Heterogeneity of Obsessive-Compulsive Disorder: A Literature Review

6 downloads 0 Views 148KB Size Report
heterogeneity of this disorder. A computerized literature search (MEDLINE: 1964–2001) was used to collect studies addressing the heterogeneity of OCD.
REVIEW

Heterogeneity of Obsessive-Compulsive Disorder: A Literature Review Christine Lochner, MA, and Dan J. Stein, MD, PhD

Significant advances have been made in characterizing the phenomenology and psychobiology of obsessive-compulsive disorder (OCD) in recent years. In many ways, such advances suggest a conceptualization of OCD as a relatively homogeneous neuropsychiatric entity, underpinned by particular mechanisms that manifest in universal symptoms. Nevertheless, some data have pointed to the heterogeneity of this disorder. A computerized literature search (MEDLINE: 1964–2001) was used to collect studies addressing the heterogeneity of OCD. In addition, reviews of the phenomenology, psychobiology, family studies, and treatment of OCD were examined in an attempt to collate data addressing this issue. There is a growing consensus that some subtypes of OCD are valid and provide a useful means of integrating data on its symptomatology, neurobiology, and treatment response; for example, OCD with comorbid tics is characterized by earlier onset, a particular range of OCD symptoms, and worse response to selective serotonin reuptake inhibitors. The heterogeneity of OCD has important clinical and research implications. (HARV REV PSYCHIATRY 2003;11:113–132.) Compulsive, dopamine, impulsive, obsessive-compulsive disorder, OCD spectrum disorders, serotonin, subtypes

Significant advances have recently been made in characterizing the phenomenology and psychobiology of obsessivecompulsive disorder (OCD). In the clinic, the diagnosis of OCD is made with increasing frequency,1 and in the research setting, the empirical investigation of OCD has increased.2

From the MRC Unit on Anxiety Disorders, Department of Psychiatry, University of Stellenbosch, Cape Town, South Africa. This work was supported by the Medical Research Council of South Africa. Original manuscript received 29 August 2002, accepted subject to revision 15 October 2002; revised manuscript received 21 November 2002. Reprint requests: Christine Lochner, MA, MRC Unit on Anxiety Disorders, University of Stellenbosch, P.O. Box 19063, Tygerberg 7505, Cape Town, South Africa. Email: [email protected] c 2003 President and Fellows of Harvard College 

DOI: 10.1080/10673220390217926

Rigorous studies have addressed the epidemiology,3,4 symptomatology,5,6 neuroanatomy,7,8 neurochemistry,9–11 pharmacotherapy,12–14 and psychotherapy15,16 of OCD. Such advances have contributed to the initial conceptualization of OCD as a relatively homogeneous and specific neuropsychiatric entity, underpinned by particular mechanisms that manifest in universal symptoms. Until relatively recently, the predominant approach to this disorder derived from psychodynamic theory, which posited that OCD emerges as the result of unconscious conflicts.17 In response, however, to increased evidence that OCD is mediated by specific brain regions and by particular neurochemical systems, a neuropsychiatric approach has come to be generally preferred.10,11,18,19 At the same time, research findings have undercut the view that OCD is a homogeneous disorder. Although the cardinal symptoms of OCD are remarkably consistent across cultures, its features and course are variable.20,21 This heterogeneity has possibly confounded clinical and biological investigation and may explain why there have been so many inconsistent findings in studies of OCD. Subtyping OCD on the basis of phenomenology or psychobiology may serve several purposes, perhaps allowing for a more precise determination of the pathogenesis of OCD symptoms, for a

113

Harv Rev Psychiatry

114

Lochner and Stein

more accurate projection of future outcomes, and for better treatment. In this article, and with a view to identifying results that are significant for clinicians and researchers, we review studies that have addressed heterogeneity in the phenomenology, psychobiology, family studies, and treatment response of OCD.

METHODS A computerized MEDLINE search (1964–2001) of the OCD literature was conducted to collate articles that addressed the heterogeneity of this disorder. MEDLINE search terms included “obsessive-compulsive disorder,” “obsessivecompulsive spectrum,” “subtypes” and “subtyping,” and “heterogeneity.” In addition, reviews of the phenomenology, psychobiology, family studies, and treatment of OCD were examined as a means of obtaining data on the heterogeneity of this disorder. Relevant empirical studies are summarized and presented herein.

RESULTS: PHENOMENOLOGY Symptom Clusters The symptoms used to define OCD are diverse and include a range of obsessions and compulsions. The predominant symptoms in OCD have been well documented and include (1) concerns about contamination or illness, along with compulsive cleaning or washing, (2) obsessive doubt, along with checking rituals, (3) concerns about, and compulsions regarding, symmetry, orderliness, and numbers, (4) hoarding/collecting rituals, and (5) obsessional slowness.5,6,22 An alternative strategy to focusing simply on specific symptom types has been to explore symptom clusters or factors; studies have documented that the various OCD symptoms cluster into different “factors.”23–28 An early principalcomponents factor analysis of the Maudsley Obsessional Compulsive Inventory (MOCI) in 100 patients yielded four factors: “checking,” “cleaning,” “slowness,” and “doubting.”26 The MOCI comprises only 30 items, however, which are biased toward the symptoms of cleaning and checking, while other symptoms, such as aggressive obsessions and hoarding compulsions, are underrepresented.23 Furthermore, at any one time, OCD patients may have symptoms from more than one of these four clusters, and symptoms may evolve over time from one symptom cluster to another.5,6 Van Oppen and colleagues27 evaluated the factor structure of a similar scale—the Padua Inventory29 —and five factors were identified: “impulses,” “washing,” “checking,” “rumination,” and “precision.”

May/June 2003

The Yale-Brown Obsessive-Compulsive Scale symptom checklist (Y-BOCS)30 corrects the item-selection bias of the MOCI and Padua Inventory.23 Baer’s factor analysis of the Y-BOCS yielded three factors: “symmetry/hoarding,” “contamination/cleaning,” and “pure obsessions.”23 Leckman and colleagues24 more recently identified four different dimensional factors using the Y-BOCS: “obsessions and checking,” “symmetry and ordering,” “cleanliness and washing,” and “hoarding.” Using the same instrument, Summerfeldt and colleagues25 confirmed these findings with their specification of “obsessions/checking,” “symmetry/ordering,” “contamination/cleaning,” and “hoarding.” A recent study by Calamari and colleagues28 identified five definitive symptom-based groupings based on the Y-BOCS symptom checklist: “harming,” “hoarding,” “contamination,” “certainty,” and “obsessionals”; the core symptoms of these identified subgroups were comparable to factors identified in previous studies with the Y-BOCS.23–25 Drawing on the work of Janet (reviewed by Pitman),31 Rasmussen and Eisen32 have suggested that OCD can be subtyped on the basis of three core features—namely, abnormal risk assessment, pathological doubt, and incompleteness. These core features are related to the clinical features of OCD and to comorbid disorders. More specifically, symptoms involving incompleteness are likely to be associated with tics and compulsive personality traits, while other symptoms are likely to be associated with increased anxiety and comorbid anxiety disorders.32 Baer23 has provided empirical data partially consistent with such a thesis, noting that the “symmetry/hoarding” cluster of symptoms, which is often characterized by incompleteness, was significantly related to tics (Tourette’s Syndrome [TS] or chronic tic disorder) and to obsessive-compulsive personality disorder. In terms of prevalence of the various OCD symptom subtypes, an examination of 65 studies that classified patients according to such subtypes found that patients with primarily cleaning or checking compulsions predominated, accounting for 75% of the treatment population.33 Patients with multiple compulsions or other compulsions such as exactness, counting, hoarding, or slowness rituals were underrepresented, making up only 12% of the subjects— which is markedly less than clinical epidemiological estimates.33 Early retrospective studies found a relationship between the type of OCD symptom at baseline and other demographic and clinical variables, including comorbidity. For example, a study by Khanna and Mukherjee34 suggested that checkers can be sociodemographically and clinically differentiated from washers. Another study found a significantly higher rate of sexual and religious obsessions, and a significantly lower rate of checking rituals, in OCD patients with comorbid bipolar disorder, compared to nonbipolar

Harv Rev Psychiatry

Lochner and Stein

Volume 11, Number 3

115

OCD patients.35 Frost and colleagues36 found that, compared to nonhoarding OCD and other anxiety disorder patients, OCD patients with hoarding scored higher on anxiety, depression, and social disability. In contrast, however, to the above findings that linked OCD symptomatology at baseline with other clinical variables (such as comorbidity), a prospective longitudinal study of 79 children and adolescents with OCD5 found no significant relationship between the type of OCD symptom at baseline and age, gender, or duration of illness. Similarly, in a series of 250 OCD patients, Rasmussen and Eisen37 found no significant relationship between the type of symptom and age at onset, gender, course of illness, or comorbid conditions. It is nevertheless possible that the above studies did not include enough subjects having potentially unique symptoms,38 and thus lacked the power to show a relationship between rarer symptoms and demographic or clinical variables. For example, it has been suggested that “obsessional slowness” (the tendency towards pathological orderliness and having to undertake tasks in a precise and particular pattern), as originally characterized, can be differentiated from slowness secondary to rituals.39 Later authors have argued, however, that such cases can invariably be reanalyzed as secondary to obsessions, compulsions, or avoidance strategies,40,41 and therefore do not carry particular clinical significance. Symptoms may differ in OCD patients along several other variables, such as insight, duration of illness, continuity of symptoms, ratio of obsessions to compulsions, bizarreness of obsessions, fixity of belief, control over symptoms, resistance to symptoms, and overall severity. We discuss insight next and will return to some of the other variables in the later discussion of treatment response.

last 15 years’ research on hoarding behavior, Damecour and Charron50 found that a number of studies agreed that patients with hoarding show poor insight, lack of resistance to the compulsion to hoard, and poor treatment motivation. Conversely, Matsunaga and colleagues47 found that OCD patients with poor insight were relatively (although not significantly) more likely to have hoarding and repeating rituals, as well as symmetry obsessions. Other variables have also been associated with level of insight. In one study, poor insight was linked with greater severity of OCD symptoms, higher frequency of a history of psychiatric disorders during childhood, and higher frequency of schizophrenia spectrum disorders in first-degree relatives.51 A number of studies have replicated the finding of an association between poor insight and severe OCD.47,52 In another study, poor insight was linked with the presence of health concerns.53 Current age, age of onset, and course may also be associated with the level of insight; for instance, juvenile OCD has been associated with frequent absence of insight.54 Matsunaga and colleagues47 found that OCD patients with poor insight tended to have a younger age of onset and a longer duration of illness, and were less likely to married, than those with good insight. It has also been found that OCD patients with poor insight are more likely to have comorbid cluster A (especially schizotypal) or cluster C (especially obsessive-compulsive) personality disorders (PDs) than patients with good insight.47 This finding is consistent with data from another study showing that patients with psychotic or delusional OCD symptoms have a relatively increased rate of cluster A PDs.55 In sum, poor insight appears to be most consistently associated with hoarding behavior, younger age of onset, and increased rates of comorbid cluster A PDs.

