Continuing Education Activity

Lithium pioneered mood stabilization and continues to be the preferred first-line treatment choice despite the availability of newer mood stabilizers. Although lithium is approved by the U.S. Food and Drug Administration (FDA) for treating bipolar I disorder, it is often underutilized due to concerns about potential adverse effects and its status as an older drug. Lithium is prescribed for managing acute manic and mixed episodes and maintenance treatment in patients aged 7 or older. In addition, lithium is prescribed off-label for treating major depressive disorder as an adjunct therapy, managing bipolar disorder without a history of mania, addressing vascular headaches, and alleviating neutropenia. This activity outlines the indications and contraindications for lithium use, furnishes guidelines for its administration and monitoring, assesses lithium toxicity, and highlights the role of the interprofessional team in caring for patients undergoing or potentially undergoing lithium therapy.

Objectives:

• Differentiate between the indications and contraindications for lithium use in bipolar disorder and other conditions.
• Implement proper dosing strategies for initiating and titrating lithium therapy, considering patient-specific factors.
• Apply knowledge of drug interactions to select appropriate concomitant medications and maintain therapeutic lithium levels within the therapeutic range while prescribing lithium.
• Collaborate with other healthcare professionals to optimize comprehensive patient care and address concerns for patients on lithium therapy.

Indications

Lithium pioneered mood stabilization and remained the primary choice for first-line treatment. Although lithium is approved by the U.S. Food and Drug Administration (FDA) for treating bipolar I disorder, it is often underutilized due to concerns about potential adverse effects and its status as an older drug. Lithium is prescribed for managing acute manic and mixed episodes and maintenance treatment in patients aged 7 or older.[1] The sustained-release (SR) lithium formulation has received FDA approval for use in individuals aged 12 or older.

Lithium is also prescribed off-label for treating major depressive disorder as an adjunct therapy, managing bipolar disorder without a history of mania, addressing vascular headaches, and alleviating neutropenia. However, lithium should only be used for these conditions in cases where alternative agents have proven ineffective.[2] Individuals with rapid cycling and mixed-state manifestations of bipolar disorder typically exhibit limited responsiveness to lithium treatment. In instances where monotherapy for depression proves inadequate, it is advisable to augment the existing antidepressant regimen with lithium. The administration of lithium augmentation should span 2 to 4 weeks. If a positive response becomes evident, sustaining lithium augmentation for 12 months is recommended.[3]

Mechanism of Action

Lithium's precise mechanism of action is still under investigation and not fully comprehended yet. Lithium induces changes in sodium transport within nerve and muscle cells, and it also influences the metabolism of neurotransmitters, particularly catecholamines and serotonin.[4] Lithium may alter intracellular signaling via second messenger systems by inhibiting inositol monophosphate. This inhibitory action subsequently impacts neurotransmission mediated by the phosphatidylinositol secondary messenger system. Furthermore, lithium diminishes the activity of protein kinase C, leading to modifications in genomic expression associated with neurotransmission. Lithium seems to elevate cytoprotective proteins, potentially triggering neurogenesis and increasing the gray matter volume.[5]

Pharmacokinetics

Absorption: Lithium is readily absorbed from the gastrointestinal tract. Peak plasma concentrations of lithium are attained within 0.25 to 3 hours following oral intake of immediate-release formulations and between 2 and 6 hours with SR formulations.[6]

Distribution: The distribution of lithium in the body closely resembles that of total body water. Upon reaching equilibrium, the apparent lithium distribution volume can range from 0.7 to 1 L/kg. The binding of lithium to plasma proteins is minimal.

Metabolism: Lithium undergoes no metabolic transformation within humans and is excreted in its original form through the urine.

Elimination: Lithium is primarily excreted through urine, and the amount expelled is directly proportional to its concentration in the serum. Nevertheless, approximately 80% of the excreted lithium undergoes reabsorption within the proximal tubule of the nephron. The elimination half-life of lithium ranges from 18 to 36 hours.

Administration

Available Dosage Forms and Strength

Lithium is typically administered orally, either in the form of pills, capsules, or liquid. The tablet form is available in a controlled-release variant of 450 mg or as a slow-release formulation of 300 mg. Capsules are available in strengths of 150 mg, 300 mg, and 600 mg. The liquid formulation of lithium is available as an 8 mEq/5 mL oral solution.

