Lithium is a mood-stabilizing agent.428
Lithium is used for the treatment of acute manic and mixed episodes associated with bipolar I disorder in adults and pediatric patients ≥7 years of age (≥12 years of age for extended-release formulations).404, 405, 428 Lithium is also used for maintenance treatment of bipolar I disorder in adults and pediatric patients ≥7 years of age (≥12 years of age for extended-release formulations).404, 405, 428
Extensive experience and data from randomized controlled studies have shown lithium to be effective in the treatment of acute mania in adults and pediatric patients with bipolar disorder.111, 112, 116, 410, 411, 412, 413, 414, 415, 416, 417
The efficacy of lithium for the treatment of acute manic or mixed episodes associated with bipolar I disorder in pediatric patients 7-17 years of age was established in an 8-week, randomized, double-blind, placebo-controlled trial.112, 428 The trial enrolled 81 patients with bipolar I disorder and a Young Mania Rating Scale (YMRS) score ≥20; patients were randomized in a 2:1 ratio to receive lithium or placebo for 8 weeks.112, 428 In this trial, lithium (at a mean serum level of 0.98 mEq/L) was substantially more effective than placebo for decreasing acute manic or mixed states as measured by the YMRS.428 Efficacy of lithium as a maintenance treatment for bipolar I disorder in pediatric patients 7-17 years of age was established in a 28-week randomized withdrawal study enrolling 31 patients who had been stabilized on a therapeutic dosage of lithium.113, 428 This study found that patients who continued to receive lithium after stabilization were less likely to discontinue treatment due to mood symptoms than patients who switched to placebo.113, 428
A Cochrane review of 36 studies enrolling 4220 patients of all ages experiencing manic episodes in the context of bipolar disorder found lithium was more effective than placebo for the treatment of acute mania.111 Limited comparative data suggest the efficacy of lithium is generally similar to that of other treatments (i.e., valproate, carbamazepine, risperidone, quetiapine, haloperidol); however, lithium may be marginally less effective than olanzapine for acute mania, based on the results of 2 studies enrolling 180 patients.111 Another analysis specific to pediatric patients found lithium may be less effective than risperidone for the treatment of acute mania in prepubertal patients with protracted manic/mixed episodes and comorbid attention deficit hyperactivity disorder (ADHD).116 An additional 6-week, randomized, double-blind trial compared lithium to quetiapine in patients 10-17 years of age experiencing an acute manic/mixed episode associated with bipolar I disorder and found, while both treatments led to improvements in manic symptoms, greater improvements were observed with quetiapine.117
Randomized controlled trials have also found maintenance treatment with lithium is effective for preventing return of symptoms associated with bipolar disorder in adults and pediatric patients.113, 114, 115 A Cochrane review of 9 studies enrolling 825 patients of all ages with mood disorders found lithium was more effective than placebo for preventing relapse in bipolar disorder.114 Similarly, an updated systematic review and meta-analysis of randomized controlled trial data in adults found maintenance lithium treatment was associated with a substantially lower risk of new bipolar disorder mood episodes compared to placebo.115
Legacy practice guidelines from the American Psychological Association (APA) recommend lithium plus an antipsychotic agent or valproate plus an antipsychotic agent for first-line treatment of patients with severe manic or mixed episodes associated with bipolar I disorder; patients with less severe symptoms may be treated with lithium, valproate, or antipsychotic monotherapy.109 Selection of a specific treatment should be based on clinical factors such as illness severity, associated features (e.g., rapid cycling, psychosis), and patient preference, with particular attention to adverse effect profiles.109 Manic or mixed episodes with psychotic features usually require treatment with an antipsychotic agent.109 Atypical antipsychotics are generally preferred over typical antipsychotics because of their more benign adverse effect profile.109 Following remission of an acute episode, maintenance pharmacologic treatment is recommended; first-line options for maintenance therapy include lithium and valproate.109 The guideline states, for patients treated with an antipsychotic medication during the acute episode, need for ongoing antipsychotic therapy should be reassessed upon entering the maintenance phase; antipsychotic agents should generally be discontinued, unless they are required to control persistent psychosis or prevent recurrence.109
Guidelines from the Department of Veterans Affairs and Department of Defense (VA/DoD) recommend lithium or quetiapine monotherapy for the treatment of acute mania in patients with bipolar disorder.110 If lithium or quetiapine is not selected based on patient preference or characteristics, olanzapine, paliperidone, or risperidone are recommended as alternative treatments.110 If none of these therapies are considered suitable based on patient preference or characteristics, other suggested options include aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, valproate, or ziprasidone.110 For patients who experience breakthrough episodes of mania or unsatisfactory response to initial treatment, lithium or valproate in combination with an antipsychotic agent (haloperidol, asenapine, quetiapine, olanzapine, or risperidone) is recommended.110 For prevention of mania recurrence, lithium or quetiapine is recommended; alternatives include olanzapine, paliperidone, or risperidone.110
Depression Associated with Bipolar Disorder
