Exploring the use of immunomethylomics in the characterization of depressed patients: A proof-of-concept study.

Alterations in DNA methylation and inflammation could represent valid biomarkers for the stratification of patients with major depressive disorder (MDD). This study explored the use of DNA-methylation based immunological cell-type profiles in the context of MDD and symptom severity over time. In 119 individuals with MDD, DNA-methylation was assessed on whole blood using the Illumina Infinium MethylationEPIC 850 k BeadChip. Quality control and data processing, as well as cell type estimation was conducted using the RnBeads package. The cell type composition was estimated using epigenome-wide DNA methylation signatures, applying the Houseman method, considering six cell types (neutrophils, natural killer cells (NK), B cells, CD4 + T cells, CD8 + T cells and monocytes). Two cytokines (IL-6 and IL-1ß) and hsCRP were quantified in serum. We performed a hierarchical cluster analysis on the six estimated cell-types and tested the differences between these clusters in relation to the two cytokines and hsCRP, depression severity at baseline, and after 6 weeks of treatment (celecoxib/placebo + vortioxetine). We performed a second cluster analysis with cell-types and cytokines combined. ANCOVA was used to test for differences across clusters. We applied the Bonferroni correction. After quality control, we included 113 participants. Two clusters were identified, cluster 1 was high in CD4 + cells and NK, cluster 2 was high in CD8 + T-cells and B-cells, with similar fractions of neutrophils and monocytes. The clusters were not associated with either of the two cytokines and hsCRP, or depression severity at baseline, but cluster 1 showed higher depression severity after 6 weeks, corrected for baseline (p = 0.0060). The second cluster analysis found similar results: cluster 1 was low in CD8 + T-cells, B-cells, and IL-1ß. Cluster 2 was low in CD4 + cells and natural killer cells. Neutrophils, monocytes, IL-6 and hsCRP were not different between the clusters. Participants in cluster 1 showed higher depression severity at baseline than cluster 2 (p = 0.034), but no difference in depression severity after 6 weeks. DNA-methylation based cell-type profiles may be valuable in the immunological characterization and stratification of patients with MDD. Future models should consider the inclusion of more cell-types and cytokines for better a prediction of treatment outcomes.

Neurological, Metabolic, and Psychopathological Correlates of Lifetime Suicidal Behaviour in Major Depressive Disorder without Current Suicide Ideation.

INTRODUCTION: Suicidal behaviour (SB) has a complex aetiology. Although suicidal ideation (SI) is considered the most important risk factor for future attempts, many people who engage in SB do not report it. METHODS: We investigated neurological, metabolic, and psychopathological correlates of lifetime SB in two independent groups of patients with major depression (sample 1: n = 230; age: 18-65 years; sample 2: n = 258; age >60 years) who did not report SI during an index episode. RESULTS: Among adults (sample 1), SB was reported by 141 subjects (58.7%) and severe SB by 33 (15%). After controlling for interactions, four risk factors for SB emerged: male gender (OR 2.55; 95% CI: 1.06-6.12), negative self-perception (OR 1.76; 95% CI: 1.08-2.87), subthreshold hypomania (OR 4.50; 95% CI: 1.57-12.85), and sexual abuse (OR 3.09; 95% CI: 1.28-7.48). The presence of at least two of these factors had the best accuracy in predicting SB: sensitivity = 57.6% (39.2-74.5); specificity = 75.1% (68.5-82.0); PPV = 27.9% (20.9-37.2); NPV = 91.4% (87.6-94.1). In older patients (sample 2), 23 subjects (9%) reported previous suicide attempts, which were characterized by earlier onset (25 years: OR 0.95: 0.92-0.98), impaired verbal performance (verbal fluency: OR 0.95: 0.89-0.99), higher HDL cholesterol levels (OR 1.04: 1.00-1.07) and more dyskinesias (OR 2.86: 1.22-6.70). CONCLUSION: Our findings suggest that SB is common in major depressive disorder, even when SI is not reported. In these individuals it is feasible and recommended to investigate both psychiatric and organic risk factors. The predictive power of models excluding SI is comparable to that of models including SI.

