Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Obsessive–compulsive disorder (OCD): Practical strategies

for pharmacological and somatic treatment in adults$
Naomi A. Fineberg a,b,c,n, Samar Reghunandanan a, Helen B. Simpson d,e,
Katharine A. Phillips f, Margaret A. Richter g, Keith Matthews h, Dan J. Stein i,
Jitender Sareen j, Angus Brown a, Debbie Sookman k
a
Highly Specialized Obsessive Compulsive and Related Disorders Service, Hertfordshire Partnership University NHS Foundation Trust, Rosanne House,
Parkway ,Welwyn Garden City, Hertfordshire, AL8 6HG, UK
b
Postgraduate Medical School, University of Hertfordshire, College Lane, Hatfield, UK
c
University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Box 189, Cambridge CB2 2QQ, UK
d
College of Physicians and Surgeons at Columbia University, New York, NY, USA
e
Anxiety Disorders Clinic and the Centre for OCD and Related Disorders at the New York State Psychiatric Institute, New York, NY, USA
f
Rhode Island Hospital and the Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI, USA
g
Frederick W. Thompson Anxiety Disorders Centre, Sunnybrook Health Sciences Centre and Department of Psychiatry, University of Toronto, Toronto, Ontario,
Canada
h
Division of Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
i
Department of Psychiatry, University of Cape Town, Cape Town, South Africa
j
Departments of Psychiatry, Psychology and Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
k
Obsessive Compulsive Disorder Clinic, Department of Psychology, McGill University Health Centre, and Department of Psychiatry, McGill University,
Montreal, PQ, Canada.

art ic l e i nf o a b s t r a c t

Article history: This narrative review gathers together a range of international experts to critically appraise the existing
Received 30 June 2014 trial-based evidence relating to the efficacy and tolerability of pharmacotherapy for obsessive
Received in revised form compulsive disorder in adults. We discuss the diagnostic evaluation and clinical characteristics followed
26 November 2014
by treatment options suitable for the clinician working from primary through to specialist psychiatric
Accepted 4 December 2014
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.
Keywords: Owing to better tolerability, SSRIs are acknowledged as the first-line pharmacological treatment of
Obsessive choice. For those patients for whom first line treatments have been ineffective, evidence supports the
Compulsive
use of adjunctive antipsychotic medication, and some evidence supports the use of high-dose SSRIs.
Pharmacotherapy
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.

1. Introduction

Obsessive–compulsive disorder (OCD) is a common and often

enduring neuropsychiatric disorder. It affects 2–3% of the adult
☆
Disclaimer The advice we are providing is as accurate and comprehensive as
population (and 1% of children) regardless of ethnicity, geography
possible but it is only general advice and it is up to doctors reading this article to
make their own clinical judgment when interpreting the information and deciding
or socioeconomic status (Robins et al., 1984; Weissman et al., 1994;
how best to apply it to the treatment of patients. Patients should not use this Heyman et al., 2003; Wittchen and Jacobi, 2005). The magnitude
information as a substitute for the individual advice they may receive from of psychosocial impairment is high (Hollander et al, 2010). OCD is
consulting their own doctor an illness that is poorly recognized and patients usually present for
n
Corresponding author at: National Obsessive Compulsive Disorders Specialist
treatment late in the course of the disorder. The average duration
Service, Hertfordshire Partnership University NHS Foundation Trust, Queen Eliza-
beth II Hospital, Welwyn Garden City, Hertfordshire AL7 4HQ, UK. of untreated illness has been reported to be as long as 17 years
E-mail address: naomi.fineberg@hpft.nhs.uk (N.A. Fineberg). (Hollander and Wong, 1998). Treatment delay is associated with a

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., Obsessive–compulsive 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
2 N.A. Fineberg et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
poorer outcome, whereas effective pharmacological treatment
improves health-related quality of life (HRQOL), highlighting the
importance of early diagnosis and intervention. Relapse, on the
other hand, is associated with loss of HRQOL (Hollander et al,
2010), emphasizing the importance of relapse prevention in
maintaining well-being.
The range of effective pharmacological treatments is limited.
However, the results of studies performed in specialist centers suggest
more encouraging outcomes could be expected. ‘Technical treatment
failure’ seems to be a common cause for apparent refractoriness—that
is, patients have not received an adequate dose, duration or type of
treatment. This article synthesizes the available evidence relating to
pharmacotherapy in adults, from the perspective of the clinician, for
clinicians working in primary care, and for specialist psychiatric
services. We extend our review to consider the referral of treatment-
refractory cases for neurosurgical treatment at highly specialised
centers. If pharmacological treatment delivery, according to the best
available evidence, can be optimized, it is to be hoped that the overall
standard of care for OCD patients might be improved.
2. Screening for ‘high-likelihood’ OCD: settings and tools
Early and accurate recognition and diagnosis is a key element in
effective treatment. Patients can be reluctant to discuss their symp-
toms, and the diagnosis is often missed. Clinicians therefore need to be
vigilant and proactively inquire about symptoms of OCD in patients
presenting with affective and anxiety syndromes, since OCD is
frequently comorbid with these disorders, and in their presence, the
diagnosis could be missed (Fullana et al., 2009). Obsessive–compulsive
(OC) symptoms are also common in patients with schizophrenia, aff-
ecting around one fifth of cases (Mukhopadhaya et al., 2009; de Haan
et al., 2013). OCD is highly familial, and roughly 10% of first degree
relatives of adult OCD probands are themselves affected (Pauls et al.,
1995). Significantly higher rates of OCD (approximately 20%) are rep-
orted in the relatives of childhood-onset cases (Pauls, 2010). Recent
findings, that individuals with OCD from families where multiple
members are affected are less likely to present for treatment (Dell'
Osso, 2012 [Oral Presentation ICOCS]), suggest that the clinician should
pay particular attention to the possibility of untreated disorder in the
family members of existing OCD patients, for whom ‘normalization’ or
denial of pathology may occur.
The Mini International Neuropsychiatric Interview (MINI) (Sheehan
et al., 1998) is a well-validated structured screening interview that is
compatible with ICD-10 and DSM-IV. It has the advantage of having
been translated into several languages. Ultra-brief screening instru-
ments, such as the five-item Zohar-Fineberg OC Screen, may also be of
value to identify people with an increased likelihood of OCD, and may
also be applied in non-psychiatric healthcare settings known to attr-
act a high frequency of patients with OCD or body dysmorphic diso-
rder (BDD), such as dermatology or cosmetic surgery clinics (Fineberg
et al., 2008).
