72: Lithium

The Swedish chemistry student Arfwedson discovered lithium in 1817.^8,131 Lithium derives its name from the Greek word for stone, lithos, from which it was first isolated. The therapeutic use of lithium has a long history beginning in the mid 19th century, when lithium salts were used to treat individuals with gout and were noted to improve symptoms of mania and depression.¹¹⁶ The soft drink 7-Up was originally formulated with lithium as its “active ingredient.”⁸ During the 1930s and 1940s, lithium was used as a salt substitute (“Westsal”) for patients with congestive heart failure but was discontinued after several cases of acute lithium poisoning were described.⁸⁷ The beneficial effects of lithium on bipolar disorder were “rediscovered” by Cade in 1949, when he noticed the calming effect of lithium carbonate on guinea pigs.⁵² The same year, however, the US Food and Drug Administration (FDA) banned the use of lithium in response to reported poisonings.¹³⁹ The FDA lifted the ban in 1970 and approved the use of lithium for the treatment of mania.

Currently, lithium is the most efficient long-term therapy for treatment and prevention of bipolar affective disorders,^51,81 with a demonstrated antisuicidal effect and an ability to improve the manic and depressive symptoms of the illness, as well as to augment the therapeutic efficacy of other therapies that have failed to achieve symptom remission.^{16,45,53,78,81,108,111,131} Investigations on the use of lithium for compulsive gambling have also demonstrated beneficial results,⁹³ and it is under investigation for use in neurodegenerative disorders such as Alzheimer disease, stroke, amyotrophic lateral sclerosis, Huntington disease, multiple sclerosis, and traumatic brain injury.^{23,47,142,199} In most industrialized nations, approximately one in 1000 persons is prescribed one or more of the various lithium formulations.^84,121,122

Lithium, the simplest xenobiotic in the modern pharmacopoeia, has a complex mechanism of action that has not been completely elucidated even after more than 50 years of clinical use. Psychotropics modifying monoamine neurotransmission form the basis of modern psychopharmacology. The current paradigm of neuropsychiatric therapeutics implies that because xenobiotics that affect the neurotransmission of dopamine are most efficacious, this receptor-drug exemplar defines the disease. Multiple lines of investigation have shown that beyond simple monoamine balance, the interaction between multiple signaling cascades, neurotrophic and neuroprotective systems is not only involved in the pathogenesis of mood disorders, but also the cellular and molecular means of the action of lithium.¹⁵⁵ Additionally, the understanding that a particular receptor only undergoes a single agonist-receptor activation has been replaced by the growing comprehension that agonist binding causes activation of multiple pathways of downstream signaling, with a myriad of results.²⁵ Lithium illustrates this new paradigm through its multiple direct and indirect effects.

Clinically, the therapeutic effects of lithium and similar mood-stabilizing pharmaceuticals become evident only after chronic administration, so their mechanism of action is unlikely solely the result of acute biochemical interactions. One of the central processes involved in the therapeutic effects of lithium, and potentially the pathogenesis of mood disorders, is its interaction with the β form of glycogen synthase kinase 3 (GSK-3). GSK-3β is a serine/threonine kinase originally described with the regulation of glycogen synthesis in response to insulin.²⁵ Subsequently it has been shown to influence multiple systems, including gene transcription, neuronal function and neurogenesis, synaptic plasticity, and the circadian cycle, as well as cellular structure, apoptosis, and cell death. In fact, GSK-3β phosphorylates more than 100 substrates, with a suggestion of many more.¹⁰¹ Each of these systems are implicated in the pathophysiology of mood disorders.^25,155

Postmortem tissue from the ventral prefrontal cortex of patients with major depressive disorder showed elevated GSK-3β activity as well as decreased activity in the GSK-3β modifying enzyme, Akt (also known as protein kinase B).^102,103 GSK-3β is inadequately inhibited in association with mood disorders and is inhibited in humans treated with lithium.¹⁰¹ Overactivity of this enzyme is associated with neuronal degeneration and sensitivity to apoptotic stimulation. Dysregulation of GSK-3β is implicated in tumor growth and the neurofibrillary tangles of Alzheimer disease.^56,191 It also is a key regulator of neuronal cell fate, with a proapoptotic effect in many settings.^{5,22,24,26,101,118,131,161} It is involved in regulating the activity of β-catenin, Jun, and cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), transcription factors important in embryonic patterning, cell proliferation, neuronal modeling and plasticity, neuronal signal transduction, memory consolidation, and cytoskeletal remodeling. Its other targets include transcription factors such as c-Jun, nuclear factor activated T-cells, proteins bound to microtubules (Tau, microtubule-associated protein 1B, kinesin light chain), cell cycle mediators (cyclin D), and metabolic regulators (glycogen synthase, pyruvate dehydrogenase).^153,155 Hypoxia contributes to increased GSK-3β activity, which may be counteracted or inhibited with mood-stabilizing drugs. Vascular depression, or depression after stroke, is an organic model of major depression.^94,133 The finding that this depressive state responds similarly to intervention with mood stabilizers lends further support to the GSK-3β hypothesis.^{70,79,90,150,190}

