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Obsessive– compulsive disorder (OCD): Practical strategiesfor pharmacological and somatic treatment in adults $

Naomi A. Fineberga ,b ,c,n , Samar Reghunandanan a , Helen B. Simpson d ,e ,Katharine A. Phillips f , Margaret A. Richterg , Keith Matthews h , Dan J. Steini, Jitender Sareen j, Angus Browna , Debbie Sookmank

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, Hat eld, 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, USAe Anxiety Disorders Clinic and the Centre for OCD and Related Disorders at the New York State Psychiatric Institute, New York, NY, USAf 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,Canadah 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, Canadak Obsessive Compulsive Disorder Clinic, Department of Psychology, McGill University Health Centre, and Department of Psychiatry, McGill University,Montreal, PQ, Canada.

a r t i c l e i n f o

Article history:Received 30 June 2014Received in revised form

26 November 2014Accepted 4 December 2014

Keywords:ObsessiveCompulsivePharmacotherapy

a b s t r a c t

This narrative review gathers together a range of international experts to critically appraise the existingtrial-based evidence relating to the ef cacy and tolerability of pharmacotherapy for obsessivecompulsive disorder in adults. We discuss the diagnostic evaluation and clinical characteristics followedby treatment options suitable for the clinician working from primary through to specialist psychiatriccare. 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 theuse 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, includingablative lesion neurosurgery and deep brain stimulation, are reserved for severely symptomaticindividuals who have not experienced sustained response to both pharmacological and cognitivebehavior therapies.

& 2015 Published by Elsevier Ireland Ltd.

1. Introduction

Obsessive– compulsive disorder (OCD) is a common and oftenenduring neuropsychiatric disorder. It affects 2 – 3% of the adultpopulation (and 1% of children) regardless of ethnicity, geographyor socioeconomic status (Robins et al.,1984; Weissman et al., 1994;Heyman et al., 2003; Wittchen and Jacobi, 2005). The magnitudeof psychosocial impairment is high (Hollander et al, 2010). OCD isan illness that is poorly recognized and patients usually present fortreatment late in the course of the disorder. The average durationof untreated illness has been reported to be as long as 17 years(Hollander and Wong, 1998). Treatment delay is associated with a

Contents lists available at ScienceDirect

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

Psychiatry Research

http://dx.doi.org/10.1016/j.psychres.2014.12.0030165-1781/ & 2015 Published by Elsevier Ireland Ltd.

☆ Disclaimer The advice we are providing is as accurate and comprehensive aspossible but it is only general advice and it is up to doctors reading this article tomake their own clinical judgment when interpreting the information and decidinghow best to apply it to the treatment of patients. Patients should not use thisinformation as a substitute for the individual advice they may receive fromconsulting their own doctor

n Corresponding author at: National Obsessive Compulsive Disorders SpecialistService, Hertfordshire Partnership University NHS Foundation Trust, Queen Eliza-beth II Hospital, Welwyn Garden City, Hertfordshire AL7 4HQ, UK.

E-mail address: naomi. [email protected] (N.A. Fineberg).

Please cite this article as: Fineberg, N.A., et al., Obsessive– compulsive disorder (OCD): Practical strategies for pharmacological andsomatic treatment in adults. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2014.12.003 i

Psychiatry Research ∎ (∎∎∎∎ ) ∎∎∎ – ∎∎∎

http://www.sciencedirect.com/science/journal/01651781http://www.elsevier.com/locate/psychreshttp://dx.doi.org/10.1016/j.psychres.2014.12.003mailto:[email protected]:[email protected]:[email protected]://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003mailto:[email protected]://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://dx.doi.org/10.1016/j.psychres.2014.12.003http://www.elsevier.com/locate/psychreshttp://www.sciencedirect.com/science/journal/01651781


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poorer outcome, whereas effective pharmacological treatmentimproves health-related quality of life (HRQOL), highlighting theimportance of early diagnosis and intervention. Relapse, on theother hand, is associated with loss of HRQOL (Hollander et al,2010), emphasizing the importance of relapse prevention inmaintaining 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 treatmentfailure’ seems to be a common cause for apparent refractoriness — thatis, patients have not received an adequate dose, duration or type of treatment. This article synthesizes the available evidence relating topharmacotherapy in adults, from the perspective of the clinician, forclinicians working in primary care, and for specialist psychiatricservices. We extend our review to consider the referral of treatment-refractory cases for neurosurgical treatment at highly specialisedcenters. If pharmacological treatment delivery, according to the bestavailable evidence, can be optimized, it is to be hoped that the overallstandard 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 ineffective treatment. Patients can be reluctant to discuss their symp-toms, and the diagnosis is often missed. Clinicians therefore need to bevigilant and proactively inquire about symptoms of OCD in patientspresenting with affective and anxiety syndromes, since OCD isfrequently comorbid with these disorders, and in their presence, thediagnosis could be missed (Fullana et al., 2009). Obsessive– compulsive(OC) symptoms are also common in patients with schizophrenia, aff-ecting around one fth of cases (Mukhopadhaya et al., 2009; de Haanet al., 2013). OCD is highly familial, and roughly 10% of rst degreerelatives of adult OCD probands are themselves affected (Pauls et al.,1995). Signi cantly higher rates of OCD (approximately 20%) are rep-orted in the relatives of childhood-onset cases ( Pauls, 2010). Recent

ndings, that individuals with OCD from families where multiplemembers are affected are less likely to present for treatment (Dell'Osso, 2012 [Oral Presentation ICOCS]), suggest that the clinician shouldpay particular attention to the possibility of untreated disorder in thefamily members of existing OCD patients, for whom ‘normalization ’ ordenial of pathology may occur.

The Mini International Neuropsychiatric Interview (MINI) (Sheehanet al., 1998) is a well-validated structured screening interview that iscompatible with ICD-10 and DSM-IV. It has the advantage of havingbeen translated into several languages. Ultra-brief screening instru-ments, such as the ve-item Zohar-Fineberg OC Screen, may also be of value to identify people with an increased likelihood of OCD, and mayalso 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 (Fineberget al., 2008).

