72: Lithium

HISTORY AND EPIDEMIOLOGY

The Swedish chemistry student Arfwedson discovered lithium in 1817.^8,131 Lithium derives its name from the Greek word for stone, lithos, from which it was first isolated. The therapeutic use of lithium has a long history beginning in the mid 19th century, when lithium salts were used to treat individuals with gout and were noted to improve symptoms of mania and depression.¹¹⁶ The soft drink 7-Up was originally formulated with lithium as its “active ingredient.”⁸ During the 1930s and 1940s, lithium was used as a salt substitute (“Westsal”) for patients with congestive heart failure but was discontinued after several cases of acute lithium poisoning were described.⁸⁷ The beneficial effects of lithium on bipolar disorder were “rediscovered” by Cade in 1949, when he noticed the calming effect of lithium carbonate on guinea pigs.⁵² The same year, however, the US Food and Drug Administration (FDA) banned the use of lithium in response to reported poisonings.¹³⁹ The FDA lifted the ban in 1970 and approved the use of lithium for the treatment of mania.

Currently, lithium is the most efficient long-term therapy for treatment and prevention of bipolar affective disorders,^51,81 with a demonstrated antisuicidal effect and an ability to improve the manic and depressive symptoms of the illness, as well as to augment the therapeutic efficacy of other therapies that have failed to achieve symptom remission.^{16,45,53,78,81,108,111,131} Investigations on the use of lithium for compulsive gambling have also demonstrated beneficial results,⁹³ and it is under investigation for use in neurodegenerative disorders such as Alzheimer disease, stroke, amyotrophic lateral sclerosis, Huntington disease, multiple sclerosis, and traumatic brain injury.^{23,47,142,199} In most industrialized nations, approximately one in 1000 persons is prescribed one or more of the various lithium formulations.^84,121,122

PHARMACOLOGY

Lithium, the simplest xenobiotic in the modern pharmacopoeia, has a complex mechanism of action that has not been completely elucidated even after more than 50 years of clinical use. Psychotropics modifying monoamine neurotransmission form the basis of modern psychopharmacology. The current paradigm of neuropsychiatric therapeutics implies that because xenobiotics that affect the neurotransmission of dopamine are most efficacious, this receptor-drug exemplar defines the disease. Multiple lines of investigation have shown that beyond simple monoamine balance, the interaction between multiple signaling cascades, neurotrophic and neuroprotective systems is not only involved in the pathogenesis of mood disorders, but also the cellular and molecular means of the action of lithium.¹⁵⁵ Additionally, the understanding that a particular receptor only undergoes a single agonist-receptor activation has been replaced by the growing comprehension that agonist binding causes activation of multiple pathways of downstream signaling, with a myriad of results.²⁵ Lithium illustrates this new paradigm through its multiple direct and ...