Chronic Lithium Therapy Research Articles

Polyuria in a patient on chronic lithium therapy: a case report and literature review

Lithium (Li) has been associated with several forms of renal injury, the most prevalent being impaired urinary concentrating ability, which is reported in individuals on chronic lithium therapy. Lithium is the most common drug implicated in acquired nephrogenic diabetes insipidus (NDI). Prevalence of NDI correlates with the Li dose and the duration of therapy. Here we report an elderly male, presented with hypotonic polyuria while being on prolonged Li therapy for more than 20 years for bipolar affective disorder. Further evaluation confirmed the diagnosis of Li induced NDI as the aetiology for polyuria which responded to Li dose reduction and Thiazide therapy. Proper evaluation of a patient presenting with hypotonic polyuria with water deprivation followed by a desmopressin challenge is necessary before diagnosis, as therapy differs according to the type of the disease. Usually the concentration defect is at least partially reversible with drug discontinuation. Amiloride minimizes lithium accumulation in collecting tubule cells and is recommended for those patients, in whom Lithium therapy cannot be discontinued. Sri Lanka Journal of Diabetes, Endocrinology and Metabolism 2015; 5: 34-37

A Case of Lithium-Induced Polyendocrinopathy Including Thyroid Storm

Chronic lithium therapy can adversely affect thyroid, parathyroid, and kidney function. We present a 67-year-old man on chronic lithium therapy for bipolar disorder who developed thyroid storm, hypercalcemia, and nephrogenic diabetes insipidus following lithium intoxication. Diagnostic studies revealed no infectious precipitant of thyroid storm, with negative thyroid stimulating immunoglobulin and antithyroid peroxidase antibody levels. Thyroid ultrasound demonstrated small thyroid glands with decreased blood flow, not suggestive of Graves' disease. The patient's symptoms improved on only a few weeks of antithyroid drug and was discharged home without thyroid medications. His thyroid function followed a thyroiditis pattern when it dipped into the hypothyroid range before returning to normal without further interventions. To our knowledge, this is the first reported case of lithium-induced thyroiditis precipitating a thyroid storm and the third reported occurrence of thyroid storm in the context of thyroiditis. The patient's hospital course was further complicated by the development of hypercalcemia and nephrogenic diabetes insipidus requiring specialized treatments. We review the literature on mechanisms and treatment of lithium-induced thyroid dysfunction, hypercalcemia, and diabetes insipidus. Lithium-treated patients should have periodic thyroid function tests, and electrolyte measurements, especially following lithium dose adjustment.

Sinus Node Dysfunction in Association With Chronic Lithium Therapy: A Case Report and Review of Literature

Lithium is derived from the Greek word "lithia" which means "stone." Since its discovery by the Swedish chemist Arfedsson in the year 1817, it has been used for treatment of gout, hypertension, uremia, and rheumatism. Currently, lithium is the treatment of choice for the long-term control of mania and to prevent relapse in bipolar disorder. It has a narrow therapeutic index (0.6-1.2 mEq/L). Lithium overdose has been associated with a wide range of cardiovascular complications including cardiac arrhythmias and interstitial myocarditis. We present a review of published cases relevant to lithium-related cardiotoxicity.

Lithium Therapy and Hyperparathyroidism: An Evidence‐Based Assessment

Prolonged therapeutic exposure to lithium compounds can have adverse consequences on calcium homeostasis. A unique form of hyperparathyroidism appears to be causally linked to chronic lithium exposure. We provide a comprehensive review of relevant literature using a structured, evidence-based approach. Published data were identified from systematic electronic literature searches. References are assigned a level of evidence according to a validated classification schema. Level III and V evidence supports an etiologic link between sustained lithium therapy and both hypercalcemia and hyperparathormonemia (grade C recommendation). Level V evidence supports the use of preoperative parathyroid imaging if a focused exploration is planned (grade C recommendation). Level V evidence supports the use of intraoperative parathyroid hormone monitoring to guide appropriate surgical therapy (grade C recommendation). There is conflicting and equally weighted level V evidence supporting a routine preoperative plan of bilateral neck exploration versus selective unilateral exploration (no recommendation). There may be a role for calcimimetic drug therapy as an alternate, nonsurgical means of controlling lithium-associated hyperparathyroidism (grade C recommendation). Evidence-based recommendations support screening of patients on chronic lithium therapy for hypercalcemia. Appropriate surgical therapy may consist of either a bilateral or a unilateral approach when performed by an experienced endocrine surgeon. Focused approaches should be guided by preoperative imaging and intraoperative hormone monitoring. Calcimimetic therapy is a potential alternative to parathyroidectomy.

