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Case of Mania Due to Prednisone—Clarithromycin Interaction

Case of Mania Due to Prednisone—Clarithromycin Interaction 778 The Canadian Journal of Psychiatry Vol 42, No 7 References prudent. She received no medications and over the next 5 days 1. Lehmann HE, Ban TA. The history of the psychopharmacology of schizophrenia. Can J gradually recovered to normal functioning. She returned to Psychiatry 1997;42:152–62. work within 2 weeks. Follow-up at one and 4 months revealed 2. Kline NS. Use of Rauwolfia Serpentina Benth in neuropsychiatric conditions. Ann N Y Acad Sci 1954;59:107–32. no evidence of psychiatric illness. 3. Sen G, Bose KC. Rauwolfia serpentina: a new Indian drug for insanity and high blood pressure. Indian Medical World 1931;11:194–201. 4. Cott J. Medicinal plants and dietary supplements: sources for innovative treatments or This case is of interest because of the apparent interaction adjuncts. Psychopharmacol Bull 1995;31:131–7. between clarithromycin and prednisone. Though she may have developed manic symptoms with the use of prednisone Vinod S Bhatara, MD, MS only, possible drug interactions were added to the diagnostic Sioux Falls, South Dakota differential for several reasons: she had received a relatively Sanjay Gupta, MD low dose of corticosteroid; she had taken the steroid over a Olean, New York brief duration; and there was a temporal relationship between medication initiation and illness. Clarithromycin has advantages over the prototype Case of Mania Due to Prednisone–Clarithromycin macrolide antibiotic, erythromycin, because of its higher Interaction tissue concentrations and extended antibacterial spectrum. Case reports and controlled studies, however, have reported Dear Sir: clinically significant inhibitory effects on the metabolism of coadministered CYP 3A4 substrates. The proposed mecha- Mood disorders are the most prevalent of the acute neuro- nism involves macrolide-induced induction of microsomal psychiatric complications associated with glucocorticoid use enzymes and formation of inactive CYP P450 metabolite (1). Prospective and retrospective analyses have shown a complexes (3). In contrast to inhibitory drug interactions that significant correlation between daily dose and frequency of are competitive in nature, the noncompetitive inhibition of a psychiatric syndromes (2). Comprehensive risk factor assess- P450 enzyme by a mechanism-based inhibitor can com- ment, however, necessitates the consideration of pharmaco- pletely block the metabolism of a drug, with the potential for kinetic factors that may contribute to these syndromes. profound clinical consequences. We present a case of acute mania possibly related to a prednisone–clarithromycin interaction. This interaction was Following oral administration, prednisone is converted to considered on the basis of clarithromycin’s ability to inhibit the biologically active steroid, prednisolone. The importance the specific cytochrome (CYP) P450 enzyme responsible for of CYP P450-dependent hydroxylation for the latter has been the metabolic clearance of prednisolone, the biologically demonstrated in humans (4). In addition, CYP 3A4 is identi- active moiety of prednisone. fied as the specific isoenzyme involved in the oxidative metabolism of prednisolone to its major unconjugated meta- Ms W, a 30-year-old registered nurse, presented with a bolite, 6-ß-hydroxyprednisolone (4,5). one-week history of progressive mental decompensation characterized by disorganized thoughts and behaviour, pres- Presumably, the acute manic episode was due to elevated sured speech, increased energy, reduced need for sleep, and plasma levels of unbound prednisolone that resulted from labile affect. The patient and her coworker described her CYP 3A4 inhibition by clarithromycin. The importance of delusional paranoia and reported a decline in her functioning considering drug interactions involving the specific isoform at work. Her only past psychiatric treatment was a 2-week CYP 3A4 has been an area of intense recent study (6). This course of biofeedback for college-related stress. case illustrates a diverse nonpsychotropic drug interaction with clinical implications for the psychopharmacologist. Ms W’s medical history was significant for acute sinusitis, which had been diagnosed 10 days prior to admission. She References had been started on clarithromycin 1000 mg/day and pred- 1. Lewis DA, Smith RE. Steroid-induced psychiatric syndromes: a report of 14 cases and a review of the literature. J Affect Disord 1983;5:319–32. nisone 20 mg/day at this time. After 2 days, she increased the 2. The Boston Collaborative Drug Surveillance Program. Acute adverse reactions to prednisone corticosteroid dose, as instructed, to 40 mg/day. A further in relation to dosage. Clin Pharmacol Ther 1972;13:694–8. 3. Periti P, Mazzei T, Mini E, Novelli A. Pharmacokinetic drug interactions of macrolides. Clin increase to 60 mg/day was recommended, but after 5 days the Pharmacokinet 1992;23:106–31. patient discontinued both medications for unknown reasons. 4. Waxman DJ, Attisano C, Guengerich FP, Lapenson DP. Human liver microsomal steroid metabolism: identification of the major steroid hormone 6ß-hydroxylase cytochrome P-450 It was determined, therefore, that she had taken a 30 mg enzyme. Arch Biochem Biophys 1988;263:424–36. average daily dose of prednisone for 5 days. She had also been 5. Frey BM, Frey FJ. Clinical pharmacokinetics of prednisone and prednisolone. Clin Pharma- cokinet 1990;19:126–46. taking oral contraceptives and famciclovir, both of which she 6. Ketter TA, Flockhart DA, Post RM, Denicoff K, Pazzaglia PJ, Marangell LB, and others. The emerging role of cytochrome P450 3A in psychopharmacology. J Clin Psychopharmacol had also stopped taking prior to admission. She had no other 1995;15:387–98. significant past medical history. Though management with antipsychotics and mood stabi- Ryan Finkenbine, MD lizers was strongly considered, it was felt that a brief period Harry S Gill, PharmD of observation in a safe supportive environment would be Charleston, South Carolina http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Canadian Journal of Psychiatry SAGE

