Lithium

Lithium is used for the acute treatment of manic and mixed episodes associated with bipolar I disorder and for maintenance treatment of bipolar I disorder in patients 7 years of age and older. It is a prescription medicine called a mood-stabilizing agent.

Lithium is also available as extended-release tablets. These are used to treat manic episodes of bipolar disorder (also called manic-depressive illness), and as maintenance therapy, which reduces the frequency of manic episodes and diminishes the intensity of those episodes that may occur.

Typical symptoms of mania include fast speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, elation, poor judgment, aggressiveness, and possibly hostility. When given to a patient experiencing a manic episode, lithium may help relieve symptoms within 1 to 3 weeks.

Lithium is available as lithium carbonate (tablets, capsules, extended-release tablets) or lithium citrate (oral solution). The mechanism of action of lithium as a mood-stabilizing agent is unknown. Preclinical studies have shown that lithium alters sodium transport in nerve and muscle cells and causes a shift towards a breakdown of neurotransmitters inside the nerve cells, although the specific way lithium works in mania is unknown.

Lithium first received U.S. approval in 1970 and remains one of the longest-established treatments for bipolar disorder. It is available only as a generic medicine and as the brand Lithobid (extended-release tablets).

Lithium carries a Boxed Warning for lithium toxicity, the most serious type of warning the FDA requires.

Too much lithium in your blood (lithium toxicity)

Lithium toxicity that can cause death may happen even if the lithium level in your blood is close to the right level for you. Your healthcare provider will need to monitor your blood levels of lithium to find the best dose for you. Take your lithium exactly as your healthcare provider tells you to take it. Stop taking lithium and call your healthcare provider right away if you have any symptoms of lithium toxicity including:

• abnormal heartbeat
• vomiting
• diarrhea
• drowsiness
• weak muscles
• blurred vision
• clumsiness
• ringing in your ears
• muscle twitching

Other symptoms may include:

• lightheadedness
• confusion
• bloating
• mood changes
• slurred speech
• breathing problems
• seizure
• coma

Facilities for prompt and accurate serum lithium determinations should be available before treatment is started, and your blood levels will be checked regularly throughout treatment.

Do not take lithium if you are allergic to lithium or any of the ingredients in your lithium medication.

Before taking lithium, tell your healthcare provider if you:

• have kidney problems
• have heart problems
• have breathing problems
• have thyroid problems
• are pregnant or plan to become pregnant. Lithium may harm your unborn baby.
• are breastfeeding or plan to breastfeed. Lithium can pass into your breastmilk and may harm your baby. You should not breastfeed during treatment with lithium. Talk to your healthcare provider about the best way to feed your baby if you take lithium.

Before starting lithium, your healthcare provider will check your kidney function, vital signs, serum electrolytes, and thyroid function, and will review the other medicines you take. If you are a woman of childbearing potential, pregnancy status and potential should be considered.

Tell your healthcare provider about all the medicines you take, including prescription, over-the-counter medicines, vitamins, and herbal supplements. Using lithium with certain other medicines may affect each other, causing possible side effects.

Pregnancy

Lithium may cause fetal harm when administered to a pregnant woman. Data from lithium birth registries suggest an increase in cardiac and other anomalies, especially Ebstein's anomaly. If you are of childbearing potential, or if you become pregnant while taking this drug, talk to your healthcare provider about the potential hazard to the fetus.

Fetal echocardiography between 16 and 20 weeks gestation may be considered in a woman with first-trimester lithium exposure because of the potential increased risk of cardiac malformations.

Lithium toxicity may occur in newborns who were exposed to lithium in late pregnancy. A floppy baby syndrome including neurological, cardiac, and hepatic abnormalities that are similar to those seen with lithium toxicity in adults has been observed. If lithium is continued during pregnancy, serum lithium concentrations are monitored and the dose adjusted, and the dose is usually decreased or stopped two to three days before the expected delivery date to reduce the risk of maternal and neonatal toxicity.

Breastfeeding

Lithium is present in human milk, with breast milk levels measured at 0.12 to 0.7 mEq, or 40 to 45% of maternal plasma levels. Infants exposed to lithium during breastfeeding may have plasma levels that are 30 to 40% of maternal plasma levels. Signs and symptoms of lithium toxicity such as hypertonia, hypothermia, cyanosis, and ECG changes have been reported in some breastfed newborns and infants. Breastfeeding is not recommended with maternal lithium use.

Children

The safety and effectiveness of lithium have been established in children aged 7 to 17 years with bipolar I disorder. Safety and effectiveness have not been established in children under 7 years of age. For the extended-release tablets, safety and effectiveness in patients below the age of 12 have not been established, and use in patients under 12 is not recommended.

Older adults

Older adults often respond to reduced dosage and may show signs of toxicity at serum concentrations ordinarily tolerated by other patients. Because lithium is substantially removed by the kidneys and older adults are more likely to have decreased kidney function, dose selection should be cautious and kidney function may need to be monitored.

