Recognition of and interest in obsessive-compulsive (OC) phenomena in schizophrenia has been long-standing. However, controversy remains regarding the classification of people with both OC features and schizophrenia (OC-schizophrenia) because clinical and biological implications, as well as the best treatment approaches, are poorly understood.1 For much of the past century, it was thought that OC phenomena in a patient with schizophrenia was part of the psychotic illness,2–4 with some investigators suggesting that the presence of OC symptoms augured a better prognosis.5,6 However, recent studies have shown that OC-schizophrenia usually has a worse clinical course and long-term outcome than schizophrenia without OC features (non-OC schizophrenia).1,7
Furthermore, in a controlled study, we have shown that patients with OC-schizophrenia exhibit greater prefrontal impairments and worse functioning when compared with matched patients with non-OC schizophrenia.8–10 These clinical and neuropsychological findings recently were corroborated by other investigators10 and further support an earlier retrospective study that reported similar conclusions.7
OC Phenomena in Schizophrenia
Before the Diagnostic and Statistical Manual of Mental Disorders, third edition,11 obsessive-compulsive disorder (OCD) was considered a neurotic condition and therefore distinct from psychotic disorders. This distinction, however, has been difficult to maintain in clinical practice, and is no longer supported in our present nosology. Both the obsessions and delusions rest on false, unreal, or excessive ideas. Conventional clinical wisdom requires that obsessions be experienced by the patient as alien or ego dystonic (neurotic), in contrast to ego syntonic (psychotic), delusions. Therefore, it is argued, patients with obsessions should be able to recognize these thoughts as pathological intrusions coming from within their own mind and they should work on resisting these preoccupations and their accompanying ritualistic behaviors or compulsions. In contrast, delusions are conceptualized as false beliefs that are actively embraced by the patient and difficult to dislodge without antipsychotic medication.
Thus, the distinction between obsessions and delusions is based on the preservation of insight and the ability to reject the intrusive thoughts and resist carrying out the accompanying behaviors. Such simple and clear distinctions break down in clinical practice, as a patient's insight may vary over time and at different phases of illness. To overcome such diagnostic dilemmas, clinicians have coined terms such as a psychotic or malignant OCD to describe otherwise nonpsychotic patients who show little or no insight with regard to their obsessions being false beliefs.
Recent clinical and research evidence shows that, in patients with OCD, insight is neither universal nor constant, and that many patients with OCD lose insight into the pathological nature of their preoccupations.12 Patients with OCD demonstrate varying degrees of insight, extending from being fully aware that their obsessions are false to a complete loss of insight. Those with a complete loss of insight are said to have “psychotic OCD.”13,14
However, given the variable nature of insight in OCD, the concept of ego syntonic versus ego dystonic does not provide a reliable or valid basis for distinguishing psychotic delusions from neurotic obsessions. Especially in clinical practice, obsessions and delusions may overlap during the course of the treatment, making it difficult to identify the “real OC symptoms” in a patient with schizophrenia.14,15
Due to the absence of clear and well-defined diagnostic criteria for OC-schizophrenia, in addition to quite disparate study conditions, reported prevalence rates vary widely, ranging from 1.1% to 59.2% among patients with schizophrenia.16–18 Studies in more recent years show an increasing tendency to diagnose OCD or OC symptoms in patients with schizophrenia, reflecting not only the general trend of increased recognition of OCD since the introduction of effective pharmacotherapy19 but also the modifications in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV),20 which allowed the diagnosis of OCD with schizophrenia.
A recent, large, long-term, prospective epidemiological study found that, in newly diagnosed schizophrenia, the prevalence of co-occurring anxiety disorders was 10% to 20%.21 However, in 90% of the cases, presence of OC symptoms was unrecognized by treating clinicians.
A review of the literature and clinical findings suggests OC-schizophrenia may best be conceptualized as consisting of three groups.22 The first group includes patients with long-standing OC symptoms that predate the onset of psychosis. These patients met DSM-IV criteria for OCD before subsequently developing delusions in the course of chronic and often treatment-refractory illness. These patients may exhibit varying degrees of insight into and resistance to their obsessive-compulsive symptoms and often are refractory to anti-OCD medications. People in this category have previously met the criteria for classical OCD but may currently meet the criteria for schizophrenia. These patients have traditionally been referred to as having “psychotic or malignant” OCD.
The second group consists of patients with new-onset OC symptoms concurrent with or following the onset of schizophrenia. They have an unequivocal diagnosis of schizophrenia and exhibit little or no insight regarding OC symptoms. People in this group often have a worse clinical course and treatment outcome than people with non-OC schizophrenia.
