Obsessive compulsive disorder (OCD) with schizotypy vs. schizophrenia with OCD: diagnostic dilemmas and therapeutic implications

Journal of Psychiatric Research 39 (2005) 399 408 JOURNAL OF PSYCHIATRIC RESEARCH www.elsevier.com/locate/jpsychires Obsessive compulsive disorder (OCD) with schizotypy vs. schizophrenia with OCD: diagnostic dilemmas and therapeutic implications M. Poyurovsky a, *, L.M. Koran b a Research Unit, Tirat Carmel Mental Health Center and Rappaport Faculty of Medicine, Israel Institute of Technology, Technion, 9 Eshkol Street, Haifa, Tirat Carmel 30200, Israel b Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA Received 23 April 2004; received in revised form 25 August 2004; accepted 21 September 2004 Abstract Although schizophrenia and obsessive compulsive disorder (OCD) are distinct diagnostic entities, there are substantial areas of overlap between the two disorders in clinical characteristics, affected brain areas and pharmacotherapy. Though OCD patients apparently do not have increased risk for developing schizophrenia, schizotypal personality disorder has consistently been found in OCD patients. Compelling evidence also points to an increased rate of OCD in schizophrenia patients. Accurate diagnosis of both disorders in their pure and overlapping forms is necessary in order to evaluate etiological mechanisms underlying schizophrenia and OCD, and to provide adequate treatment and prognosis. In this review, we address some aspects of the current status of research pertinent to the OCD schizophrenia interface and suggest further steps towards the clinical and etiological identification of homogeneous subgroups on the putative OCD schizophrenia axis. Ó 2004 Elsevier Ltd. All rights reserved. Keywords: Schizophrenia; Obsessive compulsive; Schizotypal; Pharmacotherapy; Phenomenology; Diagnostic entity 1. Introduction * Corresponding author. Tel.: +972 4 8559349; fax: +972 4 8559330. E-mail address: poyurovs@tx.technion.ac.il (M. Poyurovsky). Obsessive compulsive disorder (OCD) and schizophrenia have notable areas of overlap. Both disorders affect men and women equally, have a chronic course and a similar distribution of age-at-onset, with a trend towards earlier age of onset for OCD. A significant neurodevelopmental component and overlapping brain areas (prefrontal cortex, anterior cingulate, caudate nucleus and thalamus) have been consistently implicated in both disorders. (for review see Tibbo and Warneke, 1999;Gross-Isseroff et al., 2003). Therapeutic efficacy of antipsychotic agents and serotonin reuptake inhibitors (SRIs) in both schizophrenia and OCD also suggests pathophysiological overlap between the two disorders. Hence, it is not surprising that a complex association between schizophrenia and OCD exists on the psychopathological level. Despite the existence of a substantial convergence on neurobiological and phenomenological levels, schizophrenia and OCD are distinct clinical entities. Accurate diagnosis of both disorders in their pure and overlapping forms is necessary for adequate treatment planning and prognosis, as well as for conducting research into the disordersõ etiology. This review highlights some aspects of the current research pertinent to the OCD schizophrenia interface and suggests further steps to identify clinically and etiologically relevant homogeneous subgroups and their boundaries on the putative OCD schizophrenia axis. 0022-3956/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2004.09.004

400 M. Poyurovsky, L.M. Koran / Journal of Psychiatric Research 39 (2005) 399 408 2. OCD and schizophrenia-spectrum disorders 2.1. Schizophrenia in OCD patients Early studies found that patients with obsessional neurosis were at no greater risk for developing schizophrenia than the general population (Goodwin et al., 1969). This was later supported by Eisen and Rasmussen (1993) who, evaluating a large cohort of patients with DSM-III-R diagnosis of OCD, found that 4% (18 of 475) met criteria for both OCD and schizophrenia. Given that this study was cross-sectional, the temporal interrelationship between the two disorders could not be addressed and some patients may have had a primary diagnosis of schizophrenia. Recently, Nestadt et al. (2001) found that first-degree relatives of OCD patients did not have an increased rate of schizophrenia compared to healthy controls, although probands with comorbid OCD and schizophrenia were excluded from the study. Overall, although none of these studies explicitly and prospectively evaluated the incidence of schizophrenia in individuals with OCD, it seems that OCD patients are not at particular risk for developing schizophrenia (Table 1). 