Antidepressant and Antimanic Medications: Lithium
Lithium was available and used medically in the early 1800s as a treatment for gout, diabetes, and epilepsy, and it was used in the 1870s to treat mood disorders, which were thought to result from uric acid deposits in the brain. It was more than 20 years from the time that Cade (1949) reported its efficacy in mania that it was introduced into clinical practice in the United States.
Lithium is the prototypical antimanic drug and the one against which others are measured. It is the only drug currently approved by the FDA for acute or maintenance treatment of mania and continues to be the drug of choice. However, other antimanic agents may offer advantages that need to be considered when choosing an initial medication.
Lithium has been shown to be effective in the acute treatment of mania compared with placebo and with antipsychotic drugs (Prien et al. 1972). Response rates with lithium range from 60% to 80% in “classic” bipolar disorder. It may be less effective than anticonvulsant antimanic drugs in patients with dysphoric mania (i.e., mania with prominent anxiety or depressive symptoms) or rapid cycling. Other conditions associated with lithium nonresponse are listed in
As with antidepressant treatments, there is a time lag in the onset of the therapeutic action of lithium, with the full effects often taking from 1 to 4 weeks to occur. This time lag is especially important with lithium because manic patients are difficult to manage and have extremely poor judgment, making the risk of self-injury or injury to others very real. For this reason, an antipsychotic medication or benzodiazepine is usually required until the therapeutic effects occur.
Lithium is rapidly and completely absorbed, is not protein-bound, and does not undergo metabolism. Peak plasma levels are achieved within 2-4 hours, and the mean half-life is 18 hours (range: 14-30 hours) in young patients. Ninety-five percent of the drug is excreted by the kidneys, with excretion proportionate to plasma concentrations. Because lithium is filtered through the proximal tubules, factors that affect glomerular filtration rate will alter lithium clearance. Because sodium is also filtered through the proximal tubule, a decrease in plasma sodium can increase lithium reabsorption in the proximal tubule and cause an increase in plasma lithium levels; conversely, an increase in plasma lithium levels can cause an increase in sodium excretion, depleting plasma sodium.
Lithium is most commonly prepared as the carbonate form, although lithium citrate is also available. Most preparations come in 300-mg tablets or capsules. Therapeutic total dosages of lithium are quite variable, ranging from 600 mg/day to as high as 2,100 mg/day. Lithium doses are usually divided (bid or tid) until the therapeutic total daily dose is established, and then either twice-daily or bedtime dosing is adequate. Given the compliance issues usually involved in the treatment of patients with bipolar disorder, dosing should be as simple as possible, making one daily dose at bedtime the most desirable, if tolerated.
Because of the potential for serious toxicity, plasma levels of lithium are routinely used to establish a therapeutic dose. The usual therapeutic range is between 0.5 and 1.5 mEq/L. In the acute-treatment phase, plasma lithium levels between 0.8 and 1.3 mEq/L are recommended in order to maximize therapeutic effect. Lithium levels above 0.8 mEq/L are associated with fewer relapses into mania or depression—but greater noncompliance due to side effects—than levels between 0.4 and 0.6 mEq/L (Gelenberg et al. 1989).
Lithium has a narrow “therapeutic window,” with little benefit for most patients from blood levels below 0.4 mEq/L and serious toxicity often occurring above 2.0 mEq/L. A doubling of the usual daily dose can possibly result in toxic blood levels. Side effects related to high lithium levels include tremor and gastrointestinal disturbances. Serious lithium toxicity usually also involves symptoms related to the CNS, including somnolence, confusion, dysarthria, hypotension, cardiac arrhythmias, pyramidal tract signs, and coma. Lithium toxicity can cause permanent CNS damage.
Lithium should be used cautiously in young or elderly patients because of increased differences in pharmacokinetics in these groups. Elderly patients appear to be more sensitive to side effects from lithium and have a higher rate of confusion compared with younger patients (Abou-Saleh 1992). Lithium has been reported to cause fetal heart anomalies, but recent data suggest that the incidence is low, so risks versus benefits must be weighed (L. S. Cohen et al. 1994). Because lithium is excreted in breast milk in significant quantities, breast feeding should be approached with caution.
Lithium can cause short-term side effects, including tremor, gastric irritation, nausea, abdominal cramping, diarrhea, vomiting, increased white blood cell count (up to 15,000 cells/mm3), polyuria and polydipsia, dermatitis, extrapyramidal reactions, fatigue and muscle weakness, and flattening or inversion of T waves and/or flattening of U waves on an electrocardiogram. Long-term side effects include weight gain, hypothyroidism (5%-30%), diabetes insipidus, decreased glomerular filtration rate, hyperthyroidism, and hyperparathyroidism.
Antidepressant and Antimanic Medications
Combined Medication and Psychotherapy
Treatment-Resistant Mood Disorders
Treatment of Mood Disorders in the Medically Ill Patient
Strategies and Tactics in the Treatment of Depression
Revision date: June 20, 2011
Last revised: by Andrew G. Epstein, M.D.