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Lithium has been used for the treatment of acute bipolar mania for over 50 years. Five studies have demonstrated that lithium is superior to placebo (176–180). Pooled data from these studies reveal that 87 (70%) of 124 patients displayed at least partial reduction of mania with lithium. However, the use of a crossover design in four of these trials (176–179), nonrandom assignment in two studies (177, 178), and variations in diagnostic criteria and trial duration limit interpretation of the results of all but one trial (180). Nevertheless, in the only placebo-controlled, parallel-design trial in which lithium served as an active comparator to divalproex, lithium and divalproex exerted comparable efficacy (180). In active comparator trials, lithium displayed efficacy comparable to that of carbamazepine (181, 182), risperidone (183), olanzapine (184), and chlorpromazine and other typical antipsychotics (185–190). Among active comparator trials, however, only three (185, 186, 189) were likely to be of sufficient size to detect possible differences in efficacy between treatments. Open studies (191–194) and randomized, active comparator-controlled studies (195–197) indicate that lithium is likely to be effective for treatment of pure or elated mania but is less often effective in the treatment of mixed states.

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a) Side effects

Up to 75% of patients treated with lithium experience some side effects (41, 198). These side effects vary in clinical significance; most are either minor or can be reduced or eliminated by lowering the lithium dose or changing the dosage schedule. For example, Schou (199) reported a 30% reduction in side effects among patients treated with an average lithium level of 0.68 meq/liter compared with those treated with an average level of 0.85 meq/liter. Side effects that appear to be related to peak serum levels (e.g., tremor that peaks within 1 to 2 hours of a dose) may be reduced or eliminated by using a slow-release preparation or changing to a single bedtime dose.

Dose-related side effects of lithium include polyuria, polydipsia, weight gain, cognitive problems (e.g., dulling, impaired memory, poor concentration, confusion, mental slowness), tremor, sedation or lethargy, impaired coordination, gastrointestinal distress (e.g., nausea, vomiting, dyspepsia, diarrhea), hair loss, benign leukocytosis, acne, and edema (200). Side effects that persist despite dosage adjustment may be managed with other medications (e.g., beta-blockers for tremor; diuretics for polyuria, polydipsia, or edema; topical antibiotics or retinoic acid for acne). Gastrointestinal disturbances can be managed by administering lithium with meals or changing lithium preparations (especially to lithium citrate).

Lithium may cause benign ECG changes associated with repolarization. Less commonly, cardiac conduction abnormalities have been associated with lithium treatment. Anecdotal reports have linked lithium with other ECG changes, including the exacerbation of existing arrhythmias and, less commonly, the development of new arrhythmias (201).

The most common renal effect of lithium is impaired concentrating capacity caused by reduced renal response to ADH, manifested as polyuria, polydipsia, or both (202, 203). Although the polyuria associated with early lithium treatment may resolve, persistent polyuria (ranging from mild and well tolerated to severe nephrogenic diabetes insipidus) may occur. Polyuria can frequently be managed by changing to a once-daily bedtime dose. If the polyuria persists, management includes ensuring that fluid intake is adequate and that the lithium dose is as low as possible. If these measures do not ameliorate the problem, then concurrent administration of a thiazide diuretic (e.g., hydrochlorothiazide at a dose of 50 mg/day) may be helpful. The lithium dose will usually need to be decreased (typically by 50%) to account for the increased reabsorption induced by thiazides (198). In addition, potassium levels will need to be monitored, and potassium replacement may be necessary. Amiloride, a potassium-sparing diuretic, is reported to be effective in treating lithium-induced polyuria and polydipsia (203). Its advantages are that it does not alter lithium levels and does not cause potassium depletion. Amiloride may be started at 5 mg b.i.d. and may be increased to 10 mg b.i.d. as needed (204).

Hypothyroidism occurs in 5%–35% of patients treated with lithium. It occurs more frequently in women, tends to appear after 6–18 months of lithium treatment, and may be associated with rapid cycling (41, 80, 198, 205). Lithium-induced hypothyroidism is not a contraindication to continuing lithium and is easily treated by the administration of levothyroxine (198, 205). In addition to the other signs and symptoms of hypothyroidism, patients with bipolar disorder are at risk of developing depression or rapid cycling. If these symptoms occur in the presence of laboratory evidence of suboptimal thyroid functioning, then thyroid supplementation, discontinuation of lithium, or both should be considered (206–208). Hyperparathyroidism has also been noted with lithium treatment (209–211).

