Assessing motivation for treatment in eating disorders: psychometric validation of the Italian version of the Autonomous and Controlled Motivation for Treatment Questionnaire (ACMTQ-ITA).

PURPOSE: Treatment resistance is a significant challenge in addressing eating disorders (EDs). The Autonomous and Controlled Motivation for Treatment Questionnaire (ACMTQ) has been previously validated in ED populations to assess patients' motivation for treatment. This study aimed to validate the ACMTQ in the Italian language (ACMTQ-ITA) and evaluate its psychometric properties. METHODS: We recruited a clinical sample of adults aged 18 or older, diagnosed with EDs, proficient in the Italian language, and providing written informed consent. Participants with psychiatric comorbidities such as schizophrenia, bipolar disorder, and substance use disorder were excluded from the study. Validity of the ACMTQ-ITA was assessed using reliability analysis with Cronbach's α and McDonald's ω estimates, and Confirmatory Factor Analysis (CFA). RESULTS: Results from the reliability analysis confirmed the internal consistency of the Autonomous Motivation (AM) factor (α = 0.82, ω = 0.82), the Controlled Motivation (CM) factor (α = 0.76, ω = 0.77), and the ACMTQ-ITA overall score (α = 0.79). The CFA confirmed the two-factor solution (i.e., AM and CM) identified in the original validation of the ACMTQ (Comparative Fit Index = 0.92, Akaike Information Criterion = 3427.26, Bayesian Information Criterion = 3486.82; Root Mean Square Error of Approximation = 0.08, Standardized Root Mean Square Residual = 0.09). CONCLUSION: The ACMTQ-ITA emerged as a valid and reliable tool for measuring motivation for treatment in individuals with EDs. Its implementation may facilitate the comprehension of treatment motivation, offering valuable clinical insights and implications for health management practices. LEVEL OF EVIDENCE: Level V, descriptive studies.

Severe enduring anorexia nervosa (SE-AN) treatment options and their effectiveness: a review of literature.

INTRODUCTION:  For nearly 20% of patients diagnosed with Anorexia Nervosa (AN), the eating disorder (ED) is prolonged and becomes long-lasting. It has been reported that patients diagnosed with Severe Enduring Anorexia Nervosa (SE-AN) have worse ED symptoms, higher rates of lifetime hospitalization, and lower psychosocial well-being compared to patients with shorter disease duration. OBJECTIVES:  This review aims to describe the treatments proposed to date and their effectiveness on SE-AN-related outcomes. METHODS:  We conducted a PubMed search for studies addressing the issue of treatment approach to SE-AN adults, that were published between 2003 and 2023, peer-reviewed, written in the English language, and available in full-text. Next, we inductively created relevant macro-themes by synthesizing the data from the included articles. RESULTS:  Of 251 PubMed studies, 25 articles were considered for data extraction, all published between 2003 and 2022. We identified three macro-themes. The first macro-theme, "Psychotherapy", mostly takes into consideration treatment effectiveness of cognitive behavioral therapy (CBT). Various reports determined its greater effectiveness compared to Specialist Supportive Clinical Management (SSCM), and one study proved that outpatient CBT is a valid alternative to hospitalization. The second one involves "Pharmacological Treatments". Research on dronabinol, a synthetic orexigenic cannabinoid, antipsychotics (in particular, olanzapine and haloperidol), and ketamine showed some mixed results regarding the often-complementary areas of weight gain and improvement in ED-related symptoms. Regarding the third macro-theme, "Brain Stimulation Therapies," such as Repetitive Transcranial Magnetic Stimulation (rTMS) and Deep Brain Stimulation (DBS), we found promising results in improving ED-related psychological traits (such as mood and anxiety), affective regulation, and quality of life. However, we have observed divergent results regarding outcome measures such as BMI and weight gain. CONCLUSIONS:  SE-AN patients are predicted to encounter both medical complications and psychological distress of increasing severity that will inevitably affect their quality of life; to our knowledge, research evidence on treatment options for SE-AN remains limited, and the methodological quality of studies is generally low. These findings denote the need to focus future research efforts on effective treatment strategies specific to long-lasting EDs.

For nearly 20% of patients diagnosed with Anorexia Nervosa, the eating disorder is prolonged and becomes long-lasting. Those patients have worse ED symptoms, higher rates of lifetime hospitalization, and lower psychosocial well-being compared to patients with shorter disease duration. This review aims to describe the treatments proposed to date and their effectiveness on severe enduring anorexia nervosa related outcomes. The data obtained show how the intervention techniques primarily used in these patients are psychotherapy (in particular, cognitive behavioral therapy and Specialist Supportive Clinical Management), pharmacological treatments, and Brain Stimulation Therapies (such as Repetitive Transcranial Magnetic Stimulation and Deep Brain Stimulation). To our knowledge, research evidence on treatment options for SE-AN remains limited and these findings denote the need to focus future research efforts on effective treatment strategies specific to long-lasting eating disorders.

