Does the “Silver Bullet” Lose its Shine Over the Time? Assessment of Loss of Lithium Response in a Preliminary Sample of Bipolar Disorder Outpatients

Abstract

Background:Though often perceived as a “silver bullet” treatment for bipolar disorder (BD), lithium has seldom reported to lose its efficacy over the time.Objective:The aim of the present study was to assess cases of refractoriness toward restarted lithium in BD patients who failed to preserve maintenance.Method:Treatment trajectories associated with re-instituted lithium following loss of achieved lithium-based maintenance in BD were retrospectively reviewed for 37 BD-I patients (median age 52 years; F:M=17:20 or 46% of the total) over an 8.1-month period on average.Results:In our sample only 4 cases (roughly 11% of the total, of whom F:M=2:2) developed refractoriness towards lithium after its discontinuation. Thirty-three controls (F:M=15:18) maintained lithium response at the time of re-institution. No statistically significant difference between cases and controls was observed with respect to a number of demographic and clinical features but for time spent before first trial ever with lithium in life (8.5 vs. 3 years; U=24.5, Z=-2.048, p=.041) and length of lithium discontinuation until new therapeutic attempt (5.5 vs. 2 years; U=8, Z=-2.927, p=.003) between cases vs. controls respectively. Tapering off of lithium was significantly faster among cases vs. controls (1 vs. 7 days; U=22, Z=-2.187), though both subgroups had worrisome high rates of poor adherence overall.Conclusion:Although intrinsic limitations of the present preliminary assessment hamper the validity and generalizability of overall results, stating the clinical relevance of the topic further prospective research is warranted. The eventual occurrence of lithium refractoriness may indeed be associated with peculiar course trajectories and therapeutic outcomes ultimately urging the prescribing clinicians to put efforts in preserving maintenance of BD in the absence of any conclusive research insight on the matter.

An Oldie but Goodie: Lithium in the Treatment of Bipolar Disorder through Neuroprotective and Neurotrophic Mechanisms

“…Of note, two forms of acquired nonresponse to lithium that develop over the treatment course in patients who have previously shown adequate response have been reported. The first type of nonresponse is discontinuation-induced refractoriness, is when patients who have showed good long-term response to lithium then discontinue treatment, and after experiencing a major recurrence, do not respond to lithium at previously effective doses [ 38 ]. The second type of nonresponse is the development of a pharmacodynamic tolerance to lithium, described as mild, brief, or infrequent symptoms starting to occur then progressively increasing in severity, duration, or frequency, until the original pattern of illness prior to treatment recurs, even while maintaining lithium treatment [ 39 ].…”

Whole Genome Expression Analyses of miRNAs and mRNAs Suggest the Involvement of miR-320a and miR-155-3p and their Targeted Genes in Lithium Response in Bipolar Disorder

“…However, there is general consensus that lithium has a certain degree of effectiveness in about 60% of patients, while it is ineffective in about 1/3 [5,6]. Additionally, loss of efficacy can be observed after discontinuation in patients previously showing a good response to the drug [7]. Lithium has also been shown to protect against mood switching [8].…”

Lithium-discontinuation-induced treatment refractoriness revisited

“…Six case reports with a total of 11 patients and six naturalistic cohort studies including 403 patients were identified. In addition to those originally reviewed by de Vries ( 2013 ), we have included two further studies (Cakir et al 2017 ; Fornaro et al 2016 ) published subsequently. Furthermore, we uncovered a large-scale nationwide health care registry study assessing the efficacy of pharmacotherapy in individuals with bipolar disorder who had previously discontinued lithium (Holm et al 2022 ).…”