Schizophrenia with Obsessive-Compulsive Features: Review of Clinical and Conceptual Issues

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1 Review Clinical Psychopharmacology and Neuroscience 2009; 7(1): 9-14 ISSN Copyright c 2009 Korean College of Neuropsychopharmacology online ML Comm Schizophrenia with Obsessive-Compulsive Features: Review of Clinical and Conceptual Issues Michael Y. Hwang 1, Sun Young Yum 2, Jun Soo Kwon 3 1 Department of Psychiatry, Associate Chief of Staff for Mental Health & Behavioral Science, The Commonwealth Medical College of Pennsylvania, PA, 2 Department of Psychiatry, Director Research and Education, Wilkes-Barre VAMC, PA, USA 3 Department of Psychiatry & Behavioral Sciences, Seoul National University College of Medicine, Seoul, Korea Obsessive-compulsive (OC) phenomenon in schizophrenia has been clinically challenging and conceptually controversial over the years. However, significance and neurobiological implications remain poorly understood. Recent interest in schizophrenic comorbidity has been in part aided by progress in our understanding of neurobiology and modifications in DSM-IV that permitted additional diagnoses of axis-i disorder in patients with schizophrenia. In addition, advances in pharmacological treatment and understanding of neurobiological basis in OCD as well as other anxiety disorders increased clinician and research interests in schizophrenic patients with OC phenomena. However, earlier restrictive diagnostic concepts and yet to be clarified clinical and neurobiological implications of the OC phenomena in schizophrenia continues to present challenge in clinical practice. In early years the OC symptom was thought to be rare in patients with schizophrenia and when it occurs it was thought to be associated with benign clinical courses and better outcome. This belief, however, was contended in 1990 s with establishment of neurobiological basis of the OCD. Researchers have subsequently noted greater prevalence rates and worse clinical course and outcome. Controlled studies with specific anti-ocd pharmacotherapy and new generation antipsychotic treatment have also been conducted in recent years. Further evidences are needed to explore the neurobiological basis and clinical significance of OC phenomena within the context of broader schizophrenic spectrum disorder and its pathophysiology. KEY WORDS:Schizophrenia; Obsessive-compulsive disorder; Comorbid; Diagnosis; Treatment. INTRODUCTION Received: December 17, 2008 / Revised: February 9, 2009 Accepted: February 10, 2009 Address for correspondence: Michael Y. Hwang, MD Department of Psychiatry, Associate Chief of Staff for Mental Health & Behavioral Science, The Commonwealth Medical College of Pennsylvania, 1111 East End Blvd, Wilkes-Barre, PA 18711, USA Tel: , Fax: michael.hwang@va.gov Psychotic obsessive-compulsive (OC) phenomenon has been described in various forms in schizophrenia for over a century. Recent interest in the psychiatric comorbidity once again brought the OC phenomena in schizophrenia to the forefront of clinical and research interest. 1) The OC symptoms in schizophrenia include diverse phenomenological manifestations such contamination, sexual, religious, aggressive, and somatic themes with or without accompanying compulsions such as cleaning, checking, hoarding, repeating, or arranging. Many early clinicians such as Westphal, 2) Kraepelin, 3) Stengel, 4) and Bleuler 5) considered such OC phenomena as a prodrome or an integral part of the psychotic illness. This conceptual view has been debated during most part of the last century under the restrictive diagnostic practice that was based broadly on two distinct categorical diagnoses, namely neurotic and psychotic disorders. Such restrictive diagnostic criteria resulted in impeding exploration of comorbid neurotic conditions in patients with schizophrenia. Consequently there has been little progress and explorations to understand the phenomenological and neurobiological significance of OC phenomenon in schizophrenia. Furthermore, lack of specific treatment in patients with psychotic OCD challenged the clinicians in their practice. During the past decade, there has been increasing clinical recognition and expanding knowledge in neurobiological correlates of the psychopathology in schizophrenia. This was mainly due to the continuing attempt to find more clinically meaningful and neurobiologically based subtyping strategy in schizophrenic spectrum disorder. The earlier classical (e.g., simple, paranoid, disorganized or hebephrenic, and undifferentiated), and more recent positive and negative symptom based subtyping strategy 6) are based on the assumption that the schizophrenic disorder is a heterogeneous condition with diverse clinical 9