2.2. Schizotypal personality disorder in OCD patients Schizotypal personality disorder (SPD) shares common phenomenological, biological, genetic and treatment response characteristics with schizophrenia (Siever and Davis, 2004). Inter-correlation between schizotypal and OC dimensions has been consistently found in non-clinical samples of students selected on the basis of self-report scales of schizotypy (Roth and Baribeau, 2000; Dinn et al., 2002), as well as in the treatment-seeking OCD population (Norman et al., 1996; Rossi and Daneluzzo, 2002). Nevertheless, the rate of occurrence of SPD in OCD is yet to be clarified. The observed rates vary substantially (0 50%) (Rasmussen and Tsuang, 1986; Jenike et al., 1986; Baer et al., 1990; Black et al., 1993; Eisen and Rasmussen, 1993; Samuels et al., 2000; Sobin et al., 2000; Matsunaga et al., 2000) (Table 1). This may be accounted for by differences in the definition of schizotypal features (categorical vs. dimensional), method of evaluation (structured interview vs. chart review) and the patient population studied. Despite their methodological differences, studies are consistent in demonstrating that OCD patients with associated SPD exhibit a more deteriorative course and poorer prognosis than those with pure OCD (Baer et al., 1992; Eisen and Rasmussen, 1993; Ravizza et al., 1995). None of these studies, however, was prospective. The clinical validity of the OCD schizotypy association has also been supported by showing differences in demographic and clinical characteristics of OCD patients with and without schizotypal features (Eisen and Rasmussen, 1993; Matsunaga et al., 2000; Sobin et al., 2000; Albert et al., 2002). Specifically, early age of onset, male gender, counting compulsions and a history of specific phobia substantially increased the odds of schizotypy in patients with lifetime OCD. Furthermore, neurocognitive findings lend some credence to the division of OCD into subgroups based on the presence of schizotypy. Whereas patients with pure OCD display impaired performance on measures sensitive to orbitofrontal cortex (alternation learning, response inhibition, delayed memory), OCD patients with SPD perform poorly on tests sensitive to both orbitofrontal and dorsolateral prefrontal cortex (e.g., executive function) (Harris and Dinn, 2003). Deficits in cognitive performance on tests sensitive to dorsolateral prefrontal cortex are consistently found in patients with schizophrenia and SPD (Mitropoulou et al., 2002). An additional validator of the OCD SPD association is the differential treatment approach required in patients with both disorders as compared to those with OCD alone. Compelling evidence indicates that the presence of SPD predicts poor response to standard pharmacological (SSRIs) and behavioral intervention in OCD patients (Jenike et al., 1986; Minichiello et al., 1988; Baer et al., 1992; Fals-Stewart and Lucente, 1993; Mundo et al., 1995; Moritz et al., 2004). Moreover, the presence of SPD is a good predictor of response to low-dose antipsychotic agents (pimozide, olanzapine) added to SSRIs (McDougle et al., 1990; Bogetto et al., 2000). It is of note that therapeutic efficacy of low-dose antipsychotics has been demonstrated in non-ocd related SPD (Coccaro, 1998; Koenigsberg et al., 2003). Overall, a category of OCD with schizotypal features seems to have clinical and predictive validity and probably etiological specificity. However, a lack of well-designed controlled studies evaluating neurobiological and neurocognitive markers and predictors of treatment response in OCD patients with and without schizotypal features precludes comprehensive characterization of an OCD SPD subgroup. 2.3. OCD with poor insight Traditionally, awareness of the senselessness of obsessions, referred to as insight, has been considered fundamental to the diagnosis of OCD, and lack of insight as a hallmark of delusion. Patients with OCD, however, exhibit a wide range of insight, and roughly 5 25% are characterized by partial insight or lack of insight (Lelliot et al., 1988; Eisen and Rasmussen, 1993; Foa and Kozak, 1995). In addition, a small subset of patients experiences delusional transformation of obsessions (Insel and Akiskal, 1986). Preliminary evidence suggests that OCD patients with poor insight do not differ substantially from those with full insight in demographic and clinical characteristics (Eisen and