Long-Term Lithium Therapy Leading to Hyperparathyroidism: A Case Report

This paper reviews the effect of chronic lithium therapy on serum calcium level and parathyroid glands, its pathogenesis, and treatment options. We examined the case of a lithium-treated patient who had recurrent hypercalcemia to better understand the disease process. Primary hyperparathyroidism is a rare but potentially life-threatening side effect of long-term lithium therapy. Careful patient selection and long-term follow-up can reduce morbidity. As much as 15% of lithium-treated patients become hypercalcemic. By routinely monitoring serum calcium levels, healthcare providers can improve the quality of life of this patient group.

Glutamate as a spectroscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal cortisol

While an excess of glucocorticoids is associated with hippocampal pathology in mood disorders, lithium exerts robust neuroprotective and neurotrophic effects. Here, 21 stably remitted bipolar I patients who had been on chronic lithium maintenance therapy, on average, for more than a decade, and 19 carefully matched healthy controls were studied using 3 T (1)H-magnetic resonance spectroscopy of left and right hippocampus. Salivary cortisol samples were obtained to assess activity of the hypothalamus-pituitary-adrenal system. Absolute concentrations of N-acetylaspartate (NAA), choline-containing compounds and total creatine were similar in euthymic bipolar patients and healthy controls. Hippocampal glutamate concentrations were significantly increased as an effect of patient status (patients>controls) and laterality (left hippocampus>right hippocampus). Hippocampal glutamate content (Glu) was strongly correlated with NAA. Across groups and within the patient group, diurnal saliva cortisol levels showed a significant inverse relationship with both Glu and NAA. Taken together, these results add to the concept of bipolar disorder as an illness involving disturbed hippocampal structural plasticity under the opposing influences of lithium and glucocorticoids.

Protracted presyncope and profound bradycardia due to lithium toxicity

Multiple complications can occur as the result of chronic lithium therapy needed for the treatment of bipolar disorder. We present the case of a 54 year-old male, who developed lithium renal and subsequent cardiac toxicity. His symptoms of chest pain and presyncope were related to severe sinus node toxicity and dysfunction requiring temporary transvenous pacing and continuous hemodialysis. We discuss his case in detail his presentation and hospital course and give an overview of lithium induced renal and cardiac toxicities.

Lithium and risk for Alzheimer's disease in elderly patients with bipolar disorder

Bipolar disorder is associated with increased risk for dementia. We compared the prevalence of Alzheimer's disease between 66 elderly euthymic patients with bipolar disorder who were on chronic lithium therapy and 48 similar patients without recent lithium therapy. The prevalence of dementia in the whole sample was 19% v. 7% in an age-comparable population. Alzheimer's disease was diagnosed in 3 patients (5%) on lithium and in 16 patients (33%) who were not on lithium (P<0.001). Our case-control data suggest that lithium treatment reduced the prevalence of Alzheimer's disease in patients with bipolar disorder to levels in the general elderly population. This is in accordance with reports that lithium inhibits crucial processes in the pathogenesis of Alzheimer's disease.

Une prise en charge périopératoire « usuelle » peut conduire à un coma hyperosmolaire chez les patients traités par lithium

A 55-year-old woman with bipolar disorder who had been taking lithium for several years developed hyperosmolar coma following osteosynthesis of a hip fracture. The coma was attributed to decompensation of undiagnosed nephrogenic diabetes insipidus due to chronic lithium intake. The lengthy perioperative fasting and large fluid loading (necessitated by the anesthetic technique) led to acute hypernatremia. Closer monitoring and a different anesthetic strategy might have avoided this classical complication of chronic lithium therapy. The patient recovered after symptomatic treatment. We discuss the perioperative management of patients taking (or having taken) lithium, based on a review of the literature.

