Two polygenic mouse models of major depressive disorders identify TMEM161B as a potential biomarker of disease in humans.

Treatments are only partially effective in major depressive disorders (MDD) but no biomarker exists to predict symptom improvement in patients. Animal models are essential tools in the development of antidepressant medications, but while recent genetic studies have demonstrated the polygenic contribution to MDD, current models are limited to either mimic the effect of a single gene or environmental factor. We developed in the past a model of depressive-like behaviors in mice (H/Rouen), using selective breeding based on behavioral reaction after an acute mild stress in the tail suspension test. Here, we propose a new mouse model of depression (H-TST) generated from a more complex genetic background and based on the same selection process. We first demonstrated that H/Rouen and H-TST mice had similar phenotypes and were more sensitive to glutamate-related antidepressant medications than selective serotonin reuptake inhibitors. We then conducted an exome sequencing on the two mouse models and showed that they had damaging variants in 174 identical genes, which have also been associated with MDD in humans. Among these genes, we showed a higher expression level of Tmem161b in brain and blood of our two mouse models. Changes in TMEM161B expression level was also observed in blood of MDD patients when compared with controls, and after 8-week treatment with duloxetine, mainly in good responders to treatment. Altogether, our results introduce H/Rouen and H-TST as the two first polygenic animal models of MDD and demonstrate their ability to identify biomarkers of the disease and to develop rapid and effective antidepressant medications.

A loss-of-function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa.

Dowling Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by acquired, slowly progressive reticulated pigmented lesions primarily involving flexural skin areas. Mutations in KRT5, POGLUT-1 and POFUT-1 genes have been associated with DDD, and loss-of-function mutations in PSENEN, a subunit of the gamma-secretase complex, were found in patients presenting with DDD or DDD comorbid with hidradenitis suppurativa (HS). A nonsense mutation in NCSTN, another subunit of the gamma-secretase, was already described in a patient suffering from HS and DDD but whether NCSTN could be considered a novel gene for DDD is still debated. Here, we enrolled a four-generation family with HS and DDD. Through Whole Exome Sequencing (WES) we identified a novel nonsense mutation in the NCSTN gene in all the affected family members. To study the impact of this variant, we isolated outer root sheath cells from patients' hair follicles. We showed that this variant leads to a premature stop codon, activates a nonsense-mediated mRNA decay, and causes NCSTN haploinsufficiency in affected individuals. In fact, cells treated with gentamicin, a readthrough agent, had the NCSTN levels corrected. Moreover, we observed that this haploinsufficiency also affects other subunits of the gamma-secretase complex, possibly causing DDD. Our findings clearly support NCSTN as a novel DDD gene and suggest carefully investigating this co-occurrence in HS patients carrying a mutation in the NCSTN gene.

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.

Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression.

OBJECTIVES: The aim of this study was to repurpose a drug for the treatment of bipolar depression. METHODS: A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal-like (NT2-N) cells. A compound library of 960 approved, off-patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co-cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive-like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats). RESULTS: The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal-like cells. Transcriptomic analysis in induced pluripotent stem cell-derived neuron/astrocyte co-cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive-like behaviours, trimetazidine exhibited antidepressant-like activity with reduced anhedonia and reduced immobility in the forced swim test. CONCLUSION: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.

Risperidone response in patients with schizophrenia drives DNA methylation changes in immune and neuronal systems.

Background: The choice of efficient antipsychotic therapy for schizophrenia relies on a time-consuming trial-and-error approach, whereas the social and economic burdens of the disease call for faster alternatives. Material & methods: In a search for predictive biomarkers of antipsychotic response, blood methylomes of 28 patients were analyzed before and 4 weeks into risperidone therapy. Results: Several CpGs exhibiting response-specific temporal dynamics were identified in otherwise temporally stable methylomes and noticeable global response-related differences were observed between good and bad responders. These were associated with genes involved in immunity, neurotransmission and neuronal development. Polymorphisms in many of these genes were previously linked with schizophrenia etiology and antipsychotic response. Conclusion: Antipsychotic response seems to be shaped by both stable and medication-induced methylation differences.