Lithium has been used for the treatment of depression associated with bipolar disorder (bipolar depression)†.109, 110, 118, 119, 120 However, evidence to support its efficacy for acute bipolar depression is limited, and it remains unclear whether lithium is more effective than placebo for this use.118, 119 The largest randomized controlled trial of lithium for acute bipolar depression compared the medication to quetiapine and placebo; this trial found quetiapine 600 mg per day was more effective than placebo and lithium for improving depressive symptoms (as measured by change in the Montgomery-Asberg Depression Rating Scale [MADRS] total score from baseline to week 8).120 Lithium was not substantially more effective than placebo for improving MADRS scores.120 However, the mean serum lithium concentration achieved in this trial was on the low end of the target range (0.61 mEq/L), and only 64.4% of patients receiving lithium attained serum levels within the target range of 0.6-1.2 mEq/L.118, 120
Legacy guidelines from APA published in 2002 state the first-line pharmacological treatment for bipolar depression is initiation of either lithium or lamotrigine.109 For severely ill patients, clinicians may initiate simultaneous treatment with lithium and an antidepressant.109 If an acute episode of bipolar depression does not respond to first-line medications at optimal doses, next steps include adding lamotrigine, bupropion, or paroxetine; alternative next steps may include adding other newer antidepressants (e.g., a selective serotonin reuptake inhibitor [SSRI] or venlafaxine) or a monoamine oxidase (MAO) inhibitor.109
More recent guidelines from the VA/DoD recommend quetiapine monotherapy for the treatment of acute bipolar depression; if quetiapine is not selected (based on patient preference and characteristics), cariprazine, lumateperone, lurasidone, or olanzapine monotherapy is recommended.110 The guideline states there is insufficient evidence to recommend for or against antidepressants or lamotrigine as monotherapy for acute bipolar depression; however, lamotrigine may be used in combination with lithium or quetiapine for the treatment of acute bipolar depression.110 For prevention of recurrence of bipolar depressive episodes, lamotrigine monotherapy is recommended; other suggested options include lithium or quetiapine monotherapy.110 If lithium or quetiapine is not selected based on patient preference and characteristics, olanzapine monotherapy is suggested as an alternative; olanzapine, lurasidone, or quetiapine may also be used in combination with lithium or valproate for the prevention of recurrent bipolar depressive episodes.110
Lithium has been used to augment antidepressant treatment in patients with major depressive disorder†.121, 122 However, current guidelines from the VA/DoD state there is insufficient evidence to recommend for or against lithium augmentation in patients with major depressive disorder.123
Lithium has been used for the prevention of cluster headaches† in a limited number of patients.124, 125, 126, 127 The American Headache Society states lithium is “possibly effective” for this use based on evidence from 2 randomized controlled trials.126 However, because the evidence base for lithium in the prevention of cluster headaches is limited and lithium has a narrow therapeutic window, it is typically reserved for patients who do not respond to other preventive therapies (i.e., verapamil).127
Dispensing and Administration Precautions
Lithium is administered orally in divided doses (e.g., 2 or 3 times daily).404, 405, 428 Lithium carbonate is commercially available as conventional tablets, extended-release tablets, and capsules.404, 405, 428 Lithium citrate is commercially available only as an oral solution.428 Extended-release preparations of lithium should be swallowed intact and should not be chewed, crushed, or split in half.404, 405 Lithium citrate oral solution may be used in patients unable to swallow capsules or tablets; 5 mL of a commercially available solution contains about 8 mEq of lithium and is approximately equivalent to 300 mg of lithium carbonate as conventional tablets or capsules.428
Individualize the dosage according to serum lithium concentrations, patient tolerance, and clinical response.404, 405, 428 The manufacturers state that serum lithium concentrations should be determined 3 days (drawn 12 hours after the previous oral dose and just prior to the next dose) after therapy initiation during the acute phase of therapy with the conventional tablets, capsules or liquid and then regularly until the serum concentration and clinical condition of the patient have been stabilized.428 When extended-release preparations are used, serum lithium concentrations generally should be monitored twice weekly (drawn immediately prior to the next dose [i.e., 8-12 hours after previous dose]) during initiation of the acute phase of therapy and until the serum concentration and clinical condition of the patient have been stabilized.404, 405 Thereafter, serum concentrations should be monitored at least every 2 months in most patients.404, 405 Additional monitoring of serum lithium concentrations is recommended after any change in dosage, change in concomitant medications (e.g., diuretics, nonsteroidal anti-inflammatory agents [NSAIAs], renin-angiotensin system antagonists, metronidazole), marked increase or decrease in routine physical activity, or in the event of a concomitant disease.428
Total reliance must not be placed on serum lithium concentrations alone; accurate patient evaluation requires both careful clinical and laboratory evaluation.404, 405, 428
Adverse effects such as nausea and general discomfort may develop during the first few days of initial therapy.428 Fine hand tremor, polyuria, or thirst may also occur during the acute phase, and can persist throughout treatment.428 Continuation of lithium, administering doses with food, or temporary reduction or cessation in dosage may help to mitigate these adverse effects.428
