ADVANCES IN THE NEUROBIOLOGY OF OBSESSIVE-COMPULSIVE DISORDER

OBSESSIVE-COMPULSIVE SPECTRUM DISORDERS

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ADVANCES IN THE NEUROBIOLOGY OF OBSESSIVECOMPULSIVE DISORDER Implications for Conceptualizing Putative Obsessive-Compulsive and Spectrum Disorders Dan J. Stein, MB

For many decades, obsessive-compulsive disorder (OCD) was considered one of the exemplars of a psychogenic condition.88In the past 20 years, however, data about the neurobiological underpinnings of OCD have steadily accumulated. Interest in OCD also has encouraged work on a hypothesized spectrum of related disorders that are character38, @, 86, ized by an overlapping phenomenology and psych~biology.~~~ Nevertheless, the question of how best to delineate this spectrum remains unanswered,82perhaps partly because the underlying mechanisms of OCD and putative spectrum disorders remain incompletely understood. This article reviews current advances in the neurochemistry, neuroanatomy, neurogenetics, neuroimmunology, and neuroethology of OCD and then uses this information to consider different approaches toward the concept of an obsessive-compulsive spectrum and its neurobiology. This work was supported by the Medical Research Council Unit of South Africa.

From the Medical Research Council Unit on Anxiety Disorders, University of Stellenbosch, Cape Town, South Africa

THE PSYCHIATRIC CLINICS OF NORTH AMERICA

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VOLUME 23 NUMBER 3 * SEPTEMBER 2000

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NEUROBIOLOGY

This section focuses on the neurochemistry, neuroanatomy, neurogenetics, neuroimmunology, and neuroethology of OCD. Although understanding in each of these areas has grown remarkably, many questions remain unanswered. This discussion highlights the main findings. Neurochemistry

Psychopharmacologic studies indicate that the serotonin (5-HT)neurotransmitter system and several other neurochemical systems have a crucial role in mediating OCD. Early reports that clomipramine, a tricyclic antidepressant (TCA) and 5-HT reuptake inhibitor (SRI), was effective in the treatment of patients with OCD encouraged a series of studies by neurobiologically oriented researchers on the 5-HT system in patients with this disorder. Several studies supported the hypothesis that the 5-HT system has a crucial role in OCD. First, the long-term administration of selective SRIs (SSRIs) was demonstrated to be more effective than that of noradrenergic reuptake inhibitors in the treatment of OCD.l12 This finding is apparent not only in adults but also in children and adolescents with OCD.56All of the SSRIs studied to date in patients with OCD have been found to be effective for its treatment. The selective efficacy of SRIs in patients with OCD contrasts markedly with data on major depression, in which SRIs and noradrenergic reuptake inhibitors are effective. Second, acute administration of 5-HT agonists, such as m-chlorophenylpiperazine (mCPP), was found to exacerbate OCD symptoms.27,lT3 Also, the neuroendocrine response to mCPP administration is blunted in patients with OCD compared with healthy controls. Such data arguably suggest that 5-HT receptors mediating behavioral response (perhaps in frontal areas) are increased, whereas 5-HT receptors mediating neuroendocrine response (perhaps in the hypothalamus) are decrea~ed.2~ Findings in studies of 5-HT agonists in patients with OCD are conflicting, h ~ w e v e rwhich ,~ may reflect methodologic differences, heterogeneity in OCD, or differences in neurochemistry among different 5-HT agonists (e.g., mCPP differs from 6-chloro-2-[l-piperazinyl]-pyrazine[MK-2121, which did not lead to OCD symptom exacerbation, in also having affinity for the 5-HT1, receptor). Third, the effective treatment of OCD with SRIs leads to a decrease in cerebrospinal fluid (CSF) levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA)'09and to normalization of the neuroendocrine and behavioral responses to mCPP.26,114 Although such findings do not necessarily associate serotonergic dysfunction per se with OCD, they certainly reinforce the impression that the 5-HT system is involved in the mediation of OCD. Nevertheless, evidence shows a role for several other neurotransmitter systems in OCD. First, only approximately 50% to 60% of OCD

