Psychiatric Annals

Case Report 

Lithium and Lisinopril Interaction, Lithium Toxicities, and Relative Preservation of Renal Function in a Patient with Bipolar Disorder

Patricia Krisar-White, MD; Judy Perry-Rose, MD; Mujeeb U. Shad, MD, MSCS

Abstract

The patient was a 53-year-old man diagnosed with bipolar disorder at age 18 years who had experienced multiple manic relapses each time his lithium was discontinued due to medication-nonadherence or lithium toxicities. However, after each relapse, lithium had to be used again because the patient did not respond to other mood stabilizers. The manic symptoms during his relapses were severe enough to result in repeated hospitalizations due to violent and criminal behaviors. These behaviors resulted in the patient being placed for 20 years under the custody of the psychiatric security review board, which supervises people who successfully use the insanity defense to a criminal charge and reviews their rehabilitative needs before they are reintegrated into the community. However, despite repeated lithium toxicities, the patient's renal function returned to a relatively normal level each time after resolution of the lithium toxicity. The only noticeable change in the patient's renal function was some compromise in lithium clearance, requiring lithium dose reduction from 450 to 300 mg twice daily without losing efficacy, even at lithium levels of 0.4 to 0.6 mmol/L (Table 1).

Table 1:

Timeline of Lithium Doses, Lithium Levels, Creatinine Levels, eGFR, Electrolyte Levels, Clinical Picture, and Adverse Events

This case came to our attention when the dose of an angiotensin-converting enzyme inhibitor (ACEI), lisinopril, was doubled from 20 to 40 mg/day to manage worsening hypertension, which had been effectively managed with concomitant use of metoprolol and 20 mg of lisinopril for several years without any effect on lithium levels or renal function. The increase in lisinopril dose resulted in a gradual increase in creatinine levels until eventually the patient developed lithium toxicity and a significant electrolyte imbalance. As a result, both lithium and lisinopril had to be discontinued, but within 2 days the patient became floridly manic. Knowing that this patient did not respond to any other mood stabilizer, lithium had to be restarted gradually up to a dose of 600 mg daily, which resulted in a quick recovery from manic relapse as well as normalization of renal function and electrolytes, as has been observed several times previously in this patient. None of these toxicities were associated with alcohol intoxication or any other substance use. This patient's hypertension was successfully treated after the addition of amlodipine.

The most consistent findings from previous reports of interaction between lithium and ACEIs include gradual development of lithium toxicity and creatinine elevation occurring from several weeks to months1–3 or even several years later.4 However, the results have been variable in terms of clinical presentation,1–4 doses of lithium and ACEIs,1–3 and electrolyte levels (especially sodium).1 This was especially true for interactions between lithium and the ACEI lisinopril.1 In their review of three cases (from a total of 10) taking lisinopril, Lehman and Ritz1 reported variability in toxic lithium levels (2.1, 3.8, and 4.5 mEq/L, respectively) at relatively low doses of lisinopril (unknown, 20, and 10 mg/day, respectively) and lithium (about 900, 1,500, and 900 mg/day, respectively).1 In contrast, the patient in this case developed lithium toxicity with a relatively lower lithium dose of 600 mg/day but only after the dose of lisinopril of 20 mg/day, which had remained constant for 5 years, was increased to 40 mg/day. Despite the low lithium dose, our patient experienced more significant renal dysfunction than observed in most previously documented reports1–3 with a significant increase in creatinine levels (2 mg/dL) and significant hyponatremia (132 mEq/L). However, our patient did not develop permanent renal damage despite re-exposure to lithium after lisinopril was discontinued. In another case report,2 renal function remained relatively normal despite a 5-fold increase in lithium level several weeks…

The patient was a 53-year-old man diagnosed with bipolar disorder at age 18 years who had experienced multiple manic relapses each time his lithium was discontinued due to medication-nonadherence or lithium toxicities. However, after each relapse, lithium had to be used again because the patient did not respond to other mood stabilizers. The manic symptoms during his relapses were severe enough to result in repeated hospitalizations due to violent and criminal behaviors. These behaviors resulted in the patient being placed for 20 years under the custody of the psychiatric security review board, which supervises people who successfully use the insanity defense to a criminal charge and reviews their rehabilitative needs before they are reintegrated into the community. However, despite repeated lithium toxicities, the patient's renal function returned to a relatively normal level each time after resolution of the lithium toxicity. The only noticeable change in the patient's renal function was some compromise in lithium clearance, requiring lithium dose reduction from 450 to 300 mg twice daily without losing efficacy, even at lithium levels of 0.4 to 0.6 mmol/L (Table 1).