When transitioning a patient from the immediate-release capsules to the extended-release tablets, the same total daily dose should be given and divided into twice daily dosages.404 When the prior dosage is not available in the exact dosage equivalent of the extended-release product, initiate the extended-release regimen at the closest dosage equivalent below the original daily dosage.404 If the daily dosage is split into unequal divided doses, administer the larger dose in the evening.404 Once patients have transitioned to the extended-release tablets, monitor serum levels at 1<2 week intervals and adjust dosage as necessary until serum concentrations and clinical condition are stable.404
Lithium carbonate conventional tablets and capsules should be stored in tight, child-resistant containers protected from moisture at 20-25°C (with excursions permitted to 15-30°C).428 Lithium carbonate extended-release tablets should be stored between 15-30°C.404, 405
Lithium citrate oral solution should be stored in tight, child-resistant containers at 20-25°C (with excursions permitted to 15-30°C).428
Dosage of lithium carbonate is expressed in terms of the salt,404, 405, 428 while dosage of lithium citrate is expressed in terms of lithium.428
Bipolar I Disorder, Acute Manic and Mixed Episodes
During acute episodes of bipolar I disorder in adult patients weighing >30 kg, the manufacturers recommend an initial lithium dosage of 900 mg daily as conventional capsules or tablets of lithium carbonate or 15 mL (about 24 mEq of lithium) of lithium citrate oral solution daily, given in 3 divided doses.428 Dosage should then be titrated by 300 mg as conventional capsules or tablets or 5 mL (about 8 mEq of lithium) of oral solution every 3 days to a target serum level of 0.8 to 1.2 mEq/L.428 The usual dosage of lithium required to attain target serum levels is a dosage of 1.2 to 1.8 g daily as conventional capsules or tablets or 20 to 30 mL (about 32 to 48 mEq of lithium) of oral solution, given in 2 to 3 divided doses.428 Alternatively, the usual initial dosage of lithium carbonate of 1.8 g daily may be administered as extended-release tablets of lithium carbonate, given in 2 or 3 divided doses.404, 405 This dosage generally provides serum lithium concentrations of 1 to 1.5 mEq/L.404, 405 If manifestations of lithium toxicity occur, the medication should be temporarily discontinued for 24-48 hours, then resumed at a lower dosage depending on the reason for toxicity.404, 405
Dosage must be individualized according to serum lithium concentrations, patient tolerance, and clinical response.404, 405, 428 The manufacturers state that serum lithium concentrations should be determined 3 days (drawn 12 hours after the previous oral dose) after therapy initiation during the acute phase of therapy with the conventional tablets, capsules, or oral solution and then regularly until the serum concentration and clinical condition of the patient have been stabilized.428 The manufacturers of extended-release lithium carbonate tablets state that serum lithium concentrations should be determined twice weekly (drawn immediately prior to the next dose [i.e., 8-12 hours after previous dose]) during the acute phase of therapy when the medication is initiated, and until the serum concentration and clinical status of the patient are stable.404, 405 Additional monitoring of serum lithium concentrations is recommended after any change in dosage, change in concomitant medications (e.g., diuretics, NSAIAs, renin-angiotensin system antagonists, metronidazole), marked increase or decrease in routine physical activity, or in the event of a concomitant disease.404, 405, 428
Bipolar Disorder, Maintenance Therapy
The usual adult maintenance dosage is 600 mg to 1.8 g daily of lithium carbonate as conventional tablets or capsules, or 10-30 mL of lithium citrate oral solution (about 16-48 mEq) daily, given in 2 or 3 divided doses.428 This dosage generally provides serum lithium concentrations of 0.8-1 mEq/L.428 Alternatively, the usual maintenance dosage of lithium carbonate of 900 mg to 1.2 g daily may be administered as extended-release tablets, given in 2 or 3 divided doses.404, 405 This dosage generally provides serum lithium concentrations of 0.6 to 1.2 mEq/L.404, 405
Maintenance dosage of lithium should be based on steady-state serum lithium concentrations determined immediately prior to the next oral dose (i.e., 8-12 hours after the previous lithium dose).428 Manufacturers of lithium carbonate as conventional tablets or capsules, or lithium citrate oral solution recommend maintaining steady-state serum lithium concentrations at 0.8 to 1 mEq/L,428 while manufacturers of extended-release tablets recommend maintaining lithium concentrations at 0.6 to 1.2 mEq/L, using the minimum effective dosage that produces serum concentrations in this range, while avoiding excessive adverse effects.404, 405 Some experts recommend targeting a standard serum lithium concentration of 0.6 to 0.8 mEq/L, with the option to target a lower level (0.4 to 0.6 mEq/L) if tolerance is poor or a higher level (0.8 to 1 mEq/L) if response is insufficient.429 During maintenance therapy, serum lithium concentrations are generally determined at least every 2 months in patients whose disease is well controlled.404, 405
Bipolar I Disorder, Acute Manic and Mixed Episodes
During acute episodes of bipolar I disorder in pediatric patients ≥7 years of age who weigh 20<30 kg, the manufacturers recommend an initial lithium dosage of 600 mg daily as conventional capsules or tablets of lithium carbonate or 10 mL (about 16 mEq of lithium) of lithium citrate oral solution daily, given in 2 divided doses.428 The initial lithium dosage in pediatric patients ≥7 years of age weighing >30 kg is 900 mg daily as conventional capsules or tablets of lithium carbonate or 15 mL (about 24 mEq of lithium) of lithium citrate oral solution daily, given in 3 divided doses.428 Dosage may then be titrated once weekly in patients weighing 20<30 kg, or every 3 days in patients weighing >30 kg in increments of 300 mg as conventional capsules or tablets or 5 mL (about 8 mEq of lithium) as oral solution to a target serum level of 0.8 to 1.2 mEq/L.428 The usual dosage of lithium required to attain target serum levels in patients weighing 20<30 kg is 600 mg to 1.5 g daily as conventional capsules or tablets or 10 to 25 mL (about 16 to 40 mEq of lithium) of oral solution daily, given in 2 to 3 divided doses.428 In patients weighing >30 kg, the usual dosage required to attain target serum levels is 1.2 to 1.8 g daily as conventional capsules or tablets or 20-30 mL (about 32 to 48 mEq of lithium) of oral solution, given in 2 to 3 divided doses.428 Alternatively, the usual initial dosage of lithium carbonate of 1.8 g daily may be administered in patients ≥12 years of age as extended-release tablets of lithium carbonate, given in 2 or 3 divided doses.404, 405
