Clozapine and Paroxetine in the Treatment of Schizophrenia With Obsessive-Compulsive Features
To the Editor: Patients whose schizophrenia is characterized by marked obsessive-compulsive features can be difficult to treat successfully and often require a combination treatment (1). If the psychosis in such patients does not respond to a neuroleptic and they are treated with clozapine alone, their obsessions may not improve, and some reports suggest that they may worsen (2). We report a patient with schizophrenia with obsessive-compulsive features who was resistant to multiple pharmacological trials of various antipsychotic and anti-obsessive-compulsive regimens but responded to a combination of clozapine and paroxetine.
Mr. A, a 32-year-old man with schizophrenia whose psychosis had not responded to treatment for the past 4 years, was admitted to our unit for evaluation and management. He was quite delusional but also had prominent negative symptoms. In addition to these classic features, he had disabling obsessive-compulsive symptoms such as the need to repeat his steps and continually retrace every public transit ride he took. His obsessive-compulsive symptoms prevented him from functioning independently, even though he was an intelligent and well-informed college graduate. Previous lengthy trials of perphenazine and risperidone (targeting the psychosis) as well as sertraline (targeting the obsessive-compulsive symptoms) were unsuccessful in controlling Mr. A’s psychotic and obsessive-compulsive symptoms, respectively. When he came to our unit, he was weaned off of his medication and underwent a 2-week drug washout period. During this time, he remained psychotic with nearly constant obsessive-compulsive symptoms, such as picking at his clothes, and resistance to outings off the unit because of his “need” to undertake various rituals and tasks while off the ward. At the end of this 2-week period, clozapine was started and slowly titrated up to a level of 200 mg per day. After treatment with clozapine for 1 month, there was improvement in some of the “positive” psychotic symptoms (delusions), but there was mild worsening of others (hostility, grandiosity) as rated by clinical team members’ subjective impressions. However, while he was receiving clozapine, there was no improvement in his obsessive-compulsive symptoms; rather, the treatment team felt that there was an accentuation of his obsessions during this time. Paroxetine was then added to the clozapine regimen, and a dose of 30 mg per day was reached by 2 weeks. The paroxetine was well tolerated, and blood levels of clozapine remained stable (in the range of 150 ng/ml) during paroxetine treatment. The addition of paroxetine resulted in a significant reduction in obsessive-compulsive symptoms (over a period of 14 weeks), as demonstrated by a decrease in his total Yale-Brown Obsessive Compulsive Scale score from 30 to 15 and in his Yale-Brown obsessional subscale score from 16 to 9. During this same period, his positive symptoms (rated on the Brief Psychiatric Rating Scale) declined by 40%. After 14 weeks on the combined treatment of clozapine and paroxetine, his Clinical Global Impression scale score, which had been 6 (severely ill) before the initiation of clozapine, fell to 3 (mildly ill).
With this severely ill patient with treatment-refractory schizophrenia and obsessive-compulsive symptoms, a combination of clozapine and the selective serotonin reuptake inhibitor paroxetine resulted in significant clinical improvement in both psychotic and obsessive-compulsive symptoms. While paroxetine has been reported by some to increase clozapine levels (3), in Mr. A, this did not happen. However, because paroxetine is largely metabolized by the cytochrome P450 IID6 (CYPIID6) enzyme (4) and clozapine is predominantly metabolized by the CYPIA2 and partly by the CYPIIIA enzymes (5), perhaps the lack of increase in his clozapine blood level should not be that surprising. Moreover, we have reported previously on another case (6) in which paroxetine was added to clozapine without affecting blood levels of clozapine. Nonetheless, given the potential interaction, until more data are collected, clozapine levels should be monitored closely during initial phases of paroxetine therapy. In addition, prospective studies are required to fully assess the optimal pharmacological management of patients who have treatment-refractory psychosis with obsessive-compulsive features.
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