Lithium


Article Author:
Krutika Chokhawala


Article Editor:
Abdolreza Saadabadi


Editors In Chief:
Scott Klenzak
Barry Liskow
Brian Farah


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
5/11/2019 12:35:52 AM

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 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. [1]

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.[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 is thought 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 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. [4]

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.[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 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. [7]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.

Monitoring

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.

Toxicity

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.

Enhancing Healthcare Team Outcomes

Lithium is generally prescribed by the psychiatrist but the drug levels are often monitored by the primary care provider, mental health nurse, pharmacist, and the internist. Lithium continues to be a first line treatment option for mood stabilization. It is important 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, the drug should not be prescribed.


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Lithium - Questions

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Which of the following adverse effects of lithium do not persist with long-term therapy?



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Which of the following is not an adverse effect of lithium?



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Which drug is not associated with fluid retention?



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Which of the following is true about lithium?



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Which of the following is most likely to cause diabetes insipidus?



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What causes the polyuria associated with lithium use?



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A recognized side effect of treatment with lithium carbonate is:



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Which of the following is not an adverse effect of lithium?



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Which of the following is responsible for polyuria caused by lithium?



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Which medication can cause nephrogenic diabetes?



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Which medication is known to cause thyroid enlargement?



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Which of the following is NOT a side effect of lithium?



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Which of the following drugs is known to act by recycling the phosphatidylinositol second messenger system?



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A patient on lithium is unlikely to develop which of the following?



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When an individual sweats, what happens to lithium levels?



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How does lithium affect general anesthesia?



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Lithium is usually excreted by which organ?



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Which of the following tests needs to be monitored on patients treated with lithium carbonate?



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Which of the following is not part of the teaching for a patient with bipolar disorder who is being treated with lithium?



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A 29-year-old patient with a good understanding of being on lithium therapy will do which of the following?



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A patient is seen in the emergency department after overdosing on lithium. She is complaining of nausea, vomiting, and blurred vision. Lithium level is 3.1 mEq/L. Which is not part of the management of lithium toxicity?



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Serum lithium levels should NOT exceed what level?



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Which of the following frequently offered pieces of advice about lithium is inappropriate?



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How many days does it take to reach optimal response with lithium therapy?



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Which of the following teratogenic drug is known to cause Ebstein anomaly?



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Which of the following is a recognized side effect lithium carbonate?



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What is therapeutic level for the drug lithium?



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Which of these side effects is lithium most likely to cause?



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What psychiatric medication requires caution when prescribed for a breastfeeding woman?



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Which of the following is least likely to increase lithium levels?



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Which of the following side effects is most often associated with lithium?



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At what point during pregnancy does lithium undergo major pharmacokinetic changes?



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A patient being treated for a psychiatric condition develops polyuria and polydipsia after a few weeks on a medication. Which drug is most commonly associated with these side effects?



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An inpatient with bipolar disorder has been on lithium for 2 weeks and becomes depressed. Select the correct statement.



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Lithium blood levels are least likely to be increased by concomitant administration of which of the following?



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What is the most common urological side effect of lithium?



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A 31-year old patient presents with complaints of fatigue, constipation, weight gain, and severe itching due to dry skin. She mentions that she has recently started to feel "down" for no apparent reason. Her symptoms started about 3 months ago and have gotten worse. Which of the following medications may be responsible for her symptoms?



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Which drug will most likely have a warning that it may raise or lower serum sodium concentration?



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Lithium is prescribed for a patient with bipolar disorder. Which of the following adverse effects are most common? Select all that apply.



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A nursing student is starting a clinical rotation on the psychiatric unit today. Exhausted from staying up late reviewing several chapters on bipolar disorder for a quiz this week, the student is drawing a blank on lithium therapy, as the instructor is asking about side effects and nursing implications. Trying to decide whether to guess or admit they have forgotten, a friend rushes to answer the question after recognizing their duress. What statements made by the helpful friend are correct regarding lithium therapy? Select all that apply.



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Lithium - References

References

Self-harm, Unintentional Injury, and Suicide in Bipolar Disorder During Maintenance Mood Stabilizer Treatment: A UK Population-Based Electronic Health Records Study., Hayes JF,Pitman A,Marston L,Walters K,Geddes JR,King M,Osborn DP,, JAMA psychiatry, 2016 May 11     [PubMed]
Effect of Lithium on Neurocognitive Functioning., Rybakowski JK,, Current Alzheimer research, 2016 Apr 15     [PubMed]
Sheng R,Zhang LS,Han R,Gao B,Liu XQ,Qin ZH, Combined prostaglandin E1 and lithium exert potent neuroprotection in a rat model of cerebral ischemia. Acta pharmacologica Sinica. 2011 Mar;     [PubMed]
Perveen T,Haider S,Mumtaz W,Razi F,Tabassum S,Haleem DJ, Attenuation of stress-induced behavioral deficits by lithium administration via serotonin metabolism. Pharmacological reports : PR. 2013;     [PubMed]
Sajatovic M, Treatment of bipolar disorder in older adults. International journal of geriatric psychiatry. 2002 Sep;     [PubMed]
Tabibzadeh N,Vrtovsnik F,Serrano F,Vidal-Petiot E,Flamant M, [Chronic metabolic and renal disorders related to lithium salts treatment]. La Revue de medecine interne. 2019 Feb 28;     [PubMed]
Poels EMP,Bijma HH,Galbally M,Bergink V, Lithium during pregnancy and after delivery: a review. International journal of bipolar disorders. 2018 Dec 2;     [PubMed]
Cipriani A,Hawton K,Stockton S,Geddes JR, Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ (Clinical research ed.). 2013 Jun 27     [PubMed]

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