Continuing Education Activity

Despite the availability of newer mood stabilizers, lithium continues to be a first-line treatment for bipolar disorder. It is often underutilized because of the potential for side effects, and perhaps because it is an older drug. This activity outlines the indications and contraindications for lithium use, provides instructions for administration and monitoring, and reviews lithium toxicity. This activity highlights the role of the interprofessional team in caring for patients who are undergoing, or who may undergo lithium therapy.

Objectives:

• Identify the indications for lithium therapy.
• Describe the potential adverse effects of lithium therapy.
• Explain the need for monitoring lithium levels.
• Review the importance of a well-coordinated interprofessional team in caring for patients undergoing lithium therapy.

Indications

Lithium was the first mood stabilizer and is still the first-line treatment option, but is underutilized because it is an older drug. Lithium is a commonly prescribed drug for a manic episode in bipolar disorder as well as maintenance therapy of bipolar disorder in a patient with a history of a manic episode. The primary target symptoms of lithium are mania and unstable mood.[1]

Lithium is also prescribed for major depressive disorder as an adjunct therapy, bipolar disorder without a history of mania, treatment of vascular headaches, and neutropenia. These are off-label uses, meaning they are not FDA-approved. Patients with rapid cycling and mixed state types of bipolar disorder generally do less well on lithium.

Mechanism of Action

The mechanism of action of lithium is not known. It is rapidly absorbed, has a small volume of distribution, and is excreted in the urine unchanged (there is no metabolism of lithium).

Lithium modifies sodium transport in nerve and muscle cells. It alters the metabolism of neurotransmitters, specifically catecholamines and serotonin.[2] It may alter intracellular signaling via second messenger systems by inhibition of inositol monophosphate. This inhibition, in turn, affects neurotransmission through the phosphatidylinositol secondary messenger system. Lithium also decreases protein kinase C activity, which alters genomic expression associated with neurotransmission. Lithium appears to increase cytoprotective proteins and possibly activates neurogenesis and increases gray matter volume.[3]

The half-life of lithium is 18 to 30 hours. It has lower absorption on an empty stomach.

Administration

Lithium is administered orally in pill form, capsule, or liquid. The tablet is available in a controlled release 450 mg tablet or a slow-release formulation in a 300 mg tablet. Capsules are available in 150 mg, 300 mg, and 600 mg strength. The liquid formulation is available as 8 mEq/5 mL strength. The dosage usually starts at 300 mg twice or three times a day.[4]

It takes about 1 to 3 weeks for lithium to show the effects and remission of symptoms. Many patients show only a partial reduction of symptoms, and some may be nonresponders. In cases where the patient does not display an adequate response, consider monitoring plasma levels, and titrating the dose. A single nighttime dose may be a consideration to minimize side effects in stabilized patients. Lower doses and lower serum levels of lithium are preferable in elderly patients. If patients do not show an adequate response, the clinician should consider augmentation. The preferred agents are valproate, lamotrigine, and atypical antipsychotics like risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.

Lithium should be tapered gradually over three months. Rapid discontinuation increases the risk of relapse. Certain medications increase serum lithium levels, including diuretics (especially thiazides), non-steroidal anti-inflammatory drugs like ibuprofen and COX-2 inhibitors, and angiotensin-converting enzyme inhibitors. Metronidazole raises lithium levels by decreasing its renal clearance. Carbamazepine, phenytoin, and methyldopa may increase the toxicity of lithium.

Adverse Effects

Lithium can cause several adverse effects. Typically the side effects are dose-related. Notable side effects include: 

• Cardiac: Bradycardia, flattened or inverted T waves, heart block, and sick sinus syndrome.
• CNS: Confusion, memory problems, new or worsening tremor, hyperreflexia, clonus, slurred speech, ataxia, stupor, delirium, coma, and seizures (rarely). These effects are theoretically due to excess action on the same sites that mediate therapeutic action.[5] 
• Renal: Nephrogenic diabetes insipidus with polyuria and polydipsia. These side effects are due to lithium's action on ion transport.[6]
• Hematologic: Leukocytosis and aplastic anemia
• Gastroenterologic: Diarrhea and nausea
• Endocrinal: Euthyroid goiter or hypothyroid goiter
• Other: Acne, rash, and weight gain. Lithium-induced weight gain is more common in women than in men.

