Lithium CeuLITHIUM
ABIMBOLA FARINDE, PhD., PharmD Abimbola Farinde, PhD., PharmD is a healthcare professional and professor who has gained experience in the field and practice of mental health, geriatrics, and pharmacy. She has worked with active duty soldiers with dual diagnoses of a traumatic brain injury and a psychiatric disorder providing medication therapy management and disease state management. Dr. Farinde has also worked with mentally impaired and developmentally disabled individuals at a state supported living center. Her different practice experiences have allowed her to develop and enhance her clinical and medical writing skills over the years. Dr. Farinde always strives to maintain a commitment towards achieving professional growth as she transitions from one phase of her career to the next.
DANA BARTLETT, RN, BSN, MSN, MA, CSPI
Dana Bartlett is a professional nurse and author. His clinical experience includes 16 years of ICU and ER experience and over 27 years as a poison control center information specialist. Dana has published numerous CE and journal articles, written NCLEX material, textbook chapters, and more than 100 online CE articles, and done editing and reviewing for publishers such as Elsevier, Lippincott, and Thieme. He has written widely on the subject of toxicology and was a contributing editor, toxicology section, for Critical Care Nurse journal. He is currently employed at the Connecticut Poison Control Center. He lives in Wappingers Falls, NY. ABSTRACT
Lithium is an antimanic agent that causes mood stabilization in patients who have bipolar disorder. Lithium is effective for the treatment of manic episodes, and it is also a first-choice drug for maintenance treatment of bipolar disorder. The safe and effective use of lithium requires close monitoring of the patient symptoms and of the patient’s lithium levels, as well as a thorough understanding of the potential complications and adverse effects of lithium therapy.
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Policy Statement This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. Continuing Education Credit Designation This educational activity is credited for 2.5 hours at completion of the activity. Pharmacology content is 2.5 hours. Statement of Learning Need Lithium is a well known antimanic agent in patients with bipolar disorder. There are other uses of lithium that are off label and in combination with other medication used to treat symptoms of bipolar disorder. Clinicians who treat bipolar disorder infrequently may be unfamiliar with all of the helpful uses of lithium, especially in special populations and for patients diagnosed with mixed mood states. Course Purpose To inform health clinicians of the indications, uses, contraindications and potential side effects of lithium. Target Audience Advanced Practice Registered Nurses, Registered Nurses, and other Interdisciplinary Health Team Members. Disclosures Abimbola Farinde, PhD., PharmD, Dana Bartlett, RN, BSN, MSN, MA, CSPI, William Cook, PhD, Douglas Lawrence, MA, Kellie Wilson, PharmD, Jennifer McAnally, DNP, PMHNP-BC, Susan DePasquale, MSN, PMHNP-BC – all have no disclosures. There is no commercial support.
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Self-Assessment of Knowledge Pre-Test:
1. Lithium is an antimanic agent that acts as ________________ in patients who have bipolar disorder.
a. a hallucinogen b. a mood stabilizer c. an antipsychotic d. an antidepressant
2. For _________________, lithium is often combined with an
antipsychotic.
a. hypomania b. severe mania c. mild mania d. moderate mania
3. Bipolar disorder is a psychiatric disorder characterized by
episodes of
a. depression followed by periods of lethargy. b. anxiety and concomitant depression. c. mania, hypomania, and major depression. d. anger and anxiety, followed by periods of calm.
4. A patient with mild renal impairment
a. may not take lithium. b. must reduce the recommended dose. c. may take lithium but with caution. d. may take lithium but a low sodium diet is recommended.
5. The use of lithium during the first trimester of pregnancy may
cause a serious fetal cardiac malformation called
a. Epstein-Barr syndrome. b. Ebstein’s anomaly. c. Brugada syndrome. d. Stevens-Johnson syndrome.
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Introduction
Lithium is a first-line choice for treating and preventing manic episodes in patients who have bipolar disorder. Decades of experience and study trials have proven that lithium can be a safe and effective drug. Lithium use requires close monitoring of the patient’s physical symptoms and trends in lithium levels given its narrow therapeutic window. The patient should be provided with a thorough understanding of the potential complications and adverse effects of lithium. The basic pharmacological profile, aspects of lithium toxicity, and clinical pearls of lithium use are raised in the following sections.
Pharmacological Profile
Lithium has a labeled use as a treatment for patients with mood disorders. There is evidence that lithium can also be useful, in combination with other medications, for other off-label uses. Patients prescribed lithium are routinely monitored for physical symptoms of toxicity and for elevated serum levels that could lead to serious side effects, such as renal impairment or thyroid dysfunction.
There are considerable drug-drug interactions with the combined use of lithium and other drugs that require close monitoring to prevent a serious outcome. This section addresses these specific considerations. Category
Lithium is categorized as an antimanic and mood stabilizing agent.1-3 Mechanism of Action
The mechanism of action by lithium causes mood stabilization in patients who have bipolar disorder is not known. Lithium is rapidly absorbed and there is no metabolism of lithium, so it is excreted unchanged.1-3
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Drug Uses Bipolar Disorder:
Lithium is used as a treatment of manic episodes and as maintenance treatment in patients who have bipolar disorder.1-3
Bipolar Depression:
Lithium is used off-label for bipolar depression as an adjunct with an antidepressant to treat symptoms of depression.1-3
Dosing: Adult Immediate Release:
Begin at 300 mg, three times a day. Increase the dose by assessing the patient’s response and how well the dose is tolerated. The maintenance dose is usually 900 mg – 1800 mg a day in three-four divided doses.1 Extended Release:
Begin at 450 mg twice a day (or less). Increase the dose by assessing the patient’s response and toleration of the dose. The usual maintenance dose is 900 mg – 1800 mg a day, in two divided doses.1,2
Dosing: Geriatric
Geriatric dosing follows the same recommended guidelines that have been published for adult dosing.1
Dosing Adjustment: Hepatic Impairment
There are no standard or recommended dosing adjustments for patients who have hepatic impairment.1
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Dosing Adjustment: Renal Impairment
There are no standard or recommended dosing adjustments for patients who have renal impairment.1 Lithium is excreted by the kidneys and in patients who have renal impairment, lithium levels may become elevated and lithium poisoning and renal damage can occur. If a patient’s renal function, as reflected by the creatinine clearance (CrCL), is severely impaired, lithium should only be used if absolutely needed and with close monitoring of the patient and serum lithium levels.1 CrCl 30 to 89 mL/minute:
Start with a low dose and titrate up slowly and with frequent monitoring.1
CrCl < 30 mL/minute:
Avoid use for patients with CrCL < 30 mL/minute. The use of lithium in patients who have renal impairment should be done cautiously.1 If the renal function, as reflected by the creatinine clearance (CrCL) is severely impaired, lithium may be contraindicated.1
Creatinine Clearance (CrCL) Creatinine clearance (CrCl) is a test that estimates glomerular filtration rate, GFR. The GFR is a highly accurate reflection of kidney function but directly measuring GFR is complex and invasive and using the CrCl is an acceptable and widely used substitute method of estimating GFR. Creatinine clearance is determined by measuring serum creatinine and measuring the amount of creatinine in a 24-hour urine collection. The patient’s age and body weight and the results of the tests are used with standard formulas like the Cockcroft-Gault equation or the Modification of Diet in Renal Disease equation to establish a CrCl value. Normal CrCl for men is 107 – 139 mL/minute Normal CrCl for women is 87 – 107 mL/min
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Available Forms1,2
