Predictors of lithium response in bipolar disorder

Abstract

While lithium is generally regarded as the first-line agent for patients with bipolar disorder, it does not work for everyone, which raises the question: can we predict who will be most likely to respond? In this paper, we review the most compelling clinical, biologic, and genetic predictors of lithium response in bipolar disorder. Among clinical factors, the strongest predictors of good response are fewer hospitalizations preceding treatment, an episodic course characterized by an illness pattern of mania followed by depression, and a later age at onset of bipolar disorder. While several biologic predictors have been studied, the results are preliminary and require replication with studies of larger patient samples over longer observation periods. Neuroimaging is a particularly promising method given that it might concurrently illuminate pathophysiologic underpinnings of bipolar disorder, the mechanism of action of lithium, and potential predictors of lithium response. The first genome-wide association study of lithium response was recently completed. No definitive results emerged, perhaps because the study was underpowered. With major new initiatives in progress aiming to identify genes and genetic variations associated with lithium response, there is much reason to be hopeful that clinically useful information might be generated within the next several years. This could ultimately translate into tests that could guide the choice of mood-stabilizing medication for patients. In addition, it might facilitate pharmacologic research aimed at developing newer, more effective medications that might act more quickly and yield fewer side effects.

Lithium Pharmacogenetics: Where Do We Stand?

“…This observation supported the hypothesis that lithium responders may constitute the core phenotype of BPD, thus representing a suitable subphenotype for genetic studies [Alda, ]. However, regardless of the approach used to stratify patients pharmacogenetic studies have so far failed to identify reliable predictive markers of response [Tighe et al, ]. One important limiting factor is the high phenotypic complexity and heterogeneity of lithium response.…”

“…Although 30% of chronically treated patients show full remission of symptoms, about 70% do not respond sufficiently and need to be switched to other mood stabilizers [Geddes and Miklowitz, 2013]. Interestingly, responders to lithium tend to show a distinct clinical presentation characterized by an episodic course of illness, absence of rapid cycling, fewer hospitalizations preceding treatment, and a low number of psychiatric comorbidities [Alda, 2015;Grof et al, 1993;Tighe et al, 2011]. This observation supported the hypothesis that lithium responders may constitute the core phenotype of BPD, thus representing a suitable subphenotype for genetic studies [Alda, 2015].…”

PRN OPINION PAPER: Application of precision medicine across pharmacy specialty areas

“…Psychiatric clinicians commonly employ patient‐specific factors (eg, demographics, comorbidities, and symptoms), patient preference, and family history of response to guide medication selection. However, with the exception of lithium, there are little data to support many of these strategies . In reality, the overarching principle in psychiatry for medication selection is largely trial‐and‐error.…”

“…However, with the exception of lithium, there are little data to support many of these strategies. 16 In reality, the overarching principle in psychiatry for medication selection is largely trial-and-error. Other factors influencing medication response include ensuring the correct diagnosis is made, appropriate dose titration, patient acceptance/understanding of illness, influence of stigma on taking medications, Therapeutic drug monitoring is one objective method to help maximize the effectiveness and reduce adverse events for certain psychiatric medications (eg, clozapine, lithium, and nortriptyline).…”

Need exists for genetic predictors of lithium response

“…Patients with bipolar disorder respond differentially to lithium; some predictors of good response, including a family history of such, are known, though their predictive power is modest 1. As other medications are available for this illness, it would be valuable to identify biomarkers, including genetic ones, with greater ability to accurately forecast which patients will respond to lithium and which will not.…”