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Keywords:

  • intoxication;
  • lithium

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Abstract  The aim of the present study was to determine the relationships between serum lithium level, duration of lithium intoxication, severity of symptoms, and the outcome of the disease. Subjects with a serum lithium level of ≥1.2 mEq/L were included in the study. Seventy-eight patients with lithium intoxication were identified between 1 July 1999 and 31 December 2002. The demographic characteristics, clinical manifestations, and concomitant medications were recorded. Most patients with acute lithium intoxication had mild symptoms, independent of the serum lithium levels. In patients with chronic lithium intoxication, the frequency of severe symptoms was higher than in those with acute intoxication. None of the 78 intoxicated patients in the present survey died or suffered from persistent neurological sequelae. Patients with concomitant medications, older age, and existing neurological illness may have an increased susceptibility to lithium toxicity. Regular monitoring of serum lithium level is essential for lithium-treated patients. Clinicians should pay attention to patients with pre-existing neurological illness, older age, or receiving medications that may interact with lithium.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Over the past 50 years, lithium has been a mainstay in the treatment of patients with bipolar disorders.1 The efficacy of lithium therapy in the treatment of acute mania and long-term prophylaxis against recurrent bipolar disorders is well-established. Toxicity associated with lithium treatment is prevalent: 75–90% of patients treated with lithium have symptoms and signs of toxicity at some point during their treatment.2 Many minor side-effects may occur at serum levels of 0.6–1.2 mEq/L, although serum lithium concentrations ranging from 0.6 to 1.2 mEq/L have been demonstrated to be efficacious in the treatment of bipolar patients.3,4 Symptoms and signs of mild intoxication (with levels >1.5 mEq/L) include marked tremor, nausea, diarrhea, blurred vision, vertigo, confusion, and increased deep tendon reflexes. With levels >2.5 mEq/L, patients may experience more severe neurological complications such as seizures, coma, cardiac dysrrhythmia, and permanent neurological impairment.5

There are two types of lithium intoxication: acute and chronic.6 Acute lithium intoxication occurs when the patient ingests it as a suicide attempt or overdoses himself/herself accidentally. Chronic lithium intoxication occurs when the patient's lithium dosage has been increased or when his/her renal function has been impaired, resulting in an increase in serum lithium levels. Other factors that might increase the risk of chronic lithium intoxication in previous stable patients include drug–drug interactions, concurrent illness resulting in decreased circulating volume, and alternations in potassium or sodium serum concentrations. The magnitude of the serum lithium level and the duration of exposure to a high level of lithium are both correlated with risk of adverse effects.2,7

We have reviewed the records of 78 patients with lithium intoxication to determine the relationships between serum lithium levels, duration of lithium intoxication (acute or chronic), severity of symptoms, and the clinical outcome.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

In the laboratory of Taipei City Psychiatric Center, the therapeutic serum levels of lithium are set to 0.6–1.2 mEq/L. The staff in the laboratory automatically notify the treating physicians when their patients’ serum lithium levels reach 1.2 mEq/L or more. If the subjects were inpatients on the psychiatric ward or in the emergency room, they would receive symptom evaluation and medication adjustment immediately. If the subjects were outpatients presenting intoxication symptoms, the physicians would perform lithium level measurement immediately and adjust the dosage  according  to  the  lithium  level.  If  the  subjects did not have intoxication symptoms and the lithium intoxication was accidentally found by routine lithium level measurement, they would be informed by phone calls and encouraged to visit the clinics immediately. The time between the blood sampling and the medical evaluation varied from a few minutes to a few days.

We carried out a retrospective study in Taipei City Psychiatric Center, where 78 patients with lithium intoxication were identified between 1 July 1999 and 31 December 2002. We also collected another 53 subjects whose lithium levels were <1.2 mEq/L as a control group. Each chart was then individually reviewed by one of the authors (MLL).

We collected the following data: patient's characteristics (age, sex, body height, and bodyweight); diagnosis or indication for the use of lithium; blood urea nitrogen levels; serum creatinine levels; and lithium dosage. In addition, we also obtained the data of patients’ concomitant uses of psychotropic drugs or other medications.

