Skip to main content
SpringerLink
Log in

Drug Interactions with Lithium

A Guide for Clinicians

  • Disease Management
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Long term lithium treatment will often be combined with other pharmacological treatments, due to the need to treat insomnia or anxiety, breakthrough episodes, co-existing psychiatric (schizoaffective psychoses) or non-psychiatric (particularly in elderly patients) disorders, or self-medication with over-the-counter preparations. Adverse drug reactions resulting from such combined medication are primarily pharmacokinetic, and much more rarely pharmacodynamic, in nature. The main risk in such interactions is an increase in the plasma lithium concentration due to decreased renal lithium clearance.

A serotonin (5-hydroxytryptamine; 5-HT) syndrome resulting from the combination of lithium and serotonergic antidepressants such as selective serotonin reuptake inhibitors, or neurotoxic reactions resulting most often from high doses of lithium and antipsychotics, may be observed. In addition, increases in the intra-red blood cell concentration of lithium may occur with simultaneous anti-psychotic administration. Marked electroencephalogram changes and tonic-clonic seizures have been observed with the combination of lithium and clozapine.

Combined administration of lithium and anticonvulsants is generally considered to be well tolerated. Potential pharmacokinetic interactions with anticonvulsants appear to be of minor importance.

One of the most significant interactions with lithium is the decrease in renal lithium clearance which occurs with most nonsteroidal anti-inflammatory drugs, including ketorolac. Conversely, aspirin (acetylsalicylic acid) and sulindac do not increase steady-state plasma lithium concentrations.

Another well known interaction is the clinically relevant reduction of renal lithium clearance by combined administration of diuretics. Special caution should be exercised when prescribing thiazides for long term use in patients receiving lithium medication. Potassium-sparing compounds, excluding furosemide (frusemide), can also increase plasma lithium concentrations. Risk of lithium intoxication is increased by simultaneous administration of ACE inhibitors. Finally, a case of a patient with lithium intoxication caused by combined medication with the angiotensin II receptor antagonist losartan potassium (losartan) has been reported.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Prien RF, Klett CJ, Caffey EM. Polypharmacy in the psychiatric treatment of elderly hospitalized patients: a survey of 12 veterans administration hospitals. Dis Nerv Syst 1976; 37: 333–6

    Google Scholar 

  2. Schüssler G, Müller-Oerlinghausen B. Polypharmacy in psychiatric practice. Compr Psychiatry 1984; 25: 566–74

    Article  PubMed  Google Scholar 

  3. Kanowski S, Müller-Oerlinghausen B, 1973. Need for additional medication in outpatients during 3 years of prophylactic lithium treatment. In: Ban TA, Boissier JR, Gessa GJ, et al., editors. Proceedings of the VIIIth CINP Congress, Copenhagen, 1972. Amsterdam: North Holland Publishing Company, 1973: 105–8

    Google Scholar 

  4. Degkwitz R, Consbruch U, Haddenbrock S, et al. Therapeutische Risiken bei der Langzeitbehandlung mit Neuroleptika und Lithium. Nervenarzt 1976; 47: 81–7

    PubMed  CAS  Google Scholar 

  5. Bech P, Vendsborg PB, Rafaelsen OJ. Lithium maintenance treatment of manic-melancholic patients: its role in the daily routine. Acta Psychiatr Scand 1976; 53: 70–81

    Article  PubMed  CAS  Google Scholar 

  6. Müller-Oerlinghausen B. 10 Jahre Lithium-Katamnese. Nervenarzt 1977; 48: 483–93

    PubMed  Google Scholar 

  7. Vestergaard P, Amdisen A, Hansen HE, et al. Lithium treatment and kidney function. Acta Psychiatr Scand 1979; 60: 504–20

    Article  PubMed  CAS  Google Scholar 

  8. Bauer M, Linden M, Schaaf B, et al. Adverse events and tolerability of the combination of fluoxetine/lithium compared with fluoxetine. J Clin Psychopharmacology 1996; 16: 130–4

