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Functional and structural connectivity alterations in short- and long-range projections have been reported across neurodevelopmental disorders (NDD). Interhemispheric callosal projection neurons (CPN) represent one of the major long-range projections in the brain, which are particularly important for higher-order cognitive function and flexibility. However, whether a causal relationship exists between interhemispheric connectivity alterations and cognitive deficits in NDD remains elusive. Here, we focused on CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the X-linked Cyclin-dependent kinase-like 5 (CDKL5) gene. We found an increase in homotopic interhemispheric connectivity and functional hyperconnectivity across higher cognitive areas in adult male and female CDKL5-deficient mice by resting-state functional MRI (rs-fMRI) analysis. This was accompanied by an increase in the number of callosal synaptic inputs but decrease in local synaptic connectivity in the cingulate cortex of juvenile CDKL5-deficient mice, suggesting an impairment in excitatory synapse development and a differential role of CDKL5 across excitatory neuron subtypes. These deficits were associated with significant cognitive impairments in CDKL5 KO mice. Selective deletion of CDKL5 in the largest subtype of CPN likewise resulted in an increase of functional callosal inputs, without however significantly altering intracortical cingulate networks. Notably, such callosal-specific changes were sufficient to cause cognitive deficits. Finally, when CDKL5 was selectively re-expressed only in this CPN subtype, in otherwise CDKL5-deficient mice, it was sufficient to prevent the cognitive impairments of CDKL5 mutants. Together, these results reveal a novel role of CDKL5 by demonstrating that it is both necessary and sufficient for proper CPN connectivity and cognitive function and flexibility, and further validates a causal relationship between CPN dysfunction and cognitive impairment in a model of NDD.

Mars exploration has recently witnessed major interest within the scientific community, particularly because unmanned aerial robotic platforms offer reliable alternatives for acquiring and collecting data and information from the Red Planet. However, the specific conditions of the Martian environment result in a restricted flight envelope when flying close to Mars and then landing on the surface of Mars. Therefore, in addition to the requirement to develop an aerial platform suitable for operations on Mars, autonomous navigation strategies and robust controllers are also needed for exploration tasks. It is argued that hexacopters with their relatively compact design represent a promising solution for autonomous exploration tasks on Mars, overcoming at the same time the limitations of wheel-based rovers. This research focuses on the design of a Mars hexacopter for a scouting mission in the Jezero region of Mars. The configuration and architecture of the hexacopter follow NASA conceptual study of the Mars science helicopter. Then, the mission profile for mapping the Belva crater is examined, followed by a detailed approach to implement and test observer-based navigation and control strategies. A comprehensive simulated experiments environment based on the integration of robot operating system and Ardupilot is also presented, used to validate the overall system architecture and mission parameters considering both the morphological shape of the explored crater and the atmospheric conditions of Mars.

This paper addresses the lateral wind gust estimation and compensation problem for racecar models. A wind-sensorless solution, i.e. a solution not using direct wind measures, is proposed. More precisely, by modeling the wind disturbance as a fully unknown input signal, an input-state observer is derived using only information about the vehicle’s longitudinal speed and lateral pose relative to the road. The observer is characterized by a simple structure, explicit closed-form, direct implementability on a micro-controller, and dead-beat property, i.e. it ensures the convergence of the estimation error in a finite time. Moreover, leveraging on the reconstructed wind data, a backstepping wind-compensation controller is also proposed, allowing asymptotic tracking of a path with desired curvature and providing the end-user with a free control parameter specifying the desired tracking speed. Formal proofs of the estimation error and tracking error convergence are given. Performance evaluation of the proposed solution is obtained in simulation by closing in the loop the full nonlinear model of a real racecar, the Robocar system, with the proposed estimation and control method. Both the estimator and the controller are shown to outperform existing solutions, even in the presence of noisy measurements.

AbstractBackgroundVortioxetine has demonstrated dose-dependent efficacy in patients with major depressive disorder (MDD), with the greatest effect observed with vortioxetine 20 mg/day. This analysis further explored the clinical relevance of the more rapid and greater improvement in depressive symptoms observed with vortioxetine 20 mg/day vs 10 mg/day.MethodsAnalysis of pooled data from six short-term (8-week), randomized, placebo-controlled, fixed-dose studies of vortioxetine 20 mg/day in patients with MDD (N= 2620). Symptomatic response (≥50% decrease in Montgomery–Åsberg Depression Rating Scale [MADRS] total score), sustained symptomatic response, and remission (MADRS total score ≤10) were assessed by vortioxetine dosage (20 or 10 mg/day).ResultsAfter 8 weeks, 51.4% of patients receiving vortioxetine 20 mg/day had achieved symptomatic response vs 46.0% of those receiving vortioxetine 10 mg/day (P< .05). Significantly more patients achieved symptomatic response vs placebo from week 2 onwards for vortioxetine 20 mg/day and from week 6 onwards for vortioxetine 10 mg/day (both P≤ .05). Sustained response was achieved from week 4 for 26.0% of patients receiving vortioxetine 20 mg/day vs 19.1% of those receiving vortioxetine 10 mg/day (P <.01), increasing to 36.0% and 29.8%, respectively, over the 8-week treatment period (P <.05). At week 8, 32.0% of patients receiving vortioxetine 20 mg/day were in remission vs 28.2% of those receiving vortioxetine 10 mg/day (P= .09). Rates of adverse events and treatment withdrawal were not increased during the week following vortioxetine dose up-titration to 20 mg/day.ConclusionVortioxetine 20 mg/day provides more rapid and more sustained symptomatic response than vortioxetine 10 mg/day in patients with MDD, without compromising tolerability.

ABSTRACTIntroductionThe coronavirus (COVID-19) pandemic has led to as well as exacerbated mental health disorders, leading to increased use of psychotropic medications. Co-administration of COVID-19 and psychotropic medications may result in drug-drug interactions (DDIs), that may compromise both the safety and efficacy of both medications.Areas coveredThis review provides an update of the current evidence on DDIs between COVID-19 and psychotropic medications. The interactions are categorized into pharmacokinetic, pharmacodynamic, and other relevant types. A thorough literature search was conducted using electronic databases to identify relevant studies, and extract data to highlight potential DDIs, clinical implications, and management strategies.Expert opinionUnderstanding and managing potential DDIs between COVID-19 and psychotropic medications is paramount to ensuring safe and effective treatment of patients with COVID-19 and mental illness. Awareness of the diverse spectrum of DDIs, vigilant monitoring, and judicious dose modifications, while choosing pharmacotherapeutic options with low risk of interaction whenever possible, are necessary. Ongoing and future investigations should continue to review the dynamic landscape of COVID-19 therapeutic modalities and their interactions with psychotropic medications.

