Occupational stress is a trigger for Rebecca Wilde, a 32-year-old tech worker in Buckinghamshire. Four years ago, work pressures combined with family issues affected her sleep, leading to a severe manic episode. She was hospitalised for a month and a half, and diagnosed with type 1 bipolar disorder, also known as bipolar 1, a mood condition that can have devastating consequences if not managed well. Mania, and sometimes psychosis, is present in type 1.
Wilde was experiencing both: at one point, she thought she could talk to dogs. She was put on the antipsychotic drug olanzapine and another mood stabiliser, lithium. She has now been taking lithium alone for a year, and it has been transformative. “On the lithium, I definitely feel like me,” she says.
While Wilde was transitioning to lithium only, researchers were furiously debating the evidence around the drug. In 2023, the journal Bipolar Disorders published an editorial co-written by editor-in-chief Gin S Malhi, titled “Lithium first: not merely first line”. This asserted that lithium should be considered not only as one of several possible initial treatments for bipolar disorder, but as the first and foremost of these. Lithium “needs to be championed”, maintains Malhi, a visiting psychiatry professor at Oxford University.
But the publication ignited a storm. “It enraged me to see this editorial,” says Haim Belmaker, emeritus professor of psychiatry at Ben-Gurion University of the Negev, in Beersheba, Israel. In the absence of new data, “to me it was a terrible hubris for them to come out and suddenly, in a triumphal way, say that lithium was great”. Belmaker fired off a letter to the editor calling it a mistake to consider lithium the gold standard. This was published after eight peer reviews – a highly unusual amount of scrutiny. Three other commentaries then waded into the debate.
This is not the only heated dispute among lithium researchers from the past couple of years. A 2024 critique led to professors trading words such as “pseudoscience” and “extraordinarily venomous”. Feuds such as these point to the high stakes over the declining popularity of lithium.
Medicinal lithium is remarkable. There is more evidence of lithium’s effectiveness in managing bipolar disorder than for any other medicine. As a naturally occurring ion, lithium can’t be patented. And unlike most medicines, it’s not metabolised by the body.
Malhi explains why this is significant: “With lithium, the body can be thought of simply as a bucket of water with input and output of fluid. Then, whatever lithium you add gives you a plasma level. It means we can accurately make changes with sensitivity around plasma levels and clinical response and tolerability.”
Belmaker argues that lithium’s simplicity has made it alluring, but for some people this has hardened into an almost dogmatic belief in its superiority. Indeed, words such as “mystique” and “magic” pop up in the scientific literature around the medicine. It’s still not known how lithium works to stabilise moods.
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Lithium’s potential to treat mood disorders began being discussed in earnest in the middle of the 20th century and was popularised in the 1960s and 70s. Research slowed after the 90s, when anticonvulsant and antipsychotic medicines started to be used for bipolar. Since then there’s been a decline in expertise about lithium, says Allan Young, chair of mood disorders at King’s College London. Resistance to the use of lithium has been building for decades.
A key reason is that lithium is cumbersome to manage. It works only within a very narrow range of doses; beyond this, lithium toxicity can develop quickly, sometimes fatally. Serious side-effects include damage to the kidneys, thyroid and parathyroid. Other side-effects, such as excessive thirst and urination, can disturb sleep.
Wilde, a keen runner, has noticed this. Initially, lithium would cause her hands to tremble with dehydration. So she’s more careful about replenishing liquids and electrolytes. This has involved more night-time toilet visits, which she calls “more of an annoyance than anything”.
Overall, lithium proponents argue that concerns about side-effects are exaggerated, including by health workers who may wrongly attribute kidney issues to lithium. The alternatives can also carry side-effects; Wilde experienced stubborn weight gain from an antipsychotic drug.
The anticonvulsant sodium valproate provides another example. According to Young, when valproate was marketed as a mood stabiliser in the 1990s, pharmaceutical companies described it as safer during pregnancy than lithium, which can increase the likelihood of a baby being born with a heart defect. “That almost certainly turned out to be erroneous, because if anything, we think valproate is worse than lithium” for foetuses, Young says. But the damage had been done: “We saw a real step back in interest in terms of lithium.”
Because lithium is so finicky, plasma levels need to be checked with regular blood tests: initially weekly, and then every several months. Eating disorders and sudden weight loss can make lithium risky. In comparison, “other drugs can be started rather cavalierly”, according to Belmaker.
It can take months or even years to know how well someone is responding to lithium. This depends on a certain continuity of care and flow of information between clinicians. Yet some argue that all these requirements are actually a benefit of lithium, as they make close monitoring of the patient essential.
This may depend on each patient’s capacity to speak up for themselves. Wilde is organised and active, so she does not mind following up on communications among her various public and private doctors, and getting blood and organ tests every few months: “It’s worth the faff.” However, she acknowledges that she is young and relatively healthy, and lives close to medical care. The calculus might be different for someone with health complications, mobility issues, or routines frequently disrupted by mania or depression.