3. Diagnosis: DSM-IV, DSM-5, ICD-10 and new developments

Contemporary pharmacological treatment trials have relied on theDSM-IV (American Psychiatric Association, 1994) for diagnosis andrecruitment. Thus, ‘evidence-based ’ pharmacotherapy is largely basedupon establishing ef cacy in patients with DSM-IV OCD. There aresome shortcomings in the DSM-IV OCD criteria, such as lack of agreement on where to place the diagnostic threshold, differentiationof speci c 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

disorders, including BDD (body dysmorphic disorder), hoardingdisorder, 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 separateDSM-5 category of ‘obsessive – compulsive and related disorders ’(Leckman et al., 2010; American Psychiatric Association, 2013). Onlyfairly minimal changes were made to the diagnostic criteria in DSM-5.However, two substantive changes were made to speci ers as

follows: (1) addition of a speci er for patients with a current or pasttic 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 speci er to include good or fairinsight, poor insight, and absent insight/delusional OCD beliefs.

The World Health Organization's International Classi cation 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 lessprescriptive, which may provide added utility for the clinician butmay also reduce speci city. For instance, the ICD-10 does notexpressly exclude ‘worries about real life problems ’ (as in general-ized anxiety disorder) and does not require obsessions to be timeconsuming, thereby relaxing the threshold for the ICD-10 diag-nosis relative to DSM-IV and DSM-5 and allowing inclusion of lesssevere cases or those with an overlap with anxiety-related worriesor mood-related ruminations.

4. Evaluating symptom severity, global disability, andfunctional impairment

The Yale– Brown Obsessive– Compulsive Scale (Y – BOCS)(Goodman et al., 1989a, 1989b) has emerged as the pivotal ratingscale for OCD severity in adults and has been used to evaluateef cacy for most of the available pharmacological treatments.The Y – BOCS is a 10-item observer-rated instrument. It has beenadapted as a self-rated tool ( Steketee et al., 1996). It measures theoverall severity of obsessions and compulsions separately and incombination. Items include duration, interference, distress, abil-ity to resist and control. Of these, the item measuring resistanceis 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 isrelatively brief and sensitive to change and has established util-ity in measuring clinical progress in the clinical as well as theresearch setting.

Other scales that may be used as alternative OCD-outcomemeasures, and that have also been shown to be sensitive to changein OCD populations, include the Comprehensive PsychopathologicalRating Scale (CPRS) OCD scale (Åsberg et al., 1978), the NationalInstitute for Mental Health Global Obsessive– Compulsive Scale (Inselet al., 1983b), the Dimensional Y – BOCS (Rosario-Campos et al., 2006),which allows evaluation of individual OCD dimensions, and theObsessive– Compulsive Inventory-Revised (OCI-R) (Foa et al., 2002).Complementary instruments that have been used in OCD populationsinclude the Clinical Global Impression Severity and ImprovementScales (Guy, 1976), Sheehan Disability Scale (SDS) (Sheehan et al.,1996) and the Medical Outcomes Survey 36-Item Short Form SurveyInstrument (SF-36) (Ware and Sherbourne, 1992 ), which measure,respectively, global illness severity and improvement, illness-relatedpsychosocial impairment and health-related quality of life. OCD isassociated with considerable functional impairment and executivedysfunction. The Cognitive Assessment Instrument of Obsessions andCompulsions (CAIOC-13) (Dittrich et al., 2011) is a new scale designedto measure OCD-related functional impairment in the clinical setting.

Its sensitivity to change has not yet been evaluated.

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5. De ning treatment-response, remission, recovery, relapseand resistance

Substantial improvement can be achieved in many patients, butfor approximately 50% the treatment response is incomplete.Pallanti et al. (2002) advocated the use of standardized operationalcriteria across treatment trials, proposing that a meaningful clinicalresponse could be conservatively represented by an improvement

of25–

35% in the baseline Y –

BOCS score, or a score of ‘

much’

or‘

verymuch improved ’ on the Clinical Global Impression of ImprovementScale. According to Pallanti et al. (2002), ‘remission ’ necessitated atotal Y – BOCS score of less than 16 (out of a total scale score of 40).‘Partial response ’, in contrast, was de ned as an improvement inbaseline Y – BOCS scores of 25– 35% and ‘relapse ’ following a periodof 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 notrepresent clinical remission as de ned by many clinician/research-ers: patients meet the criteria for admission into some studies atthis level. Stein et al. (2007) proposed a more stringent remissioncriterion, requiring the total Y – BOCS score to be reduced to 10 orless, and in the eld of CBT, Sookman and Steketee (2010) de nedremission as no longer meeting OCD DSM criteria and a YBOCSscore ¼ or o 7.

The de nition of a meaningful clinical response or remission andthe concept of ‘relapse ’ continue to spark debate and can be dif cultto apply to an illness that usually has a chronic uctuating course ora progressively worsening course when untreated, and shows onlypartial response to long-term pharmacological treatment ( Simpsonet al., 2006; Farris et al., 2013). Plausible relapse criteria include aworsening of post-baseline Y – BOCS of Z 50%, a ve-point worsen-ing of the total Y – BOCS score, a, total Y – BOCS scoreZ 19, and CGI-Iscores of ‘much ’ or ‘very much worse ’ (Fineberg et al., 2007a,2007b). All these different de nitions used in the eld can lead tovery different claims about ef cacy and about relapse (Simpsonet al., 2005).