Insight

Gender

Traditionally, awareness of the senselessness of obsessions is referred to as insight, and the accompanying struggle against the obsessions is referred to as resistance.42 There is growing recognition of the extent to which insight into symptoms varies in OCD individuals.43–47 A subtype of “poor insight” was included in the DSM-IV criteria for OCD.48 A recent review of insight among OCD patients concluded, however, that OCD cannot satisfactorily be dichotomized into those with good and poor insight, and that the notion of a continuum of beliefs is more appropriate.49 It has been suggested that patients at the severe end of this spectrum are best described as having an “obsessive-compulsive psychosis.”43 Although a few researchers have posited a relationship between type of OCD symptom and level of insight,47,50 the available data on the association between insight and symptom subtypes are relatively limited. In a summary of the

Although there are some inconsistencies, gender-related differences have been observed in OCD symptomatology. Cleaning symptoms34,56–62 and aggressive obsessions58 have been reported to be more common in females with OCD, while primary obsessive slowness,56 obsessions/compulsions (symmetry and exactness5,58 and numbers),63,64 touching rituals,65 and sexual56,58 or “odd”58 symptoms have been found to be more common in OCD males. It should be noted, however, that some studies provide contrasting findings, such as increased contamination obsessions in males.65 Zohar66 suggested that, similar to adults, there may also be gender differences in the symptom types in children and adolescents with OCD (e.g., more checking behavior in boys, and more cleaning behavior in girls). Evidence shows that the course of OCD may also be affected by gender. For example, in addition to evidence that OCD has a worse course in males,57 some studies indicate that males predominate

Harv Rev Psychiatry

116

Lochner and Stein

in childhood OCD6,57,58,67 and are more likely to have a chronic rather than episodic course.57,68,69 It should be noted, however, that not all studies agree that the course of OCD is worse in males.58 Several studies have found that gender may significantly affect comorbidity. Increased comorbidity of depression,57,67 eating disorders,56,57,67,70–72 and panic attacks58 has been reported in females with OCD, and increased comorbidity of social phobia,56,59 substance-related disorders,56,67 and hypomanic episodes35,56,58 has been reported in OCD males. These findings are generally consistent with the prevalence rates of such disorders in non-OCD populations. Based on reports of increased comorbidity of depression in women with OCD,57,67 it has been suggested that the greater frequency of later-onset OCD in women is partially explained by the wellknown association of depression and obsessive-compulsive phenomena.67 Furthermore, differential PD pathology between males and females has been noted. For example, in a study of PDs and social and interpersonal features among Japanese patients with OCD, it was found that cluster A PDs, especially schizotypal PD, were more frequently diagnosed in males, and borderline and dependent PDs, in females.73 Evidence from twin and family studies supports a role for gender in the genetics of OCD. For example, a recent segregation analysis of families provided some evidence for a major gene underlying OCD.74 Of particular interest in this study was evidence for genetic heterogeneity on the basis of sex of the proband—which supports the hypothesis of different genetic/environmental exposures in at least some families with OCD.74 Similarly, on the basis of their segregation analysis, Cavallini and colleagues75 suggested a dominant model of transmission with penetrance differing in males and females. The possibility of gender differences in genetic susceptibility for OCD has also been suggested by Camarena and colleagues.76 This particular study replicated the findings of a sexually dimorphic effect of the MAO-A gene in OCD (an excess of allele 1 in OCD females with major depressive disorder was confirmed), indicating that OCD females have lower MAO-A activity than OCD males. Arguably, the worse outcomes for OCD males could be explained by early brain trauma or similar neurological dysfunction. It is notable that when compared to female patients, male patients appear to have more neurological soft signs, which include abnormalities of fine motor coordination, as well as visual-spatial dysfunction and involuntary and mirror movements.77 (Similarly, OCD males are more likely to have tics—see discussion below.) By comparison, females may present with OCD during the menarche,37 the premenstrual phase,78 pregnancy,79,80 puerperium,81,82 and even menopause (Lochner C et al., unpublished data). Based on such findings, it may be hypothesized that some forms of OCD may involve gender-specific mechanisms, including

May/June 2003

hormonal and genetic ones83–85 (see below). Further work is necessary to delineate the precise mechanisms involved. In general, there do appear to be gender differences in the genetics, course, and clinical manifestations of OCD. Gender differences in comorbid psychiatric disorders generally match the gender differences for these disorders in non-OCD population. Overall, when compared to women with OCD, males with OCD appear to have earlier onset, a more severe course, and more neurological soft signs.

Age of Onset There appears to be much continuity between the clinical presentation of OCD in childhood and that in adulthood.5,86–90 For example, Rapoport and colleagues87 found that obsessive-compulsive symptoms typically changed over time (from childhood to adulthood) but that almost all subjects at some time experienced excess washing as one of their symptoms. Nevertheless, differences between child and adult OCD are also apparent, including differences in the gender distribution, patterns of comorbidity, and familial loading.91 Thus, it has been suggested that childhood-onset OCD represents a phenomenologically and etiologically distinct subtype of OCD, bearing a close genetic relationship to tic disorders and possibly sharing a common or similar pathogenesis.54,91 For example, a recent study by do Rosario-Campos and colleagues92 found that early onset was associated with higher frequencies of sensory phenomena and of comorbid tic disorders, and with higher severity and frequency of tic-like compulsions. Likewise, in contrast to adults, children with OCD often present with pure compulsions—for example, washing compulsions and repeating compulsions.86 It has also been suggested that patients with a very early onset of OCD (younger than six years old) were more likely to have compulsions rather than obsessions.6,93 These compulsions would typically include elaborate washing or checking rituals without cognitive obsessions.94 As indicated earlier, however, the relationship between symptom clusters and variables such as age and gender has not always been consistent across studies. Relatively little work has focused on OCD in the elderly. One nonreplicated study found that compared to younger patients, elderly patients had a later age at onset.95 Weiss and Jenike96 recently found that in an OCD patient population of over 1000, onset of OCD after 50 years of age is rare (only 5 cases in the entire sample).96 In an investigation of possible family subtypes, Nestadt and colleagues74 found that age of onset of obsessivecompulsive symptoms in the case proband is strongly related to familiality; no case of OCD symptoms was detected in the relatives of patients whose age of onset was 18 years or older. Similar findings by others97,98 support the hypothesis that familial loading for OCD is associated with early onset.

Harv Rev Psychiatry Volume 11, Number 3

Thus, early age of onset may be valuable in characterizing a familial subtype of OCD (see “Results: Family Studies” below). To summarize, when compared to later-onset OCD, childhood-onset OCD is associated with higher rates of compulsions and comorbid tic disorders. In addition, childhood-onset OCD appears to be much more strongly genetically transmitted.

Comorbidity Some researchers have attempted to identify OCD subgroups by examining comorbid conditions. It has been suggested that a range of comorbid Axis I disorders is commonly seen in OCD, with depression the most frequent of these.5 In addition, a study by Eisen and colleagues99 found that the most common Axis I lifetime comorbid diagnosis was major depressive disorder (55%), followed by social phobia (23%), simple phobia (21%), and generalized anxiety disorder (GAD; 20%). Comorbidity with posttraumatic stress disorder (PTSD) has also been shown.100 Increasing attention has also been paid to overlapping phenomenological and neurobiological features of OCD and obsessive-compulsive spectrum disorders (OCSDs), such as body dysmorphic disorder (BDD), TS, and trichotillomania. A study by Du Toit and colleagues101 showed that 57.6% of the 85 participants with OCD currently met criteria for at least one putative OCSD, and that 67.1% had a lifetime history of at least one comorbid OCSD. In that study, the OCSDs with the highest prevalence were compulsive self-injury (22.4%), compulsive buying (10.6%), and intermittent explosive disorder (10.6%). Bienvenu and colleagues102 investigated the relationship of OCD to somatoform disorders, eating disorders, pathologic “grooming” conditions, and other impulse-control disorders using blinded family-study methodology, and found that BDD, hypochondriasis, any eating disorder, and any grooming condition occurred more frequently in OCD relatives. A family study using similar methodology found that only GAD and agoraphobia were more common in case relatives than in control relatives (independent of a diagnosis of OCD) and that these disorders share a common familial etiology with OCD.74 Emerging evidence shows that obsessions and compulsions are more often comorbid with schizophrenia than was previously thought.42 For instance, from a total of 475 OCD patients, Eisen and Rasmussen103 identified 14% as having psychotic symptoms in addition to the diagnosis of OCD. Compared to the OCD patients without psychosis, probands with OCD and psychotic features were more likely to be male, be single, have a deteriorative course, and have had their first professional contact at a younger age.103 Data from a study by Perugi and colleagues35 also indicate that when comorbidity occurs with bipolar and unipolar affective disor-

Lochner and Stein

117

ders, it has a differential impact on the clinical characteristics, comorbidity, and course of OCD. Indeed, in a consecutive series of 315 OCD outpatients, 15.7% had such comorbidity (mostly with bipolar II disorder).35 It has also been found that a tic history among individuals with OCD was likely to distinguish a genetically meaningful subtype. For example, there appears to be an association between tics, male gender, early age of onset, and disruptive behavior disorders in younger patients.104 Also, a range of studies comparing OCD patients with and without tics has reported interesting differences in symptomatology and the rates of specific obsessions and compulsions.105–108 In a comparison of patients with OCD alone and patients with both OCD and TS, for example, the former group was more likely to have (1) contamination obsessions and compulsions, (2) fear of not saying the right thing, and (3) BDD, while the latter group was more likely to have (1) an obsession with the need for symmetry accompanied by magical thinking, (2) fear of doing something embarrassing or of blurting out an obscenity, (3) intrusive violent or sexual images and thoughts, (4) touching compulsions, (4) blinking or staring rituals, (5) self-injurious compulsions, (6) hoarding, and (7) counting.109 Other studies reached similar conclusions,24,105,106,108,110–112 with some exceptions.111 The neurobiology of OCD with tics is discussed further below. A range of comorbid Axis II disorders has also been found in OCD patients, with those of cluster C the most prevalent.113–119 Mavissakalian and colleagues118 found an association between increased PD traits and symptom severity, while the most important correlate of PD on regression analysis was dysphoric mood. Similarly, Baer and Jenike120 found a correlation between an increased number of PDs and symptom severity, as well as an interesting correlation between the presence of a cluster A PD and symptom severity. Schizotypal traits have been associated with obsessive-compulsive symptoms among psychiatric outpatients.103,121,122 Offering further validation of a schizotypy subtype in OCD, Sobin and colleagues123 found that 50% of their OCD sample manifested mild to severe schizotypal traits. Schizotypy in their sample of 119 OCD patients was associated with three clinical features that have previously been associated with psychosis—counting compulsions, learning disabilities, and phobia. As mentioned earlier, schizotypal PD was found to be more common in OCD patients whose insight remained poor even after treatment47 (see “Insight” above). Comorbid schizotypal PD in OCD patients with poor insight may be associated with worse prognosis (see “Results: Treatment” below). Although it was previously thought that obsessivecompulsive neurosis was related to obsessive-compulsive character,124 Samuels and colleagues125 found that case probands and case relatives had a high prevalence of

Harv Rev Psychiatry

118

Lochner and Stein

obsessive-compulsive PD (OCPD) and high neuroticism scores, and that neuroticism was associated with OCPD in case, but not control, relatives. These results suggest that neuroticism and OCPD may share a common familial etiology with OCD. Overall, OCD has high rates of comorbidity with a numbers of Axis I and II disorders. Among Axis I disorders, MDD, OCSDs, and tic disorders are among those most often comorbid with OCD; OCD with tics may represent a genetically meaningful subtype. Among Axis II disorders, Cluster C traits are commonly comorbid with OCD, and OCD patients with schizotypal PD may represent a subtype with a relatively poor prognosis.

Course Several studies support theories of OCD as an illness with fluctuating severity68 and varied clinical manifestations that change over time.6 The course of OCD has been differentiated into different groups, including episodic and continuous/chronic,69 with OCD being chronic in approximately half of all cases.126 It has been suggested that factors such as age, gender, and severity of childhood OCD symptomatology may play a role in the course of the condition (i.e., as episodic or chronic).69 In one study, for example,68 it was found that in childhood, more females than males have an episodic course of OCD, whereas just as many females as males suffered from OCD, either chronically or episodically, in adulthood. In agreement with studies indicating that patients with an episodic course of the disorder may be a distinct subgroup within the whole group of obsessive-compulsive patients, multivariate stepwise discriminant analysis revealed a positive and significant relationship between episodic course, on the one hand, and family history of mood disorders, lifetime comorbidity for panic and bipolar II disorders, late age of onset, and negative correlation with GAD, on the other.127 In a retrospective study of 62 OCD patients, the long-term course of OCD and its relationship to depression were investigated. Five courses of OCD were differentiated: continuous and unchanging (27.4%), continuous with deterioration (9.7%), continuous with improvement (24.4%), episodic with partial remission (24.2%), and episodic with full remission (11.3%). There was no difference between primary versus secondary depression on the prognosis of OCD, and there was also no difference between continuous versus episodic course on either primary or secondary depression.128 In one study, however, it was found that severity of OCD in childhood plays a determining role in the course and outcome of OCD; that is, longer duration of obsessive-compulsive symptoms in childhood (chronic course) predicts a poor outcome (presence of OCD) in adulthood.68 Furthermore, some studies have found a correlation between continuous course

May/June 2003

and poorer response to pharmacotherapy129,130 (see “Results: Treatment” below). It remains unclear what factors predict a chronic deteriorative course.32

RESULTS: PSYCHOBIOLOGY Tics The relationship between OCD and tics has long been a subject of speculation; patients with OCD have been found to have high rates (37–59%) of tics and tic disorders in some studies.110,131 Furthermore, family studies of OCD probands have revealed tics in at least 17% of adult patients and increased rates of tics in their first-degree relatives.98,106 Similarly, an OCD family study found that younger age of onset of OCD symptoms and possibly male gender in probands were associated with increased tic disorders in relatives (see “Results: Family Studies” below), suggesting that tic disorders constitute an alternate expression of the familial OCD phenotype.132 It has been found that certain obsessions and compulsions are more common in OCD patients with tics; for example, one of the three symptom clusters identified by Baer23 —“symmetry/hoarding”—was significantly related to comorbid OCPD or a lifetime history of TS or chronic tic disorder. Together with the familial transmission and treatment data (see below), this finding suggests that these patients may represent a meaningful OCD subtype. Clinical research has documented this bidirectional overlap between TS and OCD from phenomenological, comorbidity, and familial-history perspectives.133 Conversely, a subgroup of patients with TS has OCD,124 with observed rates ranging from 12 to 90%.134,135 Interestingly, tics were found more useful than obsessions or compulsions in distinguishing relatives of patients with OCD from relatives of control subjects. OCD and tics may also both be seen after neuroimmunological insult (see “Neuroimmunology” below). Regional cerebral blood flow patterns in individuals with obsessive-compulsive behavior in families affected by TS are comparable to their relatives with TS, and differ from individuals with primary OCD but with no family history of tic disorders.136 Together with previously discussed data, this finding supports the hypothesis that at least some forms of OCD are genetically related to TS.137 Such an hypothesis would explain the frequent comorbidity of OCD and TS, the familial relationships between the two disorders, and the neurochemical overlap in their treatment.

