Lithium use in special populations

Abstract

Lithium, a monovalent cation, was first used for the treatment of mania in the 1940s. Half a century into its use, the drug continues to be the preeminent choice for bipolar disorder with antimanic, antidepressant (modest) and antisuicidal property. Lithium is the “gold standard” mood stabilizer against which potential mood stabilizer agents are judged. The therapeutic uses of lithium also include use as an augmenting agent in depression, schizoaffective disorder, aggression, impulse control disorder, eating disorders, attention deficit disorder and in certain subsets of alcoholism. Lithium has been used in many medical disorders, especially cluster headache and dermatological disorders (seborrheic dermatitis, eczematoid dermatitis, genital herpes).[1] The drug is however associated with neurologic, endocrine, cardiovascular, renal, dermatologic and gastrointestinal adverse effects and possible teratogenicity. HISTORY Lithium was first discovered and defined by Johan August Arfvedson in 1817 when he did an analysis of the mineral petalite [LiAl(Si2O5)2]. Petalite was first found by Brazilian scientist Josá Bonifécio Andrade e Silva in 1800. Lepidolite, spodumene, petalite and amblygonite are the more important minerals containing lithium. It was Arfwedson's laboratory chief John Jacob Berzelius who named this alkali metal “lithion.” Arfvedson was never able to fully isolate lithium, and it wasn't until 1855 that it was isolated by William Thomas Brande. Brande and Sir Humphrey Davy earlier had done electrolysis on lithium oxide in 1818. Lithium was first produced commercially in 1923 by Metallgesellschaft AG.[2] The use of lithium for medicinal purposes can be traced back 1,800 years to the Greek physician Galen, who treated patients with mania by having them bathe in alkaline springs and drink the water, which probably contained lithium. In 1843 Alexander Ure introduced lithium into modern medicine, and he showed the in vitro reduction of weight of a uric acid bladder stone in a lithium carbonate solution. Sir Alfred Garrod later discovered that gouty uric acid deposits also were soluble in lithium solution. The view in that time was that uric acid imbalances caused a wide range of diseases, and Armand Trousseau and Alexander Haig proposed that mania and depression also may result from this imbalance and lithium may be effective in these conditions. In the 1840s, lithium was mixed with carbonate or citrate to form a salt and was used to treat gout, epilepsy, diabetes, cancer and insomnia. In the 1870s, the then American Surgeon General William Hammond had provided anecdotal evidence for the use of lithium bromide in the treatment of acute mania. In the 1880s and 1890s the Lange brothers Carl and Fritz used lithium in depression, and Carl Lange was the first to systematically use lithium in the acute and prophylactic treatment of depression.[2] The introduction of lithium preparations and tablets in the 1900s brought to the fore the toxic effects of the drug; and there were reports of weakness, tremor, diarrhea, vomiting and deaths. The drug disappeared from the British Pharmacopoeia by 1932, but later in the 1940s it was used as a sodium substitute in low sodium diets; but the reports of severe intoxication led to its removal from American markets in 1949.[1] The appearance in 1949 in the Medical Journal of Australia of a paper entitled “Lithium salts in the treatment of psychotic excitement” by John F. J. Cade was an unspectacular entry into a new era of psychiatry. Manic patients showed improvement, with the patient becoming calmer after four to five days. There was no improvement in the excited schizophrenic patients, though there was a calming effect. There was no improvement or deepening of depression. The paper also gave details of initial dosage, maintenance doses, appearance of toxic symptoms and warning about lithium over-dosage.[3] Most of the subsequent evidence on lithium was gathered by the European trials, especially by Mogens Abelin Schou from Denmark.[4] The earliest report of lithium treatment in North America was published in 1960. Between 1950 and 1974, 782 papers were published on lithium from Europe, 353 papers from North America and 95 papers from other continents; and this led to the establishment of lithium as an efficacious and well-tolerated drug in mania. The clinical significance of lithium was recognized in a special section of the American Journal of Psychiatry in 1968. In 1970 it was approved by the United States Food and Drug Administration (USFDA) for the treatment of mania, and in 1974 it was approved for maintenance therapy of patients with mania [Table 1].[5]Table 1: Landmarks in the history of lithiumLITHIUM USE AND CARDIOVASCULAR DISEASES Lithium is shown to produce a variety of cardiovascular effects in man and experimental animals. These effects are more profound during lithium intoxication, though they can occur at therapeutic levels of lithium. These effects include hypotension, bradycardia (acute effects more common, though profound bradycardia as a late consequence of chronic lithium poisoning has also been reported),[6] decreased cardiac output, cardiac arrhythmias (heart blocks and bradyarrhythmias, especially during intoxication) and possible antiarrhythmic action against experimentally induced arrhythmias.[7] Lithium, however, does not have clinically significant effect on blood pressure. Lithium may also induce various electrocardiographic (ECG) changes, including nonspecific T-wave flattening, dysfunction of sinus node, atrioventricular conduction disturbances and reversible premature ventricular contractions. However, the effect of lithium on QT interval has not been fully elucidated.