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Background: Gender differences have been reported in the severity and psychopathological features of major depressive disorders among adults but are poorly reported in adolescent samples. Objective: This study aimed to examine gender differences in the psychopathology of mixed depression among adolescents. Methods: We analyzed 341 outpatients with the current major depressive episode (MDE) retrospectively to identify patients with DSM-5 MDE with mixed features. We compared examiner-rated depressive and (hypo)manic symptoms and self- and parent-reported symptoms between sexes. Results: We identified 76 patients with an MDE with mixed features (67.1% females, 32.9% with bipolar disorder). Depression severity was significantly greater in females versus males (CDRS-R total score 56.2 vs. 48.2, p = 0.014). Depressive symptoms were significantly and independently found to be more severe among females in a logistic regression model, including excessive fatigue (OR 1.68; p = 0.025), low self-esteem (OR 1.67; p = 0.04), excessive weeping (OR 1.62; p = 0.021), and CBCL AAA index (OR 1.04; p = 0.015). None of the depressive symptoms scored greater in males. Males had higher levels of motor activity (2.12 vs. 1.69; p = 0.048) and pressured speech (1.80 vs. 1.24; p = 0.004). Self-rated anxiety (69.3 vs. 56.8, p = 0.047) and CBCL AAA index (207 vs. 189; p = 0.007) were higher in females. Conclusion: Adolescent depression with mixed features is more severe in women, with a higher expression of core affective symptoms and excessive fatigue. While in males, slightly higher levels of psychomotor activation are reported, in females, emotional dysregulation and excessive weeping may subtend a difference in a broader spectrum of mixed features.

Early identification of bipolar disorder may provide appropriate support and treatment, however there is no current evidence for statistically predicting whether a child will develop bipolar disorder. Machine learning methods offer an opportunity for developing empirically-based predictors of bipolar disorder. This study examined whether bipolar disorder can be predicted using clinical data and machine learning algorithms. 492 children, ages 6-18 at baseline, were recruited from longitudinal case-control family studies. Participants were assessed at baseline, then followed-up after 10 years. In addition to sociodemographic data, children were assessed with psychometric scales, structured diagnostic interviews, and cognitive and social functioning assessments. Using the Balanced Random Forest algorithm, we examined whether the diagnostic outcome of full or subsyndromal bipolar disorder could be predicted from baseline data. 45 children (10%) developed bipolar disorder at follow-up. The model predicted subsequent bipolar disorder with 75% sensitivity, 76% specificity, and an Area Under the Receiver Operating Characteristics of 75%. Predictors best differentiating between children who did or did not develop bipolar disorder were the Child Behavioral Checklist Externalizing and Internalizing behaviors, the Child Behavioral Checklist Total t-score, problematic school functions indexed through the Child Behavioral Checklist School Competence scale, and the Child Behavioral Checklist Anxiety/Depression and Aggression scales. Our study provides the first quantitative model to predict bipolar disorder. Longitudinal prediction may help clinicians assess children with emergent psychopathology for future risk of bipolar disorder, an area of clinical and scientific importance. Machine learning algorithms could be implemented to alert clinicians to risk for bipolar disorder.

Access to the emergency department (ED) for acute psychiatric problems, especially for suicide attempts (SA), has increased in the last decade. This increase has exceptionally accelerated after the COVID-19 pandemic. The aim of this project was to study the increase in acute psychiatric care demand of children and adolescents in the short and medium term after the pandemic, in relation to public health measures and in comparison with a pre pandemic reference period. We retrospectively studied 5445 child psychiatric (CP) consultations requested for any reason and for suicide attempt (SA), suicidal ideation (SI) and non-suicidal self-injury (NSSI) in a pediatric ED during three different pandemic periods in Italy (from March 2020 to May 2022) and compared them to a pre-pandemic reference period (from January 2018 to February 2020). Monthly CP consultations for any reason increased significantly by 2.2 times from 70.9 in 2018 to 157 in 2022 (p < 0.001). During the pandemic, monthly CP consultations for any reason increased significantly from 75/month in the first lockdown to 153/month in the second lockdown, remaining stable in the following year. CP consultations for SA increased significantly from 5/month in the first lockdown to 16/month in the second. Consultations for SI increased gradually but significantly from the pre-pandemic period to the end of the pandemic. Juveniles evaluated for SA during the pandemic vs. pre-pandemic more frequently attempted suicide by self-poisoning and less frequently by precipitation, and they were more likely to be diagnosed with a major depressive disorder. CP consultations for any reason and for suicide attempts significantly increased in the decade before the pandemic and peaked in the second lockdown period in Italy.

