Berrettini, Wade H.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Abstract Bipolar disorder (BD) is characterized by disrupted circadian rhythms and neuronal loss. Lithium is neuroprotective and used to treat BD, but outcomes are variable. Past research identified that circadian rhythms in BD patient neurons are associated with lithium response (Li-R) or non-response (Li-NR). However, the underlying cellular mechanisms remain unknown. To study interactions among circadian clock genes and cell survival, and their role in BD and predicting lithium response, we tested selected genes (PER1, BMAL1 and REV-ERBα) and small molecule modulators of ROR/REV-ERB nuclear receptors in models of cell survival using mouse neurons and stem-cell derived neuronal progenitor cells (NPC) from BD patients and controls. In apoptosis assays using staurosporine (STS), lithium was neuroprotective. Knockdown of PER1, BMAL1 and REV-ERBα modified cell survival across models. In NPCs, reduced expression of PER1 and BMAL1 led to more extensive cell death in Li-NR vs. Li-R. Reduced REV-ERBα expression caused more extensive cell death in BD vs. control NPCs, without distinguishing Li-R and Li-NR. In IMHN, The REV-ERB agonist GSK4112 had strong effects on circadian rhythm amplitude, and was neuroprotective in mouse neurons and control NPCs, but not in BD NPCs. Expression of cell survival genes following STS and GSK4112 treatments revealed BD-associated, and Li-R associated differences in expression profiles. We conclude that the neuroprotective response to lithium is similar in NPCs from Li-R and Li-NR. However, knockdown of circadian clock genes or stimulation of REV-ERBs reveal distinct contributions to cell death in BD patient NPCs, some of which distinguish Li-R and Li-NR.

Abstract Bipolar disorder (BD) is characterized by mood episodes, disrupted circadian rhythms and gray matter reduction in the brain. Lithium is an effective pharmacotherapy for BD, but not all patients respond to treatment. Lithium has neuroprotective properties and beneficial effects on circadian rhythms that may distinguish lithium responders (Li-R) from non-responders (Li-NR). The circadian clock regulates molecular pathways involved in apoptosis and cell survival, but how this overlap impacts BD and/or lithium responsiveness is unknown. In primary fibroblasts from Li-R/Li-NR BD patients and controls, we found patterns of co-expression among circadian clock and cell survival genes that distinguished BD vs. control, and Li-R vs. Li-NR cells. In cellular models of apoptosis using staurosporine (STS), lithium preferentially protected fibroblasts against apoptosis in BD vs. control samples, regardless of Li-R/Li-NR status. When examining the effects of lithium treatment of cells in vitro, caspase activation by lithium correlated with period alteration, but the relationship differed in control, Li-R and Li-NR samples. Knockdown of Per1 and Per3 in mouse fibroblasts altered caspase activity, cell death and circadian rhythms in an opposite manner. In BD cells, genetic variation in PER1 and PER3 predicted sensitivity to apoptosis in a manner consistent with knockdown studies. We conclude that distinct patterns of coordination between circadian clock and cell survival genes in BD may help predict lithium response.

AbstractBackgroundBipolar 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.MethodsIn 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.ResultsSubjects 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.ConclusionsExposure 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.

AbstractBackgroundLithium 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.MethodsThe 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.ResultsA 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.ConclusionsIn 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.