Section 3.4.1

Lithium

General Description

Lithium is an element and is the lightest of the alkali metals similar to sodium, potassium, magnesium, and calcium. Lithium is available as a carbonate (Li2CO3) for oral use in rapidly acting capsules and tablets (eskalith, lithonate and lithotabs), slow-release tablets (lithobid), controlled-release tablets (eskalith CR) tablets. Lithium citrate is also available as a syrup.

Indications for Medication

Lithium is effective in bipolar disorder, schizoaffective disorder, major depressive disorder, schizophrenia and impulse control disorders. There is also research data on some effectiveness for premenstrual dysphoric disorder, intermittent explosive behaviors in borderline personality disorder, bulimia nervosa and episodic or binge drinking. Research data also shows lithium's benefit in treating aggressive or self-injurious behavior.

For bipolar disorder, lithium has been proven effective in both short-term treatment and the prophylaxis of the illness in approximately 70% of patients. Both manic and depressive episodes respond to lithium. However, the response to lithium treatment can take a relatively long time, so manic episodes are usually treated with antipsychotics and lithium, and the depressive episodes are usually treated with antidepressants and lithium.

For bipolar disorder, studies report that lithium maintenance halves the number of recurrences and the recurrences are less severe. The prophylactic effect of lithium, however, may not develop for several months. A recurrence of bipolar symptoms within the first 2-3 months of treatment should not be taken as an indication that lithium is not effective.

For schizoaffective disorder, the use of lithium is often helpful. Lithium may be used both in the short-term treatment and in the prophylaxis of the illness. As with bipolar disorders, other psychiatric medications are often used in the acute treatment and the long-term maintenance of the illness. The more cyclic nature of this illness, the more beneficial the lithium.

For major depressive disorder, the chief indication for lithium is as an adjuvant treatment added to other antidepressants to convert an antidepressant non-responder into a responder. Lithium alone may be effective for those major depressions which are actually bipolar disorder patients (who have not yet had a manic episode).

For schizophrenia, patients who cannot take antipsychotic drugs may benefit from a trial of lithium. In addition, lithium may be of special benefit in those patients with intermittent angry outbursts.

For impulse control disorders, lithium is effective in reducing intermittent explosive episodes. This efficacy appears to be especially apparent when episodes of rage or violence are not premeditated and are seemingly untriggered. The angry outbursts in patients with mental retardation may also be reduced with lithium.

Clinical Guidelines

Before starting lithium, the clinician should conduct a routine laboratory work-up and (if possible) a physical examination. The laboratory work-up should include a serum creatinine level, an electrolyte screen, thyroid function tests including TSH, a complete blood count (optional), electrocardiogram (over age 40 or history of cardiac disease) and a pregnancy test (if there is any risk of the patient being pregnant).

For most adult patients, it is reasonable to start lithium at 300mg three times daily. The starting dose in patients who are elderly or who have renal impairment should be lower, possibly 300mg once or twice daily. The usual eventual dosage range is between 900 to 2100mg a day, given in two or three divided doses. Serum levels of lithium can be obtained after five days. The lithium dosage should be adjusted to obtain a lithium level between 0.8 to 1.2mEq per L (during acute episodes).

Lithium levels are usually obtained 12 hours after the last dose. Lithium levels in patients treated with slow-release preparations are approximately 30% higher than the levels obtained with other preparations. The use of divided doses reduces gastric upset and avoids a single large peak in lithium levels. There is debate over whether multiple small daily peaks are clinically superior to a single large daily peak.

The lithium level can be monitored as often as weekly for the first month and then biweekly for the next month. After six months it may be appropriate to check the patient's lithium level every two months. If the patient has been stable for a year, checking lithium levels two to four times a year may be sufficient.

In acute mania, if the lithium produces no clinical response after four weeks at therapeutic levels, slightly high serum levels of lithium (up to 1.4mEq per L) may be tried if there are no severe adverse effects. Other drugs should be given therapeutic trials at this point. Continued rapid cycling may respond to the addition of L-thyroxine. The substitution or the addition of carbamazepine or valproic acid may be useful.

The decision to maintain a patient on lithium is usually based on the severity of the illness and the risk of adverse effects from lithium. Maintenance serum levels of lithium can be lower than those needed for short-term treatment. Such levels are usually kept between 0.6 and 1.0mEq per L, although some researchers have reported successful prophylaxis with serum levels as low as 0.4mEq per L. In addition to periodic measurement of lithium levels, serum creatinine and TSH levels should be monitored every 3-6 months in these patients.

Adverse Effects

The most common adverse effects from lithium treatment are increased thirst, polyuria, gastric distress, weight gain, tremor, fatigue and mild cognitive impairment. Gastric distress may include nausea, vomiting and diarrhea. Dividing the doses, administering the drug with meals or switching to different lithium preparations can reduce gastric distress.

The most common adverse renal effect of lithium is polyuria with secondary polydipsia. The symptom is particularly problematic for 20-25% of treated patients. When polyuria is significant, the patient's renal function should be evaluated and followed with a 24-hour urine collection for creatinine clearance. This syndrome can be treated with chlorothiazide, hydrochlorothiazide or amiloride.

Lithium also affects thyroid function causing a generally benign and often transient diminution in the concentrations of circular thyroid hormones. Literature reports have attributed goiter (3-4%), benign reversible exophthalmos and hypothyroidism (5%) to long-term lithium treatment. Around 50% of patients receiving long-term lithium treatment have an abnormal thyrotropin-releasing hormone (TRH) response and approximately 30% have elevated levels of TSH.

If thyroid dysfunction develops, thyroid supplementation can be administered safely. In these conditions, TSH levels should be measured and checked periodically. Lithium induced hypothyroidism should be considered when evaluating depressive episodes that emerge during lithium therapy.

The most common cardiac effects are T wave flattening or inversion. The changes are benign and disappear after the lithium is excreted from the body. Lithium treatment is contraindicated in patients with sick sinus syndrome.

The most prevalent dermatological effects include acneiform, follicular and maculopapular eruptions. Pretibial ulceration and worsening of psoriasis are also prevalent. Alopecia has been reported. Many of these skin conditions respond to changing lithium preparations or the usual dermatological measures. Sometimes these conditions may force lithium discontinuation.

Lithium should not be administered to pregnant women in the first trimester because of the risk of birth defects, specifically Ebstein's anomaly. Lithium administered during the final months of pregnancy can result in babies who are lithium-toxic at birth. Lithium is excreted in breast milk and should not be used while a woman is breast-feeding.

Lithium toxicity includes symptoms of vomiting, profuse diarrhea, severe tremor, ataxia, coma and seizures. Neurological signs of mental confusion, hyperreflexia and dysarthria can proceed to coma and death. Lithium toxicity requires immediate medical attention.

Drug-Drug Interactions

Many diuretics and prostaglandin synthetase inhibitors can increase lithium levels to toxic levels. Osmotic diuretics, carbonic anhydrase inhibitors and xanthines can reduce lithium levels to below therapeutic levels.

Antipsychotic and lithium, co-administered, may result in a synergistic increase in the symptoms of lithium-induced neurological adverse effects. The co-administration of lithium with anticonvulsants, including carbamazepine may also aggravate neurological symptoms.

Lithium also interacts with a wide variety of other medications, causing changes in the blood level of lithium. These drugs include antibiotics, tricyclic antidepressants, anti-inflammatory agents, antipsychotics, and cardiovascular drugs, among others. The clinician should consult a PDR to clarify possible interactions.

The consent form for this medication is "Mood Stabilizing Medication (Lithium)".