Table 1 Rate of occurrence of schizophrenia-spectrum disorders in patients with OCD Authors Study sample Study design and diagnostic criteria Prevalence of schizophrenia-spectrum disorders in OCD Comments Schizophrenia in OCD Eisen and Rasmussen (1993) 475 OCD patients Semistructured interview, DSM-III-R criteria 4% (18/475) 82% of OCD schizophrenia patients had deteriorative course of illness Schizotypal personality disorder in OCD Jenike et al. (1986) 43 OCD patients Chart review, DSM-III for SPD 33% (14/43) OCD SPD patients had poorer prognosis Rasmussen and Tsuang (1986) 44 OCD patients Semistructured interview 0% Baer et al. (1990) 96 OCD patients SCID for DSM-III personality disorders 5% (5/96) SPD a predictor of poor outcome in OCD Black et al. (1993) 32 OCD patients; 33 controls SCID for DSM-III personality disorders 18.8% (6/32) in OCD. 3% (1/33) f controls had SPD OCD patients also had more cluster C personality disorders Eisen and Rasmussen (1993) 475 OCD patients Semistructured interview, DSM-III-R criteria for OCD and SPD Sobin et al. (2000) 119 OCD patients SIS for schizotypy; self-rated 50% had mild to severe positive schizotypy signs Samuels et al. (2000) 72 OC probands, 72 controls and their first-degree relatives Direct interview, SADS-LA, SIDP-R 0% (0/72) of OCD and 1.4% (1/72) of control probands had SPD 3% (14/475) 79% of OCD SPD patients were men and 69% had a deteriorative course OCD patients with schizotypy had earlier age of onset, more comorbid diagnoses and learning disability OCD probands had a higher prevalence of OCPD Matsunaga et al. (2000) 94 OCD patients SCID-II for personality disorders 23% (9/40) of men and 4% (2/54) of women had SPD SADS-LA, the schedule for affective disorders and schizophrenia lifetime anxiety (Mannuzza et al., 1986); SIDP-R, the revised structured instrument for the diagnosis of personality disorders (Pfohl et al., 1987); SIS, the structured interview for schizotypy (Kendler et al., 1989); SPD, schizotypal personality disorder. M. Poyurovsky, L.M. Koran / Journal of Psychiatric Research 39 (2005) 399 408 401

402 M. Poyurovsky, L.M. Koran / Journal of Psychiatric Research 39 (2005) 399 408 Rasmussen, 1993; Marazziti et al., 2002; Eisen et al., 2004). In addition, a majority of studies has found that OCD patients with poor insight or even delusional thinking are as likely to respond to SRIs or cognitive behavioral therapy as patients with better insight (Lelliot et al., 1988; Neziroglu et al., 1999; Eisen et al., 2001). Insight in OCD may fluctuate with environmental influences (e.g., stress) or may parallel response to treatment. Thus, in an open-label 16 week study with sertraline a decrease in OCD symptom severity with corresponding improvement in insight was observed (Eisen et al., 2001). This study is noteworthy in that it utilized a standardized multi-dimensional instrument, the Brown Assessment of Beliefs Scale (BABS), designed for the assessment of insight in OCD and related disorders (Eisen et al., 1998). Similarly, at the end of a six-month trial with combined clomipramine and cognitive behavioral therapy, 56% (14 of 25) of patients no longer exhibited poor insight, and this improvement was associated with reduced severity of OC and depressive symptoms (Matsunaga et al., 2002). In contrast to studies underscoring similarities between OCD with and without insight, some studies report that OCD with poor insight is associated with more severe symptomatology, a higher non-response rate and poorer prognosis (Catapano et al., 2001; Ezregovesi et al., 2001; Matsunaga et al., 2002; Hollander et al., 2003). One possible explanation for these discrepant findings is that a subset