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Major depressive disorder (MDD) is a highly prevalent psychiatric condition characterised by a heterogeneous clinical presentation and an estimated twin-based heritability of ~40-50 %. Different clinical MDD subtypes might partly reflect distinctive underlying genetics. This study aims to investigate if polygenic risk scores (PRSs) for different psychiatric disorders, personality traits, and substance use-related traits may be associated with different clinical subtypes of MDD (i.e., MDD with melancholic or psychotic features), higher symptom severity, or different clusters of depressive symptoms (i.e., sadness symptoms, typical neurovegetative symptoms, detachment symptoms, and negative thoughts).The target sample included 1149 patients with MDD, recruited by the European Group for the Study of Resistant Depression. PRSs for 25 psychiatric disorders and traits were computed based on the most recent publicly available summary statistics of the largest genome-wide association studies. PRSs were then used as predictors in regression models, adjusting for age, sex, population stratification, and recruitment sites.Patients with MDD having higher PRS for MDD and loneliness were more likely to exhibit melancholic features of MDD (p = 0.0009 and p = 0.005, respectively). Moreover, patients with higher PRS for alcohol intake and post-traumatic stress disorder were more likely to experience greater typical neurovegetative symptoms (p = 0.0012 and p = 0.0045, respectively).The proportion of phenotypic variance explained by the PRSs was limited.This study suggests that melancholic features and typical neurovegetative symptoms of MDD may show distinctive underlying genetics. Our findings provide a new contribution to the understanding of the genetic heterogeneity of MDD.

Background: Psychiatric disorders are complex, multifactorial illnesses with a demonstrated biological component in their etiopathogenesis. Epigenetic modifications, through the modulation of DNA methylation, histone modifications and RNA interference, tune tissue-specific gene expression patterns and play a relevant role in the etiology of psychiatric illnesses. Objective: This review aims to discuss the epigenetic mechanisms involved in psychiatric disorders, their modulation by environmental factors and their interactions with genetic variants, in order to provide a comprehensive picture of their mutual crosstalk. Methods: In accordance with the PRISMA guidelines, systematic searches of Medline, EMBASE, PsycINFO, Web of Science, Scopus, and the Cochrane Library were conducted. Results: Exposure to environmental factors, such as poor socio-economic status, obstetric complications, migration, and early life stressors, may lead to stable changes in gene expression and neural circuit function, playing a role in the risk of psychiatric diseases. The most replicated genes involved by studies using different techniques are discussed. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions and they interact with genetic variants in determining the risk of psychiatric disorders. Conclusion: An increasing amount of evidence suggests that epigenetics plays a pivotal role in the etiopathogenesis of psychiatric disorders. New therapeutic approaches may work by reversing detrimental epigenetic changes that occurred during the lifespan.

Major depressive disorder (MDD) is one of the leading causes of disability worldwide. Polymorphisms in cytochrome P450 genes (CYP450) were demonstrated to play a significant role in antidepressant response and side effects, but their effect in real-world clinical practice is poorly known. We determined the metabolic status of CYP2C19 based on the combination of *1, *2, *3 and *17 alleles extracted from genome-wide data in 1239 patients with MDD, pharmacologically treated in a naturalistic setting. Symptom improvement and side effects were assessed using the Montgomery and Åsberg Depression Rating Scale and the Udvalg for Kliniske Undersøgelse scale, respectively. We tested if symptom improvement, response and side effects were associated with CYP2C19 metabolic status adjusting for potential confounders. We considered patients treated with drugs for depression having CYP2C19 genotyping recommended by guidelines (T1 Drugs); secondarily, with all psychotropic drugs having CYP2C19 as relevant metabolic path (T2 Drugs). In the group treated with T1 drugs (n = 540), poor metabolizers (PMs) showed higher response and higher symptom improvement compared to normal metabolizers (p = 0.023 and p = 0.009, respectively), but also higher risk of autonomic and neurological side effects (p = 0.022 and p = 0.022 respectively). In patients treated with T2 drugs (n = 801), similar results were found. No associations between metabolizer status and other types of side effects were found (psychic and other side effects). Our study suggests potential advantages of CYP2C19 pharmacogenetic testing to guide treatment prescription, that may not be limited to the drugs currently recommended by guidelines.

Introduction Anxiety disorders are leading contributors to the global disease burden, highly prevalent across the lifespan, and associated with substantially increased morbidity and early mortality. Objectives The aim of this study was to examine age-related changes across a wide range of physiological measures in middle-aged and older adults with a lifetime history of anxiety disorders compared to healthy controls. Methods The UK Biobank study recruited >500,000 adults, aged 37-73, between 2006-2010. We used generalised additive models to estimate non-linear associations between age and hand-grip strength, cardiovascular function, body composition, lung function and heel bone mineral density in cases vs. controls. Results The main dataset included 332,078 adults (mean age = 56.37 years; 52.65% females). In both sexes, individuals with anxiety disorders had lower hand-grip strength and blood pressure than healthy controls, while their pulse rate and body composition measures were higher. Case-control differences were larger when considering individuals with chronic and/or severe anxiety disorders, and differences in body composition were modulated by depression comorbidity status. Differences in age-related physiological changes between female anxiety disorder cases and healthy controls were most evident for blood pressure, pulse rate and body composition, while in males for hand-grip strength, blood pressure and body composition. Most differences in physiological measures between cases and controls tended to decrease with age increase. Conclusions Individuals with a lifetime history of anxiety disorders differed from healthy controls across multiple physiological measures, with some evidence of case-control differences by age. The differences observed varied by chronicity/severity and depression comorbidity. Disclosure JM receives studentship funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and Eli Lilly and Company Limited. CML is a member of the Scientific Advisory Board of Myriad Neuroscience. CF and THH declare no relevant conflict of

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.

Background We aimed to investigate the prescription pattern of pregabalin augmentation of antidepressants in major depressive disorder (MDD) and to explore variables associated with add-on pregabalin treatment. Methods 1410 MDD patients participated in this naturalistic European multicenter study with retrospective assessment of treatment response. Analyses of covariance, chi-squared tests, and binary logistic regressions were accomplished to determine differences in socio-demographic and clinical characteristics between MDD patients with and without pregabalin augmentation. Results Add-on pregabalin was established in 102 (7.23%) MDD patients. Compared to those without receiving pregabalin, pregabalin-treated patients were characterized by a significantly higher likelihood for older age (mean: 54.74 ± 13.08 vs 49.93 ± 14.13 years), unemployment (78.43% vs 51.23%), melancholic features (83.33% vs 58.94%), inpatient treatment (72.55% vs 31.65%), previous psychiatric hospitalizations (13.52 ± 24.82 vs 4.96 ± 19.93 weeks), any somatic comorbidity (68.63% vs 44.57%), comorbid hypertension (37.25% vs 17.51%), more severe depressive symptom severity at the onset of the current episode (mean MADRS: 37.55 ± 9.00 vs 33.79 ± 7.52), receiving augmentation/combination treatment strategies in general (mean number of psychotropic drugs: 3.64 ± 0.92 vs 2.07 ± 1.17), and with antidepressants (50.00% vs 27.91%) and antipsychotics (46.08% vs 24.08%) in particular. Limitations Due to its observational cross-sectional study design, our patient sample might not be fully representative for MDD patients in primary care settings. Conclusions Our findings suggest that add-on pregabalin is particularly administered in more severe/difficult-to-treat MDD conditions, whereas no association between the prescription of adjunctive pregabalin and comorbid anxiety symptoms could be determined.