The most common way to treat schizophrenia is antipsychotic medication. However, not all antipsychotics work for all patients. The only way to find a suitable antipsychotic is to prescribe one and wait, sometimes for months, to see if it works. Finding an alternative to this trial-and-error method would help reduce patient suffering and costs for healthcare systems. The idea is to look in the DNA of our blood cells for specific marks that can change in response to our lifestyle or health condition. These marks could help us predict how patients will react to the drug. In other words, they can serve as biomarkers of antipsychotic response. The current work examined the blood of schizophrenia patients before and 4 weeks after starting medication. The patients who did not respond well to the drug had different marks on the genes involved in immune defense and nervous system functioning. Some of these genes also play roles in the development of schizophrenia, whereas others can directly affect what happens to the drug in the patient's body. Although marks that predict how patients will react were not identified with certainty, valuable targets for future research were identified.

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<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.

Use of multiple polygenic risk scores for distinguishing schizophrenia-spectrum disorder and affective psychosis categories in a first-episode sample; the EU-GEI study.

BACKGROUND: Schizophrenia (SZ), bipolar disorder (BD) and depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUropean Network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) first episode case-control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD). METHODS: Participants (842 cases, 1284 controls) from 16 European EU-GEI sites were successfully genotyped following standard quality control procedures. The sample was stratified based on genomic ancestry and analyses were done only on the subsample representing the European population (573 cases, 1005 controls). Using PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons. RESULTS: In case-control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case-case comparisons, both PRS-SZ [odds ratio (OR) = 0.7, 95% confidence interval (CI) 0.54-0.92] and PRS-D (OR = 1.31, 95% CI 1.06-1.61) differentiated AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR = 2.14, 95% CI 1.23-3.74). CONCLUSIONS: Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards the potential usefulness of PRSs in specific populations such as high-risk or early psychosis phases.

Desloratadine, an FDA-approved cationic amphiphilic drug, inhibits SARS-CoV-2 infection in cell culture and primary human nasal epithelial cells by blocking viral entry.

The 2019 global coronavirus (COVID-19) pandemic has brought the world to a grinding halt, highlighting the urgent need for therapeutic and preventive solutions to slow the spread of emerging viruses. The objective of this study was to assess the anti-SARS-CoV-2 effectiveness of 8 FDA-approved cationic amphiphilic drugs (CADs). SARS-CoV-2-infected Vero cells, Calu-3 cells and primary Human Nasal Epithelial Cells (HNEC) were used to investigate the effects of CADs and revealed their antiviral mode of action. Among the CADs tested, desloratadine, a commonly used antiallergic, well-tolerated with no major side effects, potently reduced the production of SARS-CoV-2 RNA in Vero-E6 cells. Interestingly, desloratadine was also effective against HCoV-229E and HCoV-OC43 showing that it possessed broad-spectrum anti-coronavirus activity. Investigation of its mode of action revealed that it targeted an early step of virus lifecycle and blocked SARS-CoV-2 entry through the endosomal pathway. Finally, the ex vivo kinetic of the antiviral effect of desloratadine was evaluated on primary Human Nasal Epithelial Cells (HNEC), showing a significant delay of viral RNA production with a maximal reduction reached after 72 h of treatment. Thus, this treatment could provide a substantial contribution to prophylaxis and systemic therapy of COVID-19 or other coronaviruses infections and requires further studies.

Transcriptome Meta-Analysis Confirms the Hidradenitis Suppurativa Pathogenic Triad: Upregulated Inflammation, Altered Epithelial Organization, and Dysregulated Metabolic Signaling.

