Psychosomatics 39:281-282, June 1998
© 1998 The Academy of Psychosomatic Medine
Lithium, ACE Inhibitors, NSAIDs, and Verapamil
A Possible Fatal Combination
Sanjay S. Chandragiri, M.D.,
Elias Pasol, M.D., and
Rollin M. Gallagher, M.D., M.P.H.
Received July 24, 1996; revised September 20, 1996; accepted October 1, 1996. From the Department of Psychiatry and Behavioral Sciences, State University of New York at Stony Brook. Address reprint requests to Dr. Chandragiri, Department of Psychiatry, Health Sciences Center, T–10, 020, Stony Brook, NY 11794–8101.
Key Words: Case Report • Lithium • ACE • NSAID • Drug Interactions
Since lithium's approval by the Food and Drug Administration in 1969, it has been the first-line drug in the treatment for bipolar affective disorder and is now used to treat other psychiatric disorders as well. However, lithium's narrow therapeutic index requires regular monitoring of serum levels. Many drugs interact with lithium, increasing its blood level with the potential to precipitate lithium toxicity. We describe the case of a patient on lithium in whom the addition of lisinopril, aspirin, and the calcium channel blocker verapamil increased lithium to potentially fatal levels.
Case Report
Mrs. P., a 55-year-old woman with a history of bipolar affective disorder since age 35, had taken lithium for the past 17 years without toxicity. Her son brought her to the emergency room with a history of gradual onset of slurred speech and confusion over several days. Six weeks prior, she had suffered a cerebrovascular accident (CVA) with transient right hemiparesis and expressive aphasia. She was diagnosed to be hypertensive after the CVA and was started on lisinopril (Zestril) 10 mg/day, verapamil 240 mg/day, and aspirin 325 mg/day. Her lithium dose was continued unchanged at 900 mg/day.
In the emergency room, her serum lithium level was 4.9 mEq/L and her serum creatinine 2.3, whereas other laboratory parameters were normal. A computed tomography scan of the head did not reveal any new lesions. She was admitted to the medical intensive care unit and started on hemodialysis. Lithium and verapamil were discontinued. She was dialyzed twice over 2 days. Her creatinine level reverted to within normal range, and her serum lithium level lowered to 0.8 mEq/L. Her mental status gradually improved but had not returned back to normal 2 days after admission. At this time, she was transferred from the intensive care unit to the psychiatric inpatient unit for further management.
On the psychiatric unit, she was observed without psychotropic medication and continued on aspirin and lisinopril. Her serum lithium level gradually came down to <0.1 mEq/L over the next 5 days. Her mental status improved, and her cognition returned to normal (Mini-Mental State Exam score: 28/30). She did not display any untoward behavior. She was discharged on the 6th day on lisinopril and aspirin and scheduled to see her regular psychiatrist in another city the following week to consider a different mood stabilizer.
Discussion
As this case illustrates, physicians must exercise caution when combining lithium with other medications. The increasing popularity of angiotensin-converting enzyme (ACE) inhibitors (to which class lisinopril belongs) requires a heightened awareness of the propensity of these medications to increase serum lithium concentrations.1 Two investigations of this potential interaction have yielded conflicting results. Das Gupta et al.2 conducted a prospective evaluation of this interaction, analyzing the effects of enalapril on serum lithium disposition in nine healthy lithium-naive volunteers. Overall, the authors were unable to detect a statistically significant difference in lithium concentrations during any phase of the study. The authors acknowledged the limitations of their study, including short duration of exposure, a small sample size, and a sample that was not representative of the population of patients most likely to receive this combination. Finley and colleagues3 conducted a longitudinal case-controlled study of this potential interaction in 20 psychiatric patients initiated on ACE inhibitors for the treatment of hypertension. The authors reported an average increase of 36.1% in serum lithium concentrations, with four patients presenting with presumed lithium toxicity. Despite the paucity of research, the interaction of lithium and ACE inhibitors has clinically relevant consequences.2 Captopril, enalapril, and lisinopril have all been implicated in this interaction.1 The time course of patient presentation suggests that the development of toxicity may be gradual in onset, with symptoms typically manifesting after 3–5 weeks of coadministration.1 The precise mechanism of this interaction has yet to be determined, but varying theories are proposed, including sodium depletion4 and ACE inhibitor-induced renal insufficiency.5
Evidence exists that aspirin increases serum lithium concentrations minimally.6 NSAIDs (nonsteroidal anti-inflammatory drug), including aspirin, reduce renal excretion of ACE inhibitors, with a corresponding increase in circulating drug concentrations.7
Verapamil, a calcium channel blocker with possible antimanic properties, has been reported to interact with lithium, resulting in neurotoxicity manifested by ataxia, dysarthria, tremor, and nausea.8,9 Caution is advised in the use of lithium and verapamil together.8
The patient in this report was on lisinopril, which is known to increase serum lithium concentration,1,3 and aspirin, which is known to increase the concentration of both lithium;6 and lisinopril.7 In addition, she was on verapamil, which could have potentiated the neurotoxic effects of lithium.8,9 A literature review did not reveal any published report that a combination of the above-mentioned drugs result in increased lithium levels. The potentially fatal level of lithium concentration in this patient highlights the clinical relevance of the interaction. The growing use of ACE inhibitors, the common use of NSAIDs, and the use of verapamil as both an antihypertensive and a second-line drug in bipolar affective disorder make it imperative that primary care physicians and psychiatrists be made aware of the clinical relevance of these interactions. Further studies of these interactions will hopefully lead to guidelines on combining lithium with NSAIDs, ACE inhibitors, and verapamil.
REFERENCES
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Price WA, Giannini AJ: Neurotoxicity caused by lithium-verapamil synergism. J Clin Pharmacol 1986; 26:717–719[Medline]
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