About two-thirds of patients with major depressive disorder (MDD) fail to achieve symptom remission after the initial antidepressant treatment. Despite a role of genetic factors was proven, the specific underpinnings are not fully understood yet. Polygenic risk scores (PRSs), which summarise the additive effect of multiple risk variants across the genome, might provide insights into the underlying genetics. This study aims to investigate the possible association of PRSs for bipolar disorder, MDD, neuroticism, and schizophrenia (SCZ) with antidepressant non-response or non-remission in patients with MDD. PRSs were calculated at eight genome-wide P-thresholds based on publicly available summary statistics of the largest genome-wide association studies. Logistic regressions were performed between PRSs and non-response or non-remission in six European clinical samples, adjusting for age, sex, baseline symptom severity, recruitment sites, and population stratification. Results were meta-analysed across samples, including up to 3,637 individuals. Bonferroni correction was applied. In the meta-analysis, no result was significant after Bonferroni correction. The top result was found for MDD-PRS and non-remission (p = 0.004), with patients in the highest vs. lowest PRS quintile being more likely not to achieve remission (OR=1.5, 95% CI=1.11–1.98, p = 0.007). Nominal associations were also found between MDD-PRS and non-response (p = 0.013), as well as between SCZ-PRS and non-remission (p = 0.035). Although PRSs are still not able to predict non-response or non-remission, our results are in line with previous works; methodological improvements in PRSs calculation may improve their predictive performance and have a meaningful role in precision psychiatry.

In Italy, although the number of foreign-born residents has grown exponentially, there are no data on mortality risk among migrants who have alcohol use disorders (AUDs). We examined the mortality risk and causes of death for natives and non-natives in a cohort of individuals treated for AUDs in Northern Italy in the period from 01/01/1975 to 31/12/2016. We highlight important characteristics of non-natives compared to Italians: 1) a younger age and a higher proportion of females; 2) a better health status; 3) a better social capital 4) a lower risk of death. We found differences in mortality between the various areas of origin, with a higher risk among participants born in Asia and African countries other than Mediterranean. The excess mortality compared to the reference population (SMRs) was at least three times for Italians and two times for migrants. While the non-native patients with AUDs have in general better health than Italians with AUDs, our results highlighted higher percentage of dropouts from treatment and lower access to Mental Health Services, suggesting that barriers to the access and completion of therapeutic programs still exist.

Depression is a leading cause of disability worldwide and, despite the availability of numerous antidepressants, the lack of standardized criteria to apply personalized prescription is still a major issue. Pharmacogenetic (PGx) markers in cytochrome P450 (CYP450) genes are already usable to guide antidepressant choice/titration according to clinical guidelines; they are an important step toward personalized psychiatry as they can reduce the time to identify an effective and tolerated treatment. Clinical application is still limited due to the financial and organizational challenges, but the number of services providing genotyping of pharmacogenes is increasing, with encouraging projections of cost-effectiveness. Critical aspects that emerged from the available studies are the importance of integration of genotyping results in electronic medical records, standardization, and regular updates of decision support systems, training and collaboration of different professionals, need of longer follow-ups to estimate cost-effectiveness, and importance of avoiding inequalities in access to genotyping. Diversities exist among the groups of patients to whom genotyping is offered (pre-emptive or reactive testing) and the type of clinical services (e.g., hospitals and primary care), currently without a consensus on which is the best approach. Future studies should aim to clarify these issues, as well as consider and compare PGx applications among different countries and healthcare systems. Finally, the extension of genotyping outside pharmacokinetic genes should be considered as a key step to improve the clinical impact of PGx, as this could significantly increase the variance explained in treatment outcomes.

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 noradrenergicand 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 maleand 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.

Contains fulltext : 287461.pdf (Publisher’s version ) (Open Access) Clinical and genomic studies have shown an overlap between neuropsychiatric disorders and insulin resistance (IR)-related somatic conditions, including obesity, type 2 diabetes, and cardiovascular diseases. Impaired cognition is often observed among neuropsychiatric disorders, where multiple cognitive domains may be affected. In this review, we aimed to summarise previous evidence on the relationship between IR-related diseases/traits and cognitive performance in the large UK Biobank study cohort. Electronic searches were conducted on PubMed, Scopus, and Web of Science until April 2022. Eighteen articles met the inclusion criteria and were qualitatively reviewed. Overall, there is substantial evidence for an association between IR-related cardio-metabolic diseases/traits and worse performance on various cognitive domains, which is largely independent of possible confoundings. The most consistent findings referred to IR-related associations with poorer verbal and numerical reasoning ability, as well as slower processing speed. The observed associations might be mediated by alterations in immune-inflammation, brain integrity/connectivity, and/or comorbid somatic or psychiatric diseases/traits. Our findings provide impetus for further research into the underlying neurobiology and possible new therapeutic targets.

Antipsychotic polypharmacy in psychotic disorders is widespread despite international guidelines favoring monotherapy. Previous evidence indicates the utility of low-dose partial dopamine agonist (PDAs) add-ons to mitigate antipsychotic-induced metabolic adverse effects or hyperprolactinemia. However, clinicians are often concerned about using PDAs combined with high-potency, full dopaminergic antagonists (FDAs) due to the risk of psychosis relapse. We, therefore, conducted a literature review to find studies investigating the effects of combined treatment with PDAs (i.e. aripiprazole, cariprazine and brexpiprazole) and FDAs having a strong D-2 receptor binding affinity. Twenty studies examining the combination aripiprazole - high-potency FDAs were included, while no study was available on combinations with cariprazine or brexpiprazole. Studies reporting clinical improvement suggested that this may require a relatively long time (similar to 11 weeks), while studies that found symptom worsening observed this happening in a shorter timeframe (similar to 3 weeks). Patients with longer illness duration who received add-on aripiprazole on ongoing FDA monotherapy may be at greater risk for symptomatologic worsening. Especially in these cases, close clinical monitoring is therefore recommended during the first few weeks of combined treatment. These indications may be beneficial to psychiatrists who consider using this treatment strategy. Well-powered randomized clinical trials are needed to derive more solid clinical recommendations. Copyright (C) 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Background While the association between relationship status and the development of depressive symptoms in the general population were reported previously, its relation to the severity and the course of major depressive disorder (MDD) as well as the treatment patterns and response rates needs to be elucidated. Methods The present international multicenter cross-sectional study performed by the European Group for the Study of Resistant Depression (GSRD) investigated socio-demographic and clinical patterns of relationship status in a real-world sample of 1410 adult in- and outpatients with MDD as primary diagnosis. Results While 49.9% of all MDD patients were partnered, 25.4% were separated, and 24.8% were single. Single relationship status was linked to younger mean age, earlier mean age of onset, and current suicidal risk. Being separated was related to older mean age, unemployment, greater symptom severity, current suicidal risk, and add-on treatment strategies. Partnered relationship status was associated with less frequent current suicidal risk. Limitations The retrospective assessment of treatment response that was exclusively based on psychopharmacotherapeutic strategies should be critically considered and weighed while interpreting the present results providing novel insights into the complex interaction of relationship status with the clinical phenotype of MDD. Conclusions Although MDD patients living in relationships do not seem to be omitted from the evolution of MDD, they may be spared from chronicity and suicidality. Hence, being aware of the current relationship status might support clinicians in the diagnostic and therapeutic process towards optimized management of such challenging clinical phenomena and their negative consequences.