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patients report exacerbation of symptoms after acute administration of mCPP or demonstrate a decrease in OCD symptoms after long-term administration of a SRI. Meta-analytic trials of OCD therapies, although flawed, provide preliminary evidence that agents with less selective serotonergic effects are more effective in the treatment of OCD.” 93 Patients with comorbid chronic motor tics (CMTs) are less likely to respond to treatment with an SRI and more likely to respond to augmentation of SRIs with a classic antipsychotic agent (i.e., dopamine Other factors that may be involved in OCD include the opioid system,44o x y t o ~ i nand ~ ~vasopressin,2and gonadal Ultimately, mechanisms distal to neurotransmitter receptors require in~estigati0n.l~ Neuroanatomy

Modern brain imaging techniques have had a key role in delineating the neuroanatomy of OCD. Structural and functional studies have provided strong evidence that OCD symptoms are mediated by basal ganglia circuits. Functional studies have included at-rest studies, symptom provocation studies, and studies before and after SRI pharmacotherapy. Several structural studies have found that basal ganglia volume is 83 decreased in patients with OCD compared with healthy controls.M), Inconsistency exists among studies, however, with some showing increased basal ganglia volumes in patients with OCDs4or no differences among patients with OCD and controls.43Such inconsistency may indicate that volumes of the basal ganglia change over time or that brain imaging differences are confined to certain subpopulations of OCD. For example, in one CT studyg0increased ventricular-brain ratio was found in patients with increased neurologic soft signs. Functional studies demonstrate that, at rest, patients with OCD have increased brain activity in the basal ganglia, that this activity increases during exposure to feared stimuli, and that this hyperactivity decreases after successful SRI pharmacotherapy or cognitive-behavioral therapy for OCD?5,81Neuroimaging data arguably provide some support for a ”striatal topography model,” which hypothesizes that ventromedial caudate dysfunction is associated with obsessions and compulsions of OCD, whereas putamen dysfunction leads to the sensorimotor systems of Tourette syndrome (TS).81 Evidence also shows, however, that brain structures other than the basal ganglia may have a role in mediating OCD symptoms. Frontal lobe lesions may be associated with OCD,45frontal lobe abnormalities have been seen in structural studies,20and frontal lobe hyperactivity occurs in functional imaging studies of OCD.81Whether frontal lobe activation in imaging studies reflects a primary deficit in OCD or a compensatory response to basal ganglia dysfunction is unclear.35Given the functional importance of cortico-striated loops,16it is perhaps most accurate to state simply that it is these circuits that mediate OCD. Nevertheless, temporal lobe abnormalities also may be present in some

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patients with OCD,39and these patients have been reported to respond to anticonvulsant treatment.“ Neuropsychological research and neurosurgery studies are consistent with the importance of basal ganglia circuits in OCD. Neuropsychological studies demonstrate various dysfunctions, including problems in suppressing responses to irrelevant stimuli.91Neurosurgical interruption of cortico-striatal pathways may be useful in the management of patients with treatment-refractory OCD. These studies do not differentiate between pathology in the basal ganglia per se and functionally related structures in frontal cortex. Neurogenetics

Evidence that genetic factors have a significant role in the development of OCD is growing. The earliest evidence for the importance of genetic factors emerged from family studies suggesting increased frequency of OCD in families of OCD patients. For example, Lewis58 reported obsessive traits in 37% of parents and 21% of siblings of patients with obsessive neurosis. Similarly anecdotal descriptions of monozygotic twins with OCD have long been published in the psychiatric literature, and early twin series from Japan36and England9 found increased concordance of OCD in monozygotic compared with dizygotic twins. Although these first studies suffered from various methodologic flaws, more recent studies have used explicit diagnostic criteria and structured diagnostic interviews, direct assessment of relatives by an interviewer blind to proband status, and control groups. Pauls et a1,77 for example, confirmed an increased risk for OCD and subsyndromal OCD in relatives of OCD probands (10.3%and 7.9%, respectively) compared with those of controls (1.9%and 2%, respectively). The prevalence of tics (TS and CMTs) was significantly greater among relatives of probands than in comparison subjects (4.6% versus 1.0%, respectively). These data support earlier work by the same investigators suggesting a genetic relationship between OCD and CMT disorder^.^^ The findings of family studies have encouraged investigators to search for specific genetic abnormalities in OCD. No study has succeeded in clearly identifying a vulnerability gene for OCD or TS.5O Nevertheless, several interesting candidate genes have been proposed. Patients with chromosome 22911 deletions often demonstrate obsessivecompulsive symptoms, and the gene for catechol-0-methyltransferase (COMT), which is involved in the inactivation of catecholamines, maps to this region. One study”’ found that a common functional allele of this gene, which results in a threefold to fourfold reduction in enzyme activity, is associated with OCD in Caucasian men. On the other hand, these COMT findings are insufficient to explain completely genetic vulnerability to OCD. They seem to be limited to men, and only 48% of the men had the LIL genotype (the only genotype with an increased risk).

