The lancet. Psychiatry · 2026
Brain lithium temporospatial kinetics in bipolar disorder: a repeated-measures 7Li MRI study of dosing regimens in Germany.
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Ritter Philipp, Edelmann Katinka, Thelwall Peter Edward, Boumezbeur Fawzi, Bauer Michael, Werner Annett, Hall Gerard, Kavanagh Oisín, Cousins David Andrew
Аннотация
BACKGROUND: 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.
METHODS: 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.
FINDINGS: 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.
INTERPRETATION: 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.
FUNDING: Baszucki Brain Research Foundation and Deutsche Forschungsgemeinschaft (German Research Foundation).
METHODS: 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.
FINDINGS: 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.
INTERPRETATION: 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.
FUNDING: Baszucki Brain Research Foundation and Deutsche Forschungsgemeinschaft (German Research Foundation).