Genetic factors and symptom dimensions associated with antidepressant treatment outcomes: clues for new potential therapeutic targets?

Treatment response and resistance in major depressive disorder (MDD) show a significant genetic component, but previous studies had limited power also due to MDD heterogeneity. This literature review focuses on the genetic factors associated with treatment outcomes in MDD, exploring their overlap with those associated with clinically relevant symptom dimensions. We searched PubMed for: (1) genome-wide association studies (GWASs) or whole exome sequencing studies (WESs) that investigated efficacy outcomes in MDD; (2) studies examining the association between MDD treatment outcomes and specific depressive symptom dimensions; and (3) GWASs of the identified symptom dimensions. We identified 13 GWASs and one WES of treatment outcomes in MDD, reporting several significant loci, genes, and gene sets involved in gene expression, immune system regulation, synaptic transmission and plasticity, neurogenesis and differentiation. Nine symptom dimensions were associated with poor treatment outcomes and studied by previous GWASs (anxiety, neuroticism, anhedonia, cognitive functioning, melancholia, suicide attempt, psychosis, sleep, sociability). Four genes were associated with both treatment outcomes and these symptom dimensions: CGREF1 (anxiety); MCHR1 (neuroticism); FTO and NRXN3 (sleep). Other overlapping signals were found when considering genes suggestively associated with treatment outcomes. Genetic studies of treatment outcomes showed convergence at the level of biological processes, despite no replication at gene or variant level. The genetic signals overlapping with symptom dimensions of interest may point to shared biological mechanisms and potential targets for new treatments tailored to the individual patient's clinical profile.

Suicide ideation and male-female differences in major depressive disorder.

OBJECTIVE: This study aimed to explore male-female differences in suicide ideation (SI) and suicide risk factors in major depressive disorder (MDD). METHODS: We analysed 482 adults (sample 1) and 438 elderly outpatients (sample 2) with MDD. Sample 1 was treated with different antidepressant combinations (escitalopram; bupropion plus escitalopram; venlafaxine plus mirtazapine) and assessed by means of the Concise Health Risk Tracking (SI), Quick Inventory of Depressive Symptomatology, Altman Mania Rating Scale and Psychiatric Diagnostic Screening Questionnaire. Sample 2 was treated with venlafaxine and assessed using the Hamilton scale for depression, Anxiety Sensitivity Index and Penn State Worry Questionnaire for anxiety, Beck Scale for Suicide Ideation and Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: In sample 1, females had greater depression severity (O.R 0.961 99%CI: 0.929 - 0.995), males reported more alcohol abuse (O.R 1.299 99%CI: 1.118 - 1.509) and active SI (O.R 1.109 99%CI: 1.005 - 1.255). In sample 2 men showed more severe SI (O.R 1.067; 99%CI: 1.014 - 1.122) and weight loss (OR = 5.89 99%CI: 1.01 - 34.19), women more gastrointestinal symptoms. CONCLUSIONS: In these selected samples, although women had more severe depression, men had more suicide risk factors. Such differences might contribute to men's increased suicide risk.

In major depressive disorder sex differences affect the clinical expression of depressive episodes. In comparison to men, women endorse higher levels of overall depression in adult MDD and more somatic anxiety and gastrointestinal symptoms in late-life MDD.After controlling for confounding variables, males have more severe SI and a larger number of suicide risk factors (eg. alcohol abuse; weight loss). The association between male sex and SI is detectable in both adults and elderly patients with MDD.Further studies are necessary to elucidate how sex differences in suicide ideation and suicide risk factors are related to men's increased suicide risk.

Mirtazapine blood levels and antidepressant response.