Hollander et al. (2010) attempted to validate the previouslyempirical responder and relapse criteria ( Pallanti et al., 2002) bycorrelating functional disability (using the SDS) and health-rela-ted quality of life (HR-QoL) (using the SF-36) with Y – BOCS scorechanges. A statistically signi cant and clinically relevant distinctionin functioning/HR-QoL measures was observed between respondersand non-responders when treatment-response was de ned as atleast 25% improvement in the Y – BOCS score relative to baseline.This indicates that a 25% improvement in the baseline Y – BOCS is aclinically relevant change and represents a minimal partial resp-onse. Likewise, relapse, when de ned as a ve-point worsening of the remission Y – BOCS correlated with a signi cant deterioration inHR-QoL and social function; patients who relapsed according to thiscriterion had statistically signi cantly poorer outcomes on the SDSand SF-36 than those who did not ( Hollander et al., 2010). However,this approach has limitations when starting with a very low Y – BOCSscore and, importantly, a 25% improvement rate often re ects con-tinued substantial symptomatology.

Levels of ‘treatment resistance ’ have been de ned according tothe numbers of failed treatments ( Pallanti et al., 2002), and theterm ‘ treatment refractory ’ has been reserved for those who do notrespond to ‘all available treatments. ’ A drawback of the latter app-roach is that it is currently unclear which speci c evidence basedtreatments ‘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,

given that dimensions may determine treatment outcome. Of thedimensions so far identi ed, 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 isoften ‘ego-syntonic ’, and the Y – BOCS is not a specic measure of this disorder. Frost et al. have developed speci c measures forhoarding (Frost et al., 2012). Analysis of one large trials database

indicates that the ‘

hoarding/symmetry’

dimension predicts a pooreroutcome to SSRI treatment compared with other OCD dimensions(Stein et al., 2008). Nevertheless, the responsiveness of hoardingsymptoms to pharmacotherapy remains unclear, given other studiessuggesting positive outcome for select patients ( Saxena, 2011).

Research into the ‘ early onset ’ OCD subtype has been hamperedby the use of different age limits for its de nition (Mataix-Colset al., 2010) and uncertainty around the developmental stability of obsessive– compulsive symptoms. Also, it is unclear whether thissubtype refers to those with an early onset of sub-clinical symp-toms or the full disorder. There is a signi cant confounding effectbetween early onset OCD, duration of untreated illness and tic-related OCD (see below). Research has shown that children withearly 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 youngpeople 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 attentionde cit hyperactivity disorder (ADHD), oppositional de ant disor-der, and trichotillomania (reviewed and referenced in Geller et al.(2012)). A preponderance of symptoms such as symmetry andordering/arranging compulsions has been noted in individualswith this subtype across many cultures. In a large Brazilian adultcohort, OCD patients with comorbid tic, compared to those with-out tic, showed more aggressive, sexual/religious and hoardingsymptoms, were more likely to be males, and showed increasedlevels 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-behavioralinterventions, 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 planningtreatment, although unfortunately studies that focus on OCD withcomorbid disorders are few, and we do not have robust evidence toguide us. Anxiety and affective disorder occur in over half of treatment-seeking cases. Compounds with a ‘broad spectrum ’ of anxiolytic and antidepressant ef cacy, such as SSRIs and clomipra-mine, may be of considerable value in these cases. A study byHoehn-Saric et al. (2000) showed preferential ef cacy for the SSRIsertraline over the non-SRI desipramine in depressed patients withOCD, emphasizing the importance of choosing a compound withintrinsic ef cacy in OCD in the presence of co-morbid disorder.

There is increasing recognition of the prevalenceof bipolar affectivesymptoms and emotional lability in some patients with OCD ( Fineberget al., 2013a). For cases with such comorbidity, adjunctive treatmentwith mood stabilizers — e.g., topiramate (Berlin et al., 2011) or quetia-

pine (Denys et al., 2004) could be helpful, although there is as yet

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insuf cient clinical trials' evidence to speci cally recommend their usein patients with comorbid OCD. Substance use disorders have beenfound to occur at relatively high rates in some epidemiological OCDsamples (Ruscio et al., 2010), but their prevalence in clinical cohorts isnot usually reported as being elevated (reviewed in Fineberg et al.(2013a)). ADHD rates may also be elevated (Geller et al., 2007). Forexample, in a selected sample of individuals with childhood-onsetOCD with and without co-morbid tic, ADHD rates were elevated

compared to the general population rate, and there was a strongassociation between ADHD and clinically signi cant hoarding behavior(Sheppard et al., 2010). Putative obsessive– compulsive spectrumdisorders, 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 thesedisorders on treatment outcome in the comorbid patient is not wellunderstood.

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). ObsessiveCompulsive symptoms may have their onset during treatment withsecond generation antipsychotics (such as clozapine) in schizophre-nia. This could be related to their serotonin receptor antagonisticeffects suggesting a pharmacodynamic mechanism as a possibleetiology for the origin of these symptoms ( Schönfelder et al., 2011;Schirmbeck and Zink, 2012). It remains unclear to what extenttreatment with pharmacotherapy or CBT can be helpful in thesecomorbid 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 (Schönfelderet 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 andupdated by some of the coauthors ( Fineberg and Brown, 2011;Fineberg et al., 2012, 2013c). Placebo-referenced ef cacy in adulthoodOCD has been established for the available SSRIs (uvoxamine,

uoxetine, sertraline, paroxetine, citalopram and escitalopram) in alarge series of studies spanning nearly 20 years (reviewed andreferenced in Fineberg et al. (2012)). A meta-analysis of SSRI versusplacebo that included 17 selected studies (3097 participants) unequi-vocally demonstrated the ef cacy of SSRIs in OCD (Soomro et al.,2008). The above analysis indicated that SSRIs are nearly twice aslikely as placebo to produce a clinical response (de ned as a Z 25%reduction in Y – BOCS from baseline). Evidence for the ef cacy of clomipramine as an ef cacious agent in adults and children and itssuperiority 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 relativeto clomipramine, head-to-head comparison studies tend to demon-strate equivalent ef cacy (reviewed and referenced in Fineberg et al.(2005, 2012)). SSRIs, compared to clomipramine, have better overallacceptability and tolerability and for this reason SSRIs are generallythe preferred option for rst-line treatment when compared toclomipramine. For this reason, the UK National Institute for Healthand Clinical Excellence (NICE) (2006) recommended an SSRI as rst-line treatment, with clomipramine reserved for those patients whoeither fail to respond or cannot tolerate an SSRI. The American

Psychiatric Association Practice Guidelines (Koran et al., 2007; Koran

& Simpson., 2013) also recommend an SSRI as the rst line of treatment.