2 10 M.Y. Hwang, et al. manifestations with specific underlying neurobiological pathogenesis. Further understanding of OC phenomena and its biological pathogenesis may thus enhance our ability to construct more clinically meaningful and neurobiologically relevant subtyping strategy in schizophrenic illness. 7) In this context we will review the clinical and neurobiological issues in OC schizophrenia. CLINICAL EVIDENCE The clinical evidence for comorbidity between OCD and various neurological disorders has been established over the years. 8) These neuropsychiatric disorders include Tourettes syndrome (TS), autism, Sydenham s chorea, trichotillomania, dissociative and eating disorders. They may also exhibit overlap of overvalued ideations with occasional delusional manifestations. These psychotic OC manifestations failed to conform to the traditional diagnostic system challenging clinicians and researchers. 1) Many early clinicians including Westphal 2) in 1878 hypothesized that OC syndrome was a variant or a prodrome of schizophrenic process and Bleuler 5) noted some of these patients with chronic obsession were in fact schizophrenic patient in attempt to reconcile the apparent diagnostic contradictions. Stenge l4) further hypothesized a possible interaction between the neurotic OC manifestations and psychotic reactions during the course of psychotic illness as a part of adaptive defense mechanism. Early epidemiological and clinical studies by Jaherresis 9) and Rosen 10) reported generally a low rate of OC symptoms in schizophrenia, 1.1% and 3.5% respectively, concluding that these patients with coexisting conditions tended to have a comparatively benign clinical course and better outcome. These findings have also been challenged in recent years. Insel and Akiskal 11) observed that the OCD may be a psychopathological spectrum disorder varying along continuum of insight, thus a patient at severe end of the spectrum may be described as having an obsessive-compulsive psychosis in contrast to the neurotic OCD processing intact insight. They further postulated that a shift from neurotic obsession (neurosis) to a psychotic obsessional delusion may occur with loss of the resistance to intrusive thoughts and the insight is lost. Based on this novel concept of dynamic state of resistance and insight in patients with OCD, a number of epidemiological and clinical studies including NIMH Epidemiological Catchment Area (ECA) study utilizing DIS that has less emphasis on insight reported much greater prevalence of comorbidity (12%) between OCD in schizophrenia. 12) Other well controlled retrospective review studies also noted a greater prevalence of OCD (12.8%) among the chronic schizophrenic population. 13) These studies also found that OC schizophrenic subgroup had worse clinical course and outcome, especially in the areas of social relationships, employment, symptom severity, and global functioning. They postulated that a persistent OC symptom in schizophrenia serve as a predictor for poor long term outcome. In a community outpatient studies with a structured clinical questionnaire (DSM-IIIR-SCID), comorbidity rate ranged from 15% to 50% mostly due to variations in the study design and criteria for OC symptoms in schizophrenia. Many also observed worse outcomes among the OC schizophrenic group. In general most well controlled epidemiological studies reported 10-20% prevalence rate of OCD in schizophrenia. 14) Unlike many of these studies that examined chronic schizophrenia with a poorly defined study criteria and design for co-existing axis-i conditions, Craig et al. prospectively examined newly diagnosed first admission patients with schizophrenia and affective disorders using structured clinical interview (SCID). 15) This longitudinal study design allows ascertaining diagnoses of psychotic and anxiety disorders at more than one point in time. This methodological approach significantly improved the diagnostic reliability and also allowed determination of persistence and newly onset anxiety symptoms and disorders during two-year study period. Furthermore, the longitudinal examination of two sets of anxiety symptoms across three diagnostic groups of psychotic disorders enabled the investigators to address the specificity of comorbid associations and their impact on clinical course using identical assessments. Their study confirmed high prevalence rate of comorbid anxiety disorders and symptoms in new onset schizophrenia and schizoaffective disorders (10.5%). Furthermore, the study found symptom resolution, as well as, a new onset of anxiety disorders during the first 24- month of psychotic illness. This study also examined clinician recognition and treatment of these comorbid anxiety symptoms in patients diagnosed with psychotic disorders and reported that only about 10% with comorbid OC symptoms were diagnosed by the treating clinicians. However, despite this low rate of clinician recognition, 20% or more received medication treatment that was appropriate for the comorbid anxiety symptoms. BIOLOGICAL STUDIES Neurobiology of OCD and schizophrenia has been extensively studied in recent years; however, there is scarcity of controlled studies of patients with OC schizophrenia. The predominant neurobiological evidence implicates dorsolateral prefrontal cortex dysfunction in schizophrenia,

