Lithium, a silvery-white alkali metal, was discovered in 1817 when Swedish chemist Johan August identified it within the mineral petalite. Photograph used for representational purposes only
| Photo Credit: Dnn87, CC BY 3.0
In a significant stride towards bolstering strategic resources, Prime Minister Narendra Modi’s recent visit to the United States last month culminated in the launching of a collaborative initiative focused on recovering and processing critical minerals, notably lithium. This partnership underscores the rising importance of lithium in various sectors, from energy storage to pharmaceuticals. Lithium, denoted by the symbol Li, has atomic number 3 and is a silvery-white alkali metal. It was discovered in 1817 when Swedish chemist Johan August identified it within the mineral petalite. In 1821, William Brande successfully isolated lithium in its elemental form through the electrolysis of lithium oxide.
Due to continuing exploration, measured and indicated lithium resources have increased substantially worldwide, totalling about 105 million tons as per the U.S. geological survey in 2024. Major lithium reserves are concentrated in South America’s ‘Lithium Triangle’—encompassing parts of Bolivia, Argentina, and Chile. Australia is the leading producer, extracting lithium from hard-rock spodumene deposits. India’s lithium deposits are in Reasi (Jammu & Kashmir) and Mandya (Karnataka), with exploration ongoing in Rajasthan, Chhattisgarh, Jharkhand, and Himachal Pradesh. The recent Indo-U.S. initiative aims to recover and process lithium.
Lithium’s journey in medicine
In 1859, Alfred Baring Garrod published a paper in The London and Edinburgh Monthly Journal of Medical Science examining lithium’s potential to dissolve uric acid crystals, proposing its use for gout treatment. The hypothesis stemmed from chemical observations rather than clinical trials. While lithium salts showed promise in vitro, therapeutic applications were limited by toxicity and impractical dosing. The study marked one of the earliest discussions on lithium’s physiological effects, but its medical relevance remained uncertain.
In 1949, Australian psychiatrist John Cade published a seminal paper in the Medical Journal of Australia detailing his discovery of lithium’s antimanic properties. Cade hypothesised that mania was linked to a metabolic imbalance and conducted experiments, injecting guinea pigs with urine from manic patients, observing toxic effects. He administered various compounds to identify the poisonous substance, noting that lithium carbonate has a calming impact on the animals without sedation. Translating these findings to clinical practice, Cade treated ten patients with mania using lithium salts, reporting significant mood stabilisation and reduction in manic symptoms. This groundbreaking study introduced lithium as an effective treatment for mood disorders like acute mania and bipolar disorder.
Melbourne’s Noack and Trautner (1951) and French psychiatrists Despinoy and De Romeuf (1951) independently tested lithium in manic patients, reporting effectiveness. Despite initial scepticism and concerns over toxicity, further studies, notably by Danish psychiatrist Mogens Schou in the 1950s and 60s, confirmed lithium’s efficacy as a mood stabiliser. By 1970, lithium was approved for the treatment of bipolar disorder in the United States.
Mechanism of action and ongoing mysteries
Lithium’s exact mechanism in stabilising mood disorders is not fully understood. It is hypothesised that it influences neurotransmitter activity and intracellular signalling pathways, by competing with sodium ions due to their chemical similarities as alkali metals. This competition may alter neuronal excitability and neurotransmission. Despite its long history of use, the precise biological underpinnings of lithium’s mood-stabilising effects continue to be a research subject. Lithium has a narrow therapeutic window (0.6–1.2 mEq/L), requiring regular monitoring to prevent toxicity. It is absorbed orally, distributed evenly in total bodywater, and is excreted unchanged via kidneys, necessitating renal function monitoring. It is not used in pregnant women.
With lithium, the difference between an effective dose and a toxic dose is small. At therapeutic levels, lithium stabilises mood, but even slight elevations can lead to toxicity, causing neurological, renal, and cardiac complications. Lithium also interferes with thyroid function, leading to hypothyroidism. Over time, this can lead to fatigue, weight gain, and depressive symptoms, further complicating bipolar disorder management. Lithium exemplifies the Paracelsus’ principle—”the dose makes the poison”—whereby a slight deviation from the therapeutic range can turn it from a life-saving mood stabiliser into a toxic agent. It also has a delayed onset of action—often requiring weeks to show full effects—which means that more rapid-acting medications are usually preferred in acute manic episodes.
Second-generation antipsychotics have emerged as viable alternatives to lithium due to their mechanism of action and better safety profile. Unlike lithium, which acts as the source of bipolar disorder by inhibiting sodium-GPCR protein pumps in neurons, SGAs act at a downstream level by modulating neurotransmitter activity, particularly dopamine and serotonin. This difference means that while lithium exerts its effects at the root of the disorder by stabilising neuronal activity, SGAs regulate the symptoms more directly by blocking excessive neurotransmitter action.
Indications for Lithium Use
Despite the increasing use of SGAs, lithium remains the drug of choice for specific bipolar disorder presentations, maniac episodes and suicidal tendency prevention. It is most effective for classic euphoric mania and bipolar disorder with a strong genetic component. Lithium uniquely reduces the risk of suicide in bipolar patients, a benefit that SGAs do not replicate. Its mood-stabilising properties are particularly valuable in preventing relapses, ensuring long-term remission, and managing treatment-resistant cases.
What prompted John Cade to hypothesise lithium for mood stabilisation remains a greater mystery than the unknowns surrounding its mechanism of action. His work was published in 1949 when the relationship between medical research and ethics fundamentally differed from today’s standards. Cade’s experiments immediately after WW-2 reflected an era where scientific curiosity often operated in a vacuum, independent of ethical considerations. With the establishment of modern research ethics, including informed consent, clinical trial regulations, and oversight committees, such an experiment—would not even be possible today. Yet, these historical inquiries remind us that medical advancements have often emerged from unconventional and ethically questionable explorations.
In addition to its role in psychiatry, lithium is indispensable in battery technology, nuclear energy, ceramics, and lubricants.It plays a crucial part in carbon neutrality by enabling renewable energy storage.
(Dr. C. Aravinda is an academic and public health physician. The views expressed are personal. aravindaaiimsjr10@hotmail.com)
Published – March 17, 2025 05:41 pm IST
