Lithium (medication)
Certain lithium compounds, also known as lithium salts, are used as psychiatric medication, primarily for bipolar disorder and for major depressive disorder. Lithium is taken orally.
Common side effects include increased urination, shakiness of the hands, and increased thirst. Serious side effects include hypothyroidism, diabetes insipidus, and lithium toxicity. Blood level monitoring is recommended to decrease the risk of potential toxicity. If levels become too high, diarrhea, vomiting, poor coordination, sleepiness, and ringing in the ears may occur.
Lithium is teratogenic and can cause birth defects at high doses, especially during the first trimester of pregnancy. The use of lithium while breastfeeding is controversial; however, many international health authorities advise against it, and the long-term outcomes of perinatal lithium exposure have not been studied. The American Academy of Pediatrics lists lithium as contraindicated for pregnancy and lactation. The United States Food and Drug Administration categorizes lithium as having positive evidence of risk for pregnancy and possible hazardous risk for lactation.
Lithium salts are classified as mood stabilizers. Lithium's mechanism of action is not known.
In the nineteenth century, lithium was used in people who had gout, epilepsy, and cancer. Its use in the treatment of mental disorders began with Carl Lange in Denmark and William Alexander Hammond in New York City, who used lithium to treat mania from the 1870s onwards, based on now-discredited theories involving its effect on uric acid. Use of lithium for mental disorders was re-established in 1948 by John Cade in Australia.
Lithium carbonate is on the World Health Organization's List of Essential Medicines, and is available as a generic medication. In 2023, it was the 187th most commonly prescribed medication in the United States, with more than 2million prescriptions. It appears to be underused in older people, and in certain countries, for reasons including patients' negative beliefs about lithium.
Medical uses
In 1970, lithium was approved by the United States Food and Drug Administration for the treatment of bipolar disorder, which remains its primary use in the United States. It is sometimes used when other treatments are not effective in a number of other conditions, including major depression, schizophrenia, disorders of impulse control, and some psychiatric disorders in children. Because the FDA has not approved lithium for the treatment of other disorders, such use is off-label. Lithium is unique among medications in that it is proven to prevent suicide in mood disorders such as bipolar disorder and recurrent major depression.The mechanisms of biological action of lithium are only partially understood. For instance, studies of lithium-treated patients with bipolar disorder show that, among many other effects, lithium partially reverses telomere shortening in these patients and also increases mitochondrial function, although how lithium produces these pharmacological effects is not understood. Even the exact mechanisms involved in lithium toxicity are not fully understood.
Bipolar disorder
Lithium is primarily used as a maintenance drug in the treatment of bipolar disorder to stabilize mood and prevent manic episodes. It is also effective in the acute treatment of manic episodes. It is effective for mania within the first 7 days of treatment.For acute treatment, although recommended by treatment guidelines for the treatment of depression in bipolar disorder, the evidence that lithium is superior to placebo for acute bipolar depression is low-quality. Atypical antipsychotics are considered more effective for treating acute bipolar depressive episodes. Lithium is effective for the long term prevention of bipolar depressive episodes.
Lithium treatment was previously considered to be unsuitable for children, however more recent studies show its effectiveness for treatment of early-onset bipolar disorder in children as young as eight. The required dosage is slightly less than the toxic level, requiring close monitoring of blood levels of lithium during treatment. Within the therapeutic range there is a dose-response relationship.
A limited amount of evidence suggests lithium carbonate may contribute to the treatment of substance use disorders for some people with bipolar disorder. People with bipolar disorder are at a 3 times higher risk for dementia. Lithium reduces the risk of dementia by 50% among people with bipolar disorder.
Schizophrenic disorders
Lithium is recommended for the treatment of schizophrenic disorders only after other antipsychotics have failed; it has limited effectiveness when used alone. The results of different clinical studies of the efficacy of combining lithium with antipsychotic therapy for treating schizophrenic disorders have varied.Major depressive disorder
Lithium is widely prescribed as an adjunct treatment for depression.Augmentation
If therapy with antidepressants does not fully treat and discontinue the symptoms of major depressive disorder then a second augmentation agent is sometimes added to the therapy. Lithium is one of the few augmentation agents for antidepressants to demonstrate efficacy in treating MDD in multiple randomized controlled trials and it has been prescribed for this purpose since the 1980s. A 2019 systematic review found some evidence of the clinical utility of adjunctive lithium, but the majority of supportive evidence is dated.While SSRIs have been mentioned above as a drug class in which lithium is used to augment, there are other classes in which lithium is added to increase effectiveness. Such classes are antipsychotics as well as antiepileptic drugs. Lamotrigine and topiramate are two specific antiepileptic drugs in which lithium is used to augment.