ABSTRACTIntroductionMental health disorders, especially depressive and anxiety disorders, are associated with substantial health-related burden. While the second-generation antidepressants are widely accepted as first-line pharmacological treatment for major depressive disorder (MDD), patient response to such treatment is variable, with more than half failing to achieve complete remission, and residual symptoms are frequently present.Areas coveredHere, the pharmacodynamics of venlafaxine XR are reviewed in relation to its role as both a selective serotonin reuptake inhibitor (SSRI) and a serotonin-norepinephrine-reuptake inhibitor (SNRI), and we look at how these pharmacodynamic properties can be harnessed to guide clinical practice, asking the question ‘is it possible to develop a symptom-cluster-based approach to the treatment of MDD with comorbid anxiety utilizing venlafaxine XR?.’ Additionally, three illustrative clinical cases provide practical examples of the utility of venlafaxine-XR in real-world clinical practice. The place of venlafaxine XR in managing fatigue/low energy, a frequent residual symptom in MDD, is explored using pooled data from clinical trials of venlafaxine XR.Expert opinionVenlafaxine XR should be considered as a first-line treatment for MDD with or without comorbid anxiety, and there are clear pharmacodynamic signals supporting a symptom cluster-based treatment paradigm for venlafaxine XR.

AbstractBackgroundAnalysis of efficacy and tolerability of vortioxetine 20 mg/day, and optimal timing of dose adjustment, in patients with major depressive disorder (MDD).MethodsPooled analysis of six randomized, fixed-dose studies of vortioxetine 5 to 20 mg/day. Mean change from baseline in Montgomery–Åsberg Depression Rating Scale (MADRS) total score was analyzed by vortioxetine dose using a mixed model for repeated measures. Tolerability was assessed over the 8-week treatment period and from day 8 (ie, following dose increase to 20 mg/day). Data from three randomized, flexible-dose studies were examined for frequency and timing of dose adjustment.ResultsA clear dose–response relationship for vortioxetine was confirmed in terms of improvement in MADRS total score. Significant differences vs placebo were seen for vortioxetine 20 mg/day from week 2 onwards; vortioxetine 10 mg did not separate from placebo until week 4. At week 8, mean change in MADRS total score from baseline was significantly greater for vortioxetine 20 mg/day vs 10 mg/day (difference, −1.03 points; P< .05). Incidence of adverse events was not increased in patients who received vortioxetine 20 mg/day vs 10 mg/day. In flexible-dose studies, dosage was increased to 20 mg/day after 1 week in 48.0% of patients; final dosage was 20 mg/day in 64.3% of patients.ConclusionsVortioxetine 20 mg is significantly more effective than vortioxetine 10 mg in patients with MDD, with a similar tolerability profile. In flexible-dose studies, almost half of all patients received 20 mg/day after 1 week and two-thirds received 20 mg/day as their final dosage.

This brief addresses the robust lateral control problem for self-driving racecars. It proposes a discrete-time estimation and control solution consisting of a delayed unknown input-state observer (UIO) and a robust tracking controller. Based on a nominal vehicle model, describing its motion with respect to a generic desired trajectory and requiring no information about the surrounding environment, the observer reconstructs the total force disturbance signal, resulting from imperfect knowledge of the time-varying tire-road interface characteristics, presence of other vehicles nearby, wind gusts, and other model uncertainty. Then, the controller actively compensates the estimated force and asymptotically steers the tracking error to zero. The brief also presents a closed-loop stability proof of the method, ensuring perfect asymptotic estimation and tracking by the controlled vehicle. The proposed solution advantageously needs no a-priori information about the total disturbance boundedness, additional variables to model uncertainty, or observer parameters to be tuned. Its effectiveness and superiority to existing methods are studied in theory and shown in simulations where a full racecar model, based on the vehicle dynamics blockset, is required to track aggressive maneuvers. Through a faster and more accurate disturbance estimation, the solution robustly ensures better dynamic responses even with measurement noise.

Purpose: Reduced bone mineral density (BMD) and increase risk of fragility fracture are common complication of anorexia nervosa (AN). BMD by dual-energy X-ray absorptiometry (DXA) present several limits in subjects with AN. This study aimed to evaluate the usefulness of the new Radiofrequency echographic multispectrometry (REMS) technique in the assessment of bone status in young women with AN. Methods: In a cohort of 50 subjects with restrictive AN and in 30 healthy controls, we measured BMD at the lumbar spine (LS-BMD), at femoral neck (FN-BMD) and total hip (TH-BMD) using both DXA and REMS technique. Results: BMD evaluated by DXA and REMS technique at all measurement sites were all significantly (p&lt; 0.01) lower in subjects suffering from AN subjects than in controls. Good correlations were detected between BMD by DXA and BMD by REMS measurements at LS (r= 0.64, p&lt; 0.01) at FN (r= 0.86, p&lt; 0.01) and at TH (r= 0.84, p&lt; 0.01) in subjects suffering from AN. Moreover, Bland–Altman analysis confirmed the good agreement between the two techniques. The subjects suffering from AN with previous vertebral fragility fractures presented lower values of both BMD-LS and BMD-TH by DXA and by REMS with respect to those without fractures; however, the difference was significant only for BMD-TH by REMS (p&lt; 0.05). Conclusions: Our data suggest that REMS technique due to its characteristic of precision and reproducibility may represent an important tool for the evaluation of the changes in bone status in AN young women, especially during the fertile age and in case of pregnancy and breastfeeding. Level of evidence: Level of evidence: level III cohort study.

ABSTRACTIntroductionLurasidone is an atypical antipsychotic agent approved in the European Union for the treatment of schizophrenia in adults and adolescents (13–17 years). Clinical trials have shown a generally favorable balance between efficacy and tolerability.Areas coveredThis paper provides a review and commentary regarding the use of lurasidone in adults and adolescents with schizophrenia. The available information about efficacy, tolerability, dosing, and switching is analyzed, highlighting the strategies that may be most useful in real-world clinical practice. Virtual case studies, designed based on the authors’ clinical experience with real-world patients, are provided.Expert opinionLurasidone is efficacious in adolescents and adults in a wide range of symptoms of schizophrenia. Choosing the right dose for each patient and combining lurasidone with other medications is key to treatment success. Lurasidone has proven effective both in adolescents and adults in treating the acute phase of schizophrenia and reducing the risk of relapse. It has shown a relatively favorable tolerability profile, with minimal effects on metabolic parameters and prolactin levels.

