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Lithium: Pediatric drug information

Lithium: Pediatric drug information
(For additional information see "Lithium: Drug information" and see "Lithium: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Monitoring:

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.

Brand Names: US
  • Lithobid
Brand Names: Canada
  • APO-Lithium Carbonate;
  • Carbolith;
  • DOM-Lithium Carbonate;
  • Lithane;
  • Lithmax;
  • PMS-Lithium Carbonate
Therapeutic Category
  • Antidepressant, Miscellaneous;
  • Antimanic Agent
Dosing: Pediatric

Note: Lithium oral solution has been discontinued in the United States for >1 year. Monitor serum concentrations and clinical response (efficacy and toxicity) to determine proper dose. Each 5 mL of lithium oral solution contains 8 mEq of lithium ion, equivalent to the amount of lithium in 300 mg of lithium carbonate immediate-release capsules/tablets.

Bipolar disorder: Oral:

Immediate release: Children ≥7 years and Adolescents: Limited data available in weight <20 kg: Note: Dosing in weight <20 kg extrapolated from clinical experience (Gal 2007).

Lithium carbonate capsule or tablet:

Patient weight <30 kg: Initial: 300 mg twice daily, increase dose at weekly intervals in 300 mg/day increments as tolerated to clinical response and goals based on type of therapy (acute or maintenance).

Acute therapy: Titrate dose to 600 to 1,500 mg/day in divided doses and target serum lithium concentration of 0.8 to 1.2 mEq/L; a maximum dose is not described in the manufacturer labeling; in trials, weight-dependent maximum daily doses were reported: Patients <23 kg: 900 mg/day; patients ≥23 kg: 40 mg/kg/day and doses were not further increased if serum lithium concentration was ≥1.4 mEq/L. In a multicenter, double-blind, placebo-controlled efficacy trial for treatment of acute mania, the mean effective daily dose was 956 ± 225 mg/day. For all patients in the trial (regardless of weight) the mean final dose was: 30.5 ± 8.7 mg/kg/day (Findling 2011; Findling 2013; Findling 2015).

Maintenance therapy: Titrate dose to 600 to 1,200 mg/day in divided doses and target serum trough concentration of 0.8 to 1 mEq/L as tolerated.

Patient weight ≥30 kg: Initial: 300 mg 3 times daily, increase dose in 300 mg/day increments every 3 days as tolerated to clinical response and goals based on type of therapy (acute or maintenance).

Acute therapy: Titrate dose to 600 mg twice or 3 times daily and target serum lithium concentration of 0.8 to 1.2 mEq/L; a maximum dose is not described in the manufacturer labeling; in trials, reported doses did not exceed a maximum daily dose of 40 mg/kg/day and doses were not further increased if serum lithium concentration was ≥1.4 mEq/L. In a multicenter, double-blind, placebo-controlled efficacy trial for treatment of acute mania, the mean effective daily dose was 1,583 ± 524 mg/day. For all patients in the trial (regardless of weight) the mean final dose was 30.5 ± 8.7 mg/kg/day (Findling 2011; Findling 2013; Findling 2015).

Maintenance therapy: Titrate dose to 300 to 600 mg twice or 3 times daily and target serum trough concentration of 0.8 to 1 mEq/L as tolerated; in a long-term trial, doses were not further increased if serum lithium concentration was ≥1.4 mEq/L (Findling 2013).

Lithium oral solution:

Patient weight <30 kg: Initial: 8 mEq twice daily, increase dose at weekly intervals in 8 mEq increments as tolerated to clinical response and goals based on type of therapy (acute or maintenance).

Acute therapy: Titrate dose to 16 to 40 mEq/day in divided doses and target serum lithium concentration of 0.8 to 1.2 mEq/L; a maximum dose is not described in the manufacturer labeling; in trials, weight-dependent maximum daily doses were reported: Patients <23 kg: 900 mg of lithium carbonate/day; patients ≥23 kg: 40 mg of lithium carbonate/kg/day and doses were not further increased if serum lithium concentration was ≥1.4 mEq/L (Findling 2011; Findling 2013; Findling 2015).

Maintenance therapy: Titrate dose to 16 to 32 mEq/day in divided doses and target serum trough concentration of 0.8 to 1 mEq/L as tolerated and doses were not further increased if serum lithium concentration was ≥1.4 mEq/L (Findling 2011; Findling 2013; Findling 2015).

Patient weight ≥30 kg: Initial: 8 mEq 3 times daily, increase dose in 8 mEq increments every 3 days as tolerated to clinical response and goals based on type of therapy (acute or maintenance).

Acute therapy: Titrate dose to 16 mEq twice or 3 times daily and target serum lithium concentration of 0.8 to 1.2 mEq/L; maximum doses are not described in the manufacturer labeling; in trials, reported doses did not exceed a maximum daily dose of: 40 mg of lithium carbonate/kg/day and doses were not further increased if serum lithium concentration was ≥1.4 mEq/L (Findling 2011; Findling 2013; Findling 2015).

Maintenance therapy: Titrate dose to 8 to 16 mEq twice or 3 times daily and target serum trough concentration of 0.8 to 1 mEq/L as tolerated; in a long-term trial, doses were not further increased if serum lithium concentration was ≥1.4 mEq/L (Findling 2013).

Extended release: Children ≥12 years and Adolescents: Weight-based usual daily dosing administered in 2 divided doses: <22 kg: 600 mg/day; 22 to 41 kg: 900 mg/day, and >41 kg: 1,200 mg/day (Kliegman 2016). In an open-label trial of 27 subjects (age range: 12 to 18 years), an initial dose of 15 mg/kg/dose twice daily, maximum initial dose: 600 mg/dose, with dose titration at weekly intervals as tolerated to target serum lithium concentration of 1 to 1.2 mEq/L was used (Patel 2006). In adults, therapy is initiated at a low dose (eg, 450 mg 2 times daily or less); increased gradually based on response and tolerability (APA 2002); the usual adult dosage is 900 to 1,800 mg/day in 2 divided doses.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Immediate release: Children ≥7 years and Adolescents:

CrCl >89 mL/minute: No dosage adjustment required.

CrCl 30 to 89 mL/minute: Initiate therapy with low dose; titrate slowly with frequent monitoring.

CrCl <30 mL/minute: Avoid use.

Extended release: Children ≥12 years and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; monitor renal function closely during therapy and re-evaluate treatment with any changes in renal function.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Adult

(For additional information see "Lithium: Drug information")

Note: Lithium oral solution has been discontinued in the United States for >1 year.

