Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via Google Scholar Articles by Brownlowe, K. Articles by Sola, C. Search for Related Content PubMed Citation Articles by Brownlowe, K. Articles by Sola, C. Nicotine Atypical Neuroleptics Syndromes Secondary to General Medical Disorders

Clozapine Toxicity in Smoking Cessation and With Ciprofloxacin • Case Report

TO THE EDITOR: We read with interest the case series by Sandson and colleagues¹ reviewing clozapine’s potential drug–drug interactions. Here, we describe one patient who experienced two such interactions.

A 64-year old woman with schizoaffective disorder on clozapine long-term was admitted with urosepsis manifested as a urinary tract infection, hypotension, somnolence, irritability, and cool extremities. On admission, neurologic exam was nonfocal, and ECG revealed a QTc interval of 512 msec. The psychiatry department advised withholding her clozapine and agreed that her mental-status changes were likely secondary to urosepsis-induced delirium. Because of persistent cardiac concerns, the cardiology department completed a trans-thoracic echocardiogram, which demonstrated reduction of left-ventricle systolic contractility, with global hypokinesis, suggestive of a non-ischemic cardiomyopathy. She had no known history of coronary-artery disease.

She did have, however, a smoking history of approximately one pack of cigarettes daily for decades, and during that same time-frame, her clozapine dosing had remained stable. However, 6 months before this admission, she began smoking cessation, with variable success. As she became increasingly ill several days before her hospitalization, she had abruptly stopped smoking altogether. Understanding the interaction of clozapine with smoking, it was postulated that clozapine toxicity led to her myocarditis. This hypothesis could not be tested because her clozapine had been stopped at the time of her admission, several days before discovery of her smoking cessation. Off clozapine, she remained psychiatrically stable; her myocarditis gradually improved, and she was discharged to her previous living situation.

One month later, she was admitted to the Psychiatry Department with a gross psychotic decompensation. Trials of ziprasidone and olanzapine were unsuccessful. Given her historical benefit from clozapine, it was gently reintroduced, with significant attention paid to her cardiac status. Psychotic symptoms remitted with no evidence of recurrent intolerance of clozapine.

Four months later, she was readmitted with confusion and irritability, after starting on ciprofloxacin for a urinary tract infection. Clozapine levels were elevated, at 1,498 ng/ml. Again, the clozapine was withheld and the patient treated supportively. Irritability and confusion resolved, but her psychosis began to return as her clozapine levels dropped. Clozapine was again slowly reintroduced, with remission of psychosis and a clozapine level of 787 ng/ml at discharge.

Discussion

Our patient experienced two of the interactions mentioned in Sandson’s case series.¹ Although her smoking habit remained stable—during which smoking caused an induction of the CYP1A2 isoenzyme,²—stable clozapine dosing provided therapeutic blood levels. With smoking cessation, metabolism induction also ceased, producing a toxic accumulation of clozapine and subsequent myocarditis in response to the newly-decreased activity of CYP1A2. Also, ciprofloxacin inhibits both the 1A2 and 3A4 isoenzymes,³ two routes through which clozapine is metabolized,⁴ leading to the accumulation of clozapine in our patient.

Finally, this case should be added to the literature involving successful clozapine re-challenge after the incidence of myocarditis.⁵

Clozapine remains an effective treatment for patients with psychotic illness resistant to other antipsychotic medications, although its use requires additional vigilance not only to possible drug–drug interactions, but also to habits like smoking.

REFERENCES

1. Sandson NB, Cozza KL, Armstrong SC, et al: Clozapine case series. Psychosomatics 2007; 48:170–175[Abstract/Free Full Text]
2. Schrenk D, Brockmeier D, Morike K, et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort study of healthy Caucasian volunteers. Eur J Clin Pharmacol 1998; 53:361–367[CrossRef][Medline]
3. Batty KT, Davis TM, Ilett KF, et al: The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects. B J Clin Pharmacol 1995; 39:305–311
4. Eiermann B, Engel G, Johansson I, et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Br J Clin Pharmacol 1997; 44:439–446[CrossRef][Medline]
5. Reid P, McArthur M, Pridmore S: Clozapine rechallenge after myocarditis. Aust N Z J Psychiatry 2001; 35:249[CrossRef][Medline]

Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via Google Scholar Articles by Brownlowe, K. Articles by Sola, C. Search for Related Content PubMed Citation Articles by Brownlowe, K. Articles by Sola, C. Nicotine Atypical Neuroleptics Syndromes Secondary to General Medical Disorders

Get information about faster international access.

Privacy Policy

Copyright © 2008 Academy of Psychosomatic Medicine. All rights reserved.

Home | Search | Current Issue | Past Issues | Subscribe | All APPI Journals | Help | Contact Us