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Lithium: Updated Human Knowledge Using an Evidence-Based Approach

Part II: Clinical Pharmacology and Therapeutic Monitoring

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Abstract

After a single dose, lithium, usually given as carbonate, reaches a peak plasma concentration at 1.0–2.0 hours for standard-release dosage forms, and 4–5 hours for sustained-release forms. Its bioavailability is 80–100%, its total clearance 10–40 mL/min and its elimination half-life is 18–36 hours. Use of the sustained-release formulation results in 30–50% reductions in peak plasma concentrations without major changes in the area under the plasma concentration curve.

Lithium distribution to the brain, evaluated using 7Li magnetic resonance spectroscopy, showed brain concentrations to be approximately half those in serum, occasionally increasing to 75–80%. Brain concentrations were weakly correlated with serum concentrations.

Lithium is almost exclusively excreted via the kidney as a free ion and lithium clearance is considered to decrease with aging. No gender- or race-related differences in kinetics have been demonstrated. Renal insufficiency is associated with a considerable reduction in renal clearance of lithium and is considered a contraindication to its use, especially if a sodium-poor diet is required. During the last months of pregnancy, lithium clearance increases by 30–50% as a result of an increase in glomerular filtration rate. Lithium also passes freely from maternal plasma into breast milk.

Numerous kinetic interactions have been described for lithium, usually involving a decrease in the drug’s clearance and therefore increasing its potential toxicity.

Clinical pharmacology studies performed in healthy volunteers have investigated a possible effect of lithium on cognitive functions. Most of these studies reported a slight, negative effect on vigilance, alertness, learning and short-term memory after long-term administration only.

Because of the narrow therapeutic range of lithium, therapeutic monitoring is the basis for optimal use and administration of this drug. Lithium dosages should be adjusted on the basis of the serum concentration drawn (optimally) 12 hours after the last dose. In patients receiving once-daily administration, the serum concentration at 24 hours should serve as the control value.

The efficacy of lithium is clearly dose-dependent and reliably correlates with serum concentrations. It is now generally accepted that concentrations should be maintained between 0.6 and 0.8 mmol/L, although some authors still favour 0.8–1.2 mmol/L. With sustained-release preparations, and because of the later peak of serum lithium concentration, it is advised to keep serum concentrations within the upper range (0.8–1 mmol/L), rather than 0.6–0.8 mmol/L for standard formulations. It is controversial whether a reduced concentration is required in elderly people.

The usual maintenance daily dose is 25–35 mmol (lithium carbonate 925–1300 mg) for patients aged <40 years; 20–25 mmol (740–925 mg) for those aged 40–60 years; and 15–20 mmol (550–740 mg) for patients aged >60 years. The initial recommended dose is usually 12–24 mmol (450–900 mg) per day, depending on age and bodyweight. The classical administration schedule is two or three times daily, although there is no strong evidence in favour of a three-times-daily schedule, and compliance with the midday dose is questionable. With a modern sustained-release preparation, the twice-daily schedule is well established, although one single evening dose is being recommended by a number of expert panels.

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Acknowledgements

We would like to thank Sandra Ter Pelle for her help and expertise in preparing the manuscript. No sources of funding were used to assist in the preparation of this review. Dr Aubry has acted as a consultant for Vifor SA (Galenica group) in Switzerland. He has received honoraria from Astra-Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Janssen and Eli Lilly for conferences and seminars. Dr Grandjean acts as a regular consultant for Vifor SA (Galenica group) in Switzerland, and has provided expert reports on lithium for various health authorities. He has also provided clinical work and expert reports to a number of pharmaceutical companies, including Sanofi-Pasteur, Novartis, Zambon, Menarini, Roche and Labatec-Pharma, and has received honoraria from Bristol-Myers Squibb, Boehringer Ingelheim and Zambon for conferences and seminars.

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  1. Phidalsa Institute for Clinical Investigation, Geneva, Switzerland

    Etienne Marc Grandjean

  2. Bipolar Programme, Department of Psychiatry, Geneva, Switzerland

    Jean-Michel Aubry

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  1. Etienne Marc Grandjean
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  2. Jean-Michel Aubry
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Correspondence to Jean-Michel Aubry.

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Grandjean, E.M., Aubry, JM. Lithium: Updated Human Knowledge Using an Evidence-Based Approach. CNS Drugs 23, 331–349 (2009). https://doi.org/10.2165/00023210-200923040-00005

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