Note: Safety: Only prescribe in settings where serum concentration monitoring is available. Toxic effects occur with serum concentrations ≥1.5 mEq/L and may be seen in some patients with serum concentrations as low as 1.2 mEq/L (Janicak 2021). Formulations: Available formulations include oral IR tablets and capsules as carbonate salt (initially dosed 2 to 3 times daily), ER carbonate tablets (initially dosed 2 times daily), and oral solution as citrate salt (initially dosed 2 to 3 times daily); if initial dose is ≤300 mg/day, may initiate as once daily regardless of formulation (Gitlin 2021). Lithium citrate 5 mL (8 mEq) oral solution is equivalent to carbonate 300 mg tablets/capsules. Lithium oral solution has been discontinued in the United States for >1 year. All doses in this monograph are expressed as the equivalent amounts of lithium carbonate salt. To convert between formulations, see Dosing Conversion below. Conversion to once-daily dosing: To improve tolerability, initiate total daily doses >300 mg/day with 2 or 3 divided daily doses. After several weeks at an established dose and stable serum concentrations, may consolidate schedule to a single dose of immediate release or extended release at bedtime (Carter 2013).

Bipolar disorder

Bipolar disorder (monotherapy or combination therapy):

Acute mania, acute episodes with mixed features (labeled use), acute hypomania (off-label use), or acute bipolar major depression (alternative agent) (off-label use): For most patients, a therapeutic response occurs with serum concentrations between 0.8 and 1.2 mEq/L; some respond to lower levels (eg, 0.6 mEq/L). For treatment of acute severe mania, typically given in combination with an antipsychotic or antiseizure drug (CANMAT/ISBD [Yatham 2018]; Janicak 2021; Stovall 2020).

Oral: Immediate release or extended release: Initial: 600 to 900 mg/day in 2 to 3 divided doses based on chosen formulation; increase based on response and tolerability by 300 to 600 mg every 1 to 5 days to usual therapeutic dose range of 900 mg/day to 1.8 g/day in 1 to 3 divided doses based on tolerability or chosen formulation. After 5 to 7 days at a stable therapeutic dose, further adjust as needed based on clinical response, tolerability, and serum concentration (Calabrese 2005; Janicak 2021; manufacturer's labeling). Also see “Note: Formulations” and “Note: Conversion to Once-Daily Dosing” above.

Maintenance treatment to prevent manic or depressed episodes: Note: Continue regimen (ie, monotherapy or combination) that was used to achieve control of the acute episode; a lower dose and serum concentration at the lower end of the therapeutic range may suffice for some patients. (CANMAT/ISBD [Yatham 2018]).

Major depressive disorder, unipolar

Major depressive disorder, unipolar (alternative agent; adjunctive therapy) (off-label use): For most patients, a therapeutic response occurs with serum concentrations between 0.6 and 1.2 mEq/L; some respond to lower serum concentrations (Gitlin 2021; Nierenberg 2006). Peak clinical improvement may take up to 6 weeks when lithium is used for antidepressant augmentation for acute depression (APA 2010; Stein 1993).

Oral: Immediate release or extended release: Initial: 300 to 600 mg/day in 1 to 2 divided doses; may increase based on response and tolerability every 1 to 5 days to a target dose of 600 mg to 1.2 g/day in 1 to 3 divided doses based on tolerability or chosen formulation (Bauer 2003; Gitlin 2021). Also see “Note: Formulations” and “Note: Conversion to Once-Daily Dosing” above.

Dosing conversion: To convert between IR and ER capsules/tablets, administer the same total daily dose. Initially administer IR daily dose in 2 to 3 divided doses and ER daily dose in 2 divided doses. If initial dose is ≤300 mg/day, may initiate as once daily regardless of formulation (Gitlin 2021). After several weeks at an established dose, may consolidate schedule to a single dose of immediate release or extended release at bedtime (Carter 2013; Janicak 2021). When taken as a single dose per day, serum trough concentrations are 10% to 26% higher compared to serum trough concentrations with divided doses, due to changes in renal excretion (Mitchell 2001; Singh 2011). Individual dosage adjustments may be necessary.

Discontinuation of therapy: Gradual dose reduction is advised to avoid disease recurrence unless discontinuation is due to significant adverse effects. If it is necessary to switch to a different drug during acute treatment, decrease the lithium dose over 1 to 2 weeks (eg, by 300 mg each day or every other day) (Kupka 2021; Stovall 2021). In order to detect disease recurrence when discontinuing maintenance treatment for bipolar disorder, decrease lithium over several weeks to months when feasible (Post 2021).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS

Note: Lithium is primarily excreted via the kidneys and clearance correlates directly with glomerular filtration rate (Clericetti 1991; Kamper 1989). Because of the risk of lithium-related nephrotoxicity, routine monitoring of serum lithium levels and kidney function are recommended in patients with reduced kidney function (Rej 2015).

Altered kidney function: Oral:

CrCl ≥60 mL/minute: No dosage adjustment necessary (expert opinion).

CrCl 30 to <60 mL/minute: Initiate at low doses (eg, 150 to 300 mg/day) in 1 to 2 divided doses, titrate slowly based on clinical response and tolerability, monitor levels frequently (expert opinion).

CrCl <30 mL/minute: Avoid use (manufacturer's labeling; expert opinion).

Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Younger patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Bilbao-Meseguer 2018; Udy 2010).

Oral: No data available. Consider dose adjustments based on serum lithium levels (expert opinion).

Hemodialysis, intermittent (thrice weekly): Dialyzable (80%) (Engels 2019); lithium levels drawn immediately post hemodialysis may be inaccurate/falsely low as equilibration of lithium from tissue compartments into the blood stream occurs (also known as "rebound"):

Oral: Avoid use when possible. Consider use of an alternative therapy, especially in patients with significant residual kidney function due to risk of lithium-induced kidney damage. If necessary, initiate therapy at 300 mg 3 times weekly after dialysis; gradually titrate based on clinical response, tolerability, and serum lithium levels (Engels 2019; McGrane 2021; expert opinion). In some patients, daily dosing may be required to achieve targeted lithium serum levels (Engels 2019; McGrane 2021).