    Article  CAS  Google Scholar 

  9. Jefferson JW, Greist JH, Baudhuin M. Lithium: interactions with other drugs. J Clin Psychopharmacol 1981; 1: 124–34

    Article  PubMed  CAS  Google Scholar 

  10. Jefferson JW, Greist JH, Acherman DL. Lithium encyclopedia for clinical practice. 2nd ed. Washington, DC: American Psychiatric Press, 1987

    Google Scholar 

  11. Schou M. Clinically significant lithium interactions. Review and recommendations. Eur J Psychiatry 1987; 1: 42–7

    Google Scholar 

  12. Johnson FN, editor. Lithium therapy monographs. Vol. 1. Lithium combination treatment. Basel, Switzerland: Karger, 1987

    Google Scholar 

  13. Griffin JP, D’Arcy PF, Speirs CJ. A manual of adverse drug interactions: lithium salts. London, Boston, Durban, Singapore: Wright, 1988: 373–8

    Google Scholar 

  14. DasGupta K, Jefferson JW. The use of lithium in the medically ill. Gen Hosp Psychiatry 1990; 12: 83–97

    Article  PubMed  CAS  Google Scholar 

  15. Foster JR. Use of lithium in elderly psychiatric patients: a review of the literature. Lithium 1992; 3: 77–93

    Google Scholar 

  16. Finley PR, Warner MD, Peabody CA. Clinical relevance of drug interactions with lithium. Clin Pharmacokinet 1995; 29:172–91

    Article  PubMed  CAS  Google Scholar 

  17. Harvey NS, Merriman S. Review of clinically important drug interactions with lithium. Drug Saf 1994; 10: 455–63

    Article  PubMed  CAS  Google Scholar 

  18. Freeman MP, Stoll AL. Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry 1998; 155: 12–21

    PubMed  CAS  Google Scholar 

  19. Jefferson JW, Ayd FJ. Combining lithium and antidepressants. J Clin Psychopharmacol 1983; 3: 303–7

    Article  PubMed  CAS  Google Scholar 

  20. Bauer M, Zaninelle R, Müller-Oerlinghausen B, et al. Paroxetine and amitriptyline augmentation of lithium in the treatment of major depression: a double-blind study. J Clin Psychopharmacol. In press

  21. Gabriel E, Karobath M, Lenz G. Extrapyramidale Symptomatik bei Kombination der Lithium-Langzeittherapie mit Nortriptylin. Nervenarzt 1976; 47: 46–8

    PubMed  CAS  Google Scholar 

  22. Solomon JG. Seizures during lithium-amitriptyline. Postgrad Med 1979; 66: 145–8

    PubMed  CAS  Google Scholar 

  23. Albrecht J, Müller-Oerlinghausen B. EKG-Veränderungen unter akuter und chronischer Applikation von Lithium. Pharmacopsychiatry 1977; 10: 325–33

    Article  CAS  Google Scholar 

  24. Müller-Oerlinghausen B. Lithium long-term treatment — does it act via serotonin? Pharmacopsychiatry 1985; 18: 214–7

    Article  PubMed  Google Scholar 

  25. Bauer M. The combined use of lithium and SSRIs. J Serotonin Res 1995; 2: 69–76

    CAS  Google Scholar 

  26. Ohman R, Spigset O. Serotonin syndrome induced by fluvoxamine-lithium interaction. Pharmacopsychiatry 1993; 26: 263–4

    Article  PubMed  CAS  Google Scholar 

  27. Mekler G, Woggon B. A case of serotonin syndrome caused by venlafaxine and lithium. Pharmacopsychiatry 1997; 30: 272–3

    Article  PubMed  CAS  Google Scholar 

  28. Baumann P, Nil R, Souche A, et al. A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin Psychopharmacol 1996; 16: 307–14

