Lithium therapy in bipolar disorder: a balancing act?
Authors: Gin S Malhi
Journal: The Lancet (2015)

Quite reasonably, patients with bipolar disorder want treatment that provides sustained relief from their illness without incurring serious side-effects. Functionally, this translates to the resumption of purpose and enjoyment. But of the numerous drugs available for the management of bipolar disorder, only lithium seems to truly stabilise mood.1Goodwin G Malhi GS What is a mood stabilizer?.Psychol Med. 2007; 37: 609-614Crossref PubMed Scopus (37) Google Scholar Its status as an effective prophylactic agent was convincingly reinstated by the findings of the randomised, open-label BALANCE trial,2Geddes JR Goodwin GM Rendell J et al.Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial.Lancet. 2010; 375: 385-395Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar which corroborated empirical knowledge. The BALANCE investigators showed that lithium alone, or lithium plus valproate, are more likely to prevent relapse than valproate monotherapy, and prophylaxis with lithium monotherapy might be on a par with lithium plus valproate. Hence, despite fluctuating popularity, lithium remains a first-line option for the treatment and prophylaxis of bipolar disorder in therapeutic guidelines.3Malhi GS Tanious M Das P Berk M The science and practice of lithium therapy.Aust N Z J Psychiatry. 2012; 46: 192-211Crossref PubMed Scopus (135) Google Scholar However, use of lithium in practice is limited by concerns about safety and adverse effects with long-term use. Extending previous research that examined the short-term tolerability of lithium,4McKnight RF Adida M Budge K Stockton S Goodwin GM Geddes JR Lithium toxicity profile: a systematic review and meta-analysis.Lancet. 2012; 379: 721-728Summary Full Text Full Text PDF PubMed Scopus (576) Google Scholar in The Lancet Brian Shine and colleagues5Shine B McKnight RF Leaver L Geddes JR Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data.Lancet. 2015; (published online May 21.)http://dx.doi.org/S0140-6736(14)61842-0PubMed Google Scholar have drawn on a large set of data to determine the long-term effects of lithium on renal and endocrine function. Data from 4678 patients were included in the study, of whom 2795 had their serum lithium measured more than once. Shine and colleagues' findings show that lithium was associated with increased risk of stage three chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1·73m2; hazard ratio 1·93, 95% CI 1·76–2·12), hypothyroidism (thyrotropin activity >5·5 mU/L; 2·31, 2·05–2·60), and hypercalcaemia (1·43, 1·21–1·69). These findings send a key message to clinicians to monitor lithium therapy closely from the outset. Both thyroid hormone secretion and renal function can decline with long-term lithium use and can, in some cases, lead to hypothyroidism and stage three chronic kidney disease. Interestingly, these complications are more likely to occur in women than in men, and are detected early in the course of lithium treatment. In addition, long-term lithium therapy can also cause hypercalcaemia (ie, total plasma calcium concentration ≥2·6 mmol/L). All adverse effects are more likely to occur when plasma lithium concentration is high. Therefore, patients receiving lithium therapy should have thyroid function, renal clearance, and blood calcium concentrations assessed carefully at the beginning of therapy and monitored closely thereafter. Shine and colleagues5Shine B McKnight RF Leaver L Geddes JR Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data.Lancet. 2015; (published online May 21.)http://dx.doi.org/S0140-6736(14)61842-0PubMed Google Scholar provide clear evidence of the potential risks associated with long-term lithium treatment. But because bipolar disorder typically emerges at a young age6Duffy A The early natural history of bipolar disorder: what we have learned from longitudinal high-risk research.Can J Psychiatry. 2010; 55: 477-485PubMed Google Scholar and requires lifelong treatment, these findings prompt the question: how can these hazards be navigated? The answer is twofold. First, avoid sustained periods during which plasma lithium concentrations are high to diminish the risk of serious adverse effects. Second, all the parameters that need regular assessment, such as thyroid and renal function tests and plasma lithium and calcium concentrations, can be measured reliably and easily. However, the treatment of type I bipolar disorder, the subtype best suited to lithium therapy,7Gershon S Chengappa KNR Malhi GS Lithium specificity in bipolar illness: a classic agent for the classic disorder.Bipolar Disord. 