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.

Social withdrawal is an early manifestation of several neuropsychiatric disorders, and it is characterised by a gradual disengagement from social interactions, potentially leading to complete isolation. This study investigated the association between social withdrawal at baseline and short-term symptom remission in five independent cohorts, including patients with major depressive disorder (MDD), bipolar spectrum disorders, and schizophrenia. Measures of social withdrawal were derived in each study, and clinical remission was estimated based on the psychopathological severity assessed after short-term psychopharmacological treatment (12weeks). Logistic regression was performed in each sample, adjusting for age and baseline psychopathological severity residualised for social withdrawal. Results were then meta-analysed across samples within a random-effect framework. A total of 4461 patients were included in the analyses (3195 patients with MDD, 655 with bipolar spectrum disorders and 611 with schizophrenia). The meta-analysis showed that higher baseline levels of social withdrawal were associated with a decreased likelihood of short-term remission (ORadj=0.67, 95% CI, 0.58-0.79, P=5.28×10−7), with the strongest effect in patients with schizophrenia. Overall, our study highlighted the need to address social withdrawal in the early phases of the disease to promote symptom remission in patients with major psychiatric disorders. Understanding the neurobiology underlying social withdrawal may aid the development of medications that can specifically reverse social impairment, thereby fostering clinical remission. Int Clin Psychopharmacol 37: 38-45 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Over 20 years after the initial report of gene variants within the central nervous system modulating antidepressant response, we are now facing for the first time routine clinical pharmacogenetic applications. The scientific community is divided between enthusiasm and skepticism. It seems clear that the benefit of existing tools is not huge, at least for the central nervous system gene variants, while it is generally accepted for the metabolic gene variants. Findings from large international consortia suggest for the first time in psychiatric genetic research history that cumulative scores comprising many variants across the whole genome may reliably constitute liability factors for psychiatric disorders, this approach will most likely improve also present pharmacogenetic tools. A composite genetic score complemented with clinical risk factors for each patient is the most promising approach for a more effective method of targeted treatment for patients with depression.

BACKGROUND: The present multicenter study aimed at defining the clinical profile of patients with major depressive disorder (MDD) and comorbid migraine. METHODS: Demographic and clinical information for 1410 MDD patients with vs without concurrent migraine were compared by descriptive statistics, analyses of covariance, and binary logistic regression analyses. RESULTS: The point prevalence rate for comorbid migraine was 13.5% for female and 6.2% for male patients. MDD + migraine patients were significantly younger, heavier, more likely female, of non-Caucasian origin, outpatient, and suffering from asthma. The presence of MDD + migraine resulted in a significantly higher functional disability. First-line antidepressant treatment strategy revealed a trend towards agomelatine. Second-generation antipsychotics were significantly less often administered for augmentation treatment in migraineurs. Overall, MDD + migraine patients tended to respond worse to their pharmacotherapy. CONCLUSION: Treatment guidelines for comorbid depression and migraine are warranted to ensure optimal efficacy and avoid possible pitfalls in psychopharmacotherapy, including serotonin syndrome., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

The treatment of depression represents a major challenge for healthcare systems and choosing among the many available drugs without objective guidance criteria is an error-prone process. Recently, pharmacogenetic biomarkers entered in prescribing guidelines, giving clinicians the possibility to use this additional tool to guide prescription and improve therapeutic outcomes. This marked an important step towards precision psychiatry, which aim is to integrate biological and environmental information to personalise treatments. Only genetic variants in cytochrome enzymes are endorsed by prescribing guidelines, but in the future polygenic predictors of treatment outcomes may be translated into the clinic. The integration of genetics with other relevant information (e.g., concomitant diseases and treatments, drug plasma levels) could be managed in a standardised way through ad hoc software. The overcoming of the current obstacles (e.g., staff training, genotyping and informatics facilities) can lead to a broad implementation of precision psychiatry and represent a revolution for psychiatric care.Key points Precision psychiatry aims to integrate biological and environmental information to personalise treatments and complement clinical judgement Pharmacogenetic biomarkers in cytochrome genes were included in prescribing guidelines and represented an important step towards precision psychiatry Therapeutic drug monitoring is an important and cost-effective tool which should be integrated with genetic testing and clinical evaluation in order to optimise pharmacotherapy Other individual factors relevant to pharmacotherapy response (e.g., individual’s symptom profile, concomitant diseases) can be integrated with genetic information through artificial intelligence to provide treatment recommendations The creation of pharmacogenetic services within healthcare systems is a challenging and multi-step process, education of health professionals, promotion by institutions and regulatory bodies, economic and ethical barriers are the main issues.

BackgroundMood disorders are characterised by pronounced symptom heterogeneity, which presents a substantial challenge both to clinical practice and research. Identification of subgroups of individuals with homogeneous symptom profiles that cut across current diagnostic categories could provide insights in to the transdiagnostic relevance of individual symptoms, which current categorical diagnostic systems cannot impart.AimsTo identify groups of people with homogeneous clinical characteristics, using symptoms of manic and/or irritable mood, and explore differences between groups in diagnoses, functional outcomes and genetic liability.MethodWe used latent class analysis on eight binary self-reported symptoms of manic and irritable mood in the UK Biobank and PROTECT studies, to investigate how individuals formed latent subgroups. We tested associations between the latent classes and diagnoses of psychiatric disorders, sociodemographic characteristics and polygenic risk scores.ResultsFive latent classes were derived in UK Biobank (N = 42 183) and were replicated in the independent PROTECT cohort (N = 4445), including ‘minimally affected’, ‘inactive restless’, active restless’, ‘focused creative’ and ‘extensively affected’ individuals. These classes differed in disorder risk, polygenic risk score and functional outcomes. One class that experienced disruptive episodes of mostly irritable mood largely comprised cases of depression/anxiety, and a class of individuals with increased confidence/creativity reported comparatively lower disruptiveness and functional impairment.ConclusionsFindings suggest that data-driven investigations of psychopathological symptoms that include sub-diagnostic threshold conditions can complement research of clinical diagnoses. Improved classification systems of psychopathology could investigate a weighted approach to symptoms, toward a more dimensional classification of mood disorders.

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.

Background: Cognitive dysfunction is a core manifestation of schizophrenia and one of the best predictors of long-term disability. Genes increasing risk for schizophrenia may partly act through the modulation of cognition.Methods: We imputed the expression of 130 genes recently prioritized for association with schizophrenia, using PsychENCODE variant weights and genotypes of patients with schizophrenia in CATIE. Processing speed, reasoning, verbal memory, working memory, vigilance, and a composite cognitive score were used as phenotypes. We performed linear regression models for each cognitive measure and gene expression score, adjusting for age, years of education, antipsychotic treatment, years since the first antipsychotic treatment and population principal components.Results: We included 425 patients and expression scores of 91 genes (others had no heritable expression; Bonferroni corrected alpha = 5.49e-4). No gene expression score was associated with cognitive measures, though ENOX1 expression was very close to the threshold for verbal memory (p = 6e-4) and processing speed (p = 7 e-4). Other genes were nominally associated with multiple phenotypes (MAN2A1 and PCGF3).Conclusion: A better understanding of the mechanisms mediating cognitive dysfunction in schizophrenia may help in the definition of disease prognosis and in the identification of new treatments, as the treatment of cognitive impairment remains an unmet therapeutic need.