Neuropsychiatry Studies Several neurological disorders may result in OCD symptoms, although such patients may form only a small

Harv Rev Psychiatry

Lochner and Stein

Volume 11, Number 3

proportion of those having OCD.138 Conversely, OCD patients differ in extent and location of neuropsychiatric impairment,77 and these differences may be useful in subtyping the disorder. Neuropsychiatric heterogeneity may be seen with regard to neurological soft signs, neuropsychological function, electroencephalography (EEG), and brain imaging. OCD patients have elevated levels of neurological soft signs compared to normal controls.139 Hymas and colleagues140 found that patients with obsessional slowness invariably had increased neurological soft signs. In addition, it has been suggested that patients with increased neurological soft signs may have increased ventricular-brain ratio in comparison to normal controls.141 Increased neurological soft signs may also predict poor response to pharmacotherapy.139,142 Furthermore, a specific OCD clinical profile may be correlated to organicity; for instance, Thomson and Jensen143 compared 61 child and adolescent OCD patients with 177 matched control patients for organic features as assessed by neurological signs, electrophysiological abnormalities, specific developmental disorder, and attention deficit. Significantly more OCD patients than controls were assigned to the organic class, with neurological soft signs being the most sensitive and specific indicator of organicity. Behavioral problems and loss of temper were significantly more frequent in the nonorganic class, whereas symptoms of phobia and depression were more often present in the organic class. Yaryura-Tobias and colleagues144 also investigated an “organic” and a control, “nonorganic” group of OCD patients and found some differences in their clinical profiles. A subgroup of OCD patients has abnormal EEGs.77 Similarly, Deltito145 suggested that some OCD patients have symptoms like those of temporal lobe epilepsy, such as irritability, confusion, psychosis, or other cognitive impairments—which may well have implications for treatment. Quantitative EEG patterns have also been reported to differ between responders and nonresponders to medication.146 Functional neuroimaging studies have advanced the understanding of the brain mediation of OCD by orbitofrontalsubcortical circuitry,147 but much is still unknown.148 Indeed, it has been suggested that phenotypic heterogeneity may account for many of the inconsistencies among previous neuroimaging studies of OCD.7,149–152 Slowness of thinking (bradyphrenia) and slowness of movement (bradykinesia) are symptoms of subcortical neurological disorders— for example, those of the basal ganglia, such as Parkinson’s disease.149,150 Similarly, obsessional slowness in OCD patients may reflect basal ganglia damage, but rather than being a separate group of OCD patients, these patients may simply be a subtype with more severe psychopathology. Functional brain imaging has documented that OCD patients have increased prefrontal activity compared to

119

normals.19 Positron emission tomography studies of OCD have consistently identified hypermetabolism in the orbitofrontal cortex, the caudate nucleus, and (sometimes) the anterior cingulate cortex.7,147,151 OCD patients with more motoric symptoms (e.g., tics) may also be more likely than OCD patients without such symptoms to have involvement of the putamen,152 although this hypothesis remains to be validated. It has also been suggested that patients with tic-related OCD may have more abnormal motor cortex excitability than OCD patients without tics.153 Relatively few studies have explored functional brain imaging in acquired OCD (i.e., OCD associated with neurologic disorders). In a review of the brain SPECT scans of patients with various neurological conditions also presenting with OCD, Hugo and colleagues154 reported that all of these patients demonstrated decreased blood flow in the temporal lobes and had cortical perfusion abnormalities in the frontal lobes. Indeed, abnormal blood flow may be seen in a number of different brain regions in acquired OCD.154 In a study investigating OCD associated with brain lesions, Berthier and colleagues155 found that in a patient group with acquired OCD, neuroimaging disclosed abnormalities in a variety of regions involving either the cerebral cortex (frontal, temporal, or cingulate regions), the basal ganglia, or both. The study also suggested that patients with focal brain lesions (acquired OCD) had a negative familial history and later age of onset of OCD symptoms than patients with idiopathic OCD.155 There have been some efforts to use factor analyses to identify neural correlates of symptom clusters. For example, Rauch and Savage156 found the severity of religious/ aggressive/sexual obsessions and checking was positively related with regional cerebral blood flow in the striatum bilaterally. Distinct trends were also observed for the other factors, or symptom dimensions. These findings provide support for the hypothesis that dysfunction within separate neurocircuitry systems may principally mediate particular symptom clusters. In brief, neurological soft signs are common among OCD patients and may be associated with an “organic” subtype of OCD. Functional neuroimaging studies have suggested that OCD patients have increased prefrontal activity and hypermetabolism in the orbitofrontal cortex, the caudate nucleus, and other regions.

Neuroimmunology Sydenham’s chorea is an involuntary movement disorder that develops in some children following a group A betahemolytic streptococcal (GABHS) infection. Some of these patients’ movements either are or resemble tics. Indeed, Swedo and Leonard157 noted that a proportion of patients with Sydenham’s chorea meet diagnostic criteria for OCD

Harv Rev Psychiatry

120

Lochner and Stein

and often have tics. This condition is also characterized by increased antineural antibodies, suggesting that an autoimmune process may be responsible for basal ganglia damage and OCD in these patients.158 Conversely, an increasing body of evidence provides support for the postulate that OCD and tic disorders may arise from poststreptococcal autoimmunity.159 The term PANDAS (for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) refers to patients with tics and obsessivecompulsive symptoms induced by streptoccocal infections.160 Leonard and Swedo160 provide five criteria for this condition: presence of OCD or tic disorder; prepubertal symptom onset; sudden onset or episodic course of symptoms; temporal association between streptococcal infections and exacerbation of neuropsychiatric symptoms; and neurological abnormalities. It has been found that expression of D8/17 (a particular B-lymphocyte antigen) was significantly higher in children with PANDAS, in Sydenham’s chorea,161 and in childhoodonset OCD or TS, compared to normal controls.162 Indeed, the identification of subtypes such as PANDAS may allow for testing of models of pathogenesis and also potentially lead to the development of novel treatment and prevention strategies.60 Both antibiotic prophylaxis to prevent streptococcal-triggered exacerbations and immunomodulatory interventions (such as intravenous immunoglobulin or therapeutic plasma exchange) have been studied.160 With regard to the latter treatment strategy, long-term (2–5 years) follow-up revealed continued symptom improvement for the majority of patients, particularly when antibiotic prophylaxis had been effective in preventing recurrent streptococcal infections.160

Psychological Trauma Clinicians have long described the emergence of obsessivecompulsive symptoms in the aftermath of psychological trauma. This concept lost ground as psychodynamic theories about OCD become less popular and as neurobiological data on OCD emerged. Certainly, clinicians should be reminded not to confuse OCD and PTSD.163 Nevertheless, recent work suggests that in some cases of OCD, psychological trauma may play a role.164,165 This putative subtype of OCD remains poorly understood.

RESULTS: FAMILY STUDIES Family studies of OCD have suggested that OCD is a heterogeneous condition, with some cases being familial and others being isolated.166 Early studies completed prior to 1970 suggested that OCD is a familial disorder.167–171 Prevalence rates among first-degree relatives of OCD probands have been reported as ranging between 0.7% and 4.5%.5,172,173

May/June 2003

Findings from more recent systematic studies have provided further support for a familial component for the expression of some forms of OCD.97,98,131,174–177 In a recent study conducted to determine whether OCD is familial and to investigate possible familial subtypes, it was found that age of onset of OCD is valuable in characterizing a familial subtype178 (see “Age of Onset” above). Several studies support the hypothesis that familial loading for OCD is associated with early onset.97,178 In addition, Pauls and colleagues98 found that the relatives of probands with early onset were at higher risk for both OCD and tics, supporting the concept that early age of onset characterizes a familial subtype of OCD. Furthermore, it has been reported that OCD patients and their family members also have a high prevalence of various putative OCSDs (including BDD and pathological grooming behaviors).102 Bellodi and colleagues179 found that the risk for OCSDs (in particular, OCD and tic disorders) is higher in families of patients with eating disorders, suggesting that eating disorders may also characterize a phenomenological and familial OCD subtype.

RESULTS: TREATMENT Several studies have supported the hypothesis that the serotonin system plays an important role in OCD. Serotonin reuptake inhibitors (SRIs) were found more effective than noradrenergic reuptake inhibitors in the treatment of OCD.9 This result is apparent not only in adults with OCD, but also in children and adolescents with OCD.180 Indeed, about 40–60% of OCD patients respond to the first trial of an SRI.13 A proportion of nonresponders to a single SRI will respond to administration of a second SRI.181 While serotonin is the neurotransmitter most commonly implicated in obsessive-compulsive and related disorders, there is also evidence for dopaminergic mediation of these conditions.11,182 Indeed, augmentation of SRIs with dopamine blockers has been found useful in treatment-refractory OCD.183

Symptom Subtypes Studies are conflicting about whether any particular symptom subtype of OCD is easier to treat or more likely to benefit from particular treatments. Some studies129,130 have found that cleaning rituals have been associated with poorer response to medication. Also, the presence of hoarding obsessions and compulsions has been associated with poorer response to SRIs184 and behavioral therapy.185 A recent study examining the long-term course of OCD in patients treated with both SRIs and behavioral therapy found the presence of obsessions of sexual/religious content to be a unique factor related to a poorer long-term outcome.186

Harv Rev Psychiatry

Lochner and Stein

Volume 11, Number 3

Some studies have suggested that variables such as sex, age, severity, and duration of OCD may predict pharmacotherapy outcome. For example, Alarcon and colleagues129 showed that higher initial scores on the Y-BOCS were associated with poorer response to treatment. In addition, the combination of longer length of illness, continuous course, and predominance of compulsive behaviors has been found to be associated with poorer response to medication.129,130 Different follow-up studies of childhood, adolescent, and adulthood OCD have also linked initial severity of OCD to post-treatment severity.68,184,187 There are other studies, however, that have found that these variables did not predict poor response in pharmacotherapy trials.188,189 No consistent predictors of outcome have been identified for the psychotherapy of OCD. Some studies have found that cleaning symptoms may respond best to exposure methods,61,190 whereas checking rituals predicted poorer outcome in some behavioral therapy studies.61,191 Other studies have found, however, no differences in treatment response between patients with cleaning and checking.192 More recently, it has been suggested that improvement with behavioral therapy is more likely only with patients having either cleaning or checking compulsions, but not both.33 There is a relative absence of documentation concerning the outcome of behavioral therapy for obsessive-compulsive symptoms other than cleaning and checking; other subgroups (such as patients with ordering compulsions, hoarding rituals, or obsessional slowness) have rarely been included in trials of such therapy.33 This lack of data is perhaps not surprising in that some studies have suggested that patients with noncleaning compulsions may be more likely not to enter behavioral therapy.193 Even so, several studies have found that patients with noncleaning compulsions and obsessions (e.g., those with obsessional slowness or in whom obsessions predominate) are unresponsive to behavioral therapy.15,59,191,194,195 In addition to different symptom subtypes, other related variables, such as bizarreness, fixity, control, and resistance to symptoms, have been found not to correlate significantly with response to behavioral therapy.44 Overall, it appears that OCD patients with cleaning rituals, hoarding, and sexual/religious obsessions may respond more poorly than others to treatment. Patients with primarily obsessions or with cleaning compulsions may respond poorly to behavioral therapy.

Insight The available literature on insight as a predictor of response to behavioral therapy is inconsistent, and the data concerning insight and medication response are sparse.42 It has been suggested that OCD patients with poor insight may have a different treatment response than patients with better

121

insight,42 but the relationship between the degree of insight and outcome of therapy remains unclear.49 Recently, in a study evaluating which clinical variables might influence the anti-OCD effect of proserotonergic drugs, nonresponders had a higher frequency of “poor insight”;196 indeed, poor insight was found to be the best predictor of poor drug-treatment response. Nevertheless, the treatment of OCD patients with poor insight may sometimes lead to a shift to good insight with concomitant improvement of OCD severity and depressive status.47 Matsunaga and colleagues47 also found that in OCD, comorbid schizotypal PD compromised prognosis; both OCD with poor insight and comorbid schizotypal PD were found to be associated with failure to gain better insight during treatment. Additional research is needed in order to address this issue.