Bipolar disorder is heterogeneous in phenomenology, illness trajectory, and response to treatment. Despite evidence for the efficacy of multimodal­ity interventions, the majority of persons affected by this disorder do not achieve and sustain full syndromal recovery. It is eagerly anticipated that combining datasets across various information sources (e.g., hierarchical “multi‐omic” measures, electronic health records), analyzed using advanced computational methods (e.g., machine learning), will inform future diagnosis and treatment selection. In the interim, identifying clinically meaningful subgroups of persons with the disorder having differential response to specific treatments at point‐of‐care is an empirical priority. This paper endeavours to synthesize salient domains in the clinical characterization of the adult patient with bipolar disorder, with the overarching aim to improve health outcomes by informing patient management and treatment considerations. Extant data indicate that characterizing select domains in bipolar disorder provides actionable information and guides shared decision making. For example, it is robustly established that the presence of mixed features – especially during depressive episodes – and of physical and psychiatric comorbidities informs illness trajectory, response to treatment, and suicide risk. In addition, early environmental exposures (e.g., sexual and physical abuse, emotional neglect) are highly associated with more complicated illness presentations, inviting the need for developmentally‐oriented and integrated treatment approaches. There have been significant advances in validating subtypes of bipolar disorder (e.g., bipolar I vs. II disorder), particularly in regard to pharmacological interventions. As with other severe mental disorders, social functioning, interpersonal/family relationships and internalized stigma are domains highly relevant to relapse risk, health outcomes, and quality of life. The elevated standardized mortality ratio for completed suicide and suicidal behaviour in bipolar disorder invites the need for characterization of this domain in all patients. The framework of this paper is to describe all the above salient domains, providing a synthesis of extant literature and recommendations for decision support tools and clinical metrics that can be implemented at point‐of‐care.

AbstractBackgroundPrevious researches highlighted among patients with schizophrenia spectrum disorders (SSD) a significant presence of autistic traits, which seem to influence clinical and functional outcomes. The aim of this study was to further deepen the investigation, evaluating how patients with SSD with or without autistic traits may differ with respect to levels of functioning, self-esteem, resilience, and coping profiles.MethodsAs part of the add-on autism spectrum study of the Italian Network for Research on Psychoses, 164 outpatients with schizophrenia (SCZ) were recruited at eight Italian University psychiatric clinics. Subjects were grouped depending on the presence of significant autistic traits according to the Adult Autism Subthreshold Spectrum (AdAS Spectrum) instrument (“AT group” vs “No AT group”). Other instruments employed were: Autism Spectrum Quotient (AQ), Specific Levels of Functioning (SLOF), Self-Esteem Rating scale (SERS), Resilience Scale for Adults (RSA), and brief-COPE.ResultsThe “AT group” reported significantly higher scores than the “No AT group” on SLOF activities of community livingbut significantly lower scores on work skillssubscale. The same group scored significantly lower also on SERS total score and RSA perception of the selfsubscale. Higher scores were reported on COPE self-blame, use of emotional supportand humordomains in the AT group. Several correlations were found between specific dimensions of the instruments.ConclusionOur findings suggest the presence of specific patterns of functioning, resilience, and coping abilities among SSD patients with autistic traits.

AbstractIn the last decades, increasing attention has been provided to socio-cultural and neurobiological factors involved in the psychopathology of feeding and eating disorders (FED), encouraging a multifactorial approach. In this framework, several authors stressed an association between FED and other kinds of psychiatric disorders from both a psychopathological and a neurobiological point of view. In particular, many promising contributions are focusing on the possible link between FED and autism spectrum disorder (ASD). Growing interest about this association rose from the frequently reported evidence of ASD-like traits amongst FED patients and abnormal eating behaviors amongst patients with ASD. This narrative review overview aims to summarize the most relevant findings about the overlap between different kinds of FED and the autism spectrum, taking into account the most recent hypotheses about the psychopathology of both these conditions. While most of the studies focused on anorexia nervosa, both ASD and autistic traits seem to be detectable also in other kinds of FED. In addition, the recently increased interest toward a dimensional approach to psychopathology led to progressively broadening the concept of ASD, focusing on its subthreshold and gender-specific manifestations and on its link with other psychiatric conditions, including FED. Globally the studies summarized here provide further support to theoretical models featuring a neurodevelopmental approach for mental disorders. In particular, FED have been conceptualized as a possible psychopathological trajectory of a neurodevelopmental alteration, toward which female gender would act as one of many predisposing factors.

Objective: Recent studies demonstrate the poor psychosocial outcomes associated with bipolar disorder. Occupational functioning, a key indicator of psychosocial disability, is often severely affected by the disorder. The authors describe the effect of acute treatment with interpersonal and social rhythm therapy on occupational functioning over a period of approximately 2.5 years. Method: Patients with bipolar I disorder were randomly assigned to receive either acute and maintenance interpersonal and social rhythm therapy, acute and maintenance intensive clinical management, acute interpersonal and social rhythm therapy and maintenance intensive clinical management, or acute intensive clinical management and maintenance interpersonal and social rhythm therapy, all with appropriate pharmacotherapy. Occupational functioning was measured with the UCLA Social Attainment Scale at baseline, at the end of acute treatment, and after 1 and 2 years of maintenance treatment. Results: The main effect of treatment did not reach conventional levels of statistical significance; however, the authors observed a significant time by initial treatment interaction. Participants initially assigned to interpersonal and social rhythm therapy showed more rapid improvement in occupational functioning than those initially assigned to intensive clinical management, primarily accounted for by greater improvement in occupational functioning during the acute treatment phase. At the end of 2 years of maintenance treatment, there were no differences between the treatment groups. A gender effect was also observed, with women who initially received interpersonal and social rhythm therapy showing more marked and rapid improvement. There was no effect of maintenance treatment assignment on occupational functioning outcomes. Conclusions: In this study, interpersonal and social rhythm therapy, with its emphasis on amelioration of interpersonal and role functioning, improved occupational functioning significantly more rapidly than did a psychoeducational and supportive approach with no such emphasis on functional capacities.

