Neurobiology of Brain Disorders || Obsessive–Compulsive Disorder

Neurobiology of Brain Disordershttp://dx.doi.org/10.1016/B978-0-12-398270-4.00038-0 © 2015 Elsevier Inc. All rights reserved.

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C H A P T E R

38Obsessive–Compulsive Disorder

Nastassja Koen, Dan J. SteinDepartment of Psychiatry, University of Cape Town, Groote Schuur Hospital, Cape Town, South Africa

O U T L I N E

Introduction 622

Epidemiology of Obsessive–Compulsive Disorder 622Prevalence 622Age of Onset 622Demographic Risk Factors 622

Gender 622Culture and Ethnicity 623Socioeconomic Status 623

Impact of Disease 623

Clinical Considerations in Obsessive–Compulsive Disorder 623Diagnosis 623Symptomatology 623

Symmetry 623Forbidden Thoughts (Sexual, Aggressive,

and Somatic Obsessions; Checking Compulsions) 623

Cleaning (Contamination and Washing) 624Hoarding 624

Differential Diagnoses 624Symptom Severity 625Comorbidity 625

Natural History and Course of the Disease 626

Pathogenesis of Obsessive–Compulsive Disorder 626Cognitive–Affective Factors 626Neurobiological Factors 626

Neuroanatomy 626Neurochemistry 628

Neuroendocrinology 630Neuroimmunology 630Neuroethology 630

Genetic Factors 631

Treatment of Obsessive–Compulsive Disorder 632Pharmacotherapy 632

First Line Treatment 632Treatment Resistance 633Experimental Treatments 633

Non-Pharmacological Somatic Treatments 633Electroconvulsive Therapy 633Repetitive Transcranial Magnetic Stimulation 634Ablative Neurosurgery 634Deep Brain Stimulation 634

Psychological Therapy 634Combined Treatment 635

Obsessive–Compulsive Spectrum Disorders 635Phenomenological Correlates 635Neurobiological Correlates 636Neurogenetic Correlates 636Pharmacotherapeutic Correlates 636

Obsessive–Compulsive Disorder in Pediatric Populations 636

Conclusion 637

Questions for Further Research 637

References 637

38. OBSESSIVE–COMPULSIVE DISORDER622

V. DISEASES OF HIGHER FUNCTION

INTRODUCTION

From a historical perspective, obsessive–compulsive disorder (OCD) was once viewed as a rarity. Today, it is recognized as a common and debilitating disorder. In the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), OCD was categorized as an anxiety disorder.1 However, it has now been included as part of a new grouping of obsessive–compulsive and related dis-orders in DSM-5.2 There is a substantial evidence base to support moving OCD out of the section on anxiety dis-orders. Most frequently, it is noted that obsessions and compulsions (rather than anxiety) characterize OCD and the related disorders and that this group of disorders dif-fers significantly from the anxiety disorders in terms of pathogenesis and treatment.

OCD is often represented in literary, scientific, and popular culture media, with such varied allusions as Lady Macbeth’s compulsive hand washing: “Out, damned spot!” (Shakespeare’s Macbeth, Act V, Scene 1) and Howard Hughes’s exceedingly reclusive and erratic behavior (as depicted in the 2004 Martin Scorsese film The Aviator). OCD is widely conceptualized as a neu-ropsychiatric disorder, in which dysfunctional neural circuitry and neurochemical changes culminate in char-acteristic symptomatology. This chapter reviews the current understanding of OCD, including epidemiol-ogy, disease burden, pathogenesis and natural history, clinical assessment and diagnostic criteria, and available treatment modalities. OCD-related disorders such as trichotillomania, as well as pediatric OCD, will also be discussed briefly.

EPIDEMIOLOGY OF OBSESSIVE–COMPULSIVE DISORDER

Prevalence

In the 1980s, the first large-scale and standardized epidemiological data on OCD were obtained as part of the Epidemiologic Catchment Area (ECA) study.3 OCD was ranked as the fourth most common psychiatric dis-order, with lifetime prevalence reported to be about 2.5% (range 1.9–3.3%), and representative data collected from five US communities and more than 18,500 individu-als. Before this study, OCD had been regarded as a rare disorder, affecting only about 0.005% of the population. Thus, the ECA study revolutionized the epidemiological understanding of OCD, with prevalence rates reported as 25–60 times greater than had been estimated in previ-ous clinical samples.3

Because of this remarkable diversion from prior find-ings, the validity of the ECA study has been challenged. A number of small follow-up studies published shortly

after the ECA, as well as one larger follow-up investiga-tion, criticized the reliability of the National Institute of Mental Health Diagnostic Interview Schedule (DIS), the psychiatric assessment tool designed for lay interview-ers and used in the ECA to establish diagnostic status. It was reported that the DIS showed poor diagnostic validity, as evidenced by the very low temporal stability between those participants interviewed during the ini-tial ECA study (wave 1) and those assessed 1 year later.

However, more recent epidemiological studies employing clinician-administered diagnostic inter-views have supported the ECA study findings, with OCD emerging as one of the most common psychiat-ric disorders in adult populations. For example, in the National Comorbidity Survey Replication (NCS-R), lifetime prevalence of OCD was reported to be 2.3%,4 a finding comparable to that of the ECA. Large-scale epi-demiological data collected in the European Union have also supported the ECA study findings. In their critical review and appraisal of 27 studies of a range of mental disorders, Wittchen and Jacobi found that the 12 month population prevalence of OCD ranged from 0.1 to 2.3%.5 Taken together, these cross-national findings suggest that, universally, OCD is a prevalent disorder. The earlier underestimation of the prevalence of this disorder may have been attributable to a number of factors, includ-ing a reluctance of affected individuals to seek care, a lack of routine screening by health professionals, and misdiagnosis.

Age of Onset

Age of onset of OCD is typically bimodal, with indi-viduals presenting either during childhood/adoles-cence or later in life. Juvenile-onset OCD is particularly evident in males, while pregnancy-related events (e.g. miscarriage) may precipitate symptoms in women of childbearing age. Symptom onset before age 18 is par-ticularly prevalent in first degree relatives of probands with OCD, suggesting that juvenile-onset OCD may be more highly heritable than later-onset disease.

Demographic Risk Factors

GenderOverall, disease prevalence seems to be fairly equal

in males and females. Although some clinical and epide-miological studies have shown a slight female prepon-derance,3,6 this is far less definitive than in the anxiety disorders. However, gender-related clinical differences have been noted in these individuals. For example, symptom onset may be earlier and more insidious in males, with the illness then following a chronic progres-sion with a greater likelihood of comorbid tic disorders.

CLINICAL CONSIDERATIONS IN OBSESSIvE–COMPULSIvE DISORDER 623


Culture and EthnicityMost studies to date have focused on Caucasian indi-

viduals with OCD. While there is evidence of trans-cultural homogeneity in this disorder, it has also been suggested that its prevalence is lower in certain ethnic groups. For example, findings from the ECA indicated lower prevalence rates among black individuals.3 How-ever, the paucity and methodological shortcomings of these studies have limited their generalizability.

Socioeconomic StatusAlthough the ECA reported that unemployed individ-

uals with lower socioeconomic status were more likely to develop OCD,3 this may well be a reflection of the per-sonal and societal functional impairment experienced by these individuals. Conflicting evidence that adoles-cents with OCD are more likely to be of middle to upper socioeconomic classes seems to support this notion.

Impact of Disease

OCD is often associated with serious and diverse direct and indirect health costs. Individuals with this disorder may have problems in a number of functional domains, including interpersonal difficulties (including relationship impairment), loss of employment, and poor instrumental role performance (i.e. domestic, academic, or work functioning). Compared with both the general population and those with other psychiatric or biomedi-cal disorders, overall quality of life is also significantly affected in individuals with OCD. On a societal level, loss of productivity and increased use of health-care services may lead to inflated fiscal disease burden.

Unfortunately, individuals with OCD tend to delay their presentation to health-care services,6 and misdi-agnosis remains an obstacle in primary and specialized settings. Thus, there is often a substantial lag between symptom onset and treatment initiation, which worsens the impact of this disorder. Therefore, early diagnosis and effective treatment of OCD are essential to curtail its multidimensional sequelae.

CLINICAL CONSIDERATIONS IN OBSESSIVE–COMPULSIVE DISORDER

Diagnosis

The hallmark clinical characteristics of OCD are obses-sions (persistent, recurrent, intrusive, and inappropriate thoughts or images) and compulsions (repetitive behav-iors or mental acts aimed at reducing anxiety symptoms) which are not secondary to a general medical condition or substance misuse, and are not better explained by the symptoms of another mental disorder2 (Table 38.1).

The diagnosis of OCD requires comprehensive psychi-atric history taking and examination.

