Brain lithium temporospatial kinetics in bipolar disorder: a repeated-measures ⁷Li MRI study of dosing regimens in...

Lithium remains a first-line treatment for bipolar disorder, but practice varies regarding dosing frequency. Although once-daily and twice-daily regimens are similarly effective, they produce serum lithium profiles that differ over the day, and whether greater fluctuations with once-daily dosing are attenuated in the brain is unclear. The aim of this study was to evaluate whether brain lithium profiles differed across the day with once-daily versus twice-daily dosing regimens.

In this repeated-measures, cross-sectional imaging study, euthymic individuals (aged 18-50 years) with bipolar disorder type I or II receiving stable lithium carbonate treatment were recruited at four psychiatric outpatient departments in Dresden, Germany. In the week before assessment, participants received lithium at 2000 h (full once-daily dose or evening dose of the twice-daily regimen) and 0800 (twice-daily regimen only; withheld until after the 0800 h sampling on assessment day). The core assessment was a 1-day protocol in which participants underwent three consecutive ⁷Li MRI scans and matched serum sampling over a 10-h period (0800, 1400, and 1800h). Whole-brain lithium measurements across timepoints were compared according to regimen using the brain observable lithium threshold region-of-interest approach. Secondary analyses modelled tissue-specific profiles, derived from the Newcastle lithium image voxel evaluation pipeline, and examined the relationship between serum lithium concentration and brain ⁷Li MRI signal intensity using repeated-measures ANOVA, linear mixed-effects models, and population pharmacokinetics. This study was informed by people with lived experience of bipolar disorder and long-term lithium treatment through patient and public involvement and engagement activities.

Between April 19, 2022, and Dec 9, 2023, 44 eligible participants were recruited, of whom three withdrew before assessment. Therefore, 41 euthymic individuals (all White European; 21 [51%] female and 20 [49%] male; mean age 39·2 years [SD 9·8]) with bipolar disorder receiving stable lithium carbonate treatment (20 in the once-daily dosing group and 21 in the twice-daily dosing group) were evaluated. At 12 h post dose (0800 h), brain ⁷Li MRI signal intensity and serum lithium concentrations were equivalent across regimens. In the once-daily group, serum lithium declined across the day, whereas in the twice-daily group it increased after the morning dose and then decreased. Brain ⁷Li MRI signal intensity closely mirrored these regimen-specific serum profiles. Brain ⁷Li MRI signal intensity was higher in white matter than grey matter in both regimens and brain-to-serum ratios indicated more rapid equilibration in grey matter compared with cerebrospinal fluid and white matter.

Brain lithium concentrations followed serum concentrations closely across the day but aligned between regimens at the standard 12-h post-dose sampling timepoint. These findings directly inform ongoing discussions about the applicability of a common reference range across regimens. The difference in brain and serum profiles of lithium with once-daily and twice-daily dosing might inform regimen selection and therapeutic monitoring strategies in clinical practice.

Baszucki Brain Research Foundation and Deutsche Forschungsgemeinschaft (German Research Foundation).