Mood Stabilizers: Lithium Carbonate and Antiepileptics

Julia Jackson

LITHIUM CARBONATE (LITHOTABS, ESKALITH, LITHANE, LITHOBID) AND LITHIUM CITRATE (CIBALITH-S)

Currently, lithium carbonate is approved by the FDA for the treatment of manic episodes of bipolar disorders and for maintenance therapy of bipolar patients. Lithium carbonate is FDA approved for persons 12 years of age and older; however, pediatric approval was based solely on literature supporting its use in adults with bipolar disorder. Over the past three decades, lithium carbonate has been investigated in the treatment of many child and adolescent disorders, but especially in the treatment of children with severe aggression directed toward self or others, children with bipolar or similar disorders, and behaviorally disturbed children whose parents are known lithium responders. One major impetus for this research was that typical antipsychotic agents, which were historically used often to control severe behavioral disorders and sometimes mania, not only could cause cognitive dulling when used in sufficient dosage to control symptoms, but also carried significant risk of causing tardive dyskinesia when used on a long-term basis (Platt et al., 1984).

Pharmacokinetics of Lithium Carbonate

The lithium ion is readily absorbed from the gastrointestinal tract and is most commonly administered in the form of lithium carbonate (Li₂CO₃), a highly soluble salt. Peak plasma concentrations occur within 2 to 4 hours, and complete absorption takes place within approximately 8 hours (Baldessarini, 1990). Approximately 95% of a single dose of lithium is excreted by the kidneys, with up to two-thirds of an acute dose being excreted within 6 to 12 hours. The serum half-life is approximately 20 to 24 hours. Depletion of the sodium ion causes a clinically significant degree of lithium retention by the kidneys. Steady-state serum lithium levels typically occur within 5 to 8 days of repeated identical daily doses of lithium carbonate. Although lithium pharmacokinetics
differs considerably among individuals, they are fairly stable over time for a given person (Baldessarini and Stephens, 1970).

Vitiello et al. (1988) and Malone et al. (1995) studied the pharmacokinetics of lithium carbonate in children. Both discovered a trend toward a shorter elimination half-life and a significantly higher total renal clearance of lithium. The clinical significance of this is that a steady state of lithium is reached more rapidly in children than in adults, and therapeutic levels can be achieved more quickly.

Contraindications for Lithium Carbonate Administration

Administration of lithium carbonate is relatively contraindicated in individuals with significant renal or cardiovascular disease, severe debilitation, severe dehydration, or sodium depletion because these conditions are associated with a very high risk of lithium toxicity. Patients with such disorders should be thoroughly assessed, usually in consultation with the person providing medical care, before beginning lithium therapy.

Except under urgent circumstances, adolescents who are likely to become pregnant should not be administered lithium; this is particularly true of those in early pregnancy. Lithium carbonate is associated with a significant increase in cardiac teratogenicity, especially with Ebstein’s anomaly. A significantly increased incidence of other cardiac anomalies has also been reported. Kallen and Tandberg (1983) reported that 7% of the infants of women who used lithium in early pregnancy had serious heart defects other than Ebstein’s anomaly. Nursing should not be undertaken during treatment with lithium as lithium is excreted in human milk.

Significant thyroid disease is a relative contraindication to lithium carbonate therapy; however, with careful monitoring of thyroid function and the use of supplemental thyroid preparations when necessary, it may be used when other drugs are not effective and the potential benefits outweigh the risks.

Interactions of Lithium Carbonate with Other Drugs

There are several reports that increased neuroleptic toxicity with an encephalo-pathic syndrome or neuroleptic malignant syndrome may occur when lithium and neuroleptics are used concomitantly, but this has usually been seen with high doses. The simultaneous use of lithium and neuroleptic agents, however, may be indicated in some cases of mania or schizoaffective psychoses, and many patients have received both a neuroleptic and lithium with no untoward effects.

Elevations in lithium serum concentration and increased risk of neurotoxic lithium effects may occur when carbamazepine and lithium are used simultaneously because carbamazepine decreases lithium renal clearance. Use of calcium channel blockers in conjunction with lithium treatment has resulted in neurotoxicity including ataxia, tremors, and gastrointestinal symptoms.

Many other drugs may increase or decrease serum lithium levels by influencing its absorption or excretion by the kidneys. For example, cyclooxyneganse-2 (COX-2) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), metronidazole, enalapril, and losartan increase plasma lithium levels. By contrast, sodium bicarbonate, alkalinizing agents, and xanthine preparations lower serum lithium concentrations. Frequent serum drug monitoring should be employed when these types of medications are used together.

Lithium Toxicity

One major difficulty associated with the administration of lithium carbonate is its low therapeutic index; lithium toxicity is closely related to serum lithium levels and may occur at doses of lithium carbonate close to those necessary to achieve therapeutic serum lithium levels. Adverse or side effects are those unwanted symptoms that occur at therapeutic serum lithium levels, whereas toxic effects occur when serum lithium levels exceed therapeutic levels. However, this is not absolute,
as patients who are unusually sensitive to lithium may develop toxic signs at serum levels below 1.0 mEq/L (Physicians’ Desk Reference [PDR], 2000).

Lithium toxicity may be heralded by diarrhea, vomiting, mild ataxia, coarse tremor, muscular weakness and fasciculations (twitches), drowsiness, sedation, slurred speech, and impaired coordination. Patients and/or their caretakers must be made familiar with the symptoms of early lithium toxicity and instructed to discontinue lithium immediately and contact their physician if such signs occur. Increasingly severe and life-threatening toxic effects, including cardiac arrhythmias and severe central nervous system difficulties such as impaired consciousness, confusion, stupor, seizures, coma, and death, may occur with further elevations in serum lithium levels.