Peritoneal dialysis: Dialyzable (less than hemodialysis) (Brown 1981; Wilson 1971):

Oral: Avoid use when possible. Consider use of an alternative therapy, especially in patients with significant residual kidney function due to risk of lithium-induced kidney damage. If necessary, start at low dose (eg, 150 mg daily); gradually titrate based on clinical response, tolerability, and serum lithium levels (expert opinion).

CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) and minimal residual kidney function unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important.

Oral: Avoid use (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important.

Oral: Avoid use (expert opinion).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, as carbonate:

Generic: 150 mg, 300 mg, 600 mg

Solution, Oral, as citrate:

Generic: 8 mEq/5 mL (500 mL [DSC])

Tablet, Oral, as carbonate:

Generic: 300 mg

Tablet Extended Release, Oral, as carbonate:

Lithobid: 300 mg [contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #6 aluminum lake]

Generic: 300 mg, 450 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as carbonate:

Carbolith: 150 mg, 300 mg [contains fd&c yellow #6 (sunset yellow)]

Carbolith: 600 mg [contains brilliant blue fcf (fd&c blue #1)]

Lithane: 150 mg, 300 mg

Generic: 150 mg, 300 mg, 600 mg

Tablet Extended Release, Oral, as carbonate:

Lithmax: 300 mg

Product Availability

Lithium oral solution has been discontinued in the United States for >1 year.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Lithium: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/017812s034,018421s033,018558s028lbl.pdf#page=20

Administration: Pediatric

Oral: Administer with meals to decrease GI upset. Do not crush or chew extended release dosage form; swallow whole

Administration: Adult

Oral: Administer with meals to decrease GI upset. ER tablets must be swallowed whole; do not crush or chew.

Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. If tablet is scored, may cut in half. Options include to switch to IR capsule or tablet; be aware that the peak serum concentration is reached much faster than the extended release and if capsules are opened or tablets crushed, this could be reached even faster and patient may experience stomach upset or nausea. Alternatively, switch to oral solution but be aware of appropriate dose conversion since the liquid form is a different lithium salt. Of note, lithium clearance is impacted by body weight, so as patient loses weight after bariatric surgery, dose adjustments may be necessary. Therapeutic drug monitoring recommended.

Storage/Stability

Store between 15°C and 30°C (59°F to 86°F). Protect tablets and capsules from moisture.

Use

Immediate release: Treatment of bipolar disorder as monotherapy for the management of acute mania and with mixed features and maintenance therapy (FDA approved in ages ≥7 years and adults).

Extended release: Treatment of bipolar disorder for the management of acute manic episodes and maintenance therapy (FDA approved in ages ≥12 years and adults).

Medication Safety Issues
Sound-alike/look-alike issues:

Eskalith may be confused with Estratest.

Lithium may be confused with lanthanum, Ultram.

Lithobid may be confused with Levbid, Lithostat.

Other safety concerns:

Do not confuse mEq (milliequivalent) with mg (milligram). Note: 300 mg lithium carbonate or citrate contain 8 mEq lithium. Dosage should be written in mg (milligrams) to avoid confusion.

Check prescriptions for unusually high volumes of the syrup for dosing errors.

Adverse Reactions (Significant): Considerations
Cardiac effects

Lithium may cause cardiac arrhythmia, including bradycardia, sinoatrial dysfunction (SA block), abnormal T waves on ECG (T-wave inversion), and ST-segment depression (Ref). Additional cardiovascular affects have occurred, including peripheral edema, hypotension, and cardiovascular collapse (Ref). Brugada syndrome (Brugada ECG pattern) may be unmasked with lithium therapy (Ref). In a scientific statement from the American Heart Association, lithium has been determined to be an agent that may cause direct myocardial toxicity that is reversible upon discontinuation (magnitude: major) (Ref).

Mechanism: Serum concentration-related; affects various ion channels in the myocardium, in particular Na/K channels, and leads to decreased intracellular potassium levels. These changes alter the normal functioning of the myocardium, leading to conduction disturbances and ECG abnormalities (Ref).

Onset: Varied; may occur within days of initiation of medication, dose increase, or addition of interacting medication or be delayed (Ref).

Risk factors:

• Higher serum levels, particularly toxic levels (>1.5 mEq/L) (Ref)

• Concurrent medications that either inhibit the excretion of lithium via the kidneys or have additive effects on the myocardium (Ref)

• Kidney impairment (Ref)

• Brugada syndrome: Family history of Brugada syndrome, family history of sudden death at a young age (Ref)

CNS effects

Lithium may cause a variety of CNS effects in adult and pediatric patients including drowsiness, sedated state, ataxia, abnormal gait, confusion, decreased alertness, disorientation, lethargy, memory impairment, slurred speech, headache, and others (Ref) . More significant manifestations may occur with elevated serum lithium levels or toxicity, such as coma, seizure (including tonic-clonic twitching), hallucination, agitation, abnormal electroencephalogram (EEG), and may proceed to death without intervention (Ref). Of note, some patients may describe decreased creativity and cognitive dulling as an adverse reaction, when it could also be a result of effective treatment of their manic episode and resultant decreased manic symptoms. CNS effects may persist indefinitely during treatment. Tolerance may or may not occur over time (Ref). Cognitive adverse reactions may be a reason for medication nonadherence, but it is unclear whether these adverse reactions are associated with lithium or bipolar disorder (Ref).

Mechanism: Dose-related; may be related to neuronal cell membrane polarization/depolarization, alterations in glutamate functioning, increases in serotonin release, inhibition of inositol monophosphatase, and alteration of CNS catecholamine levels (Ref).

Onset: Varied; may begin soon after initiation. Effects may be exacerbated with dose increases (or increased serum levels) or intentional or unintentional overdoses (Ref).

Risk factors:

• Higher doses/serum levels (Ref)

• Concurrent use of medications reducing the clearance of lithium (eg, angiotensin-converting enzyme inhibitors/angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs, diuretics) (Ref)

• Concurrent use of other CNS depressant medications (eg, sedative-hypnotics, antipsychotics, antiseizure medications, etc.) (Ref)

• Older adults (Ref)

• Preexisting neurocognitive impairment (Ref)

• Current episode of depression (Ref)

Dermatologic effects

Lithium may cause acne vulgaris and/or psoriasis (including exacerbation of acne and exacerbation of psoriasis) in patients with and without either condition at baseline. May vary from mild to severe, and occur on the face, scalp, trunk, and extremities (Ref). Plaque-type psoriasis is the most common presentation, but others may occur (Ref).