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Therefore, that other genes also are involved in susceptibility to OCD is likely. Nicolini et al,72for example, have suggested that OCD patients with and without CMTs can be differentiated on the basis of increased frequency of homozygosity for the allele A2 of TaqIA at the dopamine D, receptor locus and an increased number of the seven repeat alleles of the dopamine D, receptor locus. Neuroimmunology

Work on the neuroimmunology of OCD comprises some of the most exciting research on the neurobiology of OCD. This work can be traced back to early case reports of obsessive-compulsive symptoms in patients in whom Sydenham’s chorea had developed in the aftermath of a streptococcal infection. Using standardized OCD ratings, Swedo et allo6confirmed that patients with Sydenham’s chorea had a high prevalence of OCD. This work was of interest given that Sydenham’s chorea may involve an autoimmune response in which antibodies to the basal ganglia develop. Swedo et allo7have since reported that obsessive-compulsive symptoms can be precipitated or exacerbated simply by streptococcal throat infection. To describe such patients, these investigators coined the term pediatric autoimmune neuropsychiatric disorder associated with Streptococcus (PANDAS). Interestingly, case reports from this group indicate that patients with OCD precipitated by streptococci may initially have increased basal ganglia volume, perhaps with subsequent loss of volume. Also, such patients may respond to specific immunologic interventions, such as plasmapharesis or intravenous immunoglobulin therapy.’ Also of interest in this regard is a body of work showing that patients who expressed a particular B-lymphocyte antigen, known as 08/17, are more susceptible to poststreptococcal autoimmune sequelae. Swedo et allo6found that D8/17 expression was significantly higher in children with PANDAS and in children with Sydenham‘s chorea than in controls. Murphy et aP9 found that patients with childhood-onset OCD or TS had significantly greater D8 / 17 expression than did healthy controls. Other research also has attempted to delineate the immunologic mechanisms that may underly OCD; for example, Mittleman et a P found that OCD patients were characterized by a preponderance of CSF type 1 cytokines, consistent with a cell-mediated immune process. Neuroethology

Most work on the neurobiology of psychiatric disorders focuses on proximate mechanisms (e.g., neurotransmitter dysfunction) responsible for these conditions; however, evolutionary theory also raises questions about the distal mechanisms that are involved in pathogenesis-the evolutionary history behind the development of different dysfunctional

phenotype^.^^

OCD involves several behaviors that might well have been conserved during the course of evolution. Members of a range of species, including primates, have genetically inherited motoric and cognitive procedural strategies (i.e., fixed action patterns, learned habits, or response sets) that contribute to checking for danger, reducing contamination, and hoarding (mostly of food). An immediate hypothesis would be that dysfunction of any of these inherited programs may lead to OCD. Certainly, evidence shows that the basal ganglia are a repository for species-specific procedural strategies.61 Such a hypothesis would be strengthened by the description of disorders analogous to OCD in other species. Several such conditions may exist. Perhaps the best characterized of these, and arguably the most reminiscent of OCD, is canine acral lick dermatitis. This disorder, common in large breeds (e.g., Labrador), is characterized by excessive licking or biting of the extremities, which leads to localized alopecia and subsequent granulomatous lesions. A range of behavioral and medication interventions have been tried, but of interest to work on OCD are 99 An elegant study by Rapoport et a1 reports that SRIs are successful.89~ demonstrated that, like OCD, acral lick dermatitis responds more robustly to clomipramine than to desipramine. Several avenues of exploration have significantly contributed to an understanding of the neurobiology of OCD. Neurochemical studies point to the importance of 5-HT, dopamine, and other systems in OCD. Neuroanatomic research emphasizes the role of frontobasal ganglia circuits in OCD. Neurogenetic work indicates that certain genes, and perhaps those underlying monoamine function, may have a key role in the pathogenesis of OCD. Neuroimmunologic research suggests that, in at least a subset of patients with OCD, autoimmune mechanisms may have a role. Neuroethology hypothesizes that OCD involves dysfunction in specific evolutionarily conserved procedural strategies. These mechanisms may overlap considerably; for example, autoimmune mechanisms may lead to basal ganglia dysfunction, 5-HT and dopamine are important neurotransmitters in the basal ganglia, and these systems have genetic underpinnings with a long evolutionary history. Nevertheless, each set of studies may be used to develop an approach to a set of putative OCD-related disorders. Such different approaches are discussed in the next section. SEROTONIN SELECTIVITY

