Make lithium great again – Precisely!
Résumé
Abstract Background Despite its pivotal role in prophylaxis for bipolar-I-disorders (BD-I), variability in lithium (Li) response is poorly understood and only a third of patients show a good outcome. Converging research strands indicate that rest–activity rhythms can help characterize BD-I and might differentiate good responders (GR) and non-responders (NR). Methods Seventy outpatients with BD-I receiving Li prophylaxis were categorized as GR or NR according to the ratings on the retrospective assessment of response to lithium scale (Alda scale). Participants undertook 21 consecutive days of actigraphy monitoring of sleep quantity (SQ), sleep variability (SV) and circadian rhythmicity (CR). Results Twenty-five individuals were categorized as GR (36%). After correcting statistical analysis to minimize false discoveries, four variables (intra-daily variability; median activity level; amplitude; and relative amplitude of activity) significantly differentiated GR from NR. The odds of being classified as a GR case were greatest for individuals showing more regular/stable CR (1.41; 95% confidence interval (CI) 1.08, 2.05; p < 0.04). Also, there was a trend for lower SV to be associated with GR (odds ratio: 0.56; 95% CI 0.31, 1.01; p < 0.06). Conclusions To our knowledge, this is the largest actigraphy study of rest–activity rhythms and Li response. Circadian markers associated with fragmentation, variability, amount and/or amplitude of day and night-time activity best-identified GR. However, associations were modest and future research must determine whether these objectively measured parameters, singly or together, represent robust treatment response biomarkers. Actigraphy may offer an adjunct to multi-platform approaches aimed at developing personalized treatments or stratification of individuals with BD-I into treatment-relevant subgroups.
Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Mots clés
Domains
Evidence map
Longitudinal
Modifiers
Phenotype
Misperception of sleep
Sleep duration
Sleep efficiency
Sleep latency
major depression
patient satisfaction
patient-reported experience measures
clinical cohort
DSM-5
ICD-11
Validity of diagnosis
Diagnostic delay
Delayed early intervention
Mood stabilisers
bipolar affective disorders
depressive disorders
genetics
outcome studies
Alda scale
DNA methylation
MS-HRM
biomarkers
bipolar disorder
lithium
response
transferability
validation
Bipolar disorders
Children
Circadian rhythms
First episode
High risk
Meta-regression
Sleep quality
Youth
affective symptoms
depression
pain
Bipolar disorder
Major depression
Personality
Polygenic score
Schizophrenia
Suicidal behavior
Epigenetics
Genomics
Major depressive disorder
Mood disorders
Multi-omics
Transcriptomics
chronic kidney disease
magnetic resonance imaging
radiomics
childhood maltreatment
childhood trauma
mood recurrence
physical abuse
CKD-chronic kidney disease
kidney microcysts
nephrotoxicity
Circadian
Energy
Lifestyle
Practice guidelines
Quality
Sleep
comorbidities
prevalence
suicide
GWAS
age at onset
polarity at onset
polygenic score
antidepressants
clinical severity
expert centres
side effects
treatment-resistant depression
COVID-19
burnout
health care workers
mediation
outbreak
post-traumatic
sanitary crisis
Genetic correlation
Genome-wide association study
Pleiotropy
Polygenicity
Suicide
Suicide attempt
actigraphy
animal models
biomarker
chronobiology
circadian
clock gene
levels of analysis
light
sleep
circadian genes
machine learning
phenotype
antecedents
illness trajectories
PSQI
dimensions
variability
Infectious diseases
Systematic review
Vaccination
Cognitive function
Cohort
Memory
Obesity
Cocaine
addiction
impulsiveness
recurrent suicide attempt
resilience
serious suicide attempt
substance use disorder
Antecedents
Bipolar I disorder
Cohorts
Comorbidities
Family history
Trajectories
activity rhythms
biological rhythms
bipolar disorders
chronotype
circadian rhythms
eveningness
meta-analysis
morningness
rest
systematic review
Psychiatry
Seasonal variation
Solar insolation
Sunlight
Cognition
Handedness
Language disorders
Laterality
Neurodevelopment
Lithium
Methylation
Response variability
non-coding RNA
CRP
Childhood maltreatment
Childhood trauma
Metabolic abnormalities
Metabolic syndrome
Genotype-by-sex interaction
Sex differences
Clusters
Data set
Hierarchical agglomerative clustering
Machine learning
Alcohol use disorder
Clinical trajectory
Comorbidity
Dual diagnosis
Sequence of onset
circadian gene
early life stress
gene expression
Functioning
Maintenance treatment
Mood stabilizers
Unsupervised machine learning
Patient-reported experience measures
health services research
major depressive disorder
patient experience
psychiatry
qualitative research
quality of care
schizophrenia
severe mental illness
Bipolar Disorders
Depression
Follow-up studies
Medication adherence
lithium response
Adolescence
Mania
Meta-analysis
Psychosis
Blood-brain barrier
Neurokinetics
Pharmacodynamics
Plexus choroid
Transporters
antipsychotics
metabolic syndrome
Catatonia
Confusion
Delirium
Longitudinal study
Prediction
Recurrence
Subtype
Clinical markers
Predictors
Response
Treatment
Actigraphy
Bipolar
Course