An unusual case of polyuria in a lithium-treated patient

A 60-year-old woman, who had been taking lithium for 36 years for bipolar affective disorder, was referred to an endocrinologist by her psychiatrist for investigation of polydipsia and polyuria. Water deprivation did not concentrate her urine, nor did desmopressin, indicating the diagnosis of nephrogenic diabetes insipidus (NDI). She was started on chlorthalidone, a treatment for NDI, and her symptoms improved dramatically. Her polyuria was well controlled on chlorthalidone for 4 years, until she started feel tired and weak and her polyuria worsened. Initially these symptoms were attributed to her depression and lithium therapy. However, routine blood testing revealed a random blood glucose of 18.5 mmol/litre, thereby confirming the diagnosis of type 2 diabetes, and a corrected calcium of 3.02 mmol/litre (normal range 2.1–2.6 mmol/litre). She was started on a diabetic diet, resulting in good diabetes control (confirmed by haemoglobin A1c) and her symptoms improved. The patient's chlorthalidone was stopped as thiazide diuretics can cause hypercalcaemia and her calcium was repeated. The repeat value was higher at 3.07 mmol/litre and her parathormone was alsoelevated at 11.24 pmol/litre, confirming hyperparathyroidism. A parathyroid adenoma was sought but a nuclear medicine scan (Tc99m ssesta-MIBI; technetium 99m-sesta 2-methoxy isobutyl isonitrille) and ultrasound examination of the neck failed to localize an adenoma. It was felt that she had developed parathyroid hyperplasia secondary to chronic lithium therapy (Mallette and Eichhorn, 1986), so her lithium was withdrawn and replaced with sodium valproate. Her NDI and hyperparathyroidism resolved on withdrawal of lithium.

Revisiting lithium-associated hyperparathyroidism in the era of intraoperative parathyroid hormone monitoring

Chronic lithium therapy may cause hyperparathyroidism (HPT). The utility of intraoperative parathyroid hormone monitoring (IOPTH) in these patients is unknown. The authors' hypothesis was that multiglandular disease is more common in these patients, and the ability of IOPTH to predict cure may be limited. Twelve patients had HPT during chronic lithium therapy and underwent parathyroidectomy with IOPTH. Criteria for curative resection were a decrease > or =50% from baseline and into the normal range. Calcium and PTH levels were measured during follow-up. Preoperatively, mean calcium was 11.0 +/- 0.1 mg/dL, and PTH was 116 +/- 14 pg/mL. Fifty percent of patients had multiglandular disease confirmed by IOPTH levels. Mean IOPTH decrease from baseline was 74 +/- 4%. Although 10 of 12 patients met criteria for curative resection, only 8 remain normocalcemic. The 2 patients who did not meet criteria remain normocalcemic. Mean postoperative calcium for all patients was 9.5 +/- 0.2 mg/dL. Of the 10 normocalcemic patients, 4 also have hyperparathormonemia (mean PTH, 119 +/- 19 pg/mL). The incidence of multiglandular disease in HPT after chronic lithium exposure is higher than standard HPT. The ability of IOPTH to predict durable normocalcemia is limited. Bilateral neck exploration should be considered for these patients regardless of whether IOPTH monitoring is used.

The effects of acute and chronic lithium treatment on rat submandibular salivation

Acute and chronic actions of lithium on salivation induced by agonists associated with receptor-linked hydrolysis of membrane inositol phospholipids (carbachol and phenylephrine) and by agonist linked to activation of adenylate cyclase (isoproterenol) were investigated. In anaesthetized rats, submandibular salivation induced by intravenous injection of carbachol, phenylephrine and isoproterenol, was measured and expressed as volume of fluid (microl) elicited per 100 mg wet weight of each gland per minute. The experiments were repeated after acute and chronic treatment of lithium (7 mg kg(-1)). The results were analysed with unpaired t-test. Chronic, but not acute lithium treatment significantly decreases carbachol- and phenylephrine-induced salivation while isoproterenol-induced salivation was not changed neither after acute nor after chronic administration of lithium. The results suggest that hyposalivation during chronic lithium therapy could be mediated by alterations in the phosphatidylinositol cycle and a consequent lack of inositol after agonist stimulation.

