LITHIUM
- Lithium is a chemical element used to treat bipolar disorder
- There are no other drugs in its class
- The mechanism by which lithium treats bipolar disorder is not completely understood
- Proposed actions include the following:
- Alters sodium transport in nerve and muscle cells and increases intraneuronal metabolism of catecholamines
- Increases GABA activity
- Increases serotonin function
- Blocks dopamine-receptor supersensitivity [2]
- Bipolar disorder - lithium is indicated in the treatment of manic episodes of bipolar disorder. Lithium is also indicated as a maintenance treatment
for individuals with a diagnosis of bipolar disorder. Maintenance therapy reduces the frequency of manic episodes and diminishes the intensity of those episodes which may occur.
- Overview
- Lithium was FDA-approved in 1970. As with many older drugs, there are few well-done studies evaluating the effectiveness of lithium.
- A Cochrane meta-analysis that looked at the effects of lithium in mood disorders is summarized below along with a randomized controlled trial that compared lithium to valproic acid in older manic patients
STUDY
Lithium for maintenance treatment of mood disorders, Cochrane meta-analysis (2001)
[PubMed abstract]
- Design: Meta-analysis of randomized controlled trials comparing lithium to placebo (9 studies, n = 825)
- Primary outcome: Prevention of relapse in recurrent mood disorders
- Findings: This systematic review indicates that lithium is an efficacious maintenance treatment for bipolar disorder. In unipolar
disorder the evidence of efficacy is less robust. This review does not cover the relative efficacy of lithium compared with other maintenance treatments, which is at present unclear.
There is no definitive evidence from this review as to whether or not lithium has an anti-suicidal effect. Systematic reviews and large scale randomised studies comparing lithium
with other maintenance treatments (e.g. anticonvulsants, antidepressants) are necessary. Outcomes relating to death and suicidal behaviour should be included in all future
maintenance studies of mood disorder.
STUDY
Lithium vs Divalproex for Mania in Older Patients with Bipolar Disorder, Am J Psychiatry (2017)
[PubMed abstract]
- Design: Randomized controlled trial (N=224, length - 9 weeks) in inpatients and outpatients ≥ 60 years old with bipolar I disorder who presented with a manic, hypomanic, or mixed episode
- Exposure: Lithium titrated to 0.8 - 0.99 mEq/L vs Divalproex titrated to 80 - 99 mcg/ml
- Primary outcomes: Efficacy (Young Mania Rating Scale) and tolerability (sedation and proportions of participants achieving target concentrations)
- Results:
- Nine-week response rates did not differ significantly between the lithium and divalproex groups (79% and 73%, respectively)
- A longitudinal mixed model of improvement (change from baseline in YMRS score) favored lithium (change in score 3.90. 97.5%CI [1.71 to 6.09])
- The groups did not differ significantly in sedation
- Similar proportions of participants in the lithium and divalproex groups achieved target concentrations (57% and 56%, respectively)
- Findings: Both lithium and divalproex were adequately tolerated and efficacious; lithium was associated with a greater
reduction in mania scores over 9 weeks
- APA 2002 recommendations on bipolar disorder
- The first-line pharmacological treatment for more severe manic or mixed episodes is the initiation of either lithium plus an antipsychotic or valproate plus an antipsychotic
- The first-line pharmacological treatment for bipolar depression is the initiation of either lithium or lamotrigine
- First-line drugs for maintenance therapy include lithium and valproate
- Initial labs
- Thyroid function (TSH)
- Electrolytes including calcium
- Kidney function (eGFR, CrCl)
- Pregnancy test
- Complete blood count (recommended by some)
- ECG - some guidelines recommend baseline ECG in certain patients before starting lithium (see cardiovascular disease below)
- Lithium levels
- Measure lithium levels 1 week after starting therapy and 1 week after every dose change
- Lithium levels should be drawn right before the next dose is due (trough levels)
- Recommended levels vary slightly depending on the reference
- Maintenance therapy: 0.6 - 1.2 mmol/L
- Potentially toxic: > 1.5 mmol/L
- Lithium half-life: 14 - 30 hours (highly dependent on renal function)
- Lithium time to steady state: 2 - 7 days [5,6]
- First 6 months of therapy
- Measure kidney function and electrolytes every 3 months
- Measure thyroid function every 3 months
- Measure lithium levels 1 week after starting therapy, 1 week after dose changes, and every 3 months
- 6 months and beyond
- Measure kidney function and electrolytes every 6 months to 1 year
- Measure thyroid function every 6 months to 1 year
- Measure lithium levels 1 week after dose changes and every 6 months. Measure lithium levels more frequently when clinically indicated (e.g. concomitant interacting drugs, symptoms of
toxicity, changes in renal function) [2,3,5]
- Overview
- There are no well-done trials that have compared lithium to placebo, so the strength of association for lithium side effects is unknown
- Lithium has a narrow therapeutic index, and the risk for toxicity is significant. When lithium levels are too high, life-threatening side effects (see symptoms of toxicity) can occur. Certain patient populations are at greater risk for toxicity (see risk factors for toxicity).