Gender and Age of Onset It has been suggested that people with later onset of OCD (who are more commonly females) have the best chance of responding to medication. For example, in the study by do Rosario-Campos and colleagues,92 the group with earlyonset OCD responded less well to treatment with SRIs than late-onset OCD patients. Likewise, another study showed that female OCD patients were more likely than males to respond to fluvoxamine therapy.197 It has also been argued that OCD females have lower MAO-A activity than OCD males76 and that this association might indicate a beneficial effect of MAO-A inhibitors in a particular subtype of OCD females. It has been suggested that male OCD patients have relatively increased neurological soft signs and tics compared to females,77 while neurological soft signs or tics have been associated, in turn, with increased ventricular-brain ratios141 and worse response to SRIs.139,198 Indeed, increased neurological soft signs have been predictive of poorer response to pharmacotherapy in some studies139 (although in others, this variable did not predict worse outcome at followup).68,142 It should be noted that not all studies agree with the finding that the course of OCD is worse in males;58 arguably, the relationship between male gender and worse course may be largely explained by taking into account those with early brain trauma or similar dysfunction. Indeed, a number of studies have indicated that age, age of onset, and gender are not significant prognostic factors.68,189 Some studies have found that gender has no effect in predicting response to SRIs in OCD.199

Comorbidity Comorbidity of mood and anxiety disorders in childhood and adolescent OCD has been found not to predict outcome

Harv Rev Psychiatry

122

Lochner and Stein

at follow-up.68 In addition, several controlled studies have shown that neither the presence nor the initial severity of depression has any impact on therapeutic outcome in adults with OCD.200,201 The SRIs fluoxetine and fluvoxamine have beneficial effects in OCD, irrespective of the presence or severity of initial depressive symptoms,11,202,203 and DeVeaugh-Geiss and colleagues189 found that comorbid depression did not predict responsiveness to clomipramine. Interestingly, it was found that although imipramine improved depressive symptoms in depressed OCD patients, this improvement did not potentiate the effects of behavioral therapy for OCD.204 Comorbid PTSD may be associated, however, with worse prognosis of OCD.205 A retrospective, case-controlled analysis by McDougle and colleagues206 found that fluvoxamine alone was less effective in OCD patients with tics than in patients without tics. In a continuation of this research, the researchers found198 that treatment-refractory OCD patients with comorbid chronic tic disorders (such as TS) responded to haloperidol augmentation of fluvoxamine, whereas this strategy was of little benefit for patients without tics. In two subsequent studies, olanzapine and risperidone (respectively) were added to the treatment of patients refractory to treatment with fluvoxamine alone,207,208 but no difference was found in response between OCD patients with and without comorbid diagnoses of chronic tic or schizotypal disorder. The comorbid diagnosis of schizophrenia and OCD (or of OCD with psychotic features) seems to portend a worse prognosis than for either condition alone. Despite the scarce literature on the topic, there is some evidence that patients with both these conditions may improve on treatment with a combination of antiobsessional and antipsychotic drugs.209,210 Nevertheless, it has been noted that administration of atypical antipsychotic agents may be associated with the first onset or worsening of obsessive-compulsive symptoms in schizophrenia.211–213 It has been suggested that comorbid PD may have prognostic significance in the treatment of OCD.214,215 Pfohl and colleagues215 noted that in 22 OCD patients who received the Structured Interview for the Diagnosis of Personality Disorder prior to treatment with clomipramine, 11 responders had significantly fewer total Axis II criteria than did the 11 nonresponders. Baer and colleagues216 have demonstrated that the presence of schizotypal, borderline, and avoidant PD, in tandem with the total number of PDs, did predict poor treatment outcome (with clomipramine). Also, a retrospective analysis of 43 OCD patients demonstrated that those with comorbid schizotypal PD (33%) were comparatively unresponsive to both pharmacotherapy217 and behavioral therapy.214 Similarly, there is evidence that schizotypal PD is not the only PD that is a consistent predictor of poor outcome in OCD.120 Hermesh and colleagues218

May/June 2003

reported that in 39 OCD patients, all of those with borderline personality (20%) failed to respond to either pharmacotherapy or behavioral therapy, primarily because of poor compliance. Some studies have failed to confirm the finding of an association in OCD patients between PDs and (poorer) treatment outcome. In the study by Steketee,219 comparisons of those OCD patients who did and did not qualify for schizotypal, histrionic, avoidant and dependent, or any other type of PD revealed only marginal associations to treatment gains. In fact, PD patients had slightly better immediate treatment outcome, although this difference was not significant. Similarly, Mavissakalian and colleagues’220 investigation of the relationship between personality and treatment outcome provided no strong support for the notion that personality factors have prognostic significance in the treatment of OCD. The finding that the presence of particular comorbid PDs in OCD may predict poor treatment outcome is open to more than one interpretation, suggesting either a specific effect of the particular Axis II disorder or a nonspecific effect of increased OCD severity. In view of the particular set of PDs that apparently affect treatment outcome (schizotypal, borderline, avoidant), there is some reason to believe that the first explanation may be correct. Nevertheless, since the total number of PD traits and diagnoses is correlated with symptom severity, there is also some basis for taking the second explanation seriously. Additional research is necessary. In sum, comorbidity of OCS with mood and anxiety disorders does not affect treatment outcome, while comorbid tics and schizophrenia both are associated with worse outcomes. Among comorbid Axis II conditions, schizotypal PD appears most clearly to predict poor treatment outcome.

Side Effects An analysis of differences between the side-effect profiles of clomipramine and more selective SRIs in OCD suggested that good response to both drugs (clomipramine and fluoxetine) was associated with initial nervousness and sexual complaints.221 More specifically, good response to clomipramine was associated with later age of OCD onset and certain early side effects that may reflect the sensitivity of responders to clomipramine’s serotonergic actions. Replication of the data is needed.

Neurobiology It has been demonstrated that patients with OCD have increased brain activity in the basal ganglia, that this hyperactivity increases further during exposure to feared stimuli, and that it decreases after successful SRI administration

Harv Rev Psychiatry

Lochner and Stein

Volume 11, Number 3

or behavioral therapy.19,156 Not all patients respond to this treatment, however—which suggests that structures other than the basal ganglia may have a role in mediating OCD symptoms. Indeed, the underlying differences in the neurobiology between responders and nonresponders to SRIs are only partly understood. As mentioned earlier, for example, there is evidence that nonresponders are more likely to have comorbid tics,206 increased neurological soft signs,139 and atypical EEGs.146 In some, but not all, studies, increased neurological soft signs predict poor response to pharmacotherapy and behavioral treatment.142,222 Some authors have suggested that OCD patients with abnormal findings on EEG may respond to anticonvulsant therapy.146 Deltito145 found that OCD patients who develop symptoms like those of temporal lobe epilepsy did better when begun on valproate prior to SRI treatment. Functional brain imaging has documented that OCD patients have increased prefrontal activity compared to normal controls,19 and it has been suggested that increased blood flow in the frontal regions predicts poor response to medication.223 More specifically, it has been found that lower pretreatment metabolism in the right orbitofrontal cortex (OFC) and anterior cingulate gyrus is associated with a better response to serotonergic drugs.224 It was also found that higher normalized metabolism in the left OFC region was associated with greater improvement in a behavioral therapy group, but with worse outcome in a fluoxetine-treated group.223 These findings indicate that OCD patients with differing patterns of metabolism may preferentially respond to behavioral therapy versus medication. Symptoms of OCD may be acutely exacerbated by administration of certain serotonin agonists. Studies of the response of OCD patients to administration of the serotonin agonist m-chlorophenylpiperazine (m-CPP) have been mixed, with some studies reporting abnormal behavioral and neuroendocrine responses,225,226 but with other studies failing to confirm these reports.227 Hollander and colleagues228 have reported that exacerbation of OCD symptoms after m-CPP administration was a negative predictor of response to pharmacotherapy (in particular, SRIs). Interestingly, exacerbation of OCD symptoms after administration of m-CPP is correlated with increased cerebral blood flow in the frontal cortex.229 It may be hypothesized that increased frontal activity in some patients with OCD is in itself a compensatory mechanism. These preliminary neurobiological findings are consistent with a hypothesis that exacerbation of OCD after administration of a serotonin autoreceptor agonist may be an indication of compensatory postsynaptic serotonergic upregulation. Such upregulation may be associated with increased frontal activity and relatively poor response to serotonergic agents.230

123

Family Studies It has been suggested that parental OCD modifies a child’s likelihood of response to medication. Leonard and colleagues187 have found that presence of parental Axis I psychiatric diagnosis predicted poorer OCD outcome. There have also been findings to the contrary, however. In a study to determine the role of familial psychiatric pathology in outpatient treatment with fluoxetine, it was found that OCD patients with parents who have OCD showed a clinically and statistically significant reduction in symptoms following treatment. In addition, Erzegovesi and colleagues196 have found that when compared to nonresponders, responders to SRIs had a significantly higher frequency of positive family history for OCD in their first-degree relatives. These findings suggest that family psychopathology—especially the presence of OCD—may predict better response to treatment. Further research would be valuable.

DISCUSSION Studies of the phenomenology, psychobiology, family relationships, and treatment response of OCD support the view that OCD is not simply a homogenous entity. Eventually, perhaps, we will be able to delineate specific subtypes of OCD that allow the correlation of particular symptomatic presentations, psychobiological mechanisms, and treatment response. In the meantime, we can posit several broad divisions within OCD that bring together data on symptomatology, psychobiology, and treatment. One such division of OCD patients is along serotonergic versus dopaminergic symptoms and pathways. While serotonin is the neurotransmitter most commonly implicated in OCD and related disorders,231,232 there is evidence for dopaminergic mediation of these conditions.11 Some OCD patients experience little or no improvement in their symptoms when treated with SRIs; it can therefore be hypothesized either that serotonin neurotransmission is different in SRI-refractory patients than in patients who are responsive to SRIs, or that the former patients have abnormalities in other systems such as dopamine.198,208 The serotonin system has been closely linked with harm avoidance or risk reduction in both preclinical and clinical studies.233 Disequilibrium of this system may be associated with increased harm avoidance in many patients, but also with a higher level of impulsive aggression in others.234 One hypothesis is that OCD patients with serotonergic dysfunction have “abnormal risk assessment,” with consequent symptoms regarding contamination and harm avoidance. Conversely, the dopamine system (linked with tics, among other things) has been closely associated with processing of context and with novelty seeking.235 OCD patients may also have cognitive symptoms (such as executive dysfunction) or motor

Harv Rev Psychiatry

124

Lochner and Stein

symptoms (such as tics). Indeed, differential involvement of these serotonergic and dopaminergic systems would then explain both differential involvement of symptoms and differential response to treatment. This neurochemical schema is generally consistent with the outlines presented by Baer23 and by Rasmussen and Eisen.32 Patients with dopaminergic dysfunction may experience “incompleteness,” along with symptoms such as hoarding or symmetry, comorbid tics, or neurological soft signs. One of the three symptom subtypes or factors identified by Baer23 —“symmetry/hoarding”—was found to be significantly related to comorbid OCPD or a lifetime history of TS or chronic tic disorder, thereby implicating dopaminergic involvement in this subtype. Since hoarding has been associated with poor response to SRIs, and dopamine antagonists have proven to be useful in the treatment of comorbid OCD and tics, it may be hypothesized that this symptom subtype is more responsive to dopamine antagonists. Moreover, other results support the existence of dopaminergic dysfunction in this symptom cluster: poor insight in OCD has been associated with hoarding236 and also with nonresponse to SRIs,196 and early onset has been linked with poorer response to SRIs92 and bears a close relationship to tic disorders.91 Nevertheless, one must be careful in drawing conclusions regarding varying dopaminergic versus serotonergic involvement in OCD. This division likely represents an overly simplistic neurochemical characterization of a disorder in which many other neurochemical and neuroimmunological systems may be involved.237 A second possible division of OCD patients relates to differences in underlying dysfunctional corticostriatal pathways. For example, lesions of the caudate nucleus are perhaps particularly likely to give rise to OCD156 and to be associated with executive dysfunction. By contrast, lesions of the putamen may be associated with tics/TS.234,238 Cerebral blood flow patterns appear different in OCD patients with and without tics,136 and different patterns of activity on functional imaging may, in turn, have implications for the treatment response.230 One might therefore hypothesize the existence of a division between OCD involving the caudate nucleus and resulting in symptoms that are more cognitive in character, and OCD involving putamen abnormalities and resulting in symptoms or stereotypies that are more motoric in character.156 This division may also reflect the differential involvement of serotonergic and dopaminergic neurons (as suggested above), with serotonergic neurons more involved in cognitive symptoms, and dopaminergic neurons more involved in motoric symptoms. This division of OCD subtypes may also be overly simplistic, however, since frontal-striatal circuits may play a role in a range of different disorders that may or may not overlap closely with OCD.239 Conversely, it is possible that other areas are involved in the neurobiology of OCD and related disorders—