Symptomatology

OCD may be subtyped according to the content of the obsessions and compulsions that are present. The Brown Longitudinal Obsessive Compulsive Study (BLOCS), a large-scale, prospective longitudinal clinical study of the natural history of OCD,6 reported some of the major symptom classes encountered.7 Non-phenomenological subtyping of OCD has also been the subject of recent work. For example, a three-tiered subclassification com-prising abnormal risk assessment, pathological doubt, and incompleteness has been put forward. However, evidence remains inconclusive. Thus, for the purposes of this chapter, the traditional four-factor phenomenological subtyping will be discussed.

SymmetryThe symptoms of OCD may concern the need for

symmetry or perfection. Typically, these individuals continue their compulsive ordering and rearranging either out of fear that harm will come to their loved ones (primary magical thinking), or because they take far lon-ger than most to complete tasks of daily living (primary obsessive slowness).7

Forbidden Thoughts (Sexual, Aggressive, and Somatic Obsessions; Checking Compulsions)

Individuals may experience intrusive and persistent fears that they may commit, or indeed already have com-mitted, sexually inappropriate, aggressive, or violent acts.7 They often feel compelled to carry out ritualistic checking, confessional, or reassurance behaviors, such as confessing to imagined crimes. Somatic obsessions may be rooted in irrational fears of body dysmorphisms (defects in physical appearance or form) or of contract-ing a life-threatening illness. While not disorder specific [individuals with hypochondriasis, body dysmorphic disorder (BDD), and major depression may all experi-ence such fears], OCD-related somatic obsessions are also accompanied by classic fears (e.g. of contamination) and compulsions (e.g. hand washing).7

Individuals with OCD may also experience obsessive fears that their own carelessness will directly lead to cat-astrophic events. For example, fear of a house fire may cause an individual to check and recheck his or her stove before leaving home.7 This ritualistic checking is often highly time consuming, and the individual may employ strategies to minimize functional impairment, such as counting the number of completed checks. While these individuals are often aware of their misperceptions, the severe anxiety they may experience when checks are not completed arguably perpetuates their compulsive



behavior. These cognitive–affective manifestations form the basis of cognitive–behavioral therapeutic techniques for treating OCD (see “Psychological Therapy”, below).

Cleaning (Contamination and Washing)This is the subtype most commonly encountered in

individuals with OCD.6,7 Fearful obsessions centered on dirt or germs often culminate in compulsive and exces-sive washing (e.g. hand washing) after contact with the feared stimulus. While this type of washing is usually in response to fears of contamination, it may also be a manifestation of obsessions with symmetry (see above). In addition, avoidance behaviors may be employed to avoid perceived contamination.

HoardingWhile hoarding was included in the original four-

factor phenomenological symptom structure, it has now been classified as a distinct, OCD-related disorder in DSM-5.2 Nonetheless, evidence suggests that hoarding is present in almost 20% of individuals with OCD and is characterized by a persistent difficulty discarding one’s possessions, driven by the fear of losing items that may be needed in future. This may result in the accumula-tion of clutter with accompanying distress or functional impairment.

Differential Diagnoses

Obsessions and compulsions may occur in a variety of psychiatric and biomedical conditions. Thus, in the clinical setting, it is important to exclude these differ-entials before definitively diagnosing OCD. While most anxiety disorders manifest with overwhelming fear, autonomic features, and avoidant behavior, OCD may be distinguished from, for example, panic disorder, by the absence of spontaneously occurring panic episodes (individuals with OCD may experience panic second-ary to obsessions). Similarly, while OCD and many psychotic disorders (e.g. schizophrenia) are associated with a chronic course and long-term functional impair-ment, the delusions of schizophrenia are often not rec-ognized as unreasonable and are thus accepted by the affected individual, whereas individuals with OCD may have varying degrees of insight into their dysfunctional beliefs.7 Similar specifiers have been included in DSM-5, so that affected individuals are described as having good or fair insight, having poor insight, or having absent insight/delusional beliefs.

OCD-related disorders should also be considered in individuals presenting with obsessions or compul-sions. However, unlike in OCD, the recurrent, intrusive thoughts and behaviors of trichotillomania and BDD are not ubiquitous, rather limited to particular contexts. Fur-thermore, OCD should be carefully distinguished from

TABLE 38.1 DSM-5 Diagnostic Criteria for Obsessive–Compulsive Disorder

A. Presence of obsessions, compulsions, or both:Obsessions are defined by (1) and (2):

(1) Recurrent and persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted and that in most individuals cause marked anxiety or distress.

(2) The individual attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action (i.e. by performing a compulsion).

Compulsions are defined by (1) and (2): (1) Repetitive behaviors (e.g. hand washing, ordering, checking)

or mental acts (e.g. praying, counting, repeating words silently) that the individual feels driven to perform in response to an obsession or according to rules that must be applied rigidly.

(2) The behaviors or mental acts are aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation; however, these behaviors or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent, or are clearly excessive.

Note: Young children may not be able to articulate the aims of these behaviors or mental acts.

B. The obsessions or compulsions are time consuming (e.g. take more than 1 hour a day) or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

C. The obsessive–compulsive symptoms are not attributable to the physiological effects of a substance (e.g. a drug of abuse, a medication) or another medical condition.

D. The disturbance is not better explained by the symptoms of another mental disorder [e.g. excessive worries, as in generalized anxiety disorder; preoccupation with appearance, as in body dysmorphic disorder; difficulty discarding or parting with possessions, as in hoarding disorder; hair pulling, as in trichotillomania (hair-pulling disorder); skin picking, as in excoriation (skin-picking) disorder; stereotypies, as in stereotypic movement disorder; ritualized eating behavior, as in eating disorders; preoccupation with substances or gambling, as in substance-related and addictive disorders; preoccupation with having an illness, as in illness anxiety disorder; sexual urges or fantasies, as in paraphilic disorders; impulses, as in disruptive, impulse-control, and conduct disorders; guilty ruminations, as in major depressive disorder; thought insertion or delusional preoccupations, as in schizophrenia spectrum and other psychotic disorders; or repetitive patterns of behavior, as in autism spectrum disorder].

Specify if:With good or fair insight: The individual recognizes that obsessive–compulsive disorder beliefs are definitely or probably not true or that they may or may not be true.With poor insight: The individual thinks obsessive–compulsive beliefs are probably true.With absent insight/delusional beliefs: The individual is completely convinced that obsessive–compulsive beliefs are true.Specify if:Tic-related: The individual has a current or past history of a tic disorder.

Source: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Press; 2013 (DSM-5).2

CLINICAL CONSIDERATIONS IN OBSESSIvE–COMPULSIvE DISORDER 625


obsessive–compulsive personality disorder (OCPD). In general, individuals with this disorder do not have obsessions and compulsions meeting the DSM criteria, but rather experience a pervasive preoccupation with orderliness, perfectionism, and interpersonal control, often to the detriment of flexibility and efficiency.1

In addition to the range of psychiatric disorders, a number of biomedical conditions should also be excluded before a diagnosis of OCD is made. For exam-ple, neurodegenerative disorders of the frontal lobe and basal ganglia (e.g. Huntington disease and Sydenham‘s chorea), cerebrovascular accidents, or even neurotoxin exposure (e.g. carbon monoxide) may present with signs and symptoms not unlike those of OCD. In these cases, thorough history taking, examination, and investiga-tions where indicated should elucidate the definitive diagnosis.

Symptom Severity

The most widely used assessment and evaluation tool for individuals with OCD is the Yale–Brown Obsessive Compulsive Scale (Y-BOCS). This is a 10-item, clinician-administered tool including five domains for obsessions and five for compulsions. Individuals are instructed to answer each domain on a Likert scale, from 0 (no symp-toms) to 4 (extreme symptoms). The Y-BOCS has shown good validity and reliability and has been shown to change with treatment. Thus, it is generally accepted as a standardized outcome measure for individuals with OCD.7 However, it cannot be used as a diagnostic instru-ment as the DSM criteria are not specifically assessed. Thus, comprehensive psychiatric history taking and examination remain the bedrock of diagnosis.

Comorbidity

OCD frequently co-occurs with other psychiatric con-ditions. To date, studies have reported that 50–90% of adults with OCD also meet the diagnostic criteria for another axis I disorder, and at least 40% for an axis II disorder.6

Of these comorbidities, major depressive disorder (MDD) has consistently been found to be the most preva-lent. Clinical and epidemiological studies have reported that approximately one-third of individuals with OCD experience concurrent MDD, and about two-thirds have a lifetime history of this comorbidity.8 Most individuals report the onset of depressive symptoms after those of OCD, suggesting secondary MDD (which may manifest in response to OCD-related functional impairment).3,7 However, a small percentage of patients experiences concurrent onset of obsessive–compulsive and depres-sive symptoms. Of these individuals, only a minority view their depression as independent of their OCD.