NHS data for medicines prescribed in England shows that in 2015/16, 51,682 patients were prescribed lithium carbonate (tablets) and 941 lithium citrate (liquid). This dwindled to 42,534 and 822 in 2023/24.
Since 2014, the National Institute for Health and Care Excellence (Nice) guidelines has recommended lithium as the only first-line maintenance treatment for bipolar disorder in the UK. Lithium would have been expected to trend up based on this guidance, as UK bipolar diagnoses more than doubled between 2001 and 2018, according to a sample of electronic medical records. Instead, lithium prescribing for patients with bipolar dropped from 31% to 16%.
Joseph Hayes, a psychiatry professor at University College London, co-authored the medical records study. With the overstretched state of the NHS and the scarcity of specialist bipolar clinics, “we’ve set up a mental healthcare service that makes it quite difficult to initiate lithium”, Hayes says. “There are clinicians who believe they can’t safely prescribe it,” even though in his experience lithium is distinct from other drugs in allowing some patients to thrive, not just get by.
“Lithium is woefully under-prescribed in the UK,” says Simon Kitchen, chief executive of the charity Bipolar UK. “Increasing lithium use means even more people living with bipolar will be able to stay well, keep out of hospital, get back into the workplace and live the lives they deserve.”
Lithium’s declining use is a worldwide trend, though especially marked in North America. In North America, Europe and Australia, between 1998 and 2020, anticonvulsants, antipsychotics and antidepressants were all prescribed more often than lithium to people with bipolar disorder. Globally, the most common reason medical professionals give for not prescribing lithium is patients’ negative beliefs.
It’s less surprising that lithium would be underused in the US – with its complicated swirl of insurance policies, medical lawsuits, and pharmaceutical advertising. On the other hand, in low- and middle-income countries, insufficient resources for monitoring lithium are especially concerning.
So a niggling question is why lithium use has also dropped in countries such as the UK. Michael Gitlin, a psychiatry professor at the University of California, Los Angeles, says that while some Europeans may view Americans “as like children who are distracted by shiny new drugs”, the shiny new drug factor isn’t limited to the US. In 2023, Gitlin, Malhi and colleagues issued a “call to arms” to stem the decline of lithium therapy.
Lithium’s venerable status may actually be working against it. Because it has been around longer than any other drug to treat bipolar disorder, it’s had longer to rack up a history of potential side-effects. Lithium has been subject to lingering stigma from the antipsychiatry movements of earlier decades and the social media-amplified stigma from the critical psychiatry movement today, according to Hayes. Some psychiatrists report that patients have formed negative impressions of lithium long before it’s suggested to them as a treatment.
There’s another risk of complacency. Because, as Young says, bipolar is “such a highly recurrent disorder”, long-term maintenance is important though sometimes underappreciated. It can be dangerous to discontinue lithium, he warns. “One of the sad situations is if someone has responded really well to lithium and then they stop it, they may not respond that well to being reintroduced. And it can be quite a rocky road to getting someone back to recovery.”
Some researchers report that it’s becoming ever more challenging to obtain research funding for lithium. Pharmaceutical companies have little incentive to fund studies or the marketing of lithium, which will never be a big earner unless they bundle it into novel compounds. “If lithium was a new drug today and someone could make a profit from it, I think drug companies would be shouting from the rooftops about how effective it is,” Hayes says.
Even getting data for research can be tough, reports Carol Crean, an associate professor in physical and materials chemistry at Surrey University. Her team has been developing less invasive methods for monitoring lithium, such as wearable sensors. Wilde already uses a bipolar symptom-tracking app; continuous monitoring technologies would give people like her more power to check their own lithium levels, as people with diabetes do for blood glucose levels. But in a vicious circle, Crean says, “With fewer people taking the drug, it can be challenging to reliably get patient samples to help progress the work.”
The increasing sophistication of technology for personalised medicine could help reverse the plummeting of lithium use. If clinicians were able to more accurately predict who would do well on lithium, it could be a gamechanger. Young is part of an EU-funded research project seeking to determine the biomarkers related to lithium response, using tools including activity sensors, blood tests, machine learning and MRI techniques to directly measure the distribution of lithium in the brain. “This is probably one of the most exciting things to happen with lithium research in decades,” says Young.
Another possibility is that as the prescription of lithium for bipolar disorder keeps falling, interest in other applications of lithium will rise. Researchers continue to investigate its protective effects against suicide and dementia, and its supplementary use in microdoses. This has generated much excitement, though some remain concerned about the potential for overhyping lithium in new ways.
These controversies remain academic for patients who will ultimately choose the least bad option for them. Since childhood, Wilde has tried to avoid medication where possible. She still recognises the limitations of any mood stabiliser: “I really don’t think it’s just lithium that’s going to keep me, or anyone really for that matter, stable.” But combined with therapy, work-life balance, physical activity, medical checks and a strong support system, lithium has helped her get back to herself. “As long as it’s working for me, I will stay on it.”