Monotherapy
There are a few old studies indicating efficacy of lithium for acute depression with lithium having the same efficacy as tricyclic antidepressants. A 2019 systemic review found that lithium monotherapy was just as effective as antidepressant monotherapy.Prevention of suicide
Lithium has been shown to reduce the risk of suicide in individuals with bipolar disorder or major depression to close to the same level as that of the general population. It is thought to exert this effect by treating the underlying mood disorder and through a reduction in impulsivity and aggressiveness. Lithium is proven to reduce the risk of suicide in mood disorders by 87% in randomized double-blind placebo-controlled trials. Some meta-analyses have not found a statistically significant association between lithium and a reduction in completed suicide, however these meta-analyses are disputed. Some evidence suggests lithium is effective in significantly reducing the risk of self-harm and unintentional injury for bipolar disorder in comparison to no treatment and to antipsychotics or valproate. In addition, lithium decreases all-cause mortality in people with bipolar disorder.The increased presence of trace amounts of lithium in drinking water is correlated with lower overall suicide rates, especially among men. Lithium in drinking water is also associated with lower rates of homicide, rape, drug arrests, and other crimes.
Cluster headaches, migraine, and hypnic headache
Studies testing prophylactic use of lithium in cluster headaches, migraine attacks, and hypnic headache indicate good efficacy.Monitoring
Those who use lithium should receive regular serum level tests and should monitor thyroid and kidney function for abnormalities, as it interferes with the regulation of sodium and water levels in the body, and can cause dehydration. Dehydration, which is compounded by heat, can result in increasing lithium levels. The dehydration is due to lithium inhibition of the action of antidiuretic hormone, which normally enables the kidney to reabsorb water from urine. This causes an inability to concentrate urine, leading to consequent loss of body water and thirst.Lithium concentrations in whole blood, plasma, serum, or urine may be measured using instrumental techniques as a guide to therapy, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdosage. In clinical settings, lithium doses are adjusted to achieve a target serum concentration, usually measured 12 hours after the last dose.
Lithium levels
According to Stahl's Prescriber's Guide, target concentrations for acute mania should be 1.0–1.5 mEq/L. 0.6–1.0 mEq/L for depression, and 0.7–1.0 mEq/L for long-term maintenance of bipolar disorder. In the elderly, lower doses and lower lithium levels are often adequate and advisable. The Maudsley and Ghaemi prescriber's guides recommend a slightly lower lithium level of 0.8‐1.0 mmol/L for acute mania.For the maintenance treatment of bipolar disorder, the International Society for Bipolar Disorders and International Study Group on Lithium guidelines recommend lithium levels of 0.6‐0.8 mmol/L. In the case of good response but poor tolerance, the guidelines recommend a level of 0.4‐0.6 mmol/L. In the case of insufficient response but good tolerance, the guidelines recommend a level of 0.8‐1.0 mmol/L.
For the maintenance treatment of the elderly, the ISBD and ISGL guidelines recommend a more conservative approach of levels of 0.4‐0.6 mmol/L, with the option to go up to 0.7 or 0.8 mmol/L at ages 65‐79, and up to a maximum of 0.7 mmol/L over age 80.
As a result of lithium's narrow therapeutic index, toxic effects can occur at serum concentrations close to therapeutic levels, necessitating close monitoring during treatment. Initially, levels are measured every 1–2 weeks until the desired serum concentration is achieved, then every 2–3 months for the first 6 months. Once stable, levels are measured every 6–12 months.
Levels of 1.2-1.5 mmol/L are considered borderline toxic. Levels above 1.5 mmol/L are considered toxic. Levels above 2.0 mmol/L may lead to disorientation, renal failure, seizures, and coma.