Immediate release: Capsules, 150 mg, 300 mg, 600 mg. Immediate release: Tablets, 300 mg. Extended release: Generic, 400 mg, 450 mg. Brand name, Lithobid, 300
mg. Solution: 8 mEq/5 mL. Contraindications
The use of lithium is contraindicated if the patient has hypersensitivity to lithium or to any of the components of the product. Lithium should not be used for patients who are debilitated or have severe cardiac or renal disease, severe dehydration, or sodium depletion.1 For immediate release preparations or solution, the concurrent use with a diuretic is contraindicated.1 US Boxed Warning
Lithium toxicity may be reflected by serum levels of the drug, and it can occur at levels that are only slightly above the therapeutic level. The ability to accurately and quickly measure serum lithium should be available.1,2 Warnings
Cardiovascular:
Lithium should be used very cautiously if the patient has significant cardiovascular disease. The use of lithium can unmask the presence of Brugada syndrome, a potentially life-threatening heart rhythm disorder. Lithium should not be used if the patient has, is suspected to have, or is at risk for having Brugada syndrome.1,2 Lithium may act as a direct myocardial toxin, and it should be used cautiously in patients who have heart failure.1,2
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Endocrine:
Lithium therapy may cause hypothyroidism. Use lithium cautiously if the patient has hypothyroidism.1,2 Fluid and Electrolytes:
Dehydration, sodium depletion, and volume depletion can cause lithium toxicity.1,2 Lithium should be avoided or used cautiously if the patient is dehydrated, volume depleted and/or sodium depleted, if the patient has any condition like diarrhea, or if the patient has an infection that may cause volume depletion.1,2
The use of lithium may cause hypercalcemia. This can occur with or
without the presence of hyperparathyroidism (an overabundance of the hormone parathyroid in the bloodstream). Older patients and women are at a higher risk for this adverse effect. Hypercalcemia and hyperparathyroidism are usually reversible once lithium therapy has been stopped but not always.1,2
Neurological:
Drowsiness is a common adverse effect of lithium. An association between lithium and pseudotumor cerebri (idiopathic intracranial hypertension), a neurological condition that can cause serious ocular adverse effects, e.g., blindness, has been reported. If pseudotumor cerebri occurs, discontinue use of lithium if possible.1,2
Psychiatric:
Use lithium cautiously if the patient is depressed or has suicidal behavior or ideation.1,2
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Renal: Chronic use of lithium can cause nephrogenic diabetes insipidus,
decreasing the concentrating ability of the kidneys. Chronic use of lithium has also caused structural changes in the kidneys like atrophy of nephrons and glomerular fibrosis.1,2 Serotonin Syndrome:
Concurrent use of lithium and other serotonergic drugs can cause serotonin syndrome. If a patient who is taking lithium develops signs/symptoms of serotonin syndrome, the patient should stop taking lithium immediately.1,2 Adverse Effects
The most common acute adverse effects of lithium are cognitive impairment (e.g., changes in affect, concentration, and memory), loose stools, nausea, polyuria, tremor, and weight gain.4 Pregnancy and Breastfeeding
Lithium crosses the placenta and using the drug during pregnancy has been associated with fetal defects, birth complications, and neonatal medical complications which may include arrhythmias, diabetes insipidus, floppy infant syndrome, and lithium toxicity.1,2
The use of lithium during the first trimester has been associated with fetal defects, primarily cardiac, including a potentially serious fetal cardiac malformation called Ebstein’s anomaly. The risk of Ebstein’s anomaly occurring is very small and lithium should not be withheld if its use is clearly indicated.1,2 Clinicians should consider using fetal echocardiography and other diagnostic tests if the mother has been taking lithium during the first trimester.
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If lithium must be used during the first trimester the lowest effective dose should be used. Serum levels should be closely followed and it may be beneficial to start therapy after the time of organogenesis. Lithium therapy should be discontinued 24 to 48 hours before delivery.1 Physiological changes of pregnancy may affect maternal serum lithium levels.1
Lithium is excreted in breast milk. The serum concentrations in nursing
infants can be considerable, 10%-50% of the maternal dose.1 Significant adverse effects like cyanosis, hypotonia, hypothermia, and ECG changes have been reported to occur in nursing infants exposed to lithium, and the use of lithium while breastfeeding is not recommended unless the benefits outweigh the risks.1,2
If lithium is used during nursing, the infant should be closely monitored
for signs of lithium toxicity and for normal growth, and it is important to be sure the infant is well hydrated. The mother’s serum lithium concentration should be measured periodically, as well.1,2
Dietary Concerns
Lithium can be taken with or without food. Patients taking lithium should be sure to maintain an adequate fluid and sodium intake.1,2 This is important in avoiding lithium toxicity as discussed above in the section discussing “Fluid and Electrolytes.”1,2
Laboratory Tests and Lithium Levels
Before starting therapy with lithium, baseline measurements of BUN, creatinine, complete blood count (CBC), calcium, electrolytes, estimated glomerular filtration rate (eGFR), and thyroid function studies should be done;1,2 recommendations for scheduling periodic measurements of these tests will be discussed later in the module. If the patient is > 40 years old, a baseline 12-lead electrocardiogram (ECG) should be done. A beta-HCG pregnancy test should be done in women of child-bearing age.1
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Lithium levels should be measured immediately before the next dose is scheduled to be given; this ensures that a steady state level is obtained.2 The normal serum lithium level is 0.6 – 1.2 mEq/L. A serum lithium level provides valuable information, but an assessment of the patient’s condition cannot be based on only the level.2
Clinical Pearls: Lithium
This section provides detailed information on issues that are of practical interest to clinicians. Many of the topics from the basic pharmacology section will be covered here, along with a discussion of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for diagnosing a manic episode. Drug Uses
Bipolar disorder is a psychiatric disorder characterized by episodes of mania, hypomania, and major depression.5 Bipolar disorder is a chronic condition that can be managed but not cured. The mania, hypomania, and depression can be quite severe and for many people, there are significant functional consequences attendant to these episodes.6
There are two types of bipolar disorder, type I and type II. Manic
episodes are a feature of type I, and lithium is a first-line choice for treating manic episodes.7,8 For severe mania, lithium is often combined with an antipsychotic. Lithium is also effective for treating mild to moderate manic episodes.7 It is one of the primary drugs used for maintenance treatment of bipolar disorder;3,9-10 it as been estimated to reduce the relapse rate by 30 percent.10
Manic Episode: DSM-5 Criteria
Criteria A through D constitute a manic episode. At least one lifetime manic episode is required for the diagnosis of bipolar I disorder.12
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DSM-5 Criteria A:
During a manic episode there is a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least one week and present most of the day, nearly every day (or any duration if hospitalization is necessary).12
DSM Criteria B:
During the period of mood disturbance and increased energy or activity, three (or more) of the following symptoms (four if the mood is only irritable) are present to a significant degree and represent a noticeable change from usual behavior:12
1. Inflated self-esteem or grandiosity. 2. Decreased need for sleep (feels rested after only three hours of sleep). 3. More talkative than usual or pressure to keep talking. 4. Flight of ideas or subjective experience that thoughts are racing. 5. Distractibility (attention too easily drawn to unimportant or irrelevant
external stimuli), as reported or observed. 6. Increase in goal-directed activity (either socially, at work or school, or
sexually) or psychomotor agitation (purposeless activity). 7. Excessive involvement in activities that have a high potential for painful
consequences (engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments).