May/June 2003

for example, the temporal lobes in musical obsessions240 and the cerebellum in trichotillomania241 —although such work is preliminary. Nevertheless, it is possible that a finer delineation of the involvement of corticostriatal pathways will ultimately shed light on the heterogeneity of OCD, with particular circuitry differentially involved across OCD subtypes. A third possible division of OCD patients arises in relation to the putative OCSDs. The grouping of these conditions is based largely on phenomenological features, biological abnormalities, family history patterns, and response to psychopharmacologic and psychological treatments.242 Some authors have suggested that one way of looking at the OCD spectrum may be in terms of compulsivity and impulsivity.242–244 This perspective is based on the tendency to associate harm avoidance with compulsivity, and novel seeking/risk seeking with impulsivity. Thus, OCD (as the prototype of a harm-avoidance disorder with serotonergic hypersensitivity and increased frontal activity)233 may fall on the compulsive end of an OCD spectrum; impulsive disorders characterized by serotonergic hyposensitivity and decreased frontal function may fall on the impulsive end; and disorders such as TS, trichotillomania, and OCPD may have both impulsive and compulsive characteristics. Dopaminergic activity is a key component of the neural circuitry of reward–reward dependence, and may play a role in some of these impulsive/compulsive conditions.245 A more detailed understanding of the psychobiology of both OCD and putative spectrum disorders is needed, however, in order to understand the relationships between these conditions. Indeed, at this stage of our knowledge, the broad, integrative hypotheses suggested above remain speculative. Nevertheless, a number of more narrow, specific subtypes of OCD do appear to be well validated, and provide a basis from which to begin to generalize more broadly. OCD patients with and without tics, for example, have been demonstrated to display differences in phenomenology, psychobiology, and treatment response. Furthermore, this subtype overlaps with a number of other distinctions noted in the literature (e.g., patients with tics are more likely to have early onset and be male). In the future, we can expect advances in the delineation of well-defined OCD subtypes characterized by specific phenomenological and psychobiological features, as well as in our more general understanding of the underpinnings of variations across the symptomatology, neurobiology, and treatment response of OCD.

CONCLUSION Several findings suggest that OCD is a heterogeneous disorder, with a range of subtypes that may be differentiated.

Harv Rev Psychiatry Volume 11, Number 3

Such subtypes may be related to symptomatology, neurobiology, familial relationships, and treatment response. Subtyping OCD is hypothesized to be a useful step in allowing more precise determination of the neurobiology of OCD symptoms, more accurate prognostication of their outcome, and better planning for its management. Identification of meaningful subtypes in OCD may prove necessary in order to unravel important questions concerning the causes of the disorder and also in order to develop specific treatment strategies for refractory patients.

REFERENCES 1. Stoll AL, Tohen M, Baldessarini RJ. Increasing frequency of the diagnosis of obsessive-compulsive disorder. Am J Psychiatry 1992;149:638–40. 2. Hollander E. Introduction. In: Hollander, E. Obsessivecompulsive related disorders. Washington, DC: American Psychiatric Press, 1993:1–16. 3. Karno M, Golding JM, Sorenson SB, Burnam MA. The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry 1988;45:1094–9. 4. Weissman MM, Bland RC, Canino GJ, Greenwald S, Hwu HG, Lee CK, et al. The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group. J Clin Psychiatry 1994;55(suppl):5–10. 5. Rasmussen SA, Tsuang MT. Clinical characteristics and family history in DSM-III obsessive-compulsive disorder. Am J Psychiatry 1986;143:317–22. 6. Rettew DC, Swedo SE, Leonard HL, Lenane MC, Rapoport JL. Obsessions and compulsions across time in 79 children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 1992;31:1050–6. 7. Saxena S, Rauch SL. Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder. Psychiatr Clin North Am 2000;23:563–86. 8. Rauch SL, Savage CR, Alpert NM, Fischman AJ, Jenike MA. The functional neuroanatomy of anxiety: a study of three disorders using positron emission tomography and symptom provocation. Biol Psychiatry 1997;42:446–52. 9. Zohar J, Insel TR. Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment, and pathophysiology. Biol Psychiatry 1987;22:667–87. 10. Zohar J, Insel TR. Drug treatment of obsessive-compulsive disorder. J Affect Disord 1987;13:193–202. 11. Goodman WK, McDougle CJ, Price LH, Riddle MA, Pauls DL, Leckman JF. Beyond the serotonin hypothesis: a role for dopamine in some forms of obsessive compulsive disorder? J Clin Psychiatry 1990;51(suppl):36–43. 12. Klein DF. Pharmacotherapy of obsessive-compulsive disorder. Encephale 1990;16:331–4. 13. Jenike MA. Pharmacologic treatment of obsessivecompulsive disorders. Psychiatr Clin North Am 1992;15:895– 919.

Lochner and Stein

125

14. Greist JH, Jefferson JW. Pharmacotherapy for obsessivecompulsive disorder. Br J Psychiatry 1998(suppl);64–70. 15. Minichiello WE, Baer L, Jenike MA. Behavior therapy for the treatment of obsessive-compulsive disorder: theory and practice. Compr Psychiatry 1988;29:123–37. 16. Greist JH. New developments in behaviour therapy for obsessive-compulsive disorder. Int Clin Psychopharmacol 1996;11(suppl 5):63–73. 17. Esman AH. Psychoanalysis and general psychiatry: obsessivecompulsive disorder as paradigm. J Am Psychoanal Assoc 1989;37:319–36. 18. Rapoport JL, Wise SP. Obsessive-compulsive disorder: evidence for basal ganglia dysfunction. Psychopharmacol Bull 1988;24:380–4. 19. Insel TR. Toward a neuroanatomy of obsessive-compulsive disorder. Arch Gen Psychiatry 1992;49:739–44. 20. Leckman JF, Zhang H, Alsobrook JP, Pauls DL. Symptom dimensions in obsessive-compulsive disorder: toward quantitative phenotypes. Am J Med Genet 2001;105:28–30. 21. Skoog G, Skoog I. A 40-year follow-up of patients with obsessive-compulsive disorder. Arch Gen Psychiatry 1999;56:121–7. 22. Nestadt G, Samuels JF, Riddle MA, Bienvenu OJ, Liang KY, Grados MA, et al. Obsessive-compulsive disorder: defining the phenotype. J Clin Psychiatry 2002;63(suppl 6):5–7. 23. Baer L. Factor analysis of symptom subtypes of obsessivecompulsive disorder and their relation to personality and tic disorders. J Clin Psychiatry 1994;55(suppl):18– 23. 24. Leckman JF, Grice DE, Boardman J, Zhang H, Vitale A, Bondi C, et al. Symptoms of obsessive-compulsive disorder. Am J Psychiatry 1997;154:911–7. 25. Summerfeldt LJ, Richter MA, Antony MM, Swinson RP. Symptom structure in obsessive-compulsive disorder: a confirmatory factor-analytic study. Behav Res Ther 1999;37:297– 311. 26. Hodgson RJ, Rachman S. Obsessional-compulsive complaints. Behav Res Ther 1977;15:389–95. 27. Van Oppen P, Hoekstra RJ, Emmelkamp PM. The structure of obsessive-compulsive symptoms. Behav Res Ther 1995;33:15– 23. 28. Calamari JE, Wiegartz PS, Janeck AS. Obsessive-compulsive disorder subgroups: a symptom-based clustering approach. Behav Res Ther 1999;37:113–25. 29. Sanavio E. Obsessions and compulsions: the Padua Inventory. Behav Res Ther 1988;26:169–77. 30. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry 1989;46:1006–11. 31. Pitman RK. Pierre Janet on obsessive-compulsive disorder (1903). Review and commentary. Arch Gen Psychiatry 1987;44:226–32. 32. Rasmussen SA, Eisen J. Phenomenology of OCD: clinical subtypes, heterogeneity and coexistence. In: Zohar Y, Insel TR, Rasmussen SA, eds. Psychobiology of OCD. New York: Springer-Verlag, 1991:13–43.

Harv Rev Psychiatry

126

Lochner and Stein

33. Ball SG, Baer L, Otto MW. Symptom subtypes of obsessivecompulsive disorder in behavioral treatment studies: a quantitative review. Behav Res Ther 1996;34:47–51. 34. Khanna S, Mukherjee D. Checkers and washers: valid subtypes of obsessive-compulsive disorder. Psychopathology 1992;25:283–8. 35. Perugi G, Akiskal HS, Pfanner C, Presta S, Gemignani A, Milanfranchi A, et al. The clinical impact of bipolar and unipolar affective comorbidity on obsessive-compulsive disorder. J Affect Disord 1997;46:15–23. 36. Frost RO, Steketee G, Williams LF, Warren R. Mood, personality disorder symptoms and disability in obsessive compulsive hoarders: a comparison with clinical and nonclinical controls. Behav Res Ther 2000;38:1071–81. 37. Rasmussen SA, Eisen JL. Clinical and epidemiologic findings of significance to neuropharmacologic trials in OCD. Psychopharmacol Bull 1988;24:466–70. 38. Takeuchi A, Nakagawa A, Harai H, Nakatani E, Fujikawa S, Yoshizato C, et al. Primary obsessional slowness: long-term findings. Behav Res Ther 1997;35:445–9. 39. Rachman S. Primary obsessional slowness. Behav Res Ther 1974;12:9–18. 40. Veale D. Classification and treatment of obsessional slowness. Br J Psychiatry 1993;162:198–203. 41. Galderisi S, Mucci A, Catapano F, D’Amato AC, Maj M. Neuropsychological slowness in obsessive-compulsive patients. Is it confined to tests involving the fronto-subcortical systems? Br J Psychiatry 1995;167:394–8. 42. Attiullah N, Eisen JL, Rasmussen SA. Clinical features of obsessive-compulsive disorder. Psychiatr Clin North Am 2000;23:469–91. 43. Insel TR, Akiskal HS. Obsessive-compulsive disorder with psychotic features: a phenomenologic analysis. Am J Psychiatry 1986;143:1527–33. 44. Lelliott PT, Noshirvani HF, Basoglu M, Marks IM, Monteiro WO. Obsessive-compulsive beliefs and treatment outcome. Psychol Med 1988;18:697–702. 45. Foa EB, Kozak MJ, Goodman WK, Hollander E, Jenike MA, Rasmussen SA. DSM-IV field trial: obsessive-compulsive disorder. Am J Psychiatry 1995;152:90–6. 46. Eisen JL, Rasmussen SA, Phillips KA, Price LH, Davidson J, Lydiard RB, et al. Insight and treatment outcome in obsessivecompulsive disorder. Compr Psychiatry 2001;42:494–7. 47. Matsunaga H, Kiriike N, Matsui T, Oya K, Iwasaki Y, Koshimune K, et al. Obsessive-compulsive disorder with poor insight. Compr Psychiatry 2002;43:150–7. 48. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994. 49. Kozak MJ, Foa EB. Obsessions, overvalued ideas, and delusions in obsessive-compulsive disorder. Behav Res Ther 1994;32:343–53. 50. Damecour CL, Charron M. Hoarding: a symptom, not a syndrome. J Clin Psychiatry 1998;59:267–72. 51. Catapano F, Sperandeo R, Perris F, Lanzaro M, Maj M. Insight and resistance in patients with obsessive-compulsive disorder. Psychopathology 2001;34:62–8.