3. Diagnosis: DSM-IV, DSM-5, ICD-10 and new developments
Contemporary pharmacological treatment trials have relied on the
DSM-IV (American Psychiatric Association, 1994) for diagnosis and
recruitment. Thus, ‘evidence-based’ pharmacotherapy is largely based
upon establishing efficacy in patients with DSM-IV OCD. There are
some shortcomings in the DSM-IV OCD criteria, such as lack of
agreement on where to place the diagnostic threshold, differentiation
of specific OCD subtypes, and required duration of symptom stability.
In keeping with evidence suggesting a strong association between
OCD and a group of so-called obsessive–compulsive spectrum
Please cite this article as: Fineberg, N.A., et al., Obsessive–compulsive 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
disorders, including BDD (body dysmorphic disorder), hoarding
disorder, trichotillomania (hair-pulling disorder) and excoriation
(skin-picking) disorder), OCD has been removed from the DSM-5
‘anxiety disorders’ category and introduced into a new and separate
DSM-5 category of ‘obsessive–compulsive and related disorders’
(Leckman et al., 2010; American Psychiatric Association, 2013). Only
fairly minimal changes were made to the diagnostic criteria in DSM-5.
However, two substantive changes were made to specifiers as
follows: (1) addition of a specifier for patients with a current or past
tic disorder (who may be more responsive to antipsychotic augmen-
tation of serotonin reuptake inhibitors than those without tics) and
(2) expansion of the poor insight specifier to include good or fair
insight, poor insight, and absent insight/delusional OCD beliefs.
The World Health Organization's International Classification of
Disorders (ICD-10) diagnostic criteria (World Health Organization,
1992) (soon to be updated) are broadly consistent with those of
the DSM-IV and DSM-5, but are arguably more descriptive and less
prescriptive, which may provide added utility for the clinician but
may also reduce specificity. For instance, the ICD-10 does not
expressly exclude ‘worries about real life problems’ (as in general-
ized anxiety disorder) and does not require obsessions to be time
consuming, thereby relaxing the threshold for the ICD-10 diag-
nosis relative to DSM-IV and DSM-5 and allowing inclusion of less
severe cases or those with an overlap with anxiety-related worries
or mood-related ruminations.
4. Evaluating symptom severity, global disability, and
functional impairment
The Yale–Brown Obsessive–Compulsive Scale (Y–BOCS)
(Goodman et al., 1989a, 1989b) has emerged as the pivotal rating
scale for OCD severity in adults and has been used to evaluate
efficacy for most of the available pharmacological treatments.
The Y–BOCS is a 10-item observer-rated instrument. It has been
adapted as a self-rated tool (Steketee et al., 1996). It measures the
overall severity of obsessions and compulsions separately and in
combination. Items include duration, interference, distress, abil-
ity to resist and control. Of these, the item measuring resistance
is the least reliable, but various attempts to revise the psycho-
metric properties of the scale have not met with general support,
and it remains largely used in its original form. The Y–BOCS is
relatively brief and sensitive to change and has established util-
ity in measuring clinical progress in the clinical as well as the
research setting.
Other scales that may be used as alternative OCD-outcome
measures, and that have also been shown to be sensitive to change
in OCD populations, include the Comprehensive Psychopathological
Rating Scale (CPRS) OCD scale (Åsberg et al., 1978), the National
Institute for Mental Health Global Obsessive–Compulsive Scale (Insel
et al., 1983b), the Dimensional Y–BOCS (Rosario-Campos et al., 2006),
which allows evaluation of individual OCD dimensions, and the
Obsessive–Compulsive Inventory-Revised (OCI-R) (Foa et al., 2002).
Complementary instruments that have been used in OCD populations
include the Clinical Global Impression Severity and Improvement
Scales (Guy, 1976), Sheehan Disability Scale (SDS) (Sheehan et al.,
1996) and the Medical Outcomes Survey 36-Item Short Form Survey
Instrument (SF-36) (Ware and Sherbourne, 1992), which measure,
respectively, global illness severity and improvement, illness-related
psychosocial impairment and health-related quality of life. OCD is
associated with considerable functional impairment and executive
dysfunction. The Cognitive Assessment Instrument of Obsessions and
Compulsions (CAIOC-13) (Dittrich et al., 2011) is a new scale designed
to measure OCD-related functional impairment in the clinical setting.
Its sensitivity to change has not yet been evaluated.
 N.A. Fineberg et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
5. Defining treatment-response, remission, recovery, relapse
and resistance
Substantial improvement can be achieved in many patients, but
for approximately 50% the treatment response is incomplete.
Pallanti et al. (2002) advocated the use of standardized operational
criteria across treatment trials, proposing that a meaningful clinical
response could be conservatively represented by an improvement
of 25–35% in the baseline Y–BOCS score, or a score of ‘much’ or ‘very
much improved’ on the Clinical Global Impression of Improvement
Scale. According to Pallanti et al. (2002), ‘remission’ necessitated a
total Y–BOCS score of less than 16 (out of a total scale score of 40).
‘Partial response’, in contrast, was defined as an improvement in
baseline Y–BOCS scores of 25–35% and ‘relapse’ following a period
of remission as a worsening by 25% of the remission Y–BOCS score
(or a CGI-I score of six). However, a total YBOCS score of 15 does not
represent clinical remission as defined by many clinician/research-
ers: patients meet the criteria for admission into some studies at
this level. Stein et al. (2007) proposed a more stringent remission
criterion, requiring the total Y–BOCS score to be reduced to 10 or
less, and in the field of CBT, Sookman and Steketee (2010) defined
remission as no longer meeting OCD DSM criteria and a YBOCS
score¼or o7.
The definition of a meaningful clinical response or remission and
the concept of ‘relapse’ continue to spark debate and can be difficult
to apply to an illness that usually has a chronic fluctuating course or
a progressively worsening course when untreated, and shows only
partial response to long-term pharmacological treatment (Simpson
et al., 2006; Farris et al., 2013). Plausible relapse criteria include a
worsening of post-baseline Y–BOCS of Z50%, a five-point worsen-
ing of the total Y–BOCS score, a, total Y–BOCS score Z19, and CGI-I
scores of ‘much’ or ‘very much worse’ (Fineberg et al., 2007a,
2007b). All these different definitions used in the field can lead to
very different claims about efficacy and about relapse (Simpson
et al., 2005).
Hollander et al. (2010) attempted to validate the previously
empirical responder and relapse criteria (Pallanti et al., 2002) by
correlating functional disability (using the SDS) and health-rela-
ted quality of life (HR-QoL) (using the SF-36) with Y–BOCS score
changes. A statistically significant and clinically relevant distinction
in functioning/HR-QoL measures was observed between responders
and non-responders when treatment-response was defined as at
least 25% improvement in the Y–BOCS score relative to baseline.