In the clinical setting, depressive ruminations (usually centered on a prior event) should be carefully differenti-ated from pure obsessions (which often focus on a current or future incident and are resisted by the individual).7

There has been a relative paucity of literature on comorbid bipolar disorder (BPD) in individuals with OCD. In a comorbidity study of the ECA population, lifetime prevalence rates of bipolar and unipolar dis-ease in individuals with OCD were reported as approxi-mately 20 and 12%, respectively. More recently, it has been estimated that approximately 10% of people with OCD also meet the criteria for BPD, with the majority of these cases being BPD type II. Compared with those individuals with only OCD, those with comorbid OCD and BPD were more likely to be male, to experience hoarding and sexual obsessions, and to have a lifetime history of a comorbid substance use disorder.

Anxiety disorders may also coexist in people with OCD. For example, findings from the BLOCS showed social phobia (28%) and specific phobia (22%) emerg-ing as the most common comorbid anxiety disorders in these individuals.6

OCD-related disorders may also be highly comorbid in individuals with OCD. In their study of 315 adult OCD patients, Lochner and colleagues found that 18.1% of their total sample also exhibited hoarding.9 These high prevalence rates may be due, in part, to shared etiological mechanisms (e.g. genetic and environmental influences).7–9

In a substantial number of individuals, OCD also co-occurs with eating disorders. Participants with OCD are more likely to report disturbed eating attitudes and behaviors (e.g. drive for thinness, body dissatisfaction) than healthy controls. Several studies have substantiated these findings, with lifetime rates of comorbid anorexia nervosa and bulimia nervosa in individuals with OCD reported as 10–17% and 15–20%, respectively.8 Conversely, significant rates of OCD have also been reported in individuals with eating disorders.

The axis II disorders most commonly diagnosed in individuals with OCD are OCPD (24.6%) and avoid-ant personality disorder (15.3%).6 While less frequent, comorbid schizotypal personality disorder has also been associated with treatment resistance and poorer prog-nosis. Attention has been paid to the overlap and dis-crepancy between OCD and OCPD. Phenomenological, etiological, and treatment response similarities certainly exist between these two disorders. Although very early evidence suggested that all people with OCD may have a premorbid personality that predisposes them to develop the disorder, this theory has since been discounted. Fur-thermore, owing to evolving definitions and diagnos-tic criteria for the personality disorders, the literature on comorbid OCD and OCPD remains heterogeneous. Thus, while OCPD may not be as common a comorbidity



as had been previously thought, it is widely accepted that this personality disorder occurs more frequently in individuals with OCD than in the general population.

NATURAL HISTORY AND COURSE OF THE DISEASE

Retrospective follow-up studies of individuals with OCD have delineated the following categories of dis-ease course: continuous; waxing and waning; deterio-rative (approximately 6–14%); and episodic with full remissions between episodes (approximately 10–15% of individuals).7 According to these data, as well as clinical lore, most individuals with OCD experience a chronic, progressive course with some symptom fluctuation.1 Factors associated with decreased remission include male gender, earlier age of symptom onset, older age at intake, and greater symptom severity.

Several prospective studies have also investigated the course of disease of juvenile-onset OCD. Overall, these echo the findings of follow-up studies in adult popula-tions. For example, in a study of 25 individuals who had been diagnosed with severe OCD in childhood or adoles-cence, the psychiatric assessment conducted 2–7 years later revealed continued psychopathology.10 Only 28% of this study population (seven individuals) were symptom- free at follow-up. Findings from a 40 year follow-up study conducted by Skoog and Skoog deviated significantly from this natural history.11 These authors found that 83% of individuals showed improvement in OCD symptoms, with complete recovery in 20% and incomplete recov-ery with some subthreshold residual symptoms in 28%. This suggests that most individuals with OCD improve over time. However, as this finding has not been widely replicated, it is not yet the general consensus.

PATHOGENESIS OF OBSESSIVE–COMPULSIVE DISORDER

As is the case for many psychiatric disorders, the eti-ology and pathogenesis of OCD are multifactorial, as evidenced by its broad clinical heterogeneity.

Cognitive–Affective Factors

It has been suggested that cognitive–behavioral fac-tors in the pathogenesis of OCD are rooted in appraisal theory, that is, the idea that emotions are elicited from evaluations (appraisals) of a situation or event. The struc-tural model of appraisal comprises primary and second-ary components. In an individual’s primary appraisal of a situation, he or she evaluates its motivational relevance (i.e. its importance to his or her own well-being) and its

motivational congruence (i.e. how closely it is aligned with his or her goals). Secondary appraisal comprises an evaluation of the individual’s capacity to cope with the situation. During primary appraisal of a situation, an individual with OCD experiences intrusive obsessional thoughts. As a result, he or she tends to overestimate the risk of an unfavorable occurrence. Secondary appraisal then leads to dysfunctional coping, in the form of com-pulsive behavior or avoidance of the perceived threat. Belief domains affected in OCD include amplified sense of responsibility, need for control, overestimation of threat, and intolerance of uncertainty.

Neurobiological Factors

NeuroanatomyCorticostriatothalamocortical (CSTC) neurocircuitry

is thought to be central to the pathogenesis of OCD. In brief, this circuitry comprises a number of parallel, isolated projections. Efferent signals from the prefron-tal cortex (PFC) are transmitted to specific regions in the striatum (a subcortical area of the forebrain that is the major input center of the basal ganglia system). In healthy individuals, the PFC mediates a range of higher cognitive processes, such as planning, organization, inhibition, and controlling. Thus, in disorders associated with dysfunctional and dysregulated PFC, symptoms of disorganization, disinhibition, and inflexibility are likely to occur. The functional subterritories of the PFC are: the dorsolateral PFC (involved in learning, memory, and other executive functions); and the ventral PFC, compris-ing the posteromedial orbitofrontal PFC (motivational and affective functions) and the anterior and lateral orbi-tofrontal cortex (reverse learning, i.e. behavioral flexibil-ity after negative feedback). The orbitofrontal cortex, in particular, is central to many neurobiological models of OCD, and is often found to show abnormally reduced activation in affected individuals.

When functioning normally, the striatum serves to regulate conscious information processing by refin-ing input and output, and fine-tunes brain efficiency by mediating some non-conscious functions. From the striatum, these signals are then projected via other inter-mediate basal ganglia to the thalamus. The circuit is then closed via reciprocal projections from the thalamus back to the cortical regions from which the original signals were transmitted.

Structural and functional neuroimaging studies have given credence to the CSTC hypothesis of OCD.

STRUCTURAL NEUROIMAGING

Studies to assess volumetric changes in the brains of individuals with OCD compared with healthy con-trols have shown abnormalities in four key areas: the

PATHOGENESIS OF OBSESSIvE–COMPULSIvE DISORDER 627


caudate (a nucleus located within the basal ganglia), the orbital frontal and anterior cingulate regions (situated in the medial aspect of the cortex), the thalamus, and the cerebral white matter.

Changes in the caudate have been widely investi-gated, but findings have been mixed. Some studies have reported increased caudate volume in individuals with OCD. For example, in their 2009 meta-analysis of gray matter changes in individuals with OCD, Radua and Mataix-Cols reported increased regional gray matter volumes in bilateral lenticular nuclei, extending to the caudate nuclei.12 However, other studies have shown decreased caudate volume or indeed no volumetric change. The inconsistency of these findings may be a reflection of the heterogeneity of OCD. In other words, reduction in caudate volume (with enlarged ventricular volume) may be more evident in individuals with OCD and soft neurological signs (e.g. tics). Another explana-tory model would be that caudate volume in individuals with OCD changes over time. For example, caudate vol-ume increases in the aftermath of infection in children with streptococcal-associated OCD and/or tics, with shrinkage thereafter.

There are fewer data on the structural changes in the orbital frontal and anterior cingulate regions in individuals with OCD, and findings have again been inconsistent. Some studies have reported increased gray matter volume in posterior orbitofrontal regions, with decreased volume of the left anterior cingulate. How-ever, in their meta-analysis Radua and Mataix-Cols reported decreased volumes in bilateral dorsal medial frontal and anterior cingulate gyri.12 There is also an evidence base showing reduced bilateral orbital frontal (and amygdala) volumes.

Several studies have shown an increase in thalamic volume in individuals with OCD compared with healthy controls. Thus, an inverse relationship may exist between thalamic and orbitofrontal volumetric changes in OCD. This finding was replicated in a meta-analysis of mag-netic resonance imaging (MRI) studies in OCD by Rotge and colleagues.13 Furthermore, these authors found that the severity of obsessions or compulsions correlated significantly with the effect sizes for the left and right thalamus.

In their MRI study of 16 adults with OCD and 17 healthy controls, Mataix-Cols and colleagues found that both participant groups experienced increased subjective anxiety when exposed to symptom-provoking stimuli (i.e. pictures or imaginal scenarios relating to washing, checking, or hoarding).14 Furthermore, distinct patterns of regional activation associated with specific symptom dimensions were seen in individuals with OCD, as fol-lows: bilateral ventromedial prefrontal regions and right caudate nucleus (washing); putamen/globus pallidus, thalamus, and dorsal cortical areas (checking); and left

precentral gyrus and right orbitofrontal cortex (hoard-ing). Thus, another explanation for the heterogeneity of neuroimaging findings in individuals with OCD may be that different symptom dimensions are mediated by dysfunctions in distinct components of the frontostriato-thalamic circuitry.