Hidradenitis suppurativa (HS) is an inflammatory skin condition clinically characterized by recurrent painful deep-seated nodules, abscesses, and sinus tracks in areas bearing apocrine glands, such as axillae, breasts, groins, and buttocks. Despite many recent advances, the pathophysiological landscape of HS still demands further clarification. To elucidate HS pathogenesis, we performed a meta-analysis, set analysis, and a variant calling on selected RNA-Sequencing (RNA-Seq) studies on HS skin. Our findings corroborate the HS triad composed of upregulated inflammation, altered epithelial differentiation, and dysregulated metabolism signaling. Upregulation of specific genes, such as KRT6, KRT16, serpin-family genes, and SPRR3 confirms the early involvement of hair follicles and the impairment of barrier function in HS lesioned skin. In addition, our results suggest that adipokines could be regarded as biomarkers of HS and metabolic-related disorders. Finally, the RNA-Seq variant calling identified several mutations in HS patients, suggesting potential new HS-related genes associated with the sporadic form of this disease. Overall, this study provides insights into the molecular pathways involved in HS and identifies potential HS-related biomarkers.

Facial Emotion Recognition in Psychosis and Associations With Polygenic Risk for Schizophrenia: Findings From the Multi-Center EU-GEI Case-Control Study.

BACKGROUND AND HYPOTHESIS: Facial Emotion Recognition is a key domain of social cognition associated with psychotic disorders as a candidate intermediate phenotype. In this study, we set out to investigate global and specific facial emotion recognition deficits in first-episode psychosis, and whether polygenic liability to psychotic disorders is associated with facial emotion recognition. STUDY DESIGN: 828 First Episode Psychosis (FEP) patients and 1308 population-based controls completed assessments of the Degraded Facial Affect Recognition Task (DFAR) and a subsample of 524 FEP and 899 controls provided blood or saliva samples from which we extracted DNA, performed genotyping and computed polygenic risk scores for schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MD). STUDY RESULTS: A worse ability to globally recognize facial emotion expressions was found in patients compared with controls [B= -1.5 (0.6), 95% CI -2.7 to -0.3], with evidence for stronger effects on negative emotions (fear [B = -3.3 (1.1), 95% CI -5.3 to -1.2] and anger [B = -2.3 (1.1), 95% CI -4.6 to -0.1]) than on happiness [B = 0.3 (0.7), 95% CI -1 to 1.7]. Pooling all participants, and controlling for confounds including case/control status, facial anger recognition was associated significantly with Schizophrenia Polygenic Risk Score (SZ PRS) [B = -3.5 (1.7), 95% CI -6.9 to -0.2]. CONCLUSIONS: Psychosis is associated with impaired recognition of fear and anger, and higher SZ PRS is associated with worse facial anger recognition. Our findings provide evidence that facial emotion recognition of anger might play a role as an intermediate phenotype for psychosis.

CADPS functional mutations in patients with bipolar disorder increase the sensitivity to stress.

Bipolar disorder is a severe and chronic psychiatric disease resulting from a combination of genetic and environmental risk factors. Here, we identified a significant higher mutation rate in a gene encoding the calcium-dependent activator protein for secretion (CADPS) in 132 individuals with bipolar disorder, when compared to 184 unaffected controls or to 21,070 non-psychiatric and non-Finnish European subjects from the Exome Aggregation Consortium. We found that most of these variants resulted either in a lower abundance or a partial impairment in one of the basic functions of CADPS in regulating neuronal exocytosis, synaptic plasticity and vesicular transporter-dependent uptake of catecholamines. Heterozygous mutant mice for Cadps+/- revealed that a decreased level of CADPS leads to manic-like behaviours, changes in BDNF level and a hypersensitivity to stress. This was consistent with more childhood trauma reported in families with mutation in CADPS, and more specifically in mutated individuals. Furthermore, hyperactivity observed in mutant animals was rescued by the mood-stabilizing drug lithium. Overall, our results suggest that dysfunction in calcium-dependent vesicular exocytosis may increase the sensitivity to environmental stressors enhancing the risk of developing bipolar disorder.

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

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.

No alteration of leukocyte telomere length in first episode psychosis.

Both shorter telomeres and schizophrenia have been associated with a decrease in life expectancy. Furthermore, several studies found a shorter telomere length (TL) in schizophrenia. Understanding whether or not telomere shortening is directly related to pathophysiology of schizophrenia or is a consequence of a cumulative exposure to chronic stress is of major importance. Comparing the TL of subjects at the very beginning of the disease (FEP) and control subjects could help to decide between these two hypotheses. The aim of the present study was to compare TL between FEP subjects (N=91) and controls (N=137). After accounting for multiple potential confounders, no significant association was observed between FEP and TL. Our result is consistent with the hypothesis that psycho-social stress / adversities and stressful situations in people with schizophrenia affect TL rather than that telomere erosion contributes to the development of this disorder.

