H₂-Histamine Antagonist (Famotidine) Induced Adverse CNS Reactions with Long-Standing Secondary Mania and Epileptic Seizures

We report on the case of a 65-year-old female who was treated for one week with famotidine, a reversible H₂-histamine antagonist, due to gastric pain. Shortly after treatment began, she presented manic symptoms and developed two generalized seizures, after which famotidine was discontinued. Manic symptoms were present for three months; intermittent treatment with both carbamazepine and antipsychotic medication was necessary before her mental status was completely restored. While cimetidine and ranitidine are known to cause secondary mania, this symptom has not been described for famotidine. CNS side effects are usually short-lived and respond to discontinuation of the drug, which was not the case in our patient. During a follow-up period that has so far lasted four years, the patient has been stable without any psychiatric medication.

Adjusting the maintenance dosage of H₂-histamine antagonists has been recommended in elderly patients since age-related reduction in renal plasma flow, glomerular filtration rate and renal tubular function may be present, which can in turn elevate histamine levels in plasma and cerebrospinal fluid. Our patient, however, had normal renal function and was free of organic or psychiatric diseases, so what pathogenetic mechanism led to the remarkably long standing manic syndrome after a relatively short course of famotidine remained unknown; famotidine seems to cause the same spectrum of adverse central nervous system (CNS) reactions as other H₂-histamine antagonists.

References

• 1 Bisson C, St.-Laurent M, Michaud J- T, LeBel M. Pharmacokinetics and pharmacodynamics of rantidine and famotidine in healthy elderly subjects: a double-blind, placebo-controlled comparison.  Pharmacotherapy. 1993;  13 3-9
• 2 Catalano G, Catalano M C, Alberts V A. Famotidine-associated delirium. A series of six cases.  Psychosomatics. 1996;  37 349-355
• 3 Cantu T G, Korek J S. Central nervous system reactions to histamine-2 receptor-blockers.  Ann Intern Med. 1991;  114 1027-1034
• 4 Davis D G, Shock N. Age changes in glomerular filtration rate, effective renal plasma flow and tubular excretory capacity in adult males.  J Clin Invest. 1950;  29 469-507
• 5 Echizen H, Shoda R, Umeda N, Ishizaki T. Plasma famotidine concentration versus intragastric pH in patients with upper gastrointestinal bleeding and in health subjects.  Clin Pharmacol Ther. 1988;  44 690-698
• 6 Echizen H, Ishizaki T. Clinical pharmacokinetics of famotidine.  Clin Pharmacokinet. 1991;  21 178-194
• 7 Eisendrath S J, Ostroff J W. Rantidine-associated delirium.  Psychosomatics. 1990;  31 98-100
• 8 Ganzini L, Millar S B, Walsh J R. Drug-induced mania in the elderly.  Drugs and Aging. 1993;  3 428-435
• 9 Ghersi-Egea J F, Sautegeau A, Walther B, Minn A, Saunier C. Cimetidine inhibits cerebral and hepatic mitochondrial respiration in rat.  Toxicol Lett. 1986;  34 253-259
• 10 Henann N E, Carpenter D U, Janda S M. Famotidine-associated mental confusion in elderly patients.  Drug Intell Clin Pharm. 1988;  22 976-978
• 11 Kimelblatt B J, Cerra F B, Calleri G, Berg M J, McMillen M A, Schentag J J. Dose and serum concentration relationships in cimetidine-associated mental confusion.  Gastroenterology. 1980;  78 791-795
• 12 Kroemer H, Klotz U. Pharmacokinetics of famotidine in man.  Int J Clin Pharmacol Ther Toxicol. 1987;  25 458-463
• 13 Lakoski J M, Aghajanian G K, Gallager D W. Interaction of histamine H2-receptor antagonist with GABA and benzodiazepine binding sites in the CNS.  Eur J Pharmacol. 1983;  88 241-245
• 14 Langtry H D, Grant S M, Goa K L. Famotidine. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in peptic ulcer disease and other allied diseases.  Drugs. 1989;  38 551-590
• 15 Lebert P A, MacLeod S M, Mahon W A, Soldin S J, Vandenberghe H M. Ranitidine kinetics and dynamics. I. Oral dose studies.  Clin Pharmacol Ther. 1981;  30 539-544
• 16 Ljubicic N, Rotkvic I. Famotidine-induced mental confusion in a patient with alcoholic cirrhosis of the liver.  Gastroenterohepatol. Arh.. 1990;  9 19-20
• 17 Martinez-Mir M I, Pollard H, Moreau J. Three histamine receptors (H1, H2 and H3) visualized in the brain of human and non-human primates.  Brain Res. 1990;  526 322-327
• 18 Mogelnicki S R, Waller J L, Finlayson D C. Physostigmine reversal of cimetidine-induced mental confusion.  JAMA. 1979;  241 826-827
• 19 Nowak J Z. Interactions of histamine H2-receptor blocking drugs with noradrenergic system in rat brain and heart.  Eur J Pharmacol. 1980;  68 69-72
• 20 Odeh M, Oliven A. Central nervous system reactions associated with famotidine: report of five cases.  J Clin Gastroenterol. 1998;  27 253-254
• 21 Picotte-Prillmayer D, DiMaggio J R, Baile W F. H2 Blocker delirium.  Psychosomatics. 1995;  36 74-77
• 22 Rodgers P T, Brengel B R. Famotidine-associated mental status changes.  Pharmacotherapy. 1998;  18 404-407
• 23 Russell W L, Lopez L M. Cimetidine-induced mental status changes: case report and literature review.  American Journal of Hospital Pharmacy. 1980;  37 1667-1671
• 24 Ruat M, Traiffort E, Bouthenet M L, Schwartz J C, Hirschfeld J, Buschauer A, Schunack W. Reversible and irreversible labeling and autoradiographic localization of the cerebral histamine H2-receptor using 125 I-iodinated probes.  Proc Natl Acad Sci USA. 1990;  87 1658-1662
• 25 Segre G, Auteri A, Cerretani D. Pharmacokinetics of famotidine in the elderly.  Curr Ther Res. 1991;  50 341-346
• 26 Smith J L, Gamal M A, Chremos A N, Graham D Y. Famotidine, a new H2-receptor antagonist. Effect on parietal, nonparietal, and pepsin secretion in man.  Dig Dis Sci. 1985;  4 308-312
• 27 Stasiek C, Zetin M. Organic manic disorders.  Psychosomatics. 1985;  5 394-399
• 28 Yoshimoto K, Saima S, Echizen H, Nakamura Y, Kondo T, Yagishita Y, Ishizaki T. Famotidine-associated central nervous system reactions and plasma and cerebrospinal drug concentrations in neurosurgical patients with renal failure.  Clin Pharmacol Ther. 1994;  55 693-700
• 29 Yuan R Y, Kao C R, Sheu J J, Chen C H, Ho C S. Delirium following a switch from cimetidine to famotidine.  Ann Pharmacother. 2001;  359 1045-1048