DOCUMENT

T he use of lithium in psychiatry goes back to the mid-19th century. It became a mainstay in the late 1940s as a treatment for mania and depressive illnesses. At the time, it was a giant leap forward in treatments, but was fraught with challenges as patients grappled with unwanted side-effects that could overshadow its benefits. Its use continues, unchanged, today. Which got Otago University Associate Professor Ailsa McGregor and her collaborators thinking: surely we can do better. As a translational pharmacologist, Ailsa works to develop new medicines and clinical treatments to advance human health. She has previously led research into adapting curcumin (turmeric) and antidepressants like citalopram to reduce brain inflammation and improve functional recovery after stroke. In the case of lithium, Ailsa hopes to make an existing drug safer and more effective. “Lithium is still the gold standard treatment for bipolar disorder because it’s a really effective mood stabiliser,” Ailsa explains, “and the only one that reduces the risk of suicide. “It's a good drug because it does work for about 50% of people. But it's also a hard drug to manage.” Lithium is taken orally, and getting the dosage just right is crucial, as every patient responds differently. Too much lithium can become toxic, while too little renders it ineffective. As a result, patients need regular blood tests to ensure they’re within the “sweet spot”. “Scientists have searched for alternatives, but so far, none of the other mood stabilisers improve outcomes as much as lithium,” Ailsa explains. “However, even when people take the drug as prescribed, some still experience acute toxicity and end up in hospital.” Unfortunately, around half of those who take lithium stop treatment due to side-effects like kidney damage, weight gain, and cognitive impairment. To address this, Ailsa’s team is exploring an innovative approach: “caging” lithium in a larger molecular structure. This method aims to stabilise how the drug is absorbed into the bloodstream, allowing for a faster, more controlled response that doesn’t require blood monitoring while potentially reducing side-effects. The caging strategy has already been used for some anti-cancer drugs, such as those based on gallium, a metal element similar to lithium. Ailsa’s lab is one of just a few worldwide investigating this technique for lithium. In 2022, the Neurological Foundation awarded Ailsa a small project grant of $14,976 to test the proof-of-principle for this approach. Following that, she secured a larger grant from the Health Research Council of $150,000, which will fund her research over the next two years, with the goal of bringing the treatment to human clinical trials. Engaging with patients, particularly Māori and Pacific populations where there is an increased prevalence of bipolar disorder, is an important aspect of Ailsa’s research beyond the lab. “We are gathering feedback from patients to understand the social and cultural acceptability of lithium treatment, as well as learning what is important to them, so our efforts in the lab align with what patients want.” Ailsa says her initial Neurological Foundation grant, though relatively small, was fundamental for the research to gain momentum. “Having the scientific community see value in an idea is really important. Those small amounts are a stepping- stone to getting a project to a point where you can tap into something bigger, and grow an entirely new research area.” LITHIUM: A bittersweet pill Lithium – a metal more often associated with batteries than brain chemistry – is widely used to manage bipolar disorder. “Lithium is still the gold standard treatment for bipolar disorder because it’s a really effective mood stabiliser...” Associate P rofessor Ailsa McGregor 10 Headlines