Relationship Between Serum NMDA Receptor Antibodies and Response to Antipsychotic Treatment in First-Episode Psychosis.

BACKGROUND: When psychosis develops in NMDA receptor (NMDAR) antibody encephalitis, it usually has an acute or subacute onset, and antipsychotic treatment may be ineffective and associated with adverse effects. Serum NMDAR antibodies have been reported in a minority of patients with first-episode psychosis (FEP), but their role in psychosis onset and response to antipsychotic treatment is unclear. METHODS: Sera from 387 patients with FEP (duration of psychosis <2 years, minimally or never treated with antipsychotics) undergoing initial treatment with amisulpride as part of the OPTiMiSE (Optimization of Treatment and Management of Schizophrenia in Europe) trial (ClinicalTrials.gov number NCT01248195) were tested for NMDAR IgG antibodies using a live cell-based assay. Symptom severity was assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impressions Scale at baseline and again after 4 weeks of treatment with amisulpride. RESULTS: At baseline, 15 patients were seropositive for NMDAR antibodies and 372 were seronegative. The seropositive patients had similar symptom profiles and demographic features to seronegative patients but a shorter duration of psychosis (median 1.5 vs. 4.0 months; p = .031). Eleven seropositive and 284 seronegative patients completed 4 weeks of amisulpride treatment: after treatment, there was no between-groups difference in improvement in Positive and Negative Syndrome Scale scores or in the frequency of adverse medication effects. CONCLUSIONS: These data suggest that in FEP, NMDAR antibody seropositivity alone is not an indication for using immunotherapy instead of antipsychotic medications. Further studies are required to establish what proportion of patients with FEP who are NMDAR antibody seropositive have coexisting cerebrospinal fluid inflammatory changes or other paraclinical evidence suggestive of a likely benefit from immunotherapy.

Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study.

Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (ß = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (ß = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder.

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Antidepressant-like effect of low dose of scopolamine in the H/Rouen genetic mouse model of depression.

Rodent models of depression are useful for the investigation of cellular and neuronal mechanisms of antidepressant drugs and for the discovery of potential new targets. In this study, we examined the antidepressant-like effect of scopolamine, a non-selective muscarinic antagonist, in a genetic mouse model of depression obtained through a selective breeding strategy and called H/Rouen. In this model, we observed that scopolamine was active both in males and females at a lower dose (0.03 mg/kg) in the tail suspension test, 30 min following its administration, than observed in CD-1 mice. In addition, we showed this antidepressant-like effect was partly inhibited by an injection of 10 mg/kg of the AMPA receptor antagonist NBQX in both males and females, suggesting the antidepressant-like effect of scopolamine was mainly driven by AMPA receptors in the H/Rouen mouse line. Altogether, our results showed the high sensitivity of the H/Rouen mouse model of depression to study the antidepressant-like effects of pharmacological compounds.

Schizophrenia: Developmental Variability Interacts with Risk Factors to Cause the Disorder: Nonspecific Variability-Enhancing Factors Combine with Specific Risk Factors to Cause Schizophrenia.

A new etiological model is proposed for schizophrenia that combines variability-enhancing nonspecific factors acting during development with more specific risk factors. This model is better suited than the current etiological models of schizophrenia, based on the risk factors paradigm, for predicting and/or explaining several important findings about schizophrenia: high co-morbidity rates, low specificity of many risk factors, and persistence in the population of the associated genetic polymorphisms. Compared with similar models, e.g., de-canalization, common psychopathology factor, sexual-selection, or differential sensitivity to the environment, this proposal is more general and integrative. Recently developed research methods have proven the existence of genetic and environmental factors that enhance developmental variability. Applying such methods to newly collected or already available data can allow for testing the hypotheses upon which this model is built. If validated, this model may change the understanding of the etiology of schizophrenia, the research models, and preventionbrk paradigms.