Eating disorders in narcolepsy type 1: Evidence from a cross-sectional Italian study.

Narcolepsy type 1 is a chronic central disorder of hypersomnolence, and it is frequently accompanied by overweight, but the association between narcolepsy type 1 and eating disorders is controversial. Our study aims to compare patients with narcolepsy type 1 and controls on the symptomatology of eating disorders and to evaluate the association between clinical factors. This is a cross-sectional study, with consecutive recruitment of patients with narcolepsy type 1 attending the Outpatient Clinic for Narcolepsy at the IRCCS Istituto delle Scienze Neurologiche di Bologna (Italy) for routine follow-up visits. Healthy subjects from general populations were recruited as controls. Patients underwent a questionnaire-based assessment using the Eating Disorder Examination Questionnaire (EDE-Q), Binge Eating Scale (BES), Italian Night Eating Questionnaire (I-NEQ), Epworth Sleepiness Scale (ESS), and Narcolepsy Severity Scale (NSS). One hundred and thirty-eight patients with narcolepsy type 1 and 162 controls were enrolled. This study showed that individuals with narcolepsy type 1 reported higher scores on the EDE-Q, I-NEQ, and a higher body mass index (BMI) than the controls. The logistic regression analysis results, with EDE-Q positivity as a dependent variable, demonstrate a significant association with antidepressant drugs, female sex, and the use of sodium oxybate. We found an association between antidepressant drug consumption, the NSS total score, and female sex with BES positivity as the dependent variable. The logistic regression analysis for I-NEQ positivity found an association with antidepressant drug use. This study shows that patients with narcolepsy type 1 frequently present with comorbid eating disorder symptomatology, mainly night eating syndrome. Investigating the possible presence of eating disorders symptomatology through questionnaires is fundamental during the assessment of patients with narcolepsy type 1.

Severe-Enduring Anorexia Nervosa (SE-AN): a case series.

BACKGROUND: Anorexia Nervosa (AN) poses significant therapeutic challenges, especially in cases meeting the criteria for Severe and Enduring Anorexia Nervosa (SE-AN). This subset of AN is associated with severe medical complications, frequent use of services, and the highest mortality rate among psychiatric disorders. CASE PRESENTATION: In the present case series, 14 patients were selected from those currently or previously taken care of at the Eating Disorders Outpatients Unit of the Maggiore Hospital in Bologna between January 2012 and May 2023. This case series focuses on the effects of the disease, the treatment compliance, and the description of those variables that could help understand the great complexity of the disorder. CONCLUSION: This case series highlights the relevant issue of resistance to treatment, as well as medical and psychological complications that mark the life course of SE-AN patients. The chronicity of these disorders is determined by the overlapping of the disorder's ego-syntonic nature, the health system's difficulty in recognizing the problem in its early stages, and the presence of occupational and social impairment.

Association between adverse childhood experiences and suicidal behavior in schizophrenia spectrum disorders: A systematic review and meta-analysis.

Assessing and managing suicide behaviors is highly relevant to individuals with schizophrenia spectrum disorders. Our study aims to assess the association between adverse childhood experiences and suicidal behaviors in individuals with schizophrenia spectrum disorders. We included observational studies comparing the probability of suicide behaviors in adults with schizophrenia spectrum disorders exposed and unexposed to adverse childhood experiences. Odds ratio estimates were obtained by pooling data using a random-effects pairwise meta-analysis. Standardized criteria were used to assess the strength of the association of the pooled estimate. We found 21 eligible studies reporting outcomes for 6257 individuals from 11 countries. The primary outcome revealed an association between any suicidal behavior and adverse childhood experiences, which resulted "highly suggestive" according to validated Umbrella Criteria. Similarly, a positive association was confirmed for suicidal ideation and suicide attempt and for any subtype of adverse childhood experience. This meta-analysis showed that exposure to adverse childhood experiences strongly increases the probability of suicide behaviors in people with schizophrenia spectrum disorders.

Clinical specificity profile for novel rapid acting antidepressant drugs.