Emergence of suicidal symptoms has been reported as a potential antidepressant adverse drug reaction. Identifying risk factors associated could increase our understanding of this phenomenon and stratify individuals at higher risk. Logistic regressions were used to identify risk factors of self-reported treatment-attributed suicidal ideation (TASI). We then employed classifiers to test the predictive ability of the variables identified. A TASI GWAS, as well as SNP-based heritability estimation, were performed. GWAS replication was sought from an independent study. Significant associations were found for age and comorbid conditions, including bipolar and personality disorders. Participants reporting TASI from one antidepressant were more likely to report TASI from other antidepressants. No genetic loci associated with TAS I (p < 5e-8) were identified. Of 32 independent variants with suggestive association (p < 1e-5), 27 lead SNPs were available in a replication dataset from the GENDEP study. Only one variant showed a consistent effect and nominal association in the independent replication sample. Classifiers were able to stratify non-TASI from TASI participants (AUC = 0.77) and those reporting treatment-attributed suicide attempts (AUC = 0.85). The pattern of TASI co-occurrence across participants suggest nonspecific factors underlying its etiology. These findings provide insights into the underpinnings of TASI and serve as a proof-of-concept of the use of classifiers for risk stratification.

About two thirds of the patients with major depressive disorder (MDD) do not sufficiently respond to monotherapy with antidepressants (ADs) which makes them reliant on further treatment approaches. Hereby, combination of different ADs and augmentation with second-generation antipsychotics (SGAs) are widely used and recommended psychopharmacotherapeutic strategies. The present secondary analyses are based on an international, naturalistic, cross-sectional multicenter study conducted by the European Group for the Study of Resistant Depression. Comparing socio-demographic and clinical characteristics of 436 adult MDD patients receiving either SGAs (N = 191, 43.8%) or ADs (N = 245, 56.2%), that were additionally administered to their first-line AD psychopharmacotherapy, we aimed to identify possible trajectories of decision-making for clinicians regarding which treatment option to prefer in individual patients. Our most robust findings represent an association of SGA augmentation with the presence of psychotic symptoms, longer mean duration of lifetime psychiatric hospitalizations, employment of further augmentation strategies with mood-stabilizers and benzodiazepines, and a trend towards higher mean daily dosages of their first-line ADs and current suicidal risk. Treatment outcome was not significantly different between patients receiving either SGA augmentation or AD combination. Being aware of limitations inherent to the cross-sectional study design and the lack of randomization, more severe and rather chronic conditions in MDD seemed to encourage clinicians to choose SGA augmentation over AD combination. The fact that mood-stabilizers and/or benzodiazepines were more frequently co-administered with SGAs may represent a requirement of an overall refined psychopharmacotherapy including additional fast-acting agents with potent AD, tranquilizing and anti-suicidal effects in MDD patients experiencing challenging clinical manifestations. New glutamatergic substances seem to be promising in this regard.

Since selective serotonin reuptake inhibitors, that are recommended as first-line antidepressant psychopharmacotherapy for major depressive disorder (MDD), may not be the optimal choice for every patient, antidepressants with different modes of action exerting a distinct set of expectant effects, represent a valuable alternative. Despite the previously observed increased prescription rates of noradrenergic and specific serotonergic antidepressants (NaSSAs) particularly mirtazapine in Europe, the individual profiles of patients primarily prescribed NaSSAs in real-world settings have not been systematically investigated yet. In this secondary analysis based on a European, cross-sectional, naturalistic, multicenter study involving 1410 adult males and females with primary MDD, sociodemographic and clinical variables were compared between patients dispensed NaSSAs and those with alternative first-line antidepressants. Hereby, NaSSAs were administered in 8.6 % of the sample (mirtazapine: n = 114, mianserin: n = 7). We detected associations with older mean age, male sex, unemployment, as well as additional melancholic and catatonic features, inpatient treatment, lower mean daily dosages of the administered antidepressants but higher rates of augmentation with low-potency antipsychotics, and greater mean reductions of depressive symptoms during their current major depressive episodes. Although the study design is unsuitable to draw any causal conclusions, our findings provide a realistic picture of patients eligible for first-line antidepressant treatment with NaSSAs, especially mirtazapine, and underscore the role of this AD substance class in severe MDD. Further, they may represent a promising basis for future systematic research focusing on precision diagnostics and treatment in MDD, that would ideally result in faster responses and better outcomes, especially in the so-called difficult-to-treat conditions including treatment resistant depression.

Wild boar (Sus scrofaL.) is one of the large mammals most spread worldwide, highly adaptable, and its population rapidly increased in many areas in Europe, including Italy, where Tuscany is considered particularly suitable for wild boar. Wild boars are potential hosts for different etiological agents, such asBrucellaspp.,Leptospiraspp. and Pseudorabies virus and they can contribute to maintain and/or to disseminate some bacterial or viral pathogens to humans and domestic animals, above all-in free-range farms. In order to identify hypothetical genomic regions associated with these infection diseases, 96 samples of wild boars hunted in Tuscany during the 2018–2019 and 2019–2020 hunting seasons were considered. Diagnosis was achieved by serological tests and 42 Pseudorabies, 31 Leptospira and 15 Brucella positive animals were identified. All animals were genotyped with Geneseek Genomic Profiler Porcine HD (70 k) and a genome-wide scan was then performed. Significant markers were highlighted for Pseudorabies (two SNPs), Brucella (seven SNPs), and Leptospira (four SNPs) and they were located within, or nearby, 29 annotated genes on chromosome 6, 9, 12, 13, 14 and 18. Eight genes are implicated in viral (SEC14L1, JMJD6, SRSF2, TMPRSS2, MX1, MX2) or bacterial (COL8A1, SPIRE1) infections, seven genes (MFSD11, METTL23, CTTNBP2, BACE2, IMPA2, MPPE1 and GNAL) are involved in mental disorders and one gene (MGAT5B) is related to the Golgi complex. Results presented here provide interesting starting points for future research, validation studies and fine mapping of candidate genes involved in bacterial and viral infections in wild boar.

To identify the demographic and clinical characteristics associated with access to Emergency Departments for Suicide Attempt in a cohort of patients with Gambling disorders. We used electronic health records of inpatient and outpatient services to identify individuals who received a diagnosis of gambling disorder (ICD-9 or ICD-10 codes) in the Metropolitan area of Bologna from 2009 to 2019. In this cohort we identified accesses to Emergency Departments for suicide attempt through cross-matching with electronic records. We calculated Crude Suicide Attempt Rates; we also included the demographic-clinical variables in a multivariate Poisson regression. We identified 692 patients with a diagnosis of gambling disorder and a total of 2733 Person Years. The Crude Suicide Attempt Rate per 1000 Person Years was 9.17 (95% CI 6.20-13.58), higher for females and much higher than the general population (incidence rate ratio = 93.72). The multivariate analysis showed a higher risk of suicide attempt in the year following the first contact with a clinical service, in patients younger than 45 years, with alcohol use disorders and personality disorders. This study evidenced a high risk of access to Emergency Departments for suicide attempt in individuals with a diagnosis of gambling disorder and highlighted important demographic and clinical factors that should be considered when evaluating suicide risk in this population.