- General side effects of lithium include the following:
- Hand tremor - up to 50% of patients
- Increased thirst - up to 33% of patients
- Increased urination - up to 33% of patients
- Memory and concentration impairment
- Lethargy
- Nausea
- Diarrhea
- Weight gain
- Hair loss
- Symptoms of toxicity
- Symptoms of lithium toxicity are grouped below by the blood level where they are likely to occur
- Treatment of lithium toxicity is mainly supportive. Hemodialysis will remove lithium from the blood and can be used for severe toxicity.
- Mild (1 - 1.5 mmol/L)
- Impaired concentration
- Lethargy
- Tremor
- Muscle weakness
- Nausea
- Moderate (1.6 - 2.5 mmol/L)
- Disorientation
- Drowsiness
- Loss of coordination
- Muscle fasciculations
- Diarrhea
- Vertigo
- Blurred vision
- Nausea and vomiting
- Severe (> 2.5 mmol/L)
- Impaired consciousness
- Delirium
- Ataxia
- Generalized fasciculations
- Seizures
- Decreased renal function
- Coma
- Extrapyramidal symptoms [1,2,4]
- Risk factors for toxicity
- Febrile illness
- Medications that affect lithium levels or kidney function (see drug interactions below)
- Dehydration
- Significant cardiovascular disease
- Changes in electrolyte concentrations (especially sodium and potassium) [1]
- Kidney disease - Lithium is excreted unchanged into the renal tubule, 80% is then reabsorbed in the proximal tubule. Do not use lithium in
patients with CrCl < 30 ml/min.
- Kidney disease
- CrCl 30 - 89 ml/min: start with lower doses of lithium and titrate slowly while frequently monitoring serum lithium concentrations and for signs of lithium toxicity
- CrCl < 30 ml/min: DO NOT USE
- Liver disease
- Manufacturer makes no specific recommendation
- Cardiovascular disease
- The risk of lithium toxicity is higher in patients with significant cardiovascular disease
- Some guidelines recommend a routine ECG before starting lithium therapy in all patients over forty. Other guidelines recommend an ECG in patients with a history of
cardiovascular disease or risk factors for it.
- Nephrogenic diabetes insipidus
- Lithium may diminish renal concentrating ability leading to nephrogenic diabetes insipidus
- The condition is usually reversible upon lithium discontinuation, but some patients may develop chronic disease
- Amiloride may be considered as a therapeutic agent for lithium-induced nephrogenic diabetes insipidus
- Dehydration
- Lithium may produce polyuria which can lead to, or worsen dehydration
- Patients taking lithium should maintain adequate fluid intake (2500 - 3000 ml/day)
- Hyponatremia
- Lithium can block sodium reabsorption in the renal tubule leading to hyponatremia
- Patients should maintain a normal diet, including salt intake with adequate fluid intake (2500 - 3000 ml/day)
- Chronic kidney disease
- Lithium has been associated with chronic tubulointerstitial nephropathy
- Patients may present with nephrotic range proteinuria (> 3 g/dl), decreased renal function, and/or nephrogenic diabetes insipidus
- Thyroid disorders
- Lithium concentrates in the thyroid gland, and it may inhibit thyroid hormone synthesis leading to hypothyroidism
- Hypothyroidism occurs in 5 - 35% of patients treated with lithium, and it typically occurs within 6 - 18 months after starting therapy
- Patients on lithium should have their thyroid function monitored regularly. Lithium-induced hypothyroidism can be treated with thyroid supplementation, and it is not a
contraindication to lithium therapy.