No specific treatment for lithium toxicity is available. If signs of early lithium toxicity appear, the drug should be withheld, lithium levels determined, and the medication resumed at a lower dosage only after 24 to 48 hours. Severe lithium toxicity is life threatening and requires hospital admission, treatments to reduce the concentration of the lithium ion, and supportive measures.

Lithium’s low therapeutic index and its pharmacokinetics make it necessary to administer lithium carbonate tablets or immediate-release capsules in divided doses, usually three or four times daily, to maintain therapeutic serum levels without toxicity. Even controlled-release tablets must be administered every 12 hours. It is essential that a laboratory capable of determining serum lithium levels rapidly and accurately be readily available to the clinician. For accuracy and serial comparisons, determinations of serum lithium levels should be made when lithium concentrations are relatively stable and at the same time each day. Typically, blood is drawn 12 hours after the last dose of lithium and immediately before the morning dose (trough level).

Although some patients who are unusually sensitive to lithium may exhibit toxic effects at serum levels below 1 mEq/L, for most patients mild to moderate toxic effects occur at serum levels between 1.5 and 2 mEq/L and moderate to severe reactions occur at levels of 2 mEq/L and above.

Lithium decreases sodium reuptake by the renal tubules; hence, adequate sodium intake must be maintained. This is especially important if there is significant sodium loss during illness (e.g., sweating, vomiting, or diarrhea) or because of changes in diet or elimination of electrolytes. The importance of adequate ingestion of ordinary table salt and fluids should be emphasized. Caution during hot weather or vigorous exertion has been advised, because additional salt loss and concomitant dehydration secondary to pronounced diaphoresis may cause the serum lithium levels of patients on maintenance lithium to increase and move into the toxic range. This may also be true of sweating caused by elevated body temperature secondary to infection or heat without exercise (e.g., sauna), but some evidence suggests that heavy sweating caused by exercise may result in lowered rather than elevated serum lithium levels. Jefferson et al. (1982) studied four healthy athletes who were stabilized on lithium for 1 week before running a 20-km race. At the end of the race, the subjects were dehydrated but their serum lithium levels had decreased by 20%. The authors found that the sweat-to-serum ratio for the lithium ion was approximately four times greater than that for the sodium ion. These authors concluded that strenuous exercise with extensive perspiration was more likely to decrease rather than increase serum lithium levels, and patients were more likely to require either no change or an increase, rather than a decrease, in dosage of lithium to maintain therapeutic levels. The authors do caution, however, that any conditions that significantly alter fluid and electrolyte balance, including strenuous exercise with heavy sweating, should be carefully monitored with serum lithium levels.

Untoward Effects of Lithium Carbonate

Lithium carbonate is frequently reported to have adverse effects early in the course of treatment, though most diminish or disappear during the first weeks of
treatment. Studies show that side effects are more likely to occur in pediatric versus adult patients (Campbell et al., 1984a, 1991).

Early adverse effects include fine tremor (unresponsive to antiparkinsonism drugs), polydipsia, and polyuria that may occur during initial treatment and persist or be variably present throughout treatment. Nausea and malaise or general discomfort may initially occur but usually subside with ongoing treatment. Weight gain, headache, and other gastrointestinal complaints such as diarrhea may also occur. Taking lithium with meals or after meals or increasing the dosage more gradually may be helpful in controlling gastrointestinal symptoms.

Later adverse effects are often related to serum level, including levels in the therapeutic range; these include continued hand tremor that may worsen, polydipsia, polyuria, weight gain and edema, thyroid and renal abnormalities, dermatologic abnormalities (including acne), fatigue, leukocytosis, and other symptoms. As serum levels increase, toxicity increases and other, more severe untoward effects, discussed earlier under toxicity, appear.

The most common adverse effects of lithium carbonate in 61 children, aged 7 to 17 years and diagnosed with bipolar I disorder were nausea (66.7%), headache (65%), vomiting (55%), dizziness (36.7%), diarrhea (30%), upper abdominal pain/tremor (26.7%), and somnolence (18.3%) (Findling et al., 2011). This study involved an 8-week open-label trial of lithium with starting doses of either 300 mg twice daily or 300 mg thrice daily.

Abnormalities in renal functioning (diminution of renal concentrating ability) and morphologic structure (glomerular and interstitial fibrosis and nephron atrophy) have been reported in adults on long-term lithium maintenance. Occasional proteinuria was reported in a 14-year-old girl (Lena et al., 1978). Vetro et al. (1985) reported that after 1 year of lithium treatment, one child developed polyuria with daytime enuresis and impaired renal concentration. Other parameters of renal function did not change, and polyuria ceased within a few days of lithium’s being discontinued. Five other children on long-term lithium therapy showed transient albuminuria that remitted spontaneously, and discontinuation of treatment was not necessary (Vetro et al., 1985). At least four cases of nephrotic syndrome related to pediatric lithium treatment have been reported (Peterson et al., 2008; Sakarcan et al., 2002). In the above cases, discontinuation of lithium resulted in resolution of symptoms. Given that reemergence of proteinuria has been reported during lithium rechallenge, this should be avoided (Peterson et al., 2008). Peterson et al. (2008) argue that because the use of lithium in the pediatric population is likely to increase, periodically monitoring for urine protein, particularly during the first year of treatment, appears reasonable.

Lithium may also interfere with thyroid function, with decreased circulating thyroid hormones and increased thyroid-stimulating hormone (TSH). Vetro et al. (1985) reported that two children developed goiter with normal function after 1.5 to 2 years of lithium therapy. Findling et al. (2011) revealed that 4 out of 61 pediatric patients experienced a treatment-emergent thyroid-related adverse event during an 8-week open-label trial of lithium—hypothyroidism (N = 1) and elevated TSH levels (N = 3). Furthermore, three patients experienced significant changes in levels of antithyroglobulin AB and thyroid peroxidase (N = 1) and increased thyrotropin levels (N = 2) (Findling et al., 2011).

