Subscribe to RSS
Drug-Drug Interactions Between Lithium and Cardiovascular as Well as Anti-Inflammatory DrugsFunding: No sources of funding were used to assist with the preparation of this article.
Introduction Lithium is the gold standard in treating bipolar affective disorders. As patients become increasingly older, drug-drug interactions leading to decreased excretion of lithium represent a key issue in lithium safety. As no study considered the effect of comedications on lithium serum concentration in combination, we aimed to quantify the impact of drugs affecting renal blood flow and function and thus potentially interacting drugs (diuretics, ACE inhibitors, AT1 antagonists, and non-steroidal anti-inflammatory drugs) on lithium serum levels in addition to age, sex, and sodium and potassium serum levels as well as renal function.
Methods Retrospective data of lithium serum levels were analyzed in 501 psychiatric inpatients (2008–2015) by means of linear regression modelling.
Results The number of potentially interacting drugs was significantly associated with increasing serum levels of lithium in addition to the established factors of age, renal function, and sodium concentration. Additionally, absolute lithium levels were dependent on sex, with higher values in females. However, only NSAIDs were identified to increase lithium levels independently.
Discussion Routine clinical practice needs to focus on drugs affecting renal blood flow and function, especially on NSAIDs as over-the-counter medication that may lead to an increase in lithium serum concentration. To prevent intoxications, clinicians should carefully monitor the comedications, and they should inform patients about possible intoxications due to NSAIDs.
§ These authors contributed equally.
Received: 11 March 2020
Received: 08 April 2020
Accepted: 08 April 2020
Article published online:
27 April 2020
© 2020. Thieme. All rights reserved.
© Georg Thieme Verlag KG
Stuttgart · New York
- 1 Zivanovic O. Lithium: A classic drug—frequently discussed, but, sadly, seldom prescribed!. Aust NZ J Psychiatry 2017; 51: 886-896
- 2 McKnight RF, Adida M, Budge K. et al. Lithium toxicity profile: A systematic review and meta-analysis. Lancet 2012; 379: 721-728
- 3 Tondo L, Alda M, Bauer M. et al. Clinical use of lithium salts: Guide for users and prescribers. Int J Bipolar Disord 2019; 7: 16
- 4 Tondo L, Baldessarini RJ. Antisuicidal effects in mood disorders: Are they unique to lithium?. Pharmacopsychiatry 2018; 51: 177-188
- 5 Severus E, Bauer M, Geddes J. Efficacy and effectiveness of lithium in the long-term treatment of bipolar disorders: An update 2018. Pharmacopsychiatry 2018; 51: 173-176
- 6 Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. Int J Bipolar Disord 2016; 4: 27
- 7 Finley PR. Drug interactions with lithium: An update. Clin Pharmacokinet 2016; 55: 925-941
- 8 Timmer RT, Sands JM. Lithium intoxication. J Am Soc Nephrol 1999; 10: 666-674
- 9 Hiemke C, Bergemann N, Clement HW. et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018; 51: 9-62
- 10 Methaneethorn J. Population pharmacokinetic analyses of lithium: A systematic review. Eur J Drug Metab Pharmacokinet 2018; 43: 25-34
- 11 Handler J. Lithium and antihypertensive medication: a potentially dangerous interaction. J Clin Hypertens (Greenwich) 2009; 11: 738-742
- 12 Wilting I, Movig KLL, Moolenaar M. et al. Drug-drug interactions as a determinant of elevated lithium serum levels in daily clinical practice. Bipolar Disorders 2005; 7: 274-280
- 13 Juurlink DN, Mamdani MM, Kopp A. et al. Drug-induced lithium toxicity in the elderly: A population-based study. J Am Geriatr Soc 2004; 52: 794-798
- 14 Phelan KM, Mosholder AD, Lu S. Lithium interaction with the cyclooxygenase 2 inhibitors Rofecoxib and Celecoxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry 2003; 64: 1328-1334
- 15 Harvey NS, Merriman S. Review of clinically important drug interactions with lithium. Drug Saf 1994; 10: 455-463