DSM-5 Criteria C:
The mood disturbance is sufficiently severe to cause marked impairment in social or occupational functioning or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.12
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DSM-5 Criteria D:
The episode is not attributable to the physiological effects of a substance (a drug with addictive potential, a medication, other treatment) or to another medical condition.12
Dosing Adjustment: Geriatric Patients
The prescribing information for lithium does not have specific dosing recommendations for geriatric patients, and there is limited data on lithium administration in the elderly.13-16 The standard advice is to use the lower end of the dosing range.1,2,13
There are cogent and persuasive reasons for dosing at lower ranges in elderly. Lithium is excreted by the kidney, and glomerular filtration rate (GFR) decreases as people age.13 Older patients often have a lower lean body mass and total body water, and these changes affect the volume of distribution of lithium.13
Lithium can cause injury to the kidneys, and the risk of lithium-induced renal damage is apparently higher in geriatric patients.13,17 In addition, elderly patients are more likely to have comorbidities that increase the risk for renal impairment, like coronary artery disease, diabetes mellitus, and hypertension.18
The duration of lithium therapy has been associated with an increased risk for renal damage.19 Common adverse effects of lithium like drowsiness may be particularly harmful to older patients. Older patients have a higher risk for lithium toxicity than do younger patients due to age related changes in pharmacokinetics and pharmaodynamics.4,13
Dosing Adjustment: Hepatic Impairment
Lithium is not metabolized by the liver, and there are no standard or recommended dosing adjustments for patients who have hepatic impairment.
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Long-term use of lithium may cause mild, transient, and self-limiting elevations of serum transaminases, but discontinuation of use or changing the dose is not necessary.20 There are no reported cases of acute liver failure or chronic liver damage caused by lithium.20 Dosing Adjustment: Renal Impairment
Lithium is excreted unchanged by the kidneys, and the prescribing information states that lithium should not be used if the patient has severe renal impairment. The prescribing information recommends: CrCl 30 to 89 mL/minute: Start with a low dose and titrate up slowly and with frequent monitoring; and for CrCl < 30 mL/minute, use should be avoided.21
The Kidney Disease Improving Global Outcomes (KDIGO) guidelines
classify chronic kidney disease (CKD) by assessment of urinary albumin excretion or by estimated glomerular filtration rate (eGFR). Based on eGFR, the KDIGO recognizes five grades of CKD.21
G1: Normal, eGFR ≥ 90 mL/min/1.73 m2
G2: Mildly decreased, eGFR 60-89 mL/min/1.73 m2 G3a: Mildly to moderately decreased, eGFR 45-59 mL/min/1.73 m2 G3b: Moderately to severely decreased, eGFR 30-44 mL/min/1.73 m2 G4: Severely decreased, eGFR 15-29 mL/min/1.73 m2 G5: Kidney failure, eGFR <15 mL/min/1.73 m2
Chronic kidney disease is defined as an eGFR < 60 mL/min/1.73 m2 for three months or more, and it is unlikely that patients who have an eGFR > 60 mL/min/1.73 m2 would need downward dosing adjustments of lithium.22,23 However it should be noted that there are no standardized, accepted guidelines for prescribing lithium for patients who have renal impairment, lithium excretion depends on renal function, and lithium itself is nephrotoxic.
For patients taking lithium, baseline measurements of BUN, creatinine, eGFR, and urinalysis should be done prior to initiating lithium therapy, they should be re-measured every two to three months during the first six months
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of lithium therapy, and then measured every six to 12 months.4 For patients who have renal impairment, closer monitoring and more frequent assessment may be prudent. US Boxed Warning
Lithium toxicity may be closely related to serum levels, and it can occur at levels that are only slightly above the therapeutic level. The ability to accurately and quickly measure serum lithium should be available.1,2
Acute, acute-on-chronic, or chronic lithium toxicity can cause significant morbidity and long-term, chronic neurological damage.24-26 Timely measurement of serum lithium levels is essential for assessment and treatment of a patient who has lithium intoxication.
Serum lithium levels must be carefully interpreted. Therapeutic serum
lithium is 0.6 – 1.2 mEq/L, and a level of > 1.5 mEq/L has been defined as toxic, but the serum lithium level is not an accurate predictor of lithium toxicity nor does the level correlate well with the severity of lithium toxicity.24-27
Patients who have levels > 4.0 mEq/L may be relatively asymptomatic.24 A lithium level as low as 0.57 mEq/L has been reported to cause serious lithium poisoning.28
The lithium level - along with the patient’s clinical presentation and other laboratory test results – can be used to help determine the appropriate treatment. For example, hemodialysis is an effective treatment for lithium toxicity, and hemodialysis is recommended if 1) the serum lithium level is > 5.0 mEq/l, 2) if the level is > 4.0 mEq/L and the patient’s serum creatinine is > 2.0 mg/dL, 3) if the serum lithium level is > 2.5 mEq/L and there is evidence of serious toxicity like coma or seizures, 4) if the patient has renal insufficiency, or 5) if there is intolerance of aggressive fluid resuscitation.24
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Warnings Cardiovascular:
Prescribing information and authoritative sources advise that lithium should be used cautiously in patients who have cardiovascular disease. Lithium use has been associated with both benign and life-threatening cardiovascular adverse effects.29-36 Some of these are relatively common and they occur during otherwise uneventful use of the drug: sinus bradycardia and T wave inversion are well known adverse effects of lithium, the latter being noted in 16%-33% of all patients taking the drug.32 Other cardiovascular adverse effects happen only if the lithium level is elevated, or they have been documented in just a few case reports, e.g., Brugada syndrome and myocardial infarction.32
Because information about these adverse effects is relatively scarce, it can be difficult to determine their clinical significance or to identify which patients are susceptible and the reason. For example, ECG changes like T wave inversion and bundle branch block may persist for years and cause no harm,33 but the unmasking of the Brugada syndrome may cause cardiac arrest. The prudent clinician would carefully assess the patient’s cardiovascular health, perform a baseline 12-lead ECG before prescribing lithium, schedule follow-up exams and ECGs as needed, and determine the benefits and risks of lithium use for that patient.