We graded patients’ symptoms of lithium intoxication according to the criteria of Gadallah et al.:6 stage 0, no symptoms or simple anxiety without overt agitation; stage 1 (mild), blurring of vision, nausea, vomiting, hyperreflexia, tremors, muscle weakness, ataxia, agitation, and lethargy; stage 2 (moderate), stupor, rigidity, parkinsonism, and hypotension not associated with the use of antihypertensive drugs; and stage 3 (severe), circulatory collapse, convulsion, or coma.

Statistical analysis included descriptive statistics (mean, median, standard deviation, and percentage) of all data. Subgroups were compared using t-test and analysis of variances for continuous variables and χ2 test for categorical variables. The difference was considered to have statistical significance for P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

A total of 78 subjects with lithium levels >1.2 mEq/L and 53 subjects with lithium levels <1.2 mEq/L were included in the present study. According to the Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV) diagnostic criteria, the main psychiatric diagnosis was bipolar disorder (126 subjects), followed by schizoaffective disorder (three subjects), and major depressive disorder (two subjects).

Among 43 patients with acute lithium intoxication, 34 patients ingested overdose lithium as suicidal attempts (range, 4000–9000 mg) and nine patients accidentally overdosed lithium (range, 2400–4000 mg). Among these acute intoxicated subjects, 27 subjects ingested the sustained-release preparation of lithium. The time between the ingestion and the blood sampling varied from a 30 min to 16 h. Thirteen subjects ingested only lithium excessively, whereas 30 subjects ingested lithium excessively together with other drugs (e.g. benzodiazepines, antipsychotics, carbamazepine, or valproic acid). One patient also had a toxic carbamazepine level (18 µg/mL).

Chronic lithium intoxication occurred in 35 patients who were being treated with lithium but who developed toxicity symptoms without any change in their regular lithium dosage. These patients received routine blood sampling every 3–6 months. If the subjects had intoxication symptoms, they would receive emergent blood sampling immediately. The median maintenance dose of subjects with chronic lithium intoxication was 900 mg/day (range, 600–1600 mg/day). Among these chronic intoxicated subjects, 17 subjects ingested the sustained-release preparation of lithium. The time between the ingestion and the blood sampling varied from 6 h to 12 h.

Based on the serum lithium level, those patients were divided into four groups. The serum lithium level was <1.2 mEq/L in 53 patients (control group), 1.2–1.49 mEq/L in 40 patients (group A), 1.5–1.99 mEq/L in 19 patients (group B), 2.0–2.49 mEq/L in nine patients (group C), and ≥2.5 mEq/L in 10 patients (group D). Table 1 summarizes the demographic characteristics of the 131 patients. The mean ± SD age of patients with excessive lithium levels was 44.3 ± 12.7 years, ranging from 15 to 76 years. The mean weight of patients with lithium intoxication was 65.2 ± 13.5 kg, ranging from 40.0 to 98.0 kg. Compared with other groups, the subjects in group C and D were older. There were no significant differences in the weight, lithium dose, and gender distribution between groups.

Table 1.  Clinical characteristics of lithium intoxicated patients divided by their serum lithium levels (n = 78)
CharacteristicsControl Group (<1.2 mEq/L)Group A (1.2–1.49 mEq/L)Group B (1.5–1.99 mEq/L)Group C (2.0–2.49 mEq/L)Group D (>2.5 mEq/L)P
No. patients534019910
Age 39.7 ± 10.7 43.6 ± 11.5  38.6 ± 11.3 50.4 ± 12.9 51.5 ± 11.90.02
Sex(M/F)24/2914/266/135/44/60.28
Height (cm)161.3 ± 13.7157.9 ± 10.5160.5 ± 9.5158.8 ± 13.1157.5 ± 10.80.59
Weight (kg) 69.0 ± 15.3 64.2 ± 13.3  68.9 ± 14.3 64.2 ± 15.2 61.9 ± 10.00.64
Dose (mg/day)1037 ± 409 979 ± 352 1189 ± 382 978 ± 387 883 ± 2240.29
Lithium level (mEq/L) 0.81 ± 0.19 1.33 ± 0.15  1.69 ± 0.13 2.17 ± 0.21 2.65 ± 0.27
(1.2–1.48)(1.5–1.92)(2.0–2.42)(2.5–3.1) 
Acute intoxication21868
Chronic intoxication191132

