears to offer a superior safety prole to that of anterior capsulotomy. The quality of evidence supporting each procedure is
reective of neurosurgery as a whole. There are no randomized controlled trials, and most data is derived from prospective case series
and small unblinded cohort studies. Surgical intervention is therefore reserved for patients with severe, incapacitating OCD who have
failed an exhaustive array of expertly delivered medication trials
and intensive evidence based CBT.
10. Summary
The efcacy of SSRIs and clomipramine is well established. SSRIs
are usually preferred over clomipramine, in view of their superior
tolerability, especially as doses probably need to remain consistently
at a relatively high level to sustain effectiveness. Improvements are
usually maintained over time, as long as patients adhere to treatment. Relapse prevention, achieved through sustained treatment,
appears to be a realistic goal for most SSRI-responders. However, the
treatment response to SRIs is often incomplete, and many patients
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somatic treatment in adults. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2014.12.003i