The cardiovascular adverse effects associated with lithium use may include asystole, atrioventricular block, bradycardia, cardiomyopathy, heart failure, interstitial myocarditis, junctional rhythms, myocardial infarction, premature ventricular beats, QT prolongation SA node blocks, SA node dysfunction, ST segment and T wave changes, and ventricular fibrillation.27,29-
36 Some are common, e.g., bradycardia and T wave inversion,33 and others are rare, typically being documented by one or two case reports.31,32,34
Brugada syndrome is an uncommon genetic cardiac condition that is
characterized by ECG changes, ventricular tachy-arrhythmias, and sudden
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death.37 Patients who have Brugada syndrome may simply have ECG changes or the disease may present with syncope, palpitations, or a dangerous ventricular arrhythmia,29 and the Brugada syndrome may be unmasked by the use of lithium.1,33 This appears to be a very uncommon occurrence and there are very few documented cases.33 Prior to starting therapy with lithium, patients should be examined for the presence of Brugada syndrome and for factors for that increase the risk of the disease, e.g., family history of Brugada syndrome, palpitations, syncope, and a family history of sudden death before age 45.1 Lithium should not be prescribed for patients who have Brugada syndrome unless its use is absolutely necessary and if it is prescribed, consultation with a cardiologist and close monitoring of the patient are mandatory.1
Lithium may act as a myocardial toxin. The American Heart Association (AHA) published a review of drugs that may cause or exacerbate heart failure, and lithium was identified a direct myocardial toxin.34 The mechanism of action is not clear - possibly a direct effect of the drug on the myocardium, adrenergic stimulation, or interference with calcium ion efflux - and the AHA’s conclusions were that 1) The effect was considered to be major, 2) The level of supporting evidence was categorized as level C, meaning that very limited populations were evaluated, and the information is from case studies, consensus opinion of experts, and standards of care, and 3) The onset is intermediate or delayed, and the effect is reversible when the patient stops taking the drug.34
Thyroid Disorders:
Lithium can cause thyroid disorders. Goiter and hypothyroidism are the most common.38 Goiter is the enlargement of the thyroid gland, and it is a common adverse effect of lithium therapy, with a reported incidence of 30- 59%.38,39 It is not completely understood how lithium causes goiter, but it is likely that lithium decreases thyroid hormone secretion and release, resulting in compensatory thyroid gland enlargement.38,39
The onset of lithium-induced goiter can be weeks after after initiation of
treatment or it may be delayed for years.38,40 It typically presents as a diffuse,
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non-tender neck swelling, the TSH level is increased, the T3 and T4 levels are decreased.38 A large, visible goiter that causes signs and symptoms of compression is unusual.38 Treatment of lithium-induced goiter is the same as treatment of goiter from other etiologies.38 Discontinuing the use of lithium if a goiter develops is not recommended;38 the patient should be treated with standard care.38
Hypothyroidism has been reported in 6%-52% of all patients taking
lithium.38,39 Most cases are subclinical: the patient is asymptomatic, but the TSH level is elevated. The patient may or may not have a goiter.38 Lithium- induced hypothyroidism is more likely to happen to women over age 45, and the risk factors for developing this adverse effect may include increased age, a family history of hypothyroidism, or the presence of thyroid autoantibodies.38,39 The clinical presentation is identical to hypothyroidism from other causes, with depressed mood, fatigue, lethargy, dry skin, weight gain, and increased sensitivity to cold.38,41 Lithium-induced hypothyroidism should be treated using standard guidelines.38
Thyroid function studies should be measured before the patient begins
taking lithium, measured once or twice during the first six months of treatment, and these tests should be repeated every six to 12 months for several years;4,38 perhaps more frequently if the patient is considered high- risk.4 The presence of goiter or hypothyroidism does not mean that lithium cannot be used and if adverse effects occur, the thyroid dysfunction should be treated.38
Hypercalcemia and Parathyroid Hormone:
Lithium may cause hypercalcemia, an increased parathyroid hormone level, and hyperparathyroidism.1,4,42,43 The exact incidence of these adverse effects is not known. A retrospective case review done in 2018 found a 26% prevalence of hypercalcemia, and the risk of developing hyperparathyroidism from chronic lithium use has been estimated at 10%.42
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Many patients do not develop clinical signs and symptoms from these laboratory abnormalities.4 There are documented cases of symptomatic lithium-induced hypercalcemia, and hypercalcemia may or may not resolve after lithium use is discontinued.42,43 In addition, hypercalcemia may complicate other adverse effects of lithium like cardiovascular disorders, nephrogenic diabetes, and renal disease.44
There are four options for treating lithium-associated hypercalcemia: 1)
Discontinue lithium therapy, 2) Careful monitoring of the patient, 3) Lowering serum calcium by treatment with a calcimimetic drug, e.g., cinacalcet, and 4) Surgery.42
Psychiatric:
People who have bipolar disorder have a high risk for suicide. There is strong and consistent evidence that lithium has a protective effect and it reduces the risk for suicide.45-49 This may be the case because of litium’s effect as a mood stabilizer, which reduces aggressiveness and impulsivity.49 It may also be that a patient’s greater contact with professional health care also helps reduce the risk for suicide.49 Nevertheless, it is recommended that lithium should be used cautiously if a patient is depressed or has suicidal behavior or ideation.1 Serotonin Syndrome:
Lithium used in combination with serotonergic drugs, e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, can cause serotonin syndrome.50 Serotonin syndrome is a potentially fatal condition that is caused by excessive serotonergic activity. Excessive serotonergic activity occurs with the use, misuse, or abuse of drugs that 1) inhibit serotonin reuptake, 2) act as direct serotonin agonists, 3) decrease the breakdown of serotonin, 4) increase the release of serotonin, or 5) increase serotonin formation.51 Serotonin syndrome can occur with use of a single serotonergic drug but concurrent use of two serotonergic drugs, e.g., fluoxetine and lithium is a more common cause.51
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The onset of serotonin syndrome is usually within six hours of the last time a medication was taken and most patients have mild to moderate signs and symptoms like agitation, clonus, diaphoresis, fever, hyperreflexia, and tremor, but serious morbidities and fatalities caused by serotonin syndrome are possible.51 Serotonin syndrome is a clinical diagnosis; there are no tests that can confirm its presence. Treatment is symptomatic and supportive. Renal Function:
Lithium can have significant negative effects on renal function, which may include nephrogenic diabetes insipidus, nephrotic syndrome, and chronic kidney disease and end-stage renal disease.52 Nephrogenic diabetes insipidus is defined as a decreased ability to concentrate urine that is caused by decreased activity of and resistance to antidiuretic hormone (ADH).