3 Schizophrenia with OC Features 11 and the cortico-striatal-thalamic-cortex circuitry abnormality in OCD. Both disorders also involve dominantly dopamine and serotonin neurotransmitter systems in addition to other neuro-chemical and modulatory systems. 16,17) A controlled neuro-anatomical study that compared the structural abnormalities in patients with OCD, schizotypal OCD, and schizophrenia found a significant inter-group difference of the gray matter volume reductions suggesting a similar but distinct neuro-degenerative process in the three study groups. 18) Investigators have examined neuropsychological profiles of OC schizophrenia in comparison to the OCD and non-oc schizophrenic patients. While there are differences the findings suggest greater functional impairment of prefrontal cortex among the OC schizophrenic subgroup ) Further studies are warranted to verify this finding as other investigators also reported no significant difference between the comparison groups. 23,24) Our earlier neuropsychological study which examined the prefrontal functional status of demographically matched OC schizophrenia and non-oc schizophrenia found significantly worse clinical course. The study also found greater negative symptoms and prefrontal executive function impairment among the OC schizophrenic subgroup. Our observation supported earlier reports that suggested a direct correlation between the prefrontal impairment and greater negative psychotic symptom. However, we failed to find correlation between the OC symptoms and severity of positive psychotic symptom dimensions in schizophrenia. 20) TREATMENT STUDIES Conventional antipsychotic medications are generally found ineffective in treatment of patients with OC schizophrenia. A number of recent treatment studies and anecdotal case reports in recent years however indicate an adjunctive SSRI may be an effective treatment intervention. Treatment studies 25-28) have reported marked OC symptom reduction in patients with OC schizophrenia when anti- OCD regimen was added to ongoing antipsychotic medication treatment. Further clinical and research evidence however suggests that while many OC schizophrenia benefit from adjunctive SSRI regimen, there has been few case reports suggest a worsening of the symptoms and functioning. 29,30) To investigate the therapeutic efficacy of the anti-ocd treatment in OC schizophrenia a longitudinal A-B-A design treatment study was conducted. We found a marked OC symptom reduction and prefrontal executive function improvement without a significant change in positive psychotic symptom dimensions in previously treatment refractory OC schizophrenic patients. Furthermore, these clinical and neuropsychological improvements were directly correlated with adjunctive anti-ocd medication changes. Such specific OC symptom reduction and prefrontal function improvement in response to adjunctive anti-ocd treatment intervention suggests a distinct OC neuro-circuitry in patients with schizophrenia. In clinical practice, we have observed a broad range of therapeutically effective SSRI dose regimen in OC schizophrenic patients for optimal outcome. We would caution, however, that while many clinical reports suggest positive outcome, there are also worsening of clinical symptoms with the anti-oc treatment regimen in schizophrenia. 29,30) In addition, with the introduction of second and third generation antipsychotic (SGA) medication there has been emergence of clinical evidence suggesting development of de novo or exacerbation of pre-existing obsessions and compulsive symptoms in well established schizophrenia ) In recent report, Kim et al. 34) found 21.1% of schizophrenia patients receiving antipsychotic treatment reported OC symptoms, and 76.9% of these antipsychotic-related OC symptoms were associated with the clozapine treatment. The assessment was performed by direct patient interview and medical record review by the study investigators. Preliminary limited study findings indicate that these medication induced new onset OC symptoms in schizophrenia may also respond to the SSRI treatment intervention. 35,36) These clinical observations may reflect complex underlying serotonin-dopaminergic interface and further controlled studies are needed to assess the pathogenesis and treatment of OC symptoms in schizophrenia. CLINICAL CASES Case 1 A 43-year-old white male presents with a treatment refractory, undifferentiated schizophrenia. He has had an extensive psychiatric history including 16 years of institutionalization. Patient was agitated, psychotic, and continuously engaged in a number of bizarre, stereotyped behaviors including face and hand washing, ritualistic drinking, and touching of door frames before walking through them. These ritualistic behaviors persisted over the years unresponsive to the treatment, even worsening with antipsychotic medications. Treatment with various typical and atypical neuroleptics including clozapine with or without adjunctive medications including lithium, valproic acid,