8.2. Which SSRI?

There is insuf cient evidence to support the superior ef cacy ortolerability of any one SSRI in OCD. An underpowered single-blindstudy (Mundo et al., 1997) did not detect differences between

uvoxamine, paroxetine, or citalopram with just 10 patients pergroup. In a double-blind comparison study of sertraline ( n ¼ 77) anduoxetine (n ¼ 73) (Bergeron et al., 2001), no signi cant difference

was seen at the 24-week end-point on any primary ef cacy measure.However there was a non-signi cant trend towards an earlier effectin the sertraline group, and a greater number of sertraline-treatedpatients reached remission, de ned as a CGI-I score r 2 and aY – BOCS score r 11. In a 24-week study by Stein et al. (2007), sym-ptomatic improvement on escitalopram 20 mg/day and paroxetine40 mg/day appeared similar from the 12-week primary endpointonwards.

SSRIs do, however, differ from one another in terms of theselectivity and potency of effect at the serotonin transporter andtheir secondary pharmacological actions ( Stahl, 2008), and conse-quently one might predict differences in clinical ef cacy and adverseeffect pro le in OCD. Fluoxetine may be preferred in those with poortreatment adherence, such as highly impulsive individuals, in view of its long half-life. Also it tends to have only mild discontinuationeffects and, together with sertraline, is thought to be associated withthe least weight gain of the SSRIs (Serretti and Mandelli, 2010). Incontrast, discontinuation effects are particularly evident with parox-etine. Sertraline, citalopram, and escitalopram constitute a rationalchoice if cytochrome P450-related drug interactions are relevant. Therecent demonstration of prolongation of the ECG QT interval asso-ciated with higher dose-levels of citalopram (and to a lesser extentescitalopram) (FDA Drug Safety Communication, 2013) argues for adegree of caution in using higher doses of citalopram in OCD,especially if individuals are taking other medications that increasethe QT interval. However, a recent large study found no elevated riskof ventricular arrhythmia or all-cause, cardiac, or non-cardiac mor-tality associated with citalopram doses exceeding 40 mg/day ( Zivinet al., 2013), casting doubt on this warning.

8.3. Which dose?

The SSRIs uoxetine, paroxetine, sertraline, citalopram, andescitalopram have each been investigated in multiple, xed dosestudies. A positive dose– response relationship has been noted for

uoxetine, paroxetine, and escitalopram (reviewed and referencedin Fineberg et al., 2012 (2013c)). Paroxetine is effective at doses of 40 mg/day and 60 mg/day (Hollander et al., 2003a). Similar resultswere reported for uoxetine, with the greatest bene t observedwith the 60 mg/day dose ( Montgomery et al., 1993; Tollefson et al.,1994), which was also signi cantly 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 ef cacious than10 mg/day (Stein et al., 2007). The dose– response relationship isless 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 ef cacy and tolerability using a xed effects model.High SSRI doses were associated with greater ef cacy than low ormedium doses, using Y – BOCS score or proportion of responders asoutcome measures ( Bloch et al., 2010).

No dose– response relationship has been demonstrated foruvoxamine or clomipramine. Fluvoxamine has been shown to

have signi cant effect over placebo at doses ranging from 150 to

300 mg/day. Single dose studies have shown ef cacy compared





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with placebo for relatively low xed clomipramine doses (75 mg/day and 125 mg/day) (Montgomery et al., 1980). However, con-trolled studies also demonstrate ef cacy and tolerability for dosesas high as 300 mg/day of clomipramine (DeVeaugh-Geiss et al.,1989) and 80 mg/day uoxetine ( Jenike et al., 1997; Liebowitz etal., 2002). As clomipramine is associated with clinically relevantcardiotoxicity and lowers the seizure-threshold, this compoundshould 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 Fineberget al. (2012)). Exacerbation of anxiety in the early stages of OCDtreatment is uncommon. However, irrespective of dose, improve-ment can take several weeks or months to develop. Althoughstudies may show small changes in symptom scores early intreatment, these do not usually become clinically meaningful untillater in treatment; indeed it can be many weeks or several monthsbefore gains are recognized by the patient. Therefore, the patientshould be advised to persevere with treatment, despite little imm-ediate evidence of change. As observable bene ts may not appearfor 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 beattempted. The British Association for Psychopharmacology (Baldwinet al., 2005, 2014) suggests initial treatment periods beyond 12weeks may be needed to assess ef cacy. The guidelines suggest sta-rting with the lowest ef cacious daily dosage of SSRIs, which may beincreased in the face of insuf cient response at a lower dosage.However, a drawback of a slow titration approach is that if a higherdose is needed, it could take a long time to achieve a response, whichcould be problematic, especially with more severely ill patients. Incontrast, the APA guidelines (Koran et al., 2007) recommend upwardtitration of SSRI doses to maximum FDA-approved doses by 4– 6weeks, 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 maynot go on to respond to treatment. As the treatment effect takesconsiderable time to develop, it is important to ensure (a) that anadequate trial of treatment has been achieved, so as to avoidpremature discontinuation of a treatment that could turn out to beeffective, and (b) that methods for evaluating the clinical responseare 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 enhanceadherence ( Santana et al., 2010).

Routine baseline assessment is recommended. Following the initialtreatment phase, reassessment allows differentiation into catego-ries based on degree of response — e.g., ‘full response’ (4 35% Y – BOCSchange), partial response (25 – 35% Y – BOCS change), no response(o 25% Y – BOCS change) (Pallanti et al., 2002). In the event of a full

response, treatment may be continued into a maintenance phase (see

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 withcognitive behavior therapy (CBT) for OCD. In the case of sustainedpartial response or no response, a trial of another SSRI or clomipra-mine (also see below) could be considered and similar strategies as inthe case of the rst trial may be followed.