[8] At therapeutic concentration, T-wave flattening is seen in 30–100% of lithium-treated population. Depressed sinus node function was significantly more common in a lithium-treated population than in an age-stratified reference group. Clinically significant dysfunction, however, seems to be uncommon, with a prevalence of only 0–46% of lithium treatment in a pacemaker population. Mechanism by which lithium depresses sinus node function is not fully understood. Animal experiments indicate that lithium depresses the intracellular potassium (IK) concentration. In addition, lithium replaces intracellular calcium (ICa). Interaction between lithium and IK, ICa, the sodium/ calcium (Na/ Ca) exchange currents and sodium/ potassium (N/ K) pump have been suggested. These disturbances seem to induce various electrophysiological changes, including a decrease of the depolarization rate and reduced electrical impulse propagation.[9] Lithium reduces the mobilization of calcium ion from intracellular pools by inositol triphosphate (IP3)-dependent calcium channels. Lithium inhibits the G protein transduction mechanism linked to type I cholinergic receptors and blocks inositol monophosphatase. Moreover, lithium reduces the production of cyclic adenosine monophosphate (cAMP) and inhibits the influx of calcium ion by limiting its channel opening, and these may interfere with SA and AV node function.[10] There is also evidence that hypotensive and cardiac-depressant effects of lithium chloride are mediated by activation of adenosine triphosphate-sensitive potassium channels.[7] It has also been suggested that lithium might decrease the sensitivity of the sinus node to sympathetic stimulation.[9] In experimental studies, lithium has been shown to enter cardiac cells, displace cations and result in intracellular metabolic changes; including intracellular potassium depletion, which may be one of the mechanisms resulting in T-wave changes on ECG. Calcium channel blockers (especially verapamil) and beta blockers have a synergistic effect with lithium on the severity of bradycardia. SA and AV nodes depend to a large extent on calcium influx for action potentials that maintain their automaticity, and its suppression by calcium channel blockers causes sinus bradycardia and prolongs AV conduction time. Both beta blockers and lithium reduce the production of the second messenger, cAMP, and in turn inhibit the opening of the calcium ion influx.[10] The drugs that impair renal function, like angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagionists and certain diuretics, might predispose to lithium toxicity with resultant cardiac manifestations.[1] Conversely, bronchodilators can increase lithium excretion and reduce lithium levels and trigger a relapse.[11] A patient on lithium who develops myocardial infarction may be treated by temporary lithium discontinuation or by lithium continuation with frequent blood-level monitoring in cases where there is a high chance of relapse. Lithium patient can undergo coronary artery bypass graft (CABG) safely under close supervision. In such cases, lithium should be stopped prior to surgery and restarted at lower dose with serum lithium monitoring. Lithium is known to exacerbate or ameliorate congestive cardiac failure; and in all cases where it exacerbates CCF, lithium may be discontinued. Attention should be paid to hydration status, electrolyte balance and drug interactions in patients with cardiac complications [Table 2].[11]Table 2: Cardiovascular effects of lithiumLITHIUM USE AND ENDOCRINE DISORDERS Lithium is associated with a 7% (2-15%) increase of clinical hypothyroidism, 5% risk of goiter and rarely (0.7%) hyperthyroidism. Subclinical hypothyroidism (approximately 19%) is considered more common than clinical hypothyroidism, and minor elevation of thyroid stimulating hormone (TSH) may normalize without treatment. Chemical hypothyroidism with lithium is around 50%. Lithium is highly concentrated in the thyroid gland against a concentration gradient, probably by active transport. Lithium interferes with glandular release of thyroid hormones (T4 and T3) by decreasing the endocytosis of thyroid hormone-laden thyroglobulin on the luminal side of the thyroid follicle; this causes a transient thyrotropin elevation in more than a third of lithium carbonate-treated patients.[12] The glandular release inhibition is mediated by cyclic adenosine monophosphate (cAMP) within the thyrocyte.[13] Lithium at higher doses may block iodine uptake and organification within the thyroid. Lithium was found to stimulate cell proliferation in the absence of thyrotropin stimulation; but under thyrotropin stimulation, lithium diminished thyrocyte proliferation, especially when used at higher concentrations.[14] Lithium affects many aspects of cellular and humoral immunity in vitro and in vivo. Prevalence of specific thyroid antibodies among lithium-treated patients varies across studies. Women are known to express thyroid autoimmunity more frequently than men, and it is more in the middle age range. So also thyroid autoimmunity has been found associated with affective disorders, irrespective of lithium use. So it is unclear as to whether lithium per se can induce thyroid autoimmunity.[15] There is evidence that females, patients with rapid cycling and patients with an underlying autoimmune thyroiditis are more prone to lithium-induced hypothyroidism.[16] A study showed that 74% cases of hypothyroidism developed in the first two years of treatment.