Lithium and Its Role in Psychiatry

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, with the first large randomized study of lithium treatment of acute mania finding lithium comparably effective to the antipsychotic chlorpromazine. 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.

As pointed out by Grunze, however, few studies of lithium in acute mania were undertaken with the methodological rigor required today for regulatory approval of a drug's use. By coincidence, the first rigorously designed study to demonstrate the efficacy of lithium for acute mania was Bowden's seminal study of divalproex sodium for the treatment of acute mania in 1994, which was designed to study that drug for FDA approval; by including lithium as an active comparator, the study also demonstrated lithium's efficacy. 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. Since that study, pooled data from trials of topiramate for mania failed to demonstrate a benefit for that drug, but it did re-confirm the efficacy of lithium for acutely manic patients. 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. 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. The adjunctive use of typical (including haloperidol) and atypical (e.g., aripiprazole, asenapine, 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 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. 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. 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.

Geddes and colleagues 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 non-significant effect on relapse to depression (relative risk = 0.72, 95% CI = 0.49 to 1.07). 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).

Lithium was compared to olanzapine for the prevention of relapse of bipolar I disorder in a randomized, controlled, double-blind trial. 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.

A number of studies have examined outcomes for subjects stabilized on an antipsychotic added to lithium or valproate and then randomized to remain on lithium or valproate and the antipsychotic or lithium or valproate plus placebo. Notably, these studies include aripiprazole, quetiapine, and ziprasidone; they are enriched designs intended to study the impact of the antipsychotic primarily, but do suggest that those patients who are stabilized on lithium or valproate plus one of those antipsychotics remain on both drugs.

A study was completed specifically to examine whether combination treatment with lithium and valproate together is more effective than either of those two drugs as monotherapy to prevent recurrence in bipolar I disorder. BALANCE is a randomized, open-label trial of lithium, divalproex sodium, or the combination for maintenance treatment in bipolar disorder. Participants were stabilized on both drugs during a 4 to 8-week open-label run-in phase (to screen for tolerability), then randomized to continue on lithium (titrated to at 0.4–1.0 mmol/L), divalproex sodium (750 mg, 1,250 mg, or valproic acid serum concentration at least 50 µg/ml), or the combination, with the primary outcome measure being time to intervention for a mood episode. While combination treatment was superior to divalproex sodium (hazard ratio 0.59, 95% CI 0.42–0.83) and lithium was also superior to divalproex (HR 0.71, 95% CI 0.71–1.00), combination therapy was not superior to lithium (HR 0.82, 95% CI 0.58–1.17). This suggests that the role for valproate monotherapy (i.e., not in combination with lithium) is limited, and that lithium alone or in combination with valproate is the preferred treatment.

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 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. A re-analysis 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.

Lithium in Rapid-cycling Bipolar Disorder

Rapid cycling is no longer included as a course specifier in DSM-5, but continues to be used conceptually by clinicians. Rapid-cycling is defined in DSM-IV-TR as four or more distinct mood episodes (either of opposite poles, or of the same pole after at least 8 weeks of partial or full recovery) within a 12-month period; patients with this course are notoriously difficult to treat and to stabilize. Some have concluded that lithium is less effective than other drugs (e.g., divalproex sodium) for this specific course of bipolar disorder, but an ambitious clinical trial and a large body of naturalistic data suggest that lithium is no less ineffective than other compounds for rapid-cycling. Calabrese and colleagues compared lithium to divalproex sodium in rapid-cycling patients stabilized on both drugs and found no difference between drugs on time-to-episode-recurrence. As testament to the difficulty of treating rapid-cycling, only 60 of the original 254 subjects, who were randomized to the two study conditions, achieved stabilization. In a cohort of 360 patients treated for bipolar disorder in Sardinia, time to recurrence was no different for the patients with or without a rapid-cycling course.