However, decisions about further treatment should re ect notonly the percent improvement in symptoms but also the severity

of remaining symptoms. For example, if a patient's symptoms areinitially very severe, even a response of 4 35% magnitude may stillre ect fully symptomatic ongoing OCD; in such cases, the clinicianwill want to pursue additional treatment with the aim of furtherimproving 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 anotherpharmacological treatment (see sections 8.8.1 to 8.8.7), even at anearly stage of treatment-resistance.

8.6. Combined CBT and pharmacotherapy

Although many specialist centers offer combined treatment, thedegree to which adding CBT to SSRI improves outcomes compared tomonotherapy, either in the short-term or the long-term, is animportant area of continued investigation. Evidence indicates thatpatients who respond only partially to an SRI fare better, compared toSRI 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 stillunclear whether both treatments carried out simultaneously from thestart have any advantage over implementing just one or the other. Forexample, some studies suggest that combined CBT and pharma-cotherapy out-performs CBT monotherapy, whereas other studiesreported that there is no difference (reviewed in Fineberg and Brown(2011)). The APA Practice Guidelines (Koran et al., 2007; Koran andSimpson, 2013) suggest using either an SRI or CBT alone as rst-linetreatment. According to a cost-effectiveness analysis, the UK NICEguidelines (NICE 2006) recommend the use of combined CBT plusan SRI only in more severe or treatment-resistant cases.An 8-weekacute-phase randomized controlled study in 108 adults with OCD andpartial SSRI response (Simpson et al., 2008) demonstrated that theaddition of 17 sessions of twice a week CBT with exposure andresponse prevention to SSRI was superior to the addition of stressmanagement training. Thus, at the very least, a trial of combined CBTplus SSRI treatment would be appropriate for those patients failing torespond adequately to SSRI monotherapy. However, as these andother authors have pointed out,17 sessions were not suf cient to helpmost of these patients achieve minimal symptoms and longer trials of CBT would be indicated. A follow-up study investigated respondersfrom this study treated with up to 24 weeks of maintenancetreatment ( Foa et al., 2013). The difference in Y – BOCS scores betweentreatment conditions remained signi cant and similar in magnitudeat 8 weeks and 24 weeks later (total Y – BOCS score in those receivingExposure and Response Prevention versus Stress Management Train-ing: at 8 weeks: 14.3 versus 22.7; p o 0.001 and at 24 weeks: 14.69versus 21.37; p ¼ 0.005), further strengthening support for the role of combination therapy in individuals who had a partial response to SRImonotherapy. However, there was no between-group difference inthe rate of change in Y – BOCS scores during the maintenance phaseand the proportion of responders who entered the maintenancephase and who maintained their response status did not signi cantlydiffer between the two treatment groups. The observed group diff-erence at the end of the maintenance phase may thus be attributed tothe group difference after acute treatment, which was sustained

during the maintenance phase.





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8.7. Relapse prevention (continuation and maintenance treatment)

The natural course of OCD was traditionally considered to bechronic and relapsing, and follow-up studies in clinical cohortssuggested that remission is uncommon ( Eisen et al., 2013). How-ever, a recent epidemiological study suggests that approximately50% of community-based cases followed up for approximately 30years appear to have achieved remission by the age of 50 years,

noting that only a minority (40%) sought professional treatmentfor their OCD (Fineberg et al., 2013b). More severe illness and alonger duration of illness were both associated with a lowerlikelihood 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 longitudinalstudy by Eisen et al. (2013), participants with primary obsessionswere more likely to experience a remission, whereas those withprimary hoarding were less likely to remit, and over half of theparticipants who remitted subsequently relapsed. Participantswith obsessive – compulsive personality disorder were more thantwice as likely to relapse. Participants were also particularly vuln-erable to relapse if they experienced partial remission rather thanfull remission, emphasizing the importance of achieving full rem-ission as a treatment target.

A series of controlled studies in adults with OCD have shownthat, irrespective of duration of treatment (up to 2 years), disconti-nuation of pharmacotherapy is usually, but not always, associatedwith symptomatic relapse (reviewed in Fineberg et al. (2013c)). Inthe early clomipramine studies, symptoms re-emerged within a fewweeks of stopping medication, whereas improvement to a levelnear to that prior to discontinuation was achieved by reinstatementof clomipramine (reviewed in Fineberg et al. (2007c)). In contrast,the placebo-controlled relapse prevention studies of SSRIs in OCDproduced mixed results. Studies with sertraline ( Koran et al., 2002)and uoxetine (Romano et al., 2001), which may have been under-powered, did not nd a signi cant difference between continuationtreatment on active drug or placebo, although patients remainingon higher (60 mg/day) uoxetine doses showed signi cantly lowerrelapse rates than those on placebo ( Romano et al., 2001). More-over, continued improvement in Y – BOCS, NIMH-OC, CGI scores, andquality-of-life measures was associated with sertraline treatment asopposed 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) andescitalopram (Fineberg and Craig, 2007a). A meta-analysis detectedoverall superiority of SSRIs compared to placebo in preventingrelapse amongst adult treatment responders ( Fineberg et al.,2007c). Viewed collectively, the results suggest that SSRIs areeffective at preventing relapse and that medication, as long as it iscontinued, confers protection against relapse. Moreover evidencealso suggests a positive impact of maintenance SSRI treatment (asopposed to discontinuation) on quality of life and psychosocialfunctioning (Hollander et al., 2010).