Mood disorders are recurrent/chronic diseases with variable clinical remission rates. Available antidepressants are not effective in all patients and often show a relevant response latency, with a range of adverse events, including weight gain and sexual dysfunction. Novel rapid agents were developed with the aim of overcoming at least in part these issues. Novel drugs target glutamate, gamma-aminobutyric acid, orexin, and other receptors, providing a broader range of pharmacodynamic mechanisms, that is, expected to increase the possibility of personalizing treatments on the individual clinical profile. These new drugs were developed with the aim of combining a rapid action, a tolerable profile, and higher effectiveness on specific symptoms, which were relatively poorly targeted by standard antidepressants, such as anhedonia and response to reward, suicidal ideation/behaviours, insomnia, cognitive deficits, and irritability. This review discusses the clinical specificity profile of new antidepressants, namely 4-chlorokynurenine (AV-101), dextromethorphan-bupropion, pregn-4-en-20-yn-3-one (PH-10), pimavanserin, PRAX-114, psilocybin, esmethadone (REL-1017/dextromethadone), seltorexant (JNJ-42847922/MIN-202), and zuranolone (SAGE-217). The main aim is to provide an overview of the efficacy/tolerability of these compounds in patients with mood disorders having different symptom/comorbidity patterns, to help clinicians in the optimization of the risk/benefit ratio when prescribing these drugs.

Eating Disorders and Disturbed Eating Behaviors Underlying Body Weight Differences in Patients Affected by Endometriosis: Preliminary Results from an Italian Cross-Sectional Study.

This study aimed to characterize the prevalence of eating disorders (EDs), disturbed eating behaviors (DEBs), and emotional eating attitudes (EEAs) among patients affected by endometriosis in order to understand a potential crosslink between this impacting gynecological disease and a Body Mass Index shift. A total of 30 patients were recruited at an endometriosis outpatient clinic in Bologna and were assessed by using standardized instruments and specific questionnaires for EDs, DEBs, and EEAs. Sociodemographic information and endometriosis clinical features and history information were collected by adopting a specific questionnaire. Retrospective reports of lifetime Body Mass Index (BMI) changes, current BMI, peak pain severity during the last menstrual period, and the average of pain intensity during the last intermenstrual period were used for a correlation with the mean score from eating-behavior scales' assessment. The preliminary results indicate that, although only 3.33% of endometriosis patients are affected by ED, statistically significant differences at the mean scores of DEBs and EEAs assessment scales were found by stratifying patients on the basis of BMI levels at risk for infertility and coronary heart disease and on the basis of moderate/severe pain levels. The enrichment of the sample size and the recruitment of the control group to complete the study enrollment will allow us to investigate more complex and strong correlation findings and to assess the prevalence of EDs among endometriosis patients.

Hyperthyroidism and depression: a clinical case of atypical thyrotoxicosis manifestation.

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.

Melancholic features and typical neurovegetative symptoms of major depressive disorder show specific polygenic patterns.

BACKGROUND: 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). METHODS: 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. RESULTS: 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). LIMITATIONS: The proportion of phenotypic variance explained by the PRSs was limited. CONCLUSIONS: 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.

Characterisation of medication side effects in patients with mostly resistant depression in a real-world setting.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Epidemiology and Clinical-Demographic Characteristics of Suicide Attempts in Alcohol Use Disorders in an Italian Population.

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.

The dilemma of polypharmacy in psychosis: is it worth combining partial and full dopamine modulation?

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 (~11 weeks), while studies that found symptom worsening observed this happening in a shorter timeframe (~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.

Clinical correlates and prognostic impact of binge-eating symptoms in major depressive disorder.

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: P < 0.0001; social phobia: P < 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.

COVID-19 hospitalization rates in individuals with substance or alcohol use disorders.

People with Substance or Alcohol Use Disorders (SUDs/AUDs) are likely to be more vulnerable to COVID-19 infection than the general population. We performed a cross-sectional study to compare the hospitalization rate (CHR) for COVID-19 in 2020 in patients diagnosed with SUDs or AUDs in the previous 10 years vs the population without these disorders (NAS). We included individuals who were resident in the Metropolitan Area of Bologna (Northern Italy). People with SUDs or AUDs have a greater probability of being hospitalized for COVID-19 infection compared to the general population NAS, suggesting that they suffer from worse physical symptoms/conditions than the general population. Furthermore, we found higher mortality rates during hospitalization for COVID-19 in patients with AUDs or SUDs than the general population NAS. These findings highlight the importance of a careful monitoring and early intervention measures in these patients.

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

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

Social withdrawal and neurocognitive correlates in schizophrenia.

Poor neurocognitive performance has been associated with poor functional outcome in schizophrenia (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 patient cross-sectional associations between neurocognitive domains and social withdrawal. 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 five domain scores and a composite score. Social withdrawal was measured by a specific item of the Heinrichs-Carpenter Quality of Life Scale. 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. Eight percent of the total variance of social withdrawal was explained by these three cognitive domains and additional clinical and sociodemographic factors (education years, PANSS positive symptoms score, and employment). 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.

Metabolizing status of CYP2C19 in response and side effects to medications for depression: Results from a naturalistic study.

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.

Epigenetic Basis of Psychiatric Disorders: A Narrative Review.

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.

Antidepressant efficacy is correlated with plasma levels: mega-analysis and further evidence.

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.