Many older generation antipsychotics are now known to affect GSK-3β signaling in mice.¹¹⁹ GSK-3β activity is regulated not only by first- and second-generation antipsychotics but also through 5-HT neurotransmission and activation of 5-HT_2A receptors as well as through monoamine-affecting antidepressants which modify these neurotransmitters.^{22, 23, 24, 25, 26, 27, and 28,117} Atypical antipsychotics and antagonists of D₂ dopamine receptors, as well as 5-HT_2A serotonin receptors, may exert some of their utility through inhibition of GSK-3β activity.^22,25

The link between neuropsychiatric illness and these centrally placed mediators of signaling comes from exploration of dopamine neurotransmission (Fig. 72–1). Scaffolding proteins, the β-arrestins, are traditionally associated with the termination of G protein–coupled receptor (GPCR) signaling and desensitization. After a receptor is stimulated, GPCRs are phosphorylated, leading to the β-arrestin recruitment that uncouples the receptor from the G protein and leads to GPCR internalization. β-Arrestins also act as scaffolds for the formation of a protein complex that allows for GPCRs to signal independently from G proteins.^22,24,26,71 Dopaminergic neurotransmission through GPCRs is mediated through a complex that involves Akt, β-arrestin 2 (βArr2), and protein phosphatase 2A (PP2A). Akt is a serine/threonine kinase that is additionally regulated through phosphatidylinositol-mediated signaling.²⁵ Akt activity results from an equilibrium between phosphorylation (activation) and dephosphorylation (inactivation).²⁷ Regulation of GSK-3β activity is achieved through phosphorylation of its N-terminal serine residue, leading to inhibition.¹¹⁸ The Akt-βArr2-PP2A complex, when activated, dephosphorylates (deactivates) Akt, which leads to the activation of GSK-3β through loss of inhibition (loss of phosphorylation.)^25,27,70

Lithium is a direct inhibitor of GSK-3β that can also inhibit its activity indirectly through a mechanism involving Akt activation.^26,27,48,101 Lithium activates Akt by disrupting assembly of the Akt-βArr2-PP2A complex through displacement of the magnesium cofactor required for assembly.^{25, 26, and 27} Through disruption of this complex, which normally promotes Akt inactivation, lithium promotes Akt activation, leading to increased phosphorylation (inactivation) of GSK-3β. This is demonstrated in β-arrestin knockout mice, which, unable to create this complex, are resistant to the behavioral effects of lithium.^25,27,70,101

Identification of the Akt-βArr2-PP2A signaling complex as a target of lithium lends credence to the use of lithium as an adjunct to enhance the action of atypical antipsychotics and antidepressants in poorly responsive subjects by acting through Akt–GSK-3β signaling.^25,27,101

Inhibition of GSK-3β by lithium is thought to be neuroprotective by modifying the downstream targets and effectors of GSK-3β activity.^{5,23,27,70,91,110,150,162} Lithium is implicated in the neuroprotective modulation of the bcl-2 gene, which is known for its role in preventing apoptosis and in downregulation of the proapoptotic protein p53. Lithium increases bcl-2 concentrations in cultured nervous tissue of both rats and humans.^49,129 Additional support comes from patients undergoing long-term therapy with either lithium or valproic acid (VPA) who show prefrontal cortex volumes significantly greater than in patients not treated with either agent, suggesting a protective effect in humans.^47,162 Further evidence points toward a neuroprotective and neurotrophic effect of lithium with evidence to support benefit in such diverse neurodegenerative conditions as Parkinson disease (in a mice model of Parkinson disease using N-methyl-4-pheynyl-1,2,3,6-tetrahydropyridine {MPTP}),¹⁹⁸ Huntington disease,¹⁶⁸ amyotrophic lateral sclerosis (ALS),⁶⁸ stroke and multiple sclerosis,^23,47 traumatic brain injury,¹⁹⁹ and Alzheimer disease.^{5,19,22,25,42,131,136}

It would be naive to assume that lithium has a single mechanism of action, and it is plausible that other mechanisms, such as the inhibition of inositol monophosphatases, also contribute to its pleiotropic effects on behavior. Compelling evidence has bridged a link between the current molecular targets and downstream regulators of the effects of lithium with the classic proposed mechanism of action, the inositol-depletion hypothesis.

Among the first proposed mechanisms of action of lithium was the inositol-depletion hypothesis.⁹⁰ Inositol is a six-carbon sugar that forms the backbone of a number of cellular signaling mechanisms. Lithium treatment results in a decreased myoinositol (the most biologically active stereoisomer of inositol) concentration in the cerebral cortex.^34,90,131 Abnormalities in regional brain myoinositol concentrations are thought to occur in bipolar patients. This theory is partially supported by experimental magnetic resonance spectroscopy data.^173,197 Myoinositol is phosphorylated to form phosphatidyl inositol (PIP), which is further phosphorylated and combined with diacylglycerol (DAG) to form phosphatidyl 4,5-bisphosphate (PIP₂). Upon stimulation of a cell, G protein–coupled receptors activate phospholipase C (PLC), which hydrolyzes PIP₂ to release the secondary messengers DAG and inositol 1,4,5-trisphosphate (IP₃).^34,92 Each of these secondary messengers in turn initiates a cascade of events, including activation of protein kinase C, which is important for calcium homeostasis and neurotransmitter release,^131,173 as well as independent mobilization and regulation of intracellular calcium.^149,162,173 Many extracellular signals, including some serotonin receptor subtypes, neurotrophin signaling pathways, receptor tyrosine kinase pathways, and G protein–mediated signaling, activate PLC to exert their actions.^80,154,155

