Comorbidity: Schizophrenia With Obsessive-Compulsive Disorder

The co-occurrence of obsessive-compulsive symptoms (OCS) and psychotic illness has been a challenge for clinicians and investigators for more than a century.¹ Over the past decade, interest in this area has burgeoned because of recognition of higher-than-chance comorbidity rates of schizophrenia and obsessive-compulsive disorder (OCD), and observations of appearance or exacerbation of OCS during treatment of schizophrenia with atypical antipsychotics.^2-6 Emerging neurobiological and genetic evidence suggests that persons with comorbid OCD and schizophrenia may represent a spe­cial category of the schizophrenic population.

The evidence for a putative schizo-obsessive disorder is examined and practical treatment suggestions for this subgroup of patients are outlined in this article.^7-9

Comorbidity between OCD and schizophrenia
The lifetime prevalence for schizophrenia is 1% and for OCD it is 2% to 3%.¹⁰ Comorbidity rates for OCD in the schizophrenia population are substantially higher than what would be expected to occur randomly. In the schizophrenic population, the reported prevalence of clinically significant OCS and of OCD ranges from 10% to 52% and from 7.8% to 26%, respectively.^11-23

The higher-than-expected comorbidity rate for OCD and schizophre­nia suggests a nonrandom association and possibly an integral relation between these 2 conditions.⁹ The question is whether this comorbid group with schizo-obsessive disorder represents a more severely ill group with greater brain dysfunction that could, in part, be caused by common neurodevelopmental predisposing factors, or whether the 2 conditions are part of a more complex syndrome that rep­resents a distinct diagnostic entity. The answer could be clarified in part if neurobiological studies were to dem­­onstrate a distinct neuroanatomical substrate in this comorbid group rather than the summation or superimposition of neurobiological lesions observed in the separate disorders.⁹

Clinical and research challenges
Recent studies have aimed to reduce bias and

confounding that were often inherent in older studies. Newer studies have used such methods as randomization, prospective and cross-sectional study designs, standardized diagnostic criteria, validated diagnostic tools, age-matched control groups, and stratification of patient populations according to phase of illness to increase the validity of study results.

Notwithstanding these efforts to enhance diagnostic clarity and study validity, the distinction between obsessions and delusions is often difficult to discern.⁹ Paradoxically, DSM-IV allows for the OCD specifier “with poor insight.” This stands in contrast to the definition of an obsession as being recognized by the individual as foreign to him or her (ie, ego-dystonic), and implies the presence of insight. Insel and Akiskal²⁴ proposed that “OCD represents a psychopathological spectrum varying along a continuum of insight,” and that this “obsessional delusion” does not signify a schizophrenia diagnosis. Complicating the matter further is the observation of perceptual disturbances that mimic various types of hallucinations or pseudohallucinations in some persons with OCD.²⁵

Whether obsessions can be accurately detected in the presence of psychosis remains a matter of debate.⁹ To date, there is no universally accepted method of detecting OCD in the presence of schizophrenia, although most contemporary study designs have used the Structured Clinical Interview for DSM-IV Axis I psychiatric disorders and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS).^26,27 In attempts to ascertain the reliability and validity of the Y-BOCS in this comorbid subgroup, de Haan and colleagues²⁸ examined the properties of this psychometric tool in patients with recent-onset schizophrenia and comorbid OCS. These investigations found good internal consistency and interrater reliability in this population. However, their findings concerning the divergent validity against depressive and negative symptoms were inconsistent.

Although the phenomenological delineations between obsessions and delusions often remain unclear, there is substantial evidence that OCS in schizophrenia represents more than just an expression of enduring psychosis.⁹ This evidence includes observations that conventional antipsychotic medications appear to be of limited use in the treatment of OCS in schizophrenia, the persistence of OCS even after successful treatment of the psychotic symptoms, and the effectiveness of serotonin reuptake inhibitors in the treatment of OCS in patients with schizophrenia^.29-33

Clinical relevance of OCS in schizophrenia
Early investigators concluded that the presence of OCS confers protection against cognitive deficits, functional impairment, and negative symptoms associated with schizophrenia.^34,35 Psychodynamic theories postulated that obsessions constitute a defense against psychosis and prevent progression of the disease. However, more recent studies that used rigorous methods have not tended to replicate these earlier findings.³⁶ Instead, recent studies have found that this comorbid group is burdened by a greater magnitude of cognitive def­icits, negative and positive symptoms, neurological soft signs, distress, dysfunction, hope­lessness, depression, sui­­cidal ide­ation, and suicide attempts. A few studies have not replicated some of these findings.^19,20,37-48

Pedigree and genetic studies
Pedigree and genetic studies have not found any familial relationship or shared etiology between OCD and schizophrenia in their pure forms. However, specific genotypes of polymorphisms of the same gene may differentially confer risk for the 2 disorders.

