Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Exploring the genetics of lithium response in bipolar disorders.

Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10-12, R2 = 1.9%) and continuous (P = 6.4 × 10-9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10-4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder.

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1×10- 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3ß. We also found various genes associated with BP's age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.

Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.

Perceived public stigma and perceived public exposure by persons living with bipolar disorder: A qualitative study.

BACKGROUND: Stigma impact the lives of persons living with bipolar disorder. AIM: The aim of this study was to explore how perceived public stigma is described by people living with bipolar disorder and examine the links between perceived public stigma and perceived public exposure. METHOD: Face-to-face in-depth interviews were conducted in a purposive sample of euthymic people living with bipolar disorder recruited in a mood disorder ambulatory unit. RESULTS: Thematic analysis of the transcript yielded five independent themes that were related to perceived public stigma. Perceived public stigma of bipolar disorder was modeled as comprising the three elements of public stigmas (stereotype, prejudice, and discrimination), with the addition of public exposure as a core component. CONCLUSION: The representation of bipolar disorder in society via newspapers, films/TV series, conferences, and celebrity self-disclosures is considered to have multiple impacts. People living with bipolar disorder have also reported a perceived public stigma of bipolar disorder that has both specific features and characteristics of general mental illness.

Dysfunctional temporal stages of eye-gaze perception in adults with ADHD: A high-density EEG study.

ADHD has been associated with social cognitive impairments across the lifespan, but no studies have specifically addressed the presence of abnormalities in eye-gaze processing in the adult brain. This study investigated the neural basis of eye-gaze perception in adults with ADHD using event-related potentials (ERP). Twenty-three ADHD and 23 controls performed a delayed face-matching task with neutral faces that had either direct or averted gaze. ERPs were classified using microstate analyses. ADHD and controls displayed similar P100 and N170 microstates. ADHD was associated with cluster abnormalities in the attention-sensitive P200 to direct gaze, and in the N250 related to facial recognition. For direct gaze, source localization revealed reduced activity in ADHD for the P200 in the left/midline cerebellum, as well as in a cingulate-occipital network at the N250. These results suggest brain impairments involving eye-gaze decoding in adults with ADHD, suggestive of neural signatures associated with this disorder in adulthood.

Mapping Child and Adolescent Mental Health Services and the Interface During Transition to Adult Services in Six Swiss Cantons.

Rationale: Transition in psychiatry refers to the period where young people transit from Child and Adolescent Mental Health Services (CAMHS) to Adult Mental Health Services (AMHS). Discontinuity of care during this period is well-documented but little is known about provisions and transition characteristics and policies across Switzerland. The aim of this article is to describe the architecture of public mental health providers in Switzerland and compare it to EU countries. Method: Two mapping surveys, developed previously for European countries, were adapted and sent to cantonal experts: the adapted European CAMHS Mapping Questionnaire (ECM-Q) assessing the architecture and functioning of CAMHS and the adapted Standardized Assessment Tool for Mental Health Transition (SATMeHT) to map CAMHS-AMHS interface. Results: Data were gathered from six cantons. Activity data and transition policies were comparable between Swiss regions and European countries. The percentage of young people below 19 years who were in care was above 2% in every responding canton with a higher proportion of boys than girls for patients <12 years of age. The transition occurred at the age of 18 years, civil majority, in each canton, and between 0 and 24% (3/7) and 25% and 49% (4/7) of young people were expected to transition. One canton (1/7) benefitted from written guidelines, at the CAMHS level only, regarding transition but none had guidelines for mapping CAMHS/AMHS interface even at the regional level. Conclusion: Despite the availability of resources and even if the possibilities of access to care are on average higher than in many European countries, issues regarding transition remain comparable in six Swiss cantons when compared to Europe. Meaning that beyond resources, it is the coordination between services that needs to be worked on. Importantly, implementing those changes would not require investing financial resources but rather working on the coordination between existing teams.

Environmental factors in offspring of parents with mood disorders and their role in parent-child transmission: findings from a 14-year prospective high-risk study.