- Paradoxically, lithium has also been associated with cases of hyperthyroidism
- Hypercalcemia
- Chronic lithium therapy has been associated with hyperparathyroidism and hypercalcemia
- In patients with mildly elevated calcium levels, nephrogenic diabetes insipidus should be ruled out because volume depletion can cause falsely elevated calcium levels
- Pregnancy
- Newborns exposed to lithium in utero have been shown to be at an increased risk of birth defects, particularly cardiac malformations
- A cohort study published in the NEJM in 2017 found the incidence of cardiac malformations in newborns exposed to lithium during the first trimester (N=663) was 2.41% compared
to 1.15% among nonexposed newborns. Risk of malformations was higher as daily lithium doses rose above 600 mg/day.
[PMID 28591541]
- A meta-analysis of studies that looked at lithium exposure during pregnancy and the peripartum period was published in 2020. The study found that the overall risk of any congenital anomaly was 4.1% in lithium-exposed women. First-trimester exposure and higher doses of lithium were associated with greater risk. [PMID 31623458]
- Serotonin syndrome
- Lithium has serotonergic activity and may precipitate serotonin syndrome in susceptible patients
- Psoriasis
- Lithium may worsen psoriasis
- ECG changes
- Lithium may cause T-wave flattening or inversion on an ECG
- Brugada syndrome
- Brugada syndrome is a hereditary heart condition that is associated with sudden cardiac death and unexplained syncope. It is believed to be caused by dysfunctional sodium (Na+) channels in the heart.
- On an ECG, Brugada syndrome is marked by a right bundle branch block and elevated ST segments in leads V1 - V3
- Lithium may precipitate or worsen Brugada syndrome, and it should be avoided in affected patients
- Encephalopathic syndrome
- A syndrome similar to neuroleptic malignant syndrome (NMS) has been reported in patients taking lithium with antipsychotics, particularly haloperidol. Symptoms include weakness, lethargy, fever, tremor, confusion, extrapyramidal symptoms, leukocytosis, and elevated liver enzymes. In some cases, the syndrome was followed by irreversible brain damage.
- Use caution in patients with organic brain disease and/or those receiving lithium with antipsychotics, and stop treatment if signs of neurologic toxicity occur.
- Pseudotumor cerebri
- Pseudotumor cerebri is a condition marked by increased intracranial pressure and papilledema
- Cases of pseudotumor cerebri have been reported in patients taking lithium
- NOTE: Drug
interactions presented here are NOT all-inclusive. Other interactions may
exist. The interactions presented here are meant to encompass commonly
prescribed medications and/or interactions that are well-documented. Always
consult your physician or pharmacist before taking medications concurrently.
CLICK HERE for more information on drug interactions.
- Acetazolamide (Diamox®) - acetazolamide may lower lithium levels by increasing its excretion
- ACE inhibitors - drugs that affect the RAAS system including ACE inhibitors and ARBs have the potential to raise lithium levels. If possible, lithium should not be taken with ACE inhibitors or ARBs. If concomitant therapy is necessary, frequent monitoring of lithium levels should be performed.
- Angiotensin II receptors blockers (ARBs) - drugs that affect the RAAS system including ACE inhibitors and ARBs have the potential to raise lithium levels. If possible, lithium should not be taken with ACE inhibitors or ARBs. If concomitant therapy is necessary, frequent monitoring of lithium levels should be performed.
- Antipsychotics - a syndrome similar to neuroleptic malignant syndrome (NMS) has been seen in patients taking lithium with antipsychotics, particularly haloperidol. See encephalopathic syndrome for more.
- Calcium channel blockers - diltiazem, nifedipine, and verapamil may increase the risk of lithium toxicity even when lithium levels are normal
- Carbamazepine - carbamazepine may increase the risk of lithium toxicity even when lithium levels are normal
- Diuretics
- Diuretics including thiazide diuretics, loop diuretics,
aldosterone antagonists, and ENaC inhibitors, all have the potential to raise
lithium levels. The strongest evidence for an effect is with thiazide diuretics. Other classes of diuretics have been shown to raise levels or have no effect. Patients taking diuretics should have their lithium levels and electrolytes measured frequently to monitor for changes. Lithium doses may have to be reduced when concomitant therapy is necessary.
