Abstract
The pharmacotherapeutic use of lithium in the elderly as acute and maintenance therapy in bipolar disorder and augmentation therapy for major depression is well documented. Differences in the response to lithium are explained, in part, by the effect of age-related physiological changes, comorbid conditions, and concurrent medications on the pharmacokinetics of lithium in the elderly. The pharmacokinetic profile of lithium has been studied for many years, primarily in younger adult populations. Lithium pharmacokinetics may be influenced by a number of factors including age. It was first noted several years ago that elderly individuals required lower doses of lithium to achieve serum concentrations similar to those observed in younger adults. This is due to the combination of a reduced volume of distribution and reduced renal clearance. The composition of the human body changes with aging producing an increase in body fat, a decrease in fat-free mass and a decrease in total body water. Lithium clearance decreases as the glomerular filtration rate decreases with increasing age.
The effects of other medical conditions in the elderly on the pharmacokinetics of lithium are less well delineated. Reduced lithium clearance is expected in patients with hypertension, congestive heart failure or renal dysfunction. Larger lithium maintenance doses are required in obese compared with non-obese patients.
The most clinically significant pharmacokinetic drug interactions associated with lithium involve drugs which are commonly used in the elderly. Thiazide diuretics, ACE inhibitors, and nonsteroidal anti-inflammatory drugs can increase serum lithium concentrations.
The tolerability of lithium is lower in the elderly. Neurotoxicity clearly occurs in the elderly at concentrations considered ‘therapeutic’ in general adult populations. There are no placebo-controlled randomised trials of lithium in old age and recommendations for clinical use are based on extrapolations from pharmacokinetic studies, anecdotal reports from mixed age populations and clinical experience in old age psychiatry. Serum concentrations of lithium need to be markedly reduced in the elderly population and particularly so in the very old and frail elderly.
Similar content being viewed by others
References
Young RC, Klennan GL. Mania in late-life: focus on age at onset. Am J Psychiatry 1992; 149: 867–76
Koenig HG, Blazer DG. Epidemiology of geriatric affective disorders. Clin Geriatr Med 1992; 8(2): 235–51
Kramer M, German PS, Anthony JC, et al. Patterns of mental disorders among the elderly residents of eastern Baltimore. J Am Geriatr Soc 1985; 33(4): 236–45
Yassa R, Nair V, Natase C, et al. Prevalence of bipolar disorder in a psychogeriatric population. J Affect Disord 1988; 14(3): 197–201
Post F. Affective disorders in old age. In: Paykel ES, editors. Handbook of affective disorders. New York: Guilford Press, 1982: 393–402
Loranger AW, Levine PM. Age at onset of bipolar affective illness. Arch Gen Psychiatry 1978; 35: 1345–8
Ghadirian AM, Lalinec-Michaud M, Engelsmann F. Early and late onset affective disorders: clinical and family characteristics. Ann RICP 1986; 19: 53–7
Summers WK. Mania with onset in the eighth decade: two cases and a review. J Clin Psychiatry 1983; 44: 141–3
Snowdon J. A retrospective case-note study of bipolar disorder in old age. Br J Psychiatry 1991; 158: 485–90
Young RC. Bipolar mood disorders in the elderly. Psychiatr Clin North Am 1997; 2(1): 121–36
Eastham JH, Jeste DV, Young RC. Assessment and treatment of bipolar disorder in the elderly. Drugs Aging 1998; 12(3): 205–24
McDonald W, Nemeroff CS. The diagnosis and treatment of mania in the elderly. Bull Menninger Clin 1996; 60(2): 174–96