Clomipramine, an SRI, is more effective than desipramine, a predominantly noradrenergic reuptake inhibitor, in adults and younger patients with OCD. The notion that different psychiatric conditions can be pharmacologically dissected was put forward early on by Klein,48 who demonstrated that the TCA imipramine was effective in decreasing episodic spontaneous panic, whereas benzodiazepines decreased chronic fearlike anxiety; however, the TCAs per se do not allow for a specific

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pharmacologic dissection; they are effective in treating not only depression and panic but also several other anxiety disorders and a range of apparently dissimilar disorders (e.g., enuresis). Nevertheless, specificity within the TCAs is unusual; depression, for example, responds to SRIs and noradrenergic reuptake inhibitors. Premenstrual dysphoric disorder, social phobia, and posttraumatic stress d i s ~ r d e r 'also ~ may respond selectively to the SRIs, but arguably in each of these disorders a response to agents other than the SRIs (e.g., monoamine oxidase inhibitors) occurs. In a series of studies by Rapoport et al, clomipramine proved more effective than desipramine in decreasing a range of repetitive behaviors in various patient groups. These included hair-pulling in patients with trichotillomania (TTM),lo3nail biting in patients with a severe form of such self-injurious behavior,57 obsessive-compulsive symptoms in autism,21and perhaps stereotypic movements (e.g., body rocking) in intellectually healthy adults.1° Clomipramine also is more effective than is desipramine in the treatment of body dysmorphic disorderza and in reducing self-injurious behavior.65Whether patients with TS respond preferentially to clomipramine rather than desipramine is unclear,* but the SRIs seem useful for treating OCD symptoms in such patients. Hypochondriasis seems to respond to SRIs,lS although a comparison with other agents has not been undertaken. Finally, although the SRIs apparently are useful in some patients with hypersexual symptoms,4° a small study"g did not show selective efficacy of clomipramine over desipramine. The effects of clomipramine may vary in these different disorders, being most significant in patients with OCD and BDD but less so in patients with more self-injurious behavior (e.g., TTM or nail biting) and symptoms associated with gratification (e.g., hypersexual symptoms). Controlled trials of the SRIs in patients with TTM have not shown efficacy consistently, and evidence shows that therapeutic effect is lost over time.94Based on this, in disorders in which serotonergic selectivity is clearest, the relationship to OCD may be closest. On the other hand, not all patients with OCD respond to the SRIs. The combination of an SRI with low-dose antipsychotic therapy has been demonstrated to be useful in OCD patients with comorbid CMTS.~~ No similar controlled studies in other putative spectrum disorders are available, but this combination may also be effective in patients with TS" or TTM.96 Nevertheless, this regimen has a broad range of efficacy; for example, it may also be useful in the treatment of patients with treatment-resistant depression and PTSD.59 What about other studies of serotonergic function in OCD, such as the work on CSF 5-HIAA? This measure is of considerable interest because one of the most replicated findings in biological psychiatry is the association between decreased CSF 5-HIAA and increased impulsiveaggression. This correlation has been confirmed in several psychiatric diagnoses. Given that OCD may be characterized by increased serotonergic function in some brain regions, a contrast may immediately be set

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up with decreased serotonergic function in impulsive-aggressive patients, but this contrast seems too simplistic. First, impulsive-aggression also may occur in patients with OCD and is not uncommon in patients with TS.87Second, at least some patients with OCD (perhaps those in whom the content of obsessions involves more aggression) manifest low levels of CSF 5-HIAA.53Most patients with OCD, TS, or TTM=, 74 do not demonstrate clearly increased levels of CSF 5-HIAA, but preliminary evidence shows that increased baseline levels of CSF 5-HIAA in patients with TTM predicts successful treatment response.74 Pharmacologic challenges with 5-HT agonists have been used in several disorders other than OCD. Exacerbation of symptoms may not be unique to OCD; mCPP, for example, seems anxiogenic in several In patients with TTM, however, preliminary evidence indicates that this does not occur but that patients are more likely to experience feeling "high,"97Similarly, in patients with personality disorders characterized by impulsive traitsz9and in patients with pathologic gambling,16" a euphoric or disinhibited response may occur. Do these data point to a neurobiological dissection between OCD and more impulsive disorders? Data seem too limited to draw firm conclusions, but a study of fenfluramine challenges in obsessive-compulsive personality disorder (OCPD) may shed some light on the question. Here, patients with OCPD had greater impulsive-aggressive scores and more blunted neuroendocrine responses compared with other personality disorders and normal cont r o l ~As . ~in ~ the report of decreased levels of CSF 5-HIAA in some OCD this dataset draws attention to a phenomenologic overlap of compulsive and impulsive symptoms (earlier emphasized, of course, in Freud's concept of increased anal-sadism in obsessive-compulsive neurosis) and indicates that this overlap may correlate with measures of serotonergic dysfunction. Neurochemical systems other than 5-HT and dopamine have not been widely studied in the range of putative obsessive-compulsive spectrum disorders. Nevertheless, evidence shows opioid or hormonal involvement in TS:l, 8o TTM,'" l4 and other stereotyped movements. 5-HT has been associated with several functions. Most broadly, Jacobs and F ~ r n asuggest l ~ ~ that 5-HT facilitates gross motor output and inhibits sensory information processing. They argue that destruction of the serotonin 5-HT system results in over-reactivity to environmental stimuli, while repetitive motor acts may increase serotonergic neural activity. OCD may be characterized by decreased 5-HT function in some brain regions (e.g., the basal ganglia), with comorbid impulse dyscontrol, but in contrast to the impulsive disorders, in patients with OCD, a compensatory response can be mounted by increased serotonergic activity in other regions (e.g., the frontal areas). This formulation may be redolent of the psychodynamic concept of OCD being characterized by underlying aggression, with consequent compensatory defenses. The finding that mCPP, a postsynaptic serotonin 5-HT agonist, results in increased frontal activity in patients with OCD30 may argue

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against this hypothesis. In another study of mCPP, however, this led to decreased frontal After administration of sumatriptan, a 5-HT1, agonist, to OCD patients, exacerbation of symptoms correlated with decreased frontal activity.l0’ Conversely, treatment with SRIs may allow for an amplification of compensatory responses, so appropriately modulating basal ganglia activity. In patients with baseline (compensatory) increased frontal activity, a relatively decreased response to SRI treatment may occur.1o4(Cognitive-behavioral therapy may allow patients to habituate to their impulse dyscontrol, so to speak, so that a compensatory response is no longer necessary.) In patients with disorders closely related to OCD, such as BDD, a selective response to the SRIs may occur. In patients with less closely related disorders, however, a less robust or less selective response may occur. For example, relatively fewer patients with TTM seem to respond to SSRIs, perhaps depending on baseline frontal activity.lo5In patients with TS, on the other hand, a more marked motoric component, and perhaps concomitantly greater involvement of the dopaminergic system, is present. Certain OCD symptoms, such as hoarding and symmetry compulsions, similarly may be more likely to point to a dopaminergic component. No evidence, however, shows that diminished insight in patients with OCD is accompanied by dopaminergic dysfunction; patients with poor insight OCD or near-psychotic BDD symptoms apparently also respond to SRIS.~” ANATOMIC SPECIFICITY

The influenza pandemic early in the 1900s provided some of the first evidence that obsessive-compulsive symptoms might be mediated by specific neuroanatomic circuits. Patients developed not only postencephalitic parkinsonism but also psychiatric symptoms, including obsessive-compulsive behavior. At autopsy, findings included lesions in the basal ganglia.” Later work demonstrated that several neurologic disorders of the basal ganglia are associated with obsessive-compulsive symptoms. Patients with Sydenham’s chorea, Huntington disease, and various other basal ganglia abnormalities may demonstrate obsessive-compulsive symptoms. Similarly, Palumbo et a176put forward the hypothesis of a set of developmental basal ganglia disorders. Can basal ganglia involvement be used to define a spectrum of OCD-related disorders? Evidence suggests basal ganglia involvement in patients with TS. Interestingly, the basal ganglia are especially vulnerable to prenatal and perinatal hypoxic-ischemic injury, a significant fact given that, in twins with TS, an association exists between lower birth weight and increased severity of TS.33Neuropathologic studies of TS are limited, but evidence shows involvement of striatal Some (but not all) structural studies have shown reduced basal ganglia volume,34,80, 85 whereas functional studies have shown basal ganglia abn~rrnalities.~~ Frontal findings are inconsistent but perhaps increased in patients with