Hyperthyroidism Six Years Post-BMT for Acute Myeloblastic Leukemia in a Patient on Long-Term Lithium Therapy for Bipolar Affective Disorder

Lithium is commonly used to treat bipolar affective disorder. It is well known to adversely affect thyroid function, most commonly causing hypothyroidism. Hyperthyroidism is a rare complication. Similarly, total body irradiation (TBI) associated with BMT is well known to affect thyroid function frequently causing hypothyroidism. Hyperthyroidism secondary to TBI is unusual. To have both a history of chronic lithium therapy and TBI with a BMT in patient presenting with hyperthyroidism is an extremely atypical situation. We describe a 39-year-old male who presented with primary hyperthyroidism after 18 years of lithium use for bipolar affective disorder and 6 years post-BMT for AML-M4.

Phosphorus‐Enriched Hemodialysis for the Treatment of Hypophosphatemia in a Patient with Severe Lithium Poisoning

Severe lithium poisoning requires intensive and prolonged hemodialysis (HD) treatment in addition to supportive therapy. Aggressive dialytic therapy can bring about hypophosphatemia, especially, in those patients who are normo‐ or hypophosphatemic to begin with. We report here the use of phosphorus (P)‐enriched HD in a hypophosphatemic patient with lithium poisoning. A 58‐year‐old woman with a long history of bipolar disorder treated with chronic lithium therapy presented with progressively worsening confusion and incoherent speech. She was noted to be confused with a labile mood. The serum levels were lithium 3.6 mM, creatinine 1.7 mg/dL, Na 136 mM, K 4.2 mM, CO2 21 mM, BUN 23 mg/dL, and P 2.1 mg/dL. After a conventional, 4‐h HD session, she became more hypophosphatemic with a P level of 1.8 mg/dL. A P‐enriched dialysate, prepared by adding a Fleet® oral saline laxative preparation (containing NaH2PO4.H2O and Na2HPO4.7H2O) to the “base concentrate” of a dual concentrate, bicarbonate‐based dialysate generating system to obtain a final dialysate containing 3 mg (0.97 mM) of P/dL was used. She underwent 3 subsequent HD sessions using this P‐enriched dialysate, followed by normalization of the serum levels of both lithium and P.Our data suggest that hypophosphatemic patients suffering from severe lithium poisoning requiring intensive HD therapy and becoming more hypophosphatemic as a result of the dialysis treatment can be further dialyzed with a P‐enriched dialysate both to treat the lithium poisoning and to rectify the hypophosphatemia. In general, the use of such dialysates can play an important role in the prevention and treatment of dialysis‐induced hypophosphatemia. Day Length of HD (h) Lithium level predialysis (mM) Lithium level postdialysis (mM) P level in the final dialysate (mg/dL) Serum P level postdialysis (mg/dL) 1 4 (1st session) 3.4 0.87 0 1.8 4 (2nd session) 1.53 0.59 3 3.0 2 4 (3rd session) 1.13 0.59 3 3.3 3 4 (4th session) 0.69 0.52 3 3.4

Parathyroid adenomas versus four-gland hyperplasia as the cause of primary hyperparathyroidism in patients with prolonged lithium therapy.

Chronic lithium therapy in patients with affective psychiatric disorders has been implicated as the cause of hypercalcemia and primary hyperparathyroidism. Our objective was to evaluate whether primary hyperparathyroidism was caused by an adenoma or four-gland hyperplasia. The medical records of 15 patients with affective psychiatric disorders who were treated with chronic lithium therapy from 1982 to 1997, all of whom were operated on for primary hyperparathyroidism, were reviewed. Data on age, symptoms, duration of lithium therapy, pre- and postoperative calcium levels, and parathyroid hormone levels were collected. Parathyroid histology for each patient was independently and blindly reviewed. The mean age was 58 +/- 10 years, the mean duration of lithium therapy 10.7 +/- 6 years, and the mean preoperative calcium level 11.7 +/- 0.5 mg/dl. All patients underwent bilateral neck exploration with selective resection of enlarged glands. Of the 15 patients, 14 (92%) had adenomas (11 single, 3 double), and 1 (8%) had four-gland hyperplasia. All patients were rendered eucalcemic, with a postoperative calcium level of 9.2 +/- 0.5 mg/dl ( p < 0.005). All patients resumed their lithium therapy, with 1 of 15 patients developing recurrent hyperparathyroidism 2 years following the first operation; this patient required reexploration, at which time an adenoma was resected. In our experience hyperparathyroidism in patients who have undergone prolonged therapy with lithium is associated with a high incidence of parathyroid adenomas versus four-gland hyperplasia. This suggests that lithium selectively stimulates growth of parathyroid adenomas in susceptible patients, who are best treated with adenoma excision rather than subtotal parathyroidectomy.