Hays JC, Kirshnan KR, George LK, et al. Age of first onset of bipolar disorder: demographic, family history and psychosocial correlates. Depress Anxiety 1998; 7(2): 76–82
Shulman KI, Tohen M, Satlin A, et al. Mania compared with unipolar depression in old age. Am J Psychiatry 1992; 149(3): 341–5
Dhingra U, Rabins P. Mania in the elderly: a 5–7 year follow-up. J Am Geriatr Soc 1991; 39: 581–3
Tohen M, Shulman KI, Satlin A. First-episode mania in late life. Am J Psychiatry 1994; 151(1): 130–2
O’Connell JR, Mayo JA, Flatow L, et al. Outcome of bipolar disorder on long-term treatment with lithium. Br J Psychiatry 1991; 159: 123–9
Van de Velde CD. Effectiveness of lithium carbonate in the treatment of manic-depressive illness. Am J Psychiatry 1970; 127: 345–51
Weissman MM, Leaf PJ, Tischler GL, et al. Affective disorders in five United States communities. Psychol Med 1988; 18(1): 141–53
Weissman MM, Bruce ML, Leaf PJ, et al. Affective disorders. In: Robins LN, Reiger DA, editors. Psychiatric disorders in America: the epidemiologic catchment area study. New York: Free Press, 1991:53–83
Lebowitz BD, Pearson JL, Schneider LS, et al. Diagnosis and treatment of depression in late life: consensus statement update. JAMA 1997; 278(14): 1186–90
Blazer DG. Depression in the elderly: myths and misconceptions. Psychiatr Clin North Am 1997; 20(1): 111–8
Krishnan KRR, Gadde KM. The pathophysiologic basis for late-life depression: imaging studies of the aging brain. Am J Geriatr Psychiatry 1996; 4Suppl. 1: S22–S33
Maier W, Lichtermann D, Minges J, et al. Unipolar depression in the aged: determinants of familial aggregation. J Affect Disord 1991; 23(2): 53–61
Gurland B. The impact of depression on quality of life of the elderly. Clin Geriatr Med 1992; 8(2): 377–86
Philibert RA, Richard SL, Lynch CF, et al. The effect of gender and age at onset of depression on mortality. J Clin Psychiatry 1997; 58(8): 355–60
Mittmann N, Herrmann N, Einarson TR, et al.. The efficacy, safety and tolerability of antidepressants in late life depression: a meta-analysis. J Affect Disord 1997; 46: 191–217
Frank E, Karp JF, Rush AJ. Efficacy of treatments for major depression. Psychopharmacol Bull 1993; 29: 457–75
Austin MPV, Souza FGM, Goodwin GM. Lithium augmentation in antidepressant-resistant patients: a quantitative analysis. Br J Psychiatry 1991; 159: 510–4
Lieff S, Herrmann N. Combined drug therapy for an elderly depressed patient. Am J Psychiatry 1988; 145: 1034–5
Gash AJ, Chhabra S, Eccleston D. Lithium augmentation in a case of renal impairment: risk vs benefit. J Affect Disord 1995; 35: 51–3
Camprubi ME, Puri BK. The treatment of refractory depression using paroxetine with lithium augmentation. Prog Neuro-psychopharmacol Biol Psychiatry 1995; 19: 515–7
Lafferman J, Soloman K, Ruskin P. Lithium augmentation for treatment-resistant depression in the elderly. Geriatr Psychiatry Neurol 1988; 1:49–52
Kushnir SL. Lithium-antidepressant combinations in the treatment of depressed, physically ill geriatric patients. Am J Psychiatry 1986; 143: 378–9
van Marwijk HWJ, Bekker FM, Nolen WA, et al. Lithium augmentation in geriatric depression. J Affect Disord 1990; 20: 217–23
Parker K, Herrmann N, Shulman KI, et al. Risk/benefit analysis of lithium (Li) augmentation of antidepressant therapy in a geriatric psychiatry outpatient clinic [abstract]. Clin Pharmacol Ther 1993; 53(2): 191
Jensen HV, Olafsson K, Lykke-Olesen L, et al. Combination nortriptyline and lithium in elderly depressed patients: a double-blind, placebo-controlled study. Lithium 1992; 3: 259–62
Zimmer B, Rosen J, Thornston JE, et al. Adjunctive lithium carbonate in nortriptyline-resistant elderly depressed patients. J Clin Psychopharmacol 1991; 11: 254–6