Case of Mania Due to Prednisone—Clarithromycin Interaction

Finkenbine, Ryan; Gill, Harry S
Canadian Journal of Psychiatry , Volume 42 (7): 1 – Sep 1, 1997
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References (9)

Publisher
SAGE
Copyright
© 1997 Canadian Psychiatric Association
ISSN
0706-7437
eISSN
1497-0015
DOI
10.1177/070674379704200718
pmid
9307841
Publisher site
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Abstract

778 The Canadian Journal of Psychiatry Vol 42, No 7 References prudent. She received no medications and over the next 5 days 1. Lehmann HE, Ban TA. The history of the psychopharmacology of schizophrenia. Can J gradually recovered to normal functioning. She returned to Psychiatry 1997;42:152–62. work within 2 weeks. Follow-up at one and 4 months revealed 2. Kline NS. Use of Rauwolfia Serpentina Benth in neuropsychiatric conditions. Ann N Y Acad Sci 1954;59:107–32. no evidence of psychiatric illness. 3. Sen G, Bose KC. Rauwolfia serpentina: a new Indian drug for insanity and high blood pressure. Indian Medical World 1931;11:194–201. 4. Cott J. Medicinal plants and dietary supplements: sources for innovative treatments or This case is of interest because of the apparent interaction adjuncts. Psychopharmacol Bull 1995;31:131–7. between clarithromycin and prednisone. Though she may have developed manic symptoms with the use of prednisone Vinod S Bhatara, MD, MS only, possible drug interactions were added to the diagnostic Sioux Falls, South Dakota differential for several reasons: she had received a relatively Sanjay Gupta, MD low dose of corticosteroid; she had taken the steroid over a Olean, New York brief duration; and there was a temporal relationship between medication initiation and illness. Clarithromycin has advantages over the prototype Case of Mania Due to Prednisone–Clarithromycin macrolide antibiotic, erythromycin, because of its higher Interaction tissue concentrations and extended antibacterial spectrum. Case reports and controlled studies, however, have reported Dear Sir: clinically significant inhibitory effects on the metabolism of coadministered CYP 3A4 substrates. The proposed mecha- Mood disorders are the most prevalent of the acute neuro- nism involves macrolide-induced induction of microsomal psychiatric complications associated with glucocorticoid use enzymes and formation of inactive CYP P450 metabolite (1). Prospective and retrospective analyses have shown a complexes (3). In contrast to inhibitory drug interactions that significant correlation between daily dose and frequency of are competitive in nature, the noncompetitive inhibition of a psychiatric syndromes (2). Comprehensive risk factor assess- P450 enzyme by a mechanism-based inhibitor can com- ment, however, necessitates the consideration of pharmaco- pletely block the metabolism of a drug, with the potential for kinetic factors that may contribute to these syndromes. profound clinical consequences. We present a case of acute mania possibly related to a prednisone–clarithromycin interaction. This interaction was Following oral administration, prednisone is converted to considered on the basis of clarithromycin’s ability to inhibit the biologically active steroid, prednisolone. The importance the specific cytochrome (CYP) P450 enzyme responsible for of CYP P450-dependent hydroxylation for the latter has been the metabolic clearance of prednisolone, the biologically demonstrated in humans (4). In addition, CYP 3A4 is identi- active moiety of prednisone. fied as the specific isoenzyme involved in the oxidative metabolism of prednisolone to its major unconjugated meta- Ms W, a 30-year-old registered nurse, presented with a bolite, 6-ß-hydroxyprednisolone (4,5). one-week history of progressive mental decompensation characterized by disorganized thoughts and behaviour, pres- Presumably, the acute manic episode was due to elevated sured speech, increased energy, reduced need for sleep, and plasma levels of unbound prednisolone that resulted from labile affect. The patient and her coworker described her CYP 3A4 inhibition by clarithromycin. The importance of delusional paranoia and reported a decline in her functioning considering drug interactions involving the specific isoform at work. Her only past psychiatric treatment was a 2-week CYP 3A4 has been an area of intense recent study (6). This course of biofeedback for college-related stress. case illustrates a diverse nonpsychotropic drug interaction with clinical implications for the psychopharmacologist. Ms W’s medical history was significant for acute sinusitis, which had been diagnosed 10 days prior to admission. She References had been started on clarithromycin 1000 mg/day and pred- 1. Lewis DA, Smith RE. Steroid-induced psychiatric syndromes: a report of 14 cases and a review of the literature. J Affect Disord 1983;5:319–32. nisone 20 mg/day at this time. After 2 days, she increased the 2. The Boston Collaborative Drug Surveillance Program. Acute adverse reactions to prednisone corticosteroid dose, as instructed, to 40 mg/day. A further in relation to dosage. Clin Pharmacol Ther 1972;13:694–8. 3. Periti P, Mazzei T, Mini E, Novelli A. Pharmacokinetic drug interactions of macrolides. Clin increase to 60 mg/day was recommended, but after 5 days the Pharmacokinet 1992;23:106–31. patient discontinued both medications for unknown reasons. 4. Waxman DJ, Attisano C, Guengerich FP, Lapenson DP. Human liver microsomal steroid metabolism: identification of the major steroid hormone 6ß-hydroxylase cytochrome P-450 It was determined, therefore, that she had taken a 30 mg enzyme. Arch Biochem Biophys 1988;263:424–36. average daily dose of prednisone for 5 days. She had also been 5. Frey BM, Frey FJ. Clinical pharmacokinetics of prednisone and prednisolone. Clin Pharma- cokinet 1990;19:126–46. taking oral contraceptives and famciclovir, both of which she 6. Ketter TA, Flockhart DA, Post RM, Denicoff K, Pazzaglia PJ, Marangell LB, and others. The emerging role of cytochrome P450 3A in psychopharmacology. J Clin Psychopharmacol had also stopped taking prior to admission. She had no other 1995;15:387–98. significant past medical history. Though management with antipsychotics and mood stabi- Ryan Finkenbine, MD lizers was strongly considered, it was felt that a brief period Harry S Gill, PharmD of observation in a safe supportive environment would be Charleston, South Carolina

Journal

Canadian Journal of Psychiatry – SAGE

Published: Sep 1, 1997

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