Lithium specificity in bipolar illness: a classic agent for the classic disorder

Abstract

For over half a century, lithium has been the gold standard amongst the pharmacological armamentarium used to treat bipolar disorder. Its ascendancy in this regard has been attributed partly to its primacy of discovery and clinical implementation; however, it is important to consider how it has achieved success and retained its prominence and whether this is because of its unique profile and specificity of actions. In this paper, we briefly discuss the clinical evidence in support of lithium specificity and argue for its continuing use in those patients most likely to benefit, namely, patients with 'classic' bipolar disorder. Further, we suggest that accurate characterization of 'lithium responders' through focused research is likely to yield novel treatments and assist in better understanding of the pathophysiology of the illness. In addition, the unique antisuicidal actions of lithium warrant further examination, as do its impressive properties as a prophylactic agent. This is particularly so given the high morbidity associated with bipolar disorder and its potential for suicide. Hence, in this paper, after describing the changing diagnostic backdrop against which much of the research to date has been conducted, we discuss the clinical therapeutic profile of lithium in both the acute and long-term management of bipolar disorder and its phenotypic specificity of action. We demonstrate that lithium possesses significant clinical and therapeutic efficacy that is very individual and thus remains the treatment of choice for bipolar disorder when used specifically in select patients.

Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis

“…S2 E-L and S3 A-J) (17)(18)(19)(20). For our in vitro studies, we elected to preserve the distinction made by clinicians between LiR and LiNR patients (5)(6)(7)(8) and to probe lithium's protein targets within LiR BPD neurons (SI Appendix, Figs. S1).…”

“…Additionally, axonal guidance signaling appeared most centralized; its function connected with 75% of the pathways identified in the IPA analysis. Of the 15 candidate protein targets, the one most pivotal to axonal guidance and cytoskeletal dynamics was CRMP2, originally discovered as the mediator of Sema3A's (initially named "collapsin") guidance of neurite extension and axonal growth cone development (5)(6)(7)(8)(9)(10)(11).…”

“…Such pleiotropic effects underscore our ignorance with regard to lithium's action specifically for BPD. Additionally, the safety index of lithium is narrow (5,8). In view of its prevalence (the sixth leading cause of disability worldwide), suboptimal treatment options, and absence of biomarkers for onset and progression, neuropsychiatric disorders in general-and BPD in particular-represent a pressing unmet medical need (1 in 250 sufferers die from complications of BPD).…”

Why is soft bipolar disorder so hard to define?

“…First, we need to know that 'soft bipolar' or 'subthreshold manic symptoms' are either specific to mania and bipolarity, or that we have adequately distinguished them from other pathologies. Second, we need to be comfortable that 'classic' or narrowphenotype bipolarity (episodic manicdepressive illness) (Gershon et al, 2009) and broad-phenotype bipolarity (significant mood instability) are essentially different manifestations of the same process, and that they are so intimately related that it is reasonable to use a single framework for describing both. Finally, we need to be confident that the main diagnostic decision we need to model is the distinction between depression and BDs.…”

Discontinuation of lithium because of side effects

“…Excellent Li responders are unlikely to derive the same benefit from a different mood stabilizer. 2,3 Stop ping previously effective Li prophylaxis often results in recurrences of illness 4 as well as suicide, 5 even after an extended episode-free interval and with gradual tapering of Li. Thus, discontinuing a medication that has proven highly beneficial always requires close monitoring and potentially switching back in case of a recurrence on a new medication.…”