Serial dephosphorylation of IP₃ leads to regeneration of myoinositol and recycling of the inositol pool. Two enzymes involved in this pathway are inhibited by lithium. The first enzyme, inositol 1,4-bisphosphate 1-phosphatase (IPPase), dephosphorylates the bisphosphate to inositol monophosphate (IMP). The second enzyme, inositol 1-monophosphatase (IMPase), dephosphorylates IMP to myoinositol⁴ (Fig. 72–2).

The inhibition of IMPase is interesting and important. Lithium inhibits IMPase by “uncompetitively” binding to the enzyme–substrate complex and preventing the release of phosphate. It performs this function by ­displacing a magnesium ion from the active site after hydrolysis. This is the same mechanism by which lithium directly inhibits GSK-3β.⁴⁸ Uncompetitive refers to the inhibitor binding to the enzyme-substrate complex; the higher the concentration of the substrate, the more the enzyme is inhibited.^70,86,127 Uncompetitive inhibitors only bind to the enzyme-substrate complex, inhibiting the reaction at that point. Uncompetitive inhibitor kinetics are related proportionally to the concentration of the enzyme–substrate complex and cannot be overcome by increasing the concentration of the substrate, unlike a competitive inhibitor.¹⁵⁰ This supports a theory about the pathophysiology of bipolar disorder involving an excess of myoinositol and is one reason why the mood-stabilizing effects of lithium are thought to occur only in bipolar patients.⁹⁰ The nature of the action of lithium serves as a regulator to preferentially block pathologic signaling caused by excessive myoinositol while leaving the normal signaling intact. As described, IMPase is an important step in the cellular recycling of the inositol pool and is inhibited by lithium.

Myoinositol is also generated de novo from glucose-6-phosphate by inositol synthase, which forms IMP. The inhibition of IMPase by lithium subsequently leads to myoinositol depletion by preventing the conversion of the newly synthesized IMP to myoinositol. Interestingly, VPA also inhibits inositol synthase, illustrating a potential mechanism for the synergy of these complementary mood stabilizers.^60,115 A third mechanism of intracellular diminution of inositol by lithium (as well as VPA and carbamazepine) is the effect of lithium on reducing activity and transcription of the sodium myoinositol transporter, preventing the uptake of exogenous myoinositol by the cell. This mechanism of inhibition may be overcome by increased extracellular concentration of myoinositol.⁹⁰

The result of these effects is depletion of the inositol pool available to the cell, causing a series of events at different points in the signal transduction cascade that leads to differential gene transcription and expression. This sequence ultimately is responsible for some of the observed clinical effects of lithium on the central nervous system (CNS).¹⁷⁰ Experimental data using dextroamphetamine as a model for clinical mania demonstrate increased regional inositol signaling in the human brain that is attenuated by pretreatment with lithium, lending support to the hypothesis.³¹

The inositol depletion hypothesis, while an original attempt to explain in molecular terms the therapeutic effects of lithium, does not fully elucidate nor replicate the clinical disease or response to therapy. In vivo studies with more drastic inositol depletion than that which occurs from lithium therapy fail to replicate predicted behavioral patterns. Studies in knockout mice lacking various isoforms of inositol monophosphatase fail to replicate the antidepressant or antimanic effects of lithium. The model remains an attractive one, and the flaws may represent species variation with validity more in humans with bipolar disorder than the mouse model illustrates.^23,131,169 However, there may be a synergy with other proposed mechanisms of lithium’s effect. Using a yeast model, it was shown that GSK-3β is required for de novo inositol synthesis, and that loss of GSK-3β activity leads to inositol depletion. This finding links the two targets of not only lithium, but other mood ­stabilizing pharmaceuticals.¹²

In summary, although the precise mechanism of action is unknown, some common features of investigation have emerged. The potential targets, widely found and disparate in function, all seem to be inhibited by lithium in an uncompetitive fashion, most commonly through displacement of a divalent cation, usually Mg²⁺. The systems affected by this inhibition vary widely. Downstream targets seem to modulate secondary cell messengers and intracellular signal transduction, transcription factors and gene expression, and neuronal plasticity and cellular differentiation. Further study is needed to elucidate the complex interaction of these pathways with the action of lithium to form an integrated hypothesis.