While most structural studies have focused on gray matter abnormalities in OCD, there is also evidence of white matter dysfunction in this disorder. For example, MRI studies in the field have demonstrated signifi-cantly less total white matter in individuals with OCD, compared with unaffected controls.

FUNCTIONAL NEUROIMAGING

Many neurobiological theories of the pathogenesis of OCD are derived from the results of functional imag-ing studies. In these studies, techniques are used to measure indirectly the activity levels in specific brain regions. Examples of such techniques are positron emis-sion tomography (PET) and single-photon emission computed tomography (SPECT), which can be used to determine whether certain neuroanatomical areas or structures are more active in individuals with OCD than in healthy controls.

The findings of functional neuroimaging studies have largely echoed those of structural studies. In a number of studies, individuals with OCD have shown increased activity in the orbitofrontal cortex (Fig. 38.1), cingulate, and striatum at rest and during exposure to feared stim-uli. A meta-analysis of studies using PET and SPECT to investigate brain activity in OCD partially supported these conclusions, with particular functional differ-ences noted in the orbital gyrus and head of the caudate nucleus.15 However, no other significant effect sizes were reported (including no differences in the more inclu-sive regions of the caudate, or in the thalamus, anterior

FIGURE 38.1 Increased activation in ventral corticostriatal– thalamocortical circuitry in obsessive–compulsive disorder. Source: MRC Unit on Anxiety and Stress Disorders.



cingulate, or orbitofrontal cortex). These inconsistencies may again reflect the phenotypic heterogeneity of OCD.

Magnetic resonance spectroscopy (MRS) techniques have also been used to evaluate differences in regional metabolites in the brains of individuals with OCD ver-sus healthy controls. To this end, the concentrations of metabolites such as N-acetyl aspartate (NAA), com-bined glutamate and glutamine, myo-inositol, choline, and creatinine in brain tissue are measured. Some small studies have found significantly lower levels of NAA in the striatum of adults with OCD than in matched con-trol participants. This finding has been replicated in pediatric populations with OCD, with decreased NAA levels reported in the thalami of affected children. This reduction was inversely correlated with increased symp-tom severity. As NAA is only detectable in neurons, decreased concentration would indicate decreased den-sity of healthy neurons in that brain region. In small MRS studies of juvenile-onset OCD, significantly greater glu-tamate and glutamine concentrations have been found in treatment-naïve children with OCD than in healthy controls. Following serotonergic treatment, these levels decreased significantly to concentrations comparable to those of the control subjects. Reduction in glutamate and glutamine was also associated with decreased symp-tom severity, suggesting that the mechanism of action of paroxetine may be mediated by a serotonergically modulated reduction in glutamate and glutamine in the caudate.

NEUROANATOMICAL MODELS OF DISEASE

Various models have been posited to relate CSTC dysfunction to the symptoms of OCD. In an early heu-ristic paradigm, the striatal topography model of OCD and related disorders was articulated. This model sug-gests that the clinical manifestations of OCD (and, for example, of Tourette syndrome) are governed by spe-cific dysfunctions within the striatum. Building on this original model, it has been hypothesized that the obses-sional symptoms of OCD are mediated by the caudate; motor symptoms by the putamen (a component of the dorsal striatum); and affective symptoms (anxiety) by the paralimbic CSTC circuits. Structural imaging studies showing caudate involvement in individuals with OCD (see above) support this striatal topography model of disease.

This model may be extended to include cognitive neuroscience perspectives of OCD. It has been suggested that information processing can occur either explicitly (i.e. consciously) via dorsolateral PFC and medial tem-poral structures (e.g. hippocampus) or implicitly (i.e. unconsciously) via corticostriatal systems. Thus, as OCD is viewed primarily in the context of CSTC dysfunc-tion, its pathogenesis may be understood as a disorder of implicit processing. In other words, the characteristic

intrusive thoughts and behaviors of OCD may result from failure of the thalamus to filter out input informa-tion (that is normally efficiently processed via the CSTC), which then erroneously reaches consciousness.

As mentioned above, the striatum is believed to be integral to implicit information processing. However, in OCD, striatal dysfunction necessitates involvement of those structures involved in explicit processing (e.g. medial temporal regions). Compulsive behaviors may arise thus as adaptive mechanisms to recruit these cor-ticostriatothalamic collateral structures. Thus, although relatively inefficient, input filtering at the level of the thalamus is facilitated. This pattern of thalamic deacti-vation with striatal recruitment has been demonstrated in some functional imaging studies of OCD.

While the striatal topography model focuses on sub-cortical pathology in OCD, primary cortical dysfunc-tion may also play a role in the pathogenesis of this disorder. According to a cortical excitability model of disease, intracortical neuronal inhibition is defective in individuals with OCD compared with healthy controls. Transcranial magnetic stimulation is a non-invasive technique used to induce regional neuronal activity and thereby assess neuronal inhibition. In humans, a scalp electromagnetic coil is used to transmit magnetic pulses to cortical motor output cells. Commonly used transcra-nial magnetic stimulation paradigms include the corti-cal silent period, an interruption of voluntary muscle contraction by transcranial stimulation of the contra-lateral motor cortex16; and intracortical facilitation, a paired pulse paradigm in which conditioning stimuli are applied to the motor cortex before the test stimu-lus, enabling the investigator to index excitability of the motor cortical excitatory circuits.17 The cortical silent period is significantly shortened and intracortical facili-tation significantly increased in individuals with OCD compared with healthy controls. This suggests that OCD may be associated with dysregulated cortical inhibitory and facilitatory neurotransmission.

NeurochemistrySeveral neurotransmitter systems have been impli-

cated in the pathogenesis of OCD. The three most widely investigated are the serotonergic, dopaminergic, and neuropeptidergic systems.

SEROTONIN

Serotonin [5-hydroxytryptamine (5-HT)] is a mono-amine neurotransmitter released from neurons with cell bodies in the medium-sized raphe nuclei in the mid-brain. A serotonergic hypothesis first arose from the clin-ical and experimental finding that serotonin reuptake inhibitors (SRIs) were particularly efficacious in alleviat-ing the symptoms of OCD. However, while the idea that the SRIs exert their antiobsessional effect by correcting a



fundamental abnormality in the serotonergic system is appealing, it may be that these agents actually modulate an intact system to compensate for an underlying deficit not related to serotonergic function.

Several studies have attempted to elucidate this issue. Indirect measures of serotonergic function include peripheral receptor binding in the blood; measurement of 5-HT metabolites in the cerebrospinal fluid (CSF); and pharmacological challenge studies. Although the lit-erature is vast, studies using these methods have been largely disappointing and inconsistent. More direct methods include functional imaging receptor charac-terization techniques such as SPECT. Studies using this technique and [123I](β-CIT) (a non-selective dopamine reuptake inhibitor with prominent affinity for the sero-tonin transporter) found that significantly reduced sero-tonin transporter (SERT) availability is evident in the thalamus and hypothalamus of individuals with OCD versus healthy controls. SERT availability was also sig-nificantly negatively correlated with symptom severity and positively correlated with duration of illness. How-ever, these findings have not been replicated.

Preclinical (animal) studies have also begun to delin-eate the therapeutic mechanisms of the SRIs in OCD. For example, high and low doses of the selective serotonin reuptake inhibitor (SSRI) fluoxetine significantly reduce spontaneous stereotypic behavior in deer mice. This treatment-response pattern mimics that of individuals with OCD, suggesting predictive validity of stereotypic behavior of deer mice for OCD.

It also appears that SRIs potentiate serotonergic trans-mission via autoreceptor desensitization. The timing of these receptor changes mimics the delay between SRI ini-tiation and therapeutic response that is often observed. For example, animal studies have shown that SSRI-induced changes may occur more quickly in the lateral frontal cortex than in the medial frontal cortex. This is in line with clinical observations that the SRIs tend to exert their antidepressant effect sooner than their anti-obsessional effect. Thus, high doses of SSRIs over long periods may be required to desensitize the serotonin autoreceptors.

DOPAMINE

Animal studies have suggested a dopaminergic influ-ence in producing stereotypic (“compulsive”) behavior. For example, in their study of transgenic mice in which dopamine D1 receptor-expressing neurons in regional subsets of the cortex and amygdala express a neuro-potentiating cholera toxin transgene,18 Campbell and colleagues suggested that the perseverative motor and behavioral abnormalities observed in these mice may be attributable to chronic potentiation of cortical and limbic D1 receptor-expressing neurons. This finding has been strengthened by reports that administration

of dopamine agonists (e.g. quinpirole) may induce ritualistic (compulsive) behavior in rats.