Objective: Neuroimaging studies are promising components for a new diagnostic framework for bipolar disorder, but a major issue is the potential confound of psychotropic medication upon experimental measures. Withdrawing all individuals from medication and examining only unmedicated individuals may be clinically unfeasible, and examining only unmedicated individuals may render findings less generalizable. Method: The authors review structural and functional neuroimaging studies of medicated and unmedicated patients with bipolar disorder to discern the possible confounding effect of medication. Results: Findings from studies identified on MEDLINE that included medicated individuals with bipolar disorder indicated either no significant effect or ameliorative effects of psychotropic medications on abnormal structural and functional neuroimaging measures relevant to pathophysiologic mechanisms of the disorder. Different strategies for assessing medication effects are compared. Conclusions: Neuroimaging studies of bipolar disorder ideally should recruit both unmedicated and medicated individuals. Individuals who are unable to tolerate medication withdrawal likely have more severe illness and are especially informative for research examining biomarkers of illness and treatment response.

A 41-year-old divorced woman with a 17-year history of bipolar I disorder is receiving outpatient treatment consisting of lithium pharmacotherapy and psychotherapy. She is currently living with her sons, ages 7 and 9. Her history is notable for several onsets of mania during or immediately following vacation travel. By the time the patient entered treatment with her current therapist, she was vacation phobic. Yet, as the now-single mother of two active young boys, she also recognized how much she would benefit from a change of scenery and some relief from the constant responsibility for her children and her home. Her brother and sister-in-law had offered to send to her a ticket out to the West Coast for a visit. As much as the idea of a vacation with them appealed to her, it also terrified her. When she mentioned the possibility to her psychiatrist, he agreed that there were some risks involved but that if she planned carefully, she might be able to minimize those risks.

Objective: This study examined the extent to which individuals with a lifetime diagnosis of recurrent unipolar disorder endorse experiencing manic/hypomanic symptoms over their lifetimes and compared their reports with those of patients with bipolar I disorder. Method: The study group included 117 patients with remitted recurrent unipolar depression and 106 with bipolar I. Subjects had their clinical diagnosis confirmed by the Mini International Neuropsychiatric Interview and were administered the Structured Clinical Interview for the Mood Spectrum, which assesses lifetime symptoms, traits, and lifestyles that characterize threshold and subthreshold mood episodes as well as 'temperamental' features related to mood dysregulation. Results: The patients with recurrent unipolar depression endorsed experiencing a substantial number of manic/hypomanic symptoms over their lifetimes. In both patients with recurrent unipolar depression and patients with bipolar I disorder, the number of manic/hypomanic items endorsed was related to the number of depressive items endorsed. In the group with recurrent unipolar depression, the number of manic/hypomanic items was related to an increased likelihood of endorsing paranoid and delusional thoughts and suicidal ideation. In the bipolar I group, the number of lifetime manic/hypomanic items was related to suicidal ideation and just one indicator of psychosis. Conclusions: The presence of a significant number of manic/hypomanic items in patients with recurrent unipolar depression seems to challenge the traditional unipolar-bipolar dichotomy and bridge the gap between these two categories of mood disorders. The authors argue that their mood spectrum approach is useful in making a more accurate diagnostic evaluation in patients with mood disorders.

Objective: This study sought to evaluate the relationship of obesity to demographic and clinical characteristics and treatment outcome in a group of 175 patients with bipolar I disorder who were treated for an acute affective episode and followed through a period of maintenance treatment. Method: Data were from participants entering the Maintenance Therapies for Bipolar Disorder protocol between 1991 and 2000. Analyses focused on differences in baseline demographic and clinical characteristics and in treatment outcomes between obese and nonobese patients. Results: A total of 35.4% of the patients met criteria for obesity. Significant differences between the obese and nonobese patients were observed for years of education, numbers of previous depressive and manic episodes, baseline scores on the Hamilton Rating Scale for Depression, and durations of the acute episode. A Kaplan-Meier survival analysis indicated a significantly shorter time to recurrence during the maintenance phase among obese patients. The number of patients experiencing a depressive recurrence was significantly higher in the obese than in the nonobese group. Conclusions: Obesity is correlated with a poorer outcome in patients with bipolar I disorder. Preventing and treating obesity in bipolar disorder patients could decrease the morbidity and mortality related to physical illness, enhance psychological well-being, and possibly improve the course of bipolar illness. Weight-control interventions specifically designed for patients with bipolar illness should be developed, tested, and integrated into the routine care provided for these patients.

Objective: Lifetime rates of suicide attempts among patients with bipolar I disorder were compared to rates during a 2-year period of intensive treatment with pharmacotherapy and with one of two adjunctive psychosocial interventions. Method: Subjects entered the study during an acute mood episode. Subjects were treated with primarily lithium pharmacotherapy and with either psychotherapy specific to bipolar disorder, which included help in regularizing daily routines, or nonspecific, intensive clinical management involving regular visits with empathic clinicians. Data on prior suicide attempts were obtained retrospectively from interviews with the NIMH-Life-Chart method. Data on suicide attempts during the clinical trial were collected systematically throughout the protocol. Results: The rate of suicide attempts was 1.05 per 100 person-months before patients entered the trial. Patients experienced a threefold reduction in the rate of suicide attempts during the acute treatment phase (until the patient achieved stabilization, defined by completion of 4 weeks during which the patient had a mean score of [less than or equal to] 7 on the 17-item Hamilton Depression Rating Scale and [less than or equal to] 7 on the Bech-Rafaelsen Mania Scale) and a 17.5-fold reduction during maintenance treatment. Poisson loglinear regression analysis modeling the relationship between the observed rates and the three protocol stages (pretreatment, acute, and maintenance) showed that the reductions were significant in the acute and maintenance phases, compared with the pretreatment phase. No patient with one or more suicide attempts before entering the trial attempted suicide during the protocol. Conclusions: A treatment program in a maximally supportive clinical environment can significantly reduce suicidal behavior in high-risk patients with bipolar I disorder. (Am J Psychiatry 2002; 159:1160-1164)

Method: A threshold for clinically meaningful panic-agoraphobic spectrum symptoms was defined by means of receiver operating characteristic curve analysis of total scores on the Structured Clinical Interview for Panic-Agoraphobic Spectrum in a group of 88 outpatients with and without panic disorder. This threshold was then applied to a group of 61 women with recurrent major depression, who completed a self-report version of the same instrument, in order to compare treatment outcomes for patients above and below this clinical threshold. Results: Women with high scores (>35) on the Panic-Agoraphobic Spectrum Self-Report were less likely than women with low scores (

