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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.

Item does not contain fulltext The relationship between psychiatric symptoms and thyroid function has been well known and studied since antiquity. The common view is that clinical hypothyroidism is associated with depressive symptoms, whereas the psychiatric manifestations of hyperthyroidism are agitation, emotional lability, hyperexcitability, occasionally accompanied by angry outbursts, and euphoria. The case here reported overturns this conventional medical knowledge. A 73-year-old Italian woman experienced a severe major depressive episode with psychotic and melancholic features during laboratory thyrotoxicosis. No classical clinical signs and symptoms of thyrotoxicosis were present. Psychiatric symptoms improved together with the resolution of the hyperthyroid state. Historically, different cases of so-called 'apathetic hyperthyroidism' have been described. Recent neuroimaging and animal studies provided possible neurobiological explanations, showing how the excess thyroid hormones could affect brain structures involved in the regulation of mood, leading to depression. A direct link between hyperthyroidism and depression seems to be likely. This insight may be relevant in facilitating early diagnosis of thyroid disease and the planning of therapeutic strategies.

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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.

We studied the genetic resistance to Campylobacter coli and Campylobacter jejuni in wild boar using both STR analysis and genome-wide association studies (GWAS). A total of 60 wild boars hunted in Tuscany (Italy) during the 2018/2019 hunting season were analyzed and genotyped. During postmortem operations, fecal swabs, liver samples and kidneys were collected. Two groups of animals were considered for the statistical analysis: 28 Campylobacter positive (22 for C. coli and 6 for C. jejuni) and 32 Campylobacter negative. Regarding STR analysis, 15 markers belonging to a marker panel validated by the International Society of Animal Genetics (ISAG) for swine were used: for each marker, alleles and genotype frequencies between the two groups of animals were compared using the Chi-square test and Fisher’s exact tests. To analyze the genetic variability within groups, the following parameters were computed: molecular coancestry coefficients (fij), kinship distance (Dk), inbreeding coefficient (Fi), and genetic similarities (GS). The internal relatedness (IR) was also calculated, and ANOVA was used to verify the relationships between IR and Campylobacter groups. For GWAS, the Geneseek Genomic Profiler Porcine HD (70 k), containing 62,330 SNPs, was used. No differences in the internal relatedness (IR) were observed between the two groups (F = 5.64, P = 0.065) and no significant association between STRs and SNPs and Campylobacter positivity was observed. Although genetic resistance to bacterial diseases is often regulated by multiple genes controlling different processes of the host–pathogen interaction, in our studies no candidate genes that could be directly or indirectly involved in the development of the disease were identified.

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.

Nonpharmacological antidepressant treatments are effective and well tolerated in selected patients. However, response is heterogeneous and validated biomarkers would be precious to aid treatment choice. We searched Pubmed, Scopus, and Google Scholar until May 2022 for original articles evaluating the association of genetic variables with the efficacy of nonpharmacological treatments for major depressive episodes. Most studies analyzed small sample sizes using the candidate gene approach, leading to poorly replicated findings that need to be interpreted cautiously. The few available methylome-wide and genome-wide association studies (GWASs) considered only electroconvulsive therapy (ECT) and cognitive-behavioral therapy in small samples, providing interesting findings by using polygenic risk scores. A deeper knowledge of the genetic factors implicated in treatment response may lead to a better understanding of the neurobiological mechanisms of nonpharmacological therapies for depression, and depression itself. Future GWAS are going to expand their sample size, thanks to consortia such as the gen-ECT-ic consortium.

Contains fulltext : 292377.pdf (Publisher’s version ) (Open Access) BACKGROUND: Serotonin-norepinephrine reuptake inhibitors (SNRIs) are among the most frequently prescribed antidepressants (ADs) for major depressive disorder (MDD), with an increasing trend in the last decade. Given the relative dearth of information regarding rationales for their preferred use as first-line ADs in the broad clinical routine, the present study systematically investigated real-world characteristics of MDD patients prescribed either SNRIs or other AD substances across different countries and treatment settings. METHODS: In the present secondary analyses based on a large European, multi-site, naturalistic and cross-sectional investigation with a retrospective assessment of treatment outcome, we firstly defined the proportion of MDD patients receiving SNRIs as first-line AD psychopharmacotherapy and secondly compared their sociodemographic and clinical characteristics to those patients prescribed alternative first-line ADs during their current major depressive episode (MDE). RESULTS: Within the total sample of 1410 MDD patients, 336 (23.8 %) received first-line SNRIs. Compared to other ADs, SNRIs were significantly associated with inpatient care, suicidality and treatment resistance during the current MDE, and a longer lifetime duration of psychiatric hospitalizations. Moreover, greater severity of depressive symptoms at study entry, higher daily doses of the administered ADs, as well as more frequent prescriptions of psychopharmacotherapeutic add-on strategies in general and antipsychotic augmentation in particular, were significantly related to first-line SNRIs. CONCLUSIONS: Considering the limitations of a cross-sectional and retrospective study design, our data point towards a preferred use of first-line SNRIs in a generally more severely ill MDD patients, although they did not lead to superior treatment outcomes compared to alternative ADs.

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.

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.

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.

