Lithium, the lightest solid element on the periodic table, has a central role in managing pediatric bipolar disorder. This article describes the properties of lithium as a medication. For its role in the overall treatment guidelines, see the article on bipolar disorder.
Adult Psychiatry Review
- Lithium is effective in acute mania management and bipolar prophylaxis.
- Lithium has psychoactive properties only as a positively-charged ion, Li+; to this end, it is manufactured as a salt, i.e. lithium carbonate or lithium chloride. Lithium carbonate causes less GI irritation and, thus, preferred to LiCl. Lithium citrate is available in a syrup form.
- There is no "lithium receptor." It acts on many receptors, channels, and intracellular proteins. Among other effects it inhibits intracellular adenylyl cyclase, an enzyme in the second-messenger cascade of TSH, vasopressin (ADH), and many other cell processes. A serious side effect of lithium are hypothyroidism and failure to concentrate urine.
- Lithium has low therapeutic index (ratio of toxic level to therapeutic level, 1.5mM/1.0mM = 1.5) and a narrow therapeutic range (0.8 to 1.2mM). Levels are drawn 12hrs after last dose, 4-5 days after dose change (half-life ~ 24hrs).
- Li+ is excreted by the kidney; as a tiny cation, it is freely filtered at the glomerulus and reabsorbed at the proximal tubule. Therefore, its excretion is directly related to GFR; lithium dose should be lower in the elderly and CHF patients.
- Since reabsorption of Li+ and Na+ is competitive at the proximal tubule, hyponatremia (caused by low Na+ diet, thiazides, dehydration) can lead to increase in Li+ reabsorption and toxicity, as it is returned to circulation. NSAIDs, carbamazepine, and tetracyclines can also precipitate lithium toxicity.
- Loop diuretics (furosemide) and caffeine facilitate lithium excretion.
How to Start and Monitor
- Baseline assessment: H&P (including height and weight), calculate BMI,
- Labs: UA, Upreg, TSH, free T4, CBC, CMP (electrolytes, BUN, creatinine, calcium, albumin). Repeat q3-6mo and with dose adjsutment;
- Starting dose is 300mg BID (or qPM - maybe easier on the kidney, but causes higher peak level) and titrate weekly to 1500mg +/-300mg, to plasma levels of 1.0mM. Check levels 5 days after starting treatment.
- Check lithium levels q3-6mo and after each dose adjustment; lithium levels should be drawn 12 hr after last dose (e.g. in the AM before morning dose); therapeutic plasma level is between 0.8 and 1.2mEq/L.
- If pt. who had been stable on Li absolutely needs an NSAID or HCTZ, lower the dose of Li by 50% and re-titrate.
- Sulindac is one of the few NSAIDs that has only minimal effect on serum Li level; Tylenol and aspirin are preferred.
- On an inpatient unit in may be useful to start Li safely at a higher dose with the aid of Cooper-Simpson test (a.k.a. Cooper's Method (2) circa 1973):
- Pt. should not be on Li+ prior to the test
- 600-mg challenge dose (a.k.a. lithium priming dose) of Li carbonate is given; 24-hours later a serum lithium level is drawn.
- 24-hour serum level following the test dose determines the highest safe starting dose of Li. (2)
- This approach had been tried in children in a small study, suggesting the test can be used in children as well (3).
- Results of the test give a clinician a safe target dose, not necessarily a well-tolerated dose. It may be worthwhile to start below the dose indicated by the Test and titrate up to improve tolerability.
- Knowing the target dose still allows titration to take place in a matter of days, not weeks.
|= Cooper-Simpson Test: Daily dosage required to achieve serum Li+ level of 0.6-1.21 mMol/L =|
|- 24-hour serum Li level after single loading dose(mMol/L) -||- Dosage -|
|less than 0.05||1200 mg TID***|
|0.05 - 0.09||900 mg TID***|
|0.1 - 0.14||600 mg TID***|
|0.15 - 0.19||300 mg QID|
|0.2 - 0.23||300 mg TID|
|0.23 - 0.3||300 mg BID|
|> 0.3||300 mg BID with extreme caution|
*** Depending on the reliability of the lab, patients should not be started on a dose higher than 1200mg/day (in cases when 24-hour Li level is < 0.2), to avoid risk of toxicity.
|Common||Thirst, polyuria, fatigue, nausea, diarrhea, tremor, ataxia, acne, cognitive dulling, weight gain|
|Other||benign leukocytosis, mild hypercalcemia, exacerbation of psoriasis, intermittent edema, EKG changes|
|Rare||nephorgenic diabetes insipidus, EPS worsening|
|Teratogenicity||small increase in risk in tricuspid valve disease and Ebstein's anomaly in the 1st trimester. Despite low risk, ECT and antipsychotics are preferred in pregnancy|
|Toxicity||may develop at therapeutic levels with symptoms of nausea, agitation, vomiting, diarrhea, muscle weakness, coarse tremor, renal failure; thinking of a "drunk person" can be helpful when memorizing the signs and symptoms of toxicity|
Nephrogenic Diabetes Insipidus
- Nephrogenic DI occurs in up to 40% of Li+ patients through increased water and sodium diuresis and inability of the kidney to concentrate urine.