of OCD patients with poor insight and poor prognosis is part of the schizophrenia spectrum. In support of this hypothesis, OCD patients with poor insight and associated SPD were more likely to have poor insight after treatment with SSRIs than patients with poor insight without SPD (Matsunaga et al., 2002). In addition, Catapano et al. (2001) found that one of the variables associated with lack of treatment response in OCD patients with poor insight was the presence of schizophrenia-spectrum disorders in first-degree relatives. Furthermore, OCD patients with a predominant hoarding phenotype that seems to represent a distinct subtype of the disorder, have been characterized by earlier age at onset, specific pattern of brain activity, poor response to either pharmacotherapy or cognitive behavior therapy, poorer insight and association with SPD (Winsberg et al., 1999; Frost et al., 2000; Saxena et al., 2004; Kaplan and Hollander, 2004). It is of note that the hoarding syndrome has been consistently observed in schizophrenia patients (Stein et al., 1999). Overall, OCD with or without insight seems to represent the same disorder, with patients exhibiting poor insight or delusional transformation of obsessions having a more severe form of the illness (Insel and Akiskal, 1986; Eisen et al., 2001). In contrast, OCD with poor insight and associated SPD may represent a separate subgroup characterized by distinct clinical features, treatment response and prognosis and by a relationship to the schizophrenia spectrum. Concurrent evaluation of the two dimensions, insight and schizotypy, using valid and reliable instruments [e.g., the BABS and the structured interview for schizotypy (SIS, Kendler et al., 1989)] may clarify their interrelationship in OCD patients. Controlled pharmacological trials of SSRIs with and without adjunctive antipsychotics, with longitudinal evaluation of both dimensions, are needed to validate the hypothesis regarding the existence of a schizophrenia-spectrum subtype of OCD with poor insight. 3. Schizophrenia with OC features The identification of obsessive compulsive symptoms (OCS) in schizophrenia, and the distinction of obsessions from delusions or formal thought disorders, and of compulsions from schizophrenic mannerisms and stereotypic behavior is challenging. In addition, since awareness of illness in schizophrenia patients may vary considerably (Amador et al., 1993), the relevance of core DSM-IV criteria of resistance to and insight into the nature of OCS in schizophrenia patients has also been questioned (Fenton and McGlashan, 1986). There is also a substantial overlap of delusional and obsessive phenomena. Despite these difficulties in identifying OC symptoms in schizophrenia, growing evidence indicates that in a substantial proportion of patients, obsessions and compulsions are independent of the psychotic symptoms and can be reliably identified by instruments valid for OCD [e.g., the Yale-Brown Obsessive Compulsive Scale (Y-BOCS, Goodman et al., 1989). Using the Structured Clinical Interview for DSM-IV (First et al., 1995) and rigorous DSM-IV criteria for both schizophrenia and OCS/OCD, the majority of contemporary studies reveal a considerable base rate of OC features in schizophrenia patients, supporting the validity of the schizophrenia-ocs/ocd association. Epidemiological and clinical studies estimate the rate of OC phenomena in schizophrenia as high as 3 59.2% (for details see Table 2). This wide range is accounted for by variations in the definition of obsessive compulsive features (OCD vs. OCS), diagnostic criteria applied (categorical vs. dimensional), the patient population studied (inpatients vs. outpatients vs. community residents) and the phase of the schizophrenic illness (first admission vs. chronic stage). Moreover, the apparent inflated rate of OCS/ OCD in schizophrenia in some reports (Table 2) may be accounted for by the inclusion of patients with iatrogenic (atypical antipsychotic-induced) OC phenomena. Overall these studies provide compelling evidence that the rate of occurrence of OCS/OCD in schizophrenia is considerably higher than in the general population (2 3%, Karno et al., 1988), indicating a possible pathophysiological linkage between the two disorders.