Mechanism: Dose-related; may exert toxic effects on the follicular epithelium, producing acne through neutrophilic chemotaxis and degranulation. In addition, the inflammatory cascade may become activated, leading to psoriasis. Follicular plugging may also contribute to these effects (Ref).

Onset: Varied; typically takes several months to develop, although exacerbations of existing acne or psoriasis may occur sooner (Ref).

Risk factors:

• Males (Ref)

• Preexisting moderate to severe psoriasis (Ref)

GI effects

A variety of adverse GI effects have been reported with lithium in adult and pediatric patients, including dyspepsia, diarrhea, nausea, vomiting, dysgeusia (metallic or salty taste), gastritis, and abdominal pain (Ref). Some effects (eg, nausea) my subside over time. Vomiting is typically associated with toxicity (Ref). Supratherapeutic lithium concentrations should be suspected with severe nausea, vomiting, and diarrhea (Ref).

Mechanism: Dose-related; may be related to direct irritation on the stomach lining or related to other physiological processes in the body after absorption. Potential effects of increased serotonin release may play a role in nausea, as well as general electrolyte changes (Ref).

Onset: Varied; some effects (eg, nausea, diarrhea) may occur early in treatment. Other effects may take longer to develop (Ref).

Risk factors:

• Earlier in treatment (Ref)

• Higher doses/serum levels (Ref)

• Peak lithium levels (possible association) (Ref)

• Controlled-release preparations may be associated with less upper GI cramping and nausea, but increased diarrhea compared to immediate-release formulations (Ref)

Hyperparathyroidism and hypercalcemia

Hypercalcemia has been reported with lithium treatment, which may or may not be related to drug-induced hyperparathyroidism. Symptoms may include weakness, fatigue, development of renal stones (calculi), osteoporosis, GI distress, and others. Psychiatric disturbances, including depression, may also develop, and potentially be misinterpreted as a new episode of the underlying mood disorder (Ref). Changes are usually reversible if lithium is discontinued; however, sustained hypercalcemia and parathyroid gland enlargement have been reported (Ref).

Mechanism: While unclear, lithium is thought to inhibit calcium receptors in the parathyroid gland, preventing inhibition of parathyroid hormone (PTH) release. As PTH levels rise, this alters calcium homeostasis leading to hypercalcemia (Ref).

Onset: Varied; while lithium has been observed to affect PTH levels after a single dose, more long-term exposure (ie, years) is likely required to observe clinically relevant alterations in calcium homeostasis. Progression to osteoporosis would likely take a significant exposure time as well (Ref).

Risk factors:

Exact risk factors unclear, but may include:

• Longer duration of treatment (Ref)

• Females (Ref)

Hypothyroidism

Lithium treatment has been associated with various thyroid function abnormalities, but most commonly hypothyroidism in adult and pediatric patients (Ref). Patients may present with typical hypothyroidism signs and symptoms, including lethargy, impaired cognition, weight gain, dry skin, and cold intolerance. Additionally, depressive symptoms may worsen/emerge and be misinterpreted as a component of the underlying mood disorder (Ref).

Mechanism: While unclear, it is thought that lithium has varied effects on thyroid hormone production and regulation, including inhibition of iodine uptake in the thyroid, inhibition of thyroid hormone synthesis and release, and hepatic conversion of free thyroxine (Ref).

Onset: Hypothyroid features, either symptomatic or lab-value based, generally occur after years of lithium treatment. While acute changes have been noted within the first month of treatment, it is much more likely after several years of use (Ref).

Risk factors:

• Females (Ref)

• Older adults (Ref)

• Family history of hypothyroidism (Ref)

• Presence of antithyroid antibodies (Ref)

Lithium toxicity

Lithium is classified as a narrow-therapeutic index drug, requiring close monitoring to ensure patients’ serum levels are maintained within the therapeutic range. Supratherapeutic levels, even slight elevations above 1.5 mEq/L, may lead to increased adverse reactions and toxicity. Notably, toxicity can occur at any level (Ref). General symptoms of low-grade lithium toxicity may include weakness, tremor (new-onset or worsening), mild ataxia, poor concentration, tinnitus, nausea, and diarrhea. More significant toxicity may result in vomiting, gross/coarse tremor, slurred speech, confusion, nystagmus disorder, dysarthria, and lethargy. If not treated, it may lead to seizure (tonic-clonic), coma, neurological damage, and death (Ref). Permanent neurotoxicity, described as the syndrome of irreversible lithium-effectuated neurotoxicity (SILENT), has been reported with acute and chronic lithium toxicity (Ref).

Mechanism: Lithium toxicity is an augmented presentation of the various adverse reactions seen with treatment (Ref).

Onset: Varied; may occur within minutes of ingestion (mostly GI effects), but more significant symptoms may take over an hour or more to manifest. There are also reports of delayed symptom onset several days after ingestion (Ref).

Risk factors:

• Higher doses/serum levels (Ref)

• Concurrent use of drugs or medications (eg, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors/angiotensin II receptor antagonists) that increase serum levels (Ref)

• Acute alterations in serum electrolytes or dehydration (Ref)

• Older adults (may manifest symptoms at lower comparative serum levels) (Ref)

• Kidney impairment (Ref)

Nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus may occur (Ref). The ability of the kidney to retain free water may become impaired, leading to dehydration and electrolyte disturbances, most notably hypernatremia. Additionally, serum lithium levels may increase due to the decreased dilutional effect from decreased whole body water. Symptoms of nephrogenic diabetes insipidus and its related hypernatremia may include polyuria, polydipsia, lethargy, and irritability. More severe cases may progress to muscle twitching, coma, seizures, and death. Nephrogenic diabetes insipidus may persist after prolonged lithium therapy despite discontinuation (Ref).

Mechanism: Dose- and duration-related. Lithium-related changes in the collecting tubules of the kidney decrease sensitivity to antidiuretic hormone, leading to decreased concentrating ability and increased production of dilute urine. Lithium may reduce aquaporin-2 water channels within the collecting duct, causing reduction of water reabsorption (Ref). As total body stores of free water decrease, the sensation of thirst increases to compensate (Ref).

Onset: Varied; typical onset within 2 to 4 months of initiation but may occur earlier or later (Ref).