A small number of case reports have described exacerbation or first occurrences of psoriasis associated with lithium treatment (212). Some of these patients improved with appropriate dermatologic treatment or when the lithium dose was lowered. In some cases, however, lithium seemed to block the effects of dermatologic treatment, with psoriasis clearing only after lithium was discontinued. In addition, patients occasionally experience severe pustular acne that does not respond well to standard dermatologic treatments and only resolves once the lithium treatment is discontinued (212). This is in contrast to the more common mild to moderate acne that can occur with lithium treatment, which is usually responsive to standard treatments (198).

Approximately 10%–20% of patients receiving long-term lithium treatment (i.e., for more than 10 years) display morphological kidney changes—usually interstitial fibrosis, tubular atrophy, and sometimes glomerular sclerosis. These changes may be associated with impairment of water reabsorption but not with reduction in glomerular filtration rate or development of renal insufficiency (41, 198, 213–216). Although irreversible renal failure caused by lithium has not been unequivocally established, there are a number of case reports of probable lithium-induced renal insufficiency (215, 217, 218). Additionally, several studies have shown that a small percentage of patients treated with lithium may develop rising serum creatinine concentrations after 10 years or more of treatment (215, 218).

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b) Toxicity/overdose

Toxic effects of lithium become more likely as the serum level rises (219). Most patients will experience some toxic effects with levels above 1.5 meq/liter; levels above 2.0 meq/liter are commonly associated with life-threatening side effects. For many patients, the therapeutic range within which beneficial effects outweigh toxic effects is quite narrow, so that small changes in serum level may lead to clinically significant alterations in the beneficial and harmful effects of lithium. Elderly patients may experience toxic effects at lower levels and have a correspondingly narrower therapeutic window (138).

Signs and symptoms of early intoxication (with levels above 1.5 meq/liter) include marked tremor, nausea and diarrhea, blurred vision, vertigo, confusion, and increased deep tendon reflexes. With levels above 2.5 meq/liter, patients may experience more severe neurological complications and eventually experience seizures, coma, cardiac dysrhythmia, and permanent neurological impairment. The magnitude of the serum level and the duration of exposure to a high level of lithium are both correlated with risk of adverse effects (219). Therefore, rapid steps to reduce the serum level are essential. In addition, during treatment for severe intoxication, patients may experience "secondary peaks" during which the serum level rises after a period of relative decline; the clinician must therefore continue to monitor serum levels during treatment for severe intoxication. The patient with lithium intoxication should be treated with supportive care (e.g., maintenance of fluid and electrolyte balance), and steps should be taken to prevent further absorption of the medication (e.g., gastric lavage or, in the alert patient, induction of emesis).

Hemodialysis is the only reliable method of rapidly removing excess lithium from the body and is more effective than peritoneal dialysis for this purpose (220). Criteria for the use of hemodialysis in lithium intoxication are not firmly established, and the decision to dialyze must take into account both the patient's clinical status and the serum lithium level (219, 221). When serum lithium levels are below 2.5 meq/liter, hemodialysis usually is unnecessary. The need for hemodialysis differs in patients who have developed toxicity after an acute overdose compared with those who have developed gradual toxicity or have an acute overdose superimposed on long-term lithium treatment. In acute poisoning, hemodialysis is generally required with serum lithium levels over 6–8 meq/liter, whereas hemodialysis may be needed with serum levels over 4 meq/liter in those who have been on long-term regimens of lithium treatment. Hemodialysis may also be necessary at lower serum levels in patients who are more susceptible to complications because of underlying illnesses (e.g., cardiac disease, renal impairment). Regardless of serum lithium level, hemodialysis is generally indicated in patients with progressive clinical deterioration or severe clinical signs of intoxication such as coma, convulsions, cardiovascular symptoms, or respiratory failure (219, 221). Because serum levels of lithium may rebound after initial hemodialysis, repeat dialysis may be needed (219, 222).