- 16 Grunfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol 2009; 5: 270-276
- 17 Hommers L, Fischer M, Reif-Leonhard C. et al. The combination of lithium and ACE inhibitors: Hazardous, critical, possible?. Clin Drug Investig 2019; 39: 485-489
- 18 Nunes RP. Lithium interactions with non-steroidal anti-inflammatory drugs and diuretics – a review. Arch Clin Psychiat 2018; 45: 38-40
- 19 Loboz KK, Shenfield GM. Drug combinations and impaired renal function – the “triple whammy. Br J Clin Pharmacol 2004; 59: 239-243
- 20 Scherf-Clavel M, Albert E, Zieher S. et al. Dried blood spot testing for estimation of renal function and analysis of metformin and sitagliptin concentrations in diabetic patients: A cross-sectional study. Eur J Clin Pharmacol 2019; 75: 809-816
- 21 Janka Z, Szentistvanyi I, Rimanoczy A. et al. The influence of external sodium and potassium on lithium uptake by primary brain cell cultures at “therapeutic” lithium concentration. Psychopharmacology 1980; 71: 159-163
- 22 Wijeratne C, Draper B. Reformulation of current recommendations for target serum lithium concentration according to clinical indication, age and physical comorbidity. Aust NZ J Psychiatry 2011; 45: 1026-1032
- 23 Levey AS, Bosch JP, Lewis JB. et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461-470
- 24 Cohen J. Statistical Power Analysis for the Behavioral Sciences. Second ed Hillsdale, NJ: Lawrence Erlbaum Associates; 1988
- 25 Sproule BA, Hardy BG, Shulman KI. Differential pharmacokinetics of lithium in elderly patients. Drugs & Aging 2000; 16: 165-177
- 26 Shi S, Klotz U. Age-related changes in pharmacokinetics. Current Drug Metabolis 2011; 12: 601-610
- 27 Bredella MA. Sex differences in body composition. In: Mauvais-Jarvis F, ed. Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity. Springer; 2017: 9-27
- 28 Jefferson JW, Kalin NH. Serum lithium levels and long-term diuretic use. Jama 1979; 241: 1134-1136
- 29 Finley PR, O'Brien JG, Coleman RW. Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction. J Clin Psychopharmacol 1996; 16: 68-71
- 30 Blanche P, Raynaud E, Kerob D. et al. Lithium intoxication in an elderly patient after combined treatment with losartan. Eur J Clin Pharmacol 1997; 52: 501
- 31 Leung M, Remick RA. Potential drug interaction between lithium and valsartan. J Clin Psychopharmacol 2000; 20: 392-393
- 32 Ma CC, Shiah IS, Chang SW. et al. Telmisartan-induced lithium intoxication in a patient with schizoaffective disorder. Psychiatry Clin Neurosci 2012; 66: 165-166
- 33 Ragheb M. The clinical significance of lithium-nonsteroidal anti-inflammatory drug interactions. J Clin Psychopharmacol 1990; 10: 350-354
- 34 Camin RM, Cols M, Chevarria JL. et al. Acute kidney injury secondary to a combination of renin-angiotensin system inhibitors, diuretics and NSAIDS: “The Triple Whammy. Nefrologia 2015; 35: 197-206
- 35 Gong R, Wang P, Dworkin L. What we need to know about the effect of lithium on the kidney. Am J Physiol Renal Physiol 2016; 311: F1168-F1171
- 36 Malhi GS, Berk M. Is the safety of lithium no longer in the balance?. Lancet 2012; 379: 690-692
- 37 Nielsen RE, Kessing LV, Nolen WA. et al. Lithium and renal impairment: a review on a still hot topic. Pharmacopsychiatry 2018; 51: 200-205
- 38 Bisogni V, Rossitto G, Reghin F. et al. Antihypertensive therapy in patients on chronic lithium treatment for bipolar disorders. J Hypertens 2016; 34: 20-28
- 39 Prieto-Garcia L, Pericacho M, Sancho-Martinez SM. et al. Mechanisms of triple whammy acute kidney injury. Pharmacol Ther 2016; 167: 132-145
- 40 Whelton A, Hamilton CW. Nonsteroidal anti-inflammatory drugs: Effects on kidney function. J Clin Pharmacol 1991; 31: 588-598
- 41 Fijorek K, Puskulluoglu M, Tomaszewska D. et al. Serum potassium, sodium and calcium levels in healthy individuals – literature review and data analysis. Folia Med Cracov 2014; 54: 53-70