BACKGROUND: The factors involved in the transmission of mood disorders are only partially elucidated. Aside from genes, the family environment might play a crucial role in parent-child transmission. Our goals were to (1) assess the associations of parental bipolar disorder (BPD) and Major Depressive Disorder (MDD) with individual or shared family environmental factors, including traumatic events in offspring, parental separation, family cohesion and parental attitudes; and 2) test whether these factors were mediators of the association between exposure to parental mood disorders and the onset of these disorders in offspring. METHODS: The sample stems from an ongoing family high-risk study of mood disorders conducted in the French-speaking part of Switzerland. Given the strong impact of the age of onset of parental disorders on their transmission to children, parental disorders were dichotomized according to the onset (cut-off 21 years). Probands with early-onset (n = 30) and later-onset BPD (n = 51), early-onset (n = 21) and later-onset MDD (n = 47) and controls (n = 65), along with their spouses (n = 193) and offspring (n = 388; < 18 years on study inclusion), were assessed over a mean follow-up duration of 14 years (s.d: 4.6). The environmental measures were based on reports by offspring collected before the onset of their first mood episode. RESULTS: Offspring of probands with later-onset BPD and offspring of probands with both early-onset and later-onset MDD reported traumatic events more frequently than comparison offspring, whereas exposure to parental separation was more frequent in all groups of high-risk offspring. Moreover, several familial environment scores including parenting attitudes differed between offspring of probands with BPD and comparison offspring. However, none of these factors were mediators of the parent-child transmission of BPD. Among the environmental factors, traumatic events were shown to be modest mediators of the transmission of early-onset MDD. CONCLUSIONS: Our data do not support the implication of the assessed environmental factors in the parent-child transmission of BPD. In contrast to BPD, traumatic events partially mediate the parent-child transmission of early-onset MDD, which has important implications for intervention and prevention. Early therapeutic efforts in offspring exposed to these events are likely to reduce their deleterious impact on the risk of subsequent MDD.

Investigating the phenotypic and genetic associations between personality traits and suicidal behavior across major mental health diagnoses.

Personality traits influence risk for suicidal behavior. We examined phenotype- and genotype-level associations between the Big Five personality traits and suicidal ideation and attempt in major depressive, bipolar and schizoaffective disorder, and schizophrenia patients (N = 3012) using fixed- and random-effects inverse variance-weighted meta-analyses. Suicidal ideations were more likely to be reported by patients with higher neuroticism and lower extraversion phenotypic scores, but showed no significant association with polygenic load for these personality traits. Our findings provide new insights into the association between personality and suicidal behavior across mental illnesses and suggest that the genetic component of personality traits is unlikely to have strong causal effects on suicidal behavior.

Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach.

BACKGROUND: Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment. AIMS: To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder. METHOD: This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework. RESULTS: The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data. CONCLUSIONS: Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.

Quality of life and subjective sleep-related measures in bipolar disorder and major depressive disorder.

PURPOSE: Diminished quality of life (QoL) has been reported in patients with mood disorders. QoL has also been shown to be decreased by sleep disturbances. Since sleep disorders are common in mood disorders, the aim of this study was to determine whether sleep characteristics are associated to QoL among patients with Bipolar Disorder (BD) and unipolar Major Depressive Disorders (MDD). METHODS: QoL was assessed in 170 patients with mood disorders (61 BD and 109 MDD), who also completed questionnaires measuring the severity of insomnia, sleepiness, chronotype preference and obstructive sleep apnea (OSA) probability index. RESULTS: Analyses showed that BD and MDD groups had similar QoL and sleep measures but the MDD group had higher OSA scores. In BD, correlations indicated a relationship between QoL and insomnia complaints and sleepiness, whereas in MDD, correlations indicated an association between QoL and insomnia complaints and OSA score. In both groups, QoL was related to depressive symptomatology. Linear regressions showed that, in BD, QoL was related to insomnia complaints and sleepiness even in the euthymic state, whereas in MDD, QoL was related to insomnia complaints but not in euthymic patients. CONCLUSION: QoL is related to sleep differently in BD and MDD. The results suggest that insomnia and sleepiness are particularly high in BD even when patients are euthymic. These findings suggest that focusing on insomnia and sleepiness during different mood states of BD could increase QoL.

