Pathway-Specific Polygenic Scores for Predicting Clinical Lithium Treatment Response in Patients With Bipolar Disorder.

Background: Polygenic scores (PGSs) hold the potential to identify patients who respond favorably to specific psychiatric treatments. However, their biological interpretation remains unclear. In this study, we developed pathway-specific PGSs (PS) for lithium response and assessed their association with clinical lithium response in patients with bipolar disorder.

A cross-disorder analysis of CNVs finds novel loci and dose-dependent relationships of genes to psychiatric traits.

Rare copy number variants (CNVs) are a key component of the genetic basis of psychiatric conditions, but have not been well characterized for most. We conducted a genome-wide CNV analysis across six diagnostic categories (N = 574,965): autism (ASD), ADHD, bipolar disorder (BD), major depressive disorder (MDD), PTSD, and schizophrenia (SCZ). We identified 35 genome-wide significant associations at 18 loci, including novel associations in SCZ ( - ) and in the combined cross-disorder analysis ( ).

Psychiatric disorders converge on common pathways but diverge in cellular context, spatial distribution, and directionality of genetic effects.

Psychiatric conditions share common genes, but mechanisms that differentiate diagnoses remain unclear. We present a multidimensional framework for functional analysis of rare copy number variants (CNVs) across 6 diagnostic categories, including schizophrenia (SCZ), autism (ASD), bipolar disorder (BD), depression (MDD), PTSD, and ADHD (N = 574,965). Using gene-set burden analysis (GSBA), we tested duplication (DUP) and deletion (DEL) burden across 2,645 functional gene sets defined by the intersections of pathways, cell types, and cortical regions.

Immune, Developmental, and Synaptic Pathways Define Bipolar Disorder Clinical Heterogeneity.

Importance: The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity.

A New Measure of Mnemonic Discrimination Applicable to Recognition Memory Tests With Continuous Variation in Novel Stimulus Interference.

Background: Mnemonic discrimination (MD) involves distinguishing new stimuli from highly similar memories; it is impaired in the elderly and individuals with neuropsychiatric disorders and may also probe hippocampal dentate gyrus function. Measuring MD is, therefore, highly relevant; however, the gold-standard MD test, the mnemonic similarity task (MST), is rarely used in clinical research. Thus, it would be useful to develop a novel MD index applicable to recognition memory tasks that are commonly used in clinical research.

Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 bipolar disorder risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci and prioritized 17 likely causal SNPs for bipolar disorder.

Transcriptomic and epigenomic consequences of heterozygous loss-of-function mutations in AKAP11, a shared risk gene for bipolar disorder and schizophrenia.

The gene A-kinase anchoring protein 11 (AKAP11) recently emerged as a shared risk factor between bipolar disorder and schizophrenia, driven by large-effect loss-of-function (LoF) variants. Recent research has uncovered the neurophysiological characteristics and synapse proteomics profile of Akap11-mutant mouse models. Considering the role of AKAP11 in binding cAMP-dependent protein kinase A (PKA) and mediating phosphorylation of numerous substrates, such as transcription factors and epigenetic regulators, and given that chromatin alterations have been implicated in the brains of patients with bipolar disorder and schizophrenia, it is crucial to uncover the transcriptomic and chromatin dysregulations following the heterozygous knockout of AKAP11, particularly in human neurons.

Minimizing neonatal hypothyroidism induced by lithium exposure through breast milk.

Background: Lithium-induced hypothyroidism in the neonate is a growing concern for lactating mothers. Maternal hypothyroidism in the postpartum period could lead to hypothyroidism in the infant via maternal compromised thyroid hormones (likely T4) in breast milk, and lithium in breast milk could have a direct effect on the neonatal thyroid axis over lithium carbonate direct administration.

Methods: We have studied the effects of lithium exposure on neonatal pups through two different modes of exposure: direct oral administration of lithium carbonate and indirect exposure of lithium from breast milk from dams.

Polygenic Scores and Mood Disorder Onsets in the Context of Family History and Early Psychopathology.

