Clinical predictors of non‐response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study

Abstract

Background: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. Methods:The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse.Results: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. Conclusions:In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

Lithium use associated with symptom severity in comorbid bipolar disorder I and migraine

“…A recent published study done by Lin et al. ( 2021 ) found that those with BD and a history of migraine taking lithium had higher rates of relapses—defined by episodes of mania, depression, mixed episodes, hospitalization, or the need for medication changes in order to obtain better mood stabilization—than those with BD and no history of migraine taking lithium. Our research expands these findings by identifying the specific mood state (mania) that is affected by this interaction.…”

“…Despite the physiological parallels in neuronal excitability patterns between individuals with migraine and lithium responders in BD, a recent study reported that a history of migraine is associated with higher rate of relapse during lithium treatment (Lin et al., 2021 ). This relationship between lithium response and migraine history seems contradictory given the putative underlying neuronal mechanisms connecting the two conditions.…”

Correction of depression‐associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder

“…PGBD was an 11‐site prospective, nonrandomized open trial of LiM. The study was designed to identify genetic markers of lithium response during the maintenance phase in BD type I and details of the study have been published previously 28,29 . In brief, adult subjects (>18 years old) with BD type 1 could enter the study at any illness phase including depressed, manic, hypomanic, or mixed.…”

“…The study was designed to identify genetic markers of lithium response during the maintenance phase in BD type I and details of the study have been published previously. 28,29 In brief, adult subjects (>18 years old) with BD type 1 could enter the study at any illness phase including depressed, manic, hypomanic, or mixed. To transition to LiM, subjects either switched to lithium from another medication or underwent dose adjustment of prior lithium treatment to optimize the likelihood of response to monotherapy.…”

“…Long-term (2-year) follow-up through maintenance has been reported previously and was not considered in these analyses. 29 Lithium nonresponders (Li-NR) were subjects who were unable to stabilize or suffered a mood relapse prior to entering maintenance. Mood stability was defined by the absence of a mood episode relapse and a score ≤2 on the Clinician Global Inventory for Bipolar Disorder (CGI-BP).…”