Human radioligand studies of dopaminergic func-tion in OCD have also been increasing. For example, [123I](β-CIT) SPECT studies of psychotropic-naïve adults with OCD found that these individuals exhibit increased dopamine transporter binding in the basal ganglia, com-pared with unaffected controls. In addition, dopamine D2 receptor binding in the basal ganglia is significantly lower, and D1 receptors are downregulated in the stria-tum of individuals with OCD compared with healthy controls. Taken together, these findings seem to suggest that there is a higher synaptic concentration of dopa-mine in the basal ganglia of people with OCD than in the general population.

Several pharmacological studies have also elucidated the role of dopamine in the pathogenesis of OCD. While the response rate of individuals with tic-related OCD to SSRIs (e.g. fluvoxamine) is only about 50–60%, augmen-tation with dopamine antagonists (e.g. haloperidol, a typical neuroleptic) may yield more promising results. In addition, the atypical neuroleptics (e.g. risperidone), which also function as dopamine antagonists, have shown efficacy in treating refractory OCD without tics. These heterogeneous responses may be attributable to differences between OCD subtypes.

NEUROPEPTIDES

Neuropeptides that may play a role in the patho-genesis of OCD include arginine vasopressin (AVP), oxytocin, adrenocorticotropic hormone (ACTH), corti-cotropin-releasing factor (CRF), somatostatin, and the opioid system. AVP (also known as antidiuretic hor-mone) is an endogenous peptide hormone synthesized in the hypothalamus. Most of the synthesized volume is stored in vesicles in the posterior pituitary before secre-tion into the circulation, where AVP regulates homeosta-sis via its mediating effects on renal tubular absorption and peripheral vascular resistance. However, some of the hormone is released directly into the brain, where it has been implicated in memory formation and the development of grooming behaviors. In an early clinical study, Altemus and colleagues found that individuals with OCD exhibited significantly higher levels of AVP in the CSF, and significantly increased secretion of AVP into the plasma in response to hypertonic saline admin-istration.19 However, this finding has not been replicated more recently, as investigators have failed to find sig-nificant differences in CSF AVP concentrations between individuals with OCD, those with Tourette syndrome (TS), and healthy controls. Thus, more work is required to delineate this relationship further.

Oxytocin is a major neuromodulator that is synthe-sized in the hypothalamus and either stored in the pos-terior pituitary or released directly into the CNS. It is



structurally and functionally related to AVP and may play a role in grooming and maternal behavior (as well as sexual arousal). Both animal and human studies have shown an association between oxytocin and the develop-ment of obsessive–compulsive symptoms. For example, this neuropeptide has been found to induce maternal and reproductive behaviors in rats primed with gonadal steroids, which may explain the onset of OCD during pregnancy or in the puerperium. Human clinical stud-ies have complemented these findings, reporting higher CSF oxytocin levels in individuals with non-tic-related OCD than in unaffected controls. Oxytocin levels may also be correlated with symptom severity.

CRF is a polypeptide hormone secreted by the para-ventricular nucleus (PVN) of the hypothalamus in response to stress. Its main function is to stimulate the anterior pituitary to secrete ACTH. ACTH is an impor-tant component of the hypothalamic–pituitary–adrenal axis (HPA) (see “Neuroendocrinology”, below) and stimulates corticosteroid production and release. Studies relating ACTH and CRF to OCD in humans have yielded inconsistent results. While there is some evidence that basal plasma and post-CRF-administration CRF lev-els are lower in individuals with OCD than in healthy controls, this finding has not been widely replicated. One explanation for these inconsistencies may be the non-specific nature of CRF and ACTH. Both are stress hormones, and thus sensitive to alterations during any chronic illness.

Somatostatin is a regulatory (inhibitory) hormone that modulates neurotransmission and cell proliferation via interaction with G-protein coupled somatostatin recep-tors. It is produced by neuroendocrine neurons of the periventricular nucleus of the hypothalamus and acts to inhibit the release of numerous secondary hormones. Animal studies have shown that somatostatin delays the termination of avoidance behaviors (reminiscent of per-sistent repetition in people with OCD) and can produce stereotypies. Human studies have supported these find-ings, with individuals with OCD exhibiting higher levels of CSF somatostatin than healthy controls.

Endogenous opioid peptides include the endor-phins, enkephalins, endomorphins, and dynorphins, all of which mediate reward pathways and successful task completion. Thus, dysfunctions of these pathways may account for the self-doubt often experienced by individuals with OCD. Early clinical studies suggested that higher levels of antibodies for prodynorphin (a polypeptide precursor) were present in individuals with OCD than in healthy volunteers and disease con-trols. However, more recent therapeutic trials of the efficacy of opioid antagonists in OCD have produced disappointing results and further work is required to investigate the role of neuropeptides in the pathogen-esis of this disorder.

NeuroendocrinologyAbnormalities in the HPA axis have been well docu-

mented in the anxiety disorders. The role of this endo-crine system in the development of OCD has also been investigated. For example, multiple studies have shown increased 24 hour urinary cortisol levels as well as increased serum cortisol concentration in individu-als with OCD compared with control subjects. How-ever, dexamethasone suppression testing in OCD has yielded inconsistent results, with some studies showing non-suppression and others failing to demonstrate any abnormalities. Thus, the HPA axis may be less central to the pathogenesis of OCD than in anxiety disorders. Fur-ther work in this area is warranted to elucidate fully the role of the HPA axis and other endocrine abnormalities in OCD.

NeuroimmunologyIn their clinical study of 80 children (aged 5–17) with

a diagnosis of tic disorder, Singer and colleagues found that 42 participants described acute symptom onset or exacerbation.20 Of this subgroup, approximately 35% reported that the exacerbation was historically associ-ated with an infection, most commonly streptococcal.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) com-prise a subset of pediatric OCD cases that meet the fol-lowing criteria: presence of OCD and/or a tic disorder; prepubertal onset; episodic course of symptom sever-ity; association with group A β-hemolytic streptococcal (GABHS) infection; and association with neurological abnormalities. PANDAS were initially designated fol-lowing the observation that OCD was common in Syden-ham’s chorea (a neurological manifestation of acute rheumatic fever), as well as an early suggestion that the basal ganglia damage characteristic of Sydenham’s chorea may be mediated by antineuronal antibodies as part of an autoimmune response to GABHS. A number of clinical studies strengthened the case for this subtyp-ing, showing that a subset of children with OCD and TS had antineuronal antibodies and exhibited characteris-tic clinical features of abrupt symptom onset and dis-crete, episodic exacerbations, often with demonstrable GABHS infection.

NeuroethologyThere is a significant body of work examining ani-

mal models of OCD. The symptoms of this disorder are reminiscent of maladaptive, repetitive behavior patterns in animals (including perseverative and stereotyped motor activities). The pathogenesis of these behaviors in animals has also been found to overlap with the neu-robiological mechanisms underlying OCD (e.g. excess dopaminergic activity in the basal ganglia). In early



animal studies, serotonergic drugs were found to show selective efficacy in treating excessive behaviors, such as the repetitive licking of paws or flank that characterizes canine acral lick dermatitis. These findings mimic the typical pharmacological response pattern of individuals with OCD.

In two noteworthy reviews, Joel and colleagues sum-marized the five most studied animal models to date: quinpirole-induced compulsive checking; marble bury-ing; signal attenuation; spontaneous stereotypy in deer mice; and decreased alternation induced by 8-hydroxy-2-(di-n-propylamino)-tetralin hydrobromide (8-OHDPAT), a serotonin receptor agonist.21,22 They also evaluated the face validity (derived from the phenomenological simi-larities between the animal behavior and the correspond-ing symptoms in humans), predictive validity (derived from similarities in treatment response), and construct validity (derived from similarities in pathogenesis) of these animal models. There is some evidence that opto-genetic techniques (i.e. combining genetics and optics to allow precise manipulation of electrical and biochemi-cal neural events using fiberoptic light) may be applied to these and other animal models to identify specific neurocircuits driving repetitive behavior. For example, hyperactivation of the glutamatergic pathway between the orbitofrontal cortex and ventromedial striatum may produce compulsive (grooming) behavior in mice.23 Taken together, animal models may be of great value in uncovering the pathogenesis of OCD in humans, in elu-cidating its symptom dimensions, and in detecting novel treatment targets and strategies.

Genetic Factors

There has been much interest in elucidating the genetic factors contributing to OCD. There seems to be an element of heritability in the pathogenesis of this dis-order. While a number of methodological approaches has been employed, the four most informative have been family, twin, candidate gene, and genome-wide associa-tion studies (GWAS).