Flint LAJ, Rifat SL. A prospective study of lithium agumentation in antidepressant-resistant geriatric depression. J Clin Psychopharmacol 1994; 14: 353–6
Austin LS, Arana GW, Melvin JA. Toxicity resulting from lithium augmentation of antidepressant treatment in elderly patients. J Clin Psychiatry 1990; 51(8): 344–5
Amdisen A, Schou M. Biochemistry of depression. Lancet 1967; I: 507
Carson SW. Lithium. In: Evans WE, Schentag JJ, Jusko WJ, editors. Applied pharmacokinetics: principles of therapeutic drug monitoring. 3rd ed. Vancouver (WA): Applied Therapeutics, Inc., 1992: 34–1–34–26
Nielsen-Kudsk F, Amdisen A. Analysis of the pharmacokinetics of lithium in man. Eur J Clin Pharmacol 1979; 16: 271–7
Amdisen A. Serum level monitoring and clinical pharmacokinetics of lithium. Clin Pharmacokinet 1977; 2: 73–92
Lehmann K, Merten K. Die elimination von lithium in abhangigkeit vom lebensalter bei gesunden und nieren-insuffizienten. Int J Clin Pharmacol 1974; 10(4): 292–8
Perry PJ, Dunner FJ, Hahn RL, et al. Lithium kinetics in single daily dosing. Acta Psychiatr Scand 1981; 64: 281–94
Platman SR, Fieve RR. Biochemical aspects of lithium in affective disorders. Arch Gen Psychiatry 1968; 19: 659–63
Amdisen A, Gottfries L, Jacobsson L, et al. Grave lithium intoxication with fatal outcome. Acta Psychiatr Scand 1974; Suppl. 255: 25–33
Fyro B, Petterson U, Sedvall G. Pharmacokinetics of lithium in manic-depressive patients. Acta Psychiatr Scand 1973; 49: 237–47
Yukawa E, Nomiyama N, Higuchi S, et al. Lithium population pharmacokinetics from routine clinical data: role of patient characteristics for estimating dosing regimens. Ther Drug Monit 1993; 15: 75–82
Taright N, Mentre F, Mallet A, et al. Nonparametric estimation of population characteristics of the kinetics of lithium from observational and experimental data: individualization of chronic dosign regimen using a new Bayesian approach. Ther Drug Monit 1994; 16: 258–69
Jermain DM, Crismon ML, Martin ES. Population pharmacokinetics of lithium. Clin Pharm 1991; 10: 376–81
Goodnick PJ, Fieve RR, Meltzer HL, et al. Lithium elimination half-life and duration of therapy. Clin Pharmacol Ther 1981; 29(1): 47–50
Reiss RA, Haas CE, Karki SD, et al. Lithium pharmackinetics in the obese. Clin Pharmacol Ther 1994; 55: 392–8
Lauritsen BJ, Mellerup ET, Plenge P, et al. Serum lithium concentrations around the clock with different treatment regimens and the diurnal variation of the renal lithium clearance. Acta Psychiatr Scand 1981; 64: 314–9
Hewick DS, Newbury P, Hopwood S, et al. Age as a factor affecting lithium therapy. J Clin Pharmacol 1977; 4(2): 201–5
Slater V, Milanes F, Talcott V, et al. Influence of age on lithium therapy. South Med J 1984; 77(2): 153–4,158
Vestergaard P, Schou M. The effect of age on lithium dosage requirements. Pharmacopsychiatry 1984; 17: 199–201
Greil W, Stoltzenburg MC, Mairhofer ML, et al. Lithium dos-age in the elderly: a study with matched age groups. J Affect Disord 1985; 9: 1–4
Coppen A, Abou-Saleh MT. Lithium therapy: from clinical trials to practical management. Acta Psychiatr Scand 1988; 78(6): 754–62
Bender AD. Effect of age on intestinal absorption: implications for drug absorption in the elderly. J Am Geriatr Soc 1968; 16(12): 1331–9
Geokas MC, Haverback BJ. The aging gastrointestinal tract. Am J Surgery 1969; 117: 881–92
Greenblatt DJ, Sellers EM, Shader RI. Drug disposition in old age. N Engl J Med 1982; 306(18): 1081–8
Turner N, Scarpace PJ, Lowenthal DT. Geriatric pharmacology: basic and clinical considerations. Annu Rev Pharmacol Toxicol 1992; 32: 271–302