Antidiuretic hormone is a hormone that is secreted by the posterior pituitary gland, and its primary function is maintaining normal body fluid osmolarity. In the kidneys, ADH increases the water permeability of the collecting tubules, causing water to be reabsorbed rather than excreted as urine. Lithium causes resistance to ADH and inhibits ADH activity.52,53
Lithium is the most common cause of nephrogenic diabetes insipidus.53 In long-term users of the drug, the prevalence of nephrogenic diabetes insipidus has been reported to be 50-73%.53 The primary characteristics of nephrogenic diabetes insipidus are nocturia, polydipsia, and polyuria (often defined as a urine output > 3000 mL/24).52,54 Hypernatremia can occur, as well.55 The primary risk factor for nephrogenic diabetes insipidus is the duration of the lithium therapy; the longer the duration, the greater the risk.53 Non-responsiveness to lithium and the use of slow-release preparations may also increase the risk.56 Although polyuria is one of the primary signs of nephrogenic diabetes insipidus, many patients who are prescribed lithium will develop polyuria but only 15∼20% will develop nephrogenic diabetes insipidus.57
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Lithium-induced nephrogenic diabetes insipidus can be reversible, partly reversible, or it can become permanent. It may be reversible if the duration of lithium therapy is relatively brief, e.g., two to six years.53 However, it is not known at what point nephrogenic diabetes insipidus becomes irreversible.56 If discontinuing treatment with lithium is not possible, a low-sodium diet should be prescribed, and the potassium-sparing diuretic amiloride, a thiazide diuretic, an NSAID, or desmopressin can be used.54
Nephrotic syndrome is a rare complication of lithium therapy.57 It is caused by glomerular injury, and it is characterized by urinary excretion of > 3 g of protein a day, hypoalbuminemia (< 3 g/dL), and peripheral edema.52,54 The mechanism of action by which lithium causes nephrotic syndrome is not known.57 If nephrotic syndrome occurs, fluid restriction should be started and if possible, lithium therapy should be discontinued.52,58 In some cases, corticosteroids were successfully used to treat nephrotic syndrome.52,58
A mild decline in renal functioning of approximately 15-30% is common
in patients on long-term lithium therapy.52,59 Lithium can damage the kidneys, and long-term lithium therapy has been associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD).52,56,59-61
The major risk factors for CKD and ESRD include duration of treatment, the cumulative dose, and repeated episodes of high serum lithium level.52,56,59 Acute lithium intoxication, comorbidities (e.g., diabetes mellitus, hypertension), and advanced age have also been identified as risk factors.52 The onset of a decline in renal function appears to occur after 10-15 years of use.60 The latent period between the beginning of lithium therapy and the onset of ESRD has been reported to be 20-27 years.52,56,60
Fortunately, CKD and ESRD are uncommon complications of lithium
therapy: the prevalence of ESRD in chronic lithium users has typically been found to be < 1.0%.56,61 ESRD has occasionally been reported to be higher.52
Also, some researchers have questioned the relationship between the drug and CKD and ESRD. Chang, et al. (2020) wrote that “... older lithium users
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commonly have chronic kidney disease (CKD), although rates are not different compared to community-dwelling non-lithium older patients.”59
Davis, et al. (2018) noted that “... there continues to be evidence which suggests that lithium may not increase the risk of CKD ... Our analysis suggests there is no effect of stable lithium maintenance therapy (lithium levels in therapeutic range) on the rate of change in eGFR over time.”56
Post (2018) questioned whether lithium therapy caused reduction in eGFR, the author noted that recent literature reviews suggest that decreased renal function is related to episodes of lithium toxicity.60 Chang, et al. (2020) wrote that some research had shown no increase in prevalence of ESRD in patients taking lithium.59 Pregnancy and Breastfeeding
Treating a pregnant patient who has bipolar disorder and takes lithium is pregnant is a complex clinical challenge, and there are five primary issues to consider. Effect of Pregnancy on Bipolar Disorder:
It is not clear if pregnancy decreases or increases increase the risk of mood disorders or if the disease has no effect on the course of the illness.62,63 A literature review done by Salim, et al. (2018) concluded: “The extant literature cannot answer the question of how pregnancy affects the course of bipolar disorder …”63 Continuing Lithium Therapy During Pregnancy:
The decision to continue lithium therapy during pregnancy should be made on a case-by-case basis. The benefits and risks of doing so must be carefully considered by the patient and the clinician, and the patient should be advised of how the disorder will be managed, e.g., frequent monitoring of serum levels, dosing adjustments.
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Using lithium during pregnancy can cause harm to a fetus and/or a neonate; however, discontinuing lithium therapy or not using lithium may increase the risk for mood episodes.64,65 Lithium can be safely used during pregnancy.64 Hendrick (2019) recommended that patients who have moderate to severe bipolar disorder should be treated with lithium or continue lithium therapy during pregnancy.65
Risks of Lithium Therapy During Pregnancy:
Lithium therapy during the first trimester has been associated with an increased risk of spontaneous abortion.66 However, this risk may be disease- specific and may not be caused by the drug.66 A recently published literature review by Sharma, et al. (2020) concluded that lithium use during the first trimester has not been associated with an increased risk for spontaneous abortion.64
Lithium moves easily and efficiently across the placenta.64 The use of
lithium during the first-trimester pregnancy has been associated with cardiac abnormalities - Ebstein’s anomaly is the one most often mentioned - and increased birth weight.64,66,67 Exposure during the second and third trimester has been associated with lithium toxicity in the infant, premature labor, polyhydramnios, and neonatal complications of cardiomegaly, gastrointestinal bleeding, goiter and hypothyroidism, hepatomegaly and jaundice, hypoglycemia, nephrogenic diabetes insipidus, premature labor, and shock.66-
68 Maternal lithium toxicity has been associated with neonatal cyanosis hypotonicity, hypothyroidism, neuromuscular abnormalities, lower Apgar scores, and longer hospital stays and nephrogenic diabetes insipidus.67-69
Lithium does not appear to negatively influence a child’s neurologic
development.67,69 The use of lithium during the first trimester has consistently been associated with an increased, significant risk for fetal cardiac malformations.64,66,69,70 The incidence of this complication is not known, but recently published studies and literature reviews have found that the risk is not high, lower than the traditionally reported estimates and that the association is dose-dependent; the higher the dose, the greater the risk.69,70
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Dosing Lithium During Pregnancy:
Because of physiologic changes like increased hepatic and renal activity, increased glomerular filtration of the drug, and an increased plasma volume that occur during pregnancy, lithium levels decrease during pregnancy.64,67,69 The decrease can be significant, up to 34%, it is the highest in the third trimester, and a decrease in serum lithium level has been reported to occur in up to 62.1% of patients.67 During the second and third trimester, the dose of lithium may need to be as much as twice the dose used before pregnancy.62
Lithium therapy should be stopped twenty-four to 48 hours before
delivery.66-68 Doing so can help prevent neonatal complications.66-68 After delivery the dose should be returned to the pre-pregnancy dose.62
Preconception Care and Monitoring During Pregnancy:
With close monitoring, lithium can be safely used for pregnant women.64
Preconception counseling about the risks and benefits of using lithium during pregnancy should be done several months before becoming pregnant or done immediately if the patient becomes pregnant and is taking lithium.64 The lowest effective dose should be used.64 The patient should be monitored for episodes of depression, hypomania, and mania.62,64
There should be counselling of the patient to stay well hydrated.62 All
pregnant women should abstain from using alcohol, tobacco, and illicit drugs.64 Counseling about alcohol, tobacco, and illicit drugs is especially important because many people who have bipolar disorder have a substance use disorder.3
Screening for fetal cardiac abnormalities should be done at 16-18 weeks
gestation using fetal echocardiography and high-level ultrasonography.62,68
Newborns should be monitored for the presence of lithium toxicity for 10 days after birth.62
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Breastfeeding
There are several ways of determining — or in this case, making an informed decision — if lithium can be safely used during breastfeeding. Excretion into Breast Milk:
Lithium is excreted into breast milk.1,71,72,73 However, the amount is highly variable.71 A literature review by Imaz, et al. (2019) found that the mean concentration of lithium in breast milk was 0.34 mEq/L, the milk to maternal serum level ratio averaged 0.49,73 and the authors concluded: 1) the amount of lithium excreted into breast milk is low, 2) the mean concentration of lithium in breast milk and the milk to maternal serum level ratio cannot be used to determine if a nursing infant will or will not be adversely affected by lithium in breast milk, and 3) multiple factors determine the concentration of lithium in breast milk.73
Nursing Infant’s Lithium Level:
The serum lithium level of a nursing infant can be measured directly, and it can be compared to the mother’ serum level. A literature review by Newmark, et al. (2019) found that the serum lithium levels of nursing infants ranged from 0.04 to 0.97 mEq/l and in most cases, the serum level was < 0.6 mEq/L, the lower limit of therapeutic normal for adults.72 Imaz, et al. (2019) found that the mean serum lithium level in nursing infants was 0.26 mEq/L, the range was 0.02 to 1.40 mEq/L and in most cases, the level was < 0.3 mEq/L.73
The serum lithium level in nursing infants has been found to be 10-67%
of the maternal serum lithium level with and the average is 32%.71,72 The infant plasma (I/P) ratio is the infant’s plasma level of a drug divided by the mother’s plasma level.73 An I/P ratio of <10% has been considered acceptable and an I/P of > 25% unacceptable73 and in their review, Imaz et al. (2019) found a mean I/P ratio of 0.28% with a range of 0.04 to 2.00.