OBJECTIVE: Therapeutic drug monitoring (TDM) is an important tool for treatment optimisation. Its usefulness has recently been demonstrated for some first-line antidepressants; however, few studies have been reported on the relationship between blood levels of mirtazapine and its antidepressant effects. The aim of this study was to investigate the association between blood concentration of mirtazapine and antidepressant response. METHODS: 59 outpatients treated with mirtazapine for depression were recruited and followed up for three months in a naturalistic setting. Hamilton Depression Rating Scale-21 (HAMD-21) was administered at baseline, month 1, and month 3 to assess antidepressant response. Mirtazapine serum concentration was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between serum concentration of mirtazapine and antidepressant response. RESULTS: Our results showed no overall association between serum concentration of mirtazapine and symptom improvement at month 1 and month 3. A marginally significantly higher serum concentration of mirtazapine was found in responders vs non-responders at month 3. CONCLUSIONS: The study suggests that serum concentration of mirtazapine is not strongly associated with the antidepressant efficacy of mirtazapine. This is probably attributed to its pharmacodynamic profile, even though higher blood levels seem to be marginally more effective.

Mirtazapine plasma levels association with response is mild and do not follow the same curve of other antidepressantsMirtazapine higher plasma levels may show some benefit in a subgroup of patientsTherapeutic drug monitoring may help during antidepressant treatment.

Depressive symptoms and neuroticism-related traits are the main factors associated with wellbeing independent of the history of lifetime depression in the UK Biobank.

BACKGROUND: Wellbeing has a fundamental role in determining life expectancy and major depressive disorder (MDD) is one of the main modulating factors of wellbeing. This study evaluated the modulators of wellbeing in individuals with lifetime recurrent MDD (RMDD), single-episode MDD (SMDD) and no MDD in the UK Biobank. METHODS: Scores of happiness, meaningful life and satisfaction about functioning were condensed in a functioning-wellbeing score (FWS). We evaluated depression and anxiety characteristics, neuroticism-related traits, physical diseases, lifestyle and polygenic risk scores (PRSs) of psychiatric disorders. Other than individual predictors, we estimated the cumulative contribution to FWS of each group of predictors. We tested the indirect role of neuroticism on FWS through the modulation of depression manifestations using a mediation analysis. RESULTS: We identified 47 966, 21 117 and 207 423 individuals with lifetime RMDD, SMDD and no MDD, respectively. Depression symptoms and personality showed the largest impact on FWS (variance explained ~20%), particularly self-harm, worthlessness feelings during the worst depression, chronic depression, loneliness and neuroticism. Personality played a stronger role in SMDD. Anxiety characteristics showed a higher effect in SMDD and no MDD groups. Neuroticism played indirect effects through specific depressive symptoms that modulated FWS. Physical diseases and lifestyle explained only 4-5% of FWS variance. The PRS of MDD showed the largest effect on FWS compared to other PRSs. CONCLUSIONS: This was the first study to comprehensively evaluate the predictors of wellbeing in relation to the history of MDD. The identified variables are important to identify individuals at risk and promote wellbeing.

Emotion dysregulation in bipolar disorder compared to other mental illnesses: a systematic review and meta-analysis.

People with bipolar disorder (BD) often present emotion dysregulation (ED), a pattern of emotional expression interfering with goal-directed behavior. ED is a transdiagnostic construct, and it is unclear whether it manifests itself similarly in other conditions, such as major depressive disorder (MDD) or borderline personality disorder (BPD), or has specific features in BD. The present systematic review and meta-analysis explored ED and adopted emotion regulation (ER) strategies in BD compared with other psychiatric conditions. PubMed/MEDLINE, EMBASE, Scopus, and PsycINFO databases were systematically searched from inception to April 28th, 2022. Studies implementing validated instruments assessing ED or ER strategies in BD and other psychiatric disorders were reviewed, and meta-analyses were conducted. Twenty-nine studies yielding multiple comparisons were included. BD was compared to MDD in 20 studies (n = 2451), to BPD in six studies (n = 1001), to attention deficit hyperactivity disorder in three studies (n = 232), to anxiety disorders in two studies (n = 320), to schizophrenia in one study (n = 223), and to post-traumatic stress disorder in one study (n = 31). BD patients did not differ from MDD patients in adopting most adaptive and maladaptive ER strategies. However, small-to-moderate differences in positive rumination and risk-taking behaviors were observed. In contrast, patients with BPD presented an overall higher degree of ED and more maladaptive ER strategies. There were insufficient data for a meta-analytic comparison with other psychiatric disorders. The present report further supports the idea that ED is a transdiagnostic construct spanning a continuum across different psychiatric disorders, outlining specific clinical features that could represent potential therapeutic targets.