Objective: Suicide is a major public health problem and it has a prominent genetic component. We performed a genome-wide association study (GWAS) of suicidal behaviour severity. Methods: Suicide behaviour severity was assessed within the Schedules for Clinical Assessment in Neuropsychiatry in our mood disorder sample (n = 3506) for the GWAS. We also performed polygenic risk score analyses to explore genetic sharing between suicidal behaviour severity and a number of phenotypes, including bipolar disorder, major depressive disorder, alcoholism, post-traumatic stress disorder, impulsivity, insomnia, educational attainment, loneliness, maltreatment, and amygdala volume. Results: We did not detect genome-wide significant findings at the single-marker or gene level. We report a number of suggestive single-marker and gene-based findings. Our polygenic risk score analyses did not yield significant findings with these phenotypes. Conclusions: Larger sample sizes are required to detect moderate effects.

Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20–30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.

Despite plenty of effective antidepressant (AD) treatments, the outcome of major depressive disorder (MDD) is often unsatisfactory, probably due to improvable exploitation of available therapies. This European, cross-sectional, naturalistic multicenter study investigated the frequency of additional psychotherapy in terms of a manual-driven psychotherapy (MDP) in 1410 adult in- and outpatients with MDD, who were primarily treated with AD psychopharmacotherapy. Socio-demographic and clinical patterns were compared between patients receiving both treatments and those lacking concomitant MDP. In a total of 1279 MDD patients (90.7%) with known status of additional MDP, those undergoing a psychopharmacotherapy-MDP combination (31.2%) were younger, higher educated, more often employed and less severely ill with lower odds for suicidality as compared to patients receiving exclusively psychopharmacotherapy (68.8%). They experienced an earlier mean age of MDD onset, melancholic features, comorbid asthma and migraine and received lower daily doses of their first-line ADs. While agomelatine was more often established in these patients, MDD patients without MDP received selective serotonin reuptake inhibitors more frequently. These two patient groups did not differ in terms of response, non-response and treatment resistant depression (TRD). Accordingly, the employment of additional MDP could not be related to better treatment outcomes in MDD. The fact that MDP was applied in a minority of patients with rather beneficial socio-demographic and clinical characteristics might reflect inferior accessibility of these psychotherapeutic techniques for socially and economically disadvantaged populations., SCOPUS: ar.j, info:eu-repo/semantics/published

To date, scarce evidence exists around the application of subgingival air polishing during treatment of severe periodontitis. The aim of this study was to evaluate the benefits of subgingival air polishing during non-surgical treatment of deep bleeding pockets in stages III–IV periodontitis patients Forty patients with stages III–IV periodontitis were selected, and pockets with probing depth (PD) 5–9 mm and bleeding on probing (BoP) were selected as experimental sites. All patients underwent a full-mouth session of erythritol powder supragingival air polishing and ultrasonic instrumentation. Test group received additional subgingival air polishing at experimental sites. The proportion of experimental sites shifting to PD ≤ 4 mm and no BoP at 3 months (i.e., non-bleeding closed pockets, NBCPs) was regarded as the primary outcome variable. The proportion of NBCP was comparable between test and control group (47.9 and 44.7%, respectively). Baseline PD of 7–9 mm, multi-rooted teeth and the presence of plaque negatively influenced the probability of obtaining NBCP. The additional application of subgingival air polishing does not seem to provide any significant clinical advantage in achieving closure at moderate to deep bleeding pockets in treatment of stages III–IV periodontitis patients. The study was registered on Clinical Trials.gov (NCT04264624). While air polishing can play a role in biofilm removal at supragingival and shallow sites, ultrasonic root surface debridement alone is still the choice for initial treatment of deep bleeding periodontal pockets.

Contains fulltext : 237832.pdf (Publisher’s version ) (Open Access) Levels of sociability are continuously distributed in the general population, and decreased sociability represents an early manifestation of several brain disorders. Here, we investigated the genetic underpinnings of sociability in the population. We performed a genome-wide association study (GWAS) of a sociability score based on four social functioning-related self-report questions from 342,461 adults in the UK Biobank. Subsequently we performed gene-wide and functional follow-up analyses. Robustness analyses were performed in the form of GWAS split-half validation analyses, as well as analyses excluding neuropsychiatric cases. Using genetic correlation analyses as well as polygenic risk score analyses we investigated genetic links of our sociability score to brain disorders and social behavior outcomes. Individuals with autism spectrum disorders, bipolar disorder, depression, and schizophrenia had a lower sociability score. The score was significantly heritable (SNP h(2) of 6%). We identified 18 independent loci and 56 gene-wide significant genes, including genes like ARNTL, DRD2, and ELAVL2. Many associated variants are thought to have deleterious effects on gene products and our results were robust. The sociability score showed negative genetic correlations with autism spectrum, disorders, depression, schizophrenia, and two sociability-related traits-loneliness and social anxiety-but not with bipolar disorder or Alzheimer's disease. Polygenic risk scores of our sociability GWAS were associated with social behavior outcomes within individuals with bipolar disorder and with major depressive disorder. Variation in population sociability scores has a genetic component, which is relevant to several psychiatric disorders. Our findings provide clues towards biological pathways underlying sociability.

Background: Major Depressive Disorder(MDD) and its frequent partial response to antidepressants are a major health concern and therefore an important focus of research. Despite the efforts, MDD pathogenesis and the mechanisms of antidepressant action are only partially understood. In the last few years, the need of rethinking the classification of depressive disorders and psychiatric disorders, in general, has been suggested, in order to provide a nosology that reflects more closely the biological background associated with disease pathogenesis and its role/significance in treatment. The classification proposed by the National Institute of Mental Health (NIMH), namely the research domain criteria (RDoC), may represent a key framework to guide research in this direction. Methods: A literature search was performed on PubMed and Google Scholar databases in order to retrieve data regarding Antidepressants effects on specific RDoC constructs. Further, the targets of drugs of interest were identified through the Drug bank database, and their possible function within RDoC constructs was discussed. Discussion: In this review, we summarize and discuss the significance of the results of pre-clinical and clinical studies investigating specific RDoC paradigms relevant to depressive phenotypes and antidepressant effects. Conclusion: The RDoC framework may facilitate a more specific use of antidepressants based on the individual’s spectrum of symptoms and the development of new compounds that target specific depressive symptoms.

Aim To assess the efficacy of a commercially available adjunctive phototherapy protocol ("Perio-1") in treatment of periodontitis. Materials and methods In an examiner-blind, randomized, controlled, split-mouth, multicentre study, 60 periodontitis patients received root surface debridement (RSD) in sextants either alone (control sextants) or with the adjunctive phototherapy protocol (test sextants). Re-evaluation was performed at 6, 12 and 24 weeks. Results No statistically significant differences in mean (± standard deviation) clinical attachment level (CAL) change from baseline to week 24 were observed between test (-1.00 ± 1.16 mm) and control sextants (-0.87 ± 0.79 mm) at sites with probing pocket depths (PPDs) ≥5 mm ("deep sites") at baseline (p = .212). Comparisons between test and control sextants for all other parameters (CAL change at all sites, PPD change at deep sites/all sites, bleeding on probing, plaque scores), and for all change intervals, failed to identify any statistically significant differences. Conclusions The phototherapy protocol did not provide any additional clinical benefits over those achieved by RSD alone. (German Clinical Trials Register DRKS00011229).