Dosage must be individualized according to serum lithium concentrations, patient tolerance, and clinical response.404, 405, 428 The manufacturers state that serum lithium concentrations should be determined 3 days (drawn 12 hours after the previous dose) after therapy initiation during the acute phase of therapy with the conventional tablets, capsules or liquid and then regularly until the serum concentration and clinical condition of the patient have been stabilized.428 The manufacturers of extended-release lithium carbonate tablets state that serum lithium concentrations should be determined twice weekly (drawn immediately prior to the next dose [i.e., 8-12 hours after previous dose]) during the acute phase of therapy when the medication is initiated, and until the serum concentration and clinical status of the patient are stable.404, 405 Additional monitoring of serum lithium concentrations is recommended after any change in dosage, change in concomitant medications (e.g., diuretics, NSAIAs, renin-angiotensin system antagonists, metronidazole), marked increase or decrease in routine physical activity, or in the event of a concomitant disease.428
Bipolar Disorder, Maintenance Therapy
The usual maintenance dosage in pediatric patients weighing 20<30 kg is 600 mg to 1.2 g daily of lithium carbonate or 10<20 mL (16-32 mEq) of lithium citrate, given in divided doses.428 This dosage generally provides serum lithium concentrations of 0.8 to 1 mEq/L.428 The usual maintenance dosage in pediatric patients >30 kg is 600 mg to 1.8 g daily of lithium carbonate or 10<30 mL (16-48 mEq) of lithium citrate, given in divided doses.428 This dosage generally provides serum lithium concentrations of 0.8 to 1 mEq/L.428 Alternatively, in children ≥12 years of age, a dosage of 900 mg to 1.2 g daily may be administered as extended-release lithium carbonate tablets, given in 2 or 3 divided doses.404, 405 This dosage generally provides serum lithium concentrations of 0.6 to 1.2 mEq/L.404, 405
Maintenance dosage of lithium should be based on steady-state serum lithium concentrations determined immediately prior to the next oral dose (i.e., 8-12 hours after the previous lithium dose).428 Manufacturers of lithium carbonate as conventional tablets or capsules, or lithium citrate oral solution recommend maintaining steady-state serum lithium concentrations at 0.8-1 mEq/L,428 while manufacturers of extended-release tablets recommend maintaining lithium concentrations at 0.6-1.2 mEq/L, using the minimum effective dosage that produces serum concentrations in this range, while avoiding excessive adverse effects.404, 405 Some experts recommend targeting a standard serum lithium concentration of 0.6-0.8 mEq/L, with the option to target a lower level (0.4-0.6 mEq/L) if tolerance is poor or a higher level (0.8-1 mEq/L) if response is insufficient.429 During maintenance therapy, serum lithium concentrations are generally determined at least every 2 months in patients whose disease is well controlled.404, 405
The manufacturer does not provide specific dosage recommendations in hepatic impairment.428
Slow titration and lower initial dosages of lithium are recommended in patients with mild to moderate renal impairment (creatinine clearance [ClCr] 30-89 mL/minute based on Cockroft-Gault).428 Frequent monitoring of serum lithium concentrations and for signs of lithium toxicity are also recommended in these patients.428
Avoid lithium therapy in patients with severe renal impairment (ClCr<30 mL/minute).428
Although the manufacturer does not provide specific dosage recommendations in geriatric patients, due to the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and other medication therapy in this population, patients in this age group should receive initial dosages of lithium on the lower end of the usual range.404, 405, 428 Geriatric patients often respond to a reduce dosage, and may exhibit signs of toxicity at serum concentrations tolerated by other patients.404, 405, 428
Lithium is substantially excreted by the kidneys and the risk of severe adverse reactions may be increased in patients with impaired renal function.405 Because geriatric patients may have decreased renal function, renal function should be monitored and dosage adjusted accordingly.404, 405, 428
The renal excretion of lithium increases during pregnancy; therefore, if the decision is made to continue lithium, the dosage generally needs to be increased, serum concentrations monitored, and the dosage of lithium adjusted as needed.428 Sodium restriction and the administration of diuretic agents should be avoided.428 Additionally, the lithium dosage should be reduced 2-3 days prior to the expected delivery date to reduce the risk of postpartum lithium toxicity.428 At delivery, the vascular volume rapidly decreases and renal clearance may return to pre-pregnancy levels.428 Lithium may then be resumed during the postpartum period at preconception dosages in medically stable patients as long as lithium levels are closely monitored.428
A boxed warning is included in the prescribing information for lithium regarding the risk of lithium toxicity.404, 405, 428 The risk of lithium toxicity is increased at steady-state serum lithium concentrations of ≥1.5 mEq/L, but some patients who are sensitive to the effects of lithium may develop toxicity at serum concentrations close to the therapeutic range of 0.8 to 1.2 mEq/L.428 Since lithium can take up to 24 hours after administration to distribute into the CNS, the onset of acute symptoms of toxicity may be delayed.428 Serum lithium concentrations above 3 mEq/L can result in progression to seizures, coma, and irreversible brain damage.428