Family studies to date have shown that OCD has sig-nificant familial aggregation, occurring more frequently in relatives of affected probands (individuals with the disorder) than in those of control subjects. For example, in their meta-analysis of five studies, Hettema and col-leagues found that the risk of developing OCD was 8.2% in relatives of probands compared with only 2.0% in relatives of unaffected individuals.24 Such studies have also delineated a familial relationship between OCD and tic disorders. In two important genetic studies, Pauls and colleagues25,26 found not only a higher frequency of OCD and subthreshold OCD in relatives of affected pro-bands compared with comparison participants, but also a higher rate of TS and chronic tics in these individuals.26

Furthermore, the prevalence of OCD without either TS or chronic tics was elevated in first degree relatives of people with both OCD and TS, and those with TS only.25 These data suggest an autosomal dominant pattern of inheritance, with incomplete penetrance.

The few twin studies of OCD to date have strength-ened the case for heritability in this disorder. In their review of these studies,27 van Grootheest and colleagues found an estimated heritability of 27–47% in adults (and 45–65% in children). Disease concordance among monozygotic twins (approximately 87%) has also been reported to be far higher than in their dizygotic counter-parts (approximately 47%). Thus, taken together, family and twin studies suggest that OCD risk is often inherited.

However, in order to identify specific candidate genes that may confer an increased risk of OCD, a candidate gene approach is required. In these studies, discrete genes that may be associated with OCD risk or course of disease are identified and characterized. The choice of candidate gene to be analyzed is often based on underly-ing neurobiological mechanisms of disease (see above). Thus, in OCD, serotonergic genes (e.g. those coding for the 5-HT receptors), dopaminergic genes (e.g. those related to the dopamine transporter), noradrenergic genes (e.g. the catechol-O-methyltransferase gene), and glutamatergic genes (e.g. the glutamate receptor, iono-tropic, kainite gene) have been studied. However, owing to the complex phenotype and multifactorial etiology of OCD, it is doubtful that a single causative gene will be identified. Instead, the development of this disorder is likely to be the result of the combined effect of multiple genes. In a meta-analysis of gene association studies published in 2013, Taylor reported a significant associa-tion between OCD and two serotonin-related polymor-phisms.28 A secondary meta-analysis identified another 18 polymorphisms with significant odds ratios. This adds credence to a polygenic model of OCD, with most genes having a modest association with the disorder.

Although a candidate approach is useful in identify-ing specific high-risk genes in OCD, it is also inherently limited. Arbitrary gene selection, insufficient gene cover-age, and negligible potential for new gene discovery are characteristically identified as shortcomings of candidate gene studies. A genome-wide (whole exome) association approach addresses these limitations and is increasingly being used in genetic studies on OCD. For example, in their genome-wide linkage analysis of 56 individuals from seven families (identified through pediatric OCD probands), Hanna and colleagues found evidence for linkage (i.e. the tendency of proximally located genes to be inherited together) on chromosome 9.29 Similarly, in a genome-wide linkage analysis study of 219 families, Shugart and colleagues found suggestive linkage signals on a number of chromosomes, with the strongest evi-dence for linkage emerging for chromosome 3.30 Despite



being more cost, time, and labor intensive than a candi-date gene approach, future GWAS would be of value in further elucidating the genetic etiology of OCD.

TREATMENT OF OBSESSIVE–COMPULSIVE DISORDER

A range of pharmacotherapeutic and psychological interventions has shown efficacy in treating individuals with OCD. SRIs and exposure and response prevention (ERP) are the most widely used therapeutic modalities.

Pharmacotherapy

First Line TreatmentThe role of the serotonergic system in the pathogen-

esis of OCD is well documented and has already been discussed. Thus, it is not surprising that the mainstay of pharmacotherapy for this disorder is the SRIs, primarily clomipramine and the SSRIs.

In the 1960s, clomipramine, a tricyclic antidepressant with marked serotonergic activity, was found to relieve obsessive–compulsive symptoms. Unlike the other tri-cyclics that did not show such efficacy, this agent was found to block potently serotonin reuptake. Thus, inter-est in a serotonergic pathogenesis of OCD was sparked. Before the discovery of the SSRIs, clomipramine was widely considered the standard pharmacotherapy for OCD. In an early large multicenter trial of individuals with OCD and no comorbid depression,31 clomipramine (flexibly dosed to a maximum of 300 mg/day) yielded a statistically and clinically significant improvement in symptoms, when compared to placebo. However, this improvement was not maintained after treatment

discontinuation. Furthermore, the adverse side-effect profile reported by individuals with OCD with and without comorbid depression was problematic. Owing to its receptor binding profile, clomipramine is often associated with symptoms typical of anticholinergic blockers (e.g. constipation, dry mouth, blurred vision), antihistaminic (H1) binding (e.g. sedation, weight gain), and α-adrenergic blockade (e.g. postural hypotension). Like the other tricyclics, clomipramine may also be lethal when taken in overdose, owing to QT interval prolon-gation. Thus, there was a need for an intervention with comparable efficacy but improved tolerability compared with clomipramine.

In the 1980s, SSRIs were adopted as pharmacotherapy for individuals with OCD. While early meta-analyses suggested that clomipramine may be more efficacious than the SSRIs, these publications had numerous meth-odological limitations, and direct head-to-head studies have shown equal efficacy between SSRIs and clomip-ramine. Furthermore, SSRIs are generally better toler-ated and are associated with far fewer adverse effects than clomipramine. Fluoxetine, fluvoxamine, sertraline, and paroxetine have all shown superior efficacy in treat-ing individuals with OCD compared with placebo, and all have received US Food and Drug Administration (FDA) approval for clinical use in OCD. A Cochrane review of placebo-controlled randomized controlled trials (RCTs) and quasi-RCTs examining the efficacy of SSRIs in OCD found that these agents were more effec-tive than placebo in achieving clinical response at post-treatment.32 Pooled effect sizes were similar between individual SSRIs (Fig. 38.2).

In the clinical setting, however, differences in side-effect profile and tolerability between SSRIs may influ-ence treatment decisions. For example, weight gain is

FIGURE 38.2 Comparison of single-photon emission computed tomography (SPECT) images before and after treatment with the selective serotonin reuptake inhibitor citalopram in individuals with obsessive–compulsive dis-order. Source: MRC Unit on Anxiety and Stress Disorders.

TREATMENT OF OBSESSIvE–COMPULSIvE DISORDER 633


more common with paroxetine use, while insomnia and agitation are most often associated with fluoxetine and sertraline use.

Despite some interest in the use of agents other than the SRIs in the acute treatment of individuals with OCD, evidence remains unconvincing. For example, clini-cal trials of monotherapy with venlafaxine (a serotonin and norepinephrine reuptake inhibitor) and with clon-azepam (a benzodiazepine) have yielded inconsistent results. Thus, SSRIs remain the first line choice for indi-viduals with this disorder.

In general, SSRI treatment should be commenced at a low to moderate dose, and then titrated slowly upwards to the maximum tolerated. In their meta-analysis of SSRI dose–response relationships in OCD, Bloch and colleagues found that higher doses of SSRIs were associated with improved treatment efficacy compared with low or medium doses.33 However, these higher doses were also associated with higher participant dropout rates due to adverse effects. Thus, efficacy and tolerability should be balanced to opti-mize treatment adherence.

Acute treatment at the maximally tolerated dose should be undertaken for at least 6–12 weeks. Once a therapeutic response is observed, maintenance therapy should be continued for at least 1 year, and then dis-continued gradually to minimize the risk of symptom relapse. In the long term, there is evidence that some individuals can be maintained at lower therapeutic doses without worsening of symptoms. Further work is warranted to confirm this preliminary result, as reduced-dose maintenance therapy has clear tolerability and adherence benefits.

Treatment ResistanceCurrently, the Y-BOCS is the most widely used stan-

dardized rating instrument to measure an individual’s response to treatment. Full treatment response has been defined by some as a reduction of at least 35% in Y-BOCS score, partial response as a reduction between 25 and 35%, and no response as a reduction of less than 25%. Unfortunately, up to 40% of individuals treated with an optimal SSRI trial exhibit only partial or no response to treatment.

For patients who experience a partial response to SSRI treatment, second line interventions include augmenta-tion strategies. While a number of agents have been used in the clinical setting, the strongest evidence supports the low-dose second generation (atypical) antipsychot-ics, including risperidone, olanzapine, and quetiapine. Early data suggested that these agents should be used specifically in individuals with OCD and comorbid tic disorder, but it is now widely accepted that they are effi-cacious in tic-related and non-tic-related OCD. Haloper-idol, a first generation (typical) antipsychotic, showed

some promise as a useful augmentation agent, but its adverse side-effect profile (and the availability and effi-cacy of the better tolerated atypical antipsychotics) has limited its use.

Experimental TreatmentsAlthough various novel and experimental pharma-

cotherapies for OCD have been investigated, findings have been largely disappointing. Nonetheless, ongoing work in this area is important for continued therapeutic development.

