Lithium concentration and recurrence risk during maintenance treatment of bipolar disorder: Multicenter cohort and meta-analysis

Chih Wei Hsu, Andre F. Carvalho, Shang Ying Tsai, Liang Jen Wang, Ping Tao Tseng, Pao Yen Lin, Yu Kang Tu, Eduard Vieta, Marco Solmi, Chi Fa Hung, Hung Yu Kao

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


Objective: To compare differences in efficacy during maintenance treatment for bipolar disorder (BD) according to lithium serum levels. A multicenter retrospective cohort study and a dose-response meta-analysis were conducted. Methods: The cohort study was conducted in Taiwan from 2001 to 2019 to identify patients with euthymic BD according to different serum levels (<0.4, 0.4–0.8, and 0.8–1.2 mmol/L). We adopted adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for time to the recurrence of mood episodes having the <0.4 mmol/L group as the reference group. Moreover, we systematically searched for related articles in major databases before January 31, 2021 (PROSPERO: CRD42021235812). We used random-effects modeling to estimate the dose-response relationships between lithium serum levels and recurrence of mood episodes, which were depicted as odds ratios (ORs) with 95% CIs. Results: A total of 1406 participants (cohort: 466; meta-analysis: 940) were included. In the cohort study, the 0.4–0.8 mmol/L group was associated with a significantly lower risk of recurrences (aHR: 0.75), while the 0.8–1.2 mmol/L group had a lower risk without statistical significance (aHR: 0.77). The dose-response meta-analysis showed that with the increase in lithium serum levels, the risk decreased (linear model OR: 0.85, for every 0.1 mmol/L increase; non-linear model OR: 1.00 at 0.0 mmol/L, 0.42 at 0.4 mmol/L, and 0.27 at 0.8 mmol/L). Conclusion: Although confounding by indication cannot be excluded, the combined results suggest a significant preventative effect on the recurrence of major affective episodes among those with serum levels of 0.4–0.8 mmol/L.

Original languageEnglish
Pages (from-to)368-378
Number of pages11
JournalActa Psychiatrica Scandinavica
Issue number4
Publication statusPublished - Oct 2021


  • bipolar disorder
  • dose-response meta-analysis
  • lithium
  • maintenance treatment
  • serum level

ASJC Scopus subject areas

  • Psychiatry and Mental health


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