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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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Major depressive disorders are ranked as the single largest contributor to non-fatal health loss and biomarkers could largely improve our routine clinical activity by predicting disease course and guiding treatment. However there is still a dearth of valid biomarkers in the field of psychiatry. The initial assumption that a single biomarker can capture the myriad of complex processes proved to be naive. The purpose of this paper is to critically review the field and to illustrate the possible practical application for routine clinical care. Biomarkers derived from DNA analysis are the ones that have received the most attention. Other potential candidates include circulating transcription products, proteins, and inflammatory markers. DNA polygenic risk scores proved to be useful in other fields of medicine and preliminary results suggest that they could be useful both as risk and diagnostic biomarkers also in depression and for the choice of treatment. A number of other possible fluid biomarkers are currently under investigation for diagnosis, outcome prediction, staging, and stratification of interventions, however research is still needed before they can be used for routine clinical care. When available, clinicians may be able to receive a lab report with detailed information about disease risk, outcome prediction, and specific indications about preferred treatments.

Binge-eating (BE) symptoms are relatively common in major depressive disorder (MDD), but their prognostic role is not fully understood. This study compared two groups of patients with MDD experiencing or not BE symptoms to ascertain differences in terms of clinical manifestations, presence of bipolar features, and antidepressant treatment outcomes. The study involved 482 outpatients collected within the Combining Medications to Enhance Depression Outcomes (CO-MED) trial, who were assessed with scales for depressive and hypomanic symptomatology, suicidality, comorbid mental disorders, and childhood traumas. BE symptoms were reported in 95 patients (20%). Patients with MDD experiencing BE symptoms were characterized by higher scores of negative self-outlook ( P = 0.0018), negative outlook of future ( P = 0.0014), irritability ( P = 0.0043), comorbid anxiety disorders (generalized anxiety disorder: P = 0.0006; panic disorder: Plt; 0.0001; social phobia: Plt; 0.0001), obsessive-compulsive disorder ( P = 0.0053), hypomanic symptoms (increased talkativeness: P = 0.0029; reduced need for sleep: P = 0.0171), and suicidality (suicidal propensity: P = 0.0013; suicidal risk: P = 0.0148; lifetime suicidal behavior: P = 0.0052). BE symptoms (OR = 2.02; 95% CI = 1.06-3.84) and depression severity (OR = 1.04; 95% CI = 1.00-1.08) were independently associated with lifetime attempted suicide. The presence of BE symptoms might indicate higher severity of depressive disorder. Suicidal risk is a major issue in these patients, whereas the association between BE and bipolar features needs further research.

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.

Variation in the expression level and activity of genes involved in drug disposition and action in tissues of pharmacological importance have been increasingly investigated in patients treated with psychotropic drugs. Findings are promising, but reliable predictive biomarkers of response have yet to be identified. Here we conducted a PRISMA-compliant systematic search of PubMed, Scopus and PsycInfo up to 12 September 2020 for studies investigating RNA expression levels in cells or biofluids from patients with major depressive disorder, schizophrenia or bipolar disorder characterized for response to psychotropic drugs (antidepressants, antipsychotics or mood stabilizers) or adverse effects. Among 5497 retrieved studies, 123 (63 on antidepressants, 33 on antipsychotics and 27 on mood stabilizers) met inclusion criteria. Studies were either focused on mRNAs (n = 96), microRNAs (n = 19) or long non-coding RNAs (n = 1), with only a minority investigating both mRNAs and microRNAs levels (n = 7). The most replicated results include genes playing a role in inflammation (antidepressants), neurotransmission (antidepressants and antipsychotics) or mitochondrial function (mood stabilizers). Compared to those investigating response to antidepressants, studies focused on antipsychotics or mood stabilizers more often showed lower sample size and lacked replication. Strengths and limitations of available studies are presented and discussed in light of the specific designs, methodology and clinical characterization of included patients for transcriptomic compared to DNA-based studies. Finally, future directions of transcriptomics of psychopharmacological interventions in psychiatric disorders are discussed.

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.

Obsessive-compulsive symptoms (OCS) are often reported in patients with bipolar disorder. The aim of this study was to investigate OCS and their related clinical features in major depressive disorder (MDD). The analysis involved 482 outpatients with MDD collected within the Combining Medications to Enhance Depression outcomes trial, who were assessed with scales for depression, suicidality, irritability, hypomanic symptomatology, and other comorbid psychiatric manifestations. OCS were reported in 27% of the sample. Patients with MDD experiencing OCS were found to differ from those not experiencing OCS by a greater severity of depression (d = 0.41, P = 0.0001), more hypomanic symptoms (d = 0.48, P0.0001) and mixed features (22% vs. 10%, P = 0.001), increased levels of suicidal thoughts (d = 0.40, P = 0.0001), a lower likelihood of achieving remission after antidepressant treatment (19% vs. 33%, P = 0.0109), as well as more comorbid anxiety disorders (i.e. panic disorder: d = 0.98, P0.0001; generalized anxiety disorder: d = 0.74, P0.0001; social phobia: d = 0.71, P0.0001), and post-traumatic stress disorder (d = 0.81, P0.0001). In light of these findings, clinicians should pay more attention to the occurrence of OCS in MDD, as these symptoms may reflect greater clinical severity, poorer treatment outcome, and increased risk for bipolarity.