NEUROPEPTIDES

Despite the well-documented role of neuropeptides in the pathogenesis of OCD (see above), clinical efficacy tri-als of these agents are sparse and inconsistent. For exam-ple, in their early RCT, Epperson and colleagues failed to demonstrate any significant difference between intranasal oxytocin and placebo in treating individuals with OCD.34 The fact that peripherally administered oxytocin does not penetrate the blood–brain barrier well (< 0.003% is absorbed) may account for these disappointing findings.

GLUTAMATERGIC AGENTS

There is a growing body of evidence that glutama-tergic abnormalities may be involved in the develop-ment of OCD. This has ignited interest in the utility of glutamate-modulating agents in treating individu-als with this disorder. For example, in an open-label trial of 13 adults with treatment-resistant OCD, seven (54%) of the study participants demonstrated greater than 35% reduction in Y-BOCS scores, with five (39%) being categorized as treatment responders when given riluzole augmentation therapy 50 mg twice daily.35 This agent was well tolerated, with no serious adverse effects documented.

Similarly, 11 out of 16 SSRI-resistant cases in another study responded favorably to topiramate augmentation (mean dose 253.1 ± 93.9 mg/day).36 However, this agent (an anticonvulsant with glutamatergic properties) has also been found to induce the symptoms of OCD, and its use warrants further investigation.

Non-Pharmacological Somatic Treatments

Somatic interventions for individuals with OCD are still in the experimental stage, and should be reserved only for the most severe, resistant cases.

Electroconvulsive TherapyAlthough there have been reports of isolated success

in treating resistant cases of OCD with electroconvulsive therapy, this intervention is likely to be most useful in individuals with severe comorbid depression who are at high risk of suicide.



Repetitive Transcranial Magnetic StimulationThere is preliminary evidence of the efficacy of repetitive

transcranial magnetic stimulation (the use of high-density electromagnetic pulses delivered to the scalp to stimulate or disrupt cortical activity) in the treatment of OCD. How-ever, owing to a relative lack of evidence to date, further work is required before it is widely implemented.

Ablative NeurosurgeryNeurosurgical techniques currently under investi-

gation for the treatment of severe OCD are focused on interrupting CSTC pathways, through cingulotomy and capsulotomy. While there is some evidence of symptom improvement following these procedures, the lack of blinded, comparator-controlled follow-up studies and the irreversible nature of these interventions make them a last resort only.

Deep Brain StimulationAs a reversible, non-ablative alternative to cingulot-

omy and capsulotomy, deep brain stimulation has shown some preliminary promise. This technique involves the implantation of electrodes into neuroanatomical struc-tures believed to be involved in the pathogenesis of OCD. These electrodes remain in situ and deliver an electric current to the structures, aiming to modulate the neurocircuitry of OCD. Multidisciplinary teams in Europe and the USA have found that this intervention resulted in clinically significant symptom reduction and functional improvement in approximately two-thirds of study participants with severe or highly treatment-resis-tant OCD. However, as is the case for the other somatic treatments, deep brain stimulation may be associated with a range of serious adverse events including seizure induction, worsening depression, and asymptomatic hemorrhage, and further study on precise indications is needed.

Psychological Therapy

Expert consensus guidelines suggest that ERP should be the first line psychological therapy for individuals with OCD.37 This intervention comprises controlled, repeated, and prolonged exposure (either in vivo or ima-ginal) to stimuli that are known to provoke obsessional fear, and enforced abstinence from compulsive rituals. For example, an individual suffering from contamina-tion obsessions and compulsive hand washing would be encouraged to touch numerous foreign door handles and handrails, without then resorting to ritualistic hand washing. In the clinical setting, exposure therapy ses-sions should be hierarchical. In other words, individu-als should initially be exposed to less anxiety-provoking situations, which are then escalated gradually. The most

anxiety-provoking stimuli should not be left until the end of treatment, but rather included midway through the schedule. This will allow generalization of treatment effects, as individuals can undergo repeated exposure to the most difficult situations in a variety of contexts.

The effectiveness of ERP in treating obsessive– compulsive symptoms was arguably first shown in early animal laboratory trials. In their study of dogs in par-tially electric-gated shuttle boxes (small rooms divided in two by a hurdle), Solomon and colleagues found that compulsive ritual-like behaviors could be induced in the dogs by pairing a flickering light with an electric shock (that was delivered about 10 seconds after the light).38 The dogs soon learned that, by jumping across the hurdle into the component of the shuttle box that was not electrified, they could terminate exposure to the shock. Thereafter, they learned that they could avoid this exposure altogether by jumping across the hurdle as soon as the flickering light appeared, thus display-ing a conditioned response. Once this was observed, the electric shocks were discontinued, and it was found that the flickering light stimulus alone could induce the conditioning hurdle-jumps; thus, the dogs had acquired obsessive–compulsive-like jumping behavior to reduce the fear and anxiety associated with exposure to the flickering light. Solomon and colleagues then imple-mented an early form of ERP in their canine subjects. The height of the hurdle in the shuttle box was increased so that the dogs could no longer jump over it. Thus, when the flickering light was shown, the dogs were unable to escape – an analogue of response prevention. While initially exhibiting strong signs of fear and distress, the dogs eventually calmed down after repeated exposures to the flickering light (i.e. fear extinction).

These early animal models were applied to human studies during the 1960s and 1970s. Individuals with contamination obsessions and compulsive hand-wash-ing rituals were required to place their hands into a con-tainer with dirt and garbage, and were prevented from washing their hands for some time afterwards. While initially distressed and anxious, these individuals even-tually demonstrated fear extinction with reduced urges to wash, thus reflecting the behavior of Solomon’s dogs.

RCTs have been undertaken to examine the clini-cal efficacy of ERP in managing individuals with OCD. Using the Y-BOCS as an outcome measure, these stud-ies showed that ERP may produce clinically significant improvement in obsessive–compulsive symptoms. For example, in their study of 31 outpatients with OCD, Nakatani and colleagues randomly assigned these indi-viduals to one of three treatment groups: behavior ther-apy (BT) with or without pill placebo; autogenic training (a psychological placebo for OCD) with or without flu-voxamine (FLV); or control group (autogenic training with or without pill placebo).39 Significant symptom

OBSESSIvE–COMPULSIvE SPECTRUM DISORDERS 635


improvement was seen in both the BT and FLV groups compared with the control group. Furthermore, those in the BT group showed significantly more improvement than the FLV group. These findings were supported by a large meta-analytic study, which found substantial post-test treatment effect sizes of 1.16 (self-report measures) and 1.41 (interviewer measures) for ERP in individuals with OCD.40

In the clinical setting, evidence suggests that an acute ERP trial of 13–20 weekly sessions, each lasting for 90–120 minutes, should be undertaken. If time and resource constraints limit this implementation, a trial of seven to 12 sessions has also shown efficacy. If a favorable response to treatment is observed, mainte-nance therapy can then be continued for 3–6 months.37

However, not all individuals with OCD respond to ERP. Broadly speaking, predictors of outcome may be grouped into three main categories: treatment-related factors, individual-related factors, and environ-mental factors. In terms of treatment characteristics, psychoeducation, therapist supervision, combining situa-tional (in vivo) and imaginal exposure, and promoting com-plete response prevention improved treatment outcome. Individual characteristics that may be associated with poorer response to ERP treatment include poor insight, severe comorbid depression, and the presence of promi-nent hoarding symptoms. Finally, while there is some pre-liminary evidence that interpersonal hostility towards the individual may be associated with premature dropout and poorer ERP response, further work is required to elucidate environmental influences on treatment outcome.

There is an emerging body of work investigating the efficacy of mindfulness-based therapy in individuals with OCD. Broadly, mindfulness may be conceptualized as self-regulated attention on the immediate (present) moment, followed by orientation towards one’s experi-ence in the moment, while maintaining an open, curious, and accepting attitude. Recent controlled pilot data indi-cate that a mindfulness intervention (meditation) may be associated with a significant reduction in symptoms, compared with waiting-list control groups. However, further work in this area using larger and clinical sam-ples is needed to evaluate systematically the usefulness of mindfulness-based therapy in OCD.

Combined Treatment

Combined pharmacotherapy and ERP is sometimes used in clinical practice, despite a paucity of empirical evi-dence supporting this approach. Although some studies have reported superior efficacy of simultaneous SRI/ERP therapy compared with SRI monotherapy, these are often limited by methodological biases and low statistical power.

Nonetheless, there is some evidence that adjunctive ERP may be helpful in individuals with SRI-resistant

symptoms. Several studies have reported that ERP augmentation of SRI treatment may lead to significant symptom improvement in individuals who have shown minimal response to pharmacotherapy alone. In a large, well-controlled augmentation study, Tenneij and col-leagues randomly assigned 96 individuals with OCD who had responded to 3 months of drug treatment either to continue drug treatment alone or to receive additional behavior therapy for 6 months.41 Those individuals who had received the additional behavior therapy showed a greater symptom improvement than those who had continued with drug treatment alone.