Adult Dosage

Lithium typically requires approximately 1 to 3 weeks to manifest its effects, resulting in symptom alleviation and remission. Notably, many patients experience only a partial reduction in symptoms, and a subset may not respond to treatment. If the patient's response is inadequate, it is advisable to contemplate plasma level monitoring and adjust the dose accordingly. For stabilized patients, deliberating a single nighttime dose might be a viable option to mitigate the potential adverse effects of lithium. Preferably, lower doses and reduced serum levels of lithium are recommended for older patients. In cases of insufficient response, clinicians should contemplate augmentation strategies. The preferred agents include valproate, lamotrigine, and atypical antipsychotics such as risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. Gradual tapering of lithium over 3 months is recommended, as rapid drug discontinuation can elevate the risk of relapse. 

Bipolar I disorder

The initial dosage for lithium treatment is 600 mg, administered 2 to 3 times daily, aiming for a target serum lithium concentration range of 0.8 to 1.2 mEq/L. For maintenance treatment, the recommended dosage is between 300 and 600 mg, administered 2 to 3 times daily, aiming for a target serum lithium concentration range of 0.8 to 1.0 mEq/L. The therapeutic range can vary based on the specific disease state, renal function, and age group. Considering a lower initial lithium dosage might be prudent to mitigate the potential for adverse drug reactions for this disorder.[7] Per the International Society for Bipolar Disorders (ISBD), lithium is recognized as the gold standard for maintenance treatment, owing to its effectiveness in preventing both manic and depressive episodes.[8]

Specific Patient Populations

Renal impairment: Assessing renal function using the Cockcroft-Gault equation is imperative for adjusting the dosages in patients exhibiting mild-to-moderate impairment and creatinine clearance of 30 to 89 mL/min. Lower dosages of lithium are recommended to be administered in such cases. Regular monitoring of serum lithium concentrations and observing signs of lithium toxicity are advisable throughout the process of gradual dosage modifications. If the creatinine clearance is below 30 mL/min, it is not advisable to pursue lithium treatment.[9]

Hepatic impairment: The manufacturer's instructions for lithium do not include precise dosage adjustments for individuals with compromised liver function. 

Pregnancy considerations: Using lithium during the initial trimester heightens the likelihood of cardiac malformations, particularly the Ebstein anomaly.[10] To minimize the potential threat of lithium toxicity to both the mother and the child, discontinuation of lithium administration is recommended for 2 to 3 days before the anticipated delivery date. Following childbirth, stable patients can resume lithium at the preconception dose, with a continued emphasis on monitoring lithium serum levels. According to the American College of Obstetricians and Gynecologists (ACOG), exposure to lithium has been associated with various adverse effects, including hypoglycemia, nephrogenic diabetes insipidus, polyhydramnios, changes in thyroid function, and premature delivery. 

Pregnant patients on lithium treatment should be monitored every 4 weeks until 36 weeks of pregnancy and then weekly after that. If a mother is administered lithium during delivery, monitoring the infant for a minimum of 48 hours is crucial to detect signs of hypotonia and floppy baby syndrome. ACOG recommends fetal echocardiography for pregnant women exposed to lithium during the first trimester. Evaluating the balance between risks and benefits is essential when considering continuing lithium treatment for a pregnant patient.[11][12][13][14]

Breastfeeding considerations: Based on numerous studies, the use of lithium during lactation is not advisable. However, if the mother chooses to breastfeed her child, monitoring the lithium levels in both mother and child and the infant's thyroid function is imperative. In the event of lithium toxicity, it is recommended to discontinue breastfeeding.[15]

Pediatric patients: The safety and efficacy of lithium have not been established in individuals aged 7 or younger with bipolar I disorder. To ensure the proper dosing for pediatric patients weighing over 30 kg, it is advised to administer an initial 300 mg of medication thrice daily in a tablet or capsule form. Alternatively, 8 mEq/5 mL lithium as an oral solution can also be administered to pediatric patients thrice daily. The recommended maintenance dosage for patients weighing over 30 kg is 300 to 600 mg, administered 2 to 3 times daily. For pediatric patients weighing between 20 and 30 kg, it is advised to administer a starting dosage of 300 mg of medication twice daily in a tablet or capsule form. Alternatively, 8 mEq/5 mL lithium as an oral solution can also be administered to pediatric patients twice daily. The maintenance dosage for patients weighing between 20 and 30 kg is 600 to 1200 mg, administered daily in 2 equally divided doses.