4 12 M.Y. Hwang, et al. carbamazepine, propanolol, and benzodiazepines were found to be ineffective. A neurology consultation, includeing EEG, and brain CT scan were unremarkable. Treatment with high dose chlorpromazine (CPZ) resulted in less agitation and partial reduction in psychotic symptoms. The bizarre rituals, however, persisted and a trial of fluoxetine was started with gradual dose titration. After 2 weeks of treatment with 40 mg/day while continuing on CPZ, his rituals lessened in frequency and intensity. His self-care skills improved and he became more responsive to ward routines and to staff attempts to engage him in the treatment milieu. After a year of treatment, fluoxetine was reduced to 20 mg/day which resulted in a prompt increase in frequency and intensity of his rituals. Subsequent increase to 60 mg/day of fluoxetine for 6 weeks again brought about improvements in impulsivity and ritualistic behaviors. Patient has remained markedly improved during the past two years on CPZ and fluoxetine treatment. 26) Case 2 A 45-year-old white male with chronic paranoid schizophrenia had his first psychotic decompensation at age 18, with bizarre and persecutory delusions, hallucinations accompanied by impulsive and intrusive behaviors. Since then, he has had numerous hospitalizations and treated with a variety of antipsychotics without much improvement. During the course of illness patient developed bizarre repetitive behaviors such as ritualistic touching of objects, repeated dressing and undressing, and frequent checking rituals. These ritualistic behaviors started several years after the onset of schizophrenic symptoms. Extensive medical and neurological studies including brain CT scan were unremarkable. He was treated with a wide range of antipsychotics in addition to a variety of adjunctive medications. Trials of fluoxetine in conjunction with antipsychotic treatment resulted in increased anxiety, restlessness, and agitation. Clozapine treatment caused a rapid and marked increase in agitations and exacerbation of impulsive, ritualistic behaviors that caused severe distress and management challenges. Discontinuation of clozapine resulted in rapid reductions in impulsive and ritualistic behaviors. Subsequently, trial with Olanzapine over several weeks of gradual dose titration resulted in a substantial reduction of ritualistic symptoms and functional improvement. Case 3 A 35-year-old single white male was diagnosed at age 12 with undifferentiated schizophrenia consisting of hallucinations and paranoid delusions. Since then he has had several relapses that responded well to antipsychotic medication treatments. During one hospitalization, which was precipitated by acute onset of paranoid delusions, auditory/ visual hallucinations, and catatonic behavior, he responded poorly to the antipsychotic and adjunctive medication treatments, remaining markedly psychotic and dysfunctional. He also began to exhibit increasingly bizarre rituals that included repetitive touching of objects, opening and closing of doors, excessive water drinking, including drinking from the toilet upon restriction of water, and forcefully rubbing and injuring his own eyes. His neurological examination and brain CT scan were normal. Clomipramine (CMI)(25 mg/day) was subsequently added to ongoing fluphenazine decanoate (50 mg/2 weeks) and lithium carbonate (1,200 mg/day), and gradually increased to 50 mg/day over two weeks. After 4 weeks of 50 mg/day treatment, his rituals became markedly less frequent and less intense along with improved socialization and participation in the therapeutic milieu. When CMI was increased to 150 mg/day to achieve the recommended therapeutic dose range, patient rapidly became restless with impulsivity and agitations. Subsequent dose reduction to 50 mg/day once again resulted in a symptom relief and functional improvement. The patients neuropsychological assessments during the treatment period reflected improvements in the cognitive functioning and compulsive behaviors with changes in treatment regimen. He was eventually discharged from the long-term psychiatric facility and remained stable as an outpatient. 27) DISCUSSION These clinical vignettes illustrate clinical diversity and varied treatment responses in patients with OC schizophrenia. This diverse treatment response and earlier diagnostic predicaments continue to challenge clinicians. The first case illustrates a chronic, treatment refractory OC schizophrenia who responded well to adjunctive SSRI treatment. OC symptom reduction and the functional improvement were associated with adjunctive SSRI treatment and the dose changes. Similar clinical improvements with SSRIs in OC schizophrenia have been reported by clinicians in recent years. However, other investigators found no significant response or in fact, poor response to the adjunctive treatment regimen. Case 2 demonstrates schizophrenia with acute OC symptom exacerbation resulting from clozapine treatment and poor response to adjunctive SSRI treatment. Severe impulsivity and ritualistic behaviors often cause severe distress and functional impairment of a patient, and challenges the clinical staff. This observation is consistent with the recently emerging clinical findings of worsening or onset of new OC symptoms in