Lithium in Suicide Prevention

Lithium may have anti-suicide effects in patients with mood disorders. While there are no prospective, randomized studies designed to examine lithium's potential to reduce suicide and suicide attempts, a number of meta-analyses, smaller independent studies, and a study from two large health insurance databases generally substantiate lithium's value as a prophylactic agent against suicidal behavior in bipolar disorder.

The strongest evidence for decreased suicide in patients treated with lithium comes from a meta-analysis by Cipriani and co-workers of all randomized studies of lithium (either versus placebo or another drug) in mood disorders (including bipolar disorder and major depressive disorder [MDD]).

They found that lithium-treated patients had significantly fewer suicides and deaths from all causes. In an examination of 32 trials, 1,389 patients were randomly assigned to lithium treatment and 2,069 to other compounds. Seven trials reported any deaths by suicide; subjects treated with lithium were less likely to commit suicide (2 versus 11 suicides; odds ratio = 0.26; 95% CI = 0.09 to 0.77). When suicides plus suicidal behavior (i.e., deliberate self-harm) were examined, the results also favored the lithium-treated group (odds ratio = 0.21; 95% CI = 0.08 to 0.50). In the 11 trials reporting any deaths, all-cause mortality was lower in the lithium group (data from 11 trials; 9 versus 22 deaths; odds ratio = 0.42, 95% CI = 0.21 to 0.87).

In an analysis of databases from two large health maintenance organizations in the US, Goodwin and Goldstein found a strong effect favoring lithium compared to divalproex sodium or other anticonvulsants. The incidence of emergency department admissions for suicide attempts (31.3 versus 10.8 per 1,000 person-years; P < 0.001), suicide attempts resulting in hospitalization (10.5 versus 4.2 per 1,000 person-years; P < 0.001), and death by suicide (1.7 versus 0.7 per 1,000 person-years; P = 0.04) was lower in the group receiving at least one prescription for lithium. When adjusted for a number of demographic factors (including age and psychiatric and medical co-morbidity), they found that the risk of death by suicide was 2.7 times that for patients prescribed divalproex for a diagnosis of bipolar disorder compared to those prescribed lithium (95% CI = 1.1 to 6.3; P = 0.04). The non-randomized nature of the sample, however, leaves open the concern that the groups were clinically different, and the results confounded by indication. For instance, it is not known how many of the patients in the divalproex group had previously failed to respond to lithium and were thus a treatment-resistant group, and whether there were co-morbidities (such as anxiety disorders, personality disorders, or substance use disorders) that were present to a greater degree in the non–lithium-treated subjects. In any case, the results are strongly in favor of lithium and are consistent with other examinations of the effect of lithium on suicide.

Another meta-analysis of 33 studies investigating long-term lithium treatment between the years 1970 and 2000 yields a result that favors lithium as a potential means of suicide prevention. Of the 19 studies comparing groups with and without lithium treatment, 18 found a lower risk of suicide in the treatment group and one had no suicides in either group. Overall, the meta-analysis demonstrated a 13-fold reduction in suicidality for patients with an affective illness, leading to a largely reduced suicide risk (which nevertheless remained larger than that estimated for the general population). The rates of suicide associated with lithium treatment (0.109% to 0.224% annually) are 10 times greater than the international base rate (0.017%).

Lithium discontinuation itself may increase suicide risk. Rapid or accelerated lithium discontinuation (as may be practiced by non-compliant individuals who decide to simply stop taking their medications) may increase risk for suicidal behavior. In a sample of 165 patients who decided to discontinue lithium for a variety of reasons (whether electively or for some medical reason), there was a 14-fold increase in all suicidal acts following discontinuation of lithium. It is unclear whether the risk of suicide following lithium discontinuation exceeds that found in untreated affective illness. Lithium discontinuation may increase suicidal behavior due to higher relapse rates, higher than would be expected even if subjects had been treated with placebo or had been on no medication at all. Ultimately, although the effects of lithium are promising in the realm of suicide prevention, they have not yet been definitively determined (and are likely never to be).