Kidney problems

Lithium is eliminated primarily through the kidney, and the risk of lithium intoxication increases considerably in people with reduced kidney function. People with mild to moderate kidney impairment (creatinine clearance 30 to 89 mL/min) are started on lower doses and titrated slowly with frequent monitoring. Lithium is not recommended in severe kidney impairment (creatinine clearance less than 30 mL/min).

Serious side effects

Lithium may cause serious side effects, including:

• kidney problems. People who take lithium may have to urinate often (polyuria) and have other kidney problems that may affect how their kidneys work. These problems can happen within a few weeks of starting to take lithium or after taking lithium for a long time.
• low levels of sodium (salt) in your blood (hyponatremia). Lithium can cause you to lose sodium. Talk to your healthcare provider about your diet and how much fluid you are drinking when starting lithium. If you have been sweating more than usual or have had diarrhea, you may need extra salt and more fluids. Talk to your healthcare provider if this happens.
• neurological problems. People who take lithium with certain other medicines called antipsychotics may have symptoms such as weakness, tiredness, fever, tremors, and confusion. Talk to your healthcare provider if this happens. Ask if you are not sure about the medicines you take.
• serotonin syndrome. A potentially life-threatening problem called serotonin syndrome can happen when you take lithium while you take certain medicines called serotonergic and MAOIs. Symptoms of serotonin syndrome include agitation, seeing things that are not there, confusion, coma, rapid pulse, high or low blood pressure, dizziness, sweating, flushing, fever, tremors, stiff muscles, muscle twitching, ataxia, seizures, nausea, vomiting, diarrhea.
• thyroid problems.
• high calcium levels in your blood (hypercalcemia) and changes in your parathyroid gland (hyperparathyroidism) that may not go away when you stop taking lithium.
• heart problems. People who take lithium may find out they also have a heart problem called Brugada Syndrome. People who have unexplained fainting or who have a family history of sudden unexplained death before 45 years of age may have Brugada Syndrome and not know it. If you faint or feel abnormal heartbeats, talk to your healthcare provider right away.
• increased pressure in the brain and swelling in the eye (pseudotumor cerebri) that can cause vision problems or blindness. If you have severe headaches behind your eyes, ringing in the ears, blurred vision, double vision, or brief periods of blindness, talk to your health care provider right away.

Common side effects

The most common side effects of lithium in adults are:

• fine hand tremor
• excessive urination (polyuria)
• mild thirst
• nausea
• general discomfort when you start treatment.

The most common side effects of lithium in children aged 7 to 17 years are:

• nausea
• vomiting
• polyuria (excessive urination)
• thyroid problems
• tremor
• thirst
• dizziness
• rash/dermatitis
• gait disturbances (ataxia)
• decreased appetite
• blurry vision.

Some side effects subside with continued treatment or with a temporary reduction or cessation of dosage.

These are not all the possible side effects of lithium. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Lithium has been used to treat bipolar disorder since before modern registrational trial standards were introduced, and its adult approval dates to 1970. The efficacy data in the current FDA labeling come from a study in children and teenagers.

In an 8-week trial of 81 patients aged 7–18, lithium (mean serum 0.98 mEq/L, NCT01166425) reduced Young Mania Rating Scale (YMRS) scores significantly more than placebo (−12.9 vs −7.3; difference −5.5). Over 28 weeks of randomized withdrawal, 41.2% discontinued on lithium versus 78.6% on placebo (HR 0.28), supporting maintenance benefit.

In a 28-week randomized withdrawal analysis, 31 pediatric patients stabilized on lithium were assigned to either continue lithium or switch to placebo. The group receiving lithium demonstrated superiority to those receiving placebo in all-cause discontinuation: 7 of 17 patients (41.2%) discontinued on lithium compared with 11 of 14 (78.6%) on placebo (hazard ratio 0.28; 95% CI 0.10 to 0.78).

When lithium is given to a patient experiencing a manic episode, it may produce a normalization of symptomatology within 1 to 3 weeks.

• Take your lithium exactly as prescribed by your healthcare provider.
• Your healthcare provider will do certain blood tests before starting and during treatment with lithium.
• Your healthcare provider may change your dose if needed. Do not change your dose on your own.
• Do not double your dose if a dose is missed. Talk with your healthcare provider if you miss a dose.
• Do not stop taking lithium suddenly without talking to your healthcare provider.
• Your healthcare provider may change your lithium dose to make sure you are taking the dose that is right for you.
• If you take too much lithium, call your healthcare provider or poison control center, or go to the nearest hospital emergency room right away. In case of poisoning, call your poison control center at 1-800-222-1222.