Risk factors:

• Longer duration of treatment (Ref)

• Higher doses/serum levels (Ref)

• Any episodes of lithium toxicity (Ref)

• Extended release or multiple-daily dose regimens (Ref)

• Nonresponse to lithium (may be a risk factor) (Ref)

• Infection (Ref)

• Dehydration (Ref)

• Alcohol intoxication (Ref)

Polydipsia and polyuria

Common adverse reactions associated with lithium are polyuria and polydipsia. These reactions may vary in intensity from mild to more significant effects on overall quality of life. Patients may notice increased urinary frequency (>3 L in 24 hours) due to poor urine concentration. As a result of decreased body water stores, patients may also report increased thirst, which is independent of any dry mouth effects of the drug. May decrease in intensity over time in some patients as the kidneys compensate for this effect (Ref). Refer to "nephrogenic diabetes insipidus" for long-term complications.

Mechanism: Lithium-related changes in the collecting tubules of the kidney decrease sensitivity to antidiuretic hormone, leading to decreased concentrating ability and increased production of dilute urine. As total body stores of free water are decreased, the sensation of thirst increases to compensate (Ref).

Onset: Varied; may occur early in treatment (within days) or later in treatment (Ref).

Risk factors:

• Longer duration of treatment (Ref)

• Higher doses/serum levels episodes (Ref)

• Any episodes of lithium toxicity (Ref)

• Concurrent use of other psychotropic medications, especially antipsychotics (Ref)

• Multiple-daily dose regimens (conflicting data) (Ref)

Renal effects

Up to one-third of patients may develop some degree of decreased kidney function over the course of lithium treatment, with a smaller percentage (~5%) developing significant kidney impairment/failure (eGFR <30 mL/minute). Changes in eGFR (decreased creatinine clearance), renal concentrating defect, and other parameters have been observed in these patients. The development of polyuria/polydipsia may or may not be an early marker for later development of kidney insufficiency. Progression of kidney impairment may continue after discontinuation of lithium in some patients (Ref). Chronic kidney disease will develop in 17% to 21% of long-term users (Ref).

Mechanism: Duration-related; related to various changes in kidney morphology, including interstitial nephritis and fibrosis, nephron atrophy, and possibly glomerular damage. Hypothesized to be related to acute decreases in kidney sensitivity to antidiuretic hormone, causing gradual change in kidney function over time (Ref). Time from lithium initiation to progression to chronic kidney disease and end stage renal disease is 16.5 to 31 years, and 23 years, respectively (Ref).

Onset: Typically delayed, although acute changes may occur with acute toxicity. As lithium exposure continues over years, the rate of more significant kidney impairment increases as the alternations in kidney structure become more severe (Ref).

Risk factors:

• Longer duration of treatment (Ref)

• Older adults (Ref)

• Any episodes of lithium toxicity (Ref)

• Higher doses/serum concentrations (probable risk factor) (Ref)

• Concurrent use of other psychotropic medications, especially antipsychotics (Ref)

Sexual dysfunction

Various types of sexual dysfunction have been reported with lithium treatment, in both females and males. While the rates of the various effects are not clear (anywhere from <5% to nearly 40% in studies), they may include decreased libido, impaired sexual arousal, erectile dysfunction, and general decreased sexual satisfaction. Negative effects on orgasm are unclear. Sexual dysfunction can negatively impact patients’ quality of life (Ref).

Mechanism: Exact mechanism is unclear. Effects on promoting serotonin release may play a role, similar to the serotonin-augmenting effects of antidepressants (Ref).

Onset: Varied; may take days to weeks or longer (Ref).

Risk factors:

No clear risk factors have been described. Possible risk factors include:

• Concurrent use of benzodiazepines (Ref)

• Concurrent use of other medications that cause sexual dysfunction (eg, antidepressants) (probable risk factor) (Ref)

Tremor

Lithium may cause tremor in nearly one-quarter of patients, making it one of the most common adverse reactions. Most commonly seen as a bilateral, symmetrical hand tremor, similar to essential tremor; although, this may vary to other limbs and in symmetry (Ref). May spontaneously decrease over time as compensatory mechanisms develop within the patient (Ref). Course tremor and muscle twitching may be observed in lithium toxicity (Ref).

Mechanism: Exact mechanism is unclear; thought to be related to CNS depressant effects, leading to dysregulation of fine muscle control (Ref).

Onset: Varied; commonly begins early in treatment but can develop later in treatment (with or without a dose increase) (Ref).

Risk factors:

• Higher doses/serum levels (Ref)

• Concurrent use of medications reducing the clearance of lithium (eg, angiotensin-converting enzyme inhibitors/angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs, diuretics) (Ref)

• Concurrent use of other medications known to induce tremor (eg, antipsychotics, antidepressants) (Ref)

• Concurrent use of caffeine (Ref)

• Concurrent anxiety disorder (Ref)

• Personal or family history of essential tremor (Ref)

• Older adults (Ref)

• Concurrent substance withdrawal (especially alcohol) (Ref)

Weight gain

Weight gain is reported as one of the more common and bothersome adverse reactions of lithium. May include weight gain of 10 kg or more over time with an average increase in body weight of 6 kg (Ref). This can lead to other medical comorbidities and negative effects on mood and adherence to treatment (Ref). Many pediatric studies suggest that lithium has a low risk for weight gain (not statistically different than placebo), with many demonstrating that it is weight neutral (Ref).

Mechanism: Exact mechanism is unclear. Effects on central mechanisms related to weight gain, satiety, and metabolism are possible. In addition, increased consumption of high-calorie, sugary beverages from increased thirst due to lithium could play a role, as well as any drug-induced hypothyroidism and fluid retention (Ref).

Onset: Varied; may occur within the first few weeks of initiation, with more significant increases over time. Increases of 4 to 7 kg within the first year have been reported in the literature. While the most significant weight gain typically occurs within the first 1 to 2 years of treatment, it may continue (Ref).