Older patients: The 2023 Beers Criteria from the American Geriatric Society strongly recommend against the simultaneous use of lithium with ACE inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, or loop diuretics in older patients due to the potential risk of toxicity.[16]

Adverse Effects

Lithium can cause various adverse effects, often correlated with the dosage. The notable adverse effects of lithium include: 

• Cardiac: Bradycardia, flattened or inverted T waves, heart block, and sick sinus syndrome.

• Central nervous system: Confusion, memory problems, new or worsening tremors, hyperreflexia, clonus, slurred speech, ataxia, stupor, delirium, coma, and infrequent seizures. These effects are thought to arise from potential overstimulation of the same sites responsible for therapeutic responses.[17]

• Renal: Nephrogenic diabetes insipidus characterized by polyuria and polydipsia. These adverse effects stem from the impact of lithium on ion transport mechanisms.[18]

• Hematologic: Leukocytosis and aplastic anemia.

• Gastroenterology: Diarrhea and nausea.

• Endocrinal: Euthyroid goiter or hypothyroid goiter.

• Additional adverse effects include acne, rash, and weight gain. Lithium-induced weight gain is more frequently observed in women than men.

Drug-Drug Interactions

• Concurrent administration of diuretics, particularly thiazide, non-steroidal anti-inflammatory drugs, renin-angiotensin system antagonists, or metronidazole can elevate serum lithium concentrations. Healthcare providers are strongly advised to consistently monitor serum lithium levels and enact appropriate dosage modifications in patients as needed.[19]

• The coadministration of serotonergic agents with lithium heightens the risk of serotonin syndrome.[20]

• Patients undergoing treatment with both lithium and antipsychotics may encounter neurological adverse reactions, ranging from extrapyramidal symptoms to neuroleptic malignant syndrome. Certain individuals receiving haloperidol and lithium might develop an encephalopathy akin to neuroleptic malignant syndrome.[21]

Contraindications

Lithium is contraindicated in patients with established hypersensitivity to lithium or its excipients.

Box Warning

Lithium toxicity is associated with serum lithium concentrations and can manifest even when administered at doses close to therapeutic levels. Therefore, the clinical team should have readily accessible facilities to accurately determine serum lithium levels before initiating lithium therapy.[22]

Precautions/Warnings

Renal impairment: Lithium usage should be avoided in severe renal impairment with creatinine clearance less than 30 mL/min, especially if the patient's medical condition requires adherence to a low-sodium diet.[23]

Cardiovascular disease: Lithium is also not recommended in patients with cardiovascular disease as the drug induces reversible T-wave alterations and can unmask Brugada syndrome.[24] A cardiology consultation is required if a patient experiences unexplained palpitations and syncope.[25]

Hyponatremia: Lithium decreases sodium reabsorption in renal tubules, resulting in sodium depletion. Patients should uphold a standard diet with sufficient salt and fluid intake while undergoing lithium stabilization. Close monitoring of fluid and salt supplementation might be essential in prolonged sweating, diarrhea, and adjustments in lithium dosage. A temporary medication halt might be warranted in situations involving infections and elevated temperatures. Rapid correction of serum sodium levels less than 120 mEq/L increases the risk of central pontine myelinolysis, also known as osmotic demyelination syndrome. If neurological symptoms emerge during hyponatremia treatment, discontinuing sodium correction is recommended to avert permanent damage.[26][27]

Lithium-induced chronic kidney disease: Prolonged utilization of lithium is associated with chronic tubulointerstitial nephropathy. Instances of nephrotic syndrome, encompassing minimal change disease and focal segmental glomerulosclerosis, have been reported in patients. Discontinuation of lithium has resulted in the remission of nephrotic syndrome in some patients.[28]

Hypothyroidism and hyperthyroidism: Lithium accumulates in the thyroid gland, inhibiting thyroid synthesis and release, potentially resulting in hypothyroidism. Instances of hyperthyroidism, including Graves disease, toxic multinodular goiter, and thyroiditis, have also been documented. Vigilant monitoring of thyroid function is imperative throughout lithium treatment.[29]

Hypercalcemia and hyperparathyroidism: Extended utilization of lithium is associated with persistent hyperparathyroidism and hypercalcemia. In cases of severe hypercalcemia, it may be necessary to discontinue lithium. Therefore, monitoring serum calcium levels regularly is highly recommended.[30]

Monitoring

Before initiating lithium treatment, healthcare providers must perform kidney and thyroid function tests on patients.[29][28] In patients aged 50 or older, conducting an electrocardiogram procedure is also an essential requirement. These tests should be performed once or twice annually for patients undergoing lithium therapy. Due to lithium's association with weight gain, measuring the patient's weight before initiating treatment is crucial. Furthermore, assessing for prediabetes, diabetes, or dyslipidemia in the patient is also beneficial.

