Relevance of red blood cell Lithium concentration in the management of Lithium-treated bipolar and unipolar disorders: a systematic narrative review

Background: Despite a variability in response and a narrow therapeutic index, Lithium (Li) remains the gold standard treatment for bipolar disorders (BD), and a treatment of choice for unipolar disorders (UD). Red blood cell Li concentration (RBCLiC) and red blood cell/plasma Li ratio (LiR) have been studied in many areas of mood disorders (such as acute or chronic Li efficacy, adherence, side effects (SE), intoxication management) as well as in several research domains. This systematic review aims to synthesize the existing literature.

Methods: We conducted a systematic review, based on preferred reporting items for systematic reviews and Metanalysis (PRISMA) guidelines, of articles published between 1972 and February 2023, indexed in the following databases: EMBASE, MEDLINE, Cochrane Library. The search terms were combinations of the following headings: "Lithium AND Plasma AND Erythrocyte AND Mood disorders". The systematic review protocol was published to PROSPERO (CRD42023406154).

Results and conclusion: Out of the 252 identified studies, 57 met the selection criteria. The articles investigated the interest of RBCLiC and other blood parameters (PLiC and LiR) in various areas: (i) disease management (31 articles) (compliance/adherence (5 articles), SE/toxicity (13 articles), prediction of Li response/therapeutic efficacy for acute episode or for relapse prevention (17 articles)), (ii) Li blood parameters as trait markers of mood disorders subtypes (UD, BDI, BDII) (16 articles), (iii) Li blood parameters as state markers of mood episodes (11 articles), (iv) factors influencing Li blood parameters (age, gender, ethnicity, dosage and duration of Li treatment, co-medications with other treatments, seasonality) associated with RBCLiC or LiR (24 articles), and (v) potential pathophysiological mechanisms (30 articles).

Conclusion: Overall, this review suggests that RBCLiC or LiR could be of interest for tolerance monitoring. However, the heterogeneity of methods and results, coupled with the limited amount of data, does not allow clear conclusions to be drawn in the other areas explored in this literature review. Given the potential interest in exploring brain Li pharmacokinetics (PK)s, this review calls for further research.