Low Rate of Membrane Lithium Transport during Treatment Correlates with Outcome of Maintenance Pharmacotherapy in Bipolar Disorder

Abstract

Lithium is transported across cell membranes by an exchange diffusion process (Na(+)-Li+ countertransport) that is inhibited during lithium treatment. We hypothesized that low rates of lithium efflux (a potential manifestation of strong transport inhibition) would be associated with better clinical outcome of maintenance pharmacotherapy. We measured the erythrocyte (RBC) apparent rate constant for lithium efflux (kexch) in 22 patients with bipolar disorder who had been euthymic on lithium for 1 month. Subsequently, clinical mood ratings and in vivo RBC: plasma lithium ratios (LiR) were determined monthly. Outcome was categorized according to whether subjects completed 1 year of successful maintenance treatment (n = 10), experienced a recurrent affective episode (n = 8), or dropped out (n = 4). The kexch at the outset of the study was significantly lower (potentially because of greater transport inhibition) in 1-year completers than in patients with recurrences or those who dropped out (median kexch = 0.09, 0.24, and 0.27 h-1, respectively; P < .03). Moreover, 77% of patients with a kexch of 0.11 h-1 or lower were successfully maintained on lithium for 1 year, whereas only 23% of those with a kexch greater than or equal to 0.12 h-1 had a successful treatment outcome. LiR measured during the course of maintenance treatment was significantly higher (suggesting greater transport inhibition) in 1-year completers than in noncompleters (recurrences and dropouts). Measurement of kexch at an early point in treatment may provide a means for prospectively identifying those bipolar patients at greater risk for failure of maintenance lithium therapy.

Variability of Erythrocyte and Serum Lithium Levels Correlates with Therapist Treatment Adherence Efforts and Maintenance Treatment Outcome

“…The finding that the CV of the lithium L/D ratio relates to clinical outcome differs from a previously published negative observation derived from a sample partially overlapping the one presented here (Mallinger et al 1997). We believe this reflects differences in the subject population and sample timing.…”

“…Thus, more intensive approaches to enhancing medication adherence are needed. Another possible treatment approach for enhancing pharmacotherapy treatment adherence in this patient population might involve some of the motivational interviewing techniques being used in the treatment of substance abuse (Miller and Rollnick 1991).The finding that the CV of the lithium L/D ratio relates to clinical outcome differs from a previously published negative observation derived from a sample partially overlapping the one presented here (Mallinger et al 1997). We believe this reflects differences in the subject population and sample timing.…”

Brain-to-Serum Lithium Ratio and Age: An In Vivo Magnetic Resonance Spectroscopy Study

“…Several studies (10)(11)(12) have shown that red blood cells, neurons, and glia actively export lithium from intracellular to extracellular space. Therefore, the results seen in this study most likely show that children and adolescents extrude lithium more effectively from their brain cells than adults do.…”

Short TE 7Li‐MRS confirms Bi‐exponential lithium T2 relaxation in humans and clearly delineates two patient subtypes

“…Understanding lithium transport kinetics and free intracellular lithium mechanisms will be important for determining lithium efficacy. Mallinger et al (26) found significantly decreased erythrocyte SLC transporter exchange rates in bipolar patients who successfully responded to lithium therapy. This suggests that intracellular lithium levels in such individuals were increased, allowing the lithium ion to interact with the many intracellular pathways described above.…”