03. What is the Optimal Therapeutic Range for Lithium in Bipolar Disorder?

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Reference Serum Levels for Lithium Vary

While working in the psychiatric emergency service of my local medical center, I see a reference serum level for lithium of 0.5 to 1.5 mmol/L. But when ordering a lithium level at my community mental health center, I see a different reference range of 0.6 to 1.2. Googling therapeutic lithium levels returns a variety of different ranges, with only some of the websites including partial references.

Systematic Review Criteria Broadened

Luckily, a recent literature review in the International Journal of Bipolar Disorders examines the evidence bases for the therapeutic serum level of lithium. You might imagine a double-blind trial was run with patients on lithium monotherapy in a uniform phase of bipolar disorder with subjects randomly assigned to different regimens resulting in a priori defined fixed lithium serum ranges. If so, you are not alone; so did a panel of experts in bipolar disorder.

These were the criteria for their systematic literature review, and the number of studies they found meeting that criteria: a grand total of zero. So they broadened the criteria beyond euthymic bipolar disorder to include:

• Subjects with recurrent depression as long as each diagnosis was reported separately
• Other psychotropic medications in addition to lithium
• Non-randomized studies as long as there was no clear indication of channeling, a form of allocation bias
• Different fixed lithium levels to be compared without an a priori definition

Interpreting Seven Heterogeneous Studies

With these expanded criteria, they were able to find seven studies in the preceding 37 years. Combining these seven studies into one set of recommendations was not straightforward, as each study implemented:

• A different number of serum ranges
• Different cutoffs in serum levels from as low a 0.3 mmol/L to as high as 1.4 mmol/L
• Not all studies used the recurrence of a mood episode (either manic or depressive) as an outcome measure; a few studies used rating scales
• Three of the studies included data on tolerability and side effects

This is where the expert panel went to work to interpret the seven studies. 33 of the experts completed the questionnaire, with consensus defined as 80% agreement.

Consensus on Maintenance Treatment

A consensus was reached that:

• A serum level should be measured 12 hours (give or take 1 hour) after last dose, whether the dosing is daily or b.i.d. for immediate- or extended-release lithium
• Initial serum levels in patients on maintenance treatment with lithium should be 0.6 to 0.8 mmol/L with the option to:
  • Reduce the level to 0.4 to 0.6 mmol/L in cases of poor tolerability
  • Increase the level to 0.8 to 1.0 mmol/L in cases of insufficient response
• There is a need for an upper limit for maintenance treatment, but no agreement on what it should be (36% endorsing 1.0 and 39% endorsing 1.2 mmol/L)
• Although not a consensus, 63.6% agreed that initial target levels should be lower for those aged 65 to 79, specifically 0.4 to 0.6 mmol/L

Evidence for Acute Treatment

For acute treatment, the authors of the current literature review cite the original studies from the early 1970s establishing the efficacy of lithium compared to antipsychotic medication with target levels of:

• 0.6 to 1.3 mmol/L in multiple studies
• An outlier with an average serum level of around 0.5 mmol/L

They cite one study closest to the ideal of comparing outcomes of randomly assigned doses yielding different serum levels. In this trial with a crossover design, subjects with acute mania were randomized to alternating 10-day blocks of low, medium, or high doses of lithium or placebo.

Serum Levels and Improvement

At the end of each 10-day block, serum lithium levels were measured along with rating scales for mania:

• Serum levels less than 0.4 mmol/L led to improvement in about 30% of the blocks
• Levels over 1.2 mmol/L led to improvement in over 80%
• Levels of 0.4 to 0.8 mmol/L led to improvement in just less than 60% of the blocks
• Levels of 0.8 to 1.2mmol/L led to improvement in about 70%

Each increase in serum level to the next range led to a statistically significant improvement in rating scales for mania. Toxic symptoms requiring dosage reduction developed in 9 of 68 patients:

• 5 during high-dose periods with serum lithium levels of 1.55 mmol/L to 1.8 mmol/L
• 4 during medium-dose periods with serum levels of 1.25 mmol/L to 1.63 mmol/L

The authors of this trial concluded that serum levels up to 1.2 mmol/L result in increasing efficacy in patients with acute mania.

