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Letter to the Editor   |    
Sertraline in the Treatment of Clozapine-Induced Obsessive-Compulsive Behavior
M. SADIQUR RAHMAN, M.D.; JEFFERY J. GRACE, M.D.; MICHELE T. PATO, M.D.; BARBARA PRIEST, R.N.
Am J Psychiatry 1998;155:1626f-1626.
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Buffalo, N.Y.

Letters to the Editor

To the Editor: It has been reported that obsessive-compulsive behavior may emerge in patients treated with clozapine R4615511CHDCJFGG. This report describes treatment of clozapine-induced obsessive-compulsive behavior with sertraline, which avoids liver enzyme competition.

Mr. A, a 39-year-old white man with a 20-year history of paranoid schizophrenia, was treated with multiple traditional antipsychotic medications. He had begun a regimen of clozapine for treatment-refractory psychosis 8 years previously; he showed significant clinical improvement on a dose of 900 mg/day. After 2 years of treatment with clozapine, Mr. A developed severe obsessive-compulsive behaviors including meticulous checking and hand washing to the point of skin excoriation. For nearly 1 year subsequently, Mr. A refused to take clozapine and was treated with risperidone. During this time, his obsession with germ contamination gradually diminished but did not disappear. He was treated with clomipramine, 75 mg/day, with further reduction of obsessive-compulsive symptoms R4615511CHDBFHHB. Unfortunately, on this regimen, compared with his previous treatment with clozapine, Mr. A’s psychotic symptoms did not improve. At Mr. A’s request, risperidone and clomipramine were discontinued, and clozapine treatment was restarted. His psychotic symptoms improved significantly, but fluvoxamine was substituted to avoid both the return of compulsive behaviors and the potential anticholinergic side effects of clomipramine. Mr. A’s obsessive-compulsive behavior did indeed improve with fluvoxamine at a dose of 150 mg/day; however, his clozapine blood level began to rise above 700 ng/ml. His clozapine dose was decreased to 600 mg/day (blood level=2295 ng/ml). Clozapine was further decreased to 325 mg/day (blood level=906 ng/ml) and fluvoxamine to 50 mg/day. Although the clozapine blood level remained high, Mr. A responded poorly to these medication changes by becoming more psychotic and agitated. It appears that the addition of fluvoxamine interfered with the efficacy of clozapine, even though the plasma level was higher. This demonstrates that there was not an absolute correlation among clozapine plasma level, dose, and therapeutic response. Fluvoxamine was discontinued, and sertraline, 100 mg b.i.d., was substituted. Subsequently clozapine was raised to 475 mg/day (blood level=307 ng/ml), and Mr. A’s psychotic and obsessive-compulsive symptoms were well controlled.

The case report illustrates the emergence of obsessive-compulsive behavior with the use of clozapine. Marked increase of clozapine blood level occurred when clozapine was combined with fluvoxamine. There was, however, successful management of obsessive-compulsive behavior with sertraline without increased blood level of clozapine. The elevated clozapine level with fluvoxamine R4615511CHDCGCEIR4615511CHDCDEFE may be explained on the basis of its competitive inhibition of liver P450 isoenzymes. Clozapine is metabolized through P450 2D6 and IA2 isoenzymes. Fluvoxamine is unique among the selective serotonin reuptake inhibitors in its inhibition of P450 IA2. Thus, fluvoxamine appears to affect the serum level and efficacy of clozapine. Sertraline, on the other hand, proved to be a better choice in the treatment of clozapine-induced obsessive-compulsive behavior because it had no effect on P450 IA2 isoenzyme and moderate effect on 2D6 isoenzyme R4615511CHDBIHEA; sertraline did not affect the clozapine serum level or efficacy. Other drugs like paroxetine or fluoxetine, used in the treatment of obsessive-compulsive disorder and not metabolized by P450 IA2, should theoretically also be considered.

Baker RW, Chengappa KN, Baird JW, Steingard S, Christ MA, Schooler NR: Emergence of obsessive-compulsive symptoms during treatment with clozapine. J Clin Psychiatry  1992; 53:439–442
[PubMed]
 
Zohar J, Kaplan Z, Benjamin J: Clomipramine treatment of obsessive-compulsive symptomatology in schizophrenic patients. J Clin Psychiatry  1993; 54:385–388
[PubMed]
 
Dequardo JR, Roberts M: Elevated clozapine levels after fluvoxamine initiation (letter). Am J Psychiatry  1996; 153:840–841
 
Dumortier G, Lochu A, de Melo PC, Ghribi O, Rabreau DR, Degrassat K, Desce JM: Elevated clozapine plasma concentrations after fluvoxamine initiation (letter). Am J Psychiatry  1996; 153:738–739
 
Nemeroff CB, DeVane CL, Pollock BG: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry  1996; 153:311–320
[PubMed]
 
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References

Baker RW, Chengappa KN, Baird JW, Steingard S, Christ MA, Schooler NR: Emergence of obsessive-compulsive symptoms during treatment with clozapine. J Clin Psychiatry  1992; 53:439–442
[PubMed]
 
Zohar J, Kaplan Z, Benjamin J: Clomipramine treatment of obsessive-compulsive symptomatology in schizophrenic patients. J Clin Psychiatry  1993; 54:385–388
[PubMed]
 
Dequardo JR, Roberts M: Elevated clozapine levels after fluvoxamine initiation (letter). Am J Psychiatry  1996; 153:840–841
 
Dumortier G, Lochu A, de Melo PC, Ghribi O, Rabreau DR, Degrassat K, Desce JM: Elevated clozapine plasma concentrations after fluvoxamine initiation (letter). Am J Psychiatry  1996; 153:738–739
 
Nemeroff CB, DeVane CL, Pollock BG: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry  1996; 153:311–320
[PubMed]
 
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