Factors that increase the risk of lithium toxicity include recent fever, concomitant administration of medications that affect kidney function or increase lithium concentration by pharmacokinetic interactions (e.g., diuretics, nonsteroidal anti-inflammatory agents [NSAIAs], renin-angiotensin antagonists, metronidazole), acute lithium ingestion, impaired renal function, volume depletion or dehydration, significant cardiovascular disease, or changes in electrolyte concentrations, particularly sodium and potassium.428
Neurological symptoms of toxicity can include mild (e.g., fine tremor, lightheadedness, lack of coordination, weakness) to moderate (e.g., giddiness, apathy, drowsiness, hyperreflexia, muscle twitching, ataxia, blurred vision, tinnitus, slurred speech) symptoms, and in rare cases, neurologic sequelae may persist despite discontinuation of lithium therapy and be associated with cerebellar atrophy.428 Cardiac manifestations of lithium toxicity include myocarditis and electrocardiogram (ECG) changes (e.g., QT prolongation, ST-segment and T-wave changes).428 Renal (e.g., defects in urine concentrating, nephrogenic diabetes insipidus, renal failure), respiratory (e.g., dyspnea, aspiration pneumonia, respiratory failure), and GI symptoms (e.g., nausea, vomiting, diarrhea, bloating), can also occur during lithium toxicity.428
Patients should be monitored for signs and symptoms of lithium toxicity, and the dosage should be reduced or medication discontinued if symptoms occur.428
Other Warnings and Precautions
There is a potential association between chronic lithium therapy and decreased renal concentrating ability, which occasionally presents as nephrogenic diabetes insipidus.428 Nephrogenic diabetes insipidus manifesting as polyuria and polydipsia usually develops within weeks after starting lithium.428 Renal tubular acidosis can also occur, resulting in hyperchloremic metabolic acidosis.428 Such patients should be managed to avoid dehydration and subsequent lithium toxicity.428 This condition is usually reversible with discontinuation of lithium; however, for some patients receiving long-term lithium therapy, nephrogenic diabetes insipidus may be only partially reversible.428 Amiloride can be used for management of nephrogenic diabetes insipidus.428
Lithium can decrease sodium reabsorption in the renal tubules, potentially leading to the development of hyponatremia.428 Therefore, it is important for patients receiving lithium therapy to maintain a normal balanced diet that includes salt, and to maintain an adequate fluid intake of at least 2.5-3 liters of fluid daily during the initial stabilization period.404, 428 Reduced tolerance to lithium has been reported in cases of protracted sweating, diarrhea, or concomitant infection with elevated temperatures, which requires supplemental fluid and salt administration under careful medical supervision and reduced or suspended lithium intake until the condition resolves.404, 405, 428
Mild hyponatremia (i.e., sodium >120 mEq/L) can be asymptomatic; however, sodium levels below this threshold are usually associated with clinical symptoms, which mainly include mental status changes (e.g., altered personality, lethargy, confusion).428 Symptoms are usually more severe with faster-onset hyponatremia.428 Severe hyponatremia (i.e., sodium <115 mEq/L) is associated with symptoms of stupor, neuromuscular hyperexcitability, hyperreflexia, seizures, coma, and possibly, death.428 In the presence of severe neurologic symptoms, a faster infusion rate of sodium may be needed to correct serum sodium concentrations.428 When correcting hyponatremia, serum sodium levels should not be increased by more than 10 to 12 mEq/L in a 24-hour period, or 18 mEq/L in 48 hours.428 Patients with rapid corrections in sodium, or those with serum sodium <120 mEq/L are at greater risk of developing osmotic demyelination syndrome (previously central pontine myelinolysis), which is more common in patients with alcoholism, undernutrition, or other chronic debilitating illnesses.428 Common signs of osmotic demyelination syndrome include flaccid paralysis, dysarthria, and in severe cases with extended lesions, locked-in syndrome (generalized motor paralysis), which is often permanent.428 If neurologic symptoms start to occur during the treatment of hyponatremia, correction of serum sodium should be suspended in order to mitigate the development of permanent neurologic damage.428
Lithium-induced Chronic Kidney Disease
The most common form of chronic kidney disease associated with long-term lithium therapy is chronic tubulointerstitial nephropathy (CTIN).428 Biopsy findings in patients with lithium-induced CTIN include tubular atrophy, interstitial fibrosis, sclerotic glomeruli, tubular dilation, and nephron atrophy with cyst formation.428 The association of lithium treatment with renal function and morphologic changes has not been established.428 Patients with CTIN may present with nephrotic proteinuria (>3 g/dL), worsening renal insufficiency and/or nephrogenic diabetes insipidus.428 Postmarketing reports consistent with nephrotic syndrome in patients with or without CTIN have also been reported.428 Biopsy findings in patients with nephrotic syndrome include minimal change disease and focal segmental glomerulosclerosis.428 Discontinuation of lithium has resulted in the remission of nephrotic syndrome.428
Assess kidney function prior to and during lithium treatment.428 Routine urinalysis and other tests can be used to evaluate tubular function (e.g., urine specific gravity or osmolality following a period of water deprivation, or 24-hour urine volume) and glomerular function (e.g., serum creatinine, creatinine clearance, or proteinuria).428 During lithium therapy, progressive or sudden changes in renal function, even within the normal range, indicate the need to re-evaluate treatment.428