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The Infant’s Dose:
The infant’s dose can be calculated using the relative infant dosage (RID) formula.74 Infant dose (mg/kg/day) x 100 ÷ maternal dose (mg/kg/day). The infant dose is calculated, in this case from the concentration of the drug in breast milk. A RID of <10% has been the accepted value indicating a drug is safe to use during breastfeeding and if the RID is >25% use of the drug is contraindicated.74 Only one study was found that estimated the RID is ring infants exposed to lithium. Moretti, et al. (2003) reported that the mean RID was 12.2%, 11 of the 23 infants had a RID of between 10-25%, and one had a RID > 25%.75
Adverse Effects:
There are many published reports of nursing infants who were exposed to lithium and who did not develop adverse effects.71 The review by Newmark, et al. (2019) located 32 cases of neonatal lithium exposure and adverse effects occurred in three (9.4%).72 Two infants had feeding problems which were temporary and one had cyanosis, hypotonia, lethargy, and poor feeding.76,77 There was one child who had an increased TSH (temporary) and two cases of increased BUN and or serum creatinine.72
The use of lithium during breastfeeding has been discouraged in past.1
Some clinicians believe that with the proper precautions, it can be used safely during nursing.71 Research is limited on this topic.72,73,78 The published information is from small, short-term studies, case reports, and case series and the quality of the research has been characterized as low to moderate.73
Most of the adverse effects have been minor and temporary, but the number of reported cases of infant lithium exposure during nursing is so small that it is not possible to know what adverse effects may occur and to whom.78 Also, the adverse effects that have been reported may have been caused by the infant’s health, other medications that mother was taking, or due to lithium exposure during gestation.72
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Aside from the I/P ratio, the RID, the maternal dose, the excretion of lithium into breast milk, how much lithium a nursing infant is exposed to, and how the infant will be affected depends on many factors, may include: 1) an infant’s ability to metabolize and eliminate lithium, 2) how much milk was removed from the breast during a previous feeding, 3) when the dose of lithium was last taken in relation to feeding, 4) how much milk the child consumes during a feeding, 5) oral bioavailability, and 6) infant’s age.73,79
The decision to continue or stop lithium therapy during breastfeeding should be done after considering the risks and benefits of either approach. It must be presumed that someone taking lithium is deriving a benefit, and there are risks to the pregnant woman if she stops taking it. The benefits to an infant of breastfeeding are considerable and well-established.73 It appears that the risks from lithium in breast milk are small but it is not possible to know what the risks are or to whom and how often they may occur.
When continuing or stopping the use of lithium during breastfeeding, the only reasonable approach is a case-by-case assessment.73 If lithium therapy is to be continued, careful monitoring of the mother and the infant needs to be done.
Lithium overdose is usefully divided into two categories: 1) acute and 2) acute-on-chronic.80 An acute poisoning occurs when a lithium-naïve patient takes an overdose of lithium; acute-on-chronic occurs when a patient who has been taking lithium ingests an excessive amount. An acute-on-chronic overdose is potentially more serious because the acute ingestion adds to the pre-existing CNS tissue drug level.80 Lithium Overdose
Lithium overdose is characterized by gastrointestinal and neurologic signs and symptoms.24,27 Nausea, vomiting and diarrhea are common after an acute overdose.24 Neurologic signs in acute and acute-on-chronic overdose are common and may include ataxia (a lack of muscle control), CNS depression (mild to severe), lethargy, myoclonic jerks, slurred speech, and
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tremor.24,27 In severe overdose, coma convulsions, and encephalopathy can occur.24,27 Significant neurologic complications, e.g., serious cerebellar and cognitive dysfunction, may have a delayed onset, they can persist for weeks, months, and years and occasionally, they are irreversible and permanent.24,27,80 The latter is a condition referred to as syndrome of irreversible lithium effectuated neurotoxicity, otherwise known as SILENT.24,27
Initial treatment of a lithium overdose should include assessment and
stabilization of the patient’s airway, breathing, and circulation. Serum BUN and creatinine, electrolytes, thyroid function studies, and acetaminophen, salicylate, and lithium level should be measured, and a 12-lead ECG should be done.24,27
The inside surface of some phlebotomy tubes is coated with lithiated heparin. Using these tubes in patients with lithium overdose, or suspected lithium overdose, can result in a falsely elevated serum lithium level.24 Clinicians must make sure the tubes are not coated with lithiated heparin.24
A pregnancy test should be done if the patient is a female of child-
bearing age.24 The clinician should find out how much the patient took and when, consider the possibility of a co-ingestant, and review the patient’s past medical history. it is also important to know what prescription medications the patient takes and if renal impairment exists.
Lithium is not adsorbed by activated charcoal. If the patient is awake, has a normal gag reflex and a functioning gastrointestinal tract, whole bowel irrigation (WBI) with a polyethylene glycol solution can be used to mechanically flush any remaining lithium out of the gut.24,27 There is no antidote for lithium poisoning.80 Patients should be treated with symptomatic, supportive care, IV hydration and if needed, hemodialysis.24,27 After an overdose, the peak serum lithium level can be delayed for up to 12 hours or longer. After the initial measurement, lithium levels should be done every two to four hours; this is done to determine the trend and to determine if hydration therapy is being effective.24
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If the patient is symptomatic or has a measurable lithium level, intravenous (IV) hydration with 0.9% normal saline solution at twice the calculated maintenance fluid rate should be started.24 Isotonic saline increases renal excretion of lithium and hydration itself will help prevent retention of lithium. An acute lithium ingestion does not cause renal damage, but chronic lithium therapy can and chronic lithium therapy can also cause nephrogenic diabetes insipidus. Patients who have taken an acute-on-chronic overdose are being given isotonic saline hydration are at risk for hypernatremia so in these patients, serum sodium should be closely monitored.24,27
Hemodialysis is effective at removing lithium.24 The primary indications for hemodialysis are for patients with serious neurologic complications (regardless of the serum level), e.g., coma, seizures; and for patients with impaired renal function, e.g., a patient who is anuric and cannot eliminate lithium in the urine.24,27 Hemodialysis may also be recommended for any patient if the serum level is > 5.0 mEq/L; in patients whose lithium level is > 4.0 mEq/L and who have a serum creatinine > 2.0 mg/dL; and in patients who have a high serum level and cannot tolerate vigorous IV hydration.24
A measurable serum lithium level confirms the ingestion of the drug, but the level is just one of the factors used to decide if a patient should be dialyzed and interpreting the significance of the level must be done with the following points in mind. When was the level done? Lithium levels rise and then fall as the drug
moves into the CNS tissue and this can be a lengthy process.24 Acute ingestion versus acute-on-chronic ingestion is important to ascertain
because of (probable) lithium saturation of the CNS tissues in an acute- on-chronic ingestion; any abnormally high lithium level in these patients likely indicates a greater risk for harm.24
There is a poor correlation between lithium levels and clinical presentation.24 A patient with a high level may not be seriously ill, but severe toxicity has occurred in patients whose lithium level is in the therapeutic range.81
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The lithium level cannot predict which patients will develop serious complications.24
There are no universally accepted guidelines for using hemodialysis as
a treatment for lithium overdose. The published recommendations indicate that the decision on whether to use hemodialysis is based on clinical experience and expert opinions:27 the decision to use hemodialysis should be made based on the type of ingestion, the patient’s renal function, the clinical presentation, and the lithium level.27 The importance of each factor and its usefulness as a guide for prescribing hemodialysis must be determined by the bedside clinician.27
The movement of lithium between the intracellular and extracellular
spaces is slow and after hemodialysis, the level may decrease and then increase.80 A lithium level should be measured approximately six hours after hemodialysis has been finished and clinicians should be prepared to re-dialyze the patient if needed.80 Lithium and Sleep
Bipolar disorder is known to be associated with altered circadian rhythm and insomnia. Yin and colleagues (2006) noted that lithium was a “potent inhibitor of glycogen synthase kinase 3 (GSK3), which regulates circadian rhythm in several organisms.”81 The authors discussed how lithium works at the cellular level to target the biological clock.
