Elsevier

The Lancet

Volume 379, Issue 9817, 25 February–2 March 2012, Pages 721-728
The Lancet

Articles
Lithium toxicity profile: a systematic review and meta-analysis

https://doi.org/10.1016/S0140-6736(11)61516-XGet rights and content

Summary

Background

Lithium is a widely used and effective treatment for mood disorders. There has been concern about its safety but no adequate synthesis of the evidence for adverse effects. We aimed to undertake a clinically informative, systematic toxicity profile of lithium.

Methods

We undertook a systematic review and meta-analysis of randomised controlled trials and observational studies. We searched electronic databases, specialist journals, reference lists, textbooks, and conference abstracts. We used a hierarchy of evidence which considered randomised controlled trials, cohort studies, case-control studies, and case reports that included patients with mood disorders given lithium. Outcome measures were renal, thyroid, and parathyroid function; weight change; skin disorders; hair disorders; and teratogenicity.

Findings

We screened 5988 abstracts for eligibility and included 385 studies in the analysis. On average, glomerular filtration rate was reduced by −6·22 mL/min (95% CI −14·65 to 2·20, p=0·148) and urinary concentrating ability by 15% of normal maximum (weighted mean difference −158·43 mOsm/kg, 95% CI −229·78 to −87·07, p<0·0001). Lithium might increase risk of renal failure, but the absolute risk was small (18 of 3369 [0·5%] patients received renal replacement therapy). The prevalence of clinical hypothyroidism was increased in patients taking lithium compared with those given placebo (odds ratio [OR] 5·78, 95% CI 2·00–16·67; p=0·001), and thyroid stimulating hormone was increased on average by 4·00 iU/mL (95% CI 3·90–4·10, p<0·0001). Lithium treatment was associated with increased blood calcium (+0·09 mmol/L, 95% CI 0·02–0·17, p=0·009), and parathyroid hormone (+7·32 pg/mL, 3·42–11·23, p<0·0001). Patients receiving lithium gained more weight than did those receiving placebo (OR 1·89, 1·27–2·82, p=0·002), but not those receiving olanzapine (0·32, 0·21–0·49, p<0·0001). We recorded no significant increased risk of congenital malformations, alopecia, or skin disorders.

Interpretation

Lithium is associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. There is little evidence for a clinically significant reduction in renal function in most patients, and the risk of end-stage renal failure is low. The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy. Because of the consistent finding of a high prevalence of hyperparathyroidism, calcium concentrations should be checked before and during treatment.

Funding

National Institute for Health Research Programme Grant for Applied Research.

Introduction

Lithium is the most effective long-term therapy for bipolar disorder, protecting against both depression and mania and reducing the risk of suicide and short-term mortality.1, 2, 3 Although efficacious, lithium has some clinical disadvantages: it has a narrow therapeutic index requiring routine monitoring of serum concentrations and endocrine and renal function; a slow onset of action in acute mania; and acute effects of thirst, unpleasant taste, and tremor. Because lithium has always been an unpatented, cheap drug, it is not commercially promoted and the potential for adverse effects has been a substantial deterrent to use. Alternative drugs for bipolar disorder have increasingly been proposed, licensed, and adopted into clinical practice even when evidence for efficacy is modest and often limited to one pole of bipolar illness.

Particular concerns have been the effect of lithium on renal function and the risk from teratogenicity. Lithium commonly induces a clinically evident nephrogenic diabetes insipidus,4, 5 which would be explained by actions on tubular renal function, but of more concern is the speculative description of a specific lithium nephropathy6, 7 or disease of the renal glomerulus. However, the extent of reduction of glomerular renal function in a typical patient and the true long-term increase in risk of renal failure in well monitored patients remain poorly quantified. The risk of congenital malformations is generally thought to be high. One study reported a 400-fold increased risk of Ebstein's anomaly,8 and present clinical practice recommendations have been to avoid lithium in pregnancy when possible. An up-to-date estimate of the true risks of lithium together with a systematic assessment of the associated renal problems has not been available.

Evidence has confirmed the important therapeutic benefits of lithium relative to some of the alternative drugs that have replaced it, which might lead to wider use of lithium.1 Clinicians and patients therefore need accurate evidence of harms and benefits. We report a systematic review and meta-analysis of studies investigating the association between lithium and all reported major adverse effects, to provide a clinically informative systematic toxicity profile for lithium.

Section snippets

Search strategy and selection criteria

We searched Medline (1966–2010), Medline In-Process and other non-indexed citations (from 1966 to October, 2010), Embase (1980–2010), the Cumulative Index to Nursing and Allied Health Literature (1982–2010), PsycINFO (1806–2010), the Cochrane Library database (inception–2010), Biosis Previews (1926–2010), TOXNET database (inception–2010; webappendix), and archives of the journals Lithium, Lithium Therapy Monographs, and Teratology (search terms listed in webappendix). All relevant references

Results

The search process identified 5988 records, 385 of which fitted the inclusion criteria and were included for analysis (figure 1). The quality of evidence available varied between outcomes. High quality evidence was sparse: we identified only one systematic review (which was excluded from analysis because the data was used from the original studies included within it) and 22 RCTs. Most studies were case-control, uncontrolled cohort, or cross-sectional studies (n=197) or case reports (166). When

Discussion

The objective of this review was to synthesise what is known about the harmful effects of lithium. Findings from our study have shown that lithium is associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. We recorded no significant increased risk of congenital malformations, alopecia, or skin disorders, and little evidence for a clinically significant reduction in renal function in most patients.

The main limitations of this

References (29)

  • A Cipriani et al.

    Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials

    Am J Psychiatry

    (2005)
  • M Schou

    Lithium studies.1. Toxicity

    Acta Pharmacol Toxicol (Copenh)

    (1958)
  • R Paul et al.

    Review: meta-analysis of the effects of lithium usage on serum creatinine levels

    J Psychopharmacol

    (2010)
  • S Razvi et al.

    Subclinical thyroid disorders: significance and clinical impact

    J Clin Pathol

    (2010)
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