Table 2 Rate of occurrence of obsessive compulsive symptoms/disorder in schizophrenia Authors Study sample Study design and diagnostic criteria for OCS/OCD Prevalence of OCS/OCD in schizophrenia Comments OCD schizophrenia vs. non-ocd schizophrenia Obsessive compulsive symptoms (OCS) in schizophrenia Fenton and McGlashan (1986) Inpatients Operational criteria for OCS 12.9% (21/163) More psychopathology, poorer social functioning Bland et al. (1987) Community residents DSM-III for OCS 59.2% (11/20) Berman et al. (1995) Outpatients Operational criteria for OCS 26.5% (27/108) Younger age of onset, longer hospitalizations, poorer social functioning Dominquez et al. (1999) Outpatients Chart review, self-rated MOCI for OCS 32.7% (17/52) Ethnic differences more OCD schizophrenia patients were hispanic Fabish et al. (2001) Inpatients Operational criteria for OCS, Y-BOCS 10% 19% of the OCD schizophrenia subgroup had OCPD Obsessive compulsive disorder (OCD) in schizophrenia Karno et al. (1988) Community residents Survey interview, DSM-III 12.2% Porto et al. (1997) Outpatients SCID, DSM-IV for OCD; Y-BOCS OCS 20% (10/50) OCD 26% (13/50) Three subgroups of OCS in schizophrenia, (1) OCD unrelated to psychosis (2) OCD related but not restricted to psychosis (3) OCD as a continuum of psychosis Eisen et al. (1997) Outpatients SCID, DSM-IV for OCD; Y-BOCS 7.8% (6 /77) More OCD in schizoaffective than in schizophrenia patients Meghani et al. (1998) Outpatients Structured interview, self-report measures 31.7% (61/192) Less psychosocial function; lower self-satisfaction Poyurovsky et al. (1999) Inpatients, first-episode SCID, DSM-IV for OCD; Y-BOCS 14% (7/50) Lower formal thought disorder and affective flattening scores Tibbo et al. (2000) Outpatients SCID, DSM-IV for OCD; Y-BOCS 25% (13/52) Less negative symptoms, shorter duration of illness, better functioning, more Parkinsonian symptoms Lysaker et al. (2000) Outpatients Chart review; Y-BOCS 45% (21/ 46) More positive symptoms, emotional discomfort and cognitive impairment Bermanzohn et al. (2000) Outpatients SCID, DSM-IV for OCD; Y-BOCS 29.7% (11 / 37) Poyurovsky et al. (2001) Inpatients SCID, DSM-IV for OCD; Y-BOCS 23.5% (16 / 68) Poorer basic social functioning Craig et al. (2002) Inpatients, first-admissions SCID, DSM-III-R for OCD; OCS 16.2% (73/450) OCD 3.8% (17/450) OCS may be associated with age at onset or duration of schizophrenia Nechmad et al. (2003) Inpatients, adolescents SCID, DSM-IV for OCD; Y-BOCS 26% (13/50) Higher scores on affective flattening and blunting, positive correlation between Y-BOCS and negative, but not positive symptoms SCID, structured clinical interview for DSM-IV; Y-BOCS, Yale-Brown Obsessive Compulsive Scale; MOCI, Maudsley Obsessive Compulsive Inventory; OCPD, obsessive compulsive personality disorder. M. Poyurovsky, L.M. Koran / Journal of Psychiatric Research 39 (2005) 399 408 403

404 M. Poyurovsky, L.M. Koran / Journal of Psychiatric Research 39 (2005) 399 408 OC symptoms in schizophrenia have been detected across the life span. Thus, 26% (13 of 50) patients with childhood-onset schizophrenia (Nechmad et al., 2003) and 16% ( eight of 50) of geriatric schizophrenia patients (Poyurovsky et al, submitted) also met DSM- IV criteria for OCD. In addition, OC symptoms in schizophrenia are apparently not a sequel to chronic illness, hospitalization or neuroleptic treatment, since a comparable rate of OCD (14%, seven of 50 patients) has been noted in first-episode, predominantly drugnaïve schizophrenia patients (Poyurovsky et al., 1999). The validity of the schizophrenia OCS/OCD association is also supported by the difference in outcome in schizophrenia patients with and without OC features. Although limited by their cross-sectional design and relatively small sample sizes, most recent studies are consistent in finding that schizophrenia patients with OCS/OCD have a poorer outcome, are characterized by a lower employment record, and have more severe impairment of social behavior and lower functioning (Fenton and McGlashan, 1986; Berman et al., 1995; Lysaker et al., 2000; Hwang et al., 2000; Kruger et al., 2000; Craig et al., 2002; Ohta et al., 2003). In addition, neurocognitive tests seem to discriminate between schizophrenia patients with and without OCD: schizophrenia OCD patients perform worse on tests of executive function than