Correlation between emotion dysregulation and mood symptoms of bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: Emotion dysregulation (ED) is a transdiagnostic construct characterized by difficulties regulating intense emotions. People with bipolar disorder (BD) are more likely to show ED and use maladaptive emotion regulation strategies than adaptive ones. However, little is known about whether ED in BD is a trait or it is rather an epiphenomenon of mood symptoms. METHODS: We conducted a systematic review and meta-analysis of the evidence across major literature databases reporting correlations between measures of emotion regulation (overall ED and different emotion regulation strategies) and measures of depressive and (hypo)manic symptoms in BD from inception until April 12th, 2022. RESULTS: Fourteen studies involving 1371 individuals with BD were included in the qualitative synthesis, of which 11 reported quantitative information and were included in the meta-analysis. ED and maladaptive strategies were significantly higher during periods with more severe mood symptoms, especially depressive ones, while adaptive strategies were lower. CONCLUSION: ED significantly correlates with BD symptomatology, and it mainly occurs during mood alterations. ED may be a target for specific psychotherapeutic and pharmacological treatments, according to precision psychiatry. However, further studies are needed, including patients with mood episodes and longitudinal design, to provide more robust evidence and explore the causal direction of the associations.

Precision Medicine in Antidepressants Treatment.

Precision medicine uses innovative approaches to improve disease prevention and treatment outcomes by taking into account people's genetic backgrounds, environments, and lifestyles. Treatment of depression is particularly challenging, given that 30-50% of patients do not respond adequately to antidepressants, while those who respond may experience unpleasant adverse drug reactions (ADRs) that decrease their quality of life and compliance. This chapter aims to present the available scientific data that focus on the impact of genetic variants on the efficacy and toxicity of antidepressants. We compiled data from candidate gene and genome-wide association studies that investigated associations between pharmacodynamic and pharmacokinetic genes and response to antidepressants regarding symptom improvement and ADRs. We also summarized the existing pharmacogenetic-based treatment guidelines for antidepressants, used to guide the selection of the right antidepressant and its dose based on the patient's genetic profile, aiming to achieve maximum efficacy and minimum toxicity. Finally, we reviewed the clinical implementation of pharmacogenomics studies focusing on patients on antidepressants. The available data demonstrate that precision medicine can increase the efficacy of antidepressants and reduce the occurrence of ADRs and ultimately improve patients' quality of life.

Mental fatigue in individuals with psychiatric disorders: a scoping review.

OBJECTIVE: The aim of this study was to complete a scoping review of the published literature describing the relationship between mental fatigue and various psychiatric disorders, to better understand its frequency and clinical impact, and to provide recommendations for future clinical research. METHODS: A scoping review using PubMed/MEDLINE, Cochrane and PsychArticles databases was conducted using the keywords 'mental fatigue', 'mental tiredness' or 'mental exhaustion', and completed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols Extension for Scoping Reviews 2018 checklist. RESULTS: We extracted 10 studies fulfilling our inclusion criteria from a total of 2937 publications. Mental fatigue was studied within mood disorders, anxiety disorders, obsessive compulsive disorder and obsessive-compulsive personality disorder. A commonly used tool to measure mental fatigue in these samples was the Multidimensional Fatigue Inventory-20. Specific cognitive factors (unhelpful beliefs about sleep, symptom-focussed rumination) and personality risk factors (harm avoidance, self-directedness, cooperativeness, persistence) were relevant to predicting mental fatigue symptoms and rates of mental fatigue may vary with gender and diagnosis. CONCLUSION: Research into mental fatigue in adult psychiatric sample was limited to a few psychiatric disorders and requires further investigation.Key pointsA commonly used tool to measure mental fatigue was the Multidimensional Fatigue Inventory-20. However, more research into the validity and reliability for illness specific instruments to measure mental fatigue in psychiatric population is required.Reduction of mental fatigue was associated with improvement on quality of life.Specific cognitive factors (unhelpful beliefs about sleep, symptom-focussed rumination) and personality risk factors (harm avoidance, self-directedness, cooperativeness, persistence) were relevant to predicting mental fatigue symptoms and rates of mental fatigue may vary with gender.Reviewed articles indicated that mental fatigue presence was associated with lower odds of OCD. In addition, the results suggested that mental fatigue symptoms were more common in individuals with OCPD rather than OCD.Research into mental fatigue in adult psychiatric sample was limited to a few psychiatric disorders and requires further investigation to prevent potential misattribution as mental fatigue symptoms overlap between different psychiatric disorders.

