Citations

Abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

ABSTRACT Introduction Collagenase Clostridium Histolyticum (CCH) is commonly injected at the point of maximal curvature (POMC) for Peyronie's Disease (PD). However, many providers only evaluate the POMC at baseline and do not reassess during CCH injections. As PD plaques often extend over an extended region, it is currently unknown how much the POMC may change throughout a course of CCH treatment. Objective We sought to evaluate for changes in POMC between series among men undergoing CCH injections. Methods A prospective database has been maintained of PD men undergoing CCH injections at two institutions. POMC assessments were obtained prior to each series of injections after pharmacologic erection and were measured from the coronal margin to POMC. An analysis was performed comparing changes in POMC throughout the CCH course, including associated baseline demographic and disease characteristics. Results A total of 445 men (mean age 55.9, mean PD duration 30.6 months) underwent CCH injections from Jan 2014 through Feb 2021. The mean baseline composite curvature was 63.7° (SD 23.7), and the mean distance to curvature was 3.1 cm. Among men who completed 4 series of CCH injections, the mean improvement was 21° (SD 20.6) or 31.7% (SD 33%). In reviewing changes in POMC, the largest change observed at any point within the CCH series was a median 1 cm (IQR 0.5, 2 cm; range 0, 9.5 cm). Compared to baseline, 58% of men experienced a POMC change of 1 cm or greater, 25% 2 cm or greater, and 12% 3 cm or greater during the course of CCH treatment. Age, duration of PD, and baseline curvature were not associated with changes in POMC, although the POMC itself was associated with extent of changes, with proximal curves more likely to experience more notable changes compared to distal ones (p<0.0001). The total improvement in curve was also variably associated with change in POMC, with those experiencing greater improvements noted to have larger change in POMC (p<0.05 for changes in composite curvature and p=0.07 for percent change from baseline). These findings would suggest significant evolution of the POMC during a course of CCH, particularly among men with mid shaft or proximal curves and among those with greater curve improvements. Findings would support a role for repeat curvature assessments prior to each series of CCH injections. Conclusions Based on data from a prospective, two-institution series of PD men undergoing CCH injections, the POMC changes by ≥1 cm in the majority of men. Given the small volume injected with each CCH series, the clinical relevance of these findings and their impact on injector protocols merit further investigation. Disclosure No

Although the etiology of bipolar disorder remains uncertain, multiple studies examining neuroimaging, peripheral markers and genetics have provided important insights into the pathophysiologic processes underlying bipolar disorder. Neuroimaging studies have consistently demonstrated loss of gray matter, as well as altered activation of subcortical, anterior temporal and ventral prefrontal regions in response to emotional stimuli in bipolar disorder. Genetics studies have identified several potential candidate genes associated with increased risk for developing bipolar disorder that involve circadian rhythm, neuronal development and calcium metabolism. Notably, several groups have found decreased levels of neurotrophic factors and increased pro-inflammatory cytokines and oxidative stress markers. Together these findings provide the background for the identification of potential biomarkers for vulnerability, disease expression and to help understand the course of illness and treatment response. In other areas of medicine, validated biomarkers now inform clinical decision-making. Although the findings reviewed herein hold promise, further research involving large collaborative studies is needed to validate these potential biomarkers prior to employing them for clinical purposes. Therefore, in this positional paper from the ISBD-BIONET (biomarkers network from the International Society for Bipolar Disorders), we will discuss our view of biomarkers for these three areas: neuroimaging, peripheral measurements and genetics; and conclude the paper with our position for the next steps in the search for biomarkers for bipolar disorder.