Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

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.

Early warning signals observed in motor activity preceding mood state change in bipolar disorder.

INTRODUCTION: Alterations in motor activity are well-established symptoms of bipolar disorder, and time series of motor activity can be considered complex dynamical systems. In such systems, early warning signals (EWS) occur in a critical transition period preceding a sudden shift (tipping point) in the system. EWS are statistical observations occurring due to a system's declining ability to maintain homeostasis when approaching a tipping point. The aim was to identify critical transition periods preceding bipolar mood state changes. METHODS: Participants with a validated bipolar diagnosis were included to a one-year follow-up study, with repeated assessments of the participants' mood. Motor activity was recorded continuously by a wrist-worn actigraph. Participants assessed to have relapsed during follow-up were analyzed. Recognized EWS features were extracted from the motor activity data and analyzed by an unsupervised change point detection algorithm, capable of processing multi-dimensional data and developed to identify when the statistical property of a time series changes. RESULTS: Of 49 participants, four depressive and four hypomanic/manic relapses among six individuals occurred, recording actigraphy for 23.8 ± 0.2 h/day, for 39.8 ± 4.6 days. The algorithm detected change points in the time series and identified critical transition periods spanning 13.5 ± 7.2 days. For depressions 11.4 ± 1.8, and hypomania/mania 15.6 ± 10.2 days. CONCLUSION: The change point detection algorithm seems capable of recognizing impending mood episodes in continuous flowing data streams. Hence, we present an innovative method for forecasting approaching relapses to improve the clinical management of bipolar disorder.

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

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.

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

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.

Reduced heart rate variability during mania in a repeated naturalistic observational study.

Background: Bipolar disorder (BD) is a chronic recurrent mood disorder associated with autonomic nervous system (ANS) dysfunction, indexed by heart rate variability (HRV). Changes in HRV between mood states are sparsely studied longitudinally. We aimed to compare HRV of hospitalized manic individuals with their own euthymic selves in a naturalistic observational study. Methods: 34 individuals were included, of which 16 were lost to follow-up. Ultimately 15 patients provided reliable heart rate data in both a manic and euthymic state, using photoplethysmography (PPG) sensor wristbands overnight. We calculated HRV measures Root Mean Square of Successive Differences (RMSSD), High-frequency (HF: 0.15-0.40 Hz), Low-frequency (LF: 0.40-0.15 Hz), Very low-frequency (VLF: 0.0033-0.04 Hz), Total power and Sample Entropy in 5-min night-time resting samples. We compared HRV measures by mood state within individuals using paired t-tests and linear regression to control for age and sex. Results: HRV was lower in the manic state when compared to the euthymic state for all HRV metrics (p ≤ 0.02), with large to medium effect sizes (g = 1.24 to 0.65). HRV changes were not significantly affected by age or sex. Conclusion: This longitudinal study provides evidence of lower HRV in manic states compared to euthymia, indicating an association between ANS dysregulation and changes in bipolar mood state. This corroborates previous cross-sectional studies, although the association may be less clear or reversed in hypomanic states. Further investigation in larger longitudinal samples is warranted.

Complexity and variability analyses of motor activity distinguish mood states in bipolar disorder.

Changes in motor activity are core symptoms of mood episodes in bipolar disorder. The manic state is characterized by increased variance, augmented complexity and irregular circadian rhythmicity when compared to healthy controls. No previous studies have compared mania to euthymia intra-individually in motor activity. The aim of this study was to characterize differences in motor activity when comparing manic patients to their euthymic selves. Motor activity was collected from 16 bipolar inpatients in mania and remission. 24-h recordings and 2-h time series in the morning and evening were analyzed for mean activity, variability and complexity. Lastly, the recordings were analyzed with the similarity graph algorithm and graph theory concepts such as edges, bridges, connected components and cliques. The similarity graph measures fluctuations in activity reasonably comparable to both variability and complexity measures. However, direct comparisons are difficult as most graph measures reveal variability in constricted time windows. Compared to sample entropy, the similarity graph is less sensitive to outliers. The little-understood estimate Bridges is possibly revealing underlying dynamics in the time series. When compared to euthymia, over the duration of approximately one circadian cycle, the manic state presented reduced variability, displayed by decreased standard deviation (p = 0.013) and augmented complexity shown by increased sample entropy (p = 0.025). During mania there were also fewer edges (p = 0.039) and more bridges (p = 0.026). Similar significant changes in variability and complexity were observed in the 2-h morning and evening sequences, mainly in the estimates of the similarity graph algorithm. Finally, augmented complexity was present in morning samples during mania, displayed by increased sample entropy (p = 0.015). In conclusion, the motor activity of mania is characterized by altered complexity and variability when compared within-subject to euthymia.

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

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.