Neuroleptic malignant syndrome has been reported in a few patients who were administered neuroleptic drugs and lithium simultaneously.

Dostal (1972) reported specific adverse effects of lithium in 14 developmentally delayed adolescent males that interfered with patient management despite significant therapeutic gains. Polydipsia, polyuria, and nocturnal enuresis were so severe as to alienate staff who cared for the youngsters. These symptoms remitted within 2 weeks of discontinuing lithium (Dostal, 1972).

Premedication Workup and Periodic Monitoring for Lithium Treatment

Routine Laboratory Tests

Complete Blood Cell Count with Differential

Lithium frequently causes a clinically insignificant and reversible elevation of white blood cells, with counts commonly between 10,000 and 15,000 cells/mm³. The lithium-induced leukocytosis characteristically shows neutrophilia (increased polymorphonuclear leukocytes) and lymphocytopenia (Reisberg and Gershon, 1979). Thus, leukocytosis can usually be differentiated from one caused by infection because the increase in neutrophils is in more mature forms, whereas in infection younger forms predominate. Lithium may also increase platelet counts. Lithium-induced leukocytosis has in fact shown to be medically advantageous in some patient scenarios. For example, Mattai et al. (2009) discovered that six pediatric patients experienced a 66% increase in absolute neutrophil count (ANC) after lithium was added to their clozapine regimen, which bolstered support for the use of lithium to manage clozapine-induced neutropenia (Mattai et al., 2009).

Serum Electrolytes

Serum electrolyte levels should be determined, in particular to verify that sodium ion levels are normal, because hyponatremia decreases lithium excretion by the renal tubules.

Pregnancy Test

Lithium crosses the placenta, and data from birth registries suggest teratogenicity with increased abnormalities, including cardiac malformations, especially Ebstein anomaly. Lithium is relatively contraindicated during pregnancy, especially during the first trimester. Infants born to mothers taking lithium appear to be at increased risk for hypotonia, lethargy, cyanosis, and ECG changes (United States Pharmaco-peial Dispensing Information [USPDI], 1990). All females who could be pregnant should be tested before initiation of lithium therapy and warned that, because of lithium’s teratogenic potential for the fetus, they should take care not to become pregnant while taking the medication.

Renal Function Tests

Baseline assessment of renal functioning is essential because the kidney is the primary route of elimination of lithium. For healthy children and adolescents, a baseline serum creatinine, blood urea nitrogen (BUN) level, and urinalysis are usually adequate and should be monitored every 3 to 6 months during lithium therapy (Kowatch and Delbello, 2003). If kidney disease is suspected or abnormalities are found, a more thorough evaluation, including tests such as urinalysis (including specific gravity), 24-hour urine volume, and 24-hour urine for creatinine clearance and protein, should be performed and the patient should be referred to a nephrologist if necessary.

Thyroid Function Tests

Lithium causes thyroid abnormalities primarily by decreasing the release of thyroid hormones. This causes such findings as euthyroid goiter; hypothyroidism; decreased triiodothyronine (T₃), thyroxine (T₄), and protein-bound iodine (PBI) levels; and elevated¹³¹I and TSH levels between 5% and 15% of patients receiving long-term lithium therapy (Jefferson et al., 1987). Recommended baseline studies include thyroxine (T₄) and TSH levels. Hypothyroidism resulting from lithium treatment is thought to be related to preexisting Hashimoto thyroiditis, suggesting that determining antithyroid antibodies as part of the workup may also be useful (Rosse et al., 1989). Thyroid function tests should be monitored every 3 to 6 months throughout lithium treatment (Kowatch and Delbello, 2003). If there is suggestion of thyroid abnormality during symptom-based or lab screening, consultation with an endocrinologist should be considered.

Cardiovascular Function Tests

Various cardiac conduction and repolarization abnormalities (e.g., bradycardia) and reversible ECG abnormalities have been reported in a large percentage of adults receiving lithium. ECG changes commonly include benign, reversible T-wave changes (flattening, isoelectricity, and inversion of T waves), which are dose dependent, and an increase in the PQ interval (Jefferson et al., 1987). It has been hypothesized that lithium’s cardiotoxic effects result from its displacing and substituting for intracellular potassium. A baseline ECG should be obtained routinely in patients >40 years of age or those who have any history or clinical suggestions of cardiovascular disease. Although not considered mandatory in young, healthy patients, a baseline ECG is justifiable and useful to have for comparison, should cardiovascular abnormalities develop at some later time. If patients have or develop cardiac abnormalities, frequent ECG monitoring should be done in consultation with a cardiologist.

Calcium Metabolism Tests

Lithium may increase renal calcium reabsorption, resulting in hypocalciuria (Jefferson et al., 1987). Lithium may also cause hyperparathyroidism with hypercalcemia and hypophosphatemia, with resulting decreased bone formation or density in children. If abnormal results occur, parathyroid hormone (parathormone) levels may be determined. Lithium may also replace calcium in bone formation, especially in immature bones (USPDI, 1990). A baseline calcium level should be determined in children and adolescents, but a baseline parathormone level is not usually recommended.

Indications for Lithium Carbonate in Child and Adolescent Psychiatry

The following boxed warning appears in the package insert.

NOTE: WARNING: Lithium toxicity is closely related to serum lithium levels, and can occur at doses close to therapeutic levels. Facilities for prompt and accurate serum lithium determinations should be available before initiating therapy.

Lithium carbonate is FDA approved for the treatment of manic episodes of bipolar illness and maintenance therapy of manic-depressive patients, with a history of mania, who are at least 12 years of age. Significant normalization of manic symptomatology may require up to 3 weeks of lithium carbonate therapy; hence concomitant use of antipsychotic medication may be initially required for more rapid control of manic symptoms. See subsequent text regarding titration of dose and recommended serum lithium levels.