In cases of overdose with sustained-release preparations of lithium, development of toxicity is likely to be delayed, and the duration of toxicity is likely to be prolonged (223, 224). This should be taken into consideration in decisions about the need for initial or repeat hemodialysis (219).

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c) Implementation and dosing

Before beginning lithium treatment, the patient's general medical history should be reviewed, with special reference to those systems that might affect or be affected by lithium therapy (e.g., renal, thyroid, and cardiac functioning). In addition, pregnancy or the presence of a dermatologic disorder must be ascertained. Patient education should address potential side effects of lithium treatment as well as the need to avoid salt-restricted diets or concomitant medications that could elevate serum lithium levels (e.g., diuretics, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors). Patients should be cautioned, particularly if nephrogenic diabetes insipidus is present, that lithium toxicity might occur with dehydration from environmental heat, gastrointestinal disturbance, or inadequate fluid intake.

Laboratory measures and other diagnostic tests are generally recommended on the basis of pathophysiological knowledge and anticipated clinical decisions rather than on empirical evidence of their clinical utility. The decision to recommend a test is based on the probability of detecting a finding that would alter treatment as well as the expected benefit of such alterations in treatment. Recommended tests fall into three categories: 1) baseline measures to facilitate subsequent interpretation of laboratory tests (e.g., ECG, CBC); 2) tests to determine conditions requiring different or additional treatments (e.g., pregnancy, thyroid-stimulating hormone level); and 3) tests to determine conditions requiring alteration of the standard dosage regimen of lithium (e.g., creatinine level).

On the basis of these considerations, the following procedures are generally recommended before beginning lithium therapy: a general medical history, a physical examination, BUN and creatinine level measurement, a pregnancy test, thyroid function evaluation, and, for patients over age 40, ECG monitoring with rhythm strip. Some authorities also suggest a CBC.

Lithium is usually started in low, divided doses to minimize side effects (e.g., 300 mg t.i.d. or less, depending on the patient's weight and age), with the dose titrated upward (generally to serum concentrations of 0.5–1.2 meq/liter) according to response and side effects (225). Lithium levels should be checked after each dose increase and before the next. Steady-state levels are likely to be reached approximately 5 days after dose adjustment, but levels may need to be checked sooner if a rapid increase is necessary (e.g., in the treatment of acute mania) or if toxicity is suspected. As levels approach the upper limits of the therapeutic range (i.e., '‰¥1.0 meq/liter), they should be checked at shorter intervals after each dose increase to minimize the risk of toxicity.

Serum concentrations required for prophylaxis may be, in some cases, as high as those required for treatment of the acute episode. A controlled study by Gelenberg et al. (225) found that patients randomly assigned to a "low" lithium level (0.4–0.6 meq/liter) had fewer side effects but more illness episodes than patients in the "standard" lithium group (0.8–1.0 meq/liter). However, the lithium levels of some of the patients in the low-lithium group decreased relatively rapidly from their previous treatment levels, a decrease that could have increased their risk of relapse. Although the prophylactic efficacy of lithium levels between 0.6 and 0.8 meq/liter has not been formally studied, this range is commonly chosen by patients and their psychiatrists (226). Despite the lack of formal study, it is likely that for many patients, increases in maintenance lithium levels will result in a trade-off between greater protection from illness episodes at the cost of an increase in side effects. The "optimal" maintenance level may therefore vary somewhat from patient to patient. Some patients find that a single, daily dose facilitates treatment compliance and reduces or does not change side effects.

The clinical status of patients receiving lithium needs to be monitored especially closely. The frequency of monitoring depends on the individual patient's clinical situation but generally should be no less than every 6 months for stable patients. The optimal frequency of serum level monitoring in an individual patient depends on the stability of lithium levels over time for that patient and the degree to which the patient can be relied upon to notice and report symptoms.

In general, renal function should be tested every 2–3 months during the first 6 months of treatment, and thyroid function should be evaluated once or twice during the first 6 months of lithium treatment. Subsequently, renal and thyroid function may be checked every 6 months to 1 year in stable patients or whenever clinically indicated (e.g., in the presence of breakthrough affective symptoms, changes in side effects, or new medical or psychiatric signs or symptoms) (198, 214).

References

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