Thus, relapse prevention, through the continuation of pharma-cotherapy, represents a rational treatment target for OCD patientswho have responded to an SSRI or clomipramine. Guidelines (Koranet al., 2007) from the American Psychiatric Association (APA) reco-mmend continuation of pharmacotherapy for a minimum of 1 – 2years 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 strategyin the long-term management of OCD. The observation that a60 mg/day dose of uoxetine appeared the most effective (com-pared with 20 mg/day and 40 mg/day; 80 mg/day was notincluded) 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,

discontinuation should be gradual: the APA guidelines suggestreducing the dose by decrements of 10 – 25% every 1– 2 monthswhile observing for symptom return or exacerbation, in whichcase 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 reviewof the diagnosis is warranted along with assessment for co-morbiddisorders that might be interfering with the treatment-response.Investigations to rule out neurological or medical illnesses that maybe contributing to obsessive – compulsive symptoms — e.g., Sydenham'schorea, Tourette's syndrome, autistic spectrum disorder, or Parkin-son's disease in older adults — may also be warranted. ‘Technicaltreatment failure ’, representing a lack of adequate response totreatment 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 tocheck adherence to treatment is therefore important. Plasma levelmonitoring may also be helpful— e.g. in case of abnormal SSRI-

metabolism. Pharmacogenetic testing for metabolic enzymes suchas the cytochrome P450 enzymes 2D6, 1A2 and 2C19 is showingpromise, but requires further validation as a clinical tool and as yet isnot widely used or available(Mrazek., 2010; Brandl et al., 2012; Brandlet al., 2014). Alliance with the patient's family is important, includingdiscussion of accommodation with the patient's rituals.

Pharmacotherapy treatment options for SSRI-resistant OCDinclude the following. These options are presented in no particularorder. 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 licensingauthorities ( Koran et al., 2007). In these circumstances, it isadvisable to explain to the patient that these doses are ‘off-label’and to obtain and document informed consent. However, the datasupporting this strategy is limited. A retrospective case-note sur-vey of 26 patients with OCD on various SSRIs noted that, at the lastassessment, patients on high-dose SSRI-treatment showed signi -cant within-group improvement compared to baseline (Y – BOCS25.35 versus 20.95), although endpoint scores for the high-dosegroup remained signi cantly higher than those of a control groupof patients not requiring high-dose treatment. High dose SSRI wasalso well tolerated (Pampaloni et al., 2010). Two 16-week openlabel studies tested a higher than usual dose of escitalopram. Thestudy by Rabinowitz et al. (2008) noted that 64% of patientreceiving 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 (doserange 35– 50 mg) responded to treatment. A randomized con-trolled (non-placebo) study that compared two sertraline dosesnoted greater symptom improvement in those given 400 mg com-pared to those given 200 mg daily and both doses were welltolerated ( Ninan et al., 2006).

The APA OCD guideline (Koran et al., 2007, reviewed in Koranand Simpson (2013)) provides a list of upper doses that areoccasionally prescribed. For ‘fast-metabolizers ’ or those who havefailed to respond to conventional doses and are not experiencingundue 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 uoxetine, 450 mg/day of uvoxamine,





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100 mg/day of paroxetine and 400 mg/day of sertraline. Theauthors' clinical experience is consistent with these recommendeddoses; such doses seem most warranted when the patient has had apartial response to a lower dose and is tolerating the medicationwell. However, such an approach is not without risk. In the case of some SSRIs— e.g., citalopram and perhaps also escitalopram, whichare recognized to have a dose-dependent effect on extending theECG QT interval (although, a recent study did not show an elevated

cardiac risk on higher doses of citalopram (Zivin et al., 2013)), and inthe elderly or those with a cardiac history, caution should be exe-rcised if exceeding the licensed daily dosage and it may be advisableto monitor for adverse effects on cardiac conduction (e.g., by ECGmonitoring). The elderly may also be susceptible to SSRI-inducedelectrolyte disturbances and bleeding tendencies, and for those onanticoagulant therapy, especially if using high-dose uoxetine, theInternational Normalized Ratio (INR) may require more stringentmonitoring.

8.8.2. Trial of clomipramineAnother option would be to consider a trial of clomipramine.

While clomipramine is known to be as effective as SSRIs, the adverseeffect pro le 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 maximumof 250 mg daily should be prescribed with caution, and ECG andplasma level monitoring considered ( Szegedi et al.,1996). However, inthe event of a partial response, the option of increasing the dosageabove licensed limits up to 300 mg daily could be considered, asdosages of 300 mg daily of clomipramine have been systematicallyinvestigated in OCD and found to be acceptable (DeVeaugh-Geisset al., 1989).

8.8.3. Switch between SRIs/switch to SNRI If the response to the rst SSRI is inadequate (assuming good

adherence), or the patient fails to tolerate it, switching to anotherSSRI 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, andproposed 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 sixshould be at maximum tolerated dose, before augmentation orswitching to another SSRI is considered. However, it may some-times be appropriate to persist for longer than 12 weeks with agiven SRI, even in patients who show little improvement, since aclinical response may occur after several months ( Rasmussen et al.,1997). There have been no placebo-controlled studies demonstrat-ing ef cacy 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 onepositive result from a randomized placebo-controlled trial ( Fineberg& Brown., 2011). However, this strategy is effective in only roughlyone third of cases (Bloch et al., 2006). The bene cial effects arerelatively rapid in onset (e.g., 2– 4 weeks), and therefore prolongingexposure to adjunctive antipsychotics, if they do not appear to behelping, 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

risperidone ( Dold et al., 2013). However, a recent randomized pill-placebo controlled comparison of adjunctive risperidone and CBTnoted that those given CBT and SSRI performed better than thosegiven risperidone and SSRI (Simpson et al., 2013). In a single-blindhead-to-head comparison, adjunctive risperidone was associatedwith relatively more sexual adverse effects, whereas olanzapine wasassociated with metabolic effects and weight gain in OCD patients(Maina et al., 2008).