May/June 2003

52. Okasha A, Saad A, Khalil AH, el Dawla AS, Yehia N. Phenomenology of obsessive-compulsive disorder: a transcultural study. Compr Psychiatry 1994;35:191–7. 53. Abramowitz JS, Brigidi BD, Foa EB. Health concerns in patients with obsessive-compulsive disorder. J Anxiety Disord 1999;13:529–39. 54. Geller D, Biederman J, Jones J, Park K, Schwartz S, Shapiro S, et al. Is juvenile obsessive-compulsive disorder a developmental subtype of the disorder? A review of the pediatric literature. J Am Acad Child Adolesc Psychiatry 1998;37:420–7. 55. Pigott TA, L’Heureux F, Dubbert B, Bernstein S, Murphy DL. Obsessive compulsive disorder: comorbid conditions. J Clin Psychiatry 1994;55(suppl):15–27. 56. Bogetto F, Venturello S, Albert U, Maina G, Ravizza L. Genderrelated clinical differences in obsessive-compulsive disorder. Eur Psychiatry 1999;14:434–41. 57. Castle DJ, Deale A, Marks IM. Gender differences in obsessive compulsive disorder. Aust N Z J Psychiatry 1995;29:114–7. 58. Lensi P, Cassano GB, Correddu G, Ravagli S, Kunovac JL, Akiskal HS. Obsessive-compulsive disorder. Familialdevelopmental history, symptomatology, comorbidity and course with special reference to gender-related differences. Br J Psychiatry 1996;169:101–7. 59. Marks IM. Fears, phobias and rituals. New York: Oxford University Press, 1987. 60. Minichiello WE, Baer L, Jenike MA, Holland A. Age of onset of major subtypes of obsessive-compulsive disorder. J Anxiety Disord 1990;4:147–50. 61. Rachman S, Hodgson R. Obsessions and compulsions. Englewood Cliffs, NJ: Prentice-Hall, 1980. 62. Stern R, Cobb J. Phenomenology of obsessive-compulsive neurosis. Br J Psychiatry 1978;132:233–9. 63. Swedo SE, Rapoport JL. Phenomenology and differential diagnosis of obsessive-compulsive disorder in children and adolescents. In: Rapoport JL, ed. Obsessive-compulsive disorder in children and adolescents. Washington, DC: American Psychiatric Press, 1989:13–32. 64. Skoog G. Onset of anancastic conditions: a clinical study. Acta Psychiatr Scand 1965;suppl 184:1–82. 65. Fischer DJ, Himle JA, Hanna GL. Age and gender effects on obsessive-compulsive symptoms in children and adults. Depress Anxiety 1997;4:237–9. 66. Zohar AH. The epidemiology of obsessive-compulsive disorder in children and adolescents. Child Adolesc Psychiatr Clin N Am 1999;8:445–60. 67. Noshirvani HF, Kasvikis Y, Marks IM, Tsakiris F, Monteiro WO. Gender-divergent aetiological factors in obsessivecompulsive disorder. Br J Psychiatry 1991;158:260–3. 68. Thomsen PH. Obsessive-compulsive disorder in children and adolescents: predictors in childhood for long-term phenomenological course. Acta Psychiatr Scand 1995;92:255–9. 69. Ravizza L, Maina G, Bogetto F. Episodic and chronic obsessivecompulsive disorder. Depress Anxiety 1997;6:154–8. 70. Kasvikis JG, Tsakiris F, Marks I, Basoglu M, Noshirvani HF. Women with obsessive-compulsive disorder frequently report a past history of anorexia nervosa. Int J Eat Disord 1986;5:1069–75.

Harv Rev Psychiatry

Lochner and Stein

Volume 11, Number 3

71. Lennkh C, Strnad A, Bailer U, Biener D, Fodor G, de Zwaan M. Comorbidity of obsessive compulsive disorder in patients with eating disorders. Eat Weight Disord 1998;3:37–41. 72. Welner A, Reich T, Robins E, Fishman R, Van Doren T. Obsessive-compulsive neurosis: record, follow-up, and family studies. I. Inpatient record study. Compr Psychiatry 1976;17:527–39. 73. Matsunaga H, Kiriike N, Matsui T, Miyata A, Iwasaki Y, Fujimoto K, et al. Gender differences in social and interpersonal features and personality disorders among Japanese patients with obsessive-compulsive disorder. Compr Psychiatry 2000;41:266–72. 74. Nestadt G, Lan T, Samuels J, Riddle M, Bienvenu OJ III, Liang KY, et al. Complex segregation analysis provides compelling evidence for a major gene underlying obsessive-compulsive disorder and for heterogeneity by sex. Am J Hum Genet 2000;67:1611–6. 75. Cavallini MC, Pasquale L, Bellodi L, Smeraldi E. Complex segregation analysis for obsessive compulsive disorder and related disorders. Am J Med Genet 1999;88:38–43. 76. Camarena B, Rinetti G, Cruz C, Gomez A, de La Fuente JR, Nicolini H. Additional evidence that genetic variation of MAOA gene supports a gender subtype in obsessive-compulsive disorder. Am J Med Genet 2001;105:279–82. 77. Stein DJ, Hollander E, Simeon D, Cohen L, Islam MN, Aronowitz B. Neurological soft signs in female trichotillomania patients, obsessive-compulsive disorder patients, and healthy control subjects. J Neuropsychiatry Clin Neurosci 1994;6:184– 7. 78. Williams KE, Koran LM. Obsessive-compulsive disorder in pregnancy, the puerperium, and the premenstruum. J Clin Psychiatry 1997;58:330–4. 79. Diaz SF, Grush LR, Sichel DA, Cohen LS. Obsessivecompulsive disorder in pregnancy and the puerperium. In: Pato MT, Steketee G, eds. OCD across the life cycle. Washington, DC: American Psychiatric Press, 1997:97–112. 80. Neziroglu F, Anemone R, Yaryura-Tobias JA. Onset of obsessive-compulsive disorder in pregnancy. Am J Psychiatry 1992;149:947–50. 81. Altshuler LL, Hendrick V, Cohen LS. Course of mood and anxiety disorders during pregnancy and the postpartum period. J Clin Psychiatry 1998;59(suppl 2):29–33. 82. Maina G, Albert U, Bogetto F, Vaschetto P, Ravizza L. Recent life events and obsessive-compulsive disorder (OCD): the role of pregnancy/delivery. Psychiatry Res 1999;89:49–58. 83. Karayiorgou M, Altemus M, Galke BL, Goldman D, Murphy DL, Ott J, et al. Genotype determining low catechol-Omethyltransferase activity as a risk factor for obsessivecompulsive disorder. Proc Natl Acad Sci USA 1997;94: 4572–5. 84. Karayiorgou M, Sobin C, Blundell ML, Galke BL, Malinova L, Goldberg P, et al. Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol Psychiatry 1999;45:1178–89. 85. Camarena B, Cruz C, de la Fuente JR, Nicolini H. A higher frequency of a low activity-related allele of the MAO-A gene in

86.

87. 88. 89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

127

females with obsessive-compulsive disorder. Psychiatr Genet 1998;8:255–7. Swedo SE, Rapoport JL, Leonard H, Lenane M, Cheslow D. Obsessive-compulsive disorder in children and adolescents. Clinical phenomenology of 70 consecutive cases. Arch Gen Psychiatry 1989;46:335–41. Rapoport JL, Swedo SE, Leonard HL. Childhood obsessive compulsive disorder. J Clin Psychiatry 1992;53(suppl):11–6. Wever C, Rey JM. Juvenile obsessive-compulsive disorder. Aust N Z J Psychiatry 1997;31:105–13. Toro J, Cervera M, Osejo E, Salamero M. Obsessive-compulsive disorder in childhood and adolescence: a clinical study. J Child Psychol Psychiatry 1992;33:1025–37. Flament MF, Whitaker A, Rapoport JL, Davies M, Berg CZ, Kalikow K, et al. Obsessive compulsive disorder in adolescence: an epidemiological study. J Am Acad Child Adolesc Psychiatry 1988;27:764–71. Eichstedt JA, Arnold SL. Childhood-onset obsessivecompulsive disorder: a tic-related subtype of OCD? Clin Psychol Rev 2001;21:137–57. do Rosario-Campos MC, Leckman JF, Mercadante MT, Shavitt RG, Prado Hd HS, Sada P, et al. Adults with early-onset obsessive-compulsive disorder. Am J Psychiatry 2001;158:1899–903. Honjo S, Hirano C, Murase S, Kaneko T, Sugiyama T, Ohtaka K, et al. Obsessive-compulsive symptoms in childhood and adolescence. Acta Psychiatr Scand 1989;80:83–91. Swedo SE, Leonard HL, Rapoport JL. Childhood-onset obsessive compulsive disorder. Psychiatr Clin North Am 1992;15:767–75. Kohn R, Westlake RJ, Rasmussen SA, Marsland RT, Norman WH. Clinical features of obsessive-compulsive disorder in elderly patients. Am J Geriatr Psychiatry 1997;5:211–5. Weiss AP, Jenike MA. Late-onset obsessive-compulsive disorder: a case series. J Neuropsychiatry Clin Neurosci 2000;12:265–8. Lenane MC, Swedo SE, Leonard H, Pauls DL, Sceery W, Rapoport JL. Psychiatric disorders in first degree relatives of children and adolescents with obsessive compulsive disorder. J Am Acad Child Adolesc Psychiatry 1990;29:407–12. Pauls DL, Alsobrook JP, Goodman W, Rasmussen S, Leckman JF. A family study of obsessive-compulsive disorder. Am J Psychiatry 1995;152:76–84. Eisen JL, Goodman WK, Keller MB, Warshaw MG, DeMarco LM, Luce DD, et al. Patterns of remission and relapse in obsessive-compulsive disorder: a 2-year prospective study. J Clin Psychiatry 1999;60:346–51. Grabe HJ, Meyer C, Hapke U, Rumpf HJ, Freyberger HJ, Dilling H, et al. Lifetime-comorbidity of obsessive-compulsive disorder and subclinical obsessive-compulsive disorder in Northern Germany. Eur Arch Psychiatry Clin Neurosci 2001;251:130–5. du Toit PL, van Kradenburg J, Niehaus D, Stein DJ. Comparison of obsessive-compulsive disorder patients with and without comorbid putative obsessive-compulsive spectrum disorders using a structured clinical interview. Compr Psychiatry 2001;42:291–300.

Harv Rev Psychiatry

128

Lochner and Stein

102. Bienvenu OJ, Samuels JF, Riddle MA, Hoehn-Saric R, Liang KY, Cullen BA, et al. The relationship of obsessive-compulsive disorder to possible spectrum disorders: results from a family study. Biol Psychiatry 2000;48:287–93. 103. Eisen JL, Rasmussen SA. Obsessive compulsive disorder with psychotic features. J Clin Psychiatry 1993;54:373–9. 104. Geller DA, Biederman J, Faraone S, Agranat A, Cradock K, Hagermoser L, et al. Developmental aspects of obsessive compulsive disorder: findings in children, adolescents and adults. J Nerv Ment Dis 2001;189:471–7. 105. Leckman JF, Grice DE, Barr LC, de Vries AL, Martin C, Cohen DJ, et al. Tic-related vs. non-tic-related obsessive compulsive disorder. Anxiety 1994;1:208–15. 106. Holzer JC, Goodman WK, McDougle CJ, Baer L, Boyarsky BK, Leckman JF, et al. Obsessive-compulsive disorder with and without a chronic tic disorder: a comparison of symptoms in 70 patients. Br J Psychiatry 1994;164:469–73. 107. Miguel EC, Coffey BJ, Baer L, Savage CR, Rauch SL, Jenike MA. Phenomenology of intentional repetitive behaviors in obsessive-compulsive disorder and Tourette’s disorder. J Clin Psychiatry 1995;56:246–55. 108. Miguel EC, Baer L, Coffey BJ, Rauch SL, Savage CR, O’Sullivan RL, et al. Phenomenological differences appearing with repetitive behaviours in obsessive-compulsive disorder and Gilles de la Tourette’s syndrome. Br J Psychiatry 1997;170:140–5. 109. George MS, Trimble MR, Ring HA, Sallee FR, Robertson MM. Obsessions in obsessive-compulsive disorder with and without Gilles de la Tourette’s syndrome. Am J Psychiatry 1993;150:93–7. 110. Pitman RK, Green RC, Jenike MA, Mesulam MM. Clinical comparison of Tourette’s disorder and obsessive-compulsive disorder. Am J Psychiatry 1987;144:1166–71. 111. Cath DC, Spinhoven P, van Woerkom TC, van de Wetering BJ, Hoogduin CA, Landman AD, et al. Gilles de la Tourette’s syndrome with and without obsessive-compulsive disorder compared with obsessive-compulsive disorder without tics: which symptoms discriminate? J Nerv Ment Dis 2001;189:219–28. 112. Muller N, Putz A, Kathmann N, Lehle R, Gunther W, Straube A. Characteristics of obsessive-compulsive symptoms in Tourette’s syndrome, obsessive-compulsive disorder, and Parkinson’s disease. Psychiatry Res 1997;70:105–14. 113. Baer L, Jenike MA, Ricciardi JN 2nd, Holland AD, Seymour RJ, Minichiello WE, et al. Standardized assessment of personality disorders in obsessive-compulsive disorder. Arch Gen Psychiatry 1990;47:826–30. 114. Black DW, Noyes R Jr, Pfohl B, Goldstein RB, Blum N. Personality disorder in obsessive-compulsive volunteers, well comparison subjects, and their first-degree relatives. Am J Psychiatry 1993;150:1226–32. 115. Thomsen PH, Mikkelsen HU. Development of personality disorders in children and adolescents with obsessive-compulsive disorder. A 6- to 22-year follow-up study. Acta Psychiatr Scand 1993;87:456–62. 116. Bejerot S, Schlette P, Ekselius L, Adolfsson R, von Knorring L. Personality disorders and relationship to personality dimensions measured by the Temperament and Character Inventory

May/June 2003

117.

118.

119.