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obsessive-compulsive symptom^.^ In patients with TS, evidence shows greater-than-normal striatal dopamine transporter and, in monozygotic twins with TS, increased caudate D,-receptor binding was associated with increased CMT severity."O Nevertheless, the evidence is less clear for other putative obsessivecompulsive spectrum disorders. Only one study shows reduced putamen volume in patients with TTM." Brain imaging studies in patients with autistic disorder have been inconsistent, with conflicting evidence of hypoplasia in regions of the ~erebellum.~ Conversely, the specificity of basal ganglia dysfunction in patients with putative spectrum disorders is questionable; imaging studies have documented basal ganglia abnormalities in many psychotic, mood, anxiety, and eating disorders, and attention-deficit hyperactivity disorder (ADHD).Similarly, although neuropsychological studies of TSZ8and TTM94are, to some extent, consistent with basal ganglia pathology, they do not allow anatomic localization or diagnostic specificity. Finally, the value of neurosurgical intervention in the treatment of patients with TS is less well documented than in patients with OCD. Another way to approach a spectrum of obsessive-compulsivedisorders is to consider obsessive-compulsive symptoms in the basis of brain regions other than the basal ganglia. Patients with OCD after basal ganglia lesions may differ from those in whom symptoms are caused by frontal abnormalities (these patients typically have impulsive and compulsive symptoms) or temporal lobe disorders (these patients may have comorbid psychological abnormalities, e.g., psychosensory symptoms). Patients with certain symptoms of OCD, such as obsessional slowness, may have more diffuse neurologic damage than others. The basal ganglia mediate several phenomena, including movement, cognition, and emotion. Corticostriatal circuits include serotonergic and dopaminergic neurons.I6 The particular circuits involved in OCD and related disorders may mediate procedural strategies. Disruption of the basal ganglia results in a range of symptoms that are characterized by compulsivity (the patterns are released repeatedly) and impulsivity (patterns are released suddenly by various stimuli and may involve aggression). Symptoms mediated by the caudate (e.g., the obsessions and compulsions of OCD) may differ from those mediated by the putamen (e.g., hair-pulling).81Symptoms of impulsive aggression may be actively inhibited (in patients with OCD), more commonly expressed (in patients with TS), or the primary symptom (in patients with frontal lesions). This formulation is, to some extent, consistent with that in the previous section; in OCD frontal hyperactivity represents a compensatory response, whereas in patients with frontal lesions, control over executive functions and basic repertoires is lost. From this perspective, OCD can be contrasted with other disorders that involve dysfunctional subconscious processing. For example, in patients with PTSD, increased activity in amygalothalamic pathways seems to occur, perhaps at the expense of slower corticoamygdalic pathways. Thus, in patients with OCD, disruption of implicit processing

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occurs, necessitating the compensatory activation of explicit processing, whereas in patients with PTSD activation of implicit fear pathways overrides slower explicit circuits. This contrast is reminiscent of Freud's view of obsessive-compulsive neurosis as involving the repression of affect as opposed to hysteria involving the repression of ideas. GENETIC SPECIFICITY