Dosing information

Immediate-release tablets, capsules, and oral solution

• Adults and children over 30 kg: start at 300 mg three times daily (or 8 mEq/5 mL oral solution three times daily), increasing by 300 mg every 3 days as needed
• Children 20–30 kg: start at 300 mg twice daily, increasing by 300 mg weekly

Serum monitoring

• Check serum lithium after 3 days, drawn 12 hours after the last dose, then regularly until stabilized
• Acute manic or mixed episodes: titrate to 0.8–1.2 mEq/L
• Maintenance treatment: target 0.8–1.0 mEq/L

Extended-release tablets

• Usually given twice daily, about 12 hours apart
• With 300 mg tablets: 1800 mg daily is typical for acute mania; 900–1200 mg daily for long-term control
• Target serum lithium concentration 0.6–1.2 mEq/L
• Must be swallowed whole — never chewed or crushed

Timing of blood samples

• Draw immediately before the next dose, when concentrations are relatively stable (8–12 hours after the previous dose)

Routine monitoring frequency

• At least every two months in uncomplicated cases on maintenance therapy during remission

Additional serum lithium checks are needed after:

• Any dosage change
• Starting or stopping another medicine (e.g. diuretics, NSAIDs, renin-angiotensin system antagonists, metronidazole)
• A marked increase or decrease in strenuous physical activity
• Any other illness

Other tests

• Thyroid function: before treatment, at three months, then every six to twelve months
• Kidney function and serum calcium: monitored regularly

• Do not drive, operate heavy machinery, or do other dangerous activities when you start taking lithium, when your dose is changed, or until you know how lithium affects you. lithium can make you sleepy. Talk to your healthcare provider about these activities.
• Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your healthcare provider's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.
• Do not change the amount of salt in your diet. Changing the amount of salt in your diet could change the amount of lithium in your blood.

Because lithium decreases sodium reabsorption by the kidney tubules, it is essential to maintain a normal diet, including salt, and an adequate fluid intake (2,500 to 3,000 mL) at least during the initial stabilization period. Decreased tolerance to lithium has been reported to follow protracted sweating or diarrhea. If this happens, supplemental fluid and salt should be given under careful medical supervision and lithium intake reduced or suspended until the condition is resolved.

An infection with a raised temperature may also make a temporary dosage reduction or temporary discontinuation necessary.

Many medicines can change lithium blood levels or increase the risk of side effects. Advise your doctor and pharmacist if you are taking any over-the-counter medication, including herbal medication, or are started on a new prescription.

Medicines that can increase lithium levels and the risk of toxicity include:

• diuretics (water tablets), because diuretic-induced sodium loss may reduce lithium clearance
• nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, indomethacin, piroxicam, and COX-2 inhibitors such as celecoxib
• renin-angiotensin system antagonists, such as ACE inhibitors (for example, enalapril, captopril) and angiotensin II receptor blockers (for example, losartan)
• nitroimidazole antibiotics, such as metronidazole

Medicines that can lower lithium levels include acetazolamide, urea, xanthine preparations, alkalinizing agents such as sodium bicarbonate, and SGLT2 inhibitors.

Other important interactions:

• serotonergic drugs (SSRIs, SNRIs, MAOIs, triptans, tricyclic antidepressants, fentanyl, tramadol, tryptophan, buspirone, and St. John's Wort) can precipitate serotonin syndrome
• antipsychotics have been associated with neurotoxic reactions ranging from extrapyramidal symptoms to neuroleptic malignant syndrome
• calcium channel blockers may increase the risk of neurologic adverse reactions such as ataxia, tremors, nausea, vomiting, diarrhea, and tinnitus
• methyldopa, phenytoin, and carbamazepine may have an increased risk of adverse reactions when taken with lithium
• iodide preparations, especially potassium iodide, taken long-term with lithium may produce hypothyroidism
• neuromuscular blocking agents may have their effects prolonged by lithium

Know the medicines you take. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.

Store lithium capsules, tablets, and oral solution at room temperature, between 68F and 77F (20C and 25C). Keep capsules and tablets dry and keep in a tightly closed container.

Keep out of the reach of children.

Active ingredient: lithium carbonate, USP (tablets and capsules) and lithium citrate (oral solution).

Inactive ingredients:

Tablets: calcium stearate, microcrystalline cellulose, povidone, purified water, sodium lauryl sulfate, and sodium starch glycolate.

Capsules: talc. The capsule shells contain black monogramming ink, FD&C Red No. 40 (300 mg and 600 mg only), gelatin, and titanium dioxide. The black monogramming ink contains ammonium hydroxide, ethanol, iron oxide black, isopropyl alcohol, N-butyl alcohol, propylene glycol, and shellac glaze.

Oral solution: alcohol 0.3%, citric acid, purified water, raspberry blend, sodium benzoate, and sorbitol solution.

Inactive ingredients in extended-release tablets vary by manufacturer and may include sodium chloride, povidone, sorbitol, sodium starch glycolate, sodium lauryl sulfate, calcium stearate, hypromellose, titanium dioxide, polyethylene glycol, iron oxide red, ferric oxide yellow, magnesium stearate, microcrystalline cellulose, sodium alginate, and talc.