120. 121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

in patients with obsessive-compulsive disorder. Acta Psychiatr Scand 1998;98:243–9. Matsunaga H, Kiriike N, Miyata A, Iwasaki Y, Matsui T, Nagata T, et al. Personality disorders in patients with obsessive-compulsive disorder in Japan. Acta Psychiatr Scand 1998;98:128–34. Mavissakalian M, Hamann MS, Jones B. Correlates of DSM-III personality disorder in obsessive-compulsive disorder. Compr Psychiatry 1990;31:481–9. Mavissakalian MR, Hamann MS, Abou HS, de Groot CM. DSM-III personality disorders in generalized anxiety, panic/ agoraphobia, and obsessive-compulsive disorders. Compr Psychiatry 1993;34:243–8. Baer L, Jenike MA. Personality disorders in obsessive compulsive disorder. Psychiatr Clin North Am 1992;15:803–12. Norman RM, Davies F, Malla AK, Cortese L, Nicholson IR. Relationship of obsessive-compulsive symptomatology to anxiety, depression and schizotypy in a clinical population. Br J Clin Psychol 1996;35:553–66. McDougle CJ, Goodman WK, Price LH, Delgado PL, Krystal JH, Charney DS, et al. Neuroleptic addition in fluvoxaminerefractory obsessive-compulsive disorder. Am J Psychiatry 1990;147:652–4. Sobin C, Blundell ML, Weiller F, Gavigan C, Haiman C, Karayiorgou M. Evidence of a schizotypy subtype in OCD. J Psychiatr Res 2000;34:15–24. Goldstein WN. Obsessive-compulsive behavior, DSM-III, and a psychodynamic classification of psychopathology. Am J Psychother 1985;39:346–59. Samuels J, Nestadt G, Bienvenu OJ, Costa PT, Jr., Riddle MA, Liang KY, et al. Personality disorders and normal personality dimensions in obsessive-compulsive disorder. Br J Psychiatry 2000;177:457–62. Thomsen PH, Mikkelsen HU. Course of obsessive-compulsive disorder in children and adolescents: a prospective follow-up study of 23 Danish cases. J Am Acad Child Adolesc Psychiatry 1995;34:1432–40. Perugi G, Akiskal HS, Gemignani A, Pfanner C, Presta S, Milanfranchi A, et al. Episodic course in obsessive-compulsive disorder. Eur Arch Psychiatry Clin Neurosci 1998;248:240–4. Demal U, Lenz G, Mayrhofer A, Zapotoczky HG, Zitterl W. Obsessive-compulsive disorder and depression. A retrospective study on course and interaction. Psychopathology 1993; 26:145–50. Alarcon RD, Libb JW, Spitler D. A predictive study of obsessive-compulsive disorder response to clomipramine. J Clin Psychopharmacol 1993;13:210–3. Ravizza L, Barzega G, Bellino S, Bogetto F, Maina G. Predictors of drug treatment response in obsessive-compulsive disorder. J Clin Psychiatry 1995;56:368–73. Leonard HL, Lenane MC, Swedo SE, Rettew DC, Gershon ES, Rapoport JL. Tics and Tourette’s disorder: a 2- to 7-year follow-up of 54 obsessive-compulsive children. Am J Psychiatry 1992;149:1244–51. Leckman JF. Tourette’s Syndrome. In: Hollander E, ed. Obsessive-compulsive related disorders. Washington, DC: American Psychiatric Press, 1993: 113–38.

Harv Rev Psychiatry

Lochner and Stein

Volume 11, Number 3

133. Coffey BJ, Miguel EC, Biederman J, Baer L, Rauch SL, O’Sullivan RL, et al. Tourette’s disorder with and without obsessive-compulsive disorder in adults: are they different? J Nerv Ment Dis 1998;186:201–6. 134. Como PG. Obsessive-compulsive disorder in Tourette’s syndrome. Adv Neurol 1995;65:281–91. 135. Leckman JF, Walker DE, Goodman WK, Pauls DL, Cohen DJ. “Just right” perceptions associated with compulsive behavior in Tourette’s syndrome. Am J Psychiatry 1994;151:675–80. 136. Moriarty J, Eapen V, Costa DC, Gacinovic S, Trimble M, Ell PJ, et al. HMPAO SPET does not distinguish obsessive-compulsive and tic syndromes in families multiply affected with Gilles de la Tourette’s syndrome. Psychol Med 1997;27:737–40. 137. Pauls DL, Towbin KE, Leckman JF, Zahner GE, Cohen DJ. Gilles de la Tourette’s syndrome and obsessive-compulsive disorder. Evidence supporting a genetic relationship. Arch Gen Psychiatry 1986;43:1180–2. 138. Grimshaw L. Obsessional disorder and neurological illness. J Neurol Neurosurg Psychiatry 1964;27:229. 139. Hollander E, DeCaria CM, Sauoud J, Klein DF, Liebowitz MR. Neurological soft signs in obsessive-compulsive disorder. Arch Gen Psychiatry 1991;48:278–9. 140. Hymas N, Lees A, Bolton D, Epps K, Head D. The neurology of obsessional slowness. Brain 1991;114:2203–33. 141. Stein DJ, Hollander E, Chan S, DeCaria CM, Hilal S, Liebowitz MR, et al. Computed tomography and neurological soft signs in obsessive-compulsive disorder. Psychiatry Res 1993;50:143– 50. 142. Thienemann M, Koran LM. Do soft signs predict treatment outcome in obsessive-compulsive disorder? J Neuropsychiatry Clin Neurosci 1995;7:218–22. 143. Thomsen PH, Jensen J. Latent class analysis of organic aspects of obsessive-compulsive disorder in children and adolescents. Acta Psychiatr Scand 1991;84:391–5. 144. Yaryura-Tobias JA, Anderson MC, Neziroglu FA. Organicity in obsessive-compulsive disorder. Behav Modif 2000;24:553–65. 145. Deltito JA. Valproate pretreatment for the difficult-to-treat patient with OCD. J Clin Psychiatry 1994;55:500. 146. Prichep LS, Mas F, Hollander E, Liebowitz M, John ER, Almas M, et al. Quantitative electroencephalographic subtyping of obsessive-compulsive disorder. Psychiatry Res 1993;50: 25–32. 147. Baxter LR Jr. Positron emission tomography studies of cerebral glucose metabolism in obsessive compulsive disorder. J Clin Psychiatry 1994;55(suppl):54–9. 148. Robinson D, Wu H, Munne RA, Ashtari M, Alvir JM, Lerner G, et al. Reduced caudate nucleus volume in obsessivecompulsive disorder. Arch Gen Psychiatry 1995;52:393–8. 149. Cummings JL, Benson DF. Psychological dysfunction accompanying subcortical dementias. Annu Rev Med 1988;39:53–61. 150. Savage CR. Neuropsychology of subcortical dementias. Psychiatr Clin North Am 1997;20:911–31. 151. Saxena S, Brody AL, Schwartz JM, Baxter LR. Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry Suppl 1998;26–37. 152. Rauch SL, Baxter LR. Neuroimaging in obsessive-compulsive disorder and related disorders. In: Jenike MA, Baer L,

153.

154.

155.

156.

157.

158.

159.

160.

161.

162.

163. 164.

165.

166.

167. 168. 169.

129

Minichiello WE, eds. Obsessive-compulsive disorders: practical management. St. Louis, MO: Mosby, 1998: 289–317. Greenberg BD, Ziemann U, Cora-Locatelli G, Harmon A, Murphy DL, Keel JC, et al. Altered cortical excitability in obsessive-compulsive disorder. Neurology 2000;54:142– 7. Hugo F, Van Heerden B, Zungu-Dirwayi N, Stein DJ. Functional brain imaging in obsessive-compulsive disorder secondary to neurological lesions. Depress Anxiety 1999;10:129– 36. Berthier ML, Kulisevsky J, Gironell A, Heras JA. Obsessivecompulsive disorder associated with brain lesions: clinical phenomenology, cognitive function, and anatomic correlates. Neurology 1996;47:353–61. Rauch SL, Savage CR. Neuroimaging and neuropsychology of the striatum. Bridging basic science and clinical practice. Psychiatr Clin North Am 1997;20:741–68. Swedo SE, Leonard HL. Childhood movement disorders and obsessive compulsive disorder. J Clin Psychiatry 1994;55(suppl):32–7. Swedo SE, Leonard HL, Kiessling LS. Speculations on antineuronal antibody-mediated neuropsychiatric disorders of childhood. Pediatrics 1994;93:323–6. Allen AJ, Leonard HL, Swedo SE. Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 1995;34:307–11. Leonard HL, Swedo SE. Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Int J Neuropsychopharmacol 2001;4:191–8. Swedo SE, Leonard H, Mittleman BB, Allen AJ, Rapoport JL, Dow SP, et al. Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry 1997;154:110–2. Murphy TK, Goodman WK, Fudge MW, Williams RC, Ayoub EM, Dalal M, et al. B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette’s syndrome? Am J Psychiatry 1997;154:402–7. Pitman RK. Posttraumatic obsessive-compulsive disorder: a case study. Compr Psychiatry 1993;34:102–7. de Silva P, Marks M. The role of traumatic experiences in the genesis of obsessive-compulsive disorder. Behav Res Ther 1999;37:941–51. Trumbull DW. Obsessive-compulsive symptomatology: a goaldirected response to anticipated traumatization? Psychiatry 2001;64:309–18. Albert U, Maina G, Ravizza L, Bogetto F. An exploratory study on obsessive-compulsive disorder with and without a familial component: are there any phenomenological differences? Psychopathology 2002;35:8–16. Lewis A. Problems of obsessional illness. Proceedings of the Royal Society of Medicine 1936;29:325–36. Brown FW. Heredity in the psychoneuroses. Proceedings of the Royal Society of Medicine 1942;35:785–90. Kringlen E. Obsessional neurotics: a long-term follow-up. Br J Psychiatry 1965;111:709–22.

Harv Rev Psychiatry

130

Lochner and Stein

170. Lo WH. A follow-up study of obsessional neurotics in Hong Kong Chinese. Br J Psychiatry 1967;113:823–32. 171. Rosenberg CM. Familial aspects of obsessional neurosis. Br J Psychiatry 1967;113:405–13. 172. Insel TR, Hoover CF, Murphy DL. Parents of patients with obsessive-compulsive disorder. Psychol Med 1983;13:807–11. 173. McKeon P, Murray R. Familial aspects of obsessive-compulsive neurosis. Br J Psychiatry 1987;151:528–34. 174. Riddle MA, Scahill L, King R, Hardin MT, Towbin KE, Ort SI, et al. Obsessive compulsive disorder in children and adolescents: phenomenology and family history. J Am Acad Child Adolesc Psychiatry 1990;29:766–72. 175. Bellodi L, Sciuto G, Diaferia G, Ronchi P, Smeraldi E. Psychiatric disorders in the families of patients with obsessivecompulsive disorder. Psychiatry Res 1992;42:111–20. 176. Black DW, Noyes R, Jr., Goldstein RB, Blum N. A family study of obsessive-compulsive disorder. Arch Gen Psychiatry 1992;49:36–68. 177. Nicolini H, Weissbecker K, Mejia JM, Sanchez dC. Family study of obsessive-compulsive disorder in a Mexican population. Arch Med Res 1993;24:193–8. 178. Nestadt G, Samuels J, Riddle M, Bienvenu OJ III, Liang KY, LaBuda M, et al. A family study of obsessive-compulsive disorder. Arch Gen Psychiatry 2000;57:358–63. 179. Bellodi L, Cavallini MC, Bertelli S, Chiapparino D, Riboldi C, Smeraldi E. Morbidity risk for obsessive-compulsive spectrum disorders in first-degree relatives of patients with eating disorders. Am J Psychiatry 2001;158:563–9. 180. Leonard HL, Swedo SE, Rapoport JL, Koby EV., Lenane MC, Cheslow DL, et al. Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children and adolescents. A double-blind crossover comparison. Arch Gen Psychiatry 1989;46:1088–92. 181. Pigott TA, Pato MT, Bernstein SE, Grover GN, Hill JL, Tolliver TJ, et al. Controlled comparisons of clomipramine and fluoxetine in the treatment of obsessive-compulsive disorder. Behavioral and biological results. Arch Gen Psychiatry 1990;47:926– 32. 182. Goodman WK, McDougle CJ, Price LH. The role of serotonin and dopamine in the pathophysiology of obsessive compulsive disorder. Int Clin Psychopharmacol 1992;7(suppl 1):35–8. 183. Mohr N, Vythilingum B, Emsley RA, Stein DJ. Quetiapine augmentation of serotonin reuptake inhibitors in obsessivecompulsive disorder. Int Clin Psychopharmacol 2002;17:37– 40. 184. Mataix-Cols D, Rauch SL, Manzo PA, Jenike MA, Baer L. Use of factor-analyzed symptom dimensions to predict outcome with serotonin reuptake inhibitors and placebo in the treatment of obsessive-compulsive disorder. Am J Psychiatry 1999;156:1409–16. 185. Black DW, Monahan P, Gable J, Blum N, Clancy G, Baker P. Hoarding and treatment response in 38 nondepressed subjects with obsessive-compulsive disorder. J Clin Psychiatry 1998;59:420–5. 186. Alonso P, Menchon JM, Pifarre J, Mataix-Cols D, Torres L, Salgado P, et al. Long-term follow-up and predictors of clinical outcome in obsessive-compulsive patients treated with sero-

May/June 2003

187.