This indicates that a 25% improvement in the baseline Y–BOCS is a
clinically relevant change and represents a minimal partial resp-
onse. Likewise, relapse, when defined as a five-point worsening of
the remission Y–BOCS correlated with a significant deterioration in
HR-QoL and social function; patients who relapsed according to this
criterion had statistically significantly poorer outcomes on the SDS
and SF-36 than those who did not (Hollander et al., 2010). However,
this approach has limitations when starting with a very low Y–BOCS
score and, importantly, a 25% improvement rate often reflects con-
tinued substantial symptomatology.
Levels of ‘treatment resistance’ have been defined according to
the numbers of failed treatments (Pallanti et al., 2002), and the
term ‘treatment refractory’ has been reserved for those who do not
respond to ‘all available treatments.’ A drawback of the latter app-
roach is that it is currently unclear which specific evidence based
treatments ‘all available treatments’ refers to.
6. OCD dimensions and subtypes
Data from factor analysis, genetic, functional imaging and treat-
ment studies have suggested a dimensional model for OCD (Mataix-
Cols et al., 2010) that merits consideration in treatment planning,
Please cite this article as: Fineberg, N.A., et al., Obsessive–compulsive 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
3
given that dimensions may determine treatment outcome. Of the
dimensions so far identified, hoarding is perhaps the best rese-
arched and is thought to constitute a separate syndrome (Mataix-
Cols et al., 2010) introduced as ‘Hoarding Disorder’ in the DSM-5
(American Psychiatric Association, 2013). Compulsive hoarding is
often ‘ego-syntonic’, and the Y–BOCS is not a specific measure of
this disorder. Frost et al. have developed specific measures for
hoarding (Frost et al., 2012). Analysis of one large trials database
indicates that the ‘hoarding/symmetry’ dimension predicts a poorer
outcome to SSRI treatment compared with other OCD dimensions
(Stein et al., 2008). Nevertheless, the responsiveness of hoarding
symptoms to pharmacotherapy remains unclear, given other studies
suggesting positive outcome for select patients (Saxena, 2011).
Research into the ‘early onset’ OCD subtype has been hampered
by the use of different age limits for its definition (Mataix-Cols
et al., 2010) and uncertainty around the developmental stability of
obsessive–compulsive symptoms. Also, it is unclear whether this
subtype refers to those with an early onset of sub-clinical symp-
toms or the full disorder. There is a significant confounding effect
between early onset OCD, duration of untreated illness and tic-
related OCD (see below). Research has shown that children with
early onset illness respond well to treatment, compared to adults,
if treatment is offered without delay (Krebs and Heyman, 2010).
Longer duration of untreated illness has been associated with poo-
rer outcome (Dell’Osso et al., (2010)). Thus, it is important to ins-
titute treatment early. Overall, the treatment response in young
people with OCD may be similar to those with late-onset OCD
(Leckman et al., 2010).
The tic-related subtype of OCD may account for up to 40% of
cases diagnosed in childhood or adolescence. Children with tic-
related OCD may have a higher incidence of comorbid attention
deficit hyperactivity disorder (ADHD), oppositional defiant disor-
der, and trichotillomania (reviewed and referenced in Geller et al.
(2012)). A preponderance of symptoms such as symmetry and
ordering/arranging compulsions has been noted in individuals
with this subtype across many cultures. In a large Brazilian adult
cohort, OCD patients with comorbid tic, compared to those with-
out tic, showed more aggressive, sexual/religious and hoarding
symptoms, were more likely to be males, and showed increased
levels of comorbidity with anxiety disorders, impulse control dis-
orders, and skin picking (de Alvarenga et al., 2012). While both tic-
and non-tic-related OCD may respond to cognitive-behavioral
interventions, tic-related OCD may respond better to SSRI-
augmentation with antipsychotic than an SSRI alone (Bloch et al.,
2006; Leckman et al., 2010).
7. Psychiatric comorbidity in OCD
OCD is associated with considerable psychiatric comorbidity,
which also needs to be taken into consideration when planning
treatment, although unfortunately studies that focus on OCD with
comorbid disorders are few, and we do not have robust evidence to
guide us. Anxiety and affective disorder occur in over half of
treatment-seeking cases. Compounds with a ‘broad spectrum’ of
anxiolytic and antidepressant efficacy, such as SSRIs and clomipra-
mine, may be of considerable value in these cases. A study by
Hoehn-Saric et al. (2000) showed preferential efficacy for the SSRI
sertraline over the non-SRI desipramine in depressed patients with
OCD, emphasizing the importance of choosing a compound with
intrinsic efficacy in OCD in the presence of co-morbid disorder.
There is increasing recognition of the prevalence of bipolar affective
symptoms and emotional lability in some patients with OCD (Fineberg
et al., 2013a). For cases with such comorbidity, adjunctive treatment
with mood stabilizers—e.g., topiramate (Berlin et al., 2011) or quetia-
pine (Denys et al., 2004) could be helpful, although there is as yet
4 N.A. Fineberg et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
insufficient clinical trials' evidence to specifically recommend their use
in patients with comorbid OCD. Substance use disorders have been
found to occur at relatively high rates in some epidemiological OCD
samples (Ruscio et al., 2010), but their prevalence in clinical cohorts is
not usually reported as being elevated (reviewed in Fineberg et al.
(2013a)). ADHD rates may also be elevated (Geller et al., 2007). For
example, in a selected sample of individuals with childhood-onset
OCD with and without co-morbid tic, ADHD rates were elevated
compared to the general population rate, and there was a strong
association between ADHD and clinically significant hoarding behavior
(Sheppard et al., 2010). Putative obsessive–compulsive spectrum
disorders, including BDD, hoarding disorder, trichotillomania, hypo-
chondriasis, and obsessive compulsive personality disorder, often co-
occur with OCD and co-aggregate within families. The impact of these
disorders on treatment outcome in the comorbid patient is not well
understood.
Up to 50% of patients with schizophrenia experience obsessive–
compulsive symptoms coexisting with psychosis, and between 8%
and 46% of patients with schizophrenia also have full-blown OCD
(Poyurovsky et al., 2004; Schirmbeck and Zink, 2012). Obsessive
Compulsive symptoms may have their onset during treatment with
second generation antipsychotics (such as clozapine) in schizophre-
nia. This could be related to their serotonin receptor antagonistic
effects suggesting a pharmacodynamic mechanism as a possible
etiology for the origin of these symptoms (Schönfelder et al., 2011;
Schirmbeck and Zink, 2012). It remains unclear to what extent
treatment with pharmacotherapy or CBT can be helpful in these
comorbid cases, although a small amount of open-label data sug-
gests a trial of an SSRI (Stryjer et al., 2013), adjunctive lamotrigine
(Poyurovsky et al., 2010), or adjunctive aripiprazole (Schönfelder
et al., 2011) could be helpful.