their non-ocd schizophrenia counterparts (Berman et al., 1998; Hwang et al., 2000; Lysaker et al., 2000). The association of high severity of OC symptoms and poor executive function accounts for poor functioning in the schizophrenia OCD group (Lysaker et al., 2004). Finally, identification of a substantially higher rate of OCD-spectrum disorders, primarily body dysmorphic disorder, chronic tic disorder and trichotillomania, in schizophrenia OCD patients than in non-ocd schizophrenia patients (Tibbo et al., 2000; Poyurovsky et al., 2003a), lends additional support to the existence of an independent OC dimension in schizophrenia. Certain clinical characteristics have emerged from recent studies evaluating OC phenomena in schizophrenia (Porto et al., 1997; Eisen et al., 1997; Tibbo et al., 2000; Kruger et al., 2000; Poyurovsky et al., 2003a). OC symptoms in schizophrenia were similar in their content, severity and course to pure OCD. In roughly half the schizophrenia OCD patients studied, the onset of OCS preceded the onset of schizophrenia, thereby complicating the primary diagnosis of schizophrenia. OC symptoms seem to progress in severity with the course of illness, worsening the prognosis of schizophrenia. In addition, increasing evidence points to a heterogeneity of the schizophrenia OC clinical phenotype. Subthreshold OC symptoms, as well as typical OCD symptoms with full or partial insight and independence from psychosis, were identified in schizophrenia patients using the Structured Clinical Interview for DSM-IV (SCID, First et al., 1995) and Y-BOCS (Porto et al., 1997; Poyurovsky et al., 2003a). An alternative clinical phenotype is characterized by the combination of classical OC symptoms and OCS related to delusional and/or hallucinatory content. Finally, a small subgroup with complete intermixing of OCS and delusions/hallucinations has also been identified (Porto et al., 1997). This complex OC-delusion/hallucination symptom profile is obsessional in form and psychotic in content. New diagnostic instruments are needed to identify these atypical delusion-dependent OC phenomena in schizophrenia with sufficient validity and reliability. Concurrent use of valid and reliable instruments developed to assess awareness of illness in schizophrenia [e.g., the Scale to assess Unawareness of Mental Disorder (SUMD, Amador et al., 1993)] and insight in OCD (e.g., BABS), should be evaluated in schizophrenia OCD patients. Although data regarding pharmacotherapy of schizophrenia with OCS/OCD is scarce and based on case reports and small, mostly uncontrolled clinical trials, there is a general consensus that compared to non- OCD schizophrenia patients the schizophrenia OCS/ OCD group is difficult to treat and requires distinct therapeutic approaches. Conventional antipsychotic agents are generally ineffective in schizophrenia patients with OCD, presumably due to their limited serotonergic properties. Adjunctive anti-obsessive agents seem to be efficacious in controlling OC symptoms in some schizophrenia patients (Zohar et al., 1993; Berman et al., 1995). The fact that OC symptoms in a substantial portion of OCD schizophrenia patients do not respond to SSRI addition suggests that these symptoms in schizophrenia may result from a variety of pathophysiological states. Moreover, no predictors of OC symptom response have been established to date. The potential for clinically significant pharmacokinetic interactions of some SSRIs (fluoxetine, fluvoxamine, paroxetine) is an additional pitfall of SSRI antipsychotic agent combination. The role of atypical antipsychotics in schizophrenia OCD patients remains controversial, with initial reports indicating that clozapine, olanzapine and risperidone may induce de novo or aggravate preexisting OCS in schizophrenia patients (Poyurovsky et al., 1996; Lykouras et al., 2000; Alevizos et al., 2002). At the same time, preliminary evidence indicates that clozapine and olanzapine, either alone or in combination with SSRIs, may alleviate both schizophrenic and OC symptoms in some schizophrenia OCD patients (Zohar et al., 2002; Poyurovsky et al., 2003b). It must be noted, that the limited number of studies, uncontrolled design and small sample sizes do not allow for direct comparison of treatment response to antipsychotic SSRI combination in schizophrenia OCD and pure OCD patients.