Treatment-resistant depression (TRD) occurs in ~30% of patients with major depressive disorder (MDD) but the genetics of TRD was previously poorly investigated. Whole exome sequencing and genome-wide genotyping were available in 1209 MDD patients after quality control. Antidepressant response was compared to non-response to one treatment and non-response to two or more treatments (TRD). Differences in the risk of carrying damaging variants were tested. A score expressing the burden of variants in genes and pathways was calculated weighting each variant for its functional (Eigen) score and frequency. Gene-based and pathway-based scores were used to develop predictive models of TRD and non-response using gradient boosting in 70% of the sample (training) which were tested in the remaining 30% (testing), evaluating also the addition of clinical predictors. Independent replication was tested in STAR*D and GENDEP using exome array-based data. TRD and non-responders did not show higher risk to carry damaging variants compared to responders. Genes/pathways associated with TRD included those modulating cell survival and proliferation, neurodegeneration, and immune response. Genetic models showed significant prediction of TRD vs. response and they were improved by the addition of clinical predictors, but they were not significantly better than clinical predictors alone. Replication results were driven by clinical factors, except for a model developed in subjects treated with serotonergic antidepressants, which showed a clear improvement in prediction at the extremes of the genetic score distribution in STAR*D. These results suggested relevant biological mechanisms implicated in TRD and a new methodological approach to the prediction of TRD., SCOPUS: ar.j, info:eu-repo/semantics/published

There is still a debate, if melancholic symptoms can be seen rather as a more severe subtype of major depressive disorder (MDD) or as a separate diagnostic entity. The present European multicenter study comprising altogether 1410 MDD in- and outpatients sought to investigate the influence of the presence of melancholic features in MDD patients. Analyses of covariance, chi-squared tests, and binary logistic regression analyses were accomplished to determine differences in socio-demographic and clinical variables between MDD patients with and without melancholia. We found a prevalence rate of 60.71% for melancholic features in MDD. Compared to non-melancholic MDD patients, they were characterized by a significantly higher likelihood for higher weight, unemployment, psychotic features, suicide risk, inpatient treatment, severe depressive symptoms, receiving add-on medication strategies in general, and adjunctive treatment with antidepressants, antipsychotics, benzodiazepine (BZD)/BZD-like drugs, low-potency antipsychotics, and pregabalin in particular. With regard to the antidepressant pharmacotherapy, we found a less frequent prescription of selective serotonin reuptake inhibitors (SSRIs) in melancholic MDD. No significant between-group differences were found for treatment response, non-response, and resistance. In summary, we explored primarily variables to be associated with melancholia which can be regarded as parameters for the presence of severe/difficult-to treat MDD conditions. Even if there is no evidence to realize any specific treatment strategy in melancholic MDD patients, their prescribed medication strategies were different from those for patients without melancholia.

Bipolar disorder (BP) is a highly heritable disease, with heritability estimated between 60 and 85% by twin studies. The underlying genetic architecture was poorly understood for years since the available technology was limited to the candidate gene approach that did not allow to explore the contribution of multiple loci throughout the genome. BP is a complex disorder, which pathogenesis is influenced by a number of genetic variants, each with small effect size, and environmental exposures. Genome-wide association studies (GWAS) provided meaningful insights into the genetics of BP, including replicated genetic variants, and allowed the development of novel multi-marker methods for gene/pathway analysis and for estimating the genetic overlap between BP and other traits. However, the existing GWAS had also relevant limitations. Notably insufficient statistical power and lack of consideration of rare variants, which may be responsible for the relatively low heritability explained (~20% in the largest GWAS) compared to twin studies. The availability of data from large biobanks and automated phenotyping from electronic health records or digital phenotyping represent key steps for providing samples with adequate power for genetic analysis. Next-generation sequencing is becoming more and more feasible in terms of costs, leading to the rapid growth in the number of samples with whole-genome or whole-exome sequence data. These recent and unprecedented resources are of key importance for a more comprehensive understanding of the specific genetic factors involved in BP and their mechanistic action in determining disease onset and prognosis.

BackgroundDepression is a highly prevalent and heterogeneous disorder. This study aims to determine whether depression with atypical features shows different heritability and different degree of overlap with polygenic risk for psychiatric and immuno-metabolic traits than other depression subgroups.MethodsData included 30 069 European ancestry individuals from the UK Biobank who met criteria for lifetime major depression. Participants reporting both weight gain and hypersomnia were classified as ↑WS depression (N = 1854) and the others as non-↑WS depression (N = 28 215). Cases with non-↑WS depression were further classified as ↓WS depression (i.e. weight loss and insomnia; N = 10 142). Polygenic risk scores (PRS) for 22 traits were generated using genome-wide summary statistics (Bonferroni corrected p = 2.1 × 10−4). Single-nucleotide polymorphism (SNP)-based heritability of depression subgroups was estimated.Results↑WS depression had a higher polygenic risk for BMI [OR = 1.20 (1.15–1.26), p = 2.37 × 10−14] and C-reactive protein [OR = 1.11 (1.06–1.17), p = 8.86 × 10−06] v. non-↑WS depression and ↓WS depression. Leptin PRS was close to the significance threshold (p = 2.99 × 10−04), but the effect disappeared when considering GWAS summary statistics of leptin adjusted for BMI. PRS for daily alcohol use was inversely associated with ↑WS depression [OR = 0.88 (0.83–0.93), p = 1.04 × 10−05] v. non-↑WS depression. SNP-based heritability was not significantly different between ↑WS depression and ↓WS depression (14.3% and 12.2%, respectively).Conclusions↑WS depression shows evidence of distinct genetic predisposition to immune-metabolic traits and alcohol consumption. These genetic signals suggest that biological targets including immune-cardio-metabolic pathways may be relevant to therapies in individuals with ↑WS depression.

Background The microbiome of the oral cavity is the second-largest and diverse microbiota after the gut, harboring over 700 species of bacteria and including also fungi, viruses, and protozoa. With its diverse niches, the oral cavity is a very complex environment, where different microbes preferentially colonize different habitats. Recent data indicate that the oral microbiome has essential functions in maintaining oral and systemic health, and the emergence of 16S rRNA gene next-generation sequencing (NGS) has greatly contributed to revealing the complexity of its bacterial component. However, a detailed site-specific map of oral microorganisms (including also eukaryotes and viruses) and their relative abundance is still missing. Here, we aimed to obtain a comprehensive view of the healthy oral microbiome (HOM), including its drug-resistance features. Results The oral microbiome of twenty healthy subjects was analyzed by whole-genome sequencing (WGS) and real-time quantitative PCR microarray. Sampled oral micro-habitat included tongue dorsum, hard palate, buccal mucosa, keratinized gingiva, supragingival and subgingival plaque, and saliva with or without rinsing. Each sampled oral niche evidenced a different microbial community, including bacteria, fungi, and viruses. Alpha-diversity evidenced significant differences among the different sampled sites (p p = 0.876), strengthening the notion of a recognizable HOM. Of note, oral rinse microbiome was more representative of the whole site-specific microbiomes, compared with that of saliva. Interestingly, HOM resistome included highly prevalent genes conferring resistance to macrolide, lincosamides, streptogramin, and tetracycline. Conclusions The data obtained in 20 subjects by WGS and microarray analysis provide for the first time a comprehensive view of HOM and its resistome, contributing to a deeper understanding of the composition of oral microbiome in the healthy subject, and providing an important reference for future studies, allowing to identify microbial signatures related to functional and metabolic alterations associated with diseases, potentially useful for targeted therapies and precision medicine.