The disorder most closely linked with OCD in family studies is TS. In a fascinating brain imaging study, Moriarty et aFS found that in patients with obsessive-compulsive symptoms, regional cerebral blood flow patterns differed depending on whether a family history of TS was present, and patterns were similar to those seen in TS in patients from families with TS. Family studies of TS, however, arguably also demonstrate a link with several other disorders, including ADHD, mood disorders, conduct disorder, and substance-abuse di~0rder.l~ Anecdotal reports suggest that first-degree relatives of patients with TTM have increased rates of OCD, TTM, and mood disorders.102Christenson et all3 reported that 8% of 161 TTM patients had first-degree relatives with hair pulling. King et a147reported that in girls with hair pulling, parental history of CMTs, habits, or obsessive-compulsive symptoms was common. In a systematic family study,55 6% of first-degree relatives of TTM patients had OCD. Thus, although rates of OCD in TTM family members were higher than those found in the general population, they may not be as high as the rates of OCD in first-degree relatives of OCD patients. From the neurogenetic perspective, then, an underlying set of genes are responsible not only for OCD but for several disorders that more commonly are present in families of probands with OCD. Although TS is the most common of these, other disorders that may share a genetic component with OCD include several disorders with compulsive and impulsive features, including TTM.55Blum et a16coined the term rewarddeficiency syndrome to refer to the association between DR-D, polymorphisms and impulsive-addictive-compulsivebehavior, including TS, ADHD, substance-abuse disorders, and pathologic gambling. The relationship between phenotype and genotype in OCD and TS nevertheless remains to be elucidated; this area of work should see substantial progress in the next years. IMMUNOLOGIC SPECIFICITY

Swedo et allo7suggested several diagnostic criteria for PANDAS: presence of OCD or a CMT disorder, prepubertal symptom onset, episodic course of symptom severity, association with group A P-hemolytic streptococcal infection, and association with neurologic abnormalities. Patients with PANDAS also may demonstrate several other psychologi-

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cal abnormalities, however, including emotional liability, separation anxiety, oppositional behaviors, and motoric hyperactivity. Symptoms such as hair pulling less commonly are reported in association with streptococcal The B-lymphocyte antigen D8/ 17 has not yet been widely studied in psychiatric diagnoses other than OCD. Nevertheless, D8 / 17 expression seems high in patients with autism31but normal in patients with TTM.” Additional work is necessary to consolidate these kinds of findings and to determine whether immunologic markers can be used to define an obsessive-compulsive spectrum of disorders. Initial work correlating immunologic findings and basal ganglia involvement also deserves extension. In the interim, the combination of compulsive and impulsive symptoms reported in PANDAS is intriguing.

ETHOLOGIC SPECIFICITY

Arguably the best-studied neuroethologic model of OCD is canine acral lick dermatitis. Nevertheless, several other stereotypical symptoms occur in veterinary including locomotory stereotypies in horses, chewing in sows, hoarding in cats, feather picking in birds, and self-grooming in primates. These various conditions may involve overlapping neurobiological mechanisms; evidence shows that the serotonergic, dopaminergic, and opioid systems and corticostriatal circuits, may have a role. A detailed consideration of each of these conditions is beyond the scope of this article. One possibility, however, is that predominant stereotypic patterns in any particular species reflect that species’ past evolution and specialized functions, locomotory stereotypies are likely to develop in horses, chewing stereotypies are likely to develop in sows, and grooming stereotypies are likely to develop in primates and other social species. Similarly, in humans, stereotypic symptoms would reflect our evolutionary heritage and may revolve around issues of contamination, possible harm, symmetry, and jealousy; however, in humans, several more abstract and unusual concerns also may develop. Further understanding of the neurobiology of animal stereotypies ultimately may be useful in delineating this spectrum.100

SUMMARY

Several approaches to the spectrum of obsessive-compulsive spectrum disorders have been put forward, each based on a rather different framework. To some extent, overlaps exist among these approaches, indicating that the neurobiology of OCD and related disorders is increasingly consolidated; however, important differences exist between these approaches, and many questions are unanswered, demonstrating that

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more work is necessary to fully delineate OCD and its subtypes and their relationships to other putative obsessive compulsive spectrum disorders. Despite the need for substantial additional research on the neurobiology of the obsessive-compulsive spectrum, this construct already has heuristic value in the clinical and research setting. It reminds clinicians to ask OCD patients about comorbid spectrum disorders, and it suggests the possible value of anti-OCD agents and behavioral techniques in patients for whom treatments were previously unavailable. It reminds investi8ators to consider possibly overlapping and differentiating mechanisms in several disorders. Ultimately, the delineation of such mechanisms will allow for a more rigorous approach to the putative obsessivecompulsive spectrum disorders.

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Address reprint requests to Dan J. Stein, MB Medical Research Council Unit on Anxiety Disorders University of Stellenbosch Tygerberg 7505 South Africa e-mail: [email protected]