The catechol-O-methyltransferase (COMT) gene is a candidate gene for schizophrenia because of its role in the breakdown of dopamine in the prefrontal cortex. Zinkstok and colleagues⁴⁹ found that the COMT high activity Val allele is associated with more OCS in young patients with schizophrenia, whereas patients with the Met/Met genotype had the lowest Y-BOCS scores. These results support the hypothesis that the COMT Val-Met polymorphism may be a modifier gene for the symptoms of schizophrenia.⁴⁹

Poyurovsky and colleagues⁵⁰ examined familial aggregation of schizophrenia spectrum disorders and obsessive-compulsive–associated disorders in schizophrenia probands with and without OCD. They found that relatives of OCD-schizophrenia probands had significantly higher morbid risks for OCD-schizophrenia and obsessive-compulsive personality disorder (OCPD); they also found a trend toward higher morbid risk for OCD. When morbid risks for OCD, OCPD, and OCD-schizophrenia were pooled, the significant between-group differences became robust. These data suggest a genetic contribution to the expression of OCS in individuals with schizophrenia. In addition, they lend support for the validity of a putative schizo-obsessive diagnostic entity.⁵⁰

Neurobiology of the schizo-obsessive subgroup
Considerable work has been done to reveal the neurobiological basis of both schizophrenia and OCD.9 This research has focused primarily on elucidating key neurotransmitter systems, structural and functional neuroanatomy, and neuropsychology. How­ever, there is very limited published research that focuses specif­ically on neurobiological features unique to this putative schizo-obsessive subtype.

Neurotransmitter systems. There is a paucity of published research on unique neurotransmitter involvement in the schizo-obsessive subtype group.

However, serotonin and dopamine have most consistently emerged as the principal neurotransmitters of interest in both disorders.⁹ The dopamine hypothesis in schizophrenia has long been regarded as the fundamental neurochemical premise; however, the superior efficacy of the serotonin-dopamine receptor antagonists in the treatment of schizophrenia also supports the importance of the serotonergic system in the pathophysiology of this disorder and may reflect the modulation of dopaminergic systems by serotonin.^51,52

Conversely, in OCD a somewhat opposing picture has emerged with respect to neurotransmitter involvement.⁹ The serotonin hypothesis of OCD is supported by successful treatment of the disorder with serotonin reuptake inhibitors, pharmacological challenge studies, and cerebrospinal fluid neurotransmitter metabolite studies.⁵³ However, several lines of evidence suggest that serotonin is not the sole neurotransmitter involved in OCD. Considerable evidence supports the additional role of the dopaminergic system in this disorder.^51,53-57 Preclinical evidence of dopamine’s reciprocal modulatory effects on the serotonin system and successful treatment of refractory OCD with adjunctive dopamine receptor antagonists and serotonin-dopamine receptor antagonists have provided support for the dopamine-serotonin hypothesis of OCD.^51,53,56,57

There is a lack of neurotransmitter data in the overlap group. However, one study examined the differences in whole blood serotonin concentrations in healthy volunteers versus patients with OCD, in persons with schizophrenia with and without OCS, and in clozapine-treated schizophrenia in patients with and without clozapine-induced OCS. This study found that the groups with OCD, schizophrenia with OCS, and clozapine-treated schizophrenia with OCS had significantly lower levels of whole blood serotonin than did the healthy vol­unteers and the schizophrenia-only groups.⁵⁸