In patients receiving lithium with concomitant antipsychotic therapy, an encephalopathic syndrome, similar to or the same as neuroleptic malignant syndrome (NMS), has been reported.428 The encephalopathic syndrome is characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, blood urea nitrogen (BUN), and fasting blood glucose.428 In some instances, the encephalopathic syndrome was followed by irreversible brain damage.428 Because of the possible association of these events with concomitant lithium and antipsychotic therapy, patients receiving such combined therapy should be monitored closely for early evidence of neurologic toxicity.428 Discontinue the combination therapy promptly if signs of neurologic toxicity occur.428
Serotonin syndrome, a potentially fatal condition, can be precipitated by lithium.428 The risk of serotonin syndrome increases with concomitant administration of other serotonergic medications or medications that inhibit serotonin metabolism such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, tramadol, tryptophan, buspirone, and St. John's Wort ( Hypericum perforatum ).428
Symptoms of serotonin syndrome can include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and GI symptoms (e.g., nausea, vomiting, diarrhea).428
Monitor all patients receiving lithium for the emergence of serotonin syndrome.428 If symptoms of serotonin syndrome occur, discontinue treatment with lithium and any concomitant serotonergic agents immediately and initiate supportive care.428 If concomitant use of lithium with other serotonergic agents is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.428
Lithium concentrates in the thyroid and therefore thyroid synthesis can be inhibited, which can lead to hypothyroidism.428 Paradoxically, cases of hyperthyroidism, including Grave's disease, toxic multinodular goiter, and silent thyroiditis have been reported.428 In the presence of preexisting hypothyroidism, careful monitoring of thyroid function during lithium stabilization and maintenance allows for the correction of changing thyroid parameters and supplemental thyroid treatment if needed.428
Monitor thyroid function (T3, T4, and thyroid-stimulating hormone [TSH] concentrations) before initiating treatment, at 3 months, and every 6-12 months during ongoing lithium treatment.428 In the presence of abnormal thyroid tests, more frequent monitoring is recommended.428
Hypercalcemia and Hyperparathyroidism
Long-term lithium therapy is associated with persistent hyperparathyroidism and hypercalcemia.428 With clinical manifestations of hypercalcemia, withdrawal of lithium and a switch to another mood stabilizer may be necessary.428 Upon withdrawal of lithium, hypercalcemia may not resolve and may require surgical intervention.428 Lithium-induced cases of hyperparathyroidism are often multiglandular compared to standard cases of hyperparathyroidism.428 False hypercalcemia due to volume depletion from nephrogenic diabetes insipidus should be ruled out in patients with mild increases in serum calcium.428 Serum calcium concentrations should be monitored regularly.428
Postmarketing reports indicate a possible association between lithium and the unmasking of Brugada syndrome.428 Lithium should be avoided in patients with confirmed or suspected Brugada syndrome.428 Brugada syndrome is characterized by abnormal ECG findings and the risk of sudden death.428 Consultation with a cardiologist is recommended if lithium is being considered in a patient with suspected Brugada syndrome or with risk factors for Brugada syndrome (e.g., unexplained syncope, family history of Brugada syndrome, family history of unexplained death before 45 years of age), and in patients who develop unexplained syncope or palpitations after initiating lithium.428
Pseudotumor cerebri (increased intracranial pressure and papilledema) have been reported with lithium.428 When undetected, pseudotumor cerebri can result in enlargement of the blind spot, constriction of visual fields, and eventual blindness from optic atrophy.428
Consider discontinuation of lithium if pseudotumor cerebri occur.428
Fetal/Neonatal Morbidity and Mortality
Lithium may cause fetal toxicity (e.g., increase in cardiovascular malformations, especially Ebstein's anomaly), when administered to pregnant females during the first trimester.428 Fetal harm was also seen in animal developmental and toxicity studies.428 Lithium toxicity has been reported in neonates exposed to lithium during late pregnancy.428
Inform pregnant females of the potential fetal risk.428
Consider fetal echocardiography between 16 to 20 weeks' gestation in females with first trimester lithium exposure.428
There is potential for fetal harm when lithium is used during pregnancy.428 Reports from international birth registries suggest an increased risk of cardiovascular malformation, particularly Ebstein's anomaly, with first trimester exposure to lithium.428 Additional case-control and cohort studies indicate risk of cardiovascular malformations is likely small; however, current data are insufficient to establish a drug-associated risk.428 There are additional concerns for maternal and/or neonatal lithium toxicity during late pregnancy and during the postpartum period.428 Animal developmental and toxicity studies indicate an increased risk of fetal mortality, decreased fetal weight, increased fetal skeletal malformations, and cleft palate with oral doses of lithium that produce lithium concentrations similar to the human therapeutic range.428 Inform pregnant females of the potential fetal risk with lithium therapy.428
Consider fetal echocardiography between 16 to 20 weeks' gestation in females with first trimester lithium exposure because of the fetal risk of cardiac malformations.428
The renal excretion of lithium increases during pregnancy; therefore, if the decision is made to continue lithium, the dosage generally needs to be increased, serum concentrations monitored, and the dosage of lithium adjusted as needed.428 The lithium dosage should be reduced 2 to 3 days prior to delivery to reduce the risk of maternal and/or neonatal toxicity.428 Lithium may then be resumed during the postpartum period at preconception dosages in medically stable patients as long as lithium levels are closely monitored.428