Coyle (2007) discussed the effect of lithium in the animal model to lengthen the circadian cycle and explained that the “effective treatment of bipolar disorder must address two issues: the management of the presenting mood disturbance and the prevention of the recurrence of subsequent episodes… GSK3β may serve as the bridge between the mood-normalizing effects of the mood stabilizers and their ability to attenuate subsequent mood cycling in bipolar disorder… In the mouse, GSK3β is expressed in the suprachiasmatic nucleus and liver where its phosphorylation exhibits robust
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circadian oscillations.”81 Coyle suggested a novel off-label approach to the use of lithium to inhibit GSK3 phosphorylation and to prolong the circadian cycle.81 Lithium and Aggression
Four studies were discussed in a Canadian review of lithium efficacy in aggressive youth with comorbid drug use and attention deficit hyperactivity disorder (ADHD) where lithium with placebo to treat aggression in hospitalized youth was conducted. There were 184 children enrolled as participants in the research and the majority were male.82
Study trials were conducted between 2 to 6 weeks. One study reported
no difference in behaviors in youth with chemical dependency that were taking lithium and placebo whereas a significant difference was found between lithium and placebo on all behavioural measures studied.82 Other studies reported a mix of significant and nonsignificant results on multiple behavioural outcomes. Three studies with data that could be incorporated into a meta- analysis showed that treatment with lithium was associated with a higher odds of response or remission than placebo.82
While the evidence for lithium is inconsistent in the research, the general consensus in psychiatry is that it can show benefit in combination with other medication targeting symptoms of anxiety, mood disorder, mixed states, and hostility, aggression or violence in mood dysregulated patients in general.82
Case Studies: Lithium
The following two case studies are examples of the use of lithium in varied age groups, the benefit of combining lithium with other medication to control mood dysregulation, and the potential risks of lithium use, such as in elderly patients.83,84
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Case Study 1: Aggression and Self-harming
A 22-year-old male was admitted to a neurosurgery unit after an anger outburst during which he exhibited an automatic masticatory-like movement. The patient reportedly had no prior history of neurologic or psychiatric illness.83
The patient transferred to the neurology unit for further examination
and was diagnosed with seronegative limbic encephalitis, based on laboratory findings and brain imaging. He had primary symptoms of serious aggression and anger outbursts.83 For medical and psychiatric safety, the patient was kept in a secluded, quiet room and administered valproate 800 mg/d, levopromazine [promethazine] 75 mg/d, and risperidone 4 mg/d.83
The patient continued to show aggressive behaviors despite increases of valproate to 1,200 mg/d (96.5 µg/mL) and levomepromazine to 250 mg/d, and the patient’s serious aggression and anger outbursts persisted to the point of aggressing against medical staff and self-harming behaviors of beating on himself. Eventually, carbamazepine 500 mg/d (7.8 µg/mL) was combined, however, the patient’s symptoms were partially remitted. After lithium 1,000 mg/d (0.98 mEq/L) was added the patient’s serious aggression and anger outbursts reportedly showed a significant decrease, and he was moved out of seclusion. He was reported to communicate with medical staff in a polite manner.83
Once a level of stability was achieved, valproate, risperidone, and levomepromazine were able to be tapered to discontinue without exacerbation of the aggressive behavior. The patient was reportedly able to joke with medical staff while smiling. Collateral information from family and friends indicated the patient had returned to his premorbid state. The patient eventually discharged on combination lithium 800 mg/d (0.71 mEq/L) and carbamazepine 600 mg/d of (7.4 µg/mL) and was followed up 3 months after hospital discharge as stable and employed, as well as showing good family and social relationships.83
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Discussion
This case study of a young male patient demonstrates how combination
carbamazepine and lithium had been effective to treat aggression with a return of the patient’s behavior to his premorbid state following an acute case of encephalitis.83 The authors suggested that the combination of carbamazepine and lithium may be useful for serious aggression and anger outbursts in the acute phase of limbic encephalitis in some patients.83 Case 2: Lithium Toxicity
A 74-year-old woman with a 5-year history of bipolar affective disorder was taken to the emergency department.84 She was evaluated there for severe bilateral hand tremors, myoclonic jerks of the upper extremities, exhaustion, and slurred speech. Vital sign trends revealed a normal temperature and blood pressure of 110/70 mmHg.84
Collateral information revealed the patient began to show symptoms the day after she started using moxifloxacin 400 mg/day for the treatment of bronchiolitis. Her serum lithium concentration was 0.8 mEq/L 10 days prior to starting moxifloxacin. There were no other signs of lithium toxicity such as vomiting, diarrhea, nystagmus, or dysarthria. Cognitively, she was slightly drowsy and disoriented, and her speech was slurred.84
The dose of lithium carbonate taken was 600 mg/day. Other medications she was prescribed included haloperidol 10 mg/day, risperidone 2 mg/day at her first manic episode five years ago. A depressive episode four years prior resulted in Sertraline 25 mg/day being prescribed.84 The serum lithium concentration ranged from 0.60 to 0.80 mmol/L over the past years, and the patient had been maintained on lithium carbonate 300 mg in the morning and 300 mg at night.84
On admission, the patient’s serum lithium was elevated at 1.7 mEq/L, which was a significant elevation above earlier trends (normal laboratory values 0.5–1 mEq/L).84 She showed no renal impairment or sign of
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dehydration. Laboratory results included: fasting blood glucose 88 mg/dl, blood urea nitrogen 25 mg/dl, creatinine 0.99 mg/dl, sodium 139 mmol/L, potassium 3.4 mmol/L, calcium 9.2 mg/dl; alanine aminotransferase 13 U/L; aspartate aminotransferase 6 U/L; creatine kinase level (CK) 29 U/L; CK-MB fraction 1 ng/ml, troponin-I 0.016 ng/ml, lithium level 1.7 mEq/L, white blood cell 7.090/µl; red blood cell 4.38 M/µl, hemoglobin 12.3 g/dl, and hematocrit 39%.84 Urinalysis results were as follows: density 1,014, pH 7.5, protein 20, glucose negative, ketone 0 mg/dl, bilirubin 0 mg/dl, urobilinogen 0 mg/dl, nitrite negative, and leukocyte negative.84
A magnetic resonance imaging of the brain and electrocardiography (ECG) showed normal results. Hypoxia, hypoglycemia, hypothermia or hyperthermia, electrolyte disorders, central nervous system infection, head trauma, intracranial bleeding, and neuroleptic malignant syndrome were all ruled out and the patient was diagnosed with mild-moderate lithium toxicity.84 Lithium and moxifloxacin were immediately discontinued, and the patient was administered fluid resuscitation with less than 2 L of 0.9% saline solution for 6 hours. The patient’s serum lithium level decreased to 0.9 mEq/L after 12 hours, and other signs of toxicity diminished such as her hand tremors and myoclonic jerks. Symptoms of drowsiness and disorientation resolved 1 week later.84 Discussion
Lithium toxicity in elderly patients can be serious and life-threatening. In the case, an elderly female with a recent diagnosis of bipolar disorder and comorbid conditions, was taking lithium and other drugs, which resulted in a drug-drug interaction.84 Antidepressants and antipsychotics are known to increase the risk of lithium intoxication.84 Some case reports suggest haloperidol, risperidone or serotonin reuptake inhibitors (SSRI) may cause rare neurotoxicity but it is not clear that the toxicity is induced whether by drug interaction or effect of a single drug alone.84