Objective: Given the adverse impact of anxiety on treatment outcome in unipolar depression and the paucity of data on the rote of anxiety in bipolar disorder, the authors sought to determine the effect of anxiety on the acute treatment response of patients with bipolar I disorder. Method: The authors examined the correlates of response to the acute treatment of 124 consecutively treated patients with bipolar I disorder. Measures of anxiety included history of panic attacks and a composite variable reflecting current or past anxiety symptoms. Results: History of panic attacks proved to be a significant correlate of nonremission. Anxiety, as assessed with the composite variable, was associated with longer time to remission, as was the treatment of depressive versus manic symptoms and mixed versus manic symptoms. Patients with anxiety as assessed with the composite variable and patients with a history of panic attacks reported more severe medication side effects. They also required a greater number of medications, either sequentially or in combination, in order to achieve remission. Conclusions: The findings suggest that anxiety is a clinically meaningful correlate of poor outcome in the acute treatment of bipolar I disorder.

If appropriately implemented, open databases of instruction material may help teaching and learning by providing content for teaching activities, scaffolding, and self-assessment. The paper presents the current results of the development and implementation of a database that is expressly built for promoting exchange of questions and exercises, together with the associated solutions among teachers for STEM subjects. Besides presenting and motivating the initiative (together with reporting its current status), the manuscript lists a series of lessons that have been learned while executing the project – including the need for proper management of authorship and version control of the uploaded material. Moreover, the manuscript describes which features any open database of instruction material should implement to aid improved usability, together with a series of nontrivial theoretical and practical problems for future scientific investigations (e.g., developing taxonomies for indexing the difficulty levels of the instruction material uploaded in the database that do not suffer from the subjective interpretability associated with the existing taxonomies).

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

ABSTRACTIntroduction: Postpartum depressive disorder (PPD) is a burdensome medical condition. To date, only one treatment (Brexanolone) has undergone registrational trials and is approved in the United States with an indication for the treatment of PPD. However, other treatments are prescribed and have been tested for this condition. Herein, the authors review the available scientific evidence pertaining to the somatic treatments of PPD.Areas covered: The authors evaluate the published open-label and randomized controlled trials (RCTs), examine the biological mechanisms of PPD treatments, and evaluate how the available data translates into information that may be useful for clinical practice.Expert opinion: Antidepressants have long been the mainstay of PPD treatment, despite the limited evidence from randomized clinical trials that supports this practice. Brexanolone improves treatment options for women with PPD. However, the relatively burdensome administration and monitoring protocol, along with the high cost of the medication, limit the possibility for an extensive use of this medication. Large, randomized, controlled trials of hormonal treatments in patients with PPD are warranted. Also, treatment with mood stabilizers and/or antipsychotics in women with major depressive disorder, who meet the DSM-5 mixed features specifiers in the post-partum period, should be tested in controlled clinical trials.

Supplemental Digital Content is available in the text.This double-blind, randomized study evaluated the efficacy and safety of trazodone OAD (once-a-day) in comparison with venlafaxine XR (extended-release) in 324 patients (166 trazodone and 158 venlafaxine) with major depressive disorder (MDD). The primary efficacy endpoint was the mean change from baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) at week 8. Both treatments were effective in reducing the HAM-D-17 total score at week 8 vs. baseline (intent-to-treat: trazodone –12.9, venlafaxine –14.7; per protocol: trazodone –15.4, venlafaxine –16.4). Patients in the venlafaxine group achieved better results after 8 weeks, whereas the trazodone group achieved a statistically significant reduction in HAM-D-17 following only 7 days of treatment. The most frequent adverse events (AEs) were dizziness and somnolence in the trazodone group, and nausea and headache in the venlafaxine group. Most AEs were mild-to-moderate in severity. This study confirmed that both venlafaxine XR and trazodone OAD may represent a valid treatment option for patients with MDD.

Improving real‐life functioning is the main goal of the most advanced integrated treatment programs in people with schizophrenia. The Italian Network for Research on Psychoses previously explored, by using network analysis, the interplay among illness‐related variables, personal resources, context‐related factors and real‐life functioning in a large sample of patients with schizophrenia. The same research network has now completed a 4‐year follow‐up of the original sample. In the present study, we used network analysis to test whether the pattern of relationships among all variables investigated at baseline was similar at follow‐up. In addition, we compared the network structure of patients who were classified as recovered at follow‐up versus those who did not recover. Six hundred eighteen subjects recruited at baseline could be assessed in the follow‐up study. The network structure did not change significantly from baseline to follow‐up, and the overall strength of the connections among variables increased slightly, but not significantly. Functional capacity and everyday life skills had a high betweenness and closeness in the network at follow‐up, as they had at baseline, while psychopathological variables remained more peripheral. The network structure and connectivity of non‐recovered patients were similar to those observed in the whole sample, but very different from those in recovered subjects, in which we found few connections only. These data strongly suggest that tightly coupled symptoms/dysfunctions tend to maintain each other's activation, contributing to poor outcome in schizophrenia. Early and integrated treatment plans, targeting variables with high centrality, might prevent the emergence of self‐reinforcing networks of symptoms and dysfunctions in people with schizophrenia.

ObjectiveThe possible presence of gender-related differences in patients with bipolar disorder (BD) may have diagnostic and therapeutic implications. This multicenter study aimed to investigate gender differences in BD in the largest Italian database collected to date, on behalf of the Italian Chapter of the International Society of Bipolar Disorders.MethodsA total of 1674 patients (males: n = 714; females: n = 960) from different psychiatric departments were compared according to gender on demographic/clinical variables. Owing to the large number of variables statistically related to the dependent variable (gender) at the univariate analyses, preliminary multiple logistic regression analyses were performed. A final multivariable logistic regression was then performed, considering gender as the dependent variable and statistically significant demographic/clinical characteristics as independent variables.ResultsThe results of the final multivariable logistic regression analysis with previous statistically significant demographic and clinical variables were the following: female gender was less frequently associated with employment (odds ratio [OR] = 0.7, P< 0.01), lifetime single marital status (OR = 0.45, P< 0.01), and substance abuse in the last year (OR = 0.35, P< 0.01), whereas it was more frequently associated with a major number of lifetime major depressive episodes (OR = 1.78, P< 0.01) and psychiatric visits in the last year (OR = 1.38, P= 0.01).ConclusionFew significant differences were found between genders in BD, particularly for those clinical features that are associated with poor prognosis (substance abuse for males and number of depressive episodes for females). Transcultural studies are needed to identify cultural versus illness-related variables possibly explaining the different clinical presentation of BD in relation to gender.