2009; 11: 34-44Crossref PubMed Scopus (85) Google Scholar is often complicated by comorbid anxiety and substance misuse. Furthermore, lithium's therapeutic effect occurs at concentrations that can be toxic if maintained in the long term.8Malhi GS Tanious M Gershon S The lithiumeter: a measured approach.Bipolar Disord. 2011; 13: 219-226Crossref PubMed Scopus (46) Google Scholar These concerns reinforce a widely held view that lithium therapy is problematic. But all drugs are associated with side-effects, and long-term management often involves a risk–benefit analysis at some point in the treatment course; lithium is no exception. Maintenance of lithium concentrations at the lower end of the therapeutic range (ie, 0·6 mmol/L) can reduce the adverse outcomes associated with lithium treatment. For plasma lithium concentrations to be high enough to be efficacious, but low enough to avoid toxicity, is a delicate balance. The simple pharmacokinetics of lithium in plasma offer some assistance, but the pharmacokinetics of lithium within the brain are more complex because the blood–brain barrier insulates the brain from rapid changes in plasma lithium concentration and facilitates its accumulation in neural tissues, which can be neurotoxic.9Malhi GS Tanious M Optimal frequency of lithium administration in the treatment of bipolar disorder: clinical and dosing considerations.CNS Drugs. 2011; 25: 289-298Crossref PubMed Scopus (53) Google Scholar The movement of lithium between plasma, cerebrospinal fluid, and brain tissue is not fully understood, and future research will need to examine the effects of different doses and duration of lithium treatment on concentrations within these various compartments. For example, a low concentration of lithium in the plasma (0·2–0·4 mmol/L) has little effect on renal and thyroid function,10Aprahamian I Santos FS Santos B et al.Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension.J Clin Psychiatry. 2014; 75: e672-e678Crossref PubMed Scopus (63) Google Scholar and is achievable with alternate-day dosing.9Malhi GS Tanious M Optimal frequency of lithium administration in the treatment of bipolar disorder: clinical and dosing considerations.CNS Drugs. 2011; 25: 289-298Crossref PubMed Scopus (53) Google Scholar Lithium is without doubt the best treatment for many patients with bipolar disorder because it confers long-term mood stability and prophylaxis (figure). Lithium also reduces the risk of suicide11Cipriani A Hawton K Stockton S Geddes JR Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis.BMJ. 2013; 346: f3646Crossref PubMed Scopus (537) Google Scholar and is possibly neuroprotective.12Marmol F Lithium: bipolar disorder and neurodegenerative diseases. Possible cellular mechanisms of the therapeutic effects of lithium.Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 1761-1771Crossref PubMed Scopus (129) Google Scholar The dilemma of lithium therapy arises because, if poorly managed, lithium can compromise renal function, sometimes irreversibly, and severely disrupt endocrine homoeostasis—ultimately limiting its usefulness. Therefore, lithium therapy remains a challenge that will benefit from a better understanding of its therapeutic properties. I have received research funding from AstraZeneca, Eli Lilly, Organon, Pfizer, Servier, and Wyeth; am a speaker for AstraZeneca, Eli Lilly, Janssen-Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; and a consultant for AstraZeneca, Eli Lilly, Janssen-Cilag, Lundbeck, and Servier. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory dataLithium treatment is associated with a decline in renal function, hypothyroidism, and hypercalcaemia. Women younger than 60 years and people with lithium concentrations higher than median are at greatest risk. Because lithium remains a treatment of choice for bipolar disorder, patients need baseline measures of renal, thyroid, and parathyroid function and regular long-term monitoring. Full-Text PDF Open Access