In the second, lithium inhibits glycogen synthesis kinase 3-beta (GSK3B),⁴^–⁷ an important enzyme in pathways including the Wnt signaling cascade.⁸ Notably, mice expressing lower levels of GSK3B exhibit behaviors similar to mice treated chronically with lithium.⁹ Signaling through the GSK3B pathway may also be central to the observed neuroprotective effects of lithium.¹⁰ Of course, both InsP3 and GSK3B pathways have convergent effects—both influence the serine/threonine kinase Akt-1,⁴ for example. Expression of many other genes (typically in lymphocytes) has been shown in single studies to be influenced by lithium administration, though the relevance of these effects to lithium’s effects on mood or other phenotypes is unknown.

PHARMACOKINETICS AND PHARMACODYNAMICS

Lithium is absorbed through the gut and distributes rapidly through body water, achieving peak plasma concentrations 1 to 2 hours after a single dose. (Slower-release forms may require 4 to 5 hours to reach peak concentration, because of transit time through the gut). As a monovalent cation like sodium, lithium’s clearance relies entirely on renal function. It is not metabolized by the liver, nor is it significantly protein-bound while circulating. In general, the half-life for renal excretion is approximately 24 hours, so steady-state serum levels are typically reached after 5 days. For this reason, lithium levels are typically checked about 5 days after initiation or dose change. Because lithium distributes throughout the body, it is influenced by lean body mass—for example, among geriatric patients, lithium levels for a given dose tend to be greater than among younger patients with greater lean body (including muscle) mass. Magnetic resonance spectroscopy studies suggest that brain lithium levels are highly correlated with plasma levels, though less so in patients at the extremes of age—that is, it is possible to have supratherapeutic levels in the central nervous system (CNS) while maintaining a normal plasma lithium level.

Drugs that affect renal function, particularly reabsorption, can have profound effects on lithium clearance. Perhaps most notably from a clinical perspective, nonsteroidal antiinflammatory drugs (NSAIDs) or other COX-2 inhibitors may decrease renal blood flow and thereby increase lithium levels by up to 25%. Diuretics likewise affect lithium levels, though the nature of their effect depends on their site of action. In the kidney, lithium is primarily reabsorbed in the proximal renal tubules, with some subsequent absorption in the loop of Henle. Importantly, in contrast to sodium, no significant absorption occurs in the distal tubules. Therefore, thiazide diuretics, which act distally, will tend to increase lithium levels by up to 50%, while those that act more proximally generally have less of an effect on lithium levels.

More broadly, hydration status can affect lithium levels: individuals who become salt-avid (e.g., because of hypovolemia or hyponatremia, perhaps in the context of vomiting and diarrhea or self-induced injury, such as long-distance running) will cause their lithium levels to increase.

EVIDENCE FOR LITHIUM’S EFFICACY

Lithium in Acute Mania

Beginning with Schou’s study of lithium versus placebo for acute mania, lithium has repeatedly shown efficacy for the treatment of mania,¹¹ with the first large randomized study of lithium treatment of acute mania finding lithium comparably effective to the antipsychotic chlorpromazine.¹² Since then, multiple studies have found lithium to be superior to placebo and comparable or superior to other agents in the acute management of bipolar mania; few studies have found superiority for other drugs over lithium. A systematic review found 12 acute mania trials comparing lithium to placebo or another agent that met their criteria for data-pooling. This review of studies of lithium for acute mania found superiority for lithium over placebo and chlorpromazine, with equivalence to valproate and carbamazepine.¹³

As pointed out by Grunze,¹⁴ however, few studies of lithium in acute mania were undertaken with the methodological rigor required today for regulatory approval of a drug’s use. The first to do this was Bowden in his seminal study of divalproex sodium for the treatment of acute mania in 1994, which was designed to study that drug for FDA approval; by coincidence, the study also demonstrated lithium’s efficacy.¹⁵ This study was adequately powered (i.e., it included a large enough sample of patients to find a high probability of finding a statistically significant difference between treatments with a low probability of error), compared a drug to an agent known to be effective (lithium), and it included a placebo arm. Additionally, it was not biased by inclusion based on prior response to lithium. In this 3-week study, lithium was superior to placebo and equivalent in efficacy to divalproex sodium with a 50% response rate (defined as a 50% drop in mania scale scores) for lithium compared to 26% for placebo.¹⁵ Since that study, pooled data from trials of topiramate for mania failed to demonstrate a benefit for that drug, but did reconfirm the efficacy of lithium for acutely manic patients.¹⁶ The percentage of patients with a 50% or greater reduction in the Young Mania Rating Scale (YMRS) at day 21 was 28% with placebo (N = 427), 27% with topiramate (N = 433), and 46% with lithium (N = 227). Lithium was statistically better than placebo and topiramate on all psychometric measures other than the Montgomery-Asberg Depression Rating Scale (MADRS).

Monotherapy treatment in any phase of bipolar disorder, however, is increasingly rare, and is especially so in the treatment of acute mania.¹⁷ It appears that mania outcomes, in terms of time to response and proportion of patients who remit, may be improved with the addition of antipsychotics to lithium.¹⁸ The adjunctive use of typical (including haloperidol) and atypical (e.g., olanzapine, quetiapine, and risperidone) antipsychotics with lithium carbonate has been found to improve outcomes compared to lithium alone. The atypical antipsychotic ziprasidone, however, did not improve outcomes significantly compared to placebo when added to lithium.