The third group of patients has well-established schizophrenia with transient and varied OC symptoms during the course of the schizophrenic illness. These patients usually show little or no insight regarding their obsessions being illogical or untrue. Patients in this group may have little difference in their clinical course and prognosis compared with patients with non-OC schizophrenia.
OC symptoms once were thought to be protective against psychotic decompensation. It was suggested that the presence of OC symptoms helped people with schizophrenia maintain greater psychological integrity with a less malignant clinical course.5,6 However, recent studies have found that OC-schizophrenia is associated with greater prefrontal dysfunction, more global decline in function, poorer treatment response, and worse long-term outcome.7,8
In addition, patients with OC-schizophrenia have a more florid presentation, an earlier age of onset of psychosis, and a greater number of hospitalizations,9 as well as greater persistence of OC symptoms at 2-year follow up as compared with patients with OC symptoms coexisting with bipolar or major depressive disorder with psychotic features.21
Treatment of OC Symptoms in Schizophrenia
Until recently, OC symptoms in schizophrenia received only limited recognition; perhaps for this reason, there has been a scarcity of systematic pharmacologic studies. Recent studies have shown that adjunctive treatment with either clomipramine or selective serotonin reuptake inhibitors (SSRIs) are effective in treating OC symptoms in schizophrenia.22–26 Berman and colleagues26 found in a double-blind placebo controlled study that adjunctive clomipramine treatment led to significant improvements in both psychotic and OC symptoms in outpatients with OC-schizophrenia. A series of open treatment studies reported both clinical and neuropsychological improvements with adjunctive SSRIs in previously refractory OC-schizophrenia.22–24 More important, OC symptom response was independent of the changes in psychotic symptoms, and the optimal SSRI regimen had individual variance.
While most of the treatment studies in OC-schizophrenia reported thus far, including several case reports, have generally found positive clinical effects,27 there have been some case reports that found worsening of the symptoms with adjunctive anti-OC medication regimens.28,29
The therapeutic efficacy of the second generation antipsychotics (SGAs) for OC-schizophrenia is yet to be determined. Some case reports have found either new-onset or worsening of pre-existing OC symptoms associated with SGAs,27,30,31 while Ghaemi et al.32 found no evidence of such association with clozapine treatment from a retrospective chart review. OC symptoms induced by SGAs in patients with schizophrenia have been reported to respond to anti-OCD pharmacotherapy.31 Conversely, McDougle et al.33 reported beneficial effects of adjunctive risperidone in SSRI-refractory OCD. Further prospective controlled studies are needed to clarify the role of SGAs in OC-schizophrenia.
A 45-year-old white man presented with a 27-year history of chronic undifferentiated schizophrenia, including 16 years of institutionalization. On his last hospital admission 4 years earlier, he was agitated, psychotic, and engaged in a number of bizarre, stereotyped behaviors such as repeated face and hand washing and touching door frames in a ritualistic manner before walking through them. He remained unchanged or worsened during the next year, despite trials of various neuroleptics, both alone and in combination with lithium, carbamazepine, propranolol, and lorazepam.
A neurological workup, including EEG, brain CT scan, and skull series were unremarkable. Treatment with 1,000 mg of chlorpromazine twice per day resulted in only partial improvement of psychosis, and he benefited mainly from its sedating effects. The bizarre rituals persisted, and a clinical trial of fluoxetine was started. After 2 weeks of treatment on 40 mg per day, his rituals became less frequent and intense. His self-care skills improved, and he became more responsive to ward routines and to staff attempts to engage him in therapeutic activities. After a year of treatment, when fluoxetine was reduced to 20 mg per day, frequency and intensity of his rituals increased. A subsequent increase to 60 mg per day of fluoxetine for 6 weeks brought about marked symptom relief and improvement. The patient remained improved and stable during 2 years of follow-up with combined chlorpromazine and fluoxetine treatment.
A 35-year-old single white man with hallucinations and paranoia was diagnosed at age 12 with undifferentiated schizophrenia. Several acute psychotic episodes had been well controlled with neuroleptic treatment. However, during his most recent hospitalization, in which he presented with acute paranoid delusions, auditory/visual hallucinations, and catatonic behavior, he responded poorly to a variety of antipsychotic and adjunctive medications. Unlike previous episodes, he remained markedly psychotic and dysfunctional despite treatment. In addition, he began to exhibit bizarre compulsive rituals, including repetitive touching of objects, opening and closing of doors, drinking water, and forcefully rubbing and injuring his own eyes.
