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Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1-5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

City councils are significant, though seldom central, actors in local policy networks providing public assistance to disadvantaged residents. Mayors and council members in 12 American cities more often support than oppose public assistance initiatives. They claim that their own normative judgments are more important to their preferences and voting behavior on such matters than are public opinion, group demands, or economic considerations. While such elected officials hold a variety of justice principles, the most important of these affecting their positions on public assistance issues is the 'floors' principle. A broad ethical commitment to providing social minimums enhances support for living-wage ordinances, for linking subsidies for economic development to assistance to less advantaged citizens, and for exempting spending on social services from budget cuts. We discuss the implications of these findings for major theories of urban politics and policies--collective-action theory, regime theory, and pluralism--and for advocates on behalf of the urban poor. KEY WORDS: local public assistance policy networks, policies toward the homeless, living wage ordinances, linkage policies, social service funding, the floors principle, reconstructed pluralism, The conventional wisdom asserts that the capacity of local governments to assist their most needy residents, never very great, has declined in an era of rising conservative attitudes and fiscal [...]

Analysis of interviews with 112 elected officials in 12 American cities indicates that their support for affirmative action is more strongly influenced by the justice principles they hold than by the contextual variables normally emphasized by leading urban paradigms. Allegiance to fair equal opportunity and blocking cumulative inequalities enhances support for affirmative action, whereas allegiance to maximizing aggregate utility and retaining market allocations reduces such support. These results suggest that urban paradigms should include the moral principles of participants as well as variables describing the interests that officials represent and the economic, social, political, and cultural contexts that constrain their decisions.

This paper explores the attitudes regarding affirmative action of 112 members of city councils and school boards in twelve American cities. In-depth interviews with these officials reveal widespread support for affirmative action policies generally and for more moderate approaches to affirmative action in particular. Our analysis suggests that more aggressive forms of affirmative action-establishing quotas in hiring and setasides when awarding contracts-are especially opposed by conservatives and those in high prestige occupations and by school board members who are wary of giving priority to social justice over securing highly qualified teachers. Our analysis also suggests that extensive support for more moderate forms of affirmative action-giving preference to qualified minority candidates, requiring minority participation by companies that do business with the city, training and mentoring persons from disadvantaged groups, and taking extraordinary steps to recruit blacks and women into public offices-is rooted in concerns about morality and justice. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties., Methods: In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed., Results: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania., Conclusions: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects., Clinical Trials Registry: NCT0127253., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)