In clinical practice, an antidepressant prescription is a trial and error approach, which is time consuming and discomforting for patients. This study investigated an in silico approach for ranking antidepressants based on their hypothetical likelihood of efficacy. We predicted the transcriptomic profile of citalopram remitters by performing an in silico transcriptomic-wide association study on STAR*D GWAS data (N = 1163). The transcriptional profile of remitters was compared with 21 antidepressant-induced gene expression profiles in five human cell lines available in the connectivity-map database. Spearman correlation, Pearson correlation, and the Kolmogorov–Smirnov test were used to determine the similarity between antidepressant-induced profiles and remitter profiles, subsequently calculating the average rank of antidepressants across the three methods and a p value for each rank by using a permutation procedure. The drugs with the top ranks were those having a high positive correlation with the expression profiles of remitters and that may have higher chances of efficacy in the tested patients. In MCF7 (breast cancer cell line), escitalopram had the highest average rank, with an average rank higher than expected by chance (p = 0.0014). In A375 (human melanoma) and PC3 (prostate cancer) cell lines, escitalopram and citalopram emerged as the second-highest ranked antidepressants, respectively (p = 0.0310 and 0.0276, respectively). In HA1E (kidney) and HT29 (colon cancer) cell types, citalopram and escitalopram did not fall among top antidepressants. The correlation between citalopram remitters’ and (es)citalopram-induced expression profiles in three cell lines suggests that our approach may be useful and with future improvements, it can be applicable at the individual level to tailor treatment prescription.

Background: Predictors of treatment outcome in major depressive disorder (MDD) could contribute to evidence-based therapeutic choices. Combined pharmacotherapy and psychotherapy show increased efficacy but higher cost compared with antidepressant pharmacotherapy; baseline predictors of pharmacotherapy resistance could be used to identify patients more likely to benefit from combined treatment. Methods: We performed a proof-of-principle study of the cost-effectiveness of using previously identified pharmacogenetic and clinical risk factors (PGx-CL-R) of antidepressant resistance or clinical risk factors alone (CL-R) to guide the prescription of combined pharmacotherapy and psychotherapy vs pharmacotherapy. The cost-effectiveness of these two strategies was compared with standard care (ST, pharmacotherapy to all subjects) using a three-year Markov model. Model parameters were literature-based estimates of response to pharmacotherapy and combined treatment, costs (UK National Health System) and benefits (quality-adjusted life years [QALYs], one QALY=one year lived in perfect health). Results: CL-R was more cost-effective than PGx-CL-R: the cost of one-QALY improvement was £2341 for CL-R and £3937 for PGx-CL-R compared to ST. PGx-CL-R had similar or better cost-effectiveness compared to CL-R when 1) the cost of genotyping was £100 per subject or less or 2) the PGx-CL-R test had sensitivity ≥ 0.90 and specificity ≥ 0.85. The cost of one-QALY improvement for CL-R was £3664 and of £4110 in two independent samples. Limitations: lack of validation in large samples from the general population. Conclusions: Using clinical risk factors to predict pharmacotherapy resistance and guide the prescription of pharmacotherapy combined with psychotherapy could be a cost-effective strategy., SCOPUS: ar.j, info:eu-repo/semantics/published

BackgroundUp to 60% of patients with major depressive disorder (MDD) do not respond to the first treatment with antidepressants. Response to antidepressants is a polygenic trait, although its underpinning genetics has not been fully clarified. This study aimed to investigate if Polygenic Risk Scores (PRSs) for major psychiatric disorders and neuroticism were associated with non-response or resistance to antidepressants in MDD.MethodsPRSs for bipolar disorder, MDD, neuroticism, and schizophrenia (SCZ) were computed in 1148 MDD patients recruited by the European Group for the Study of Resistant Depression. Summary statistics from largest meta-analyses of genome-wide association studies were used as base data. Patients were classified as responders, non-responders to one treatment, non-responders to two or more treatments (treatment-resistant depression or TRD). Regression analyses were adjusted for population stratification and recruitment sites.ResultsPRSs did not predict either non-response or TRD after Bonferroni correction. However, SCZ-PRS was nominally associated with non-response (p=0.003). Patients in the highest SCZ-PRS quintile were more likely to be non-responders than those in the lowest quintile (OR=2.23, 95% CI=1.21-4.10, p=0.02). Patients in the lowest SCZ-PRS quintile showed higher response rates when they did not receive augmentation with second-generation antipsychotics (SGAs), while those in the highest SCZ-PRS quintile had a poor response independently from the treatment strategy (p=0.009).ConclusionsA higher genetic liability to SCZ may reduce responsiveness to pharmacological treatment in MDD. From a clinical point of view, our results suggest that MDD patients with low SCZ-PRS do not benefit from augmentation with SGAs.

In the post-genomic era, genetics has led to limited clinical applications in the diagnosis and treatment of major depressive disorder (MDD). Variants in genes coding for cytochrome enzymes are included in guidelines for assisting in antidepressant choice and dosing, but there are no recommendations involving genes responsible for antidepressant pharmacodynamics and no consensus applications for guiding diagnosis or prognosis. However, genetics has contributed to a better understanding of MDD pathogenesis and the mechanisms of antidepressant action, also thanks to recent methodological innovations that overcome the challenges posed by the polygenic architecture of these traits. Polygenic risk scores can be used to estimate the risk of disease at the individual level, which may have clinical relevance in cases with extremely high scores (e.g. top 1%). Genetic studies have also shed light on a wide genetic overlap between MDD and other psychiatric disorders. The relationships between genes/pathways associated with MDD and known drug targets are a promising tool for drug repurposing and identification of new pharmacological targets. Increase in power thanks to larger samples and methods integrating genetic data with gene expression, the integration of common variants and rare variants, are expected to advance our knowledge and assist in personalized psychiatry.

Since many patients with major depressive disorder (MDD) do not satisfactorily respond to initial antidepressant monotherapy, add-on treatment strategies with other psychiatric compounds are often established. The present European multicenter cross-sectional study comprising 1410 MDD in- and outpatients investigated the prescription pattern of benzodiazepines as add-on treatment in the psychopharmacotherapy of MDD. Analyses of variance, chi-squared tests, and logistic regression analyses were conducted to examine differences in socio-demographic, clinical, and treatment characteristics between benzodiazepine users and non-users. The prescription rate for adjunctive benzodiazepine treatment amounted to 31.35%. The most often administered benzodiazepines were lorazepam (11.13%), clonazepam (6.74%), and alprazolam (6.60%). Benzodiazepine users exhibited more severe depressive symptoms expressed by a higher mean Montgomery and Åsberg Depression Rating Scale total score at study entry (26.92 ± 11.07 vs 23.55 ± 11.23, p

Resilience is the ability to cope with critical situations through the use of personal and socially mediated resources. Since a lack of resilience increases the risk of developing stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), a better understanding of the biological background is of great value to provide better prevention and treatment options. Resilience is undeniably influenced by genetic factors, but very little is known about the exact underlying mechanisms. A recently published genome-wide association study (GWAS) on resilience has identified three new susceptibility loci, DCLK2, KLHL36, and SLC15A5. Further interesting results can be found in association analyses of gene variants of the stress response system, which is closely related to resilience, and PTSD and MDD. Several promising genes, such as the COMT (catechol-O-methyltransferase) gene, the serotonin transporter gene (SLC6A4), and neuropeptide Y (NPY) suggest gene × environment interaction between genetic variants, childhood adversity, and the occurrence of PTSD and MDD, indicating an impact of these genes on resilience. GWAS on PTSD and MDD provide another approach to identifying new disease-associated loci and, although the functional significance for disease development for most of these risk genes is still unknown, they are potential candidates due to the overlap of stress-related psychiatric disorders and resilience. In the future, it will be important for genetic studies to focus more on resilience than on pathological phenotypes, to develop reasonable concepts for measuring resilience, and to establish international cooperations to generate sufficiently large samples.