Lithium Dosage Schedule

Children up to 11 years of age: Not recommended (see below for studies done in this patient population).
Adolescents at least 12 years of age and adults: Dosage must be individually regulated according to clinical response and serum lithium levels. As noted earlier, the pharmacokinetics of lithium carbonate makes it necessary to administer the total daily dose in smaller doses administered three or four times daily if immediate-release tablets or syrup is used, or twice daily if controlled-release capsules are used, to minimize risk of reaching toxic serum levels of lithium. (More detailed information on administering, titrating, and monitoring lithium in children and adolescents is found in the subsequent text.)

Lithium Carbonate Dose Forms Available

Tablets (Lithotabs): 300 mg
Capsules (Eskalith): 300 mg
Controlled-release tablets (Eskalith CR): 450 mg (scored)
Slow-release tablets (Lithobid): 300 mg
Syrup (lithium citrate): 8 mEq/5 mL (8 mEq of lithium is equivalent to 300 mg of lithium carbonate)

Titration of Lithium Dosage (Ages 12 and Up)

Typically, doses of approximately 1,800 mg/day will achieve the serum lithium levels necessary to control symptoms during acute mania (between 1 and 1.5 mEq/L). During long-term maintenance, serum lithium levels usually range between 0.6 and 1.2 mEq/L; this usually requires a divided daily dose between 900 and 1,200 mg (GlaxoSmithKline, 2003). Berg et al. (1974), however, reported that a 14-year-old girl and her father, who were both diagnosed with bipolar manic-depressive disorder, required daily doses of lithium as high as 2,400 mg to achieve therapeutic levels.

Schou (1969) noted that early untoward effects, such as nausea, diarrhea, muscle weakness, thirst, urinary frequency, hand tremor, and a dazed feeling, may be caused by a too rapid rise in serum lithium levels. Lithium is a gastric irritant. A low initial dose of lithium taken after meals, which slows absorption, and gradual increases in dose will often avert the development of these symptoms. When they develop, they usually subside spontaneously within a few days.

Serum lithium levels should be monitored twice weekly during the acute manic phase and until both serum level and clinical condition have stabilized. In the maintenance phase of therapy during remission, serum lithium levels should be monitored every 3 to 6 months (Kowatch and Delbello, 2003). Lithium levels should be drawn 12 hours after the last dose and prior to the subsequent dose.

Patel et al. (2006) treated 27 adolescents (12 to 18 years old) with an initial lithium carbonate dose of 30 mg/kg/day (twice daily dosing; maximum starting dose of 600 mg PO twice daily), during a 6-week open-label trial of lithium for the treatment of bipolar depression. Seventy percent of subjects achieved a therapeutic level of 1.0 to 1.2 mEq/L over a mean of 18.4 days. The most commonly reported side effects were headache (74%), nausea/vomiting (67%), polyuria (33%), stomachache (30%), polydipsia (26%), and abdominal cramps (19%). Almost all of the side effects were judged to be mild to moderate in severity, and the authors concluded that lithium carbonate was relatively well tolerated in this trial (Patel et al., 2006).

Use of Lithium Carbonate in Children below 12 Years of Age

The therapeutic dosages of lithium carbonate used in treating children above 5 years of age with various disorders do not differ significantly from those used in treating older adolescents and adults, and the principles of administration are essentially the same (Campbell et al., 1984a). This higher-dose-per-body-weight ratio reflects the fact that higher renal lithium clearance occurs in children and adolescents than in adults.

Weller et al. (1986) published a guide for determining the initial total daily lithium dose for prepubertal children 6 to 12 years of age. The guide and summary of how it is used are presented in Table 8.1. Lower initial doses should be used for children diagnosed with mental retardation or organicity (central nervous system damage) (E. B. Weller, personal communication, 1990).

The purpose of this guide is to reach therapeutic serum lithium levels (0.6 to 1.2 mEq/L) as rapidly as possible using currently available tablet strengths without undue risk of reaching toxic serum levels. The authors administered lithium to 10 subjects diagnosed with manic-depressive illness and 5 subjects diagnosed with conduct disorder (CD), following these guidelines. Thirteen of the 15 subjects had serum lithium levels in the therapeutic range after only 5 days of treatment. Side effects were reported to be minimal, primarily mild nausea, abdominal pain, polydipsia and polyuria, and increase in preexisting enuresis. Most were transient, and none required discontinuation of lithium. As discussed earlier, some adverse effects of lithium appear to be related to excessively rapid increases in serum lithium level. It remains to be determined whether the use of the proposed lithium dosage guide will cause significantly more adverse effects or will increase their severity more
than would a more gradual titration of lithium. In cases where very rapid control of symptoms is critical, however, it may be proved to be especially useful.

TABLE 8.1 ≫ Lithium Carbonate Dosage Guide for Prepubertal School-Aged Children

Weight (kg)	8 AM Dose (mg)	12 Noon Dose (mg)	6 PM Dose (mg)	Total Daily Dose (mg)
<25	150	150	300	600
25-40	300	300	300	900
40-50	300	300	600	1,200
50-60	600	300	600	1,500
Dose specified in schedule should be maintained at least 5 days with serum lithium levels drawn every other day 12 hours after ingestion of the last lithium dose until two consecutive levels appear in the therapeutic range (0.6 to 1.2 mEq/L). Dose may then be adjusted based on serum level, side effects, or clinical response. Do not exceed 1.4 mEq/L serum level. Lower initial dose should be used for children diagnosed with mental retardation or organicity.
From Weller EB, Weller RA, Fristed MA. Lithium dosage guide for prepubertal children: a preliminary report. J Am Acad Child Psychiatry. 1986;25:92-95.