The volume of distribution of lithium is between 0.6 and 0.9 L/kg. It has no discernible protein binding and distributes freely in total body water, with the exception of the cerebrospinal fluid (CSF), from which it is actively extruded.^62,81,163 The extrusion is believed to occur through an active transport process involving sodium/lithium exchange at the arachnoid processes.⁵⁹ The immediate-release preparations of lithium are rapidly absorbed from the gastrointestinal (GI) tract. Peak serum concentrations are achieved within 1 to 2 hours. Sustained-release products demonstrate variable absorption, with a delay to peak of 4 to 5 hours.^81,182 In overdose, a longer delay to reach peak concentrations or multiple peaks may occur.^58,182 Chronic therapy prolongs the elimination of lithium, as does advancing age.⁸¹ Although lithium is rapidly absorbed, tissue distribution is a complex phenomenon, with a significant delay in reaching a steady state. Lithium exhibits preferential uptake into the kidney, thyroid, bone, and other organs and tissues such as the liver and muscle. Lithium distribution into the brain can take up to 24 hours to reach equilibrium. Lithium is concentrated in red blood cells (RBCs) by both passive diffusion and active transport. The RBC concentration may correlate closely with the brain concentration, although this does not appear to be clinically useful.⁴³ The pharmacokinetic profile of lithium is described as an open, two-compartment model.^62,81

Each 300 mg lithium carbonate tablet contains 8.12 mEq of ­lithium.⁸¹ Ingestion of a single 300 mg tablet is expected to acutely increase the serum lithium concentration by approximately 0.1 to 0.3 mEq/L (assuming a volume of distribution of approximately 0.6–0.9 L/kg and a patient weight of 50–100 kg).

Lithium undergoes no metabolic transformation and is eliminated almost entirely (95%) by the kidneys, with a small amount eliminated in the feces.⁶² Lithium is also found in sweat, saliva, and breast milk.^57,185 In an adult with normal kidney function, lithium clearance varies from 10 to 40 mL/min.^81,181 At steady-state equilibrium, total body clearance equals renal clearance.

Lithium is handled by the kidneys much in the same way as sodium. Lithium is freely filtered, and more than 80% is reabsorbed by the proximal tubule. Evidence also indicates a small amount of reabsorption by the loop of Henle and distal tubule.^{36,69,112,181} Lithium excretion is therefore dependent on factors that affect the glomerular filtration rate (GFR) or decrease sodium concentration. Any condition that makes the kidney sodium avid such as volume depletion or salt restriction increases lithium reabsorption in the proximal tubule.^82,181 Thus, risk factors for development of lithium toxicity include advanced age with its decrease in GFR; use of thiazide diuretics, nonsteroidal antiinflammatory drugs (NSAIDs), or angiotensin-converting enzyme (ACE) inhibitors; decreased sodium intake; and low-output heart failure.^101,113

The therapeutic index of lithium is narrow. The generally accepted steady-state therapeutic range of serum lithium concentrations is 0.6 to 1.0 mmol/L, although much disagreement exists about whether this serum concentration truly reflects therapeutic efficacy.^81,121 Both in therapeutic and overdose situations, clinical signs and symptoms seem to be a more valuable indicator of brain lithium concentrations.^17,140

Similar to other xenobiotics having prolonged redistributive phases and tissue burdens, lithium exposure can be divided into three main categories of toxicity: acute, acute-on-chronic, and chronic. In acute lithium toxicity, the patient has no body burden of lithium present at the time of ingestion. The toxicity that develops depends on the rates of absorption, distribution, and elimination. In chronic toxicity, the patient has a stable body burden of lithium as serum concentration is maintained in the therapeutic range, and then some factor disturbs this balance, either by enhancing absorption, or more commonly, decreasing elimination. For chronic users of lithium, small perturbations in the equilibrium between intake and elimination may lead to toxicity. In acute-on-chronic toxicity, the patient ingests an increased amount of lithium (intentionally or unintentionally) in the setting of a stable body burden. With tissue saturation, any additional lithium leads to signs and symptoms of toxicity.

Acute Toxicity

Acute ingestions of lithium-containing preparations produce clinical findings similar to that of ingestions of other metal salts, with predominant early GI symptoms. Nausea, vomiting, and diarrhea are prevalent. Significant volume losses may result from these symptoms. Patients may complain of lightheadedness and dizziness, and they may be orthostatic. Neurologic manifestations are a late finding in acute toxicity as the lithium redistributes slowly into the CNS.

Chronic Toxicity

Lithium is primarily a neurotoxin. The earliest case reports of lithium toxicity described predominantly neurologic symptoms.^175,187 Most importantly, neurotoxicity does not correlate with serum concentrations. The initial clinical condition of the patient and the duration of exposure to an elevated concentration seem to be more closely predictive of outcome than the initial serum lithium concentration.^3,9,88,167

The tremor of lithium is likely one of the most commonly encountered drug-induced tremors in clinical practice, with approximately 27% of patients developing it.¹⁴¹ The tremor can diminish over time but may increase with toxicity. Other findings of chronic toxicity include fasciculations, hyperreflexia, choreoathetoid movements, clonus, dysarthria, nystagmus, and ataxia.¹⁸² Mental status is often altered and may progress from confusion to stupor, coma, and seizures.^121,134 Electroencephalographic changes are most frequently reported as “slowing.”¹⁷¹ The progression of these symptoms follows no order, and any patient undergoing chronic therapy may have one or any combination of these features.