Renewed scientific interest in psychedelic compounds represents one of the most promising avenues for addressing the current burden of mental health disorders. Classic psychedelics are a group of compounds that exhibit structural similarities to the naturally occurring neurotransmitter serotonin (5-HT). Acting on the 5-HT type 2A receptors (HT2ARs), psychedelics induce enduring neurophysiological changes that parallel their therapeutic psychological and behavioral effects. Recent preclinical evidence suggests that the ability of psychedelics to exert their action is determined by their ability to permeate the neuronal membrane to target a pool of intracellular 5-HT2ARs. In this computational study, we employ classical molecular dynamics simulations and umbrella sampling techniques to investigate the permeation behavior of 12 selected tryptamines and to characterize the interactions that drive the process. We aim at elucidating the impact of N-alkylation, indole ring substitution and positional modifications, and protonation on their membrane permeability. Dimethylation of the primary amine group and the introduction of a methoxy group at position 5 exhibited an increase in permeability. Moreover, there is a significant influence of positional substitutions on the indole groups, and the protonation of the molecules substantially increases the energy barrier at the center of the bilayer, making the compounds highly impermeable. All the information extracted from the trends predicted by the simulations can be applied in future drug design projects to develop psychedelics with enhanced activity.

AbstractFunctional recovery is a treatment goal that goes beyond symptomatic remission and encompasses multiple aspects of schizophrenia patients’ lives, including quality of life, physical, and mental functioning. There is evidence that long-acting injectable (LAI) treatments promote adherence and reduce rehospitalisation and functional decline, which could facilitate patients’ ability to reach functional recovery. Despite this, LAIs are underused in the first-episode (FEP) and early-phase (EP) patient population, due to physician hesitancy and concerns around stigma. A Delphi panel was held to gain expert consensus on an approach to the domains and assessment of functional recovery elements in FEP and EP schizophrenia patients.A literature review and input from a steering committee of 5 experts in psychiatry informed statements development for a three-round modified Delphi process. Round one was conducted via one-to-one video conference interviews, and the successive rounds were conducted via electronic surveys, which enabled international collaboration. Statements on the different domains and assessment for functional recovery were presented to 17 psychiatrists, practicing in 7 countries (France, Italy, US, Germany, Spain, Denmark, and UK), experienced in the treatment of schizophrenia with LAIs. Several analysis rules determined whether a statement could progress to the next round and specified the level of agreement required to achieve consensus. Measures of central tendency (mode, mean) and variability (interquartile range) were reported back to help panelists look at their previous responses in the context of the overall group.A consensus was reached (defined a priori as ≥80% agreement) on all 27 statements covering the dimensions, assessment, and level of achieved functional recovery for FEP and EP patients. The following domains are important to consider when assessing functional recovery: depression, aggressive behaviour, social interaction, family functioning, education/employment, sexual functioning, and leisure activities. Additionally, panellists reached consensus that dimensions should be minimally impairing, if present (excluding sexual functioning) and asked about at every encounter with the patient (excluding sexual functioning and leisure activities). In summary, this Delphi panel yielded agreement that functional recovery is multidimensional and should be assessed regularly as part of usual care on an individual patient level in FEP and EP schizophrenia patients.FundingLundbeck Otsuka Alliance

The authors describe the development of mouth full-length cDNA encyclopedia. They report that this encyclopedia has been constructed on the basis of preparing and sequencing cDNA libraries.

DSM-5 diagnostic categories, defined by a set of psychopathological symptoms are heterogeneous conditions that may include different biological entities, with distinct etiopathogenesis, different courses and requiring different treatment management. For bipolar disorder the major evidences for this lack of validity are the long paths before a proper diagnosis, the inconsistence of treatment guidelines, the long phases of pharmacological adjustment and the low average of long-term treatment response rates. Personalized medicine for mental disorders aims to couple established clinical–pathological indexes with new molecular profiling to create diagnostic, prognostic and therapeutic strategies precisely tailored to each patient. Regarding bipolar disorder, the clinical history and presentation are still the most reliable markers in stratifying patients and guiding therapeutic management, despite the research goes to great lengths to develop new neuropsychological or biological markers that can reliably predict individual therapy effectiveness. We provide an overview of the advancements in personalized medicine in bipolar disorder, with particular attention to how psychopathology, age at onset, comorbidity, course and staging, genetic and epigenetic, imaging and biomarkers can influence treatment management and provide an integration to the conventional treatment guidelines. This approach may offer a new and rational path for the development of treatments for targeted subgroups of patients with bipolar disorder.

Ketamine has emerged as a widespread treatment for a variety of psychiatric disorders when used at sub-anesthetic doses, but the neural mechanisms underlying its acute action remain unclear. Here, we identified NMDA receptors containing the 2A subunit (GluN2A) on parvalbumin (PV)-expressing inhibitory interneurons as a pivotal target of low-dose ketamine. Genetically deleting GluN2A receptors globally or selectively from PV interneurons abolished the rapid enhancement of visual cortical responses and gamma-band oscillations by ketamine. Moreover, during the follicular phase of the estrous cycle in female mice, the ketamine response was transiently attenuated along with a concomitant decrease of grin2AmRNA expression within PV interneurons. Thus, GluN2A receptors on PV interneurons mediate the immediate actions of low-dose ketamine treatment, and fluctuations in receptor expression across the estrous cycle may underlie sex-differences in drug efficacy.

Some women affected by mood disorders experience mood instability during the premenstrual phase. Assuming that fluctuations in drug serum levels may contribute to the worsening of mood symptoms, we carried out a systematic review of available studies that investigated changes in lithium and valproate levels in relation to menstrual phases. We selected five studies; four of which assessed menstrual fluctuations in lithium serum levels and one in valproate levels. Study samples included women in their fertile age affected by bipolar disorder, epilepsy as well as healthy ones. Preliminary results showed a close relationship between cyclic premenstrual exacerbation of affective symptoms and a significant decrease in lithium levels during the luteal phase, despite stable oral doses, in bipolar women. In healthy women, lithium levels were influenced by neither menstrual cycle phases nor oral contraceptives use. Valproate serum levels in epileptic women showed a small, nonsignificant decline during the mid-luteal phase. Pharmacokinetic sex differences in adsorption, volume distribution, hepatic metabolism, and renal excretion of mood stabilizers have been supposed to partly explain such menstrual serum level fluctuations. A better understanding in this field could help to counteract the distress related to premenstrual phase, improving therapeutic management of mood disorders in women.