    Article  PubMed  CAS  Google Scholar 

  29. Breuel H-P, Müller-Oerlinghausen B, Nickelsen T, et al. Pharmacokinetic interaction between lithium and fluoxetine after single and repeated administration in young healthy volunteers. Int J Clin Pharmacol Ther 1995; 33: 415–9

    PubMed  CAS  Google Scholar 

  30. Cohen WH, Cohen NH. Lithium carbonate, haloperidol and irreversible brain damage. JAMA 1974; 230: 1283–7

    Article  PubMed  CAS  Google Scholar 

  31. Prakash RS, Kelwala S, Ban TA. Neurotoxicity with combined administration of lithium and a neuroleptic. Compr Psychiatry 1982; 23: 567–71

    Article  PubMed  CAS  Google Scholar 

  32. Normann C, Brandt C, Berger M, et al. Delirium and persistent dyskinesia induced by a lithium-neuroleptic interaction. Pharmacopsychiatry 1998; 31: 201–4

    Article  PubMed  CAS  Google Scholar 

  33. Nemes ZC, Volavka J, Lajtha A, et al. Concurrent lithium administration results in higher haloperidol levels in brain and plasma of Guinea pigs. Psychiatry Res 1987; 20: 313–6

    Article  PubMed  CAS  Google Scholar 

  34. Tupin JP, Schuller AB. Lithium and haloperidol incompatibility reviewed. Psychiat J Univ Ottawa 1978; III: 245–51

    Google Scholar 

  35. Frankel MH, Spring GK. Questions about combined lithium and haloperidol treatment. Am J Psychiatry 1982; 139: 537–8

    Google Scholar 

  36. Baastrup PC, Hollnagel P, Sorensen R, et al. Adverse reactions in treatment with lithium carbonate and haloperidol. JAMA 1976; 236: 2645–6

    Article  PubMed  CAS  Google Scholar 

  37. Goldney RD, Spence ND. Safety of the combination of lithium and neuroleptic drugs. Am J Psychiatry 1986; 143: 882–4

    PubMed  CAS  Google Scholar 

  38. Goldman SA. FDA MedWatch Report: lithium and neuroleptics in combination: the spectrum of neurotoxicity. Psychopharmacol Bull 1996; 32: 299–310

    PubMed  CAS  Google Scholar 

  39. Goldman SA. Lithium and neuroleptics in combination: is there enhancement of neurotoxicity leading to permanent sequelae? J Clin Pharmacol 1996; 36: 951–62

    PubMed  CAS  Google Scholar 

  40. Pandey GN, Goel K, Davis JM. Effects of neuroleptics drugs on lithium uptake by the human erythrocytes. Clin Pharmacol Ther 1979; 26: 96–102

    PubMed  CAS  Google Scholar 

  41. Ghadirian AM, Nair NP, Schwartz G. Effect of lithium and neuroleptic combination on lithium transport, blood pressure, and weight in bipolar patients. Biol Psychol 1989; 26: 139–44

    Article  CAS  Google Scholar 

  42. Bailine SH, Doft M. Neurotoxicity induced by combined lithium-thioridazine treatment. Biol Psychol 1986; 21: 834–7

    Article  CAS  Google Scholar 

  43. Spring GK. Neurotoxicity with combined use of lithium and thioridazine. J Clin Psychiatry 1979; 40: 135–8

    PubMed  CAS  Google Scholar 

  44. Helmchen H, Kanowski S. EEG-Veränderungen unter Lithium-Therapie. Nervenarzt 1971; 42: 144–8

    PubMed  CAS  Google Scholar 

  45. Garcia G, Crismon ML, Dorson PG. Seizures in two patients after the addition of lithium to a clozapine regimen. J Clin Psychopharmacol 1994; 14: 426–7