Neuroanatomy and neurocircuitry. In contrast to the abundance of neuroimaging studies investigating structural brain abnormalities in persons with OCD and schizophrenia separately, there is a dearth of such studies examining the comorbid subgroup. However, the considerable overlap in the neurocircuitry and specific anatomical structures implicated in each disorder may account for symptom coexpression in this subgroup of patients.^52,59,60 The functional circuitry implicated in the pathophysiology of OCD is generally believed to involve a cortico-striatal-thalamic-cortical circuit.⁶¹ Specific structures implicated in this pathway include the basal ganglia, orbitofrontal cortex, and anterior cingulate cortex.⁶²

In schizophrenia, the dorsolateral prefrontal cortex circuit contains anatomical substrates similar to those of the OCD orbitofrontal circuit.⁵² Thus, the specific neuroanatomical sites identified by structural and functional neuroimaging studies performed in each of these disorders independently show considerable over-lap in implicated structures, including the basal ganglia, thalamus, anterior cingulum, orbitofrontal cortex, and regions of the temporal cortex, although some of these findings are controversial.^59,60

Neuroimaging studies
Neuroimaging studies suggest the presence of specific neuroanatomical abnormalities in the overlap group that may differ from what is observed in the individual disorders. One MRI study of patients with juvenile-onset schizophrenia with OCS found significantly smaller left hippocampi in this group than in schizophrenia-only and control groups.63 In addition, there was an inverse correlation between illness duration and frontal lobe size in the comorbid group but not in the schizophrenia-only group.

Another MRI study of patients with juvenile-onset schizophrenia demonstrated significant enlargement of the anterior horn of the lateral ventricle and the third ventricle in patients with OCS compared with patients who did not have OCS.64 In a different study of patients with schizo­­phrenia and various degrees of OCS, functional MRI found that one subgroup exhibited a negative correlation between activation of the left dorsolateral prefrontal cortex and OCS severity.⁶⁵

Taken together, these findings suggest greater neuroanatomical dysfunction in the comorbid subgroup. Whether these findings reflect a specific pattern of dysfunction unique to this comorbid subgroup or a more severe form of illness with greater brain dysfunction is thus far unclear. The question warrants further study.

Neuropsychological testing
Several studies have compared the profiles of neurocognitive deficits in patients with schizophrenia without OCS with those of the schizo-obsessive subgroup. Most, but not all, of these studies have revealed more severe neuropsychological impairments in the comorbid subgroup.⁶⁶ Compared with their schizophrenia-only counterparts, the comorbid subgroup demonstrated greater impairment in nonverbal memory, cognitive shifting abilities, visuospatial skills, and executive function as measured by performance on the Wisconsin Card Sorting Test.^{30,37,38,67,68}

Summary
Epidemiological and biological data strongly suggest an integral relationship between OCD and schizophrenia in the comorbid subgroup of patients. The epidemiological data strongly suggest a unique relationship between these 2 disorders, given the marked degree of comorbidity that has been consistently observed and which appears to represent more than just a spurious association. Although pedigree and genetic studies of this overlap group are limited, preliminary findings suggest intriguing genetic influences on comorbid symptom expression.

The neurobiological data on each disorder suggest the involvement of common brain regions and neurotransmitter systems. However, more neuroimaging studies in the overlap group are required to determine whether specific structural abnormalities unique to this putative subtype are present Neuropsychological testing has generally revealed more severe impairment among patients in this comorbid group, which suggests a specific and active interaction between these 2 disease processes, but it has not identified a unique pattern of impairment.⁹

Hence, despite the growing body of evidence that supports the existence of a specific epidemiological, genetic, and neurobiological relationship between these 2 disorders, the association remains poorly understood. The question of whether this overlap group represents a distinct diagnostic entity or comorbid disorders that result from a greater magnitude of brain involvement, common neurodevelopmental predisposing factors, or other confounding factors is impossible to answer definitively on the basis of existing knowledge.

Further neurobiological and genetic research that focuses specifi­cally on this comorbid group is essential to clarify the nature of this proposed diagnostic entity. The current literature suggests that this comorbid subgroup probably carries a greater overall illness burden and that these patients have more distress and impairment and worse outcomes-including the possibility of higher suicide risk. These clinical issues highlight the importance of identi­fication and treatment of OCS in schizophrenia (Table) while the biological underpinnings continue to be elucidated.

References:

Drug Mentioned in This Article
Clozapine (Clozaril)

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