The Choice of Either Quetiapine or Aripiprazole as Augmentation Treatment in a European Naturalistic Sample of Patients With Major Depressive Disorder.

BACKGROUND: Augmentation with second-generation antipsychotics (SGAs) represents an evidence-based psychopharmacotherapeutic strategy recommended in case of insufficient response to the first-line antidepressant (AD) treatment in major depressive disorder (MDD). Comparative evidence regarding efficacy and prescription preferences of the individual SGAs is scarce. METHODS: In the scope of this European, multi-site, naturalistic cross-sectional investigation with retrospective assessment of treatment outcome, we compared sociodemographic and clinical characteristics of 187 MDD patients receiving either quetiapine (n = 150) or aripiprazole (n = 37) as augmentation of their first-line AD psychopharmacotherapy. RESULTS: Comorbid posttraumatic stress disorder and diabetes were significantly associated with aripiprazole augmentation in our primary and post-hoc binary logistic regression analyses. Furthermore, we identified an association between aripiprazole co-administration and the presence of additional psychotic features, higher rates of AD combination treatment, and a longer duration of psychiatric hospitalizations during the lifetime, which, however, lost significance after correcting for multiple comparisons. Regarding treatment outcome, we found a trend of higher response rates and greater reductions in severity of depressive symptoms in MDD patients dispensed quetiapine. CONCLUSIONS: Factors associated with a more chronic and severe profile of MDD seem to encourage clinicians to choose aripiprazole over quetiapine, that was, however, administered in the majority of our MDD patients, which might reflect the current approval situation allowing to prescribe exclusively quetiapine as on-label augmentation in MDD in Europe. Given the retrospective assessment of treatment response, the markedly smaller proportion of patients receiving aripiprazole augmentation generally showing an unfavorable disease profile, and the partially heterogeneous statistical robustness of our findings, further studies are required to elaborate on our observation and to generate unambiguous recommendations regarding the choice of first-line SGA augmentation in MDD.

Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts.

Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h2SNP) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71-88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h2SNP was comparable (0.25 [SE = 0.04] and 0.19 [SE = 0.02], respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

The sociodemographic and clinical profile of patients with major depressive disorder receiving SSRIs as first-line antidepressant treatment in European countries.

INTRODUCTION: Due to favorable antidepressant (AD) efficacy and tolerability, selective-serotonin reuptake inhibitors (SSRIs) are consistently recommended as substances of first choice for the treatment of major depressive disorder (MDD) in international guidelines. However, little is known about the real-world clinical correlates of patients primarily prescribed SSRIs in contrast to those receiving alternative first-line ADs. METHODS: These secondary analyses are based on a naturalistic, multinational cross-sectional study conducted by the European Group for the Study of Resistant Depression at ten research sites. We compared the socio-demographic and clinical characteristics of 1410 patients with primary MDD, who were either prescribed SSRIs or alternative substances as first-line AD treatment, using chi-squared tests, analyses of covariance, and logistic regression analyses. RESULTS: SSRIs were prescribed in 52.1% of MDD patients who showed lower odds for unemployment, current severity of depressive symptoms, melancholic features, suicidality, as well as current inpatient treatment compared to patients receiving alternative first-line ADs. Furthermore, patients prescribed SSRIs less likely received add-on therapies including AD combination and augmentation with antipsychotics, and exhibited a trend towards higher response rates. CONCLUSION: A more favorable socio-demographic and clinical profile associated with SSRIs in contrast to alternative first-line ADs may have guided European psychiatrists' treatment choice for SSRIs, rather than any relevant pharmacological differences in mechanisms of action of the investigated ADs. Our results must be cautiously interpreted in light of predictable biases resulting from the open treatment selection, the possible allocation of less severely ill patients to SSRIs as well as the cross-sectional study design that does not allow to ascertain any causal conclusions.