Lithium toxicity has been reported in neonates exposed to lithium during late pregnancy.428 Floppy baby syndrome, along with neurologic, cardiac, and hepatic abnormalities similar to that observed in adults with lithium toxicity, has been reported.428 Symptoms of floppy baby syndrome include hypotonia, respiratory distress syndrome, cyanosis, lethargy, feeding difficulties, depressed neonatal reflexes, neonatal depression, apnea, and bradycardia.428 Neonates should be monitored and supportive care provided until lithium is excreted and symptoms of toxicity disappear, which may take up to 14 days.428
Lithium carbonate is excreted into breast milk at levels measured at 0.12 to 0.7 mEq/L or 40-45% of maternal plasma concentrations.428 Infants exposed to lithium through breast-feeding may have plasma concentrations that are 30-40% of maternal plasma levels.428 Signs and symptoms of lithium toxicity, which include hypertonia, hypothermia, cyanosis, and ECG changes have been reported in some breast-fed infants and neonates.428 Increased prolactin levels have also been detected in some breast-feeding females; however, the effect on milk production is not known.428
Breast-feeding is not recommended when the mother is receiving lithium therapy; however, if the mother chooses to breast-feed, the infant should be closely monitored for signs of lithium toxicity.428 Breast-feeding should be discontinued if the infant develops lithium toxicity.428
Regular monitoring of lithium levels and thyroid function should be considered in breast-fed infants exposed to lithium.428
Safety and efficacy of lithium monotherapy (as conventional tablets, capsules, or lithium citrate oral solution) for the treatment of acute manic or mixed episodes and maintenance monotherapy of bipolar I disorder have been established in pediatric patients 7 to 17 years of age.428 Safety and efficacy were established based on an acute-phase study of 8 weeks' duration followed by a 28-week randomized withdrawal study.428
Safety and efficacy of lithium therapy (as conventional tablets, capsules, or lithium citrate oral solution) in children <7 years of age with bipolar I disorder have not been established.428
Safety and efficacy of lithium carbonate as extended-release tablets have not been established in pediatric patients <12 years of age.404, 405
Clinical studies of lithium carbonate as extended-release tablets did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.404, 405, 428 While clinical experience with lithium generally has not revealed age-related differences in response, care should be taken in dosage selection.405 Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and other medication therapy in geriatric patients, patients should receive initial dosages on the lower end of the usual range.405 Lithium is substantially excreted by the kidneys and risk of severe adverse reactions may be increased in patients with impaired renal function.405 Because geriatric patients may have decreased renal function, renal function should be monitored and dosage adjusted accordingly.405
Since lithium primarily undergoes renal elimination, hepatic impairment is not expected to have a significant impact on elimination.428
Because lithium is primarily eliminated via the kidneys, the risk of lithium toxicity increases in the setting of abnormal renal function because of reduced clearance.428 Lithium should be avoided in patients with severe renal impairment (creatinine clearance [ClCr] <30 mL/minute based on Cockroft-Gault), especially if the impairment requires a low-sodium diet.428
Slow titration and lower initial dosages of lithium are recommended in patients with mild to moderate renal impairment (ClCr 30-89 mL/minute).428 It is also recommended to frequently monitor serum lithium concentrations and for signs of lithium toxicity.428
Lithium is readily removed by hemodialysis.404, 405, 428
Common adverse effects in adults receiving lithium include fine hand tremor, polyuria, mild thirst, nausea, and general discomfort during lithium initiation.428
Common adverse effects in pediatric patients 7-17 years of age receiving lithium therapy include nausea/vomiting, polyuria, thyroid abnormalities, tremor, thirst/polydipsia, dizziness, rash/dermatitis, ataxia/gait disturbances, decreased appetite, and blurry vision.428
Lithium is not metabolized.428
Alkalinizing agents (e.g., sodium bicarbonate) may increase renal excretion of lithium, and a higher dosage of lithium may be required in patients receiving these agents concomitantly.428 Monitor plasma lithium concentrations more frequently in patients receiving alkalinizing agents and increase lithium dosage based on plasma concentrations and clinical response.428
Adverse effects have occurred in patients receiving lithium concurrently with carbamazepine or phenytoin.428 Monitor patients for adverse effects from carbamazepine or phenytoin if used concurrently with lithium.428
Neurotoxic reactions have been reported in patients receiving lithium and concomitant atypical or typical antipsychotic agents.428 These reactions range from extrapyramidal symptoms to neuroleptic malignant syndrome (NMS), as well as encephalopathic syndrome in a few patients.428 Patients receiving lithium with concomitant antipsychotic agents should be monitored for neurologic adverse effects.428
Angiotensin-converting Enzyme (ACE) Inhibitors
Concomitant administration of lithium and an ACE inhibitor (e.g., captopril, enalapril, lisinopril) may result in elevated plasma lithium concentrations and has resulted in several cases of lithium intoxication.404 If lithium is used with an ACE inhibitor, the dosage of lithium may need to be reduced and serum lithium concentrations should be monitored more frequently.404
Angiotensin-II Receptor Blockers (ARB)