Findling et al. (2011) likewise studied lithium dosing in children and adolescents suffering from bipolar I disorder. In this 8-week trial, outpatients aged 7 to 17 years were started on lithium 300 mg twice daily (if <30 kg) or 300 mg twice or thrice daily (for children >30 kg). Doses were then increased by 300 mg per week unless one of the following stop criteria occurred: a therapeutic response was obtained (CGI-I Scale score ≤2 and a 50% decrease in Young Mania Rating Scale [YMRS] score from baseline), youth experienced significant adverse events, doses exceeded 40 mg/kg/day, or the serum lithium level was expected to be >1.4 mEq/L. As mentioned previously, the most commonly observed side effects during this trial were nausea (66.7%), headache (65%), vomiting (55%), dizziness (36.7%), diarrhea (30%), upper abdominal pain/tremor (26.7%), and somnolence (18.3%). The authors concluded that lithium was well tolerated and exhibited similar side-effect profiles in all dosing arms of the study, which led them to conclude that lithium dosed at 300 mg thrice daily (with an additional 300-mg increase during the first week), followed by 300-mg weekly increases until one or more stop criteria are met will be used in upcoming randomized placebo-controlled trials (Findling et al., 2011).

Reports of Interest

Lithium has been widely looked at over the years for the treatment of pediatric bipolar disorder. Older studies consisted primarily of case reports, chart reviews, and only a few small double-blind placebo-controlled trials, though studies completed over the past decade, including larger open and double-blinded controlled trials, have offered increased clarity regarding the efficacy and tolerability of lithium in the treatment of pediatric bipolar disorder.

Lithium Carbonate in the Treatment of Youth Bipolar Disorder

Geller et al. (1998) conducted a 6-week, double-blind, placebo-controlled, parallel-groups study comparing lithium and placebo in the treatment of 25 outpatients (16 males, 9 females; mean age, 16.3 ± 1.2 years) diagnosed by DSM-III-R (American Psychiatric Association [APA], 1987) criteria with a bipolar disorder or major depressive disorder with one or more predictors of future bipolar disorder and substance dependency disorder. The mean age of onset of substance abuse disorders was approximately 6 years after the mean age of onset of subjects’ mood disorders. Subjects did not have to agree to stop their substance abuse to participate in the study. Thirteen subjects were assigned to the lithium group; of these, 10 completed the study. Twelve were assigned to the placebo group and 11 completed the study.

Efficacy was determined by ratings on the Children’s Global Assessment Scale (CGAS) and random weekly urine drug assays. “Responders” were required to have a score of ≥65. Lithium was initiated with a 600-mg dose and was titrated to yield a serum lithium level between 0.9 and 1.3 mEq/L. The total dose was divided and given at 7:00 AM and 7:00 AM daily. The subjects on lithium improved significantly more than those on placebo based on predefined response criteria. Six (60%) of the 10 completers on lithium were “responders,” compared with 1 (9.1%) of the 11 completers on placebo (P = .024). The mean daily lithium dose for the 10 completers was 1,733 ± 428 mg; the responders’ daily dose was significantly higher (1,975 ± 240 mg) than that of the nonresponders (1,368 ± 399 mg; P = .02), but there was no significant difference in their serum lithium levels (responders, 0.88 ± 0.27 mEq/L vs. nonresponders, 0.85 ± 0.3 mEq/L). After 3 weeks, the percentage of positive weekly random urine tests was significantly lower in the lithium group than in the placebo group (P = .042). When symptoms of mania and mood symptoms’ persistence were studied specifically, however, lithium did not separate from placebo. The ratings of untoward effects on the acute lithium side-effects scale showed that lithium was well tolerated. Only polyuria and polydipsia occurred significantly more frequently in the lithium group than in the placebo group. The authors concluded that lithium may be effective for the treatment of adolescents with bipolar disorder and a comorbid substance use disorder, although they acknowledged that further research was needed with larger sample sizes and longer treatment durations.

Kafantaris et al. (2003) conducted a 4-week, open trial of lithium carbonate in treating acute mania in 100 adolescents (mean age, 15.23 years; age range, 12 to 18 years; 50 males, 50 females) who had been diagnosed with bipolar I disorder and met DSM-IV criteria for a current manic or mixed episode and had a score of ≥16 on the YMRS. ADHD was a codiagnosis in 31% of patients. Immediate-release lithium was rapidly titrated to therapeutic serum levels between 0.6 and 1.2 mEq/L using Cooper’s technique (Cooper et al., 1973). Subjects (N = 46) with severe aggression and/or psychosis were treated concomitantly with antipsychotics. Mean lithium serum level at the end of week 1 was 0.90 ± 0.25 mEq/L; at endpoint (week 4), the mean serum level was 0.93 ± 0.21 mEq/L and the mean dose was 1,355 ± 389 mg/day.

Subjects were rated weekly on the YMRS, Hamilton Depression Rating Scale (HDRS, 17 item), Brief Psychiatric Rating Scale (BPRS), Clinical Global Impressions-Improvement (CGI-I) Scale, and the CGAS. Responders were defined as having both a decrease of >33% from baseline YMRS score and a ≤2 rating (much or very much improved) on the CGI-I. At the end of week 4, all the ratings showed significant improvement (P < .001). Sixty-three patients met responder criteria by the end of week 2. Remission of manic symptoms (YMRS score <6) occurred in 26 patients by week 4 and only 4 of the 23 patients with suicidal ideation at baseline had such symptoms by week 4. The authors reported that the presence of baseline psychotic features (with antipsychotic treatment), prominent depressive symptoms, comorbid diagnoses including ADHD, early onset of mood disorders, and severity of mania at initial presentation and hospitalization did not impact significantly on response to lithium at week 4.