Some patients on haloperidol and lithium may develop an encephalopathic syndrome similar to neuroleptic malignant syndrome.

Contraindications

Lithium is not recommended in patients with renal impairment. It is also not recommended in patients with cardiovascular disease. Lithium causes reversible T wave changes and can unmask Brugada syndrome. A cardiology consult is necessary if a patient experiences unexplained palpitations and syncope. It is also not advisable to consider lithium for treatment in children under 12 years of age. 

Lithium is not considered for treatment during pregnancy due to a 2 to 3 fold increase of significant congenital disabilities. Ebstein's anomaly is a cardiac defect in infants associated with lithium treatment during pregnancy. It is crucial to weigh the risks versus benefits of continuing a pregnant patient on lithium.[7] If a patient remains on lithium, monitoring should be done every four weeks until 36 weeks, and then every week after that. If a mother receives lithium during delivery, it is essential to monitor the infant for hypotonia and floppy baby syndrome for at least 48 hours. Breastfeeding is not advisable; if a lactating mother is on lithium therapy, breast milk will contain lithium.

Monitoring

Before starting treatment with lithium, it is essential to get kidney function tests and thyroid function tests. In patients above 50 years of age, an electrocardiogram is also necessary. Repeat these tests once or twice a year in patients on lithium therapy. Because lithium is associated with weight gain, it is important to weigh a patient before starting treatment. It is also beneficial to determine if the patient has prediabetes, diabetes, or dyslipidemia.

Monitoring of therapeutic levels includes trough plasma levels drawn 8 to 12 hours after the last dose. The therapeutic range is 1.0 to 1.5 mEq/L for acute treatment and 0.6 to 1.2 mEq/L for chronic therapy. Monitoring should be done every 1 to 2 weeks until reaching the desired therapeutic levels. Then, check lithium levels every 2 to 3 months for six months. It is also important to monitor patients for dehydration and lower the dose when there are signs of infection, excessive sweating, or diarrhea. Toxic levels are when the drug level is more than 2 mEq/L.

Toxicity

Lithium has a very narrow therapeutic index, and toxic levels are when the drug is above 2 mEq/L, which is very close to its therapeutic range. Lithium toxicity can cause interstitial nephritis, arrhythmia, sick sinus syndrome, hypotension, T wave abnormalities, and bradycardia. Rarely, toxicity can cause pseudotumor cerebri and seizures. Lithium toxicity has no antidote. Treatment for lithium toxicity is primarily hydration and to stop the drug. Give hydration with normal saline, which will also enhance lithium excretion. Avoid all diuretics. If the patient has severe renal dysfunction or failure, or severely altered mental status, then start with hemodialysis. 20 to 30 mg of propranolol given 2 to 3 times per day may help reduce tremors.

Enhancing Healthcare Team Outcomes

The psychiatrist generally prescribes lithium, but the drug levels are often monitored by the primary care provider, mental health nurse, pharmacist, and the internist, functioning as an interprofessional team. Lithium continues to be a first-line treatment option for mood stabilization. When prescribed, the pharmacist should carefully inspect the dosing and perform medication reconciliation, so avoid any issues with dosing and subsequent serum levels. Mental health nurses should be alert to the signs and symptoms of lithium toxicity and report such to the prescriber immediately if these are present. It is essential to maintain coordination of care in patients on /lithium therapy owing to its narrow therapeutic index and potential adverse effects and toxicity.[8]

Every patient on lithium needs close monitoring; if the patient is unlikely to comply with followup, clinicians should not prescribe them the drug; this is where the interprofessional team paradigm is most effective. [Level 5]