The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) is a descriptive syndrome of the irreversible neurologic and neuropsychiatric sequelae of lithium toxicity.^3,97,151 SILENT is defined as neurologic dysfunction that is caused by lithium in the absence of prior neurologic illness and persists for at least 2 months after cessation of the drug. Case reports support these findings and this definition. However, as is true in most case reports, confounders make wide applicability of the findings difficult. Because of the polypharmacy prevalent in psychiatry, long-term neurologic sequelae attributed to lithium are frequently described in patients using lithium in combination with other xenobiotics, such as haloperidol, chlorpromazine, carbamazepine, phenytoin, aspirin, VPA, amitriptyline, β-adrenergic antagonists, calcium channel blockers, ACE inhibitors, diuretics, and NSAIDs.^{3,65,89,128,138} However, there exist reports of patients using lithium without coingestants and no comorbid illness who sustained lasting dysfunction as a result of lithium toxicity.^{9,105,145,167} Cerebellar findings seem to predominate in patients with SILENT.^{1,2, and 3,130,151} One of the predictors of persistent neurologic dysfunction may be the concomitant finding of hyperpyrexia, an ominous finding in patients with lithium toxicity.^83,130 The mechanism of the persistent dysfunction is unclear, but demyelination and cellular loss are proposed.^3,130,165

Acute-on-Chronic Toxicity

Patients undergoing chronic therapy who acutely ingest an additional amount of lithium (either intentionally or unintentionally) are at risk for signs and symptoms of both acute and chronic toxicity. These patients may display prominent GI and neurologic symptoms and may be difficult to diagnose and manage. Serum lithium concentrations in cases of acute or chronic toxicity may be difficult to interpret, and therapy should be guided by the clinical status of the patient.

Other Systemic Manifestations of Chronic Lithium Therapy

The most common adverse effect of chronic lithium therapy is nephrogenic diabetes insipidus which can develop within weeks of the initiation of therapy and affects up to 40% of patients (Chap. 19).^85,144

Lithium inhibits the transport of sodium through the amiloride-sensitive epithelial Na⁺ channel (ENaC), which is also the main route of entry for lithium. Lithium has a twofold higher affinity than sodium for entry through this channel, without a corresponding means of extrusion and thus becomes concentrated intracellularly.^106,181,182

Lithium is believed to inhibit magnesium-dependent G proteins that activate vasopressin-sensitive adenylate cyclase, leading to decreased generation of cAMP in the cell membranes of distal tubular cells.^{35,50,180,186}

Decreased cAMP leads to reduced expression and translocation of the vasopressin-regulated water channel aquaporin-2 (AQP2), making the distal tubules resistant to the action of vasopressin, and thus unable to make a concentrated urine.^6,35,120,188 Additionally, there is potential mechanistic overlap with GSK-3β. GSK-3β exhibits tonic inhibition of cyclooxygenase-2 (COX-2). With GSK-3β inhibition by lithium, this inhibition is removed and increased COX-2 activity leads to increased prostaglandin expression in the renal medulla. Increased prostaglandin expression is important in nephrogenic diabetes insipidus through regulation of glomerular blood flow,^156,157 as well as increasing the degradation of AQP2, further decreasing the ability to form a concentrated urine.^{106,107,156,157}

Chronic lithium therapy is also associated with chronic tubulointerstitial nephropathy, as manifested by the development of renal insufficiency with little or no proteinuria and biopsy findings of tubular cysts. This association was demonstrated in a biopsy-based study of 24 chronically treated patients, although the overall prevalence of this condition is low.⁸⁵

Lithium is associated with a number of endocrine disorders. The most prevalent endocrine manifestation of chronic lithium therapy is hypothyroidism.³⁹ The etiology is multifactorial. Lithium is selectively concentrated in the thyroid gland and competes for iodide transport, synthesis of triiodothyronine (T₃), responsiveness of the gland to thyroid-stimulating hormone (TSH), release of T₃ and tetraiodothyronine (T₄), and peripheral conversion of T₄ to T₃.^39,73 Additionally, lithium decreases responsiveness of peripheral tissues to T₃ and increases antithyroglobulin antibodies if already present, it does not induce development de novo (Fig. 56–1).^13,110,143 Although hypothyroidism is most common, hyperthyroidism and frank thyrotoxicosis are also reported.^33,41,110 However, hyperthyroidism, by altering proximal tubule function, leads to decreased lithium excretion.²⁰ Thus, hyperthyroidism may lead to chronic lithium toxicity through impaired elimination, and the elevated lithium concentrations may mask the manifestations of hyperthyroidism.^18,143

The combination of hyperparathyroidism and hypercalcemia is frequently reported with chronic lithium therapy, most commonly in older women. The mechanism is thought to be modification of calcium feedback on parathyroid hormone release through alteration of a calcium-sensing receptor that prevents suppression of parathyroid hormone release in response to elevated calcium,¹⁵⁹ although stimulation of parathyroid hormone release, parathyroid gland hyperplasia, and adenomas are alternative suggested mechanisms.^{11,114,132,178}