M. Poyurovsky, L.M. Koran / Journal of Psychiatric Research 39 (2005) 399 408 405 4. Future directions Both OCD and schizophrenia research can benefit from the explicit evaluation of the schizotypy dimension in OCD and the obsessionality dimension in schizophrenia. Robins and Guze (1970) and later Kendler (1980) provided a framework for establishing boundaries of psychiatric entities. Essential components of the framework include comprehensive phenomenological description, diagnostic consistency in follow-up, and evaluation of family inheritance and treatment response. Both schizophrenia and OCD are associated with a wide range of comorbid conditions (e.g., major depressive disorder, panic disorder, social phobia). Hence, the employment of this framework may contribute to determining whether the association of OCD with schizophrenia and of schizotypy with OCD represent specific subtypes of the disorders in interest, rather than a generally high rate of comorbidity between serious disorders. Cross-sectional and follow-up studies of sufficient sample sizes are necessary to address state- and coursedependent interrelationships between obsessive compulsive and schizotypal phenomena in schizophrenia and OCD, respectively. Both categorical (DSM-based) and dimensional definitions of schizotypal and OC phenomena are necessary to comprehensively characterize their association with a primary disorder. Recruitment of epidemiological samples is essential to avoid artificial sources of comorbidity, such as patient treatment-seeking behavior, which may occur with exclusive use of clinic-based samples. An important step towards delineation of specific subgroups within the OCD schizophrenia axis may be the use of endophenotypic markers designed to reflect central psychophysiological inhibition. These markers include prepulse inhibition of the startle response, suppression of the P50 event-related potential and the antisaccade task (Braff and Freedman, 2002). They provide a means of assessing endophenotypic traits that may be more closely associated with specific neurobiological deficits than are symptoms and DSM-IV diagnoses. Patients with either schizophreniaspectrum disorders or OCD exhibit substantial deficits in filtering (inhibiting) irrelevant information and in this sense are considered to be suffering from gating disorders (Braff et al., 2001). These inhibitory endophenotypes may help reveal quantitative differences that presumably correlate with the degree of association between the two disorders. It is conceivable that either disorder (OCD, schizophrenia) is associated with a lesser degree of deficit than the association between the two disorders, and patients with milder forms of comorbidity (OCD SPD) are less impaired on endophenotypic indices than those with more severe forms (schizophrenia OCD). Furthermore, since inhibitory endophenotypes represent stable and heritable traits (Braff and Freedman, 2002), their assessment in relatives of probands with isolated and comorbid forms of disorders may contribute to their phenomenological distinction. Evaluation of familial inheritance may aid in elucidating the mechanism for the co-occurrence of comorbid disorders (Merikangas, 1990). Preliminary findings in this area of research are emerging (Poyurovsky et al., submitted). Estimating familial aggregation of schizophrenia-spectrum and OCD-related disorders in schizophrenia patients with and without OCD, the authors found no between-group difference in morbid risks for schizophrenia-spectrum disorders. In contrast, first-degree relatives of schizophrenia OCD probands had increased morbid risks for OCD-related disorders (OCD, obsessive compulsive personality disorder and schizophrenia OCD). These preliminary results, if replicated, indicate that schizophrenia patients with and without OCD have differential familial aggregation of OCD-related disorders. This, in turn, may provide additional validation for a schizophrenia OCD diagnostic entity. A study of familial aggregation of schizophrenia-spectrum and OCD-related disorders in OCD patients with and without schizotypal features is needed. 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