Timeline of Lithium Doses, Lithium Levels, Creatinine Levels, eGFR, Electrolyte Levels, Clinical Picture, and Adverse Events

Table 1:

Timeline of Lithium Doses, Lithium Levels, Creatinine Levels, eGFR, Electrolyte Levels, Clinical Picture, and Adverse Events

Treatment and Management

This case came to our attention when the dose of an angiotensin-converting enzyme inhibitor (ACEI), lisinopril, was doubled from 20 to 40 mg/day to manage worsening hypertension, which had been effectively managed with concomitant use of metoprolol and 20 mg of lisinopril for several years without any effect on lithium levels or renal function. The increase in lisinopril dose resulted in a gradual increase in creatinine levels until eventually the patient developed lithium toxicity and a significant electrolyte imbalance. As a result, both lithium and lisinopril had to be discontinued, but within 2 days the patient became floridly manic. Knowing that this patient did not respond to any other mood stabilizer, lithium had to be restarted gradually up to a dose of 600 mg daily, which resulted in a quick recovery from manic relapse as well as normalization of renal function and electrolytes, as has been observed several times previously in this patient. None of these toxicities were associated with alcohol intoxication or any other substance use. This patient's hypertension was successfully treated after the addition of amlodipine.

Discussion

The most consistent findings from previous reports of interaction between lithium and ACEIs include gradual development of lithium toxicity and creatinine elevation occurring from several weeks to months1–3 or even several years later.4 However, the results have been variable in terms of clinical presentation,1–4 doses of lithium and ACEIs,1–3 and electrolyte levels (especially sodium).1 This was especially true for interactions between lithium and the ACEI lisinopril.1 In their review of three cases (from a total of 10) taking lisinopril, Lehman and Ritz1 reported variability in toxic lithium levels (2.1, 3.8, and 4.5 mEq/L, respectively) at relatively low doses of lisinopril (unknown, 20, and 10 mg/day, respectively) and lithium (about 900, 1,500, and 900 mg/day, respectively).1 In contrast, the patient in this case developed lithium toxicity with a relatively lower lithium dose of 600 mg/day but only after the dose of lisinopril of 20 mg/day, which had remained constant for 5 years, was increased to 40 mg/day. Despite the low lithium dose, our patient experienced more significant renal dysfunction than observed in most previously documented reports1–3 with a significant increase in creatinine levels (2 mg/dL) and significant hyponatremia (132 mEq/L). However, our patient did not develop permanent renal damage despite re-exposure to lithium after lisinopril was discontinued. In another case report,2 renal function remained relatively normal despite a 5-fold increase in lithium level several weeks after switching from fosinopril to lisinopril.2 Although a study in healthy men did not show any noticeable changes in lithium levels after addition of enalapril (another ACEI) to the ongoing lithium treatment, the study only lasted 26 days, which may not have been enough time for increased lithium levels to develop.5 However, one patient in the review by Lehman and Ritz1 did develop rapid deterioration of renal function within 2 to 3 weeks of an increase in dose of enalapril (another ACEI). Overall, these findings demonstrate that ACEIs may have differential effects on lithium clearance, especially lisinopril. One of the main reasons why lisinopril appears to have higher risk for lithium toxicity is the fact that lisinopril is solely eliminated by the kidneys and may accumulate over time in presence of lithium-induced renal dysfunction.1 Moreover, lisinopril, can induce dehydration by reducing thirst with an increase in sodium retention, which in turn can increase lithium levels.1 This may explain why it takes several weeks for lithium toxicity to develop and why preexisting renal dysfunction increases the risk for lithium toxcicity.1,2 A similar argument can be made for higher risk of lithium toxicity in elderly patients than in younger patients due to lower lithium clearance.3,6 This view is also supported by the average age of about 50 years for cases reviewed by Lehman and Ritz.1

Despite a high risk of reduced lithium clearance with ACEIs, especially lisinopril, it should be noted that a retrospective case control study6 reported lithium toxicity in only 4 of 20 patients, suggesting significant inter-individual variability in lithium clearance. Of note, 13 of 20 patients in this study were taking lisinopril.6 It is not clear if the four patients who developed lithium toxicity were taking lisinopril or some other ACEI. This study did find lithium clearance being significantly correlated with age and serum creatinine but not height, weight, or change in serum sodium/potassium in a regression model. These results further support the notion that elderly patients may be uniquely predisposed to this interaction, and thus avoidance of this medication combination in all patients, especially in geriatric population, should be considered. If lisinopril has to be used with lithium, close monitoring of renal function is required.