Lithium is associated with a number of electrocardiographic (ECG) abnormalities, although the evidence for significant toxicity is ­lacking. Most reports are uncontrolled case reports without corroborating experimental data or biologic plausibility. The most commonly reported manifestation has been T-wave flattening or inversion, primarily in the precordial leads,¹⁴⁷ although prolongation of the QT interval is also noted.^109,184,192 One study associated elevated serum lithium concentrations with QT prolongation above 440 msec, although the number of patients studied was small.⁹⁶ Associations have been made between lithium and sinoatrial dysfunction, with resultant bradycardia.^{10,77,146,172,179} However, many of these cases had either electrolyte disturbances or multiple other cardioactive xenobiotics involved that would be more likely causative.^{44,172,179,189} Numerous case reports have linked lithium with an ECG pattern that is consistent with a myocardial infarction, without evidence of biochemical markers of injury.^104,152 Lithium blocks cardiac sodium channels in a transfected Chinese hamster ovary cell. This is the putative link between lithium therapy and the unmasking of a Brugada pattern as well as cardiomyopathy.^{7,46,55,193,196} For the most part, lithium has few consequential effects on cardiac function, even in overdose, and malignant dysrhythmias or significant dysfunction is very uncommon.

Developmentally, in utero exposure to lithium increases the incidence of congenital heart defects, specifically Ebstein anomaly.^57,150,195 Additionally, many effects similar to those that occur in patients undergoing chronic therapy are found in infants exposed in utero, including thyroid disease and neurotoxicity.⁷⁵

Lithium causes a leukocytosis and an increase in neutrophils. It has been proposed as an adjunct to chemotherapy-induced neutropenia, other marrow suppressive therapies, and acquired immunodeficiency syndrome (AIDS).⁵⁴ Although lithium increases the total neutrophil count, no improved clinical outcomes are documented, and its use has been superseded by recombinant colony-stimulating factors.^66,150,160

Because of the prevalence of lithium use, therapeutic drug monitoring is readily available in most settings, and concentrations should be readily obtainable.¹⁹⁴ A lithium concentration should be requested upon patient presentation and serial measurements requested or considered in most instances, especially after ingestion of sustained-release preparations. Emphasis should be placed on the lithium concentration as a marker of exposure and response to therapy but not necessarily as a determinant of toxicity or treatment. The history, clinical signs, and symptoms rather than the absolute lithium concentration should guide therapy. The sample must be sent in an appropriate lithium-free tube, because use of lithiated-heparin tubes may lead to clinically false-positive results.¹¹³ Serum electrolyte concentrations and kidney function should be monitored because kidney function is important in determining the need for more aggressive therapy, including enhanced elimination techniques such as hemodialysis. If the patient is hypernatremic, nephrogenic diabetes insipidus should be suspected, and determinations of serum and urine osmolarity and electrolytes help confirm the diagnosis (Chap. 19). If thyroid disease is suspected, thyroid function tests should be obtained. If a deliberate ingestion has occurred, a serum acetaminophen concentration should be obtained. An ECG is also indicated. The complete blood count may indicate a leukocytosis, as a stress response or due to the hematologic effects of lithium.

The initial management and stabilization should begin with assessment and, if necessary, support of airway, breathing, and circulation. Lithium rarely, if ever, affects the patient’s airway or breathing, although coingestants may. Emesis, which occurs with significant frequency after acute exposure, may lead to aspiration and respiratory compromise. After the patient is stable, the characteristics of the exposure should be determined while the physical examination and laboratory assessment commence. The formulation and nature of the product should be ascertained and most importantly, identified as immediate-release or sustained-release. Also, whether or not lithium is part of the patient’s medication regimen may help determine whether the ingestion is acute, acute-on-chronic, or chronic.

Gastrointestinal Decontamination

For patients who present after an acute overdose or an acute-on-chronic overdose, a risk benefit analysis of GI decontamination must be undertaken. Two factors should be considered. With an acute overdose and predominance of early GI symptoms, including emesis, self-decontamination may already have started. Second, immediate-release preparations are often rapidly absorbed and may not lend themselves to GI evacuation.

Few GI decontamination options are available. Lithium is a monovalent cation that does not bind readily to activated charcoal.¹²³ Because of the danger of a depressed level of consciousness, potential loss of protective airway reflexes, and generally prominent emesis, no beneficial effect from activated charcoal is expected unless indicated for treatment of a potential coingestant. Induced emesis is no longer recommended. Orogastric lavage has essentially no role in the acute management of a patient with a lithium overdose unless indicated for a coingestant. Whereas immediate-release preparations of lithium are rapidly absorbed and typically produce emesis, sustained-release formulations of lithium (ie, controlled-release tablets) compounded in a slowly dissolving film-coated formulation often make the tablet too large to fit through even the largest lavage tube.