The choice of adjunctive antipsychotic agent may depend onthe SSRI being used. For example, uoxetine/clomipramine mayinteract pharmacokinetically with risperidone. Dose- nding stu-dies of antipsychotic in OCD have not so far been performed. How-ever, the studies that investigated these compounds according tothe 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 antipsychotictreatment is required. Some evidence, including from naturalisticfollow-up data (Marazziti et al., 2005; Matsunaga et al., 2009),suggests that if the patient has responded there may be bene t incontinuing 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 anantipsychotic to their SRI, subsequently relapsed when the anti-psychotic was withdrawn. Following 12 months of successfulantipsychotic treatment, individualized collaborative care-plan-ning, taking account of treatment-tolerability, symptom pro le(e.g., the presence of tic), and history of relapse, may helpdetermine whether discontinuation of the antipsychotic is appro-priate. For those opting for long-term adjunctive antipsychoticwith a second-generation agent, metabolic monitoring may beadvisable. 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 reportsof de novo production or exacerbation of obsessive compulsivesymptoms with second generation antipsychotic in patients withschizophrenia (Schirmbeck and Zink 2012). However it is unclearwhether the same applies to patients with OCD in the presence of concomitant SRI treatment.

8.8.5. Parenteral SSRI or clomipramineThe intravenous administration of a compound increases its

bioavailability by by-passing rst pass hepato-enteric metabolism.Options include slow infusion of intravenous clomipramine orcitalopram in normal saline. While some positive results havebeen noted for up to 14 days of daily treatment ( Fallon et al., 1998),intravenous treatment is generally inconvenient and dif cult to setup on a routine basis in mental health clinics. There is also a need

for continual monitoring of cardiac activity and vital signs duringand shortly after the infusion.

8.8.6. Combining SSRI and clomipramineThis strategy should be approached cautiously; ECG and plasma

level monitoring are advisable, given the potential for pharmaco-kinetic interactions on the hepatic cytochrome P450 isoenzymesthat could lead to a dangerous build-up of clomipramine, espe-cially with co-administered uoxetine and paroxetine as well asthe risk for serotonin syndrome. Citalopram, escitalopram and to alesser extent sertraline are theoretically less likely to interactpharmacokinetically with clomipramine than other SSRIs. Small,uncontrolled case series have shown positive results for combiningan SSRI and clomipramine (Pallanti et al., 1999), although ECG

changes have been reported in cases involving the combination of





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clomipramine with uvoxamine (Szegedi et al., 1996). In a rando-mised open-label trial, nine pharmacotherapy-refractory patientswere given citalopram with clomipramine, and seven were trea-ted with citalopram alone. Signi cantly larger improvements inY – BOCS ratings were reported for those given the combination, allof whom experienced decreases of Z 35% from baseline. Thiscombination was well tolerated and did not alter the metabolismof 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) ( FDADrug Safety Communication, 2011) argues for a degree of cautionin using citalopram and clomipramine in combination. In anotherstudy, combining uoxetine with clomipramine was no moreeffective than uoxetine 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 strategiesThe following compounds are under investigation for OCD and

have already shown some evidence of ef cacy, but because they sofar lack convincing validation in controlled studies, they cannot atpresent be judged to be effective. The glutamatergic compound,memantine has appeared helpful as an adjunct to an SSRI in a fewopen-label trials and two small randomized placebo-controlledtrials (Ghaleiha et al., 2013; Haghighi et al., 2013). Preliminaryresults from open-label studies suggesting ef cacy for riluzole(Coric et al., 2005), another glutamate modulating agent, have sofar not been substantiated. In a placebo controlled trial of riluzole inchildren with refractory OCD, no signi cant difference was noted onany of the primary or secondary outcome measures ( Grant et al.,2014). The glutamatergic hypothesis has been further exploredthrough investigations of ketamine in OCD. A randomized con-trolled cross-over trial of ketamine versus placebo infusion led to4 35% reduction in YBOCS score in 50% of those infused withketamine ( n ¼ 8) (Rodriguez et al., 2013). However, in another 3-dayopen label trial of ketamine in 10 subjects with refractory OCD anddepression there were no OCD responders and although depressivesymptoms improved, the post-baseline improvement in Y – BOCSamounted to o 12% (Bloch et al., 2012). Further, ketamine has to beused cautiously, given its association with lower urinary tract(bladder) damage (Winstock et al., 2012). The 5-HT3 receptorantagonist ondansetron , administered in combination with uox-etine, demonstrated a superior effect over placebo plus uoxetineon the Y – BOCS in a randomized controlled pilot study in treatment-resistant patients ( Soltani et al., 2010). However, the results of an asyet unpublished multicentre trial did not meet the primary ef cacyendpoint to demonstrate an improvement in OCD symptoms versusplacebo (Biotechnologyevents.com 2013). Mirtazapine as monother-apy has been reported to signi cantly improve outcomes in aplacebo-controlled discontinuation study of 15 open-label mirtaza-pine responders. In the 8-week, double-blind, placebo-controlleddiscontinuation phase, the mirtazapine group's mean Y – BOCS scorefell a mean7 S.D. of 2.67 8.7 points while the placebo group'smean score rose a mean 7 S.D. of 9.17 7.5 points (Koran et al.,2005). Clonazepam, as an adjunctive to an SRI, may producesymptomatic bene t (Hewlett et al., 1992), possibly throughimproving associated anxiety. It is less suitable in those withprevious history of benzodiazepine or other substance abuse ordependence.

It has been suggested that antiepileptic mood stabilizers may, incombination with an SSRI, have a role in the treatment of OCD, butthe supporting evidence at present is not strong and further placebo-controlled trials are necessary. Positive results were obtained in asmall randomized controlled trial of lamotrigine ( Bruno et al., 2012).

Randomized placebo controlled trials of topiramate augmentation

resulted in a therapeutic effect (reducing compulsions only) in onestudy (Berlin et al., 2011) whereas another study ( Mowla et al., 2010)noted signi cant improvement in the topiramate as opposed to theplacebo group. Adjunctive pregabalin has been investigated in anopen-label case series only, with some signs of possible ef cacy(Oulis et al., 2011), as has gabapentin (Corá-Locatelli et al., 1998). Arandomized placebo-controlled trial of single dose d-amphetamineproduced short-lived bene ts (Insel et al., 1983a), while another

randomized controlled trial comparing d-amphetamine and caffeineintriguingly noted that both compounds were associated with rapidimprovement of obsessive compulsive symptoms within a week(Koran et al., 2009), hinting that stimulants such as d-amphetaminecould 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/orhome-based, or clinic-based, therapist-assisted CBT, may indicaterefractoriness to treatment. At this stage, if the symptoms remainsevere and incapacitating, it may be necessary to liaise withspecialist services offering somatic treatments such as deep brainstimulation or neurosurgery.