[14] Lithium-induced goiter is usually characterized by small, smooth and nontender nodules; in some cases, nodules may regress over time. The cause of lithium-induced thyrotoxicosis is not clear; some authorities have speculated that lithium may directly stimulate autoimmune reactions.[14] It is suggested that before starting lithium, thyroid functions have to be assessed (the determination of thyroid hormones, thyroid stimulating hormone (TSH) and baseline antithyroid antibody). Subsequently, monitoring of thyroid function is done every 6 to 12 months. It is suggested that age and should be into for thyroid in lithium-treated The might have to be to include more frequent for over the age of or and patients have frequent 6 or 12 There is no as to whether lithium treatment the risk of a treated Lithium, however, can be to these patients under monitoring of thyroid function and of thyroid Subclinical increase of the levels of calcium and are in lithium-treated reports have been there of and In all patients with monitoring of serum calcium should be when they are to lithium. there is evidence of during lithium lithium should be There is evidence of decreased and on lithium treatment. There is evidence that lithium has effect on and has the to increase the release of have suggested that lithium treatment may impair or produce in certain patients, and the risk is higher in patients the age of blood monitoring is in this of There is evidence that associated with the renal of lithium, higher lithium doses to maintain therapeutic lithium [Table effects of lithiumLITHIUM USE AND DISEASES The the potential effect of lithium is from over the and occur in of lithium-treated The of is around Lithium treatment reduces renal by and the by as of lithium treatment. evidence that there is no increase in rate after years of lithium changes, however, have been in renal of lithium-treated patients, though they be clinically in of and chronic lithium Lithium is by the and around of it is in the the other is between the of and the The sodium channel and the as the lithium which decrease and increase (especially cause serum lithium the other inhibitors, and decrease sodium and increase lithium and are to the effects of lithium on action of hormone on and Lithium interferes with the by its for and include dose potassium use of blocks the entry of lithium to and or use of and use of high levels of have been found in There is lithium use in renal and there is a that in renal function may result in decreased lithium and The risk of lithium intoxication is higher in patients with renal or Lithium is in acute renal but can be used with in patients with chronic renal Lithium has also been used in a of It is suggested that lithium should be in the or as a dose Lithium has also been used in patients with renal and are more in than used as in patients reduces lithium monitoring of renal function is during lithium and there is no monitoring on frequently serum levels should be range from every to one The other are clinical of and in certain cases, protein and [Table effects of lithiumLITHIUM USE AND DISEASES side effects of lithium were first by and in five cases, with four patients having two having These usually seem to during the first of and they not seem to as the lithium is at a first as a side effect and the of lithium The side effects with lithium treatment include dermatitis, and which is of the type is seen in of patients on lithium treatment. In some cases, is to lithium-induced The prevalence rate of such adverse effects varies from to and are the to lithium. lithium about these is not fully understood. Lithium to that are associated with the of In to lithium causes an increase in an effect that within a after of treatment. The mechanism is not but its action on is to be the of cAMP, lithium and release from but whether it has effects such as of is not to lithium use may be by and which induce the in to of lithium on the in resulting in to the [Table effects of treatment include to lithium, and dermatological to specific USE DISEASES The inositol second are in the and maintenance of smooth Lithium, its effects on cell transduction and be to the against A study has shown that lithium reduces in smooth and is a possible agent for the treatment of A study of lithium found that lithium had no over in the treatment of There is also evidence for the of of lithium monitoring of control is when lithium The bronchodilators used in the treatment of increase the excretion of a higher dose is to maintain the therapeutic of lithium in such Lithium use in chronic may Lithium treatment is also to be associated with The mechanism by which lithium is It is to be to the effect of lithium on which is for during AND Lithium is a that there is evidence for risk with lithium, though the potential may the risk in some The of in to lithium from to the rate in from to The risk of especially the drug is during The of Lithium a a higher rate of cardiovascular in in with the population. a risk around of among of lithium which is to higher than the rate in the population. the risk for with lithium is higher than in the the risk were found to significantly more than the of and complications include premature transient thyroid and However, the of these a of also has been a higher lithium concentration in serum at is found to be associated with risk of reports that the use of lithium during is associated with no significant increase of The for of on lithium some authorities have suggested the maintenance of lithium treatment for bipolar with severe of the is the potential in these cases is by the from drug