Sodium polystyrene sulfonate (SPS) is a cationic exchange resin often used for the treatment of severe hyperkalemia. It binds potassium in exchange for sodium, allowing elimination of excess potassium in the feces. Because of the similarity between potassium and lithium, use of SPS has been proposed for decontamination of patients being treated for lithium toxicity. A number of models have examined the effectiveness of this technique.^{123, 124, and 125} Use of SPS has many theoretical benefits, including demonstrated effectiveness of lithium binding compared with activated charcoal and the ability of orally administered SPS to reduce serum concentrations of intravenously administered lithium in mice.¹²³ Unfortunately, the finding that doses used to increase lithium elimination also lead to significant hypokalemia in human subjects limits the application of this technique.¹⁶⁴ In a murine model, potassium supplementation with SPS was found to mitigate this process but only at the expense of elevating lithium concentrations.¹²⁵ Two reports in the literature demonstrate increased ­lithium elimination with SPS, one in a healthy volunteer and another in a patient with an acute overdose. However, the serum potassium concentration was not reported in either case.⁷⁴ In a retrospective cohort review of 12 chronically poisoned patients, it was suggested that SPS reduced the elimination half-life of lithium by 50%. However, many of the patients had altered kidney function that was corrected at the same time as the intervention (which was not standardized), and no clinical outcomes were reported.⁷⁶ At present, use of SPS in the management of the lithium-poisoned patient cannot be routinely recommended, until further clinical trials can be performed.

Whole-bowel irrigation (WBI) is the only GI decontamination that has some demonstrated efficacy in eliminating lithium from volunteer human subjects. In one of the few clinical trials of WBI, the serum lithium concentrations of 10 normal volunteers who had ingested sustained-release lithium carbonate were plotted against time over a 72-hour period. In the second phase of the trial, when the volunteers received 2 L/h of polyethylene glycol solution one hour after the ingestion, there was a significant reduction (67%) in the serum concentration, even as early as one hour after the therapeutic intervention.¹⁷⁴ WBI is recommended for patients manifesting significant toxicity (ie, neurologic dysfunction) and who have ingested sustained-release preparations and have no contraindications (eg, protected airway, no obstruction or ileus) (Antidotes in Depth: A2).

Fluid and Electrolytes

The critical initial management of the lithium-poisoned patient should focus on restoration of intravascular volume, both in acute poisonings with GI losses and in chronic poisonings with toxic effects that are often the result of disturbances of kidney function and lithium elimination. Many patients with lithium toxicity have volume-responsive decreases in kidney function,¹⁵⁸ which can be managed by infusion of 0.9% sodium chloride solution at 1.5 to 2 times the maintenance rate. This therapy increases renal perfusion, increases the GFR, and lithium elimination. Urine output must be closely monitored and any electrolyte abnormalities corrected. Caution must be used in patients with prerenal acute kidney injury (AKI), chronic kidney disease (CKD), and congestive heart failure. Monitoring for the development of hypernatremia in patients suspected of having nephrogenic diabetes insipidus is critical.^120,181,182

Lithium-induced nephrogenic diabetes insipidus may be reversed by discontinuation of the drug and repletion of electrolytes and water. However, nonreversible effects are reported.^106,181 Clinical application of amiloride to mitigate lithium-induced polyuria is described, although the potential for volume contraction and stimulation of lithium reabsorption limits recommendation of this drug as a routine adjunct to acute care.^{30,64,106,158}

Any attempt to enhance elimination of lithium by forced diuresis using loop diuretics (furosemide), osmotic agents (mannitol), carbonic anhydrase inhibitors (acetazolamide), or phosphodiesterase inhibitors (aminophylline) should be avoided. An initial small increase in elimination may be achieved, but typically salt and water depletion subsequently develop followed by increased lithium retention. Sodium bicarbonate for urinary alkalinization should also be avoided because it does not significantly increase elimination over volume expansion with sodium chloride and may lead to hypokalemia, alkalemia, and fluid overload.

Extracorporeal Drug Removal

Debate surrounds the efficacy and practicality of using enhanced elimination techniques in cases of lithium poisoning. Lithium does have pharmacokinetic properties that make it amenable to extracorporeal removal,^{21,63,95,100,112} and with these characteristics, it would seem to be an ideal candidate for hemodialysis. In fact, hemodialysis is often recommended for treatment of acute, acute-on-chronic, and chronic lithium toxicity.^{14,63,98,148,182,199} However, some characteristics of lithium make extracorporeal elimination difficult. Lithium is predominantly localized intracellularly and diffuses slowly across cell membranes.⁶³ When traditional intermittent hemodialysis is used for chronic exposures, clearance of the blood compartment is often followed by a rebound phenomenon of redistribution from tissue stores, leading to recurrent increased serum concentrations. The clinical significance of this rebound is uncertain, but without additional elimination this can redistribute back into target tissues.³⁸ There have only been three cases reported of clinical deterioration after rebound from an extracorporeal elimination method, likely as a result of failed decontamination in an extended release ingestion.^37,40,71 An additional complicating factor is that the brain, the “target organ” of toxicity, is not amenable to a rapid artificial elimination process. Attempts have been made to correlate the serum concentration with the lithium concentration in the CSF and brain. But in the few studies where CSF concentrations were obtained, although serum and CSF lithium concentrations seemed to correlate, brain concentrations and toxicity did not.^92,99 Magnetic resonance spectroscopy studies of bipolar patients with steady-state lithium concentrations demonstrated a significant variability between brain and serum concentrations, especially within the therapeutic range.⁶⁷ In addition, because of the toxicokinetic profile of lithium, serum concentrations do not correlate well with toxicity.^81,99,182