8. Evidence-based pharmacotherapy for OCD
Detailed accounts of the evidence base for the pharmacological
treatments suggested in this paper have recently been published and
updated by some of the coauthors (Fineberg and Brown, 2011;
Fineberg et al., 2012, 2013c). Placebo-referenced efficacy in adulthood
OCD has been established for the available SSRIs (fluvoxamine,
fluoxetine, sertraline, paroxetine, citalopram and escitalopram) in a
large series of studies spanning nearly 20 years (reviewed and
referenced in Fineberg et al. (2012)). A meta-analysis of SSRI versus
placebo that included 17 selected studies (3097 participants) unequi-
vocally demonstrated the efficacy of SSRIs in OCD (Soomro et al.,
2008). The above analysis indicated that SSRIs are nearly twice as
likely as placebo to produce a clinical response (defined as a Z25%
reduction in Y–BOCS from baseline). Evidence for the efficacy of
clomipramine as an efficacious agent in adults and children and its
superiority over tricyclic antidepressants and MAOIs has been revi-
ewed by Fineberg and Gale (2005).
8.1. SSRIs or clomipramine?
While meta-analyses report a smaller effect size for SSRIs relative
to clomipramine, head-to-head comparison studies tend to demon-
strate equivalent efficacy (reviewed and referenced in Fineberg et al.
(2005, 2012)). SSRIs, compared to clomipramine, have better overall
acceptability and tolerability and for this reason SSRIs are generally
the preferred option for first-line treatment when compared to
clomipramine. For this reason, the UK National Institute for Health
and Clinical Excellence (NICE) (2006) recommended an SSRI as first-
line treatment, with clomipramine reserved for those patients who
either fail to respond or cannot tolerate an SSRI. The American
Psychiatric Association Practice Guidelines (Koran et al., 2007; Koran
Please cite this article as: Fineberg, N.A., et al., Obsessive–compulsive 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
& Simpson., 2013) also recommend an SSRI as the first line of
treatment.
8.2. Which SSRI?
There is insufficient evidence to support the superior efficacy or
tolerability of any one SSRI in OCD. An underpowered single-blind
study (Mundo et al., 1997) did not detect differences between
fluvoxamine, paroxetine, or citalopram with just 10 patients per
group. In a double-blind comparison study of sertraline (n¼77) and
fluoxetine (n¼ 73) (Bergeron et al., 2001), no significant difference
was seen at the 24-week end-point on any primary efficacy measure.
However there was a non-significant trend towards an earlier effect
in the sertraline group, and a greater number of sertraline-treated
patients reached remission, defined as a CGI-I score r2 and a
Y–BOCS score r11. In a 24-week study by Stein et al. (2007), sym-
ptomatic improvement on escitalopram 20 mg/day and paroxetine
40 mg/day appeared similar from the 12-week primary endpoint
onwards.
SSRIs do, however, differ from one another in terms of the
selectivity and potency of effect at the serotonin transporter and
their secondary pharmacological actions (Stahl, 2008), and conse-
quently one might predict differences in clinical efficacy and adverse
effect profile in OCD. Fluoxetine may be preferred in those with poor
treatment adherence, such as highly impulsive individuals, in view of
its long half-life. Also it tends to have only mild discontinuation
effects and, together with sertraline, is thought to be associated with
the least weight gain of the SSRIs (Serretti and Mandelli, 2010). In
contrast, discontinuation effects are particularly evident with parox-
etine. Sertraline, citalopram, and escitalopram constitute a rational
choice if cytochrome P450-related drug interactions are relevant. The
recent demonstration of prolongation of the ECG QT interval asso-
ciated with higher dose-levels of citalopram (and to a lesser extent
escitalopram) (FDA Drug Safety Communication, 2013) argues for a
degree of caution in using higher doses of citalopram in OCD,
especially if individuals are taking other medications that increase
the QT interval. However, a recent large study found no elevated risk
of ventricular arrhythmia or all-cause, cardiac, or non-cardiac mor-
tality associated with citalopram doses exceeding 40 mg/day (Zivin
et al., 2013), casting doubt on this warning.
8.3. Which dose?
The SSRIs fluoxetine, paroxetine, sertraline, citalopram, and
escitalopram have each been investigated in multiple, fixed dose
studies. A positive dose–response relationship has been noted for
fluoxetine, paroxetine, and escitalopram (reviewed and referenced
in Fineberg et al., 2012 (2013c)). Paroxetine is effective at doses of
40 mg/day and 60 mg/day (Hollander et al., 2003a). Similar results
were reported for fluoxetine, with the greatest benefit observed
with the 60 mg/day dose (Montgomery et al., 1993; Tollefson et al.,
1994), which was also significantly more effective than the 20 mg/
day dose in a meta-analysis (Wood et al., 1993). Likewise 20 mg/
day of escitalopram has been noted to be more efficacious than
10 mg/day (Stein et al., 2007). The dose–response relationship is
less clear-cut for sertraline and citalopram (Greist et al., 1995;
Ushijima et al., 1997; Montgomery et al., 2001). A meta-analysis of
nine SSRI studies was conducted to determine dose-related diff-
erences in efficacy and tolerability using a fixed effects model.
High SSRI doses were associated with greater efficacy than low or
medium doses, using Y–BOCS score or proportion of responders as
outcome measures (Bloch et al., 2010).
No dose–response relationship has been demonstrated for
fluvoxamine or clomipramine. Fluvoxamine has been shown to
have significant effect over placebo at doses ranging from 150 to
300 mg/day. Single dose studies have shown efficacy compared
 N.A. Fineberg et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
with placebo for relatively low fixed clomipramine doses (75 mg/
day and 125 mg/day) (Montgomery et al., 1980). However, con-
trolled studies also demonstrate efficacy and tolerability for doses
as high as 300 mg/day of clomipramine (DeVeaugh-Geiss et al.,
1989) and 80 mg/day fluoxetine (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 pre-
scribed with caution and ECG/plasma level monitoring considered.
8.4. Dose titration
In randomized controlled OCD trials of SSRIs and clomipra-
mine, improvements have been noted in obsessions and compul-
sions 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, improve-
ment 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 imm-
ediate evidence of change. As observable benefits may not appear
for several months, clinicians can feel pressured to change treat-
ments or increase SRI doses prematurely. A balance is recom-
mended 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 efficacy. The guidelines suggest sta-
rting with the lowest efficacious daily dosage of SSRIs, which may be
increased in the face of insufficient 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 4–6
weeks, thereafter waiting another 6 weeks to evaluate effectiveness.