Background Aside from the concept of seasonal affective disorder, the evidence for a seasonal pattern (SP) of major depressive disorder (MDD) is controversial. Furthermore, the effect of sex and age is still unclear. Methods This is a nationwide, registry-based study assessing all inpatient admissions in mental health hospitals due to MDD episodes according to ICD-10 (moderate (F32/33.1), severe (F32/33.2) and severe with psychotic features (F32/33.3)) in Austria across 14 years. Calculations were based on deviations from expected monthly admissions. Results The sample comprised 231,824 hospitalisations (36.8% men) for MDD. A significant SP (p=0.001) in moderate and severe depressive episodes in both women and men with decreased admission rates in the summer months and December was detected. In psychotic depression a significant SP was only evidenced in women (p = 0.002, men: p = 0.291). Patients older than 55 years had a reduced SP compared to those being younger. Limitations Only anonymised admission data of inpatient treatments were available. Hospitalization rates cannot fully be equated to the occurrence of MDD. Conclusions The current study indicates a seasonal variation in MDD symptoms that may go beyond seasonal affective disorder. Knowledge about the predictability of depressive symptoms in patients should encourage preventive strategies.

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.

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.

Post-traumatic stress disorder (PTSD) and childhood maltreatment (CMT: parental neglect; emotional, physical and sexual abuse) have been linked to bipolar disorder but they are also common in major depressive disorder (MDD). Our objective was to investigate their association with the bipolar spectrum and antidepressant treatment outcome in 482 outpatients with DSM-IV MDD treated in the Combining Medications to Enhance Depression Outcomes trial for 28 weeks Bipolar spectrum score included age of onset

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.

Background: Social withdrawal constitutes a clinical manifestation of social dysfunction in SCZ that has a high impact on the quality of life of patients. Poor neurocognitive performance has been associated with poor functional outcome in SCZ in past studies. Nonetheless, the likely association between neurocognition and social withdrawal has never been investigated. The aim of our study was to investigate in a large and heterogeneous sample of SCZ patients cross-sectional associations between neurocognitive domains and social withdrawal. Methods: The sample included 761 SCZ patients who completed the baseline visit in the CATIE study. Neurocognition was assessed by a comprehensive battery of tests resulting in 5 domain scores and a composite score. Social withdrawal was measured by a specific item of the Heinrichs-Carpenter Quality of Life Scale. Bivariate correlations, ANOVA and multiple regression analysis were conducted using STATISTICA software package (StatSoft, Inc. Tulsa, OK, USA). Statistical significance was tested at p value Results: Social withdrawal was associated with a lower score in the neurocognitive composite score and in “Verbal memory”, “Processing speed” and “Working memory” scores. “Verbal memory” score showed the strongest association with social withdrawal. 8% of the total variance of social withdrawal was explained by these three cognitive domains and additional clinical and socio-demographic factors (education years, PANSS positive symptoms score, employment). Conclusions: Our study showed that in a large and real-world representative sample of SCZ patients, social withdrawal was associated with neurocognitive deficits involving verbal memory, processing speed and working memory domains. Our results confirmed the wide heterogeneity and specificity of the correlation between neurocognitive domains and indicators of functional outcome in SCZ, underlining the role of certain neurocognitive abilities in social withdrawal.

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.

The debate around optimal target dose for first-line antidepressants (ADs) is still ongoing. Along this line, therapeutic drug monitoring (TDM) represents one of the most promising tools to improve clinical outcome. Nevertheless, a few data exist regarding the concentration-effect relationship of first-line ADs which limits TDM implementation in routine clinical practice. We conducted the first patient-level concentration-response mega-analysis including data acquired by us previously and explored the concentration dependency of first-line AD (206 subjects). Further, new data on mirtazapine are reported (18 subjects). Hamilton Depression Rating Scale-21 administered at baseline, at month 1 and month 3 was used as the measure of efficacy to assess antidepressant response (AR). When pooling all four first-line ADs together, normalized plasma levels and AR significantly fit a bell-shaped quadratic function with a progressive increase of AR up to around the upper normalized limit of the therapeutic reference range with a decrease of AR at higher serum levels. Our results complement the available evidence on the issue and the recent insights gained from dose-response studies. A concentration-dependent clinical efficacy, such as previously demonstrated for tricyclic compounds, also emerge for first-line ADs. Our study supports a role for TDM as a tool to optimize AD treatment to obtain maximum benefit.

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.