Some consensus is emerging regarding when to perform an extracorporeal elimination technique (extracorporeal treatment {ECTR}). The Extracorporeal Treatments in Poisoning Workgroup (ExTRIP) has performed an extensive analysis of the data available regarding lithium. Their most recent consensus provides the following analysis: “ECTR should be performed in severe Li poisoning,” graded (1, D). The “1” indicates that more than 85% of their members strongly recommend, and the D that there is a very low level of evidence (no observational studies or randomized controlled trials).⁶¹ Hemodialysis or an alternative extracorporeal technique is clearly indicated for three groups of patients. The first group consists of patients who are manifesting severe signs and symptoms of neurotoxicity, such as alterations in mental status or seizures. The second group consists of patients who have AKI or CKD and show signs or symptoms of lithium toxicity. Such patients are unable to eliminate their lithium burden on their own and should undergo hemodialysis. The third group consists of patients who show little or no sign of toxicity but who cannot tolerate sodium repletion therapy; these patients who should be considered for early hemodialysis include those with congestive heart failure or such “redistributive diseases” as liver failure, pancreatitis, or sepsis.

For a patient who belongs to this last group, the next step is to determine the probability that the patient will develop toxicity if elimination is not enhanced. The criteria for hemodialysis originated from a case series of 23 patients and a review of 100 other patients published in 1978, which was before the introduction of sustained-release products.⁸⁸ These recommendations have never been prospectively evaluated (or subsequently reevaluated).^15,63,72 The ExTRIP group proposes the consensus recommendations based on the classification of the overdose and categories based on serum concentrations⁶¹ (Table 72–1).

Interestingly, the above serum concentrations and recommendations are irrespective of symptomatology. Additional consensus recommends ECTR for acute neurologic dysfunction such as confusion, decreased level of consciousness, and seizures. It is also suggested to use ECTR for hyperthermia. Whether hemodialysis diminishes or enhances the risk of permanent neurologic sequelae is a subject of debate.^176,177 Although no controlled studies have analyzed this important management question, the preponderance of evidence suggests a reduced risk.^{3,9,15,63,95,99,137,148,151,166,182}

Continuous venovenous hemodialysis and continuous venovenous hemodiafiltration are two continuous renal replacement therapies (CRRTs) commonly used in the treatment of patients with AKI or volume overload and for elimination of xenobiotics.^14,29,183 Both techniques are effective in patients who are hemodynamically unstable because blood flow through the filter is pump driven and is not dependent on the arterial blood pressure.^72,135 Other continuous techniques that use patient blood pressure as the basis of flow through the system also may have application here.¹⁸³ Traditional intermittent hemodialysis (IHD) offers clearance rates that vary between 50 and 170 mL/min with blood flows of 250 mL/min or more.^{63,126,148,183} Although CRRT techniques offer lower clearance per hour than does IHD, their overall daily clearances are similar.⁶³ With continued improvements in techniques, use of high volumes, and high dialysate flow rates, clearances are improving, approaching more than half the clearance per hour achieved by IHD in some studies.⁷³² One case of a rebound concentration was reported in a patient treated with continuous arteriovenous hemodiafiltration,³² and one case with use of combined renal replacement therapies, including venovenous techniques, showed no rebound.¹⁴ Unfortunately, CRRT requires prolonged anticoagulation with its inherent risks. Nevertheless, these techniques may be beneficial in patients who are hemodynamically unstable, or they may be used in series with traditional dialysis in other patients to prevent redistribution of lithium and rebound of serum concentrations (Chap. 10).

After an initial run of an ECTR such as IHD, repeat intermittent IHD should be continued until serum lithium concentrations are consistently below 1.0 mEq/L.

Peritoneal dialysis (PD) offers no increased efficacy of clearance of lithium over the natural clearance of normal kidneys.^15,63 Although recommended in the past, given its lack of efficacy coupled with its infrequent use and potential for serious complications such as bowel perforation, PD has no role in the management of lithium-poisoned patients.

• Lithium is a simple ion with extensive current usage and extremely varied and complex clinical and pathophysiologic effects.

• It is available in multiple formulations, both immediate release and sustained release, and has an essential role in clinical psychiatry.

• Because of the complexity of the pharmacokinetic profile of lithium, toxicity may develop in a wide range of conditions and may be precipitated by both intentional overdose and therapeutic misadventure.

• The care of lithium-poisoned patients should be predicated on rapid clinical evaluation of the condition of the patient coupled with identification of the type of poisoning

• Management includes the use of volume resuscitation and WBI and hemodialysis or other extracorporeal techniques, when indicated, to prevent or treat severe neurologic morbidity and to prevent mortality.

References