Adverse events present at week 4 ratings in >10% of patients included weight gain (1 to 12 lb), 55.3%; polydipsia, 33.3%; polyuria, 25.5%; headache, 23.5%; tremor, 19.6%; gastrointestinal pain, 17.6%; nausea, 15.7%; vomiting, 13.7%; anorexia, 13.7%; and diarrhea, 13.7%.

The study authors concluded that lithium appeared efficacious in the treatment of adolescent mania when used with or without concomitant antipsychotic medication (Kafantaris et al., 2003).

Findling et al. (2006a) conducted a prospective, 8-week, open-label outpatient lithium plus divalproex combination therapy trial for 38 patients ages 5 to 17 years
with bipolar type I or II. The enrolled patients had a mean age of 10.5 years, were previously stabilized with lithium plus divalproex, and subsequently relapsed during treatment with either medication as monotherapy. During the randomized maintenance monotherapy trial, half of the patients received divalproex (target serum concentrations of 0.6 to 1.2 mmol/L), and the other half received lithium (target serum concentrations of 0.6 to 1.2 mmol/L). If subjects evidenced mood relapse by the unblinded physician monitor during the monotherapy phase, they were enrolled in the restabilization study and treated with both lithium and divalproex at doses previously required to achieve stabilization.

Outcome measures included the Children’s Depression Rating Scale-Revised (CDRS-R), and the YMRS. The Clinical Global Impressions (CGI) Scale was used to assess bipolar symptom severity (CGI-S), and the CGAS was used to determine overall functioning at both home and school. Of the 38 patients enrolled in the restabilization phase, 35 completed all 8 weeks (92.1%), whereas 2 withdrew consent and 1 was lost to follow-up. No patients ended the study because of medication intolerance.

At the end of the 8-week \restabilization study, a significant decline in YMRS, CDRS-R, CGAS, and the CGI-S scores were discovered in almost all of the enrolled patients. The authors thus concluded that most youth who initially stabilize with a combination of lithium and divalproex, and subsequently destabilize with monotherapy treatment alone, can be effectively restabilized with prior effective doses of lithium and divalproex. Limitations of the study include its open-label design, short trial duration, and subjects with comorbid diagnoses such as ADHD were allowed to receive concomitant pharmacotherapy, which may have facilitated symptom reduction during the trial, independent of the study medications (Findling et al., 2006).

Pavuluri et al. (2006) studied 38 youth, ages 4 to 17 years, with a history of preschool-onset bipolar disorder during a 12-month open-label trial. All subjects received lithium as monotherapy. Response was defined as a ≥50% decrease from baseline YMRS score. Patients who did not adequately respond to lithium monotherapy after 8 weeks, and those with symptom relapse after an initial positive response, were provided risperidone augmentation for up to 11 months. Of the 38 subjects treated with lithium monotherapy, 17 responded positively and 21 required risperidone augmentation. The response rate for youth treated with both lithium and risperidone was 85.7%. Predictors of inadequate response to lithium monotherapy included the presence of comorbid ADHD, high symptom severity at baseline, history of sexual or physical abuse, and preschool age. The authors concluded that a large percentage of youth with a history of preschool-onset bipolar disorder were either nonresponders or only partial responders to lithium when used as monotherapy. Subsequent augmentation of lithium with risperidone in these cases was judged to be effective and well tolerated during the trial (Pavuluri et al., 2006).

Only one study looked at lithium treatment for youth with bipolar depression (Patel et al., 2006). In this 6-week open-label study, 27 adolescents with an episode of depression associated with bipolar I disorder were treated with lithium 30 mg/kg (twice daily dosing), which was adjusted to achieve therapeutic serum lithium levels between 1.0 and 1.2 mEq/L. Efficacy measures included the CDRS-R and the CGI Scale for Bipolar Disorder (CGI-BP). Response rates were defined as ≥50% reduction in CDRS-R score, and remission rates were defined as a CDRS-R score ≤28 and a CGI-BP Improvement score of 1 or 2. Study results revealed a large effect size of 1.7, a lower response rate of 48%, and a remission rate of 30%. Side effects were deemed to be of mild to moderate severity, and lithium was judged to be relatively well tolerated in this study. Study authors concluded that based on this positive open-label study, lithium may be effective for the treatment of depression in adolescents with bipolar disorder. Future controlled studies are needed to replicate these findings, however (Patel et al., 2006).

Geller et al. (2012) studied 279 antimanic medication-naïve subjects, ages 6 to 15 years, with DSM-IV bipolar I disorder (manic or mixed phase) in a randomized controlled trial assessing response to lithium, risperidone, or divalproex sodium. Blinded independent evaluators conducted all assessments. Medications were increased weekly only if there was inadequate response and if the medication remained well tolerated. Maximum doses of lithium carbonate, divalproex sodium, and risperidone were 1.1 to 1.3 mEq/L, 111 to 125 µg/mL, and 4 to 6 mg, respectively, and primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement-Mania and the Modified Side Effects Form for Children and Adolescents.

Study results revealed statistically significant higher response rates for risperidone (68.5%) versus both lithium (35.6%) and divalproex sodium (24.0%). Lithium versus divalproex sodium response rates did not differ significantly. The authors concluded that risperidone is more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania (Geller et al., 2012).