Most lithium-intoxicated patients had other psychotropic drugs coadministered to them: antipsychotic drugs (38 patients), benzodiazepines (66 patients), valproic acid (15 patients), carbamazepine (14 patients), and propranolol (35 patients). Other coadministered non-psychotropic drugs included angiotensin-converting enzyme inhibitors (four patients), calcium channel antagonists (three patients), and anti-diabetic agents (four patients). None of them received concomitant diuretics or non-steroidal anti-inflammatory drugs during the study period.

According to the classification of symptom severity of lithium intoxication by Gadallah et al.6 there were 34 lithium-intoxicated patients in stage 0, 36 in stage 1, seven in stage 2, and one in stage 3. Table 2 shows the severity of symptoms and the serum lithium levels in patients with acute or chronic intoxication.

Table 2.  Severity of symptoms and serum lithium levels in patients with acute and chronic intoxication
 Stage 0Stage 1Stage 2Stage 3
Control group48500
Patients with acute intoxication
 Group A (1.2–1.49 mEq/L)18300
 Group B (1.5–1.99 mEq/L) 2600
 Group C (2.0–2.49 mEq/L) 1500
 Group D (>2.5 mEq/L) 0710
Patients with chronic intoxication
 Group A (1.2–1.49 mEq/L) 9910
 Group B (1.5–1.99 mEq/L) 4520
 Group C (2.0–2.49 mEq/L) 0111
 Group D (>2.5 mEq/L) 0020

Significant difference (P < 0.01) was found between the serum lithium levels and the severity of symptoms. In patients with chronic intoxication, the frequency of severe symptoms (stages 2 and 3) was higher than in patients with acute intoxication and in the control group (P < 0.05).

Among all intoxicated subjects, their lithium medications were held or decreased in dosage. Forty-nine subjects received intravenous normal saline and only one subject received the treatment with hemodialysis. The subject who received the treatment with hemodialysis had suffered from poliomyelitis since childhood. Mr A, 42-year-old Taiwanese man, had a 10 year history of bipolar I disorder and received lithium 1200 mg/day. The concurrent medications included propranolol 10 mg three times daily and estazolam 2 mg before bedtime. The lithium level monitoring, performed every 3–6 months, showed that the ranges were within normal limits. The last lithium level, detected 3 months prior to intoxication, was 0.96 mEq/L. Severe intoxication symptoms were noted during the visit to the clinics. He suffered from stupor, drowsiness, tremor, hyperreflexia, and hypotension. The emergency laboratory testing showed that his serum lithium level was 1.82 mEq/L. After receiving intravenous normal saline and the treatment with hemodialysis four times in 4 days, his neurological symptoms associated with lithium intoxication, improved. In the 3 month follow-up period, none of 78 intoxicated patients died or left with persistent neurological sequelae.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

In the literature a serum lithium level >2.0 mEq/L is considered life-threatening and shows severe toxic clinical manifestations resulting in permanent neurological damage.5,8 Our data, obtained in a large population of patients with lithium intoxication, did not support this contention. Our patients showed the following characteristics. First, the manifestations of lithium intoxication were not severe in most patients with serum lithium levels >2.0 mEq/L. Second, most intoxicated patients recovered spontaneously without treatment with hemodialysis. Third, none of these patients developed permanent neurological damage.

The relationship between serum lithium levels and the clinical manifestations of lithium intoxication may be related to the speed with which the serum levels rise.6 The data in the present study revealed that, at the same serum lithium levels, the patients with chronic intoxication had more severe toxicity symptoms than those with acute intoxication. This observation can be explained by the pharmacokinetics of lithium. Lithium is completely absorbed from the upper gastrointestinal tract in approximately 8 h, with peak serum level at 1–2 h after oral administration. The permeability of the blood brain barrier for lithium is less than that of other tissues of the body. The distribution of lithium in the brain is delayed by approximately 24 h as compared with that in the plasma.9 Consequently, patients with acute lithium intoxication may present with very high serum levels and do not show many symptoms. In the contrary, the brain lithium levels of patients with chronic intoxication have enough time to develop. Therefore, neurological toxicity may develop with only moderately elevated serum lithium levels.6 The severity of  toxicity symptoms might depend on the dur-ation of lithium intoxication and the serum lithium concentrations.

