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Lithium

Classification: A

Drug products: Carbolithium, Li-Liquid, Litarex, Litarex®, Lithionit®, Lithium Carbonate Capsules USP, Lithiumcarbonaat, Lithmax, Litiumkarbonat, Priadel Liquid, TERALITHE LP 400 mg

ATC code: N05AN01

Substances: lithium, lithium carbonate, lithium chloride, lithium citrate, lithium sulfate, lithium sulfate anhydrous

Summary

The therapeutic reference concentration is the same for men and women. Women may need slightly lower doses to achieve the same concentration of lithium as men. The risk of adverse effect on the thyroid gland appears to be higher in women. It is unclear if there is a difference between men and women in the risk of developing impaired kidney function.

Additional information

In a large Swedish observational study (2855 men, 4499 women ) women were more likely than men to be diagnosed with bipolar disease type II (33% of the men, 39% of the women) and to have hypomanic episodes while bipolar  disease type 1 was more common in men (50% of the men, 43% of the women) [1].

Pharmacokinetics and dosing

Clinical trials addressing sex differences of lithium pharmacokinetics are lacking.

Dosing of lithium requires tight monitoring of plasma concentration and the same reference concentration interval is used in men and women. Observational studies show that women use 80-90% of the doses men do [1]. This indicates that women may need slightly lower doses to achieve the same concentration.

Effects

A recent observational study in bipolar disease (2855 men, 4499 women) could not identify sex differences regarding therapeutic effect of lithium [1]. This is in line with previous publications [2]. However, a slightly better treatment response with lithium was detected in women in two small observational studies on patients with bipolar disease (131 men, 229 women) [3] and (27 men, 45 women) [4].

Adverse effects

An observational study (913 men, 2291 women) indicates that women seem to have a higher risk for hypothyroidism and TSH-elevation compared to men. In the lithium treated patients (n = 240), a significantly lower percentage of women (56%) compared to men (71%) fell within the 0.3–3.0 µIU/mL normal TSH window [5].

According to an observational study (265 men, 430 women) the time to develop hypothyreosis during lithium treatment was 24 months for women and 59 months for men [6]. According to that study the incidence for hypothyroidism during 100 patient years is 2.17 for women and 0.68 for men. The risk of developing hypothyroidism was highest during the first two years and in women aged 40-59 years [6]. An additional study (28 men 73 women) points towards an increased risk of hypothyroidism in women treated with lithium [7].

Several studies have analysed the risk of renal damage by lithium. According to data extracted from the British General Practice Research Database (GPRD) adjusted for age and gender, ever-use of lithium was associated with an increased risk of developing renal failure (HR: 2.5 (95%CI 1.6 to 4.0)) and renal impairment (HR: 2.7 (2.2 to 3.4)).

Patients 50 years or older are at particular risk of renal failure. Gender did not show a bivariate correlation with renal failure [8]. One observational study (26 men, 54 women, mean age 60 years) reported a higher incidence of eGFR < 60 ml/min in men (38%) as compared to women (16%) [9]. In contrast, another study (44 men, 95 women, mean age 58 years) reported lower eGFR in women as compared to men [10]. According to another observational study (54 men, 68 women, mean age 57 years) polyuria following lithium treatment was more common in women [11].

A small observational study (62 men, 108 women) reported an increased risk of kidney tumors with lithium use in both men and women (6 tumors in men, 8 in women) [12]. However, a large nation-wide registry based Danish study (4089 men, 5562 women) half treated with lithium, did not find any link between lithium and benign or malignant kidney tumors [13]. 

An observational study (22 men, 38 women) reported tremor in 54% of men treated with lithium as compared to 26% in women (p<0.05) [14].

Reproductive health issues

Lithium is excreted by the kidney and all drugs that decrease renal function may increase the plasma concentration of lithium [15]. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

The chance of being treated with lithium, adjusted for type of bipolar disease, age, and co-morbidity, expressed as odd ratio was 1.25 (95%CI 1.12-1.39) for women [1].