This case is an example of a relative perseveration of normal renal function in a patient with bipolar disorder despite repeated lithium toxicities. In addition, the case illustrates complex interplay between commonly used pharmacotherapies in medicine and psychiatry and the need for a closer and repeated monitoring for renal function and lithium levels, especially in elderly patients and those with preexisting renal dysfunction being treated with an ACEI, most notably lisinopril.

References

  1. Lehmann K, Ritz E. Angiotensin-converting enzyme inhibitors may cause renal dysfunction in patients on long-term lithium treatment. Am J Kidney Dis. 1995;25(1):82–87. https://doi.org/10.1016/0272-6386(95)90632-0 PMID: doi:10.1016/0272-6386(95)90632-0 [CrossRef]7810540
  2. Meyer JM, Dollarhide A, Tuan IL. Lithium toxicity after switch from fosinopril to lisinopril. Int Clin Psychopharmacol. 2005;20(2):115–118. PMID: doi:10.1097/00004850-200503000-00010 [CrossRef]15729089
  3. Handler J. Lithium and antihypertensive medication: a potentially dangerous interaction. J Clin Hypertens (Greenwich). 2009;11(12):738–742. https://doi.org/10.1111/j.1751-7176.2009.00181.x PMID: doi:10.1111/j.1751-7176.2009.00181.x [CrossRef]
  4. Masiran R, Abdul Aziz MF. Hypertensive bipolar: chronic lithium toxicity in patients taking ACE inhibitor. BMJ Case Rep. 2017;2017:bcr-2017-220631. http://dx.doi.org/10.1136/bcr-2017-220631 PMID:28847993
  5. DasGupta K, Jefferson JW, Kobak KA, Greist JH. The effect of enalapril on serum lithium levels in healthy men. J Clin Psychiatry. 1992;53(11):398–400. PMID:1459971
  6. Finley PR, O'Brien JG, Coleman RW. Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction. J Clin Psychopharmacol.1996;16(1):68–71. PMID: doi:10.1097/00004714-199602000-00011 [CrossRef]8834421

Timeline of Lithium Doses, Lithium Levels, Creatinine Levels, eGFR, Electrolyte Levels, Clinical Picture, and Adverse Events

August 22, 2017 November 22, 2017 December 4, 2017 January 22, 2018 February 9, 2018 February 12, 2018 February 28, 2018 March 16, 2018
Lisinopril dose 20 mg/d 20 mg BID 20 mg BID 20 mg BID Stopped - - -
Lithium dose 300 mg BID 300 mg BID 300 mg BID 300 mg BID Stopped Restart at 300 mg/d, increased to 450 mg/d 450 mg HS 600 mg HS
Lithium level (mEq/L) 0.4 (in June 2017) 1 NA NA 1.6 0.7 0.5 0.7
Creatinine (mg/dL) 0.9 1 0.9 1.1 2 1 0.9 WNL
eGFR - >60 >60 >60 37 >60 >60 -
Potassium (mEq/L) 4.6 5.3 5 5 5.5 4.9 4.4 WNL
Sodium (mEq/L) 133 136 132 135 135 136 140 WNL
Clinical picture Stable Stable Relatively stable Worsening Worsening Manic response Mania improving Remission of mania
Adverse events - - Tremors Tremors Tremors - - -
Authors

Patricia Krisar-White, MD, is a Psychiatry Resident, Department of Psychiatry, Good Samaritan Regional Medical Center and the University of Medicine Iuliu Hatieganu. Judy Perry-Rose, MD, is a Psychiatrist, Department of Psychiatry, Oregon State Hospital. Mujeeb U. Shad, MD, MSCS, is a Professor of Psychiatry, Oregon Health & Science University; and an Attending Psychiatrist, Oregon State Hospital.

Address correspondence to Mujeeb U. Shad, MD, MSCS, Oregon State Hospital, 2600 Center Street NE, Salem, OR 97301; email: shad@ohsu.edu.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/00485713-20190909-01

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