9.1. Electroconvulsive therapy (ECT)

Evidence to support the use of ECT in OCD is limited due to samplesize and study design issues, with an absence of blinded controlledtrials. 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 insuf cient evidence on which to base arecommendation 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 eld pulse. The inhibitory effect of rTMS on the increasedneuronal activity in the prefrontal subcortical circuits is hypothesizedto be bene cial in the treatment of OCD (Blom et al., 2011). Asystematic review of studies investigated the ef cacy of rTMS in OCDbetween 1996 and 2010 ( Jaafari et al., 2012) and a recently publishedmeta-analysis ( Berlim et al., 2013) obtained data from 10 randomizedcontrolled trials involving 282 subjects with OCD. The effect size forpre-post Y – BOCS score was 0.59 ( z ¼ 2.73, p ¼ 0.006) and theresponse rates were 35% and 13% for patients receiving active andsham rTMS respectively, suggesting promise in treating OCD. Themost promising target areas for stimulation included the orbitofron-tal cortex and the pre-supplementary motor area. rTMS is generally asafe and non-invasive form of treatment. Rarely, high-frequencyrTMS 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 insuf cient evidence to support the use of rTMS asa treatment for OCD, and it remains an experimental procedure.

9.3. Deep brain stimulation (DBS)

Deep brain stimulation (DBS) is a neurosurgical treatment thatinvolves the implantation of electrodes that send electrical impulsesto speci c locations in the brain, with areas selected according tothe type of symptoms to be addressed. This approach permits focal,

relatively low risk, and relatively reversible modulation of brain





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circuitry. DBS may bring about therapeutic effects in OCD bymodulating 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 nucleusmay selectively improve compulsions (Milan et al., 2010). Smallstudies with at best partially controlled designs have reportedsigni cant overall average Y – BOCS decreases ranging from 6.8

to 31 points (in severely ill patients with baseline Y –

BOCS scoresusually exceeding 30), and the average overall responder rate is50%. The procedure is reported to be ‘relatively safe’ with limitedside effects (de Koning et al., 2011). However, adverse events havebeen reported. In a study( Greenberg et al., 2006) that followed up the3-year outcomes following bilateral stimulation of ventral capsule/ventral striatum areas in 10 adult OCD patients meeting stringentcriteria for severity and treatment resistance, the following surgicaladverse effects were reported: asymptomatic hemorrhage, a singleseizure, and super cial infection. Psychiatric adverse effects includedtransient hypomanic symptoms as well as worsening of depressionand OCD when DBS was interrupted. Acute adverse effects of DBSincluded transient sadness, anxiety, and euphoria or giddiness. Anxietywas more frequent with monopolar than with bipolar stimulation.Suicide events were not noted when DBS was interrupted, andcognitive events were described as relatively benign. At the presenttime, DBS remains a highly experimental treatment, with evidencelargely based on case series.

9.4. Ablative neurosurgery

Modern ablative neurosurgical procedures are stereotacticallyguided, resulting in small and accurately placed lesions. This is mostcommonly achieved using thermal stimuli, although there is ong-oing research into the use of radiosurgical techniques such as thegamma 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 anteriorcingulate 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 arebelieved to modulate functioning within the cortico – striatal – tha-lamic circuitry. Overall the available evidence suggests that suchprocedures offer signi cant therapeutic bene ts to 30– 60% of pat-ients with otherwise highly refractory OCD. Serious adverse effectsare uncommon, but have been reported with both procedures (e.g.intracranial hemorrhage, recurrent seizures). Anterior cingulotomyappears to offer a superior safety pro le to that of anterior caps-ulotomy. The quality of evidence supporting each procedure isre ective of neurosurgery as a whole. There are no randomized con-trolled trials, and most data is derived from prospective case seriesand small unblinded cohort studies. Surgical intervention is there-fore reserved for patients with severe, incapacitating OCD who havefailed an exhaustive array of expertly delivered medication trialsand intensive evidence based CBT.

10. Summary

The ef cacy of SSRIs and clomipramine is well established. SSRIsare usually preferred over clomipramine, in view of their superiortolerability, especially as doses probably need to remain consistentlyat a relatively high level to sustain effectiveness. Improvements areusually 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

fail to reach symptomatic remission. A trial of combined CBT plusSSRI treatment would be appropriate for those patients failing torespond adequately to SSRI monotherapy. Research in other psychia-tric disorders suggests that in order to achieve optimal outcomes, notonly do clinicians need to prescribe treatments appropriately butthey should also encourage and con rm 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 bene ts and risks of continuing SRI treatment and that the risks of SRI discontinuation arefully discussed. If necessary, discontinuation should be plannedcarefully, with rescue strategies identi ed in advance. In those caseswhere response to treatment is inadequate, various pharmacologicalstrategies could be considered, of which, augmentation of SRI's withadjunctive second generation antipsychotic seems to be the mostef cacious option, based on the available evidence. Non-pharm-acological somatic treatments may play a role for those who donot respond to psychopharmacological and CBT (refractory cases).DBS and rTMS, though promising, remain experimental. Ablativeneurosurgery remains the last resort for a small group of severely illpatients who do not respond to expert delivered trials of pharma-cotherapy and CBT of optimal dosage/content, duration, and modeof delivery as assessed by experienced experts in specialty treat-ments for OCD.

Acknowledgments

The authors are members of the Accreditation Task Force of TheCanadian Institute for Obsessive Compulsive Disorders. Severalauthors are members of the European College of Neuropsychophar-macology Obsessive Compulsive and Related Disorders ResearchNetwork and the International College of Obsessive Compulsive Dis-orders, which bodies facilitate the exploration of these issues. DanStein is supported by the Medical Research Council of South Africa.

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