Article Author:
Krutika Chokhawala
Article Editor:
Abdolreza Saadabadi
3/9/2019 9:53:37 PM
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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 commonly prescribed 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.

Lithium is also prescribed for major depressive disorder as 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. 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 is thought to increase cytoprotective proteins and possibly activates neurogenesis and increases gray matter volume.

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


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 form 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 is usually started at 300 mg twice a day or 3 times a day. 

It takes about 1 to 3 weeks for lithium to show 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 considered to minimize side effects in patients who have been stabilized. Lower doses and lower serum levels of lithium are preferable in elderly patients. If patients do not show an adequate response, augmentation should be considered. The preferred agents are valproate, lamotrigine, and atypical antipsychotics like risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.

Lithium should be tapered gradually over 3 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. 
  • Renal: Nephrogenic diabetes insipidus with polyuria and polydipsia. These side effects are due to lithium's action on ion transport.
  • 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.


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 should be obtained 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. If a patient remains on lithium, monitoring should be done every 4 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 advised if a lactating mother is on lithium therapy, as the breast milk will contain lithium.


Before starting treatment with lithium, it is important to get kidney function tests and thyroid function tests. In patients above 50 years of age, an electrocardiogram must also be done. 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 treatment. Monitoring should be done every 1 to 2 weeks until the desired therapeutic levels are reached. Then, check lithium levels every 2 to 3 months for 6 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 considered to be more than 2 mEq/L.


Lithium has a very small therapeutic index, and toxic levels are usually considered 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 severe altered mental status, then start with hemodialysis. 20 to 30 mg of propranolol given 2 to 3 times per day may help reduce tremors.


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