    PubMed  CAS  Google Scholar 

  46. Bucht G, Wahlin A. Impairment of renal concentrating capacity by lithium [letter]. Lancet 1978; I: 789

    Google Scholar 

  47. Waller DG, Edwards JG, Polak A. Neuroleptics, lithium and renal function. Br J Psychiatry 1985; 146: 510–4

    Article  PubMed  CAS  Google Scholar 

  48. Linnoila M, Saario I, Maki M. Effect of treatment with diazepam or lithium and alcohol on psychomotoric skills related to driving. Eur J Clin Pharmacol 1974; 7: 337–42

    Article  PubMed  CAS  Google Scholar 

  49. Naylor GJ, McHarg A. Profound hypothermia on combined lithium carbonate and diazepam treatment [letter]. BMJ 1975; 2:22

    Article  Google Scholar 

  50. Koczerginski D, Kennedy SH, Swinson RP. Clonazepam and lithium — a toxic combination in the treatment of mania?. Int Clin Psychopharmacol 1989; 4: 195–9

    Article  PubMed  CAS  Google Scholar 

  51. Mester R, Toren P, Mizrachi I, et al. Caffeine withdrawal increases lithium blood levels. Biol Psychol 1995; 37: 348–50

    Article  CAS  Google Scholar 

  52. Chaudry RP, Waters BGH. Lithium and carbamazepine interaction. J Clin Psychiatry 1983; 44: 30–1

    Google Scholar 

  53. Kramlinger KG, Post RM. Addition of lithium carbonate to carbamazepine — hematological and thyroid effects. Am J Psychiatry 1990; 5: 615–20

    Google Scholar 

  54. Keith G, Kramlinger MD, Robert M, et al. The addition of lithium to carbamazepine. Arch Gen Psychiatry 1989; 46: 794–800

    Article  Google Scholar 

  55. Rybakowski J, Lehman W, Kanarkowski R, et al. Possible pharmacokinetic interaction of lithium and carbamazepine. Lithium 1991; 2: 183–4

    CAS  Google Scholar 

  56. Vargas C, Tannhauser M, Tannhauser SL, et al. Lithium and valproate combined administration: acute behavioural effects and drug plasma levels. Pharmacol Toxicol 1996; 79: 87–91

    Article  PubMed  CAS  Google Scholar 

  57. Cold JA, ZumBrunnen TL, Simpson MA, et al. Increased lithium serum and red blood cell concentrations during ketorolac coadministration. J Clin Psychopharmacol 1998; 18: 33–7

    Article  PubMed  CAS  Google Scholar 

  58. Reimann IW, Diener U, Frölich JC. Indomethacin but not aspirin increases plasma lithium ion levels. Arch Gen Psychiatry 1983; 40: 283–6

    Article  PubMed  CAS  Google Scholar 

  59. Ragheb MA, Powell AL. Failure of sulindac to increase serum lithium levels. J Clin Psychiatry 1986; 47: 33–4

    PubMed  CAS  Google Scholar 

  60. Havdala HS, Borison RL, Diamond BI. Potential hazards and applications of lithium in anesthesiology. Anesthesiology 1979; 50: 534–7

    Article  PubMed  CAS  Google Scholar 

  61. Schou M, Hippius H. Lithium-prophylaxe und operative Eingriffe. Münch Med Wochenschr 1983; 125: 705–6

    CAS  Google Scholar 

  62. Hill GE, Wong KC, Hodges MR. Lithium carbonate and neuromuscular blocking agents. Anesthesiology 1977; 46: 122–6

    Article  PubMed  CAS  Google Scholar 

  63. Saarnivaara L, Ertama P. Interactions of lithium/rubidium and six muscle relaxants. A study on the rat phrenic nerve-hemidiaphragm preparation. Anaesthesist 1992; 41: 760–4

    PubMed  CAS  Google Scholar 

  64. Lippmann SB, El-Mallakh R. Can electroconvulsive therapy be given during lithium treatment? Lithium 1994; 5: 205–9

    Google Scholar 

  65. Jha AK, Stein GS, Fenwick P. Negative interaction between lithium and electroconvulsive therapy: a case-control study. Br J Psychiatry 1996; 168: 241–3

