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 Mitchner¹⁹ 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 colleagues²⁴ 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-workers²⁷ 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

Lithium in Rapid-Cycling Bipolar Disorder

Rapid-cycling is defined 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.^29–32 Calabrese and colleagues³¹ 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 a testament to the difficulty of treating rapid-cycling, only 60 of the original 254 subjects achieved stabilization and were randomized to the two study conditions. 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.³²

Lithium in Suicide Prevention

Lithium may have antisuicide 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-workers³³ of all randomized studies of lithium (either versus placebo or another drug) in mood disorders (including bipolar disorder and major depressive disorder [MDD]).³³ 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 (N = 20,638) in the United States, Goodwin and Goldstein³⁴ 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 < .001), suicide attempts resulting in hospitalization (10.5 versus 4.2 per 1,000 person-years; P < .001), and death by suicide (1.7 versus 0.7 per 1,000 person-years; P = .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 = .03).³⁴ The nonrandomized nature of the sample, however, leaves open the concern that the groups were clinically different, and the results confounded by indication.³⁵ 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.³⁶ 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.³⁶ Overall, the meta-analysis demonstrated a thirteenfold 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%).³⁶

Lithium discontinuation itself may increase suicide risk. Rapid or accelerated lithium discontinuation (as may be practiced by noncompliant 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 fourteenfold increase in all suicidal acts following discontinuation of lithium.³⁷ 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.²³ 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).

Lithium in Children and Adolescents

Other Uses of Lithium

While well validated for use in the treatment of bipolar disorder, lithium has been studied with greater or lesser success through randomized trials in the treatment of other psychiatric illnesses, including unipolar MDD, schizophrenia, and alcohol dependence.

Predictors of Lithium Response

Few if any reliable predictors of lithium response have been identified. Indeed, on closer look many of the purported predictors have proven to be untrue. Thus, the bulk of evidence suggests that patients with rapid-cycling bipolar disorder respond well to lithium. Likewise, there is little convincing evidence that discontinuation of lithium decreases the likelihood of subsequent response to lithium. There is no evidence that males or females respond differentially to lithium.

Individuals with a positive family history of bipolar disorder (rather than schizophrenia) do appear to respond better to lithium. This is often interpreted, incorrectly, to mean that lithium response itself is familial, which has not been established.

Laboratory Monitoring

The standard evaluation (i.e., with evaluation of renal function, thyroid function, and cardiac rhythm) for a patient beginning lithium flows from its major potential toxicities. Specifically, standard guidelines advise checking electroly-tes, blood urea nitrogen (BUN) and creatinine, thyroid-stimulating hormone (TSH), and an electrocardiogram (ECG) in individuals 40 years or older.

Lithium levels should be checked at least 5 days after each dose change, or any time a patient reports the new onset of symptoms potentially suggestive of lithium toxicity. Guidelines also recommend following electrolytes, BUN, and creatinine up to every 2 months for the first 6 months, with a lithium level, BUN, creatinine, and thyroid function tests every 6 months to 1 year thereafter.

Lithium Dosing

Lithium carbonate is available in 300 mg capsules or tablets, as well as 300 and 450 mg slow-release forms. A liquid, lithium citrate, is also available, in 300 mg/5 ml form. For most patients, the immediate-release lithium carbonate is initiated first, with a switch to another form only to maximize tolerability if necessary.

The narrow therapeutic window for lithium treatment (see Pharmacokinetics and Pharmacodynamics, earlier in this chapter) complicates lithium dosing. Indeed, in its early application lithium levels of 0.8 to 1.2 mEq/L were advised, while more recently levels of 0.6 to 0.8—and perhaps even lower in some cases—have been advocated. The optimal dose is driven, not merely by considerations of efficacy, but by tolerability as well: that is, the “best” dose for prevention of recurrence may be too high for some patients to tolerate. Drug-drug interactions must be considered, and a list of selected interactions is provided in Table 47-1.

Table 47-1 Medications That Commonly Interact with Lithium

ACE, Angiotensin-converting enzyme; NSAIDs, nonsteroidal antiinflammatory drugs; SSRIs, selective serotonin reuptake inhibitors.

Typically, the clinician will begin with 600 mg once daily at bedtime and then increase it to 900 mg at bedtime. After 5 days, a lithium level is checked and the dose is increased or decreased as required to attain a level in the 0.6 to 0.8 mEq/L range. While nomograms exist for predicting the necessary lithium dose based on an initial test dose, because of concerns about lithium toxicity, the authors generally prefer to observe the level that results from 900 mg before titrating further.

Some data suggest that lithium may be better tolerated by patients, and possibly less likely to cause renal complications, when dosed once daily. If tolerability of a single dose becomes a problem—for example, in terms of sedation or gastrointestinal distress—divided dosing may be used. This need not be morning and night; some patients prefer dinnertime and bedtime.

Adverse Effects and Their Management

Hypothyroidism has been reported to be common in patients treated with lithium, with some studies describing a prevalence of up to 35%. However, more recent studies suggest that it is substantially less common, and is seen more often among women than men. When hypothyroidism occurs, it is typically managed with the addition of thyroid (T₄) treatment.