Attempts at pulse-loading, using either oral or intravenous clomi-
pramine, did not produce a sustained advantage in a small number of
studies, although improvements may have been evident earlier com-
pared 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 adher-
ence. 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 catego-
ries based on degree of response—e.g., ‘full response’ (435% Y–BOCS
change), partial response (25–35% Y–BOCS change), no response
(o25% Y–BOCS 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., Obsessive–compulsive 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
5
below). In the case of a partial response to SSRI in the initial stage of
treatment, the next step could be to combine drug treatment with
cognitive behavior therapy (CBT) for OCD. In the case of sustained
partial response or no response, a trial of another SSRI or clomipra-
mine (also see below) could be considered and similar strategies as in
the case of the first trial may be followed.
However, decisions about further treatment should reflect not
only the percent improvement in symptoms but also the severity
of remaining symptoms. For example, if a patient's symptoms are
initially very severe, even a response of 4 35% magnitude may still
reflect fully symptomatic ongoing OCD; in such cases, the clinician
will want to pursue additional treatment with the aim of further
improving the patient's symptoms. Likewise, in some cases e.g.
severe or complex illness, there may be clinical arguments to inc-
rease the dose of SSRI further, switch SRI or augment with another
pharmacological treatment (see sections 8.8.1 to 8.8.7), even at an
early stage of treatment-resistance.
8.6. Combined CBT and pharmacotherapy
Although many specialist centers offer combined treatment, the
degree to which adding CBT to SSRI improves outcomes compared to
monotherapy, either in the short-term or the long-term, is an
important area of continued investigation. Evidence indicates that
patients who respond only partially to an SRI fare better, compared to
SRI monotherapy, if CBT (including exposure and response preven-
tion) is added (Kampman et al., 2002; Tolin et al., 2004; Tenneij et al.,
2005; Tundo et al., 2007; Simpson et al., 2008). However, it is still
unclear whether both treatments carried out simultaneously from the
start have any advantage over implementing just one or the other. For
example, some studies suggest that combined CBT and pharma-
cotherapy out-performs CBT monotherapy, whereas other studies
reported that there is no difference (reviewed in Fineberg and Brown
(2011)). The APA Practice Guidelines (Koran et al., 2007; Koran and
Simpson, 2013) suggest using either an SRI or CBT alone as first-line
treatment. According to a cost-effectiveness analysis, the UK NICE
guidelines (NICE 2006) recommend the use of combined CBT plus
an SRI only in more severe or treatment-resistant cases.An 8-week
acute-phase randomized controlled study in 108 adults with OCD and
partial SSRI response (Simpson et al., 2008) demonstrated that the
addition of 17 sessions of twice a week CBT with exposure and
response prevention to SSRI was superior to the addition of stress
management training. Thus, at the very least, a trial of combined CBT
plus SSRI treatment would be appropriate for those patients failing to
respond adequately to SSRI monotherapy. However, as these and
other authors have pointed out, 17 sessions were not sufficient to help
most of these patients achieve minimal symptoms and longer trials of
CBT would be indicated. A follow-up study investigated responders
from this study treated with up to 24 weeks of maintenance
treatment (Foa et al., 2013). The difference in Y–BOCS scores between
treatment conditions remained significant and similar in magnitude
at 8 weeks and 24 weeks later (total Y–BOCS score in those receiving
Exposure and Response Prevention versus Stress Management Train-
ing: at 8 weeks: 14.3 versus 22.7; po0.001 and at 24 weeks: 14.69
versus 21.37; p¼0.005), further strengthening support for the role of
combination therapy in individuals who had a partial response to SRI
monotherapy. However, there was no between-group difference in
the rate of change in Y–BOCS scores during the maintenance phase
and the proportion of responders who entered the maintenance
phase and who maintained their response status did not significantly
differ between the two treatment groups. The observed group diff-
erence at the end of the maintenance phase may thus be attributed to
the group difference after acute treatment, which was sustained
during the maintenance phase.
6 N.A. Fineberg et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
8.7. Relapse prevention (continuation and maintenance treatment)
The natural course of OCD was traditionally considered to be
chronic and relapsing, and follow-up studies in clinical cohorts
suggested that remission is uncommon (Eisen et al., 2013). How-
ever, a recent epidemiological study suggests that approximately
50% of community-based cases followed up for approximately 30
years appear to have achieved remission by the age of 50 years,
noting that only a minority (40%) sought professional treatment
for their OCD (Fineberg et al., 2013b). More severe illness and a
longer duration of illness were both associated with a lower
likelihood of remission, highlighting the importance of early dete-
ction and treatment (Marcks et al., 2011; Eisen et al., 2013;
Fineberg et al., 2013b). In the recent, prospective longitudinal
study by Eisen et al. (2013), participants with primary obsessions
were more likely to experience a remission, whereas those with
primary hoarding were less likely to remit, and over half of the
participants who remitted subsequently relapsed. Participants
with obsessive–compulsive personality disorder were more than
twice as likely to relapse. Participants were also particularly vuln-
erable to relapse if they experienced partial remission rather than
full remission, emphasizing the importance of achieving full rem-
ission as a treatment target.
A series of controlled studies in adults with OCD have shown
that, irrespective of duration of treatment (up to 2 years), disconti-
nuation of pharmacotherapy is usually, but not always, associated
with symptomatic relapse (reviewed in Fineberg et al. (2013c)). In
the early clomipramine studies, symptoms re-emerged within a few
weeks of stopping medication, whereas improvement to a level
near to that prior to discontinuation was achieved by reinstatement
of clomipramine (reviewed in Fineberg et al. (2007c)). In contrast,
the placebo-controlled relapse prevention studies of SSRIs in OCD
produced mixed results. Studies with sertraline (Koran et al., 2002)
and fluoxetine (Romano et al., 2001), which may have been under-
powered, did not find a significant difference between continuation
treatment on active drug or placebo, although patients remaining
on higher (60 mg/day) fluoxetine doses showed significantly lower
relapse rates than those on placebo (Romano et al., 2001). More-
over, continued improvement in Y–BOCS, NIMH-OC, CGI scores, and
quality-of-life measures was associated with sertraline treatment as
opposed to sertraline discontinuation. Clearer advantages for stay-
ing on active treatment were shown in discontinuation studies of
paroxetine (Dunbar et al., 1995; Hollander et al., 2003b) and
escitalopram (Fineberg and Craig, 2007a). A meta-analysis detected
overall superiority of SSRIs compared to placebo in preventing
relapse amongst adult treatment responders (Fineberg et al.,
2007c). Viewed collectively, the results suggest that SSRIs are
effective at preventing relapse and that medication, as long as it is
continued, confers protection against relapse. Moreover evidence
also suggests a positive impact of maintenance SSRI treatment (as
opposed to discontinuation) on quality of life and psychosocial
functioning (Hollander et al., 2010).