This study aimed to identify factors associated with side effects of psychotropic drugs in a real-world setting enriched with treatment-resistant depression (TRD) patients.A total of 1410 depressed patients were treated in a naturalistic setting. Side effects were measured with the Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU); the total score and UKU subscales were considered. Clinical-demographic variables were tested for association with side effects in univariate and then multivariate analyses.Total, psychic and neurological side effects were associated with depressive symptom severity, while autonomic side effects were higher in those with somatic comorbidities and other side effects were lower in patients receiving trazodone. In multivariate analyses, depressive symptom severity was associated with psychic and total side effects, while generalised anxiety disorder (GAD) with neurological side effects and somatic comorbidities remained associated with autonomic side effects. Trazodone was associated with lower side effects and with augmentation treatments. Augmentation therapies showed opposite effects depending on response status, i.e. increased or decreased the risk of side effects in responders and non-responders/resistant patients, respectively.Psychic side effects may be difficult to distinguish from depressive symptoms and factors associated with different types of side effects are heterogeneous and likely interacting.

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.

Suicide is a leading cause of morbidity worldwide. Among the known risk factors, alcohol use disorders (AUDs) are particularly relevant, but data on the epidemiology and characteristics of suicide attempts (SA) in this group are lacking. We used electronic health records of national health services to identify individuals who received a diagnosis of AUD in the Metropolitan area of Bologna from 2009 to 2019. In this cohort we identified accesses to Emergency Departments for SA from 2009 to 2020. The Crude Suicide Rate (CSR) for 1,000 Person Years was 2.93, higher than the general population. The CSR was higher in females, within one year from receiving the diagnosis of AUD, in patients with psychiatric comorbidities, concomitant abuse of cannabis or benzodiazepines. As for Covid-19 pandemic, the risk ratio of SA was significantly higher in 2020 compared to 2019 in females. Our results are relevant to identify clinical risk factors for SA in patients with AUDs, which are strongly associated with suicide risk but with scarce data in the previous literature and paucity of evidence-based therapeutic interventions.

Over the last few decades, considerable progress has been achieved in understanding the aetiology of mental illness and its biological underpinnings. Genetic factors have been shown to play a substantial role, although genetics alone are not able to explain fully the heritability of these diseases. Epigenetic mechanisms, such as DNA methylation, histone modifications, and RNA interference, modulate tissue-specific gene expression and have been proven to be involved in the aetiopathogenesis of psychiatric disorders. Numerous epidemiological studies have confirmed a contribution of environmental factors, and convincing evidence suggests that socio-economic status, early life stressors, and childhood trauma impact significantly on the risk of psychiatric disorders via lifelong epigenetic modifications. This chapter will discuss in detail the different epigenetic mechanisms underlying the pathogenesis of psychiatric diseases and their interaction with genetic factors, providing an overall picture about the recent advances in psychiatric epigenomics.

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.

Objectives 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 effect on the health-related and periodontitis-related subgingival microbiome of air-polishing during non-surgical treatment of deep bleeding pockets in stage III–IV periodontitis patients. Materials and methods Forty patients with stage III–IV periodontitis were selected, and pockets with probing depth (PD) 5–9 mm and bleeding on probing 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. Subgingival microbial samples were taken from the maxillary experimental site showing the deepest PD at baseline. Primary outcome of the first part of the present study was the 3-month change in the number of experimental sites. Additional analysis of periodontal pathogens and other sub-gingival plaque bacteria sampled at one experimental site at baseline and 3 months following treatment was performed through a real-time quantitative PCR microarray. Results In the test group, a statistical increase of some health-related species was observed (Abiotropha defectiva, Capnocytophaga sputigena, and Lautropia mirabilis), together with the decrease of pathogens such as of Actinomyces israelii, Catonella morbi, Filifactor alocis, Porphyromonas endodontalis, Sele-nomonas sputigena, Tannerella forsythia, Treponema denticola, and Treponema socranskii. In the control group, statistical significance was found only in the decrease of Filifactor alocis, Tannerella forsythia, and Treponema socranskii. Conclusions The addition of erythritol-chlorhexidine powder seems to cause a shift of the periodontal micro-biome toward a more eubiotic condition compared to a conventional treatment. The study was registered on Clinical Trials.gov (NCT04264624). Clinical relevance Subgingival air-polishing could help re-establishing a eubiotic microbioma in deep bleeding periodontal pockets after initial non-surgical treatment.

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.

The study investigated the relationship between the temperature humidity index (THI) and the behaviour of 24 young fattening Limousin bulls reared in two farms in Tuscany, Italy. In each farm, six animals were undergone to ceiling fans (switched on at THI values up to 72), and six animals represented the control group. The trial lasted three days for two consecutive weeks in August 2020. Behavioural observations were conducted using scan sampling technique and eating, ruminating, drinking, resting and other social activities were registered every 5 min, from 9.30 am to 4.00 pm. Two different microclimatic conditions were evaluated to assess the effect of the ventilation system: normal (THI < 78) and alert (THI ≥ 78) conditions. Results showed that the ventilation system had significant effects increasing inactivity and lying down compared to control groups and decreasing eating and drinking activities. THI alert condition caused a significant decrease in eating and an increase in lying down behaviours. Ventilation system did not influence the animals’ cleanliness. The ceiling fans’ efficiency in changing the behaviour of young fattening bulls was demonstrated but further studies are needed to assess the ventilation system effects, especially during longer heat stress periods.

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction.Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response.Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

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.

This research analyses gender equality in the hospitality industry in the United Kingdom and Ireland. In particular, this quantitative study focuses on women who could potentially occupy a senior m...

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.