    Article  PubMed  CAS  Google Scholar 

  66. Jephcott G, Kerry RH. An anaesthetic risk. Br J Anaesth 1974; 46: 389–90

    Article  PubMed  CAS  Google Scholar 

  67. Lerer B. Studies on the role of brain cholinergic systems in the therapeutical mechanism and adverse effects of ECT and lithium. Biol Psychiatry 1985; 20: 20–40

    Article  PubMed  CAS  Google Scholar 

  68. Kerry RJ, Ludlow JM, Owen G. Diuretics are dangerous with lithium. BMJ 1980; 281: 371

    Article  PubMed  CAS  Google Scholar 

  69. Grounds AD, Walker R. Deterioration in renal function in patients taking lithium an a diuretic. Med J Aust 1992; 165: 884

    Google Scholar 

  70. Saffer D, Coppen A. Frusemide: a safe diuretic during lithium therapy? J Affect Dis 1983; 5: 289–92

    Article  PubMed  CAS  Google Scholar 

  71. Perry PJ, Calloway RA, Cook BL, et al. Theophylline-precipitated alterations of lithium clearance. Acta Psychiat Scand 1984; 69: 528–37

    Article  PubMed  CAS  Google Scholar 

  72. Shalmi M, Rasmusen H, Amtorp O, et al. Effect of chronic oral furosemide administration on the 24-hour cycle of lithium clearance and electrolyte excretion in humans. Eur J Clin Pharmacol 1990; 3: 275–80

    Article  Google Scholar 

  73. Weinrauch LA, Belok S, D’Elia JA. Decreased serum lithium during verapamil therapy. Am Heart J 1984; 108: 1378–9

    Article  PubMed  CAS  Google Scholar 

  74. Byrd GJ. Lithium carbonate and methyldopa: apparent interaction in man. Clin Toxicol 1977; 11: 1–4

    Article  PubMed  CAS  Google Scholar 

  75. Yassa R. Lithium-methyldopa interaction. Case report. Can Med Assoc J 1986; 134: 141–2

    CAS  Google Scholar 

  76. 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

    Article  PubMed  CAS  Google Scholar 

  77. 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: 82–7

    Article  PubMed  CAS  Google Scholar 

  78. Barthelmebs M, Alt-Tebacher M, Madonna O, et al. Absence of a losartan interaction with renal lithium excretion in the rat. Br J Pharmacol 1995; 4: 2166–9

    Article  Google Scholar 

  79. Burnier M, Rutschmann B, Nussberger J, et al. Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects. Hypertension 1993; 22: 339–47

    Article  PubMed  CAS  Google Scholar 

  80. Blanche P, Raynand E, Kerob D, et al. Lithium intoxication in an elderly patient after combined treatment with losartan [letter]. Eur J Clin Pharmacol 1997; 52: 501

    Article  PubMed  CAS  Google Scholar 

  81. Vincent F, Bensousan TA, Levy V, et al. Lithium concentrations during cisplatin-based chemotherapy: evidence for renal interaction [letter; comment]. Cancer Chemother Pharmacol 1995; 6: 533–4

    Article  Google Scholar 

  82. Hu M, Wu H, Chao C. Assisting effects of lithium on hypoglycemic treatment in patients with diabetes. Biological Trace Elem Res 1997; 60: 131–7

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, Freie Universität Berlin, Research Group Clinical Psychopharmacology, and Lithium Clinic Berlin, Eschenallee 3, D-14050, Berlin, Germany

    Bruno Müller-Oerlinghausen

Authors
  1. Bruno Müller-Oerlinghausen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruno Müller-Oerlinghausen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Müller-Oerlinghausen, B. Drug Interactions with Lithium. Mol Diag Ther 11, 41–48 (1999). https://doi.org/10.2165/00023210-199911010-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00023210-199911010-00004

Keywords

Search

Navigation