Thus, relapse prevention, through the continuation of pharma-
cotherapy, represents a rational treatment target for OCD patients
who have responded to an SSRI or clomipramine. Guidelines (Koran
et al., 2007) from the American Psychiatric Association (APA) reco-
mmend continuation of pharmacotherapy for a minimum of 1–2
years in treatment-responsive individuals and emphasize the imp-
ortance of long-term treatment from the outset.
There is little evidence to support dose reduction as a strategy
in the long-term management of OCD. The observation that a
60 mg/day dose of fluoxetine appeared the most effective (com-
pared with 20 mg/day and 40 mg/day; 80 mg/day was not
included) over a 24-week placebo-controlled extension phase,
suggests treatment should be continued at higher dosages for
those who needed them initially (Romano et al., 2001). If enacted,
Please cite this article as: Fineberg, N.A., et al., Obsessive–compulsive 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
discontinuation should be gradual: the APA guidelines suggest
reducing the dose by decrements of 10–25% every 1–2 months
while observing for symptom return or exacerbation, in which
case pharmacotherapy could be reinstated as a rescue strategy,
although the same level of improvement cannot be guaranteed
(Koran et al., 2007).
8.8. Managing SSRI-resistant OCD
If the response to the trial of a second SSRI is inadequate, a review
of the diagnosis is warranted along with assessment for co-morbid
disorders that might be interfering with the treatment-response.
Investigations to rule out neurological or medical illnesses that may
be contributing to obsessive–compulsive symptoms—e.g., Sydenham's
chorea, Tourette's syndrome, autistic spectrum disorder, or Parkin-
son's disease in older adults—may also be warranted. ‘Technical
treatment failure’, representing a lack of adequate response to
treatment as a result of poor adherence, and the absence of structu-
red follow-up is known to contribute to treatment failure in OCD
(Nakatani et al., 2011). As stated above, regular clinical review to
check adherence to treatment is therefore important. Plasma level
monitoring may also be helpful—e.g. in case of abnormal SSRI-
metabolism. Pharmacogenetic testing for metabolic enzymes such
as the cytochrome P450 enzymes 2D6, 1A2 and 2C19 is showing
promise, but requires further validation as a clinical tool and as yet is
not widely used or available(Mrazek., 2010; Brandl et al., 2012; Brandl
et al., 2014). Alliance with the patient's family is important, including
discussion of accommodation with the patient's rituals.
Pharmacotherapy treatment options for SSRI-resistant OCD
include the following. These options are presented in no particular
order. The available data based on the number of randomized con-
trolled trials favors augmentation with second generation anti-
psychotic.
8.8.1. High-dose SSRI
A relatively well-tolerated and pragmatic strategy is to increase
the dosage of the SSRI beyond that approved by the licensing
authorities (Koran et al., 2007). In these circumstances, it is
advisable to explain to the patient that these doses are ‘off-label’
and to obtain and document informed consent. However, the data
supporting this strategy is limited. A retrospective case-note sur-
vey of 26 patients with OCD on various SSRIs noted that, at the last
assessment, patients on high-dose SSRI-treatment showed signifi-
cant within-group improvement compared to baseline (Y–BOCS
25.35 versus 20.95), although endpoint scores for the high-dose
group remained significantly higher than those of a control group
of patients not requiring high-dose treatment. High dose SSRI was
also well tolerated (Pampaloni et al., 2010). Two 16-week open
label studies tested a higher than usual dose of escitalopram. The
study by Rabinowitz et al. (2008) noted that 64% of patient
receiving a mean dose of 33.8 mg/day at end point achieved resp-
onder status as measured on the YBOCS. In the second study
(Dougherty et al., 2009), up to 80% of those on escitalopram (dose
range 35–50 mg) responded to treatment. A randomized con-
trolled (non-placebo) study that compared two sertraline doses
noted greater symptom improvement in those given 400 mg com-
pared to those given 200 mg daily and both doses were well
tolerated (Ninan et al., 2006).
The APA OCD guideline (Koran et al., 2007, reviewed in Koran
and Simpson (2013)) provides a list of upper doses that are
occasionally prescribed. For ‘fast-metabolizers’ or those who have
failed to respond to conventional doses and are not experiencing
undue adverse effects, the Guideline (Koran et al., 2007) recom-
mends ‘occasionally prescribed’ doses of up to 60 mg/day of
escitalopram, 120 mg/day of fluoxetine, 450 mg/day of fluvoxamine,
 N.A. Fineberg et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
100 mg/day of paroxetine and 400 mg/day of sertraline. The
authors' clinical experience is consistent with these recommended
doses; such doses seem most warranted when the patient has had a
partial response to a lower dose and is tolerating the medication
well. However, such an approach is not without risk. In the case of
some SSRIs—e.g., citalopram and perhaps also escitalopram, which
are recognized to have a dose-dependent effect on extending the
ECG QT interval (although, a recent study did not show an elevated
cardiac risk on higher doses of citalopram (Zivin et al., 2013)), and in
the elderly or those with a cardiac history, caution should be exe-
rcised if exceeding the licensed daily dosage and it may be advisable
to monitor for adverse effects on cardiac conduction (e.g., by ECG
monitoring). The elderly may also be susceptible to SSRI-induced
electrolyte disturbances and bleeding tendencies, and for those on
anticoagulant therapy, especially if using high-dose fluoxetine, the
International Normalized Ratio (INR) may require more stringent
monitoring.
8.8.2. Trial of clomipramine
Another option would be to consider a trial of clomipramine.
While clomipramine is known to be as effective as SSRIs, the adverse
effect profile is generally more problematic than for SSRIs (NICE,
2006). It should be used cautiously in those with a history of
overdose. Dosages of clomipramine exceeding the licensed maximum
of 250 mg daily should be prescribed with caution, and ECG and
plasma level monitoring considered (Szegedi et al., 1996). However, in
the event of a partial response, the option of increasing the dosage
above licensed limits up to 300 mg daily could be considered, as
dosages of 300 mg daily of clomipramine have been systematically
investigated in OCD and found to be acceptable (DeVeaugh-Geiss
et al., 1989).
8.8.3. Switch between SRIs/switch to SNRI
If the response to the first SSRI is inadequate (assuming good
adherence), or the patient fails to tolerate it, switching to another
SSRI is another acceptable option. March et al. (1997) recommended
switching to another SRI if the clinical effect is incomplete after 8–
12 weeks on the maximum dose. They estimated the chance of res-
ponding to a second SRI at 40%, and to a third at even less, and
proposed switching to clomipramine after two or three failed SSRI-
trials. The American Psychiatric Association (Koran et al., 2007)
recommends continuing with an SSRI for 8–12 weeks, of which six
should be at maximum tolerated dose, before augmentation or
switching to another SSRI is considered. However, it may some-
times be appropriate to persist for longer than 12 weeks with a
given SRI, even in patients who show little improvement, since a
clinical response may occur after several months (Rasmussen et al.,
1997). There have been no placebo-controlled studies demonstrat-
ing efficacy for venlafaxine in OCD. Moreover, Denys et al. (2003)
showed that whereas switching from venlafaxine to an SSRI
improved outcomes in non-responders, the opposite was not true.