Novak LP. Aging, total body potassium, fat-free mass, and cell mass in males and females between ages 18 and 85 years. J Gerontology 1972; 27(4): 438–43
Barlett HL, Puhl SM, Hodgson JL, et al. Fat-free mass in relation to stature: ratios of fat-free mass to height in children, adults, and elderly subjects. Am J Clin Nutr 1991; 53: 1112–6
Borkan GA, Hults DE, Gerzof SG, et al. Age changes in body composition revealed by computed tomography. J Gerontology 1983; 38(6): 673–7
Stachenfeld NS, DiPietro L, Nadel ER, et al. Mechanism of attentuated thirst in aging: role of central volume receptors. Am J Physiology 1997; 272: R148–R157
Phillips PA, Rolls BJ, Ledingham JGG, et al. Reduced thirst after water deprivation in healthy elderly men. N Engl J Med 1984; 311: 753–9
Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985; 33(4): 278–85
Rowe JW, Andres R, Tobin JD, et al. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontology 1976; 31(2): 155–63
Cockcroft D, Gault M. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41
Chapron DJ, Cameron IR, White LB, et al. Observations on lithium disposition in the elderly. J Am Geriatr Soc 1982; 30(10): 651–5
Hardy BG, Shulman KI, MacKenzie SP, et al. Pharmacokinetics of lithium in the elderly. J Clin Psychopharmacol 1987; 7: 153–8
Turnheim K. Drug dosage in the elderly: is it rational? Drugs Aging 1998; 13(5): 357–79
Le Couteur DG, McLean AJ. The aging liver: drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet 1998; 34(5): 359–73
Shephard AMM. Physiological changes with aging: relevance to drug study design. In: Cutler NR, Narang PK, editors. Drug studies in the elderly: methodological concerns. New York: Plenum Medical Book Company, 1986; 49–67
Fliser D, Franek E, Joest M, et al. Renal function in the elderly: impact of hypertension and cardiac function. Kidney Int 1997; 51(4): 1196–204
Tueth MJ, Murphy TK, Evans DL. Special considerations: use of lithium in children, adolescents, and elderly populations. J Clin Psychiatry 1998; 59Suppl. 6: 66–73
Liptzin B. Treatment of mania. In: Salzman C, editor. Clinical geriatric psychopharmacology. 2nd ed. Baltimore (MD): Williams & Wilkins, 1992: 175–88
Jenike MA. Geriatric psychiatry and psychopharmacology: a clinical approach. Chicago (IL): Year Book Medical Publishers, 1989
Abernethy DR, Greenblatt DJ. Drug dispostion in obese humans: an update. Clin Pharmacokinet 1986; 11: 199–213
Karki SD, Carson SW, Gagnon A. Evaluation of total body water and disposition of lithium in elderly patients. Lithium 1992; 3: 29–33
Clericetti N, Beretta-Piccoli C. Lithium clearance in patients with chronic renal disease. Clin Nephrol 1991; 36(6): 281–9
Pandita-Gunawardena R, Donaldson D. Decreasing requirement for lithium carbonate therapy in bipolar affective disorders (hypomanic type) following the onset of chronic renal insufficiency. J R Soc Health 1998; 118(1): 35–9
Finley PR, Warner MD, Peabody CA. Clinical relevance of drug interactions with lithium. Clin Pharmacokinet 1995; 29(3): 172–91
Miller F, Menninger J. Lithium-neuroleptic neurotoxicity if dose dependent. J Clin Psychopharmacol 1987; 7: 89–91
Miller F, Menninger J, Whitcup SM. Lithium-neuroleptic neurotoxicity in the elderly bipolar patient. J Clin Psychopharmacol 1986; 6(3): 176–8
Binder EF, Cayabyab L, Ritchie DJ, et al. Diltiazem-induced psychosis and a possible diltiazem-lithium interaction. Arch Intern Med 1991; 151:373–4
Mekler G, Woggon B. A case of serotonin syndrome caused by venlafaxine and lithium. Pharmacopsychiatry 1997; 30:272–3
Bauer M, Linden M, Schaaf B, et al. Adverse events and toler-ability of the combination of fluoxetine/lithium compared with fluoxetine. J Clin Psychopharmacol 1996; 16(2): 130–4
