Prevalence and factors associated with fatigue in patients with major depressive disorder or bipolar disorder.

AIMS: To study the prevalence of fatigue and factors associated with fatigue in patients with major depressive disorder (MDD) or bipolar disorder (BD). METHODS: Two hundred fifty-three outpatients with MDD or BD at the initial assessment were used to study the prevalence of fatigue and relationship between fatigue and other clinical correlates. The severity of fatigue was measured with Iowa Fatigue Scale (IFS), and depression and anxiety symptom-severity were measured with the QIDS-16-SR (the 16-item Quick Inventory of Depressive Symptomatology - Self-Report) and Zung-SAS (Zung Self-Rating Anxiety Scale). Correlation between IFS and QIDS-16-SR total scores, QIDS-16-SR item scores or Zung-SAS total scores, and independent factors associated with fatigue was assessed with simple or multiple linear regression analysis. RESULTS: Overall, 28.4 % of MDD and 29.8 % of BD patients did not have fatigue, but 41.2 % of MDD and 45.0 % of BD patients had fatigue, and 30.4 % of MDD and 25.2 % of BD patients had severe fatigue. Depression/anxiety severity was significantly correlated with fatigue. However, after controlling current psychiatric comorbidities, demographics, some social factors, and psychotropic use, only QIDS-16-SR scores were still significantly and positively correlated with IFS scores in both MDD and BD. Differential correlations between IFS scores and item scores of QIDS-16-SR in MDD and BD were observed. LIMITATION: Cross-sectional. CONCLUSIONS: In this outpatient sample, fatigue was highly prevalent in patients with MDD or BD. The independent association of depressive severity with the severity of fatigue highlights the importance of complete resolution of depressive symptoms in treating MDD and BD.

Differential contributions of circadian clock genes to cell survival in bipolar disorder patient derived neuronal progenitor cells distinguishes lithium responders and non-responders.

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.

Possible Role of Correlation Coefficients and Network Analysis of Multiple Intracellular Proteins in Blood Cells of Patients with Bipolar Disorder in Studying the Mechanism of Lithium Responsiveness: A Proof-Concept Study.

Background: The mechanism of lithium treatment responsiveness in bipolar disorder (BD) remains unclear. The aim of this study was to explore the utility of correlation coefficients and protein-to-protein interaction (PPI) network analyses of intracellular proteins in monocytes and CD4+ lymphocytes of patients with BD in studying the potential mechanism of lithium treatment responsiveness. Methods: Patients with bipolar I or II disorder who were diagnosed with the MINI for DSM-5 and at any phase of the illness with at least mild symptom severity and received lithium (serum level ≥ 0.6 mEq/L) for 16 weeks were divided into two groups, responders (≥50% improvement in Montgomery-Asberg Depression Rating Scale and/or Young Mania Rating Scale scores from baseline) and non-responders. Twenty-eight intracellular proteins/analytes in CD4+ lymphocytes and monocytes were analyzed with a tyramine-based signal-amplified flow cytometry procedure. Correlation coefficients between analytes at baseline were estimated in both responders and non-responders and before and after lithium treatment in responders. PPI network, subnetwork, and pathway analyses were generated based on fold change/difference in studied proteins/analytes between responders and non-responders. Results: Of the 28 analytes from 12 lithium-responders and 11 lithium-non-responders, there were more significant correlations between analytes in responders than in non-responders at baseline. Of the nine lithium responders with pre- and post-lithium blood samples available, the correlations between most analytes were weakened after lithium treatment with cell-type specific patterns in CD4+ lymphocytes and monocytes. PPI network/subnetwork and pathway analyses showed that lithium response was involved in four pathways, including prolactin, leptin, neurotrophin, and brain-derived neurotrophic factor pathways. Glycogen synthase kinase 3 beta and nuclear factor NF-kappa-B p65 subunit genes were found in all four pathways. Conclusions: Using correlation coefficients, PPI network/subnetwork, and pathway analysis with multiple intracellular proteins appears to be a workable concept for studying the mechanism of lithium responsiveness in BD. Larger sample size studies are necessary to determine its utility.

Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.