Lithium in Child and Adolescent Bipolar Disorder

Lithium was first used as a pharmacological agent in 1847 by Alfred Garrod, who prescribed the medication for “brain gout” (1). However, Dr. William Hammond at Bellevue Hospital, in 1871, was the first physician to prescribe lithium for mania “to diminish the amount of blood in the cerebral vessels, and to calm any nervous excitement that may be present” (1). John Cade reintroduced lithium to modern psychiatry in 1949, when he used it to treat 10 manic patients (1). By 1970, on the basis of four controlled trials of 116 adults demonstrating an average response rate of 78%, the Food and Drug Administration (FDA) approved lithium for acute mania in adults. It was not until the early 21st century that lithium became the first FDA-approved medication for the treatment of mania in youths aged 12–17, mostly based on adult trials (2). Given the dearth of methodologically stringent studies in the pediatric population, the FDA requested the creation of the Collaborative Lithium Trials to systematically assess lithium's efficacy and safety in pediatric bipolar disorder, a process that is still unfolding (3, 4).

Mechanism of Action

The best evidence surrounding lithium's mechanism of action for antimanic properties involves the inositol depletion hypothesis (5). This hypothesis suggests that lithium dampens second messenger transmission by inhibiting inositol monophosphatase (IMPase). Since neurons cannot obtain free inositol from the plasma due to inositol's inability to cross the blood-brain barrier, neurons are solely reliant on IMPase to generate free inositol, important for neurons' second messenger systems. Therefore, when firing rates of neurons are abnormal, as in acute mania, lithium can dampen second messenger transmission. Finally, Chiu et al. (6) point to lithium's neurotrophic and angiogenic effects, which enhance synaptic plasticity.

Pharmacokinetics and Drug Interactions

After oral administration, lithium is absorbed and reaches peak serum levels in 1–3 hours. Peak neural concentrations occur about 24 hours later due to the lower permeability of the blood-brain barrier (7). Lithium then circulates unbound to plasma proteins throughout total body water until the kidneys finally excrete it un-metabolized (5). Like sodium, lithium is 70%–80% reabsorbed by the proximal renal tubules, and because this reabsorption is competitive between lithium and sodium, anything causing sodium deficiency will increase serum lithium levels (5). For example, dehydration, sodium restriction, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, thiazide diuretics, and intrinsic renal disease will all acutely cause lithium levels to increase. The elimination half-life of lithium is 24+/–8 hours and is maximal in the first few hours after peak levels are achieved (7).

Findling et al. (3) found that when specifically tested in the pediatric population (average age: 11.8 years), the average half-life was 17.9 hours, and the investigators concluded that children have a shorter elimination half-life and greater clearance compared with adults due to the fact that clearance is correlated with total body weight and fat-free mass.

Clinical Use

Optimal dosing strategies have been extensively studied in the pediatric literature. Findling et al. (8) argued for starting children, ages 7–17 and weighing 30 kg or more, on lithium 300 mg either twice or thrice daily and increasing the dose by 300 mg weekly thereafter, as tolerated to efficacy. This strategy yielded mean total daily doses of 1500.0 mg (SD=400.9 mg) and a mean weight-adjusted total daily dose of 29.1 mg/kg/day. The mean serum concentration was accordingly 1.05 mEq/L.

As in adults, target serum concentrations in pediatric acute mania range from 0.8 to 1.2 mEq/L, with toxic effects and cessation of dose escalations occurring between 1.2 and 1.4 mEq/L (3, 4). Since the clearance of lithium is decreased overnight, bedtime doses can be reduced, with subsequent improvement in tolerability as a result of the decreased dose (7). This dosing structure thus allows for less polyuria, reduces problematic sedation and fatigue, and over time may reduce renal glomerular abnormalities.

Clinical Efficacy

Although lithium has consistently proven to be efficacious and acceptable in the treatment of adult acute mania (9), the results have been less conclusive in the treatment of acute pediatric mania. Following a review of four pediatric open-label trials of lithium in mania from 1989 to 2010, which indicated a collective average response rate of 40%, more recent systematic work has assessed lithium's clinical efficacy (10).

Masi et al. (11) performed a naturalistic study in which 282 children (mean age: 13.8 years) meeting DSM-IV criteria for mania or hypomania initially received monotherapy with lithium or valproate. For those who did not respond, as defined by a Clinical Global Impression-Improvement scale (CGI-I) score of 3 or higher, the other mood stabilizer (or an antipsychotic for psychotic symptoms) was added according to clinician judgment. Sixty percent of patients treated with lithium (either monotherapy or combination) responded at 6 months. Although patients often received polypharmacy with antipsychotics, selective serotonin reuptake inhibitors, and stimulants, this study provides a real-world example indicating that polypharmacy may provide additional benefits in naturalistic settings, with lithium as a beneficial option.