His neurologic examination, including brain CT scan, was unremarkable. Clomipramine was added to the ongoing fluphenazine decanoate and lithium carbonate (600 mg twice per day) treatment regimen. Clomipramine was started at 25 mg per day and increased to 50 mg per day during a 2-week period. After 4 weeks, his rituals became less frequent and intense, with improved engagement socially and in the treatment milieu. However, when clomipramine was further increased to 150 mg per day, he became restless, hyperactive, impulsive, and agitated. Subsequent clomipramine-dose reduction to 50 mg per day once again resulted in symptom relief and functional improvement. He was discharged and followed as an outpatient, and for more than 2 years he has remained stable.
Ms. L is a 32-year-old Korean woman diagnosed with paranoid schizophrenia for 13 months. Although her psychosis was well controlled with risperidone, 5 months after initial diagnosis, she exhibited compulsive counting and checking. Due to Parkinsonian adverse effects, her treatment regimen was subsequently changed to 175 mg per day of clomipramine, 0.5 mg per day of risperidone, 15 mg per day of diazepam, and 30 mg per day of propranolol, with good control of psychotic symptoms without adverse effects.
However, her OC symptoms persisted and she was transferred to our facility with a Yale-Brown Obsessive Compulsive Scale34 score of 33 (16 for obsessions and 17 for compulsions). Clomipramine was increased to 450 mg per day for 6 weeks but resulted in intolerable anticholinergic side effects and severe tremor. Clomipramine was then changed to fluoxetine at 80 mg per day, and risperidone was titrated up to 6 mg per day.
After 2 weeks of hospitalization, the patient had only partial improvements in rituals and was discharged to initiate cognitive-behavior therapy as an outpatient. After 6 month of combination treatment of psychotherapy and pharmacotherapy, OC symptoms were in remission with continued remission of other psychotic symptoms. Ms. L is currently symptom-free on maintenance doses of 1 mg per day of risperidone, 60 mg per day of fluoxetine, and 1 mg per day of clonazepam.
Mr. G is a 35-year-old Korean man with treatment-resistant schizophrenia and coexisting OCD. At the onset of his illness 20 years earlier, he presented with persecutory delusions and ideas of reference. Several months later, he began perseverating on unrealistic beliefs of acquiring incurable infections such as HIV and subsequently developed compulsive laundering of his clothes. Three years of various medication regimens were all unsuccessful.
His OC symptoms were ego-dystonic, and the patient began to drink in response to his emotional distress related to the OC symptoms. After more than 10 years of alcohol abuse, he was diagnosed with alcoholic liver cirrhosis, and he once again sought psychiatric care at a local clinic. He presented to our hospital after 8 months of unsuccessful trials of aggressive regimen, including 15 mg per day of olanzapine, 500 mg per day of chlorpromazine, 80 mg per day of fluoxetine, 80 mg per day of fluvoxamine, and 3 mg per day of clonazepam. His OC symptoms had actually worsened, while there was no significant change in his persecutory delusions.
His total Positive And Negative Syndrome Scale (PANSS)35 score was 78 (21/17/40 for positive, negative, and general symptoms, respectively), while his Yale-Brown Obsessive Compulsive Scale score was 33 (16/17 for obsessions and compulsions, respectively). Upon hospitalization, olanzapine was tapered off, while clozapine was titrated up to 100 mg per day during a 12-day period, after which electroconvulsive therapy was initiated. After 6 doses of electro-convulsive therapy in 12 days, all treatments were held due to acute delirium.
Once delirium had cleared, clozapine was restarted, followed by fluoxetine. In addition, Mr. G also received cognitive-behavior therapy. After 53 days of hospitalization with no improvement in either OC or paranoid symptoms, he requested to be discharged due to financial difficulties. He is currently taking 600 mg per day of quetiapine, 20 mg per day of fluoxetine, and 4 mg per day of lorazepam. His symptoms remain unchanged.
Recent progress in our understanding of the neurobiology and treatment of both OCD and schizophrenia, accompanied by the modification of DSM-IV criteria, have led to increased clinical and research interests in OC phenomena in schizophrenia. However, only a limited number of studies have systematically examined the significance of OC symptoms in schizophrenic illness.
The clinical vignettes presented above illustrate varied clinical presentations and treatment responses in OC-schizophrenia. Such clinical diversity and diagnostic predicaments have challenged practicing clinicians over the years. Case #1 presents a chronic, treatment-refractory patient with OC-schizophrenia who responded well to adjunctive anti-OCD medication. Case #2 illustrates dosing variability, in which a dramatic reduction in OC symptoms and functional improvement was observed on a low dose of clomipramine followed by acute symptom exacerbation and functional deterioration on a higher but standard clomipramine regimen, which once again improved when clomipramine dose was lowered. Case #3 shows the pharmacologic fragility of these patients and the importance of psychotherapy in conjunction with medication treatments. Case #4 demonstrates clinical dilemmas and the treatment challenges associated with treating patients with OC-schizophrenia.