More recent studies are focusing on whether lithium and other mood stabilizers have neurotrophic roles in treatment. Mitsunaga et al. (2011) sought to study morphometric characteristics of the subgenual cingulate cortex (SGC), which has been implicated in the pathophysiology of mood disorders. Twenty bipolar disorder youth with a mean age of 14.6 years, and 20 age- and gender-matched controls without bipolar disorder underwent high-resolution magnetic resonance imaging. Although no differences were discovered in SGC volumes between bipolar disorder subjects and healthy controls, further analysis revealed that bipolar disorder subjects with prior mood stabilizer exposure, compared with bipolar disorder subjects without prior mood stabilizer exposure and to healthy controls, had significantly increased SGC volumes. This finding led the authors to conclude that mood stabilizer exposure may be correlated with increases in SGC size. The authors describe many limitations to the aforementioned study, however, including a small sample size, concomitant use of atypical antipsychotic medication by study subjects, which may or may not have neurotrophic properties of its own, and the presence of comorbid ADHD in study subjects, a diagnosis which currently has an unknown effects on SGC size (Mitsunaga et al., 2011).

Lithium Carbonate in the Maintenance Treatment of Youth Diagnosed with Bipolar Disorder

Kafantaris et al. (2004), using a 2-week blinded discontinuation study design, randomized 40 prior lithium responders to either lithium or placebo. Prior to the randomized discontinuation phase, lithium responders received 4 weeks of open-label lithium treatment, which yielded average serum lithium levels of 0.99 mEq/L ± 0.21. During the discontinuation phase, 19 adolescents were maintained on lithium monotherapy and 21 received placebo after a 3-day lithium taper. Study authors reported no statistical difference in mood exacerbation rates between lithium monotherapy (52.6%) and placebo (61.9%) and concluded that lithium may be ineffective for maintenance treatment of adolescent bipolar disorder (Kafantaris et al., 2004). Study limitations including small sample sizes and a relatively short open-label treatment lead-in phase prevent firm conclusions from being drawn, and additional studies are needed.

Findling et al. (2005) compared lithium carbonate and valproic acid in the maintenance treatment of youth diagnosed with bipolar disorder and found no clinically significant differences between the two drugs for this indication. This study is summarized in the valproic acid section of the text (Findling et al., 2005).

Lithium Carbonate in the Treatment of Youth with Severe Mood Dysregulation

Severe mood dysregulation (SMD) is defined as a syndrome encompassing severe nonepisodic irritability and hyperarousal in youth (Liebenluft et al., 2003). In 2009, Dickstein et al. studied lithium for the treatment of youth ages 7 to 17 years
with SMD in a randomized double-blind placebo-controlled trial (Dickstein et al., 2009). Subjects who met SMD criteria were gradually weaned off all of their outpatient psychiatric medication, in an inpatient setting, for a total of four drug half-lives. This was followed by a 2-week single-blind placebo run-in phase, after which only those who continued to meet SMD criteria (N = 25) were randomized to either lithium or placebo for the 6-week double-blind randomized controlled trial. The primary clinical outcome measure was a CGI-I score of <4 by the end of the trial. Results revealed not only a relatively small rate of improvement in the lithium group, but also no significance between group differences in outcome measures. This lead the authors to conclude that lithium may not be effective for youth with chronic irritability and hyperarousal. However, given the small sample size, these findings should be considered preliminary (Dickstein et al., 2009).

Lithium Carbonate in the Treatment of Disorders with Severe Aggression, Especially When Accompanied by Explosive Affect, Including Self-Injurious Behavior

In a double-blind, placebo-controlled study of 61 treatment-resistant hospitalized children (age range, 5.2 to 12.9 years) diagnosed with undersocialized aggressive CD, both haloperidol and lithium were found to be superior to placebo in ameliorating behavioral symptoms (Campbell et al., 1984b). Optimal doses of lithium carbonate ranged from 500 to 2,000 mg/day (mean, 1,166 mg/day); corresponding serum levels ranged from 0.32 to 1.51 mEq/L (mean, 0.99 mEq/L). The authors noted that lithium caused fewer and milder untoward effects than did haloperidol and that these effects did not appear to interfere significantly with the children’s daily routines. There was also a suggestion that lithium was particularly effective in diminishing the explosive affect and that other improvements followed (Campbell et al., 1984b).

Campbell et al. (1995) reported a double-blind, placebo-controlled study that was designed to replicate their 1984 study. Fifty treatment-resistant inpatients (46 males, 4 females; mean age, 9.4 ± 1.8 years; age range, 5.1 to 12.0 years) diagnosed with CD, undersocialized aggressive type by DSM-III (APA, 1980a) criteria and having chronic severe explosive aggressiveness were treated with lithium carbonate only or placebo. Following a 2-week, placebo baseline period during which baseline assessments were conducted and placebo responders were eliminated, the 50 remaining subjects were randomly assigned to placebo (N = 25) or lithium (N = 25) for a 6-week period; this was followed by 2 weeks of posttreatment placebo. Efficacy was assessed by ratings on the Global Clinical Judgments (Consensus) Scale, Children’s Psychiatric Rating Scale (CPRS), CGI, Clinical Global Impressions-Severity (CGI-S), and Improvement (CGI-I) Scales, Conners Teacher Questionnaire (CTQ), and the Parent-Teacher Questionnaire (PTQ). Lithium carbonate was begun at 600 mg/day and titrated individually over a 2-week period with a maximum permitted dose of 2,100 mg/day or serum lithium of 1.8 mEq/L or equivalent saliva lithium level. The mean optimal dose of lithium was 1,248 mg/day (range, 600 to 1,800 mg/day); the mean serum lithium level was 1.12 mEq/L (range, 0.53 to 1.79 mEq/L); and the mean saliva lithium level was 2.5 mEq/L (range, 1.45 to 4.44 mEq/L).

On the Global Clinical Judgments (consensus) Scale, 68% (17/25) of subjects on lithium were rated as moderately or markedly improved while only 40% (10/25) of subjects on placebo were so rated (P = .003). Further refining this measure, 40% (10/25) of the subjects of lithium were “markedly” improved versus only 4% (1/25) of the subjects on placebo. The CGI-I scores after 6 weeks were also significantly better for the lithium group (P = .044); although it was not significant whether the lithium group improved more on the CGI-S. The authors concluded that these data supported the conclusions of their earlier study and that lithium carbonate can be efficacious in treating children with CD and explosive
aggressiveness who have not responded to psychosocial treatments or medication with methylphenidate or standard neuroleptics.

