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

Abstract

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.

Predicting Serum Levels of Lithium-Treated Patients: A Supervised Machine Learning Approach

“…Second, the continuous predictive model can help clinicians adjust the medications of their patients. The current model of this study can estimate the concentration value and increase or decrease the daily dose of lithium to reach the appropriate therapeutic range [ 6 ].…”

“…Many international guidelines recommend lithium as a first-line drug, especially for bipolar disorder [ 4 , 5 ]. Even though lithium has clear beneficial effects, the therapeutic range of its serum levels is narrow (<1.2 mmol/L) [ 6 ]. Due to the narrow therapeutic index of lithium, a routine monitoring of its serum levels is suggested.…”

Comparative effectiveness of valproic acid in different serum concentrations for maintenance treatment of bipolar disorder: A retrospective cohort study using target trial emulation framework

“…These indicators were based on previous studies. 16 , 18 We followed up with patients from the index date for two years or until the occurrence of an outcome event.…”

“…We selected the following patient characteristics based on literature review and experts’ opinions, 16 , 17 , 18 including age, sex, number of psychiatric hospitalisations within the two years before the index date, medical comorbidities (hypertension, diabetes mellitus, hyperlipidaemia, rheumatic diseases, any cancer, heart diseases, peripheral vascular diseases, cerebral vascular diseases, pulmonary diseases, liver diseases, peptic ulcer diseases, renal diseases, and any bleeding), and concomitant medications (mood stabilisers, antipsychotics, antidepressants, and benzodiazepines). Details regarding the medical comorbidities and concomitant medications are provided in Appendix 3 (Table S3).…”

Lithium bidirectionally regulates depression- and mania-related brain functional alterations without worsening cognitive function in patients with bipolar disorder

“…Lithium, a well-known mood stabilizer, has long been used to treat mania in patients with bipolar disorder (BP), and as a synergist in the treatment of depression in these patients, especially those who have attempted suicide (1). These applications have been proven to be clinically effective (2)(3)(4)(5), and based on data from many double-blind randomized controlled studies and other research, lithium is the goldstandard maintenance treatment for BP (6)(7)(8)(9)(10)(11)(12)(13)(14)(15). More notably, Rybakowski modified the definition of mood stabilizer: ' A drug that if used as mono-therapy: (1) act therapeutically in mania or/and in depression; (2) acts prophylactically against manic or/and depressive episodes as demonstrated in a trial of at least 1 year's duration and (3) does not worsen any therapeutic or prophylactic aspect of the illness outlined above.'…”