The Treatment of Early Age Mania (TEAM) study (12, 13) assessed possible treatment paradigms in pediatric mania. Phase one (12) studied 279 children, ages 6-15, with DSM-IV bipolar I disorder (manic or mixed state) in a controlled, randomized 8-week study protocol. Response was defined as scoring 1 or 2 on the CGI-BP-IM scale. Phase one demonstrated risperidone's superiority to both lithium and valproate, with response rates of 68.5%, 35.6%, and 24.0%, respectively. It should be noted that at baseline, 77.1% of the patients had psychotic features. For the 64 subjects without psychosis, the greater response rate of risperidone versus lithium was not statistically significant.

Phase two studied the 89 nonresponders and 65 partial responders from phase one for an additional 8 weeks. The nonresponders were randomly switched to one of the other medications, while the partial responders received one of the other medications as an add-on. Though nonresponders who were switched to risperidone responded more frequently than those who were switched to lithium (47.6% versus 12.8%; p=0.005), the higher response rate of the partial responders receiving add-on risperidone (53%) versus add-on lithium (26.7%) was nonsignificant. Therefore, the results of the TEAM study indicate that in a pediatric population with heavy psychosis at baseline, although risperidone outperformed lithium for first-line treatment, lithium might be reasonable to add-on in children partially responding to risperidone or valproate.

Finally, Findling et al. (14) performed a randomized, double-blind placebo-controlled study of lithium in the acute treatment of mania. Eighty-one children, ages 7–17, diagnosed with DSM-IV bipolar disorder (manic or mixed episode) qualified for this 8-week study. The primary outcomes analyzed the change in Young Mania Rating Scale (YMRS) scores, while secondary measures assessed response and remission, defined as greater than 50% reduction in baseline YMRS scores, CGI-I scores of 1 or 2, YMRS scores less than 13, and CGI-severity scores less than 3, respectively. Lithium was significantly greater at reducing manic symptoms as measured on the YMRS (p=0.03). Superiority of lithium over placebo in response (32% versus 21%) and remission (26% versus 14%) fell short of statistical significance.

Several other pediatric trials discuss lithium's efficacy in maintaining stability after acute mania response (15), treating depressive symptoms of pediatric bipolar disorder (16), and improving behavior in children with conduct disorder (17).

For acute mania, however, more placebo-controlled studies, which take into account the complexity of diagnosing pediatric mania (18), are required to support the clinical consensus that lithium is a first-line treatment for pediatric bipolar disorder. However, as more children seemingly present with comorbidity, lithium's clinical efficacy–and treatment of pediatric bipolar disorder in general–may be improved with more than one mood stabilizer (11, 15).

Side Effects

The most cited adverse effects, most of which were studied in adult populations, are presented in Table 1 (5). The aforementioned clinical pediatric trials have reported the most common adverse effects associated with lithium to be gastrointestinal discomfort, weight gain, headache, and tremor (4, 10, 12, 14, 15). While less common, other potential side effects include leukocytosis, hypothyroidism, and renal tubular dysfunction. Additionally, though an association between lithium exposure and Ebstein's anomaly has been reported, no causal relationship has been established, and the absolute risk remains less than 0.1% (19). As a result of these adverse effects, treatment guidelines (18) indicate that baseline workup prior to initiating lithium includes a complete blood count, thyroid and renal function tests, and pregnancy test. Once achieving a stable lithium dose, lithium levels and renal and thyroid function tests, every 3–6 months, are warranted. In adult studies, most of the adverse effects are dose-dependent and thus improve with reduction in dosage. Other off-label treatment options for problematic adverse effects include amiloride for polyuria, beta-blockers for tremor, and levothyroxine for hypothyroidism (20).

Conclusions

Lithium is a useful and safe medication in the treatment of acute mania in children and adolescents with bipolar disorder. It is a medication that has been studied in modern psychiatry since 1949 and functions likely by depleting inositol in neurons. While it does not affect other drug levels, its own drug level, which correlates with efficacy, is affected by several medications and physical conditions. It is generally tolerated, but several treatment-emergent effects exist, such as gastrointestinal, thyroid, renal, and weight abnormalities. Though pediatric bipolar disorder includes symptoms such as irritability and other symptoms shared by other pediatric psychiatric conditions (18), lithium has increasingly proven efficacious in the treatment paradigm of pediatric bipolar disorder.

Key Points/Clinical Pearls