188.

189.

190.

191.

192.

193.

194.

195.

196.

197.

198.

199.

200.

201.

tonin reuptake inhibitors and behavioral therapy. J Clin Psychiatry 2001;62:535–40. Leonard HL, Swedo SE, Lenane MC, Rettew DC, Hamburger SD, Bartko JJ, et al. A 2- to 7-year follow-up study of 54 obsessive-compulsive children and adolescents. Arch Gen Psychiatry 1993;50:429–39. Thoren P, Asberg M, Cronholm B, Jornestedt L, Traskman L. Clomipramine treatment of obsessive-compulsive disorder. I. A controlled clinical trial. Arch Gen Psychiatry 1980;37:1281– 5. DeVeaugh-Geiss J, Katz R, Landau P. Clomipramine in the treatment of patients with obsessive-compulsive disorder: the Clomipramine Collaborative Study Group. Arch Gen Psychiatry 1991;48:730–8. Buchanan AW, Meng KS, Marks IM. What predicts improvement and compliance during the behavioral treatment of obsessive compulsive disorder? Anxiety 1996;2:22–7. Basoglu M, Lax T, Kasvikis Y, Marks I. Predictors of improvement in obsessive-compulsive disorder. J Anxiety Disord 1988;2:299–317. Foa EB, Goldstein A. Continuous exposure and complete response prevention in the treatment of obsessive-compulsive neurosis. Behav Ther 1978;9:821–9. Marks IM, Lelliott P, Basoglu M, Noshirvani H, Monteiro W, Cohen D, et al. Clomipramine, self-exposure and therapistaided exposure for obsessive-compulsive rituals. Br J Psychiatry 1988;152:522–34. Clark DA, Sugrim I, Bolton D. Primary obsessional slowness: a nursing treatment programme with a 13-year-old male adolescent. Behav Res Ther 1982;20:289–92. Christensen H, Hadzi-Pavlovic D, Andrews G, Mattick R. Behavior therapy and tricyclic medication in the treatment of obsessive-compulsive disorder: a quantitative review. J Consult Clin Psychol 1987;55:701–11. Erzegovesi S, Cavallini MC, Cavedini P, Diaferia G, Locatelli M, Bellodi L. Clinical predictors of drug response in obsessivecompulsive disorder. J Clin Psychopharmacol 2001;21:488– 92. Mundo E, Bareggi SR, Pirola R, Bellodi L. Effect of acute intravenous clomipramine and antiobsessional response to proserotonergic drugs: is gender a predictive variable? Biol Psychiatry 1999;45:290–4. McDougle CJ, Goodman WK, Leckman JF, Lee NC, Heninger GR, Price LH. Haloperidol addition in fluvoxaminerefractory obsessive-compulsive disorder. A double-blind, placebo-controlled study in patients with and without tics. Arch Gen Psychiatry 1994;51:302–8. Ackerman DL, Greenland S, Bystritsky A. Clinical characteristics of response to fluoxetine treatment of obsessivecompulsive disorder. J Clin Psychopharmacol 1998;18:185–92. den Boer JA. Psychopharmacology of comorbid obsessivecompulsive disorder and depression. J Clin Psychiatry 1997;58(suppl 8):17–9. Zitterl W, Lenz G, Mairhofer A, Zapotoczky HG. Obsessivecompulsive disorder: course and interaction with depression. A review of the literature. Psychopathology 1990;23:73– 80.

Harv Rev Psychiatry Volume 11, Number 3

202. Perse TL, Greist JH, Jefferson JW, Rosenfeld R, Dar R. Fluvoxamine treatment of obsessive-compulsive disorder. Am J Psychiatry 1987;144:1543–8. 203. Goodman WK, Price LH, Rasmussen SA, Delgado PL, Heninger GR, Charney DS. Efficacy of fluvoxamine in obsessive-compulsive disorder. A double-blind comparison with placebo. Arch Gen Psychiatry 1989;46:36–44. 204. Foa EB, Kozak MJ, Steketee GS, McCarthy PR. Treatment of depressive and obsessive-compulsive symptoms in OCD by imipramine and behaviour therapy. Br J Clin Psychol 1992;31:279–92. 205. Gershuny BS, Baer L, Jenike MA, Minichiello WE, Wilhelm S. Comorbid posttraumatic stress disorder: impact on treatment outcome for obsessive–compulsive disorder. Am J Psychiatry 2002;159:852–4. 206. McDougle CJ, Goodman WK, Leckman JF, Barr LC, Heninger GR, Price LH. The efficacy of fluvoxamine in obsessivecompulsive disorder: effects of comorbid chronic tic disorder. J Clin Psychopharmacol 1993;13:354–8. 207. Bogetto F, Bellino S, Vaschetto P, Ziero S. Olanzapine augmentation of fluvoxamine-refractory obsessive-compulsive disorder (OCD): a 12-week open trial. Psychiatry Res 2000;96:91– 8. 208. McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor–refractory obsessivecompulsive disorder. Arch Gen Psychiatry 2000;57:794–801. 209. Dowling FG, Pato MT, Pato CN. Comorbidity of obsessivecompulsive and psychotic symptoms: a review. Harv Rev Psychiatry 1995;3:75–83. 210. Ganesan V, Kumar TC, Khanna S. Obsessive-compulsive disorder and psychosis. Can J Psychiatry 2001;46:750–4. 211. Cheung EF. Obsessive-compulsive symptoms during treatment with clozapine in a patient with schizophrenia. Aust N Z J Psychiatry 2001;35:695–6. 212. Khullar A, Chue O, Tibbo P. Quetiapine and obsessivecompulsive symptoms (OCS): Case report and review of atypical antipsychotic-induced OCS. J Psychiatry Neurosci 2001;26:55–9. 213. de Haan L, Beuk N, Hoogenboom B, Dingemans P, Linszen D. Obsessive-compulsive symptoms during treatment with olanzapine and risperidone: a prospective study of 113 patients with recent-onset schizophrenia or related disorders. J Clin Psychiatry 2002;63:104–7. 214. Minichiello WE, Baer L, Jenike MA. Schizotypal personality disorder: a poor prognostic indicator for behavior therapy in the treatment of obsessive-compulsive disorder. J Anxiety Disord 1987;1:273–6. 215. Pfohl B, Black DW, Noyes R, Coryell WH, Barreira PJ. Axis I and Axis II comorbidity findings: implications for validity. In Oldham JM, ed. Personality disorders: new perspectives on diagnostic validity. Washington, DC: American Psychiatric Press, 1991. 216. Baer L, Jenike MA, Black DW, Treece C, Rosenfeld R, Greist J. Effect of Axis II diagnoses on treatment outcome with clomipramine in 55 patients with obsessive-compulsive disorder. Arch Gen Psychiatry 1992;49:862–6.

Lochner and Stein

131

217. Jenike MA, Baer L, Minichiello WE, Schwartz CE, Carey RJ Jr. Concomitant obsessive-compulsive disorder and schizotypal personality disorder. Am J Psychiatry 1986;143:530– 2. 218. Hermesh H, Shahar A, Munitz H. Obsessive-compulsive disorder and borderline personality disorder. Am J Psychiatry 1987;144:120–2. 219. Steketee G. Personality traits and disorders in obsessivecompulsives. J Anxiety Disord 1990;4:351–64. 220. Mavissakalian M, Hamann MS, Jones B. DSM-III personality disorders in obsessive-compulsive disorder: changes with treatment. Compr Psychiatry 1990;31:432–7. 221. Ackerman DL, Greenland S, Bystritsky A. Side effects as predictors of drug response in obsessive-compulsive disorder. J Clin Psychopharmacol 1999;19:459–65. 222. Bolton D, Raven P, Madronal-Luque R, Marks IM. Neurological and neuropsychological signs in obsessive compulsive disorder: interaction with behavioural treatment. Behav Res Ther 2000;38:695–708. 223. Brody AL, Saxena S, Schwartz JM, Stoessel PW, Maidment K, Phelps ME, et al. FDG-PET predictors of response to behavioral therapy and pharmacotherapy in obsessive compulsive disorder. Psychiatry Res 1998;84:1–6. 224. Saxena S, Bota RG, Brody AL. Brain-behavior relationships in obsessive-compulsive disorder. Semin Clin Neuropsychiatry 2001;6:82–101. 225. Hollander E, DeCaria CM, Nitescu A, Gully R, Suckow RF, Cooper TB, et al. Serotonergic function in obsessivecompulsive disorder. Behavioral and neuroendocrine responses to oral m-chlorophenylpiperazine and fenfluramine in patients and healthy volunteers. Arch Gen Psychiatry 1992;49:21–8. 226. Hollander E, DeCaria C, Stein D, Simeon D, Cohen L, Hwang M, et al. Behavioral response to m-CPP. Biol Psychiatry 1994;35:426–7. 227. Goodman WK, McDougle CJ, Price LH, Barr LC, Hills OF, Caplik JF, et al. m-Chlorophenylpiperazine in patients with obsessive-compulsive disorder: absence of symptom exacerbation. Biol Psychiatry 1995;38:138–49. 228. Hollander E, Cohen LJ, DeCaria C, Saoud JB, Stein DJ, Cooper TB, et al. Timing of neuroendocrine responses and effect of mCPP and fenfluramine plasma levels in OCD. Biol Psychiatry 1993;34:407–13. 229. Hollander E, Prohovnik I, Stein DJ. Increased cerebral blood flow during m-CPP exacerbation of obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci 1995;7:485–90. 230. Stein DJ, Van Heerden B, Wessels CJ, van Kradenburg J, Warwick J, Wasserman HJ. Single photon emission computed tomography of the brain with Tc-99m HMPAO during sumatriptan challenge in obsessive-compulsive disorder: investigating the functional role of the serotonin auto-receptor. Prog Neuropsychopharmacol Biol Psychiatry 1999;23:1079– 99. 231. Barr LC, Goodman WK, Price LH, McDougle CJ, Charney DS. The serotonin hypothesis of obsessive compulsive disorder: implications of pharmacologic challenge studies. J Clin Psychiatry 1992;53(suppl):17–28.

Harv Rev Psychiatry

132

Lochner and Stein

232. Barr LC, Goodman WK, Price LH. The serotonin hypothesis of obsessive compulsive disorder. Int Clin Psychopharmacol 1993;8(suppl 2):79–82. 233. Ebstein RP, Benjamin J, Belmaker RH. Personality and polymorphisms of genes involved in aminergic neurotransmission. Eur J Pharmacol 2000;410:205–14. 234. Miguel EC, Rauch SL, Jenike MA. Obsessive-compulsive disorder. Psychiatr Clin North Am 1997;20:863–83. 235. Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism. Science 1987;236:410–6. 236. Greenberg D. Compulsive hoarding. Am J Psychother 1987;41:409–16. 237. Leckman JF, Goodman WK, North WG, Chappell PB, Price LH, Pauls DL, et al. The role of central oxytocin in obsessive compulsive disorder and related normal behavior. Psychoneuroendocrinology 1994;19:723–49. 238. Singer HS, Hahn IH, Moran TH. Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette’s syndrome. Ann Neurol 1991;30:558–62. 239. Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol 1993;50:873–80.

May/June 2003

240. Zungu-Dirwayi N, Hugo F, van Heerden BB, Stein DJ. Are musical obsessions a temporal lobe phenomenon? J Neuropsychiatry Clin Neurosci 1999;11:398–400. 241. Swedo SE, Rapoport JL, Leonard HL, Schapiro MB, Rapoport SI, Grady CL. Regional cerebral glucose metabolism of women with trichotillomania. Arch Gen Psychiatry 1991;48:828– 33. 242. McElroy SL, Phillips KA, Keck PE Jr. Obsessive compulsive spectrum disorder. J Clin Psychiatry 1994;55(suppl):33– 51. 243. Stein DJ, Hollander E. The spectrum of obsessive-compulsive related disorders. In: Hollander E, ed. Obsessive-compulsive related disorders. Washington, DC: American Psychiatric Press, 1993:241–71. 244. Stein DJ, Hollander E. Impulsive aggression and obsessivecompulsive disorder. Psychiatr Annals 1993;23:389– 95. 245. Youn T, Lyoo I, Kim J, Park H, Ha K, Lee D, et al. Relationship between personality trait and regional cerebral glucose metabolism assessed with positron emission tomography. Biol Psychol 2002;60:109.