The serum lithium levels increased in this case only after the second day of moxifloxacin use. Haloperidol, risperidone, sertraline, and moxifloxacin
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were all associated with prolongation of ECG-derived corrected QT intervals. Combination of these drugs could increase the risk of QTc prolongation. However no ECG abnormalities were reported in this case.84 Also, factors such as dehydration, rigorous dieting or low salt intake, high fever, or history of anesthesia or a major operation have been reported to cause lithium toxicity in elderly patients. The patient’s symptoms and examination results did not indicate any of these conditions in this case.84
Levofloxacin, a fluoroquinolone agent, can increase serum lithium levels. When co-administered with lithium, levofloxacin has been reported to cause both renal impairment and toxicity.84 Moxifloxacin is known to be a safe and well-tolerated fluoroquinolone antibiotic agent and used often in elderly to treat respiratory infections.84 Lithium and moxifloxacin are excreted renally.84 Levofloxacin decreases the excretion of lithium by decreasing its glomerular filtration or tubular secretion. It is suggested that moxifloxacin could slow down the excretion of lithium by decreasing its glomerular filtration or tubular secretion, similar to levofloxacin.84 Further studies on potential interaction between moxifloxacin and lithium are needed. Physicians who prescribed lithium should be careful for the possible drug interactions. Considering these interactions on elderly patients receiving lithium is essential.84
Summary
Lithium is a first-line choice for the treatment of patients who have bipolar disorder, and with careful prescribing and close monitoring it can be used effectively and safely. The common adverse effects of lithium therapy are cognitive impairment and other symptoms, including weight gain. Lithium should be used cautiously if the patient is elderly or has cardiovascular disease or renal impairment, and long-term use has been associated with electrolyte disorders, thyroid dysfunction, and renal damage. Lithium should also be used very carefully and with close monitoring of pregnant patients and nursing infants.
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No antidote for lithium poisoning exists so close monitoring is critical in patients who are started on therapy. Patient rehydration and proper excretion is needed. The patient’s neurological status and the serum lithium level must be closely followed. Serum lithium levels are an important assessment tool, but it is important to remember that the level often will not correlate with the patient’s clinical condition. Careful monitoring of the serum lithium level through observation and laboratory testing is important to trend for ongoing safe use.
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Self-Assessment of Knowledge Post-Test: Please take time to help NurseCe4Less.com course planners evaluate the nursing knowledge needs met by completing the self-assessment of Knowledge Questions after reading the article, and providing feedback in the online course evaluation. Completing the study questions is optional and is NOT a course requirement.
1. Lithium is an antimanic agent that acts as ________________ in patients who have bipolar disorder.
a. a hallucinogen b. a mood stabilizer c. an antipsychotic d. an antidepressant
2. For _________________, lithium is often combined with an
antipsychotic.
a. hypomania b. severe mania c. mild mania d. moderate mania
3. Bipolar disorder is a psychiatric disorder characterized by
episodes of
a. depression followed by periods of lethargy. b. anxiety and concomitant depression. c. mania, hypomania, and major depression. d. anger and anxiety, followed by periods of calm.
4. A patient with mild renal impairment
a. may not take lithium. b. must reduce the recommended dose. c. may take lithium but with caution. d. may take lithium but a low sodium diet is recommended.
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5. The use of lithium during the first trimester of pregnancy may cause a serious fetal cardiac malformation called
a. Epstein-Barr syndrome. b. Ebstein’s anomaly. c. Brugada syndrome. d. Stevens-Johnson syndrome.
6. The use of lithium in a mother who is breastfeeding is
a. contraindicated in all circumstances. b. safe since lithium is not excreted in breast milk. c. safe since serum concentrations in nursing infants are less than
7% of the maternal dose. d. not recommended unless the benefits outweigh the risks.
7. True or False: Lithium is not useful to treat mild to moderate
manic episodes.
8. The most common acute effects of lithium include
a. cognitive impairment. b. constipation. c. weight loss. d. permanent kidney damage.
9. One of the most common thyroid disorders caused by lithium is
a. hyperthyroidism. b. the development of thyroid auto-antibodies. c. Graves’ disease. d. goiter.
10. Lithium should not be used if the patient has or may have
a. Brugada syndrome. b. a cardiovascular disease. c. Graves’ disease. d. All of the above
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11. Recommended treatment of lithium-induced goiter
a. includes discontinuing the use of lithium. b. includes administration of isotonic saline. c. is the same as treatment of goiter from other etiologies. d. is limited to the administration of naltrexone.
12. Nephrotic syndrome is caused by
a. lithium overdose. b. hepatic impairment. c. hypothyroidism. d. glomerular injury.
13. True or False: Lithium, in combination with other medication,
may benefit patients who are hostile, aggressive or violent.
a. True b. False
14. Patients who have an acute lithium overdose typically present
with neurological signs and symptoms, such as
a. hyperactivity. b. a lack of muscle control. c. a syndrome of irreversible lithium effectuated neurotoxicity. d. blindness and brainstem dysfunction.
15. The inside surface of some phlebotomy tubes is coated with
___________ and using these tubes can result in a falsely elevated serum lithium level.
a. thrombin b. sodium polystyrene sulfonate c. lithiated heparin d. potassium EDTA
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https://www.uptodate.com/contents/lithium-drug- information?search=lithium&source=search_result&selectedTitle=1~1 48&usage_type=default&display_rank=1#F189314.
2. ANI Pharmaceuticals. Lithium carbonate extended release tablet. Package Insert. ANI Pharmaceuticals. June 2018. Baudette, MN.
3. Won E, Kim YK. An oldie but goodie: Lithium in the treatment of bipolar disorder through neuroprotective and neurotrophic mechanisms. Int J Mol Sci. 2017;18(12). pii: E2679.
4. Janicak PG. Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects. UpToDate. 2019. Retrieved from https://www-uptodate-com.online.uchc.edu/contents/bipolar-disorder- in-adults-and-lithium-pharmacology-administration-and-management- of-side- effects?search=Bipolar%20disorder%20in%20adults%20and%20lithiu m:%20Pharmacology,%20administration,%20and%20side%20effects &source=search_result&selectedTitle=1~150&usage_type=default&dis play_rank=1.
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8. Konstantinos N. Fountoulakis KN, Grunze H,Vieta E, et al. The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 3: The Clinical Guidelines. Int J Neuropsychopharmacol. 2017; 20(2): 180– 195.
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14. Sajatovic M, Chen P. Geriatric bipolar disorder: Maintenance treatment. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/geriatric-bipolar-disorder- maintenance- treatment?search=Bipolar%20disorder%20geriatric&source=search_re sult&selectedTitle=2~17&usage_type=default&display_rank=
15. Dols A, Kessing LV, Strejilevich SA, et al. Do current national and international guidelines have specific recommendations for older adults with bipolar disorder? A brief report. Int J Geriatr Psychiatry. 2016; 31(12): 1295-1300.
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