Concomitant administration of lithium and an ARB (e.g., losartan) may result in elevated plasma lithium concentrations and subsequent lithium intoxication.404 If lithium is used with an ARB, the dosage of lithium may need to be reduced and serum lithium concentrations should be monitored more frequently.404
Calcium-channel Blocking (CCB) Agents
There is some evidence that CCB agents may increase the neurologic toxicity of lithium.428 Neurologic symptoms (e.g., ataxia, tremors, nausea, vomiting, diarrhea, tinnitus) have been reported in patients receiving lithium concomitantly with a CCB.428 Patient receiving lithium concomitantly with a CCB should be monitored for neurologic adverse effects.428
Sodium loss caused by diuretic use (e.g., amiloride, furosemide, spironolactone, thiazides, urea) may reduce the renal clearance of lithium and increase the risk of lithium toxicity.428 When such combinations are used, the lithium dosage may need to be decreased and more frequent monitoring of serum lithium concentrations and serum electrolytes is recommended.428
Neuromuscular Blocking Agents (NMBA)
Lithium has been reported to prolong the effects of NMBA.428 Neuromuscular blocking agents should be used with caution in patients receiving lithium,404, 405 and patients should be monitored for prolonged paralysis.428
Nonsteroidal Anti-inflammatory Agents (NSAIAs)
Concomitant use of NSAIAs (e.g., celecoxib, indomethacin, piroxicam) may decrease renal blood flow and clearance of lithium, which can increase the risk of lithium toxicity.428 Monitor serum lithium concentrations more frequently.404, 405
Concurrent use of lithium salts and iodides, especially potassium iodide, may result in hypothyroidism.404, 405 When the medications are administered concurrently, the patient should be monitored closely for signs and symptoms of hypothyroidism.428
Adverse effects have occurred in patients receiving lithium concurrently with methyldopa.428 Monitor patients for adverse effects from methyldopa when used concurrently.428
Concurrent use of metronidazole therapy with lithium may reduce renal clearance of lithium and increase the risk of lithium toxicity.404, 405 Frequent monitoring of serum lithium concentrations should be performed when the medications are administered concurrently and lithium dosage reduced based on lithium concentrations and clinical response.428
The risk of serotonin syndrome increases with concomitant administration of other serotonergic medications or medications that inhibit serotonin metabolism such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, tramadol, tryptophan, buspirone, and St. John's Wort ( Hypericum perforatum ).428
All patients receiving lithium and a concomitant serotonergic medication should be monitored for serotonin syndrome (e.g., mental status changes, autonomic instability, neuromuscular symptoms, seizures, GI symptoms), particularly during lithium initiation.428 If symptoms of serotonin syndrome occur, discontinue treatment with lithium and any concomitant serotonergic agents.428
In addition, concomitant use of lithium and fluoxetine has resulted in both increased and decreased serum lithium concentrations; therefore, patients receiving such combined therapy should be monitored closely.405
Lithium therapy can cause reduced sodium reabsorption in the kidneys, leading to sodium depletion.428 Patients should be advised to avoid substantial changes in their sodium intake while receiving lithium.428
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors
Concurrent use of lithium with an SGLT2 inhibitor may decrease plasma lithium concentrations.428 Frequent monitoring of serum lithium concentrations should be performed when the medications are administered concurrently.428
Decreased serum lithium concentrations as a result of increased urinary lithium excretion may occur when lithium is used concomitantly with acetazolamide, urea, or xanthine derivatives (e.g., aminophylline).428 Monitor plasma lithium concentrations more frequently in patients receiving these agents and increase lithium dosage based on plasma concentrations and clinical response.428
Preclinical data indicate that lithium alters sodium transport in nerve and muscle cells, and shifts intraneuronal metabolism of catecholamines; however, the specific mechanism of action of lithium in treating mania is not known.404
Following oral administration, lithium is completely absorbed in the upper GI tract.428 Peak plasma concentrations of lithium occur within 0.25-3 hours of immediate-release preparations and 2-6 hours after administration of sustained-release preparations.428 When administered to a patient experiencing a manic episode, lithium carbonate as extended-release tablets is expected to normalize symptomatology within 1-3 weeks.404 Lithium distributes into the breastmilk of lactating females.428 Plasma protein binding of lithium is negligible.428 Lithium is not metabolized and is excreted almost entirely in the urine.428 Lithium excretion in the feces is insignificant.428 About 80% of the lithium that is filtered by renal glomeruli is reabsorbed via passive diffusion in proximal renal tubules.428 The elimination half-life of lithium is approximately 18-36 hours.428 Clearance of lithium increases with increasing body weight.428 A lower dosage of lithium in pediatric patients <30 kg is expected to achieve lithium exposure similar to that in adults at recommended dosages.428
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 150 mg* | Lithium Carbonate Capsules | |
300 mg* | Lithium Carbonate Capsules | |||
600 mg* | Lithium Carbonate Capsules | |||
Tablets | 300 mg* | Lithium Carbonate Tablets (scored) | ||
Tablets, extended-release | 450 mg* | Lithium Carbonate Extended-release Tablets | ||
Tablets, extended-release, film-coated | 300 mg* | Lithium Carbonate Extended-release Film-coated Tablets | ||
Lithobid |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | 8 mEq (of lithium) per 5 mL* | Lithium Citrate Syrup |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
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