Lithium has a number of renal effects, which range from bothersome to potentially life-threatening. Perhaps the most common, polyuria (including nocturia) and consequent polydipsia, arise when lithium prevents distal tubule reabsorption of free water, antagonizing the actions of antidiuretic hormone. When necessary, they may be addressed with careful addition of a diuretic. Amiloride is often used first, as it has little effect on lithium levels. Thiazide diuretics may also be used if required, though they will increase lithium levels and often require a dose decrease of 50% and close monitoring of lithium levels. When edema (particularly common in the lower extremities) is seen in a patient with normal renal function, the diuretic spironolactone may be used, though again lithium levels and renal function will require close monitoring.

Of greater concern, long-term treatment with lithium is associated with reduction in creatinine clearance in about 10% of patients, indicating a decrease in glomerular filtration rate (GFR). Small studies suggest that glomerulosclerosis and interstitial fibrosis are seen among some patients receiving long-term lithium treatment. Beyond a certain point, this deterioration may accelerate and dramatically increase the risk of lithium toxicity, as small perturbations in GFR can have large effects on lithium levels. When creatinine rises above baseline by 25% or more, consultation with a nephrologist may be helpful to rule out other contributors to reduction in GFR (e.g., renal complications of diabetes mellitus [DM]), and discontinuation of lithium often becomes necessary once GFR decreases beyond a certain point.

While rare, lithium can cause a depression of firing at the sinoatrial node, contributing to sinus arrhythmias. Lithium may also cause benign ECG abnormalities, most typically an appearance resembling hypokalemia, including widening of the QRS complex and increased PR interval.

Weight gain is common among lithium-treated patients, and while the mechanism is not known, it is not merely a result of lithium-induced edema. Some studies suggest that up to half of lithium-treated patients will experience a 5% to 10% increase in weight. As with any medication-induced weight gain, early and aggressive intervention is warranted, focusing on both diet and exercise. A specific concern among lithium-treated patients with polydipsia is the consumption of sodas or juices high in sugar.

Cognitive complaints are common among lithium-treated patients, sometimes characterized as feeling “foggy” or “cloudy.” Adjunctive thyroid hormone is sometimes used in an attempt to ameliorate these symptoms; however, there is no well-established means of treating such complaints, other than decreasing lithium dose.

Other Bothersome Adverse Effects

Gastrointestinal adverse effects are common among lithium-treated patients, and may include upper (nausea, vomiting, and dyspepsia) and lower (diarrhea and cramping) gastrointestinal symptoms. Because slow-release formulations are absorbed lower in the gut, they are more often associated with the latter symptoms, while immediate-release formulations are more often associated with the former symptoms. In many cases, dividing dosages or dosing with food can minimize or eliminate these symptoms. If this is not the case, a switch to lithium citrate (in liquid form) may be helpful, though some patients object to the taste of this preparation.

Tremor is common with lithium treatment, even at therapeutic levels and particularly following each dose when peak levels are achieved. This tremor, which resembles a benign physiological tremor, may be exacerbated by caffeine and by anxiety. It is typically managed by changing the timing of the lithium dose (to ensure that peak levels occur during sleep) and when necessary by adding a beta-adrenergic blocker. This may be used on either an as-needed or a standing basis, depending on patient preference. Propranolol is often initiated first to establish an effective dose, then changed to atenolol for the convenience of once-daily dosing.

Both psoriasis and acne exacerbations have been associated with lithium treatment. Typically these do not require treatment discontinuation as they can be controlled with dermatological treatments.

Presentation and Management of Lithium Toxicity

As lithium levels rise above 1.2 mEq/L, initial symptoms may include slurring of speech, ataxia/unsteady gait, confusion, and agitation. Table 47-2 shows signs and symptoms of lithium toxicity, and Table 47-3 shows management of acute toxicity.

Table 47-2 Signs of Lithium Toxicity

* Absence of significant symptoms does not rule out toxicity; likewise, some symptoms may be apparent at levels as low as 1 mEq/L.

Table 47-3 Management of Lithium Toxicity

* Recommendations vary about when to initiate dialysis, though most sources agree that levels above 4 mEq/L merit immediate dialysis.

Lithium in Pregnancy and Breast-feeding

Lithium use during the first trimester of pregnancy has been associated with a potentially life-threatening cardiac abnormality, known as Ebstein’s anomaly, a spectrum of changes that typically includes insufficiency of the tricuspid valve and hypoplasia of the right ventricle. The risk appears to be about tenfold greater among children of lithium-treated patients compared to those in the general population, though the absolute risk is still quite low (on the order of 1 in 2,000). This risk must be balanced against the substantial dangers to the fetus of a mother with uncontrolled bipolar disorder during pregnancy.

The changes in maternal fluid status during pregnancy typically cause a larger volume of distribution for lithium, which can lead to a decrease in lithium levels, entailing closer monitoring of lithium during pregnancy and in some cases a dose increase. At the time of delivery, fluid shifts may likewise lead to an increase in lithium levels. However, discontinuing lithium in the peripartum period is no longer routinely advised, as it has become clear that the risk of bipolar recurrence is extremely high in this period.

Levels of lithium in breast milk are substantial, approaching 50% of maternal plasma levels. For this reason, lithium-treated mothers should not breast-feed, as the effects of lithium on newborn development are not well studied and the risk for toxicity is high.

Lithium Adherence

Recent studies document very low rates of lithium adher-ence in bipolar disorder, particularly in a cohort of patients participating in a health maintenance organization.⁵² These studies highlight the importance of careful lithium dosing and aggressive management of adverse effects.