Is Coping with Stigma by Association Role-Specific for Different Family Members? A Qualitative Study with Bipolar Disorder Patients' Relatives.

Trying to cope with stigma by association (SBA) often results in behaviors leading to social isolation and withdrawal. This study aimed at exploring the stigma-related experiences of family members of persons living with bipolar disorder (PW-BD). A semi-structured interview was conducted with relatives of PW-BD. Open-ended questions addressed three issues: awareness of public stigma of bipolar disorder, experiences of associative stigma, and ways of coping with experiences of SBA. Data were collected from a purposive sample of 21 family members. Experiences of SBA were specifically related to the different family roles. Parents had to deal with responsibility, partners with the choice of staying or not, and siblings with "a sort of duty." These specific prejudices enhanced specific coping strategies. This is the first study to highlight specific issues and coping from the perspective of family members. Based on these findings, specific targeted interventions could be developed.

Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients.

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.

Fronto-limbic neural variability as a transdiagnostic correlate of emotion dysregulation.

Emotion dysregulation is central to the development and maintenance of psychopathology, and is common across many psychiatric disorders. Neurobiological models of emotion dysregulation involve the fronto-limbic brain network, including in particular the amygdala and prefrontal cortex (PFC). Neural variability has recently been suggested as an index of cognitive flexibility. We hypothesized that within-subject neural variability in the fronto-limbic network would be related to inter-individual variation in emotion dysregulation in the context of low affective control. In a multi-site cohort (N = 166, 93 females) of healthy individuals and individuals with emotional dysregulation (attention deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), and borderline personality disorder (BPD)), we applied partial least squares (PLS), a multivariate data-driven technique, to derive latent components yielding maximal covariance between blood-oxygen level-dependent (BOLD) signal variability at rest and emotion dysregulation, as expressed by affective lability, depression and mania scores. PLS revealed one significant latent component (r = 0.62, p = 0.044), whereby greater emotion dysregulation was associated with increased neural variability in the amygdala, hippocampus, ventromedial, dorsomedial and dorsolateral PFC, insula and motor cortex, and decreased neural variability in occipital regions. This spatial pattern bears a striking resemblance to the fronto-limbic network, which is thought to subserve emotion regulation, and is impaired in individuals with ADHD, BD, and BPD. Our work supports emotion dysregulation as a transdiagnostic dimension with neurobiological underpinnings that transcend diagnostic boundaries, and adds evidence to neural variability being a relevant proxy of neural efficiency.

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders.

Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10-3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.

Prevalence of Polypharmacy and Inappropriate Medication in Adults With Intellectual Disabilities in a Hospital Setting in Switzerland.

Background: Polypharmacy and inappropriate prescription are frequent in vulnerable and multi-morbid populations. Adults with intellectual disability (ID) are at risk of being polymedicated because they often present with multiple comorbidities and challenging behaviors. Aim: The objective of this study was thus to evaluate the prevalence of potentially inappropriate medications (PIM) and polypharmacy in a hospital unit dedicated to adults with ID. Methods: A 10-month prospective observational study took place at a hospital unit specializing in the care of adults with ID in Geneva, Switzerland. Once a week, health and prescription data were collected and screened for PIM according to preset definitions. Results: Fourteen patients consented to participate, leading to 20 hospitalization events assessed during the study. Hospitalizations lasted 12.8 weeks on average. ID severities ranged from mild to profound, all degrees of severity being equally represented. One hundred percent of the patients were polymedicated (defined as five drugs or more prescribed simultaneously). A mean number of 9.4 drugs were prescribed per week, including 5.3 psychotropic drugs. The number of prescribed drugs remained stable throughout the hospitalizations. Antipsychotics were the most prescribed drug class (19% of all prescribed drugs), followed by benzodiazepines (13%) and laxatives (12%). A total of 114 PIM were recorded with an average of 5.7 PIM per hospitalization. Conclusions: This study showed that polypharmacy and inappropriate prescription are very common in adults with ID, even though the literature and expert positions advocate for deprescription in these patients. Specific prescribing and deprescribing guidelines are needed for that specific population.