Risk factors:

Unclear, but may include:

• Concurrent use of other medications that can cause weight gain (particularly other psychotropic medications) (Ref)

• Early weight gain after treatment initiation (Ref)

• Overweight/obese prior to initiation (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Frequency not defined:

Cardiovascular: Abnormal T waves on ECG (including inversion T wave on ECG and flattened T wave of ECG), bradycardia (Ataallah 2020), cardiac arrhythmia (including unmasking of Brugada Syndrome) (Ravi 2020), chest tightness, circulatory shock, cold extremities, edema, hypotension, myxedema (Ahmad Mir 2013), peripheral vascular disease (resembling Raynaud’s syndrome), prolonged QT interval on ECG, sinus node dysfunction, syncope, ventricular tachyarrhythmia

Dermatologic: Acne vulgaris (Scarfi 2013), alopecia, dermal ulcer, dermatitis, dry and/or thinning hair, exacerbation of acne (Gitlin 2016), exacerbation of psoriasis, folliculitis, pruritus, psoriasis, skin rash, xeroderma

Endocrine & metabolic: Albuminuria, dehydration, diabetes insipidus, euthyroid goiter, glycosuria, hypercalcemia (including secondary to hyperparathyroidism [McKnight 2012]), hyperglycemia, hypermagnesemia, hyperparathyroidism, hyperthyroidism, hyponatremia, weight loss

Gastrointestinal: Abdominal pain, anorexia, decreased appetite, dental caries, dysgeusia (including metallic taste and salty taste), dyspepsia, fecal incontinence, flatulence, gastritis, salivary gland disease (swelling), sialorrhea, swelling of lips, tongue changes (movement), vomiting, xerostomia

Genitourinary: Glomerulopathy (fibrosis), impotence, nephron atrophy, nephrotic syndrome (Bear 1985), oliguria, sexual disorder, urinary incontinence

Hematologic & oncologic: Leukocytosis

Hypersensitivity: Angioedema

Immunologic: Drug reaction with eosinophilia and systemic symptoms (Shreedhar 2010)

Local: Local pain (fingers and toes), local skin discoloration (fingers and toes), localized edema (ankles and wrists)

Nervous system: Abnormal electroencephalogram (diffuse slowing, potentiation, disorganization of background rhythm), abnormal gait, ataxia, bradyphrenia, cogwheel rigidity, coma, confusion, decreased mental acuity (worsening of organic brain syndromes), disorientation, dizziness, drowsiness, dystonic reaction, epileptiform seizure, extrapyramidal reaction, fatigue, hallucination, headache, hyperactive behavior (startled response), hyperactive deep tendon reflex, hyperirritability (muscle), hypertonia, idiopathic intracranial hypertension, involuntary choreoathetoid movements, lethargy, local anesthesia (skin), memory impairment, myasthenia, psychomotor impairment, reduced intellectual ability, restlessness, sedated state, seizure, slurred speech, stupor, tic disorder, vertigo

Neuromuscular & skeletal: Arthralgia, joint swelling, polyarthralgia, tremor

Ophthalmic: Blurred vision, exophthalmos, nystagmus disorder, transient scotoma

Otic: Tinnitus

Renal: Decreased creatinine clearance, interstitial nephritis, renal concentrating defect

Miscellaneous: Fever, interstitial fibrosis, iodism (elevated iodine uptake)

Postmarketing:

Endocrine & metabolic: Hypothyroidism (common: ≥10%) (Lieber 2020), nephrogenic diabetes insipidus (common: ≥10%) (Ott 2019, Rauf 2020, Schoot 2020), polydipsia (common in long-term patients: ≥10%) (Gitlin 2016), weight gain (common: ≥10%) (Gitlin 2016)

Gastrointestinal: Diarrhea (common: ≥10%) (Gitlin 2016), nausea (common: ≥10%) (Gitlin 2016)

Nervous system: Intracranial hypertension (Tan 2020)

Neuromuscular & skeletal: Lupus-like syndrome (Shukla 1982)

Renal: Polyuria (common in long-term patients: ≥10%) (Gitlin 2016)

Contraindications

Hypersensitivity to lithium or any component of the formulation.

Immediate-release capsule, solution and tablet: Severe cardiovascular or renal disease, severe debilitation, dehydration, sodium depletion, concurrent use with diuretics.

Canadian labeling: Additional contraindications (not in US manufacturer’s labeling): Brain damage; conditions requiring low sodium intake.

Warnings/Precautions

Concerns related to adverse effects:

• Pseudotumor cerebri: Pseudotumor cerebri (increased intracranial pressure and papilledema) has rarely been reported with use; undetected cases may result in blind spot enlargement, visual field constriction, and blindness secondary to optic atrophy. Discontinue therapy, if clinically possible, if syndrome occurs.

• Serotonin syndrome: Lithium can precipitate a potentially life-threatening serotonin syndrome, particularly when used in combination with other serotonergic agents (eg, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, triptans, tricyclic antidepressants, fentanyl, tramadol, buspirone, St. John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, monoamine oxidase inhibitors). Monitor patients closely for signs of serotonin syndrome, such as mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), GI symptoms (eg, nausea, vomiting, diarrhea), and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise and initiate supportive therapy.

Disease-related concerns:

• Cardiovascular disease: Generally avoid use in patients with significant cardiovascular disease due to risk of precipitation of cardiac arrhythmia; if use is unavoidable, use with extreme caution and monitor serum lithium levels and EKG closely.

• Depression/suicidal ideation: Use with caution in patients at risk of suicide (suicidal thoughts or behavior) by drug overdose; lithium has a narrow therapeutic index (Nelson 2017).

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition (Mehrizi 2012).

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Alosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Amphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor therapy

Angiotensin II Receptor Blockers: May increase the serum concentration of Lithium. Management: Initiate lithium at lower doses in patients receiving an angiotensin II receptor blocker (ARB). Consider lithium dose reductions in patients stable on lithium therapy who are initiating an ARB. Monitor lithium concentrations closely when combined. Risk D: Consider therapy modification

Angiotensin-Converting Enzyme Inhibitors: May increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor for increased concentrations/toxic effects of lithium if an ACE inhibitor is initiated/dose increased, or if switching between ACE inhibitors. Risk D: Consider therapy modification

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Antipsychotic Agents: Lithium may enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor therapy

BusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Caffeine and Caffeine Containing Products: May decrease the serum concentration of Lithium. Risk C: Monitor therapy

Calcitonin: May decrease the serum concentration of Lithium. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the neurotoxic effect of Lithium. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Lithium. Decreased or unaltered lithium concentrations have also been reported with this combination. Risk C: Monitor therapy

Calcium Polystyrene Sulfonate: May decrease the serum concentration of Lithium. Management: Consider separating administration of lithium from administration of oral calcium polystyrene sulfonate by at least 6 hours. Risk D: Consider therapy modification

CarBAMazepine: May enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapy

Carbonic Anhydrase Inhibitors: May decrease the serum concentration of Lithium. Risk C: Monitor therapy

Cyclobenzaprine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid combination