- Paradoxically, the ENaC inhibitor amiloride has been used for the treatment of lithium-induced polyuria and polydipsia
- GLP-1 analogs - GLP-1 analogs may alter lithium absorption and affect blood levels
- Methyldopa - methyldopa may increase the risk of lithium toxicity even when lithium levels are normal
- Nitroimidazole antibiotics (e.g. metronidazole) - nitroimidazole antibiotics have been found to raise lithium levels,
particularly in patients taking higher doses of lithium
- NSAIDs - NSAIDs may reduce renal blood flow and decrease lithium clearance. In studies, average trough lithium levels increased by 15 - 20% in patients taking NSAIDs. Lithium levels should be monitored closely in patients who are taking NSAIDs on a long-term basis
- Neuromuscular blocking agents - lithium may prolong the effects of neuromuscular blocking agents
- Phenytoin - phenytoin may increase the risk of lithium toxicity even when lithium levels are normal
- Pramlintide - pramlintide may alter lithium absorption and affect blood levels
- Serotonergic medications - lithium has serotonergic activity. When taken with other serotonergic medications, the risk of
serotonin syndrome may be increased.
- SGLT2 inhibitors (e.g. dapagliflozin, canagliflozin) - SGLT2 inhibitors may reduce serum lithium concentrations. Monitor lithium levels closely during SGLT2 inhibitor initiation and dosage changes.
- Sodium bicarbonate - sodium bicarbonate may lower lithium levels by increasing its excretion
- Theophylline - theophylline may lower lithium levels by increasing its excretion
- Topiramate - topiramate may increase lithium levels. Monitor lithium levels closely during concomitant therapy.
- Metabolism and clearance
- Lithium does not undergo liver metabolism
- Dosage forms
- Capsule
- Tablet
- Extended-release tablet (Lithobid®)
- Oral solution
- 8 mEq/5 ml (8 mEq is equivalent to the amount of lithium in a 300 mg tablet of lithium carbonate)
- Store at room temperature
- Comes in 500 ml bottle
- Generic/Price
- All forms of lithium have a generic and all cost < $50 for a month of therapy
- Dosing
- Standard-release lithium
- Bipolar - Acute mania
- Dosing: 1200 - 1800 mg a day given in three divided doses
- For patients with decreased renal function or concomitant interacting drugs, use lower starting dose
- May take without regard to food. Taking with food may decrease stomach upset.
- Bipolar - Maintenance therapy
- Dosing: 300 - 600 mg two to three times a day
- Adjust dose based on serum levels
- For patients with decreased renal function or concomitant interacting drugs, use lower starting dose
- Once stable, total daily dose may be given once daily in the evening [1,4]
- May take without regard to food. Taking with food may decrease stomach upset.
- Extended-release tablet (Lithobid®)
- Bipolar - Acute mania
- Dosing: 900 mg twice a day
- For patients with decreased renal function or concomitant interacting drugs, use lower starting dose
- May take without regard to food. Taking with food may decrease stomach upset.
- Bipolar - Maintenance therapy
- Dosing: 900 - 1200 mg a day given in 2 divided doses
- For patients with decreased renal function or concomitant interacting drugs, use lower starting dose
- Adjust dose based on serum levels
- When switching from lithium immediate-release to extended-release, use the same total daily dose
- May take without regard to food. Taking with food may decrease stomach upset.
- Lithium has been used in the U.S. since the 1970s
- Lithium has been associated with some long-term adverse effects, but in general, it is considered safe when monitored appropriately
- 1 - Manufacturer's Package Insert
- 2 - American Psychiatric Association Practice Guideline for the Treatment of Patients With Bipolar Disorder, Second Edition (2002)
- 3 - PMID 29718639 - The NICE Guideline on the Assessment and Management of Bipolar Disorder in Adults, Children and Young People in Primary and Secondary Care (2014)
- 4 - PMID 8047085 - Lithium in the Treatment of Mood Disorders, NEJM (1994)
- 5 - Quest Diagnostics website
- 6 - LabCorp website