As the case vignettes illustrate, the diagnosis and treatment of OC-schizophrenia can be challenging in clinical practice. Treatment response may vary from modest to marked improvement in some patients, while other patients may exhibit symptom exacerbation and decline in functioning. Our experiences suggest that the optimal therapeutic response with adjunctive clomipramine or SSRI treatment can be observed at both higher and lower dose ranges.
Treatment Recommendations in OC Schizophrenia
Adjunctive anti-OC medications including clomipramine and SSRIs have shown OC symptom relief and functional improvements in previously treatment-refractory OC-schizophrenia. However, when treatments are used in conjunction, clinicians must be mindful of the pharmacologic interactions between antipsychotic and anti-OC medications.
All SSRIs competitively inhibit microsomal P450 isoenzymes in the human liver. Fluoxetine and its active metabolite, norfluoxetine, as well as other SSRIs including paroxetine and fluvoxamine, substantially increase blood antipsychotic drug levels.36,37 Such pharmacokinetic interactions of the SSRIs can cause or exacerbate side effects of the antipsychotic drugs, including akathisia and movement disorders. Hence, the use of SSRIs as an adjunctive therapy in OC schizophrenia must be based on careful medical consideration and vigilant monitoring.
Given the current state of knowledge regarding the pharmacotherapy of OC symptoms in schizophrenia, several tentative recommendations may be made. First, treatment of OC symptoms in schizophrenia with an additional medication should be considered once patients are otherwise psychiatrically stable on a maintenance antipsychotic regimen. The use of adjunctive antidepressants in patients with 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.
Second, anti-OCD agents should be prudently selected after careful pharmacologic considerations and after monitoring the patient's therapeutic and adverse effect profiles. Of particular concern is the ability of many of these compounds to induce or exacerbate agitation or akathisia and the additional anticholinergic effects of sedation, and hypotension that are common with both clomipramine and SSRIs. Furthermore, some SSRIs may increase the blood levels of some antipsychotics by as much as 25% to 30%, potentially resulting in an even greater increase in side effects.34 Therefore, clinicians must carefully monitor for potential new adverse effects due to pharmacokinetic drug-drug interactions.
Third, patients taking clozapine should be carefully assessed to determine if their OC symptoms preceded the initiation of clozapine therapy. If the OC symptoms appear to have started or worsened with the advent of clozapine treatment, clinicians should consider switching to another atypical antipsychotic after weighing the benefits derived from clozapine against the morbidity caused by an increase in OC symptoms. If clozapine is to be continued, SSRIs might be the anti-obsessional treatment of choice, given the significant adverse effects associated with combined clozapine and CMI regimen.
Finally, pharmacotherapy should be combined with cognitive and behavioral psychotherapy in the treatment of OC schizophrenia.
Studies indicate a significant prevalence of OC-schizophrenia, a large proportion of which is clinically unrecognized, and its association with greater neuropsychological impairments, increased negative symptoms, and poorer clinical course. Although OC phenomena in schizophrenia have been recognized for a long time, too few systematic studies have examined their clinical and neurobiological significance.
Recent advances in the understanding of central nervous system dopamine–serotonin interactions and the advent of effective combined serotonin and dopamine antagonists in the pharmacotherapy of schizophrenia suggest multisystem involvement. Furthermore, the coexistence of OC and schizophrenic symptoms, and the specific response of OC symptoms to SSRI treatment, suggests a distinct neurobiological basis for the OC symptoms in OC-schizophrenia. Given that it is not yet clear whether this subgroup is best conceptualized as a distinct schizophrenic subtype, as schizophrenia with a prominent OC dimension, or as a subset of people suffering from comorbid OCD and schizophrenia, all three of these models should be considered in evaluating and treating OC schizophrenia. However, the apparent independent response of the OC symptom to the anti-OCD medications suggests that the OC phenomena in schizophrenia may arise from co-existing but distinct pathophysiological process.8,38 Combining anti-OC medications with either standard neuroleptics or SGAs, while monitoring blood levels and side effects in light of complex drug–drug interactions, may lead to improved outcomes and a better quality of life for this difficult group of schizophrenic patients.
While further controlled treatment studies are warranted, clinical and research evidence suggests that specific symptom assessment and individualized novel pharmacological treatment can lead to greater symptom relief and improved outcome in persons with OC-schizophrenia. At present, we recommend that clinicians, after careful evaluation of various clinical factors, consider adding adjunctive SSRI or clomipramine therapy along with antipsychotics for at least selective schizophrenics with severe OC features.
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