ABSTRACTIntroduction: Binge eating disorder (BED) is the most common eating disorder and was newly recognized in 2013 in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). BED is frequently associated with obesity and the metabolic syndrome, as well as with other psychiatric diseases, such as mood (49%), anxiety (41%), and substance use (22%) disorders. BED is highly prevalent and carries a high burden of mental and physical illness and disability. However, BED is frequently under-recognized and under-treated.Areas covered: This paper reviews the main pharmacological treatments for BED and provides an expert opinion based on the available evidence and on the authors’ clinical experience with patients affected by BED.Expert opinion: Several medications have proven to be effective for the treatment of BED, including Lisdexamfetamine (LDX), topiramate as well as anti-anxiety and antidepressant medications. To date, LDX is the only FDA approved medication for BED. Consequently, as a general rule, the use of an FDA approved medication should always be preferred. However, when in the presence of concomitant psychiatric conditions such as anxiety or depression, other medications that have proven efficacy in those comorbid conditions can be used and may contextually provide a benefit for BED.

ABSTRACTIntroduction:The World Health Organization recommends newborns to be breastfed but this may be challenging if the mother needs to be treated for depression, since strong evidence to inform treatment choice is missing.Areas covered:We provide a critical review of the literature to guide clinicians who are considering sertraline for the management of depression during postpartum.Expert opinion:Sertraline is one of the safest antidepressants during breastfeeding. In most cases, women already taking sertraline should be advised to breastfeed and continue the medication. We recommend to begin with low doses and to slowly increase the dose up, with careful monitoring of the newborn for adverse effects (irritability, poor feeding, or uneasy sleep, especially if the child was born premature or had low weight at birth). The target dose should be the lowest effective. When feasible, child exposure to the medication may be reduced by avoiding breastfeeding at the time when the antidepressant milk concentration is at its peak. A decision to switchto sertraline from ongoing and effective treatment should be taken only after a scrupulous evaluation of the potential risks and benefits of switching versus continuing the ongoing medication while monitoring the infant carefully.

This observational study aimed to identify internal (clinical-demographic, temperamental characteristics) and external (childhood trauma, psychosocial characteristics) factors potentially predicting remission at 12 weeks in bipolar-I patients experiencing manic episode and requiring to start or switch treatment with oral antipsychotics and/or mood stabilizers. The following scales were administered: the Young Mania Rating Scale (YMRS), the Montgomery–Asberg Depression Rating Scale (MADRS), the Functioning Assessment Short Test (FAST), and the Clinical Global Impression for Bipolar Disorders (CGI-BP). A logistic regression analysis was carried out to test the effect of the explored factors on remission rate (YMRS score ≤12), functionality, and clinical outcomes at week 12. Overall, 243 patients were enrolled and 197 (81.1%) completed the follow-up. Remission at week 12 was achieved in 200 (82.3%) patients. Marked improvements from baseline were observed in MADRS, FAST, CGI-BP mania, and bipolar illness scores. None of the factors was associated with remission, or showed strong correlations with the improvements in clinical health state. In our sample, after 12 weeks of initiation or change of oral therapy for mania in bipolar-I patients, treatment was associated with rapid improvements in symptoms and functioning in most patients. Factors predictive of remission and clinical improvements in manic symptoms were not identified.

Mixed states in bipolar disorder have been neglected, and the data concerning treatment of these conditions have been relatively obscure. To address this, we systematically reviewed published pharmacological treatment data for “mixed states/episodes” in mood disorders, including “with mixed features” in DSM–5. We searched PubMed, MEDLINE, The Cochrane Library, clinicaltrials.gov, and controlled-trials.com (with different combinations of the following keywords: “mixed states/features,” “bipolar,” “depressive symptoms/bipolar depression,” “manic symptoms,” “treatment,” “DSM–5”) through to October 2016. We applied a quality-of-evidence approach: first-degree evidence=randomized placebo-controlled studies of pharmacological interventions used as monotherapy; second-degree evidence=a similar design in the absence of a placebo or of a combination therapy as a comparative group; third-degree evidence=case reports, case series, and reviews of published studies. We found very few primary double-blind, placebo-controlled studies on the treatment of mixed states: the preponderance of available data derives from subgroup analysis performed on studies that originally involved manic patients. Future research should study the effects of treatments in mixed states defined using current criteria.

AbstractSchizophrenia is among the top ten causes of years lost due to disability. Goals of treatment are evolving beyond remission of psychotic symptoms to include physical and mental functioning, quality of life, and long-term functional recovery. Evidence has shown long-acting injectables (LAIs) are beneficial for schizophrenia patients by increasing treatment adherence and decreasing relapse and rehospitalisation. This potentially reduces disease progression and facilitates functional recovery. However, LAIs are underused and often seen as a last resort for first-episode (FEP) and early-phase (EP) patients, due to physicians’ lack of familiarity and stigma.A three-round modified Delphi panel was held to gain expert consensus on an approach to functional recovery in FEP and EP patients with LAIs. A literature review and input from a steering committee of 5 experts in psychiatry informed the development of statements. Round one was carried out via one-to-one video conference interviews, and the subsequent rounds were conducted via electronic surveys, which enabled international collaboration. Delphi panellists were 17 psychiatrists with schizophrenia treatment experience, practicing in 7 countries (France, Italy, US, Germany, Spain, Denmark, and UK). Several analysis rules determined whether a statement could progress to the next round and specified the level of agreement required to achieve consensus. Measures of central tendencies (mode, mean) and variability (interquartile range) of aggregated responses from the previous round were reported to panelists to understand their response in relation to the group.There was consensus (defined a priori as ≥80% agreement) on the 8 statements relating to long-term treatment goals and LAI links to functional recovery. LAI treatment in FEP and EP patients increases adherence and reduces treatment burden and functional decline compared to the same and other oral medication. Additionally, there was consensus that LAIs lead to better treatment outcome and functional recovery. Other important factors to achieving functional recovery include patient attitude towards treatment and psychoeducation. Furthermore, consensus was reached that functional recovery and quality of life are linked. In summary, this Delphi panel yielded agreement that functional recovery is a reachable goal for FEP and EP patients and can be enhanced using LAIs.FundingLundbeck Otsuka Alliance

Aims.We searched for very high energy (VHE) γ-ray emission from the supernova remnant Cassiopeia A

Context.Metal-poor globular clusters (GCs) can provide a probe of the earliest epoch of star formation in the Universe, being the oldest observable stellar systems. In addition, young and intermediate-age low-metallicity GCs are present in external galaxies. Nevertheless, inferring their evolutionary status by using integrated properties may suffer from large intrinsicuncertainty caused by the discrete nature of stars in stellar systems, especially in the case of faint objects.