discontinuation and relapse. have the treatment lithium prior to the during or lithium and the treatment In cardiac is at and of when the clinical lithium Lithium serum which may be by sodium and should be The increase of renal lithium excretion during may an increase of the lithium dosage, the drug should be decreased at the of to reduce the risk of toxicity to the reduction of In of hydration of the should also be Lithium has been found to reduce the rate of from to than A study that serum lithium are lower in than Lithium in serum and serum an of contained about the concentration of and serum had about the in that serum contained about one the concentration of lithium in The diminished renal in can serum levels of lithium. The lithium levels is the for rapid in with is that the effects on the of lithium levels are not many reports have effects in to lithium during the The effects include and T-wave on ECG. of the drug were in and with of in serum and and of in serum in these The American of has that lithium has been associated with significant effects on some and that be with by lithium treatment. In a to lithium, lithium serum and the blood should be [Table Lithium in and lithium is there is no effect The of in the are have been in who have been to lithium. The has to with the of and the whether the from the when is USE lower doses of lithium to serum as in A study on the use of lithium in has shown patients a dose lower than of lithium is not to be by age as lithium is not to Lithium in is by to There is a decrease in with which in a lower of per of So the dose of lithium in an have for the lithium to resulting in a higher serum lithium in the to in and also increase the serum of The of rate with age in a decrease in lithium and serum The drugs used in the like diuretics, inhibitors, calcium drugs and the serum levels of lithium. There is also a in lithium with and the prevalence of with lithium with In the at serum lithium levels which are considered in There are no of lithium in and for clinical use are on from studies, anecdotal reports and clinical in psychiatry. There is however, that the and serum of lithium to be reduced in the in the and for serum lithium are on and a study a low serum lithium concentration (approximately which may be a dose of over in a The patients between and years from to and rarely patients more than years or the should range from to and should rarely USE AND Lithium is the agent in the acute for mania in and it is the only approved by the Food and Drug Administration for the treatment of mania in 12 years and this was on of than specific clinical in Lithium may be and effective for the treatment of acute mixed in and also that lithium may be effective and for the treatment of the of in with bipolar At lithium treatment be for under 12 years of age under conditions. The and serum levels of lithium, as as its adverse are with known from It is that the serum of lithium should be between and effects have to be higher than may [Table Lithium use in and Lithium is protein and has an of of The therapeutic dose is with serum levels of The of a dose of lithium is from 12 to with and to in associated with lithium treatment is and of patients treated with lithium have symptoms and of toxicity at some during their treatment. minor side effects may occur at serum levels of and of intoxication include tremor, diarrhea, and levels patients may more severe complications such as cardiac and with may be at risk for acute are but is than There are two of lithium acute and lithium intoxication when the patient it as a or lithium intoxication when the lithium has been or when their renal function has been resulting in an increase in serum lithium that might increase the risk of chronic lithium intoxication in patients include resulting in decreased and in electrolyte (especially calcium and The of the serum lithium and the of to a high of lithium are with risk of adverse The between serum lithium and intoxication is and serum lithium may to severity of at in chronic but that the is not close and that lithium levels have a in the of a use of diuretics, angiotensin-converting enzyme inhibitors, calcium channel or drugs has been associated with lithium toxicity In interactions between lithium and are usually to A wide variety of drugs has been in lithium including and It is that in might increase lithium influx in blood and that the levels of lithium in the may be for the the between lithium and drugs is a and reversible such as have also been to increase the risk of lithium Lithium intoxication a medical a patient of lithium the serum lithium levels and also a and In of lithium may be after an acute to in the with a electrolyte at to or use of a exchange should be considered for patients with acute toxic of lithium, especially lithium are The use of sodium is however for the dose of is high and result in Most patients with lithium intoxication are and may increase lithium by but this has not been has effect on serum lithium is not of the risk of and is the of therapy and should be considered in when serum lithium levels are of that the patients lithium levels 6 lithium therapy lithium levels with severe renal or with lithium levels from to and with renal or an lithium after and levels range from to The of is a lithium after and as levels may to be or [Table Lithium has to be lithium, the “gold standard” mood in the The use of lithium in patients with cardiovascular, renal, endocrine, and dermatological is to the for patient of lithium during and and in and population and about the toxicity of lithium are also in this The of lithium during and the are