8.8.4. Adjunctive antipsychotic
Convincing evidence supports the use of adjunctive antipsycho-
tics, which may be of special value in those with tic-related OCD
(Bloch et al., 2006). Haloperidol, risperidone, quetiapine, olanza-
pine, and aripiprazole have each been associated with at least one
positive result from a randomized placebo-controlled trial (Fineberg
& Brown., 2011). However, this strategy is effective in only roughly
one third of cases (Bloch et al., 2006). The beneficial effects are
relatively rapid in onset (e.g., 2–4 weeks), and therefore prolonging
exposure to adjunctive antipsychotics, if they do not appear to be
helping, is not usually advisable. There is little evidence to dis-
criminate between antipsychotics, although at least one meta-
analysis suggests a greater effect size may be achieved with
Please cite this article as: Fineberg, N.A., et al., Obsessive–compulsive 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
7
risperidone (Dold et al., 2013). However, a recent randomized pill-
placebo 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, fluoxetine/clomipramine may
interact pharmacokinetically with risperidone. Dose-finding stu-
dies of antipsychotic in OCD have not so far been performed. How-
ever, the studies that investigated these compounds according to
the authors' judgment, tended to use low or moderate antipsy-
chotic doses. The antipsychotic dose range noted to be effect-
ive includes; haloperidol (2–4 mg/day), risperidone (1–2 mg/day),
quetiapine (150–600 mg/day), olanzapine (5–10 mg/day) and ari-
piprazole (15–30 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 benefit in
continuing the antipsychotic for at least 1 year. A small retro-
spective 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 anti-
psychotic was withdrawn. Following 12 months of successful
antipsychotic treatment, individualized collaborative care-plan-
ning, taking account of treatment-tolerability, symptom profile
(e.g., the presence of tic), and history of relapse, may help
determine whether discontinuation of the antipsychotic is appro-
priate. For those opting for long-term adjunctive antipsychotic
with a second-generation agent, metabolic monitoring may be
advisable. Evidence is accruing for metabolic complications asso-
ciated 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 first 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 difficult 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 pharmaco-
kinetic interactions on the hepatic cytochrome P450 isoenzymes
that could lead to a dangerous build-up of clomipramine, espe-
cially with co-administered fluoxetine 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
8 N.A. Fineberg et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
clomipramine with fluvoxamine (Szegedi et al., 1996). In a rando-
mised open-label trial, nine pharmacotherapy-refractory patients
were given citalopram with clomipramine, and seven were trea-
ted with citalopram alone. Significantly larger improvements in
Y–BOCS 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 dose-
levels 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 fluoxetine with clomipramine was no more
effective than fluoxetine and placebo in SSRI non-responders
(Diniz et al., 2011). No controlled studies of the co-admini-
stration of different SSRIs have been published.
8.8.7. Novel agents, as monotherapy or augmentation strategies
The following compounds are under investigation for OCD and
have already shown some evidence of efficacy, but because they so
far lack convincing validation in controlled studies, they cannot at
present be judged to be effective. The glutamatergic compound,
memantine has appeared helpful as an adjunct to an SSRI in a few
open-label trials and two small randomized placebo-controlled
trials (Ghaleiha et al., 2013; Haghighi et al., 2013). Preliminary
results from open-label studies suggesting efficacy for riluzole
(Coric et al., 2005), another glutamate modulating agent, have so
far not been substantiated. In a placebo controlled trial of riluzole in
children with refractory OCD, no significant difference was noted on
any of the primary or secondary outcome measures (Grant et al.,
2014). The glutamatergic hypothesis has been further explored
through investigations of ketamine in OCD. A randomized con-
trolled cross-over trial of ketamine versus placebo infusion led to
435% reduction in YBOCS score in 50% of those infused with
ketamine (n¼8) (Rodriguez et al., 2013). However, in another 3-day
open label trial of ketamine in 10 subjects with refractory OCD and
depression there were no OCD responders and although depressive
symptoms improved, the post-baseline improvement in Y–BOCS
amounted to o12% (Bloch et al., 2012). Further, ketamine has to be
used cautiously, given its association with lower urinary tract
(bladder) damage (Winstock et al., 2012). The 5-HT3 receptor
antagonist ondansetron, administered in combination with fluox-
etine, demonstrated a superior effect over placebo plus fluoxetine
on the Y–BOCS in a randomized controlled pilot study in treatment-
resistant patients (Soltani et al., 2010). However, the results of an as
yet unpublished multicentre trial did not meet the primary efficacy
endpoint to demonstrate an improvement in OCD symptoms versus
placebo (Biotechnologyevents.com 2013). Mirtazapine as monother-
apy has been reported to significantly improve outcomes in a
placebo-controlled discontinuation study of 15 open-label mirtaza-
pine responders. In the 8-week, double-blind, placebo-controlled
discontinuation phase, the mirtazapine group's mean Y–BOCS score
fell a mean7S.D. of 2.678.7 points while the placebo group's
mean score rose a mean7S.D. of 9.177.5 points (Koran et al.,
2005). Clonazepam, as an adjunctive to an SRI, may produce
symptomatic benefit (Hewlett et al., 1992), possibly through
improving associated anxiety. It is less suitable in those with
previous history of benzodiazepine or other substance abuse or
dependence.
It has been suggested that antiepileptic mood stabilizers may, in
combination with an SSRI, have a role in the treatment of OCD, but
the supporting evidence at present is not strong and further placebo-
controlled trials are necessary. Positive results were obtained in a
small randomized controlled trial of lamotrigine (Bruno et al., 2012).
Randomized placebo controlled trials of topiramate augmentation
Please cite this article as: Fineberg, N.A., et al., Obsessive–compulsive 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
resulted in a therapeutic effect (reducing compulsions only) in one
study (Berlin et al., 2011) whereas another study (Mowla et al., 2010)
noted significant improvement in the topiramate as opposed to the
placebo group. Adjunctive pregabalin has been investigated in an
open-label case series only, with some signs of possible efficacy
(Oulis et al., 2011), as has gabapentin (Corá-Locatelli et al., 1998). A
randomized placebo-controlled trial of single dose d-amphetamine
produced short-lived benefits (Insel et al., 1983a), while another
randomized controlled trial comparing d-amphetamine and caffeine
intriguingly noted that both compounds were associated with rapid
improvement of obsessive compulsive symptoms within a week
(Koran et al., 2009), hinting that stimulants such as d-amphetamine
could play a role in treating OCD, possibly in the context of com-
orbid ADHD.