ABSTRACTIntroduction: Aripiprazole long acting once-monthly (AOM) is approved for the treatment of schizophrenia in adults. Despite recent evidence of AOM efficacy in the acute treatment of schizophrenia, it is recommended that AOM should be started once the acute symptoms are controlled and patients are stabilized. However, there currently are no definitive guidelines exactly describing when a patient is to be considered stabilized enough to start AOM and which the patients are for whom an early AOM start is to be preferred.Areas covered: A panel of Italian clinicians experienced with real world use of AOM met to discuss the scenarios where an early (i.e., immediately after controlling the acute symptoms) start of AOM may be suggested. Real life clinical experiences were shared and a consensus was reached.Expert opinion: There are cases when the risks/benefits ratio suggests to start AOM early, i.e. immediately after the acute symptoms have been stabilized, as opposed to starting it several days/weeks after the stabilization of acute symptoms. Clinical pearls, guidelines and opinions are provided.

This paper focuses on the convergence of information in distributed systems of agents communicating over a network. The information on which the convergence is sought is not represented by real numbers, as often in the literature, rather by sets. The dynamics of the evolution of information across the network is accordingly described by set-valued iterative maps. While the study of convergence of set-valued iterative maps is highly complex in general, this paper focuses on Boolean maps, which are comprised of arbitrary combinations of unions, intersections, and complements of sets. For these important class of systems, we provide tools to study both global and local convergence. A distributed geographic information system, leading to successful information reconstruction from partial and corrupted data, is used to illustrate the applications of the proposed methods. [ABSTRACT FROM AUTHOR]

ABSTRACTIntroduction: Aripiprazole long acting once-monthly (AOM) is a long acting atypical antipsychotic with proven efficacy in schizophrenia and with a pharmacological and a side effect profile that is different from other antipsychotics. These and other characteristics make AOM a possible alternative in patients requiring a change in long acting antipsychotic treatment due to issues such as lack of efficacy or persistent side effects. Both clinical and pharmacological factors should be considered when switching antipsychotics, and specific guidelines for long acting antipsychotic switching that address all these factors are needed.Areas covered: A panel of Italian and Spanish experts in psychiatry met to discuss the strategies for the switch to AOM in patients with schizophrenia. Real life clinical experiences were shared and the clinical strategies to improve the likelihood of success were discussed.Expert Opinion: Due to its specific pharmacological and tolerability profile, AOM represents a suitable alternative for patients with schizophrenia requiring a switch to a new LAI treatment because of lack of efficacy or persistent side effects from another LAI. Possible strategies for the switch to AOM are presented in this expert consensus paper in an attempt to provide guidance throughout the entire switching process

Inhibitory neurons regulate the adaptation of neural circuits to sensory experience, but the molecular mechanisms by which experience controls the connectivity between different types of inhibitory neuron to regulate cortical plasticity are largely unknown. Here we show that exposure of dark-housed mice to light induces a gene program in cortical vasoactive intestinal peptide (VIP)-expressing neurons that is markedly distinct from that induced in excitatory neurons and other subtypes of inhibitory neuron. We identify Igf1 as one of several activity-regulated genes that are specific to VIP neurons, and demonstrate that IGF1 functions cell-autonomously in VIP neurons to increase inhibitory synaptic input onto these neurons. Our findings further suggest that in cortical VIP neurons, experience-dependent gene transcription regulates visual acuity by activating the expression of IGF1, thus promoting the inhibition of disinhibitory neurons and affecting inhibition onto cortical pyramidal neurons.

AbstractIntroduction: Treatment of major depressive disorder aims for symptom remission and recovery of function, and involves a multifaceted approach including drug therapy, evidence-based psychotherapy, and electroconvulsive therapy, according to disease severity. Antidepressant monotherapy is generally the first-line approach for moderate to severe major depressive disorder (with or without psychotherapy). In some severe cases, patients may require the addition of antipsychotic therapy, electroconvulsive therapy, or antidepressant combination therapy.Areas covered: This article examines the use of trazodone in major depressive disorder, with a focus on practical guidance regarding the use of trazodone extended-release (Contramid®).Expert opinion: The extended-release once-a-day formulation of trazodone may provide a combination of efficacy and improved tolerability over other antidepressants and over the conventional immediate-release formulation.

Although trazodone is approved and marketed in most countries worldwide for the sole treatment of Major Depressive Disorder, the use for this medication is very common for many other conditions, such as primary or secondary insomnia, Generalised Anxiety Disorder, Panic Disorder, Post-Traumatic Stress Disorder and Obsessive- Compulsive Disorder. Other, not officially approved, uses of trazodone include: the treatment of bulimia, benzodiazepine and/or alcohol dependence or abuse, fibromyalgia, degenerative diseases of the central nervous system such as dementia and other organic disorders, schizophrenia, chronic pain, and diabetic neuropathy. In addition, due to its 5HT2A receptor antagonistic action, trazodone may be used to prevent the occurrence of initial and long-term side effects of SSRI, such as anxiety, insomnia and sexual dysfunction. Despite the favorable clinical experience and the encouraging results from the studies that have tested the efficacy of trazodone for some of its off-label indications, it is paramount that large, randomized and controlled clinical trials be conducted in the near future to evaluate which of the many off-label indications are supported by a strong scientific evidence.

The purpose of this article is to provide a comprehensive review of pharmacotherapy for binge eating disorder, including new therapeutic approaches such as centrally acting sympathomimetics, nootropics, lisdexamfetamine, and substance abuse treatment agents such as acamprosate, sodium oxybate, baclofen, and naltrexone.