Vetro et al. (1985) treated 17 children, aged 3 to 12 years, with lithium, who were hospitalized for hyperaggressivity, active destruction of property, severely disturbed social adjustment, and unresponsiveness to discipline. Ten of the children had not responded to prior pharmacotherapy, including haloperidol and concomitant individual and family therapy. Lithium carbonate was titrated slowly over 2 to 3 weeks to achieve serum levels in the therapeutic range (0.6 to 1.2 mEq/L). Mean serum lithium level was 0.68 ± 0.30 mEq/L. The authors reported that 13 of the children improved enough that their abilities to adapt to their environment could be described as good, and their aggressivity had been reduced to tolerable levels. Three of the four cases that did not improve had poor compliance in taking the medication at home. The authors also noted that these children usually required continuous treatment with lithium for longer than 6 months.

DeLong and Aldershof (1987) reported that rage, aggressive outbursts, and, interestingly, encopresis responded favorably to lithium pharmacotherapy in children with behavioral disorders associated with a variety of neurologic and medical diseases, including mental retardation.

Lithium Carbonate in the Treatment of Children and Adolescents Diagnosed with CD

Malone et al. (2000) conducted a 6-week, double-blind, placebo-controlled, parallel-groups study comparing lithium carbonate and placebo in the treatment of 40 inpatients (33 males, 7 females; mean age, 12.5 years; age range, 9.5 to 17.1 years) who were diagnosed with CD by DSM-III-R (APA, 1987) criteria and hospitalized for chronic, severe aggressive behavior. Eighty-six inpatients entered the study; however, 46 were eliminated during the initial 2-week single-blind placebo baseline; 40 of this group did not meet the protocol’s aggression criteria. All 40 remaining subjects entered the 4-week treatment phase and completed the protocol; 20 subjects were assigned randomly to each group.

Efficacy was determined by ratings on the Global Clinical Judgments (Consensus) Scale (GCJCS), the CGI, and the Overt Aggression Scale (OAS). Lithium was initiated with a 600-mg dose; serum lithium levels were determined 24 hours later, and an initial target dose was calculated for each subject using a nomogram. Subsequent lithium doses were increased by 300 mg daily and given in three equal doses to reach the target dose. At the end of the study, optimal mean lithium dose was 1,425 ± 321 mg/day (range, 900 to 2,100 mg/day) with a mean steady-state therapeutic lithium level of 1.07 ± 0.19 mmol/L (range, 0.78 to 1.55 mmol/L).

On the GCJCS, 16 (80%) of the lithium group versus 6 (30%) of the placebo group were rated as “marked” or “moderately” improved on the criterion for responders (P = .004). Significantly more of the lithium group were also rated as responders on the CGI (17 [30%] vs. 4 [20%] of the placebo group; P = .004). On the OAS, the lithium group continued to show improvement over the 4-week period, whereas the placebo group showed an initial decline at week 1 but then remained rather stable. The lithium group’s mean decrease from baseline was significantly greater than that of the placebo group, with a significant interaction between treatment group and time (P = .04). Although untoward effects were frequent, they were usually mild and similar for both placebo and lithium groups. Only three adverse effects occurred significantly more on lithium: nausea in 12 of 20, vomiting in 11 of 20, and urinary frequency 11 of 20 (P ≤ .05 in all cases). The authors noted that the aggressive behavior of 40 (47.1%) of their initial 85 subjects improved significantly during the first 2 weeks secondary to hospitalization and treatment with placebo alone. For the 40 subjects who remained aggressive and entered the medication phase of the protocol, lithium was a safe and effective treatment. The authors noted that determining the long-term efficacy and safety of lithium in such subjects will require further research.

ANTIEPILEPTICS/MOOD STABILIZERS

Currently, there is robust clinical interest in the off-label use of antiepileptic drugs to treat psychiatric disorders in children and adolescents; their safety and efficacy in treating these disorders remains to be fully elucidated, however. In addition to ongoing research clarifying the question of efficacy and tolerability of antiepileptic medication in youth, research designed to delineate which specific disorders, symptoms, and patients or subgroups of patients are most likely to respond well to antiepileptic medication would be of clear value (e.g., patients with various abnormal EEG findings and patients who are mentally disabled or have other evidence of abnormal central nervous system functioning compared with affectually or behaviorally disordered patients without signs of central nervous system dysfunction).

Valproic Acid (Depakene); Divalproex Sodium (Valproic Acid and Valproate Sodium [Depakote; Depacon])

Note: The FDA has directed the manufacturers of valproic acid and its derivatives (e.g., divalproex sodium and valproate sodium) to label their products with the following Black Box warning. HEPATOTOXICITY: Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. Experience has indicated that children below the age of 2 years are at a considerable increased risk of developing fatal hepatotoxicity, especially those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation and those with organic brain disease. When valproic acid products are used in these patient groups, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. These incidents usually have occurred during the first 6 months of treatment. Serious or fatal hepatotoxicity may be preceded by nonspecific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first 6 months. TERATOGENICITY: Valproate can produce teratogenic effects such as neural tube defects (e.g., spina bifida). Accordingly, the use of valproate products in women of childbearing potential requires that the benefits of its use be weighed against the risk of injury to the fetus. PANCREATITIS: Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

In addition to the Black Box warnings described above, in 2008 the FDA issued an alert advising providers to monitor patients who are taking or starting antiepileptic medication for any changes in behavior that could indicate the emergence of depression or worsening suicidal thoughts or behavior (PDR.net, 2008).

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