5 Schizophrenia with OC Features 13 patients with schizophrenia on SGA treatment. While few clinical vignettes observed relief of SGA induced OC symptoms to SSRI treatment clinical experience indicate variable or minimal response in many patients. However, the patient responded positively to another SGA olanzapine treatment with OC symptom reduction and functional improvement. The patient described in case 3 showed a marked OC symptom reduction and functional improvement with low dose, sub-therapeutic SSRI treatment but experienced acute symptom exacerbation and functional deterioration with a standard therapeutic SSRI regimen. He improved once again upon returning to a low dose SSRI regimen. It suggests that some OC schizophrenic patients benefit from the low dose SSRI treatment but may experience acute symptom exacerbation and functional deterioration with the standard SSRI dose regimen. As rendered in above case vignettes the treatment of patients with OC schizophrenia can be challenging and difficult to predict as their clinical presentation and treatment response may vary widely. While some OC schizophrenia may show marked clinical improvements others may have more modest changes or even worsening of the symptom and functioning. These varied treatment response may be attributed to existence of more than one underlying pathogeneses and possible pharmacokinetics, clinicians must consider other factors including other neurological causes including neurotoxic effects and infectious causes. 37) All SSRI s competitively inhibit microsomal P450 isoenzymes in human liver that can substantially increase the antipsychotic blood level. 38,39) With all of the strengths and limitations of the presently available clinical studies, following tentative recommendations may be made regarding pharmacotherapy of OC schizophrenia: 1) Treatment of OC symptoms with an adjunctive anti- OCD medication in schizophrenia should be considered once the patient is otherwise psychiatrically stable on a maintenance antipsychotic regimen. The use of adjunctive anti-depressants in chronic schizophrenia in partial remission appears to be safe, but there is some evidence that administering antidepressant agents in acutely psychotic schizophrenic patients may increase the risk of symptom exacerbation. 1) 2) The anti-ocd agents should be carefully selected based on the patient s clinical profile, drug pharmacokinetics, and side effect profiles including potential to induce or exacerbate agitation/akathisia and anticholinergic effects that are common to both SSRI and SGA. Clinicians must carefully monitor for the worsening or onset of the adverse effects as SSRIs may increase blood levels of all antipsychotic medications by as much as 25-30%. 37,38) 3) Patients receiving clozapine and other atypical antipsychotics as their maintenance treatment should carefully monitored for new onset or exacerbation of pre-existing OC symptoms. Consideration might be given to switch to another antipsychotic after carefully weighing the benefits derived from the SGA treatment against the morbidity caused by an increase in OC symptoms. If the SGA treatment is to be continued, SSRI treatment intervention with careful monitoring might be considered. 4) Finally, current evidence indicates that pharmacotherapy should be combined with the cognitive-behavioral psychotherapy for an optimal outcome in treatment of OC schizophrenia. 40) CONCLUSION OC phenomena inpatients with schizophrenia has long been recognized and debated over the years. However, it remains clinically challenging and conceptually controversial due to lack of systematic clinical and neurobiological studies. Extensive epidemiological studies and clinical reports in studies show higher prevalence, worse clinical profiles, and greater cognitive impairments in comorbid OC schizophrenia. Current neurobiological research in both schizophrenia and OCD suggest evidence of multisystem pathogenic mechanisms in both disorders. Unfortunately, there is lack of systematic studies that have examined the pathophysiological implications of OC phenomena in schizophrenia. While adjunctive therapy with anti-ocd medication treatment needs to be further explored, current evidence supports treatment of a severe OC schizophrenia with anti-ocd regimen. In conclusion, management of OC schizophrenia must include careful consideration of the possible pathogenesis and employ prudent individualized pharmacological and psychotherapeutic approaches for optimal outcome. Further controlled studies to validate the clinical implications and neurobiological pathogenesis of OC phenomena within the schizophrenic syndrome are warranted. REFERENCES 1. Hwang MY, Bermanzohn (Eds.). Schizophrenia and comorbid conditions: diagnosis and treatment. Washington, DC: American Psychaitric Press; Westphal K. 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