Side effects and toxicity
One reason for lithium’s slide in popularity is its perceived side-effect profile. Toxic amounts can be lethal, and therapeutic amounts can be bothersome. Yet concerns are often exaggerated because of lack of familiarity with the drug.10,11
Intoxication. Lithium does have a narrow therapeutic index, with toxicity related to serum concentration and duration of exposure. Acute overdoses, while not benign, are often better tolerated than gradual, more tissue-saturating exposures. Idiosyncratic factors are also involved, as evidenced by documented toxicity at “therapeutic” levels and tolerability despite very high levels.
Early warnings of impending toxicity include:
- neurologic findings such as dysarthria, new or worsening tremor, and ataxia
- gastrointestinal symptoms such as anorexia, nausea, vomiting, and diarrhea.
Severe toxicity can be fatal or cause permanent neurologic (often cerebellar) damage. Causes of intoxication range from deliberate overdose to renal impairment, low-sodium diets, drug interactions, and dehydration. At particular risk are patients with lithium-induced polyuria whose access to fluid replacement is compromised.
Treatment involves reducing absorption, increasing excretion, and restoring fluid-electrolyte balance. Severe intoxication, especially if renal function is impaired, is best treated with hemodialysis.
RECOMMENDED TESTS BEFORE PRESCRIBING LITHIUM
| Test | Indication |
|---|---|
| Serum creatinine, urinalysis | To screen for renal function |
| TSH and T4 | To establish baseline thyroid function |
| CBC (optional) | If indicated by patient’s overall medical condition or because some doctors prefer to do more general screening |
| ECG (optional) | For patients with risk factors for heart disease |
| Pregnancy test | For at-risk women because of lithium’s teratogenic potential |
Neurologic. Mild neurologic complaints such as memory impairment, slow reaction time, lack of spontaneity, and lost creativity have been ascribed to lithium and may lead to noncompliance. Under such circumstances, other diagnostic considerations include breakthrough depression, hypothyroidism, other illness, hypercalcemia, other medications, and absence of hypomania.
Like valproate, lithium can cause a benign postural tremor that is usually tolerable and often transient. Should the tremor be problematic, treatment considerations include dosage reduction, switching to a slow-release preparation, reducing caffeine intake, avoiding other tremor-causing drugs such as theophylline or stimulants, and treating associated anxiety. If an anti-tremor drug is needed, a beta-blocker such as propranolol is used most commonly; other options to consider are primidone and gabapentin. Don’t forget that a worsening tremor may indicate impending toxicity.
Very rarely, lithium has been associated with pseudotumor cerebri (benign intracranial hypertension), peripheral neuropathy, and a myasthenia gravis-like syndrome.
Cardiovascular. Like many drugs, lithium can cause benign ST-T wave changes on ECG.
More serious, but fortunately quite uncommon, is lithium-induced sinus node dysfunction manifesting as a variety of bradyarrhythmias and, at times, syncopal episodes. Since normal aging is associated with a gradual loss of sinus node pacemaker cells, the elderly may be especially sensitive to this problem. Unless a pacemaker is implanted, sinus node dysfunction usually requires lithium discontinuation.
Endocrine. The association between lithium and goiter and hypothyroidism is well-recognized, with elevated risk in women and in patients with pre-existing thyroid disease. Both clinical and symptomatic subclinical hypothyroidism will improve with supplemental thyroid hormone. Less well appreciated are reports of hyperthyroidism occurring during lithium therapy or shortly after its discontinuation. Because subclinical hyperthyroidism may not be benign, careful attention must be paid to maintaining thyroid function well within the normal range.
Reports continue to accrue of lithium-related hypercalcemia and increased parathyroid hormone levels, with an occasional patient developing parathyroid hyperplasia or adenoma requiring surgical intervention.12 No specific guidelines have been established for monitoring serum calcium, but some authors have recommended periodic testing.
Weight. At least one-third of patients on lithium gain weight for a variety of reasons, such as altered lipid and carbohydrate metabolism, use of high-calorie fluids to combat polydipsia and polyuria, hypothyroidism, and the use of other drugs associated with weight gain. If weight gain occurs, recognize it early (weigh your patients) and institute appropriate dietary and exercise measures.
Hematologic. A mild, benign leukocytosis is seen sometimes during treatment with lithium. This effect has been harnessed to treat some neutropenic conditions. Lithium does not increase the risk of blood dyscrasias.
Dermatologic. Acne, psoriasis, and follicular keratosis may first appear or worsen during lithium therapy. Occasionally, otherwise successful lithium therapy has been rendered impossible by a dramatic dermatologic flare-up. Hair loss has also been associated with lithium use for unclear reasons, although hypothyroidism is occasionally a factor.
Renal. Impaired urinary concentrating ability and polyuria are common adverse effects. Both may be reversed with timely treatment discontinuation, but they may persist even after discontinuation in patients on long-term lithium treatment.12
Polyuria is largely nephrogenic in origin and, at times, can be voluminous, cause great inconvenience, and pose a risk of dehydration and lithium intoxication. Patients sometimes believe that thirst drives the polyuria and attempt to deal with it by restricting fluid intake, which can be quite dangerous. More appropriate interventions include dosage reduction (if possible) and the use of a thiazide and/or potassium-sparing diuretic. If diuretics are used, serum lithium concentrations may rise. Debate remains as to whether slow-or controlled-release preparations or single daily dosing are “kinder to the kidney.”