Lithium in Acute Bipolar Depression

The options for the pharmacological treatment of major depressive episodes in bipolar disorder, unlike those for mania, remain few. In spite of being recommended as first-line treatment in recent bipolar treatment guidelines, there are few data to support the use of lithium as an acute antidepressant in bipolar disorder. A comprehensive review by Bauer and Mitchner ¹⁹ identified only three placebo-controlled trials of lithium for bipolar depression (with a total of 62 subjects). While these trials showed a positive benefit for lithium, none was a randomized, parallel-group study; instead, they used a within-subject design in which each subject was started on lithium or placebo and then switched to the other. It is unlikely, unfortunately, that there will be any large, well-designed trials of lithium to answer this question, most prominently because there is no pharmaceutical manufacturer producing lithium that has any financial incentive to undertake such a study.

Lithium, used as monotherapy, appears to be as effective for the treatment of bipolar depression as the combination of lithium and an antidepressant. In a study comparing imipramine, paroxetine, and placebo added to lithium carbonate for the treatment of a major depressive episode in bipolar disorder, neither antidepressant added benefit beyond lithium alone.²⁰ Response rates (defined as a Hamilton Depression Rating Scale [HAM-D] score of 7 or lower) were 35% for lithium alone, compared to 39% for imipramine, and 46% for paroxetine. In a secondary analysis, subjects with lower lithium levels (less than 0.8 mEq/L) had a lower response rate compared to the adjunctive antidepressant group, suggesting, perhaps, that higher lithium levels are as effective as lithium plus an antidepressant in the treatment of bipolar depression.

Lithium for Maintenance Treatment and Relapse Prevention of Bipolar Disorder

Lithium is the archetypal maintenance treatment for bipolar disorder. From Prien’s first maintenance study of lithium (comparing it to chlorpromazine) to more recent studies using lithium as a comparator for maintenance studies of other drugs, lithium has clear benefit for maintaining response and preventing relapse in bipolar disorder.^12,²¹ Lithium’s clearest benefit in long-term use is in the prevention of relapse to mania, although relapse to depression is more common in patients with bipolar disorder. As is the case with lithium in acute mania, lithium’s efficacy compared to placebo was only confirmed in later studies designed to establish regulatory approval for newer drugs, including divalproex sodium and lamotrigine. Earlier studies were beset with methodological problems, including on–off rather than parallel group designs, lack of diagnostic clarity (e.g., the inclusion of unipolar patients), and rapid or abrupt lithium discontinuation in stable patients. Concerns about sudden discontinuation of lithium are genuine, as there is a high rate of manic relapse in these patients; inclusion of patients from these studies might artificially inflate the difference between lithium and placebo in maintenance treatment.^22,²³

Geddes and colleagues ²⁴ have completed the definitive systematic review of lithium for maintenance treatment in bipolar disorder. Having reviewed 300 studies, they included only five in their meta-analysis, limiting inclusion to randomized, double-blind, placebo-controlled trials. They found that lithium was more effective than placebo in preventing relapses to any mood episode (random effects relative risk = 0.65, 95% confidence interval [CI] = 0.50 to 0.84) and to mania (relative risk = 0.62, 95% CI = 0.40 to 0.95), with a nonsignificant effect on relapse to depression (relative risk = 0.72, 95% CI = 0.49 to 1.07).²⁴ The average risk of relapse of any kind in 1 to 2 years of follow-up was 60% for placebo, compared to 40% for lithium; this can be understood as lithium preventing one relapse for every five patients treated compared to placebo. Relapse rates to mania were 14% for lithium compared to 24% for placebo, while relapse rates to depression were 25% for placebo compared to 32% for lithium. There are some limitations and criticisms of this study, however. The outcomes were not defined uniformly across the included studies, one study included in the analysis had exclusively bipolar II subjects, and the follow-up period of 1 to 2 years is too short to adequately evaluate the benefit of lithium (as some have argued that the maintenance benefit of lithium is only apparent after 2 years of treatment).^23,²⁵

Lithium was compared to olanzapine for the prevention of relapse of bipolar I disorder in a randomized, controlled, double-blind trial.²⁶ Bipolar I patients were stabilized on a combination of lithium and olanzapine, randomized to one or the other drug, and followed for 12 months. There was no difference between drugs on the primary outcome measure or time to symptomatic relapse (YMRS or HAM-D scores of 15 or greater), although there were fewer relapses to mania/mixed (but not depressive) episodes in the olanzapine-treated group.

There remains some controversy about what adequate maintenance lithium levels should be. In order to minimize adverse effects and to increase patient acceptance of lithium treatment, lowest effective doses should be the goal. A randomized, double-blind study by Gelenberg and co-workers ²⁷ stabilized patients on a standard serum level of lithium (0.8 to 1 mmol/L), then assigned them to either remain at that level or to be maintained with a lower serum lithium level (0.4 to 0.6 mmol/L). Patients in the higher lithium level group had fewer relapses than those randomly assigned to lower lithium levels.²⁷ A reanalysis of the data, however, controlling for the rate at which the lithium dose was lowered, found no difference between groups, suggesting that lower maintenance lithium levels may be adequate for some patients.²⁸