Concomitant medications with lithium may also contribute to the clinical manifestations of lithium toxicity. Lithium removal from the body is achieved almost exclusively via renal means. As a result, any medication that alerts glomerular filtration rates or affects electrolyte exchange in the nephron may influence the pharmacokinetic disposition of lithium. Concomitant uses of diuretics, angiotensin-converting enzyme inhibitors, calcium channel antagonists, or non-steroid anti-inflammatory drugs have been associated with lithium toxicity through pharmacokinetic interactions.7,9–11 In general, documented interactions between lithium and psychotropic medications are usually attributed to pharmacodynamic mechanisms.7,9–11 Anecdotal reports have linked numerous psychotropic medications with the development of neurotoxicity without an apparent effect on the pharmacokinetic disposition of lithium. A wide variety of antipsychotic drugs has been implicated in increased lithium toxicity, including haloperidol,12,13 thioridazine,14 chlorpromazine,11 clozapine,15 and risperidone.16 Emilien and Maloteaux hypothesized that neuroleptic drugs, phenothiazines in particular, might increase lithium influx in red blood cells and that the enhanced levels of lithium in the tissue may possibly be responsible for the neurotoxic effects.17 But the neurotoxic reaction between lithium and any antipsychotic drugs is a rare and mostly reversible event.18 Other concomitant drugs, such as carbamazepine,19 valproic acid,20 propranolol,21 angiotensin-converting enzyme inhibitors,9 and calcium channel antagonists9 have also been reported to increase the risk of lithium toxicity.

In addition to an increased lithium load and the duration of exposure, individual tolerance appears to play a role in the severity of lithium intoxication. Existing neurological illness would increase the lithium's neurotoxic susceptibility.22,23 In the present study a patient with severe intoxication symptoms (stage 3) had suffered from poliomyelitis since childhood. and he also had a case of chronic lithium intoxication. These factors might add to the risk of having severe neurotoxicity symptoms.

In our study, the subjects with higher lithium levels were relatively older. Because the glomerular filtration rate and lithium clearance decrease with advanced age, old age becomes a risk factor for lithium intoxication.

The findings of the present study have some potential limitations to generalization. Our data were collected retrospectively and most subjects were outpatients. Potential biases, such as patient treatment compliance, the timing of blood sampling, and the concurrent treatment, were difficult to assess.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

In the present study, patients with acute lithium intoxication frequently had mild symptoms, despite potentially lethal levels. In contrast, patients with chronic lithium intoxication were more likely to have severe symptoms. Concomitant medications, older age, and prior neurological illness may increase the susceptibility of lithium toxicity. Stable patients under long-term lithium treatment should receive regular monitoring of serum lithium level every 3–6 months. The intervals of monitoring for serum lithium concentrations among patients with high susceptibility of lithium toxicity should be shortened.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES
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    Goff DC, Baldessarini RJ. Drug interactions with antipsychotic agents. J. Clin. Psychopharmacol. 1993; 13: 5767.
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    Shukla S, Godwin CD, Long LEB, Miller MG. Lithium–carbamazepine neurotoxicity and risk factors. Am. J. Psychiatry 1984; 141: 16041606.
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    Solomon DA, Ryan CE, Keitner GI et al. A pilot study of lithium carbonate plus divalproex sodium for the continuation and maintenance treatment of patients with bipolar I disorder. J. Clin. Psychiatry 1997; 58: 9599.
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    Becker D. Lithium and propranolol: possible synergism? J. Clin. Psychiatry 1989; 50: 473.
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    Adityanjee Balaraju KB, Ahuja GK. Prior neurologic illness and the syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). Aust. N.Z. J. Psychiatry 1989; 23: 422424.
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    Moskowitz AS, Altshuler L. Increased sensitivity to lithium-induced neurotoxicity after stroke: a case report. J. Clin. Psychopharmacol. 1991; 11: 272273.