Lithium (medication)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview[edit | edit source]

Compounds of the element lithium are commonly used as a psychiatric medication. A number of salts of lithium are used as mood-stabilizing drugs, primarily in the treatment of bipolar disorder, where they have a role in the treatment of depression and particularly of mania, both acutely and in the long term. As a mood stabilizer, lithium is probably more effective in preventing mania than depression, and reduces the risk of suicide in bipolar patients.^[1] In depression alone (unipolar disorder), lithium can be used to augment other antidepressants. Lithium carbonate (Li₂CO₃), sold under several trade names, is the most commonly prescribed, while lithium citrate (Li₃C₆H₅O₇) is also used in conventional pharmacological treatments. Lithium sulfate (Li₂SO₄) has been presented as an alternative.

Upon ingestion, lithium becomes widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing norepinephrine (noradrenaline) release and increasing serotonin synthesis.

Medical uses[edit | edit source]

Lithium treatment is used to treat mania in bipolar disorder. Initially, lithium is often used in conjunction with antipsychotic drugs as it can take up to a month for it to have an effect. Lithium is also used as prophylaxis for depression and mania in bipolar disorder. It is sometimes used for other psychiatric disorders, such as cycloid psychosis and major depressive disorder.^[2][3] Lithium possesses a very important antisuicidal effect not shown in other stabilizing medications such as antiseizure drugs.^[4][5] Nonpsychiatric applications are limited; however, its use is well established in the prophylaxis of some headaches related to cluster headaches (trigeminal autonomic cephalgias), particularly hypnic headache. An Italian pilot study in humans conducted in 2005–06 suggested lithium may improve outcomes in the neurodegenerative disease amyotrophic lateral sclerosis (ALS).^[6][7] However, a randomised, double-blind, placebo-controlled trial comparing the safety and efficacy of lithium in combination with riluzole for treatment of ALS failed to demonstrate a benefit as compared to a combination therapy over riluzole alone.^[8]

Lithium is sometimes used as an augmenting agent to increase the benefits of standard drugs used for unipolar depression. Lithium treatment was previously considered to be unsuitable for children; however, more recent studies show its effectiveness for treatment of early-onset bipolar disorder in children as young as eight. The required dosage (15–20 mg per kg of body weight) is slightly less than the toxic level, requiring blood levels of lithium to be monitored closely during treatment. To prescribe the correct dosage, the patient's entire medical history, both physical and psychological, is sometimes taken into consideration. The starting dosage of lithium should be 400–600 mg given at night and increased weekly depending on serum monitoring.^[9]

Those who use lithium should receive regular serum level tests and should monitor thyroid and kidney function for abnormalities, as it interferes with the regulation of sodium and water levels in the body, and can cause dehydration. Dehydration, which is compounded by heat, can result in increasing lithium levels. The dehydration is due to lithium inhibition of the action of antidiuretic hormone, which normally enables the kidney to reabsorb water from urine. This causes an inability to concentrate urine, leading to consequent loss of body water and thirst.^[10]

High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported.^[11]

Lithium salts have a narrow therapeutic/toxic ratio, so should not be prescribed unless facilities for monitoring plasma concentrations are available. Patients should be carefully selected. Doses are adjusted to achieve plasma concentrations of 0.4^[12][13] to 1.2 mmol Li⁺/l (lower end of the range for maintenance therapy and elderly patients, higher end for pediatric patients) on samples taken 12 hours after the preceding dose. Overdosage, usually with plasma concentrations over 1.5 mmol Li⁺/l, may be fatal, and toxic effects include tremor, ataxia, dysarthria, nystagmus, renal impairment, confusion, and convulsions. If these potentially hazardous signs occur, treatment should be stopped, plasma lithium concentrations redetermined, and steps taken to reverse lithium toxicity.

Lithium toxicity is compounded by sodium depletion. Concurrent use of diuretics that inhibit the uptake of sodium by the distal tubule (e.g. thiazides) is hazardous and should be avoided because this can cause increased resorption of lithium in the proximal convoluted tubule, leading to elevated, potentially toxic levels. In mild cases, withdrawal of lithium and administration of generous amounts of sodium and fluid will reverse the toxicity. Plasma concentrations in excess of 2.5 mmol Li⁺/l are usually associated with serious toxicity requiring emergency treatment. When toxic concentrations are reached, there may be a delay of one or two days before maximum toxicity occurs.