Himmelhoch JM, Poust RI, Mallinger AG, et al. Adjustment of lithium dose during lithium-chlorothiazide therapy. Clin Pharmacol Ther 1977; 22: 225–7
Kerry RJ, Ludlow JM, Owen G. Diuretics are dangerous with lithium. BMJ 1980; 281: 371
Macfie AC. Lithium poisoning precipitated by diuretics [letter]. BMJ 1975; 1:516
Solomon JG. Lithium toxicity precipitated by a diuretic. Psychosomatics 1980; 21: 425–9
Saffer D, Coppen A. Frusemide: a safe diuretic during lithium therapy? J Affect Disord 1983; 5: 289–92
Jefferson JW, Kalin NH. Serum lithium levels and long-term diuretic use. JAMA 1979; 241: 1134–6
Crabtree BL, Mack JE, Johnson CD, et al. Comparison of the effects of hydrochlorothiazide and furosemide on lithium disposition. Am J Psychiatry 1991; 148(8): 1060–3
Baer L, Platman SR, Kassir S, et al. Mechanisms of renal lithium handling and their relationship to mineralocorticoids: a dissociation between sodium and lithium ions. J Psychiatr Res 1971; 8: 91–105
Kosten TR, Forrest JN. Treatment of severe lithium-induced polyuria with amiloride. Am J Psychiatry 1986; 143(12): 1563–8
Batlle DC, von Riotte AB, Gaviria M, et al. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med 1985; 312: 408–14
Perry PJ, Calloway RA, Cook BL, et al. Theophylline precipitated alterations of lithium clearance. Acta Psychiatr Scand 1984; 69: 528–37
Mester R, Toren P, Mizrachi I, et al. Caffeine withdrawal increases lithium blood levels. Biol Psychiatry 1995; 37: 348–50
Finley PR, O’Brien BE, Coleman RW. Lithium and angioten-sin-converting enzyme inhibitors: evaluation of a potential interaction. J Clin Psychopharmacol 1996; 16(1): 68–71
Blanche P, Raynaud E, Kerob D, et al. Lithium intoxication in an elderly patient after combined treatment with losarten [letter]. Eur J Clin Pharmacol 1997; 52: 501
Ragheb MA, Powell AL. Failure of sulindac to increase serum lithium levels. J Clin Psychiatry 1986; 47: 33–4
Reimann IW, Diener U, Frolich JC. Indomethacin but not aspirin increases plasma lithium ion levels. Arch Gen Psychiatry 1983; 40: 283–6
Stoudemire A, Hill CD, Lewison BJ, et al. Lithium intolerance in a medical-psychiatric population. Gen Hosp Psychiatry 1998; 20: 85–90
Hardy BG, Shulman KI, Zucchero C. Gradual discontinuation of lithium augmentation in elderly pateints with unipolar depression. J Clin Psychopharmacol 1997; 17: 22–6
Head L, Dening T. Lithium in the over-65s: who is taking it and who is monitoring it? Int J Geriatr Psychiatry 1998; 13: 164–71
Sawin CT, Chopra D, Azizi F, et al. The aging thyroid: increased prevalence of elevated serum thyrotropin levels in the elderly. JAMA 1979; 242(3): 247–50
Smith RE, Helms PM. Adverse effects of lithium therapy in the acutely ill elderly patient. J Clin Psychiatry 1982; 13: 53–60
Holroyd S, Rabins PV. A retrospective chart review of lithium side effects in a geriatric outpatient population. Am J Geriatr Psychiatry 1994; 2: 346–51
Murray N, Hopwood S, Balfour DJK, et al. The influence of age on lithium efficacy and side-effects in outpatients. Psychol Med 1983; 13:53–60
Himmelhoch JM, Neil JF, May SJ, et al. Age, dementia, dyskinesias, and lithium response. Am J Psychiatry 1980; 137: 941–5
Nambudiri DE, Meyers BS, Young RC. Delayed recovery from lithium neurotoxicity. J Geriatr Psychiatry Neurol 1991; 4: 40–3
Shulman KI, Mackenzie S, Hardy BG. The clinical use of lithium carbonate in old age: a review. Prog Neuropsych Biol Psychiatry 1987; 11: 59–64
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sproule, B.A., Hardy, B.G. & Shulman, K.I. Differential Pharmacokinetics of Lithium in Elderly Patients. Drugs & Aging 16, 165–177 (2000). https://doi.org/10.2165/00002512-200016030-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002512-200016030-00002