Lithium Dosing in Bipolar Disorder Shapes Brain Exposure Patterns

For many years, doctors prescribing lithium have had to guess how the drug behaves inside a patient's brain.

Now, a new study conducted by researchers at Newcastle University and Technische Universität Dresden has used a new lithium MRI technique to reveal that brain lithium levels closely track blood concentrations throughout the day.

Understanding lithium tracking gaps in bipolar disorder

Bipolar disorder affects ~40 million people globally. The mental health condition is characterized by severe shifts in mood, energy, and activity levels. Patients navigate intense emotional states that alternate between mania and deep depression.

“Lithium is the most effective long-term treatment for bipolar disorder, preventing episodes of illness and reducing the risk of suicide. Not everyone responds to lithium, but for those who do, it is important to individualize treatment to get the best out of this medication,” explained senior author Dr. David Cousins, the director of the Newcastle Magnetic Resonance Centre and clinical senior lecturer at Newcastle University.

In clinical practice, treatment tracking depends heavily on checking drug concentrations from a blood draw at a rigid 12-hour mark after the last dose.

However, dosing frequency varies. Clinicians routinely prescribe lithium either once daily or twice daily, yet international guidelines remain split about which regimen is superior.

Previous work has either been confined to blood data, which ignores how each dosage might impact absorption in the brain, or has relied on older magnetic resonance spectroscopy techniques that were underpowered and lacked steady-state dosing comparisons.

The recent study evaluated whether brain lithium profiles differed across a 24-hour cycle between once-daily and twice-daily administration regimens.

How lithium MRI tracks dosing schedules in bipolar disorder

The trial involved 41 stable outpatients aged 18–50 with bipolar type I or II. All participants maintained a stable dose of lithium carbonate, with 20 taking it once daily and 21 taking it twice daily.

Before testing, participants followed a standardized routine with fixed sleep and fluid schedules. On the test day, they completed a 10-hour tracking window with three sequential ⁷Li MRI scans at 08:00, 14:00, and 18:00. Blood samples were collected five minutes before each scan.

To analyze the data, the team used two imaging pipelines: BolT, for whole-brain thresholding, and N-LIVE, to map tissue-specific distribution.

At the standard 12-hour monitoring mark, both whole-brain lithium levels and blood concentrations were equivalent between the two dosing groups; the once-daily cohort achieved this level despite taking an average total daily dose that was ~25% lower than the twice-daily group.

However, brain lithium levels did not stay flat. Instead, they closely mirrored blood fluctuations across the day. Once-daily dosing led to a steady daytime decline from higher nocturnal peaks, whereas twice-daily dosing provided more stable exposure.

Lithium concentrations in the brain were higher in white matter than gray matter for both groups, although gray matter equilibrated faster with the blood.

Population modeling also revealed that the drug remains in the brain much longer than in the blood, showing a brain half-life of 38.5 hours compared to a serum half-life of 18.7 hours.

Personalizing treatment and future care for bipolar disorder

Medical teams have often assumed that brain tissue actively smooths out the drug's peaks and troughs in the blood over the day, but the new study challenges this belief.

The results showed that brain and blood levels aligned at the 12-hour mark, suggesting that standard blood tests accurately reflect drug exposure in the brain for both schedules. This means that doctors can safely tailor dosing regimens to individual patient lifestyles without worrying about brain-level discrepancies.

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For example, twice-daily dosing can minimize tremors by preventing sharp drug peaks, while once-daily dosing might reduce excessive urination.

“This study shows that lithium MRI is a powerful tool for studying how the drug interacts with the brain and could support more personalized treatment in the future,” said Cousins.

“This new imaging technique allows us to directly visualize a drug in the brain and address important clinical questions. Our research program is also driving advances in the capability of this technique to maximise the scope of its application for patient benefit,” said co-author Prof. Peter Thelwall, a professor of Magnetic Resonance Physics and the director of the Centre for In Vivo Imaging at Newcastle University.

However, the study has clear limitations. The cohort excluded individuals with kidney dysfunction, diabetes, or high blood pressure, and was entirely made up of white Europeans. A notable selection bias also exists because most participants had already responded well to their medication.

Future research could expand to track drug behavior when patients first start treatment, during long-term therapy changes, and across active mood-switching phases of bipolar disorder. Future trials should also include diverse ethnic groups and investigate sex-based differences.

Combining this scanning method with point-of-care blood testing will allow high-frequency sampling to optimize personalized care.

“This may be the oldest drug available for bipolar disorder, but our findings, which provide a better understanding of how it works in practice, mean it should remain at the forefront of developments,” said Cousins.

Reference: Ritter P, Edelmann K, Thelwall PE, et al. Brain lithium temporospatial kinetics in bipolar disorder: a repeated-measures 7Li MRI study of dosing regimens in Germany. Lancet Psychiatry. 2026:S2215036626001537. doi: 10.1016/S2215-0366(26)00153-7

This article is a rework of a press release issued by Newcastle University. Material has been edited for length and content.