Monitoring therapeutic levels involves obtaining trough plasma levels drawn 8 to 12 hours following the most recent dose. The product labeling states that the recommended therapeutic range is between 0.8 and 1.2 mEq/L for acute goals or 0.8 and 1.0 mEq/L for maintenance goals.[31] Levels can fluctuate based on individual patient responses, and certain patients may maintain stability at lower therapeutic concentrations. Monitoring should be conducted every 1 to 2 weeks until the desired therapeutic levels are achieved. Subsequently, lithium levels should be obtained every 2 to 3 months for 6 months. The clinical team must also be vigilant in monitoring patients for dehydration and should consider dose reduction when signs of infection, excessive sweating, or diarrhea emerge. Serum drug concentrations exceeding 2 mEq/L indicate toxic levels.

Toxicity

Due to its narrow therapeutic index, serum levels of lithium exceeding 2 mEq/L are considered toxic, which falls within its therapeutic range. Lithium toxicity can result in interstitial nephritis, arrhythmia, sick sinus syndrome, hypotension, T-wave abnormalities, and bradycardia. In rare instances, toxicity can lead to pseudotumor cerebri and seizures. Notably, there exists no antidote for lithium toxicity. The primary approach to treating lithium toxicity involves hydration and discontinuation of the drug. Administering hydration through normal saline concurrently facilitates lithium excretion. Close monitoring is essential to prevent hypernatremia in patients receiving normal saline. Diuretic use should be avoided for patients on lithium treatment. For mitigating tremors, administering 20 to 30 mg of propranolol twice or thrice daily is recommended.

Recommendations

The guidelines established by EXtracorporeal TReatments In Poisoning (EXTRIP) are listed below.

• Initiate extracorporeal treatment for patients with severe lithium poisoning presenting with coma, myoclonus, convulsions, or cardiopulmonary collapse.

• Initiate extracorporeal treatment when impaired kidney function is evident, and the lithium concentration surpasses 4 mEq/L. Hemodialysis is also indicated in patients with altered consciousness, seizures, or life-threatening dysrhythmias, regardless of the lithium concentration.

• Consider extracorporeal treatment if the lithium concentration exceeds 5 mEq/L, significant confusion is evident, or the projected duration for reducing the lithium concentration below 1 mEq/L extends beyond 36 hours.

• Continue extracorporeal treatment until clinical improvement or lithium concentration drops below 1 mEq/L. In cases where lithium concentration measurement is unattainable, maintain extracorporeal therapies for at least 6 hours.

• Hemodialysis is the preferred extracorporeal treatment option, although continuous renal replacement therapy is also acceptable.[32]

Enhancing Healthcare Team Outcomes

Although psychiatrists typically initiate lithium prescriptions, primary care providers, mental health nurses, pharmacists, and internists collaborate as an interprofessional healthcare team to monitor drug levels. Lithium continues to be a first-line treatment option for mood stabilization in individuals. Pharmacists are critical in conducting medication reconciliation, assessing drug interactions, and emphasizing the significance of consistent adherence to lithium therapy to caregivers, thus improving compliance. Mental health nurses should maintain vigilance for signs and symptoms of lithium toxicity and promptly communicate these findings to the prescriber. Due to its narrow therapeutic index and the potential for adverse effects and toxicity, interprofessional team members must collaborate to manage lithium therapy in patients, thereby ensuring coordinated care.[33] 

In cases of lithium poisoning, it is advisable to contact toxicologists or poison control centers to obtain the latest information. A psychiatrist consultation is essential if an overdose is suspected to be intentional. A nephrologist consultation is necessary to initiate hemodialysis in case of severe poisoning. In addition, an interprofessional team approach coupled with open communication among physicians, specialists, advanced practice practitioners, pharmacists, nurses, and toxicologists is indispensable for enhancing patient outcomes associated with lithium therapy and mitigating the likelihood of toxicity.

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Disclosure: Krutika Chokhawala declares no relevant financial relationships with ineligible companies.

Disclosure: Sarah Lee declares no relevant financial relationships with ineligible companies.

Disclosure: Abdolreza Saadabadi declares no relevant financial relationships with ineligible companies.