Once Down for the Count, Lithium Lives to Fight Again

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessOnce Down for the Count, Lithium Lives to Fight AgainJim RosackJim RosackSearch for more papers by this authorPublished Online:5 Jul 2002https://doi.org/10.1176/pn.37.13.0027The importance of the topic was underscored by the overflow crowd attending a workshop on the last day of APA’s 2002 annual meeting in May. The psychiatrists simply wanted to know about the latest information on a very old “friend”—lithium.Frederick Goodwin, M.D. (right), discusses combining lithium with another mood stabilizer, while Eric Smith, M.D., looks on.Eric Smith, M.D., a PGY-2 psychiatry resident at Boston University Medical Center chaired the workshop, titled “Lithium Revisited.” He was joined by bipolar experts Frederick Goodwin, M.D., research professor of psychiatry and behavioral sciences at the George Washington University School of Medicine, and James W. Jefferson, M.D., distinguished senior scientist at the Madison Institute of Medicine and director of the Lithium Information Center, who served as discussants.Both Goodwin and Jefferson praised Smith for an excellent overview of a drug that Goodwin characterized as “born well before the chair of this workshop!”Indeed, Smith reviewed 50 years of experience in using lithium in bipolar states, noting that by far, it is the one drug in all of psychopharmacology with a “fully documented history of efficacy.” There are, Smith noted, over a dozen placebo-controlled clinical trials documenting the drug’s effects in reducing the frequency of manic episodes as well as stabilizing cycling between mania and depression, on average producing a fourfold reduction of episodes of mania or depression.Not only is the drug a well-established mood stabilizer, Smith said, but “recent research has documented that lithium has some neuroprotective effects, and it is by far the most effective treatment for reducing—by as much as 50 percent—the overwhelming mortality associated with bipolar disorder.” Lithium is the only drug that has been documented to decrease significantly both suicidal gestures and decrease the number of completed suicides among patients with bipolar disorder.“But,” Smith hedged, “it has a huge side-effect profile and correspondingly huge problems with patient compliance. Simply put, patients feel so much better taking it, but they stop taking it to avoid the side effects.”Chronic lithium therapy is commonly associated with nausea, diarrhea, dizziness, and blurry vision. In more severe cases, it is often referred to as “lithium intoxication,” which can be associated with headache, excessive sweating, electrolyte disturbances, ataxia, tremor, seizure, and in severe toxicity, coma leading to death.“Clinicians are always warned to check serum lithium levels,” Smith noted, “but you have to remember that the serum level must be correlated with the clinical response. In some people, toxicity can and does occur at what would on average be considered a therapeutic level.”The accepted therapeutic level, he noted, is being rethought, based on recent research. “A therapeutic level now seems to be in the range of 0.6 to 1.0 milliequivalents per liter rather than what older references said, which was to keep your patients between 0.8 and 1.2.” Keeping the serum levels lower achieves equal efficacy, Smith said, but can drastically reduce side effects. In addition, using long-acting lithium, given daily at bedtime, also has been shown recently to reduce side effects.Goodwin and Jefferson agreed that lithium is by far the most effective mood stabilizer. They disagreed somewhat on its side-effect profile, especially in the long-term effects of lithium therapy. Goodwin actively champions combination therapy, using lower doses of lithium along with another mood stabilizer—he often adds low doses of divalproex—and has done studies that indicate that patients on combination therapy do just as well symptomatically, while experiencing fewer side effects.Smith noted that a good number of current bipolar experts do believe in lithium and use it frequently, in spite of recent research suggesting that it has fallen out of favor.“As long as you get a good history, talk openly and candidly about the side effects of lithium with your patients, and monitor those side effects over time,” Smith concluded, “lithium is still the drug of choice in bipolar disorder. It is the most effective medication we have and, when appropriately managed, is quite safe.”The Web site for the Lithium Information Center is www.miminc.org/aboutlithinfoctr.html. ▪ ISSUES NewArchived