In long-term use, therapeutic concentrations of lithium have been thought to cause histological and functional changes in the kidney. The significance of such changes is not clear, but is of sufficient concern to discourage long-term use of lithium unless it is definitely indicated. Doctors may change a bipolar patient's medication from lithium to another mood-stabilizing drug, such as valproate (Depakote), if problems with the kidneys arise. An important potential consequence of long-term lithium use is the development of renal diabetes insipidus (inability to concentrate urine). Patients should therefore be maintained on lithium treatment after three to five years only if, on assessment, benefit persists. Conventional and sustained-release tablets are available. Preparations vary widely in bioavailability, and a change in the formulation used requires the same precautions as initiation of treatment. There are few reasons to prefer any one simple salt of lithium; the carbonate has been the more widely used, but the citrate is also available.

Lithium may be used as a treatment of seborrhoeic dermatitis (lithium gluconate 8% gel). In addition, lithium has been shown to increase production of white blood cells in the bone marrow and might be indicated in patients suffering from leukopenia.^[14]

A limited amount of evidence suggests lithium may contribute to treatment of substance abuse for some dual-disorder patients.^[15][16][17]

In 2009, Japanese researchers at Oita University reported low levels of naturally occurring lithium in drinking water supplies reduced suicide rates.^[18] A previous report had found similar data in the American state of Texas.^[19] In response, psychiatrist Peter Kramer raised the hypothetical possibility of adding lithium to drinking water as a mineral supplement rather than as a therapeutic drug.^[20] (The therapeutic dosage of lithium carbonate (tablets and capsules) or citrate (liquid) "usually ranges from 900 - 1,200 mg/day" and is adjusted according to patient response and blood levels.^[21]) This is analogous to niacin, where a low dose in multivitamin pills is taken as a vitamin supplement to prevent the niacin deficiency disease pellagra, but a high dose is prescribed as a therapeutic drug to raise high-density lipoprotein ("good" cholesterol) levels.

Mechanism of action[edit | edit source]

Unlike other psychoactive drugs, Li⁺ typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations. Li⁺ possibly produces its effects by interacting with the transport of monovalent or divalent cations in neurons. However, because it is a poor substrate at the sodium pump, it cannot maintain a membrane potential and only sustains a small gradient across biological membranes. Li⁺ is similar enough to Na⁺ that under experimental conditions, it can replace Na⁺ for production of a single action potential in neurons.

Recent research suggests three different mechanisms which may or may not act together to deliver the mood-stabilizing effect of this ion.^[22] The excitatory neurotransmitter glutamate could be involved in the effect of lithium as other mood stabilizers, such as valproate and lamotrigine, exert influence over glutamate, suggesting a possible biological explanation for mania. The other mechanisms by which lithium might help to regulate mood include the alteration of gene expression.^[23]

Lithium may also increase the release of serotonin by neurons in the brain.^[24] In vitro studies performed on serotonergic neurons from rat raphe nuclei have shown that when these neurons are treated with lithium, serotonin release is enhanced during a depolarization compared to no lithium treatment and the same depolarization.^[25]

An unrelated mechanism of action has been proposed in which lithium deactivates the GSK3β enzyme.^[26] This enzyme normally phosphorylates the Rev-Erbα transcription factor protein stabilizing it against degradation. Rev-Erbα in turn represses BMAL1, a component of the circadian clock. Hence, lithium by inhibiting GSK3β causes the degradation of Rev-Erbα and increases the expression of BMAL which dampens the circadian clock^[27] Through this mechanism, lithium is able to block the resetting of the "master clock" inside the brain; as a result, the body's natural cycle is disrupted. When the cycle is disrupted, the routine schedules of many functions (metabolism, sleep, body temperature) are disturbed. Lithium may thus restore normal brain function after it is disrupted in some people.