Background Recent evidence suggests that psychiatric symptoms share a common genetic liability across diagnostic categories. The present study investigated the effects of variants within previously identified relevant genes on specific symptom clusters, independently from the diagnosis. Methods 1550 subjects affected by Schizophrenia (SCZ), Major Depressive Disorder or Bipolar Disorder were included. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depression Rating Scale (HDRS). Principal component analysis and a further clinical refinement were used to define symptom clusters. Clusters scores were tested for association with 46 genetic variants within nine genes previously linked to one or more major psychiatric disorders by large genome wide association studies (ANK3, CACNA1C, CACNB2, FKBP5, FZD3, GRM7, ITIH3, SYNE1, TCF4). Exploratory analyses were performed in each disorder separately to further elucidate the SNPs effects. Results five PANSS clusters (Negative; Impulsiveness; Cognitive; Psychotic; Depressive) and four HDRS clusters (Core Depressive; Somatic; Psychotic-like; Insomnia) were identified. CACNA1C rs11615998 was associated with HDRS Psychotic cluster in the whole sample. In the SCZ sample, CACNA1C rs11062296 was associated with PANSS Impulsiveness cluster and CACNA1C rs2238062 was associated with PANSS negative cluster. Discussion CACNA1C rs11615998 was associated with psychotic symptoms (C-allele carriers have decreased psychotic-risk) independently from the diagnosis, in line with the evidence of a cross disorder effect of many risk variants. This gene was previously associated with SCZ and cross-disorder liability to psychiatric disorders. Our findings confirmed that deep phenotyping is pivotal to clarify the role of genetic variants on symptoms patterns.

Previous studies stratified patients with major depressive disorder (MDD) based on their clinical characteristics. This study used this approach in individuals with lifetime MDD who reported low wellbeing, a group of high clinical relevance.We selected participants in the UK Biobank (UKB) with lifetime MDD and a wellbeing score in the lowest 25 %. A wellbeing score was previously created considering happiness, belief that own life is meaningful, health satisfaction and functioning in relevant areas. In the selected group, we applied latent class analysis using mood-spectrum symptoms and personality traits as input variables, then we compared the clinical-demographic and genetic (polygenic risk scores, PRSs) characteristics of the identified classes.A total of 13,896 individuals were included and a model with five classes showed the best performance. The most common class (31.25 %) was characterised by periods of irritable mood and trait irritability with high neuroticism. A rarer class (16.49 %) showed depressive-manic mood fluctuations and risk-taking personality, higher percentage of males, atypical depressive symptoms, lower socio-economic status, higher PRS for attention-deficit hyperactivity disorder and lower PRS for education. The second most common class (29.79 %) showed worry as main personality trait with low risk of manic/irritable manifestations. The remaining classes showed an anxious-irritable personality profile and a purely depressive profile (4.92 % and 17.55 %, respectively).Our results may reflect the characteristics of UKB participants.Subthreshold manic/irritable mood fluctuations and personality traits irritability and neuroticism may distinguish the most common groups with poor wellbeing in lifetime MDD.

Objectives: Clinical variables were investigated in the ‘treatment resistant depression (TRD)- III’ sample to replicate earlier findings by the European research consortium ‘Group for the Study of Resistant Depression’ (GSRD) and enable cross-sample prediction of treatment outcome in TRD. Experimental procedures: TRD was defined by a Montgomery and Åsberg Depression Rating Scale (MADRS) score ≥22 after at least two antidepressive trials. Response was defined by a decline in MADRS score by ≥50% and below a threshold of 22. Logistic regression was applied to replicate predictors for TRD among 16 clinical variables in 916 patients. Elastic net regression was applied for prediction of treatment outcome. Results: Symptom severity (odds ratio (OR) = 3.31), psychotic symptoms (OR = 2.52), suicidal risk (OR = 1.74), generalized anxiety disorder (OR = 1.68), inpatient status (OR = 1.65), higher number of antidepressants administered previously (OR = 1.23), and lifetime depressive episodes (OR = 1.15) as well as longer duration of the current episode (OR = 1.022) increased the risk of TRD. Prediction of TRD reached an accuracy of 0.86 in the independent validation set, TRD-I. Conclusion: Symptom severity, suicidal risk, higher number of lifetime depressive episodes, and comorbid anxiety disorder were replicated as the most prominent risk factors for TRD. Significant predictors in TRD-III enabled robust prediction of treatment outcome in TRD-I., SCOPUS: ar.j, info:eu-repo/semantics/published

Objectives To evaluate the postsurgery gingival healing as well as plaque, gingival inflammation and staining levels following the use of a 0.2% chlorhexidine (CHX) solution with or without antidiscoloration system (ADS) and 0.2% hyaluronic acid (HA). Methods Patients undergoing flap surgery at sites with an intact or reduced but healthy periodontium participated in a parallel-arm RCT. After surgery, patients used the assigned mouthrinse (CHX + HA + ADS or CHX) for 21 days. At days 7 and 21, the healing process was evaluated at experimental teeth using a composite index, namely the Gingival Healing Index (GHI). GHI score was obtained as the sum of the scores related to the severity of wound dehiscence (score 1-3) and the profile of the buccal and oral aspects of the papilla (score 1-3). Therefore, GHI ranged from 2 (worst quality of healing) to 6 (optimal quality of healing). Plaque Index (PlI), Gingival Index (GI), angulated bleeding score (AngBS), and tooth and tongue staining were also assessed. Results In both groups, GHI assumed values of 5 or 6 at both days 7 and 21 in ≥50% of patients, and low median values of PlI, GI, AngBS and staining were observed during the 21-day period. Except for a significantly lower GI in CHX group at day 7, no other significant intergroup differences were found. Conclusions Postsurgery plaque control based on either CHX or CHX + HA + ADS mouthrinses results in optimal plaque control and quality of early gingival healing along with limited tooth and tongue staining.

Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects.CYP2C19 phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was percentage symptom improvement and remission. Side effect data were available at weeks 2–4, 6 and 9 in three of the investigated samples. A fixed-effects meta-analysis was performed using EM as the reference group.Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD=0.43, CI=0.19–0.66) and higher remission rates (OR=1.55, CI=1.23–1.96) compared to EMs. At weeks 2–4, PMs showed higher risk of gastro-intestinal (OR=1.26, CI=1.08–1.47), neurological (OR=1.28, CI=1.07–1.53) and sexual side effects (OR=1.52, CI=1.23–1.87; week 6 values similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups.CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs are relatively rare among Caucasians (~2%).