Lithium

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Introduction

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.

Cooper-Simpson Test

  • 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.

Adverse Effects

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.

High-Yield Facts

  • 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.

How supplied

  • 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.

References

(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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