Importance: Bipolar disorder (BD) and major depressive disorder (MDD) aggregate within families, with risk often first manifesting as early psychopathology, including attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders.

Objective: To determine whether polygenic scores (PGS) are associated with mood disorder onset independent of familial high risk for BD (FHR-BD) and early psychopathology.

Design, Setting, And Participants: This cohort study used data from 7 prospective cohorts enriched in FHR-BD from Australia, Canada, the Netherlands, Spain, and the US.

Pathway-Specific Polygenic Scores for Lithium Response for Predicting Clinical Lithium Treatment Response in Patients with Bipolar Disorder.

Background: Polygenic scores (PGSs) hold the potential to identify patients who respond favourably to specific psychiatric treatments. However, their biological interpretations remain unclear. In this study, we developed pathway-specific PGSs (PS ) for lithium response and assessed their association with clinical lithium response in patients with bipolar disorder (BD).

Day-to-day variability in activity levels detects transitions to depressive symptoms in bipolar disorder earlier than changes in sleep and mood.

Anticipating clinical transitions in bipolar disorder (BD) is essential for the development of clinically actionable predictions. Our aim was to determine what is the earliest indicator of the onset of depressive symptoms in BD. We hypothesized that changes in activity would be the earliest indicator of future depressive symptoms.

Circadian clock genes and cell survival in bipolar disorder: Insights into lithium responsiveness and molecular mechanisms in patient-derived neural progenitor cells and mouse neurons.

Bipolar disorder (BD) is characterized by disrupted circadian rhythms and neuronal loss. Lithium amplifies circadian rhythms and is neuroprotective, indicating mechanistic overlap across cellular systems. We examined the role of neuroprotection in determining lithium response and how circadian clock genes regulate apoptosis.

Prediction of Treatment Outcome in Bipolar Disorder: When Can We Expect Clinical Relevance?

Long-term pharmacological treatment is the cornerstone of the management of bipolar disorder (BD). Clinicians typically select mood-stabilizing medications from among several options through trial and error. This process could be optimized by using robust predictors of treatment response.

Genomics yields biological and phenotypic insights into bipolar disorder.

Bipolar disorder is a leading contributor to the global burden of disease. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.

The Impact of Electrophysiological Diversity on Pattern Completion in Lithium Nonresponsive Bipolar Disorder: A Computational Modeling Approach.

Introduction: Patients with bipolar disorder (BD) demonstrate episodic memory deficits, which may be hippocampal-dependent and may be attenuated in lithium responders. Induced pluripotent stem cell-derived CA3 pyramidal cell-like neurons show significant hyperexcitability in lithium-responsive BD patients, while lithium nonresponders show marked variance in hyperexcitability. We hypothesize that this variable excitability will impair episodic memory recall, as assessed by cued retrieval (pattern completion) within a computational model of the hippocampal CA3.

Day-to-day variability in sleep and activity predict the onset of a hypomanic episode in patients with bipolar disorder.

Detecting transitions in bipolar disorder (BD) is essential for implementing early interventions. Our aim was to identify the earliest indicator(s) of the onset of a hypomanic episode in BD. We hypothesized that objective changes in sleep would be the earliest indicator of a new hypomanic or manic episode.

Mood regulation in euthymic patients with a history of antidepressant-induced mania.

Introduction: The use of antidepressants in bipolar disorder (BD) remains contentious, in part due to the risk of antidepressant-induced mania (AIM). However, there is no information on the architecture of mood regulation in patients who have experienced AIM. We compared the architecture of mood regulation in euthymic patients with and without a history of AIM.

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinson's disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals.

Physical comorbidities of older age bipolar disorder (OABD) patients: A global replication analysis of prevalence and sex differences.

Objectives: To compare the prevalence of physical morbidities between older aged patients with bipolar disorder (OABD) and non-psychiatric comparisons (NC), and to analyze sex differences in prevalence.

Methods: OABD was defined as bipolar disorder among adults aged ≥50 years. Outcomes analyzed were the prevalence of diseases affecting the cardiovascular, respiratory, gastrointestinal, genitourinary, renal, musculoskeletal, and endocrine systems.