A control study of the cutaneous side effects of chronic lithium therapy

Background: To assess the nature and prevalence of skin disorders among psychiatric patients on chronic lithium therapy and to compare them with patients on other psychotropic medications. Method: 51 patients on lithium and 57 patients on other psychotropics were recruited. Dermatological assessment included a semi-structured questionnaire and clinical examination of the subjects by two dermatologists who were blind to the psychiatric diagnosis and treatment. Secondary cutaneous reaction was defined as skin eruption that developed or deteriorated after commencement of psychiatric medication. Results: Lithium treated patients developed significantly more secondary cutaneous reactions than the control group. This applied particularly to acne and psoriasis. Male patients on lithium were more likely to be affected than female patients. Conclusion: Lithium aggravates or triggers cutaneous conditions that are characterized by the pathological findings of neutrophilic infiltration. Since these cutaneous problem can be distressing to patients and may affect medication compliance, there should be heightened attention to skin problems in patients receiving lithium treatment.

Neutrophil peripheral count and human leukocyte elastase during chronic lithium carbonate therapy

Plasma levels of human polymorphonuclear elastase (PMN-E) are considered a marker of granulocyte activation and can potentially complement the peripheral neutrophil count in laboratory and pathophysiological settings. Neutrophilic leukocytosis is a well known effect of lithium therapy, but there is no information about the concomitant behaviour of PMN-E in these patients. The aim of this study was to evaluate both polymorphonuclear leukocyte count and plasma PMN-E levels in depression patients undergoing chronic lithium therapy. Absolute and differential leukocyte count in venous peripheral blood was determined by an automated method, and PMN-E evaluated by enzyme immunoassay. 39 patients (11 males, 28 females; mean age 43. ± 6 02) with depression disorders were studied, during lithium carbonate therapy. Neutrophilia (neutrophil count > 7.500±109 cells per liter) was found in 7 (18 %) patients and an increase in plasma PMN-E levels (PMN-E > 56μg per liter) in 6 (15 %), No correlations were found between neutrophil count, plasma concentration of PMN-E, plasma level of lithium and duration of therapy. The results show that in these patients, not only the PMN count but also elastase levels can exceed the normal range. The absence of correlation between these two parameters suggests that the state of PMN activation is not linked to their number in peripheral blood.

The use of lithium levels in the emergency department

Most patients on chronic maintenance lithium therapy become toxic at some point during their therapy. Lithium intoxication portends morbidity and mortality. The serum lithium concentration can be used as an adjunct to a physician’s clinical acumen in diagnosing and managing the patient with lithium intoxication.

The effect of lithium on calcium-induced changes in adrenocorticotrophin levels.

The calcium receptor (CaR) plays a central role in calcium (Ca) sensing by the parathyroid gland and other organs, including the brain. Chronic lithium (Li) therapy causes a significant alteration in Ca-sensing by the CaR-expressing parathyroid chief cells through an unknown mechanism, shifting the PTH set-point (the level of Ca that half-maximally suppresses PTH secretion) to the right. Ca is known to stimulate ACTH levels in normal subjects, and baseline ACTH levels are increased in patients with bipolar disorder. Because the stimulation of ACTH secretion by Ca likely involves the CaR, the aim of this study was to investigate the effects of Li on Ca-induced changes in ACTH levels, using Ca and citrate infusions in seven Li-treated patients and seven controls. During the Ca infusion, increments in serum-ionized Ca concentration (Ca(i)) were accompanied by increments in ACTH levels that were significantly greater in the Li-treated group, P = 0.014, by ANOVA. Also, cortisol levels increased significantly in the Li-treated, but not the control group, during the Ca infusion, P < 0.0001. There was a statistically significant shift in the midpoint of the Ca(i)/ACTH curve, to the right, in the Li-treated group, compared with the controls (P = 0.042), that was largely caused by an effect of Li on Ca(i). However, for comparable levels of Ca(i), there were no significant differences in the levels of ACTH between the two groups. Therefore, within the physiological range of Ca, there was no effect of Li on Ca(i)-induced change in ACTH levels.