Desmopressin: Lithium may diminish the therapeutic effect of Desmopressin. Desmopressin may increase the serum concentration of Lithium. Risk C: Monitor therapy

Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Dextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Eletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Eplerenone: May increase the serum concentration of Lithium. Risk C: Monitor therapy

Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Fenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Fosphenytoin: May enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapy

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy

Lasmiditan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Levomethadone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Linezolid: May enhance the serotonergic effect of Lithium. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modification

Loop Diuretics: May decrease the serum concentration of Lithium. Loop Diuretics may increase the serum concentration of Lithium. Risk C: Monitor therapy

Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Metaxalone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Methadone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Methyldopa: May enhance the adverse/toxic effect of Lithium. This may occur without notable changes in serum lithium concentrations. Risk C: Monitor therapy

Methylene Blue: May enhance the serotonergic effect of Lithium. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modification

Metoclopramide: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

MetroNIDAZOLE (Systemic): May enhance the adverse/toxic effect of Lithium. MetroNIDAZOLE (Systemic) may increase the serum concentration of Lithium. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors (Antidepressant): May enhance the serotonergic effect of Lithium. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modification

Monoamine Oxidase Inhibitors (Type B): May enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Risk X: Avoid combination

Nefazodone: May enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Neuromuscular-Blocking Agents: Lithium may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Lithium. Management: Consider reducing the lithium dose when initiating a NSAID. Monitor for increased lithium therapeutic/toxic effects if a NSAID is initiated/dose increased, or decreased effects if a NSAID is discontinued/dose decreased. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents (Topical): May increase the serum concentration of Lithium. Risk C: Monitor therapy

Ondansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Opioid Agonists: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Opioid Agonists (metabolized by CYP3A4 and CYP2D6): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Opioid Agonists (metabolized by CYP3A4): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy

Phenytoin: May enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapy

Potassium Iodate: Lithium may enhance the hypothyroid effect of Potassium Iodate. Risk C: Monitor therapy

Potassium Iodide: May enhance the hypothyroid effect of Lithium. Risk C: Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Ramosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Sargramostim: May enhance the adverse/toxic effect of Lithium. Specifically, the myeloproliferative effects may be increased. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: Serotonergic Agents (High Risk, Miscellaneous) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Serotonergic Non-Opioid CNS Depressants: Serotonergic Agents (High Risk, Miscellaneous) may enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Serotonergic Opioids (High Risk): May enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapy

Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Sertindole: Lithium may enhance the QTc-prolonging effect of Sertindole. Risk X: Avoid combination

Sodium Bicarbonate: May increase the excretion of Lithium. Risk C: Monitor therapy

Sodium Chloride: May increase the excretion of Lithium. Risk C: Monitor therapy

Sodium Polystyrene Sulfonate: May decrease the serum concentration of Lithium. Management: Consider separating administration of lithium from administration of oral sodium polystyrene sulfonate by at least 6 hours. Risk D: Consider therapy modification

St John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Tetracyclines: May increase the serum concentration of Lithium. Risk C: Monitor therapy

Theophylline Derivatives: May decrease the serum concentration of Lithium. Risk C: Monitor therapy

Thiazide and Thiazide-Like Diuretics: May decrease the excretion of Lithium. Management: Reduce the lithium dose if coadministered with thiazide or thiazide-like diuretics. Monitor serum lithium levels during coadministration with thiazide and thiazide-like diuretics. Risk D: Consider therapy modification

Topiramate: May increase the serum concentration of Lithium. Risk C: Monitor therapy

Tricyclic Antidepressants: May enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Tryptophan: Lithium may enhance the serotonergic effect of Tryptophan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Valproate Products: Lithium may increase the serum concentration of Valproate Products. Risk C: Monitor therapy

Vasopressin: Drugs Suspected of Causing Diabetes Insipidus may diminish the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic hormone effects of vasopressin may be decreased. Risk C: Monitor therapy

Dietary Considerations

May be taken with meals to avoid GI upset; maintain adequate salt and fluid intake.

Pregnancy Considerations

Lithium crosses the placenta in concentrations similar to those in the maternal plasma (Newport 2005).

Cardiac malformations in the infant, including Ebstein anomaly, are associated with use of lithium during the first trimester of pregnancy. Other adverse events including polyhydramnios, fetal/neonatal cardiac arrhythmias, hypoglycemia, diabetes insipidus, changes in thyroid function, premature delivery, floppy infant syndrome, or neonatal lithium toxicity are associated with lithium exposure when used later in pregnancy (ACOG 2008). The incidence of adverse events may be associated with higher maternal doses (Newport 2005). Fetal echocardiography should be considered if first trimester exposure occurs (ACOG 2008).

Due to pregnancy-induced physiologic changes, women who are pregnant may require dose adjustments of lithium to achieve euthymia and avoid toxicity (ACOG 2008; Grandjean 2009; Yonkers 2011).

For planned pregnancies, use of lithium during the first trimester should be avoided if possible (Grandjean 2009). However, the absolute risk of Ebstein anomaly is small and treatment for bipolar disorder should not be withheld when clinically indicated (Larsen 2015). If lithium is needed during pregnancy, the minimum effective dose should be used, maternal serum concentrations should be monitored, and consideration should be given to start therapy after the period of organogenesis; lithium should be suspended 24 to 48 hours prior to delivery or at the onset of labor when delivery is spontaneous, then restarted when the patient is medically stable after delivery (ACOG 2008; Grandjean 2009; Newport 2005).

Monitoring Parameters

Serum lithium concentrations (initiation of therapy, dose changes, changes in concurrent medications, changes in strenuous activity level, concomitant disease activity, or clinical signs indicating need for assessment); renal function including BUN and SCr (baseline, every 2 to 3 months during the first 6 months of treatment, then at least once a year in stable patients or as clinically indicated; pediatric patients may require more frequency); serum electrolytes (baseline, then periodically), serum calcium (baseline, 2 to 6 weeks after initiation, then every 6 to 12 months; repeat as clinically indicated) (Broome 2011); thyroid function (baseline, 1 to 2 times with in the first 6 months of treatment, then periodically in stable patients or as clinically indicated); beta-hCG pregnancy test for all females of child-bearing age not known to be sterile (baseline); ECG with rhythm strip (baseline for all patients over 40 years, repeat as clinical indicated), CBC with differential (baseline, repeat as clinically indicated); weight (baseline, then periodically) (APA 2002)

Reference Range

Serum lithium concentrations: Timing of serum samples: Draw trough just before next dose.