- Initial workup should include 24-hour urine output volume, and specific gravity of the first AM void. An output of 2-4L/day warrants teatment with amiloride. Li+ levels should be monitored closely when amiloride (~10mg/day) is started.
- In patients that absolutely need Li+ therapy and have 24-hour of urinary output >3.5L, hydroclorozide may be appropriate. Li+ dose should be halved when attempting to treat NDI with HCTZ.
- Long-term complications include Li-induced nephropathy (10+ years on Li+) and chronic renal disease.
Managing Lithium Overdose/Toxic Levels
- If levels are under 2mM discontinue lithium for 1-2 days, and monitor electrolytes (Na+) and renal function.
- When symtomatic, ensure ABCs, including intubation if necessary.
- Induction of vomiting/gastric lavage if overdose occurred < 4hrs ago.
- Continual gastric aspiration (NG tube) since lithium is distributed to gastric secretions in substantial concentrations
- Replace sodium with normal saline hydration if urine output is adequate. Hemodialysis is indicated in renal insufficiency and failure.
- EKG changes include bradycardia and T-wave changes.
- Activated charcoal is generally not used, since it does not bind to lithium.
Clinical Considerations in Children and Adolescents
- Lithium is not approved (but frequently used) for children <12yo.
- Lithium had been studied and found effective for short-term maintenance treatment of bipolar disorder, for decreasing aggression, and for treatment of acute depression in teens (Lewis's 769). Thus, lithium may be a good option in depressed teens who need to regain functionality sooner than would be expected from an SSRI therapy.
- Lithium is generally well tolerated in pediatric population, and more effective than other mood stabilizers in preventing relapse.
- Children may need higher doses than adults, as they have higher GFR, leading to shorter lithium half-life in circulation, higher total body water to weight ratio (lithium is distributed through TBW), and lower ratio of brain-to-serum lithium concentrations.
- Dosing can start at 300mg BID and titrated up to 1000mg daily dose for children (10-30 mg/kg) and 1600mg/day for teens. Just like with adults, maintenance treatment usually requires lower dosages.
- Elevated TSH without decrease in T4 or symptoms of hypothyroidism can be tolerated with frequent monitoring and education.
- WBC count up to 15,000 cells/mm3 in asymptomatic children can be tolerated as well.
- Encourage contraception in female adolescents.
- Consider long-acting preparation to improve compliance and decrease polyuria.
- While there is no definitive link between lithium and seizure threshold, risperidone is preferred in children with seizures.
- Lithium may take about a week to take effect in acute mania; while adults benefit from acute benzodiazepine treatment, youth may become disinhibited, according to the AACAP parameters.
- Lithium orotate is a lithium salt marketed as a supplement and available without prescription. While its efficacy had not been adequately studied, it can cause toxicity just like lithium carbonate.
- While monitoring, check T4 in addition to TSH, since elevated TSH may be inconsequential.
- Acne and weight gain can be particularly distressing to teens on lithium.
- Benign tremor can be managed with prn propranolol.
- Disruption of sodium balance (dehydration, NSAIDs, etc) is the most common cause of toxicity, not overdose.
- Dialysis is indicated if levels are greater than 3mM with sx/s of toxicity, or greater than 4mM.
- Lithium and clozapine are two drugs that have been shown do decrease suicidality.
- Eskalith is short acting Li carbonate, comes in 300mg; manufacturer recommends TID or QID dosing.
- Eskalith CR is continuous release Li carbonate capsule of 450mg, which is scored (can be split in two); manufacturer recommends BID dosing, but it is often given qPM.
- Lithobid is extended release Li carbonate, which comes in 300mg film-coated tabs which should not be split in two. AKA lithium SR. The recommended dosing is BID.
- Lithium citrate comes in syrup form.
(1) Lewis's Child and Adolescent Psychiatry 2007
(2) Cooper TB, Bergner P-E, Simpson GM: The 24-hour serum lithium level as a prognosticator of dosage requirements. Am J Psychiatry 1973; 130:601–603
(3) Malone RP,..., Cooper TB. The lithium test dose prediction method in aggressive children. Psychopharmacol Bull. 1995;31(2):379-82.
Handbook of Psychiatric Drug Therapy 2010
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