Several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium.^[28][29] This hypothesis was supported by the low Ki of lithium for human pAp-phosphatase compatible within the range of therapeutic concentrations of lithium in the plasma of patients (0.8–1 mM). Importantly, the Ki of human pAp-phosphatase is ten times lower than that of GSK3β (glycogen synthase kinase 3β). Inhibition of pAp-phosphatase by lithium leads to increased levels of pAp (3′-5′ phosphoadenosine phosphate), which was shown to inhibit PARP-1^[30]

Another mechanism proposed in 2007 is that lithium may interact with nitric oxide (NO) signalling pathway in the central nervous system, which plays a crucial role in the neural plasticity. The NO system could be involved in the antidepressant effect of lithium in the Porsolt forced swimming test in mice.^[31][32] It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test,^[33] indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of learned helplessness.

Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, leading to higher levels of inositol triphosphate.^[34] This effect was enhanced further with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression.

Side effects[edit | edit source]

The most common side effects are an overall dazed feeling and a fine tremor of hands. These side effects are generally present during the length of the treatment, but can sometimes disappear in certain patients. Other common side effects, such as nausea and headache, can be generally remedied by a higher intake of water. Lithium unbalances electrolytes; to counteract this, increased water intake is recommended.

According to an Australian study, "The incidence of hypothyroidism is six-fold higher in patients on lithium as compared to the general population. Hypothyroidism in turn increases the likelihood of developing clinical depression." ^[35]

Lithium is known to be responsible for 1-2kg of weight gain.^[36] Weight gain may be a source of low self-esteem for the clinically depressed.^[37] Because lithium competes with the receptors for the antidiuretic hormone in the kidney, it increases water output into the urine, a condition called nephrogenic diabetes insipidus. Clearance of lithium by the kidneys is usually successful with certain diuretic medications, including amiloride and triamterene.^[38] It increases the appetite and thirst ("polydypsia") and reduces the activity of thyroid hormone (hypothyroidism).^{[39][40][41][42][43]} The latter can be corrected by treatment with thyroxine. Lithium is also believed to permanently affect renal function, although this does not appear to be common.^[44]

Lithium is a well-known cause of downbeat nystagmus,^[45] which may be permanent or require several months of abstinence for improvement.^[46]

Most side effects of lithium are dose-dependent. The lowest effective dose is used to limit the risk of side effects.

Teratogenicity[edit | edit source]

Lithium is also a teratogen, causing birth defects in a small number of newborn babies.^[47] Case reports and several retrospective studies have demonstrated possible increases in the rate of a congenital heart defect known as Ebstein's anomaly, if taken during a woman's pregnancy.^[48] As a consequence, fetal echocardiography is routinely performed in pregnant women taking lithium to exclude the possibility of cardiac anomalies. Lamotrigine seems to be a possible alternative to lithium in pregnant women.^[48] Gabapentin^[49] and clonazepam^[50] are also indicated as antipanic medications during the childbearing years and during pregnancy. Valproic acid and carbamazepine also tend to be associated with teratogenicity.

Dehydration[edit | edit source]

Dehydration in patients taking lithium salts can be very hazardous, especially when combined with lithium induced nephrogenic diabetes insipidus with polyuria. Such situations include preoperative fluid regimen or other fluid inaccessibility, warm weather conditions, sporting events, and hiking.

Another danger is that rapid hydration may very quickly produce hyponatremia with its danger of toxic lithium concentrations in plasma.

Overdose[edit | edit source]

Lithium toxicity may occur in persons taking excessive amounts either accidentally or intentionally on an acute basis or in patients who accumulate high levels during ongoing chronic therapy. The manifestations include nausea, emesis, diarrhea, asthenia, ataxia, confusion, lethargy, polyuria, seizures and coma. Other toxic effects of lithium include coarse tremor, muscle twitching, convulsions and renal failure.^[51] People who survive a poisoning episode may develop persistent neurotoxicity. Several authors have described a "Syndrome of Irreversible Lithium-Effected Neurotoxicity" (SILENT), associated with episodes of acute lithium toxicity or long-term treatment within the appropriate dosage range. Symptoms are said to include cerebellar dysfunction.^[52]

Measurement in body fluids[edit | edit source]

Lithium concentrations in whole blood, plasma, serum or urine may be measured using instrumental techniques as a guide to therapy, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Serum lithium concentrations are usually in the 0.5–1.3 mmol/l range in well-controlled patients, but may increase to 1.8–2.5 mmol/l in patients who accumulate the drug over time and to 3–10 mmol/l in victims of acute overdosage.^[53][54]

References[edit | edit source]