9. Somatic treatments in OCD
Failure to respond to the above pharmacological treatments,
including combination treatment with intensive in-patient and/or
home-based, or clinic-based, therapist-assisted CBT, may indicate
refractoriness to treatment. At this stage, if the symptoms remain
severe and incapacitating, it may be necessary to liaise with
specialist services offering somatic treatments such as deep brain
stimulation or neurosurgery.
9.1. Electroconvulsive therapy (ECT)
Evidence to support the use of ECT in OCD is limited due to sample
size and study design issues, with an absence of blinded controlled
trials. The UK National Institute for Health and Clinical Excellence
(NICE 2006) and the APA Practice Guidelines on OCD (Koran et al.,
2007) concluded that there is insufficient evidence on which to base a
recommendation for the use of ECT in the treatment of OCD, esp-
ecially given potential associated risks.
9.2. Repetitive transcranial magnetic stimulation (rTMS)
RepetitiveTMS modulates neuronal activity by inducing a mag-
netic field pulse. The inhibitory effect of rTMS on the increased
neuronal activity in the prefrontal subcortical circuits is hypothesized
to be beneficial in the treatment of OCD (Blom et al., 2011). A
systematic review of studies investigated the efficacy of rTMS in OCD
between 1996 and 2010 (Jaafari et al., 2012) and a recently published
meta-analysis (Berlim et al., 2013) obtained data from 10 randomized
controlled trials involving 282 subjects with OCD. The effect size for
pre-post Y–BOCS score was 0.59 (z¼2.73, p¼0.006) and the
response rates were 35% and 13% for patients receiving active and
sham rTMS respectively, suggesting promise in treating OCD. The
most promising target areas for stimulation included the orbitofron-
tal cortex and the pre-supplementary motor area. rTMS is generally a
safe and non-invasive form of treatment. Rarely, high-frequency
rTMS may induce seizures. Other reported side effects include loc-
alized pain, paresthesias, hearing changes, thyroid stimulating hor-
mone and blood lactate level changes, and hypomania; however,
these problems are usually transient (Blom et al., 2011). However,
there is presently insufficient evidence to support the use of rTMS as
a treatment for OCD, and it remains an experimental procedure.
9.3. Deep brain stimulation (DBS)
Deep brain stimulation (DBS) is a neurosurgical treatment that
involves the implantation of electrodes that send electrical impulses
to specific locations in the brain, with areas selected according to
the type of symptoms to be addressed. This approach permits focal,
relatively low risk, and relatively reversible modulation of brain
 N.A. Fineberg et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
circuitry. DBS may bring about therapeutic effects in OCD by
modulating the cortico–striatal neurocircuitry that is widely pro-
posed to mediate OCD (Bourne et al., 2012). Stimulation of the ven-
tral capsule/ventral striatum appears to improve mood, obsessions,
and compulsions, whereas stimulation of the sub-thalamic nucleus
may selectively improve compulsions (Milan et al., 2010). Small
studies with at best partially controlled designs have reported
significant overall average Y–BOCS decreases ranging from 6.8
to 31 points (in severely ill patients with baseline Y–BOCS scores
usually exceeding 30), and the average overall responder rate is
50%. The procedure is reported to be ‘relatively safe’ with limited
side effects (de Koning et al., 2011). However, adverse events have
been reported. In a study (Greenberg et al., 2006) that followed up the
3-year outcomes following bilateral stimulation of ventral capsule/
ventral striatum areas in 10 adult OCD patients meeting stringent
criteria for severity and treatment resistance, the following surgical
adverse effects were reported: asymptomatic hemorrhage, a single
seizure, and superficial infection. Psychiatric adverse effects included
transient hypomanic symptoms as well as worsening of depression
and OCD when DBS was interrupted. Acute adverse effects of DBS
included transient sadness, anxiety, and euphoria or giddiness. Anxiety
was more frequent with monopolar than with bipolar stimulation.
Suicide events were not noted when DBS was interrupted, and
cognitive events were described as relatively benign. At the present
time, DBS remains a highly experimental treatment, with evidence
largely based on case series.
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 ong-
oing research into the use of radiosurgical techniques such as the
gamma knife. There are two procedures that are offered by the int-
ernational centers involved in the provision of such therapies. Ant-
erior 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 con-
nections 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 cortico–striatal–tha-
lamic circuitry. Overall the available evidence suggests that such
procedures offer significant therapeutic benefits to 30–60% of pat-
ients 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 profile to that of anterior caps-
ulotomy. The quality of evidence supporting each procedure is
reflective of neurosurgery as a whole. There are no randomized con-
trolled trials, and most data is derived from prospective case series
and small unblinded cohort studies. Surgical intervention is there-
fore 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 efficacy 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 treat-
ment. 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
Please cite this article as: Fineberg, N.A., et al., Obsessive–compulsive 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
9
fail to reach symptomatic remission. A trial of combined CBT plus
SSRI treatment would be appropriate for those patients failing to
respond adequately to SSRI monotherapy. Research in other psychia-
tric disorders suggests that in order to achieve optimal outcomes, not
only do clinicians need to prescribe treatments appropriately but
they should also encourage and confirm satisfactory treatment-
adherence, which requires adequate clinical follow-up and review
(Demyttenaere et al., 2001). It is important that clinicians ensure that
patients are appropriately informed about the benefits and risks of
continuing SRI treatment and that the risks of SRI discontinuation are
fully discussed. If necessary, discontinuation should be planned
carefully, with rescue strategies identified in advance. In those cases
where response to treatment is inadequate, various pharmacological
strategies could be considered, of which, augmentation of SRI's with
adjunctive second generation antipsychotic seems to be the most
efficacious option, based on the available evidence. Non-pharm-
acological somatic treatments may play a role for those who do
not respond to psychopharmacological and CBT (refractory cases).
DBS and rTMS, though promising, remain experimental. Ablative
neurosurgery remains the last resort for a small group of severely ill
patients who do not respond to expert delivered trials of pharma-
cotherapy and CBT of optimal dosage/content, duration, and mode
of delivery as assessed by experienced experts in specialty treat-
ments for OCD.
Acknowledgments
The authors are members of the Accreditation Task Force of The
Canadian Institute for Obsessive Compulsive Disorders. Several
authors are members of the European College of Neuropsychophar-
macology Obsessive Compulsive and Related Disorders Research
Network and the International College of Obsessive Compulsive Dis-
orders, which bodies facilitate the exploration of these issues. Dan
Stein is supported by the Medical Research Council of South Africa.
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