The Italian version of the Brief Assessment of Cognition in Affective Disorders: performance of patients with bipolar disorder and healthy controls.

OBJECTIVES: Cognitive deficits in Bipolar Disorder (BD) are significant enough to have an impact on daily functioning. Therefore, appropriate tools must be used to improve our understanding of the nature and severity of cognitive deficits in BD. In this study, we aimed to compare the cognitive profiles of patients with BD and healthy controls (HC) applying the Italian version of the Brief Assessment of Cognition in Affective Disorders (BAC-A). METHODS: This cross-sectional study included 127 patients with BD and 134 HC. The participants' cognitive profiles were evaluated using the Italian version of the BAC-A, which assesses verbal memory, working memory, motor speed, verbal fluency, attention & processing speed, executive functions, and two new measures of affective processing. The BAC-A raw scores were corrected using the normative data for the Italian population. In addition, we explored whether intelligence quotient (IQ) and specific clinical variables would predict the BAC-A affective, non-affective, and total composite scores of patients with BD and HC. RESULTS: HC performed better than patients with BD in all BAC-A subtests (all p < .001), except for subtests of the Affective Interference Test. (p ≥ .05). The effect sizes varied in magnitude and ranged between d = 0.02 and d = 1.27. In patients with BD, lower BAC-A composite scores were predicted by a higher number of hospitalizations. There was a significant association between IQ and BAC-A composite scores in both bipolar patients and HC. CONCLUSIONS: The Italian BAC-A is sensitive to the cognitive impairments of patients with BD in both affective and non-affective cognitive domains.

De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features.

OBJECTIVE: To determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes. METHODS: Here we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher. RESULTS: LMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms. CONCLUSION: These findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.

Polygenic risk scores for neuropsychiatric, inflammatory, and cardio-metabolic traits highlight possible genetic overlap with suicide attempt and treatment-emergent suicidal ideation.

Suicide is the second cause of death among youths. Genetics may contribute to suicidal phenotypes and their co-occurrence in other neuropsychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 24 neuropsychiatric, inflammatory, and cardio-metabolic traits/diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI). PRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts. Results were then meta-analyzed across samples, including a total of 688 patients with SA (Neff  = 2,258) and 214 with TWESI (Neff  = 785). Stratified genetic covariance analyses were performed to investigate functionally cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was associated with SA (OR = 1.24; 95% CI = 1.11-1.38; p = 1.73 × 10-4 ). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p = 4.6 × 10-3 ), loneliness (p = .009), or chronic pain (p = .016) and SA, PRSs for MDD or CAD and TWESI (p = .043 and p = .032, respectively). Genetic covariance between MDD and SA was shown in 86 gene sets related to drugs having antisuicidal effects. A higher genetic liability for MDD may underlie a higher SA risk. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.

Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature.