Children ≥7 years and Adolescents: With therapy initiation, evaluate levels after 3 days of therapy followed by weekly monitoring until patient's clinical status and drug concentrations are stable (Findling 2011; Findling 2015). With long-term therapy, serum concentrations should be evaluated ≥7 days after dosage change or as clinically indicated (Findling 2013).

Adults: Twice weekly until both patient's clinical status and levels are stable, then repeat levels every 1 to 3 months or as clinically indicated) (APA 2002).

Therapeutic:

Children ≥7 years and Adolescents:

Acute mania: A range of 0.8 to 1.2 mEq/L (SI: 0.8 to 1.2 mmol/L) has been suggested (Findling 2011; Findling 2015; Thomas 2011).

Maintenance: 0.8 to 1 mEq/L (SI: 0.8 to 1 mmol/L); a higher range of 0.8 to 1.2 mEq/L (0.8 to 1.2 mmol/L) has also been suggested (Findling 2013; Thomas 2011).

Note : In pediatric clinical trials, patients with a serum concentration ≥1.4 mEq/L had no further dose titrations (Findling 2011; Findling 2013; Findling 2015).

Adult: Acute mania: 0.5 to 1.2 mEq/L (SI: 0.5 to 1.2 mmol/L); maintenance: 0.6 to 1 mEq/L (SI: 0.6 to 1 mmol/L); a higher rate of relapse is described in subjects who are maintained <0.4 mEq/L (SI: <0.4 mmol/L) (APA 2002).

Toxic: >1.5 mEq/L (SI: >1.5 mmol/L).

Mechanism of Action

The precise mechanism of action in mood disorders is unknown. Traditionally thought to alter cation transport across cell membranes in nerve and muscle cells, influence the reuptake of serotonin and/or norepinephrine, and inhibit second messenger systems involving the phosphatidylinositol cycle (Ward 1994). May also provide neuroprotective effects by increasing glutamate clearance, inhibiting apoptotic glycogen synthase kinase activity, increasing the levels of antiapoptotic protein Bcl-2 and, enhancing the expression of neurotropic factors, including brain-derived neurotrophic factor (Sanacora 2008).

Pharmacokinetics (Adult data unless noted)

Absorption: Rapid and complete

Distribution: Vd: Initial: 0.307 L/kg; Vdss: 0.7 to 1 L/kg; decreased in elderly patients (Ward 1994)

Protein binding: Not protein bound

Metabolism: Not metabolized (Ward 1994)

Bioavailability: 80% to 100% (Ward 1994)

Half-life elimination:

Pediatric patients 7 to 17 years: t1/2(beta): 27 hours (Findling 2010)

Adults: 18 to 36 hours; prolonged in elderly patients (~28.5 hours) (Ward 1994)

Time to peak, serum: Immediate release: ~0.5 to 3 hours; Extended release: 2 to 6 hours; Solution: 15 to 60 minutes

Excretion: Urine (primarily; unchanged drug); sweat, saliva, and feces (negligible amounts)

Clearance: 80% of filtered lithium is reabsorbed in the proximal convoluted tubules; decreased in elderly patients secondary to age-related decreases in renal function (Ward 1994)

Pharmacokinetics: Additional Considerations

Pediatric: In pediatric patients, great variability in clearance was found across subjects with linear pharmacokinetics correlated to fat-free mass (Findling 2010).

Older adult: Elderly patients receiving lithium may have a decreased glomerular filtration rate and decrease in renal plasma clearance (13.7 mL/minute) (Ward 1994).

Pricing: US

Capsules (Lithium Carbonate Oral)

150 mg (per each): $0.14 - $0.19

300 mg (per each): $0.17 - $0.21

600 mg (per each): $0.36 - $0.39

Tablet, controlled release (Lithium Carbonate ER Oral)

300 mg (per each): $0.25 - $0.47

450 mg (per each): $0.46 - $0.76

Tablet, controlled release (Lithobid Oral)

300 mg (per each): $15.08

Tablets (Lithium Carbonate Oral)

300 mg (per each): $0.21 - $0.26

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Calith (TW);
  • Camcolit (BE, BH, CY, GB, IE, IQ, IR, KW, LB, LU, LY, MT, NL, OM, PK, QA, SA, SG, SY, TW, YE, ZA);
  • Camcolite (AE, JO);
  • Carbolim (BR);
  • Carbolit (CL, CO, CR, DO, GT, HN, MX, NI, PA, SV);
  • Carbolithium (IT);
  • Carlit (PY);
  • Ceglution (AR);
  • Contemnol (CZ);
  • Eskalit (AR);
  • Eskalith (BB, BM, BS, BZ, GY, JM, SR, TT);
  • Frimania (ID);
  • Hynorex Retard (DE);
  • Hypnolith (LK);
  • Licab (IN);
  • Licarb (HK, TH);
  • Licarbium (IL);
  • Liconate (MY);
  • Limas (JP);
  • Limed (TH);
  • Liskonum (AE, BH, CY, GB, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);
  • Litarex (SA);
  • Litcab (PH);
  • Lithan (KR);
  • Litheum 300 (MX);
  • Lithicarb (AU);
  • Lithicarb FC (NZ);
  • Lithin SR (BD);
  • Lithioderm (FR);
  • Lithionit (NO, SE);
  • Lithium Carbonicum (PL);
  • Lithiumkarbonat ”Oba” (DK);
  • Lithocap (IN);
  • Lithosun SR (BD);
  • Lithuril (TR);
  • Litiam ER (BD);
  • Liticarb (HN, HU);
  • Litij-karbonat (HR);
  • Litiumkarbonat ”Dak” (DK);
  • Lito (FI);
  • Litocarb (PE);
  • Manicarb SR (LK);
  • Maniprex (BE, LU);
  • Microlit (PH);
  • Milithin (GR);
  • Neurolepsin (AT);
  • Plenur (ES);
  • Priadel (BE, GB, IE, LU, NL, NZ, PT);
  • Priadel Retard (CH);
  • Prianil C.R. (EG);
  • Quilonium (ZA);
  • Quilonium-R (PH);
  • Quilonorm (AT);
  • Quilonorm Retardtabletten (CH);
  • Quilonum (AU);
  • Quilonum Retard (DE);
  • Quilonum retard (LU);
  • Sicolitio (UY);
  • Teralithe (FR);
  • Theralite (CO)


For country abbreviations used in Lexicomp (show table)
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