Lithium orotate: A superior option for lithium therapy?

Abstract

Bipolar disorder (BD) poses a significant public health concern, with roughly one-quarter of sufferers attempting suicide. BD is characterized by manic and depressive mood cycles, the recurrence of which can be effectively curtailed through lithium therapy. Unfortunately, the most frequently employed lithium salt, lithium carbonate (Li₂ CO₃ ), is associated with a host of adverse health outcomes following chronic use: these unwanted effects range from relatively minor inconveniences (e.g., polydipsia and polyuria) to potentially major complications (e.g., hypothyroidism and/or renal impairment). As these undesirable effects can limit patient compliance, an alternative lithium compound with a lesser toxicity profile would dramatically improve treatment efficacy and outcomes. Lithium orotate (LiC₅ H₃ N₂ O₄ ; henceforth referred to as LiOr), a compound largely abandoned since the late 1970s, may represent such an alternative. LiOr is proposed to cross the blood-brain barrier and enter cells more readily than Li₂ CO₃ , which will theoretically allow for reduced dosage requirements and ameliorated toxicity concerns. This review addresses the controversial history of LiOr, complete with discussions of experimental and clinical efficacy, putative mechanisms of action, adverse effects, and its potential future in therapy.

Keywords: Lithium Toxicity; Maintenance Therapy; Mania; Mood Stabilizer; Pharmacokinetics; increased therapeutic window.

FIGURE 1

Putative mechanisms underpinning the therapeutic efficacy of lithium salts in BD. GSK3β hyperactivity, PI‐cycle dysfunction and neuroinflammation have been implicated in BD etiopathogenesis. Lithium may alleviate expression of BD symptoms through amelioration of these processes, likely though mechanisms involving displacement of magnesium (thereby limiting activity) from the catalytic cores of GSK3β and IMPase

FIGURE 2

The benefits and drawbacks of Li₂CO₃ use in BD. Li₂CO₃ is a thoroughly studied compound in the management of BD. Dosage guidelines are well established, and both short‐ and long‐term toxicity concerns are well understood. Despite being the current gold standard for the control of mania and the prevention of mood episode recurrences, Li₂CO₃ is not without its share of issues, namely a narrow therapeutic window and a potentially severe toxic effect profile that may limit patient compliance

FIGURE 3

Proposed mechanisms underlying the efficacy of orotic acid as a mineral carrier. (a) Mineral orotates may display limited dissociation in biological solutions, allowing them to exist in sera as non‐dissociated, electrically neutral compounds. (b) It has been suggested that LiOr preferentially dissociates in the intracellular compartment, perhaps through mechanisms involving the uptake of orotic acid into the de novo pyrimidine synthesis pathway. (c) Given its structural similarity to non‐charged pyrimidines, LiOr may be able to make use of nucleotide transporters for passage across cell membranes, as is observed for non‐charged pyrimidines such as fluorouracil

FIGURE 4

LiOr as a replacement for Li₂CO₃ in the treatment of BD. Proponents of LiOr argue that LiOr can cross biological membranes and enter cells more readily than Li₂CO₃, allowing for lesser concentrations to be administered while maintaining an equivalent therapeutic effect. While LiOr has been found to result in higher brain concentrations of lithium than Li₂CO₃, others have noted that this may come at the cost of increased renal toxicity. More research into both benefits (e.g., increased accumulation within cells) and drawbacks (e.g., renal toxicity) is needed