The prescription pattern for lithium may differ with patients’ sex and according to some studies women are more likely to be treated with lithium than men [1]. From 1981 to 2006 more women than men were using lithium in Scandinavia [16]. A higher prevalence of bipolar disorder type 2 in women may be one explanation. The restrictions on the use of valproic acid in fertile women due to teratogenic effects [17] may also contribute to the higher use of lithium as an alternative treatment option in bipolar disease, in women.  

Updated: 2018-01-07

Date of litterature search: 2017-06-30

References

  1. Karanti A, Bobeck C, Osterman M, Kardell M, Tidemalm D, Runeson B et al. Gender differences in the treatment of patients with bipolar disorder: a study of 7354 patients. J Affect Disord. 2015;174:303-9. PubMed
  2. Viguera AC, Tondo L, Baldessarini RJ. Sex differences in response to lithium treatment. Am J Psychiatry. 2000;157:1509-11. PubMed
  3. Viguera AC, Baldessarini RJ, Tondo L. Response to lithium maintenance treatment in bipolar disorders: comparison of women and men. Bipolar Disord. 2001;3:245-52. PubMed
  4. Benedetti A, Fagiolini A, Casamassima F, Mian MS, Adamovit A, Musetti L et al. Gender differences in bipolar disorder type 1: a 48-week prospective follow-up of 72 patients treated in an Italian tertiary care center. J Nerv Ment Dis. 2007;195:93-6. PubMed
  5. Özerdem A, Tunca Z, Çımrın D, Hıdıroğlu C, Ergör G. Female vulnerability for thyroid function abnormality in bipolar disorder: role of lithium treatment. Bipolar Disord. 2014;16:72-82. PubMed
  6. Johnston AM, Eagles JM. Lithium-associated clinical hypothyroidism Prevalence and risk factors. Br J Psychiatry. 1999;175:336-9. PubMed
  7. Kusalic M, Engelsmann F. Effect of lithium maintenance therapy on thyroid and parathyroid function. J Psychiatry Neurosci. 1999;24:227-33. PubMed
  8. Close H, Reilly J, Mason JM, Kripalani M, Wilson D, Main J et al. Renal failure in lithium-treated bipolar disorder: a retrospective cohort study. PLoS One. 2014;9:e90169. PubMed
  9. Rybakowski JK, Abramowicz M, Drogowska J, Chłopocka-Woźniak M, Michalak M, Czekalski S. Screening for the markers of kidney damage in men and women on long-term lithium treatment. Med Sci Monit. 2012;18:CR656-60. PubMed
  10. Bocchetta A, Ardau R, Carta P, Ligas F, Sardu C, Pani A et al. Duration of lithium treatment is a risk factor for reduced glomerular function: a cross-sectional study. BMC Med. 2013;11:33. PubMed
  11. Kinahan JC, NiChorcorain A, Cunningham S, Freyne A, Cooney C, Barry S et al. Risk factors for polyuria in a cross-section of community psychiatric lithium-treated patients. Bipolar Disord. 2015;17:50-62. PubMed
  12. Zaidan M, Stucker F, Stengel B, Vasiliu V, Hummel A, Landais P et al. Increased risk of solid renal tumors in lithium-treated patients. Kidney Int. 2014;86:184-90. PubMed
  13. Kessing LV, Gerds TA, Feldt-Rasmussen B, Andersen PK, Licht RW. Lithium and renal and upper urinary tract tumors - results from a nationwide population-based study. Bipolar Disord. 2015;17:805-13. PubMed
  14. Henry C. Lithium side-effects and predictors of hypothyroidism in patients with bipolar disorder: sex differences. J Psychiatry Neurosci. 2002;27:104-7. PubMed
  15. Lithionit (litium). Summary of Product Characteristics. Medical Products Agency (MPA); 2017.
  16. Bramness JG, Weitoft GR, Hallas J. Use of lithium in the adult populations of Denmark, Norway and Sweden. J Affect Disord. 2009;118:224-8. PubMed
  17. Jentink J, Loane MA, Dolk H, Barisic I, Garne E, Morris JK et al. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med. 2010;362:2185-93. PubMed
  18. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2016 [cited 2017-06-20.] länk

Authors: Carl-Olav Stiller

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson