New Delhi: Lithium is the gold-standard mood stabiliser for long-term treatment of bipolar disorder. But despite decades of use, scientists still do not fully understand how the drug behaves in the brain.
Now, a new study published in The Lancet Psychiatry has used a specialised magnetic resonance imaging (MRI) technique to directly measure lithium levels in the brain and examine whether they change differently depending on whether the drug is taken once or twice daily.
People with bipolar disorder experience extreme shifts in mood and energy, shuttling between episodes of mania and episodes of major depression. About 40 million people around the world live with this neuropsychiatric condition.
Lithium is one of the most effective drugs that prevent relapses, reduce hospitalisations, and lower the risk of suicide in those suffering from bipolar disorder and treatment-resistant depression.
However, it has a narrow therapeutic window, which means the difference between an effective dose and a toxic one is small. High lithium levels can damage the kidneys and affect thyroid, metabolic, cognitive, and cardiac function.
To keep patients within this safe range, clinicians regularly monitor lithium levels using blood tests—weekly when treatment begins and every three to six months as patients adjust to the dose.
“It is uncommon but well recognised that some people can experience lithium toxicity with levels in the therapeutic range, so understanding whether these people are prone to greater brain uptake could be very valuable,” said David Cousins, co-author of the study and Director of the Newcastle Magnetic Resonance Centre at Newcastle University, UK.
Studies suggest that lithium reaches peak concentrations in the blood within a few hours of taking a tablet, depending on the formulation. In the brain, however, lithium appears to accumulate much more slowly, peaking roughly a day after a dose and remaining at lower concentrations than those measured in blood.
“Currently, monitoring of lithium treatment relies on measuring lithium levels in the blood, based on the assumption that these levels reflect lithium concentrations in the brain,” said Peter Thelwall, Professor of Magnetic Resonance Physics and Director, Centre for In Vivo Imaging, Translational and Clinical Research Institute, Newcastle University, UK. Thelwall is a co-author of the study.
Also read: Bengaluru is leading India’s mental health revolution. VCs say it’s the next big field
How was it done?
To track whether blood measurements accurately reflect lithium absorption in the brain, researchers studied 41 adults with bipolar disorder who had been taking either once-daily or twice-daily courses of lithium for at least a month. Over the course of a day, participants underwent repeated lithium MRI (⁷Li MRI) scans alongside routine blood tests.
At the standard 12-hour monitoring point used in clinical practice for bipolar disorder, brain lithium levels closely tracked changes in blood lithium levels. However, the pattern differed depending on the dosing schedule.
“This really was an unanswered question, which was why we were so excited to see the results ourselves,” said Cousins.
In people taking lithium once a day, both brain and blood levels gradually declined across the day. In those taking lithium twice daily, levels rose after the morning dose before falling again, resulting in more stable brain lithium levels over 24 hours.
“Our study challenges the assumption that the brain might smooth out fluctuations in lithium levels across the day. This is a valuable insight that shows the power of the technique, in this case, affirming the value of blood testing,” said Cousins.
Although clinicians routinely prescribe lithium either once daily or twice daily, there is no consensus on which regimen is more effective. Once-daily dosing may offer advantages for adherence and renal safety, whereas twice-daily dosing produces more stable lithium concentrations.
“What we still don’t know is whether those differences in brain exposure translate into meaningful differences in long-term efficacy or side effects,” said Dr Philip Cowen, Professor of Psychopharmacology, University Department of Psychiatry, Warneford Hospital, UK. He was not associated with the study.
These findings could help clinicians better tailor lithium treatment to individual patients, particularly when deciding between the two treatment regimens.
“It’s an important technical advance. It’s the largest repeated-measures ⁷Li MRI study so far. But it involved a highly selected group of stable patients, so it raises important questions rather than providing definitive answers,” said Cowen.
Cousins and team do not see Li-MRI replacing blood tests, but they are hopeful that it could help answer why lithium works for about a third of patients while many others experience limited or no benefit.
Previous research suggests that lithium’s effectiveness may depend, at least in part, on how the drug is distributed in the brain. If specific patterns of brain lithium can predict treatment response, clinicians may eventually be able to identify who is most likely to benefit from the drug much earlier in the course of treatment.
“Brain lithium imaging is likely to remain a research tool, or perhaps become useful in selected complex cases. We’re not yet at the stage where brain imaging can guide routine clinical decisions”.
(Edited by Theres Sudeep)