FBXL3 (F-Box and Leucine Rich Repeat Protein 3) encodes a protein that contains an F-box and several tandem leucine-rich repeats (LRR) domains. FBXL3 is part of the SCF (Skp1-Cullin-F box protein) ubiquitin ligase complex that binds and leads to phosphorylation-dependent degradation of the central clock protein cryptochromes (CRY1 and CRY2) by the proteasome and its absence causes circadian phenotypes in mice and behavioral problems. No FBXL3-related phenotypes have been described in humans. By a combination of exome sequencing and homozygosity mapping, we analyzed two consanguineous families with intellectual disability and identified homozygous loss-of-function (LoF) variants in FBXL3. In the first family, from Pakistan, an FBXL3 frameshift variant [NM_012158.2:c.885delT:p.(Leu295Phefs*25)] was the onlysegregating variant in five affected individuals in two family loops (LOD score: 3.12). In the second family, from Lebanon, we identified a nonsense variant [NM_012158.2:c.445C>T:p.(Arg149*)]. In a third patient from Italy, a likely deleterious non-synonymous variant [NM_012158.2:c.1072T>C:p.(Cys358Arg)] was identified in homozygosity. Protein 3D modeling predicted that the Cys358Arg change influences the binding with CRY2 by destabilizing the structure of the FBXL3, suggesting that this variant is also likely to be LoF. The eight affected individuals from the three families presented with a similar phenotype that included intellectual disability, developmental delay, short stature and mild facial dysmorphism, mainly large nose with a bulbous tip. The phenotypic similarity and the segregation analysis suggest that FBXL3 biallelic, LoF variants link this gene with syndromic autosomal recessive developmental delay/intellectual disability.

Sex-related effects in major depressive disorder: Results of the European Group for the Study of Resistant Depression.

BACKGROUND: Sex-related effects on the evolution and phenotype of major depressive disorder (MDD) were reported previously. METHODS: This European multicenter cross-sectional study compared sociodemographic, clinical, and treatment patterns between males and females in a real-world sample of 1410 in- and outpatients with current MDD. RESULTS: Male MDD patients (33.1%) were rather inpatients, suffered from moderate to high suicidality levels, received noradrenergic and specific serotonergic antidepressants (ADs) as first-line AD treatment, generally higher mean AD daily doses, and showed a trend towards a more frequent administration of add-on treatments. Female MDD patients (66.9%) were rather outpatients, experienced lower suicidality levels, comorbid thyroid dysfunction, migraine, asthma, and a trend towards earlier disease onset. CONCLUSIONS: The identified divergencies may contribute to the concept of male and female depressive syndromes and serve as predictors of disease severity and course, as they reflect phenomena that were repeatedly related to treatment-resistant depression (TRD). Especially the greater necessity of inpatient treatment and more complex psychopharmacotherapy in men may reflect increased therapeutic efforts undertaken to treat suicidality and to avoid TRD. Hence, considering sex may guide the diagnostic and treatment processes towards targeting challenging clinical manifestations including comorbidities and suicidality, and prevention of TRD and chronicity.

Irritable Mood and Subthreshold Hypomanic Episodes Correlate with More Severe Major Depression.

INTRODUCTION: Irritable mood (IM) and subthreshold hypomanic symptoms are reported in half and two-fifths of major depressed subjects respectively, but their clinical and prognostic meanings remain unclear. The aim of this study was to test the clinical usefulness of 2 specifiers in DSM-IV major depressive disorder (MDD): IM occurring during an index episode (IM+) and lifetime episodes of elated mood or IM with at least 2 concurrent hypomanic symptoms (subthreshold hypomanic episodes [SHEs]). METHOD: We included 482 outpatients with MDD participating in the Combining Medications to Enhance Depression Outcome study (mean age 43.14 ± 12.46 years, 144 males - 30%). The main aim of the original study was to test whether 2 different medications when given in combination as the first treatment step, compared to 1 medication, would improve antidepressant response. RESULTS: IM + subjects (N = 349; 70%) were younger and more often females, with a more severe depression, a more marked social impairment, and more psychiatric comorbidities. The IM + group was also characterized by higher levels of suicidal ideation and more cases of emotional abuse. The combination of IM+ and SHEs was associated with an even more severe clinical picture. Limitations include the post hoc method, incomplete assessment of bipolar validators (e.g., family history of bipolar illness), personality disorders and suicide attempts. CONCLUSIONS: The presence of IM and SHEs in MDD correlate with an overall more severe clinical condition.