There is also a body of work examining the efficacy of D-cycloserine, a partial agonist at the glycine modu-latory site on N-methyl-D-aspartate (NMDA) glutamate receptors, in augmenting psychological therapy in treat-ment-resistant individuals. Enhancing NMDA receptor function is hypothesized to promote synaptic plasticity during learning. For example, 100–125 mg D-cycloserine, administered to patients approximately 1–2 hours before each exposure therapy session, may be associated with significant symptom improvement, decreased number of sessions required to achieve significant clinical improve-ment, and reduced therapy dropout rate (compared with a placebo control group). Thus, it seems that combina-tion therapy may be efficacious in individuals who have responded to initial pharmacotherapy and in those who have shown treatment resistance.

OBSESSIVE–COMPULSIVE SPECTRUM DISORDERS

It has long been hypothesized that OCD may be phe-nomenologically and etiologically related to a number of other conditions along the spectrum of disease. While there is no clear consensus about which disorders should be considered along this spectrum, putative inclusions are TS, somatoform disorders such as BDD, and tricho-tillomania and skin-picking disorder. The DSM-5 chap-ter on obsessive–compulsive and related disorders now includes several of these conditions.2

Phenomenological Correlates

The hallmark feature of OCD and the related disor-ders is the presence of unwanted repetitive symptoms. Individuals with TS experience motor and vocal tics, those with BDD often experience intrusive thoughts of imagined ugliness and may resort to repetitive behaviors such as mirror checking, and trichotillomania is diagnos-tically characterized by a compulsive urge to hair pull. In all disorders, obsessive thoughts are distressing and are often only relieved by completion of the correspond-ing compulsive act. Furthermore, OCD and the related



disorders often coexist. For example, tics are more com-mon in individuals with OCD than in the general popu-lation, and people with TS often also have OCD.

However, several important phenomenological dif-ferences distinguish OCD from these disorders. For example, while the tics associated with TS are often involuntary, individuals with OCD exhibit goal-directed behavior (e.g. compulsive hand washing to relieve con-tamination-related anxiety). Individuals with BDD are preoccupied solely with their appearance, while those with OCD may experience a wide range of obsessions. Clinical comparisons have also yielded significant dif-ferences between OCD and the spectrum disorders. For example, while OCD has been found to be associated with more lifetime disability and comorbidity, treat-ment response rate among people with trichotilloma-nia is reportedly lower. Furthermore, individuals with OCD have reported more harm avoidance and mal-adaptive beliefs. These and other differences between OCD and the related disorders may indicate important discrepancies in underlying pathogenesis, which could, in turn, influence response to treatment.

Neurobiological Correlates

Structural and functional imaging studies have shown the involvement of the CSTC in individuals with TS and with BDD, suggesting an overlap in pathogenesis with OCD. Although there is some evidence to suggest a central role of the cerebellum in the pathogenesis of trichotillomania, work by Chamberlain and colleagues supports a CSTC neuroanatomical model.42 For example, in a morphometric MRI study, individuals with tricho-tillomania showed increased gray matter density in the striatal, amygdalohippocampal, and cortical regions compared with healthy controls.42

Neurogenetic Correlates

Several family and twin studies (as well as some molecular genetic data) support a genetic link between OCD and the related disorders. For example, a segrega-tion analysis study of 30 nuclear families indicated that first degree relatives of probands with TS were more likely to have TS, TS or chronic tics, and OCD compared with relatives of control subjects.43 This supports an etio-logical link between OCD, TS, and chronic tics. Similarly, a large study of 2148 female twins (1074 pairs) examin-ing genetic and environmental covariance between BDD and OCD found a significant genetic overlap between these two conditions, whereas environmental factors did not contribute substantially to their covariation.44

Candidate genetic studies of trichotillomania have also sought to identify specific genes that may predis-pose individuals to developing this disorder. While such

a gene has not yet been identified, there is evidence that common genetic risk factors may contribute to the devel-opment of trichotillomania and OCD. In a case–control association study, Hemmings and colleagues investi-gated the role of serotonergic and dopaminergic genes in mediating these disorders.45 In the study sample of 39 individuals with trichotillomania, 250 with OCD, and 152 control subjects, these authors found that the 5-HT receptor 2A (5-HT2A) gene may be involved in the molecular etiology of trichotillomania.

Bienvenu and colleagues investigated whether varia-tion in the human Sapap3 gene was associated with OCD and grooming disorders (pathological nail biting, patho-logical skin picking, and trichotillomania) in 383 fami-lies.46 This gene codes for the SAP90/PSD95-associated protein (SAPAP) family of proteins: postsynaptic den-sity (PSD) components that interact with other proteins at glutamatergic (excitatory) synapses to form essential scaffolding. Four of the six single-nucleotide polymor-phisms (SNPs) of the Sapap3 gene were associated with at least one grooming disorder, although none of the SNPs was associated with OCD. Thus, while this gene holds promise in elucidating the genetic etiology of grooming disorders and OCD, further work is required to bolster this preliminary evidence.

Pharmacotherapeutic Correlates

The association between OCD and the spectrum dis-orders is further evidenced by their treatment response pattern. Broadly, individuals with any of these condi-tions seem to show some symptom improvement when treated with SRIs. However, while SRIs are the first line pharmacotherapeutic option for individuals with OCD and BDD, those with TS have shown preferential response to dopamine antagonists (e.g. risperidone), and clomipramine showed efficacy superior to the SSRIs in individuals with trichotillomania in a systematic review and meta-analysis (while habit-reversal therapy was superior to both pharmacological agents).

Taken together, these data suggest that similarities and associations between OCD and the related disorders exist. However, significant differences have also been demonstrated. Thus, the idea of OCD and related disor-ders may be clinically useful, provided these important distinctions in diagnostic validity are borne in mind.

OBSESSIVE–COMPULSIVE DISORDER IN PEDIATRIC POPULATIONS

While the focus of this chapter has been adult OCD, pediatric populations also warrant mention, as up to 80% of individuals report symptom onset before age 18. Broadly, the clinical presentation in children and

REFERENCES 637


adolescents mimics that in adults, with obsessive– compulsive symptoms concerning contamination/washing and symmetry/ordering emerging as among the most prevalent. However, the DSM-5 stipulates that young children may not be able to articulate the aims of these behaviors or mental acts.2 Despite having a popu-lation prevalence of approximately 1–4%, pediatric OCD remains underdiagnosed and undertreated. Further-more, early-onset OCD is often associated with greater severity and poorer treatment response than in adult populations. As is the case in adults, SRIs remain the first line pharmacotherapy for children and adolescents with OCD, with the SSRIs preferable to clomipramine owing to their more favorable side-effect profile. Inclusion of CBT in the therapeutic regimen (particularly at the time of treatment initiation) has also shown efficacy in pediat-ric populations. Indeed, non-pharmacological interven-tions may be preferable in children and adolescents to avoid the adverse effects of drug treatment. However, much remains to be learned of the optimum treatment of pediatric OCD (including maintenance therapy and treatment-resistant cases), and more work in this area is warranted.

CONCLUSION

While obsessive compulsions have long been docu-mented in historical, literary, and scientific data, OCD has only recently emerged as an archetype of a neuro-psychiatric disorder. Much has already been uncovered about the neuroanatomy, neurochemistry, neuroimmu-nology, neuroendocrinology, and neuroethology of this disorder. Nonetheless, further work is needed to elu-cidate and integrate the precise factors involved in the pathogenesis of OCD, and may ultimately contribute to expanding current therapeutic strategies.

QUESTIONS FOR FURTHER RESEARCH

Although there are several animal models of OCD, additional research is needed if we are to move from bench to bedside. Do these animal models have face validity at different developmental periods, what is the precise neuroanatomical and molecular basis of compul-sive symptoms in these different models, and what is their response to a range of different interventions?

Clinical neuroscience research on OCD, including brain imaging and neurogenetics, has led to a series of neurobiological models of OCD, but much remains unknown. What light will new genetic methods includ-ing new-generation sequencing and gene expression studies shed on the neurobiology of OCD? Can new brain imaging methodologies provide new insights?

Will the integration of imaging and genetic databases, with longitudinal clinical data, lead to a better under-standing of risk and resilience factors in OCD?

Clinical trials in OCD have provided evidence for both first line interventions and some treatments of refractory cases, but much further work is needed. How effective are treatments in real-world settings (rather than in aca-demic contexts)? Will agents with novel mechanisms of action relevant to OCD (e.g. glutamatergic agents) prove efficacious? What is the optimal way to sequence phar-macotherapy, psychotherapy, and their combination in the treatment of OCD?

Epidemiological studies from around the world have shed light on the enormous public health burden of OCD. What is the cross-national prevalence of obses-sive–compulsive and related disorders as a whole? What do community studies reveal about their risk and resil-ience factors? What is the optimal way to improve the recognition, diagnosis, and treatment of OCD in primary care and low- and middle-income settings?

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Neurobiology of Brain Disorders || Obsessive–Compulsive Disorder