Take-Home Messages

My take-home point from this literature review is that in the absence of ideal randomized, placebo-controlled, double-blind studies, the best course of action is to follow a combination of:

• Guidelines from the panel of experts for maintenance treatment
• Results from the randomized trial on acute mania

Specifically, an initial level of 0.6 to 0.8 mmol/L may be targeted for adults less than 64 years of age. Clinical response should guide whether to:

• Increase the dose to yield a maximum serum level of 1.2 mmol/L in patients with acute mania
• Increase to 1.0 mmol/L for maintenance treatment
• In patients with poor tolerance for side effects, a dose as low as 0.4 to 0.6 mmol/L may be an option

As always, the lowest effective dose should be sought to minimize side effects of lithium, including nephrotoxicity.

Abstract

Lithium and its effects: does dose matter?

Mirko Manchia, M.D., Pasquale Paribello, M.D., Martina Pinna, M.D., Luca Steardo Jr., M.D., Bernardo Carpiniello, M.D., Federica Pinna, M.D., Claudia Pisanu, M.D., Alessio Squassina, M.D. & Tomas Hajek, M.D.

Background

Decades of clinical research have demonstrated the efficacy of lithium in treating acute episodes (both manic and depressive), as well as in preventing recurrences of bipolar disorder (BD). Specific to lithium is its antisuicidal effect, which appears to extend beyond its mood-stabilizing properties. Lithium’s clinical effectiveness is, to some extent, counterbalanced by its safety and tolerability profile. Indeed, monitoring of lithium levels is required by its narrow therapeutic index. There is consensus that adequate serum levels should be above 0.6 mEq/L to achieve clinical effectiveness. However, few data support the choice of this threshold, and increasing evidence suggests that lithium might have clinical and molecular effects at much lower concentrations.

Content

This narrative review is aimed at: (1) reviewing and critically interpreting the clinical evidence supporting the use of the 0.6 mEq/L threshold, (2) reporting a narrative synthesis of the evidence supporting the notion that lithium might be effective in much lower doses. Among these are epidemiological studies of lithium in water, evidence on the antisuicidal, anti-aggressive, and neuroprotective effects, including efficacy in preventing cognitive impairment progression, Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS), of lithium; and (3) revieweing biological data supporting clinically viable uses of lithium at low levels with the delineation of a mechanistic hypothesis surrounding its purported mechanism of action. The study selection was based on the authors’ preference, reflecting the varied and extensive expertise on the review subject, further enriched with an extensive pearl-growing strategy for relevant reviews and book sections.

Conclusions

Clinical and molecular effects of lithium are numerous, and its effects also appear to have a certain degree of specificity related to the dose administered. In sum, the clinical effects of lithium are maximal for mood stabilisation at concentrations higher than 0.6 mEq/l. However, lower levels may be sufficient for preventing depressive recurrences in older populations of patients, and microdoses could be effective in decreasing suicide risk, especially in patients with BD. Conversely, lithium’s ability to counteract cognitive decline appears to be exerted at subtherapeutic doses, possibly corresponding to its molecular neuroprotective effects. Indeed, lithium may reduce inflammation and induce neuroprotection even at doses several folds lower than those commonly used in clinical settings. Nevertheless, findings surrounding its purported mechanism of action are missing, and more research is needed to investigate the molecular targets of low-dose lithium adequately.

Reference

Manchia, M., M.D., Paribello, P., M.D., Pinna, M., M.D., Steardo Jr., L. M.D., Carpiniello, B. M.D., Pinna, F. M.D., Pisanu, C. M.D., Squassina, A. M.D. & Hajek, T. M.D. (2024). Lithium and its effects: does dose matter?. International Journal of Bipolar Disorders volume 12, Article number: 23.