To assess rates and lethality of suicidal behavior in studies of children and adolescents diagnosed with major depressive disorder (MDD) or bipolar disorder (BD).This PROSPERO-registered protocol (CRD-42019159676) systematically reviewed reports on suicidal behavior among juveniles (age ≤ 18 years), and pooled data on risk (% of subjects) and rates (%/year), followed by random-effects meta-analysis and multivariable linear regression modeling.Included were 41 reports (1995-2020) from 15 countries involving 104,801 juveniles (102,519 diagnosed with MDD, 2282 with BD), at risk for 0.80-12.5 years. Meta-analytically pooled suicide attempter-rates averaged 7.44%/year [95%CI: 5.63-9.25] with BD and 6.27%/year [5.13-7.41] with MDD. Meta-analysis of 5 studies with both diagnostic groups found significantly greater attempt risk with BD vs. MDD (OR = 1.59 [1.24-2.05], p 0.0001). In 6 studies, suicide rate with juvenile mood disorders averaged 125 [56.9-236]/100,000/year, similar to adult rates,30-times greater than in the general juvenile population, and higher among older adolescents. The ratio of attempts/suicides (A/S) was 52.6 among mood-disordered juveniles, indicating greater lethality than among juveniles in the general population (A/S ≥ 250), but somewhat less than in the estimated adult general population (A/S ca. 30).Rates of suicide attempts in juveniles with a major mood disorder averaged 6580/100,000/year, were greater in BD versus MDD observed under the same conditions, and greater with shorter periods of observation. Lethality (fatalities per suicide attempt) was greater in juveniles diagnosed with major affective disorders than in the juvenile general population, but less than in adults.

Recently in the field neurodegenerative diseases increasing attention has been pointed to CSF biomarkers and their integration with neuroimaging (1). Frontotemporal lobar degeneration (FTLD) refers to a heterogeneous group of clinical syndromes with different underlying proteinopathies including tau pathology. CSF biomarkers have been proposed as diagnostic and prognostic factors. Aim of our study was to evaluate the relationship between CSF tau biomarkers and structural MRI brain measures in FTLD.We included early FTLD patient. All included patients underwent lumbar puncture to evaluate amyloid, total-tau (t-tau), phospho-tau 181 (p-tau); p-tau/t-tau ratio was also calculated; brain MRI was performed to estimate whole brain volume, volume of principal deep grey matter structures and regional cortical thickness.Demographic characteristics of the 28 included patients were as follows: female/male: 9/19; mean ± SD age: 68.1 ± 7.8 years. The p-tau/t-tau ratio was significantly correlated with whole brain volume (r = 0.69; p: 0.001), left putamen volume (r = 0.55 p: 0.009), left pallidum volume (r = 0.41; p: 0.01), right accumbens area (r = 0.47; p: 0.02). P-tau/t tau ratio showed also a significant correlation with cortical thickness of left temporal lobe (r = 0.74; p: 0.001) and right lateral orbital frontal cortex (r = 0.45; p: 0.03). Linear regression showed a significant relationship between p-tau/t-tau ratio and left temporal pole (p = 0.01; rOur data suggest that CSF biomarkers, especially p-tau/t-tau ratio, could play a role as prognostic factor in FTLD. Further longitudinal investigations are needed to confirm these findings.

BackgroundMajor depressive disorder (MDD) is the second leading cause of disability and chronic disease burden in the United States. The importance of improving functional outcomes in MDD is increasingly recognized. The Symptoms of Depression Questionnaire (SDQ), a patient-reported measure, was developed to capture the heterogeneity of symptoms of MDD. REL-1017 (esmethadone HCl; d-methadone), is a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker and potential rapid antidepressant currently in Phase 3 development. In a Phase 2a trial, REL-1017 showed robust, rapid, and sustained antidepressant efficacy as adjunctive treatment in patients with MDD. The objective of this study was to assess the effects of REL-1017 on SDQ subscales to better characterize the functional implications of its therapeutic effects.MethodsA double-blind, placebo-controlled, inpatient, two-doses, 25 and 50 mg, three-arm, 1:1:1, randomized, phase 2a trial of REL-1017 was conducted at 10 centers in the United States. Least square (LS) mean scores and Cohen’s effect sizes of the total score of a 44-item of SDQ and its 5 subscales: lassitude, mood, cognitive/social functioning (SDQ-1); anxiety, agitation, anger, and irritability (SDQ-2); desire to be dead (SDQ-3); disruptions in sleep quality (SDQ-4); changes in appetite and weight (SDQ-5) were compared between REL-1017 and placebo.ResultsA total of 62 adult male and female patients (18-65 years of age) diagnosed with MDD participated in the trial. On day 14, the last day of efficacy measurement, the difference from placebo of the LS mean (90% CI) for REL-1017 25 mg and REL-1017 50 mg groups, respectively, showed improvement for both tested doses on SDQ total score (−23.2; P = .0066 [effect size: 0.9]; −26.8 P = .0014 [effect size: 1.1]). Additionally, for SDQ subscales, REL-1017 25 mg and REL-1017 50 mg groups, respectively, showed significant improvement as compared with placebo: SDQ-1 (−13.9; P = .0025 [effect size: 1.0]; −15.0; P = .0009 [effect size: 1.1]), SDQ-2 (−4.6; P = .0398 [effect size: 0.7]; −7.2; P = .0012 [effect size: 1.1]) and SDQ-4 (−2.7; P = .0055 [effect size: 1.0]; −2.8; P = .0029 [effect size: 1.0]). No significant differences were observed between the treated groups and placebo in the SDQ-3 and SDQ-5 subscales.ConclusionsIn patients with MDD, aside from improving the overall CFB compared to placebo in SDQ total score, REL-1017 resulted in clinically meaningful and statistically significant improvements in cognitive/motivational, anxiety/irritability, and sleep-specific domains. The robust, rapid, and sustained efficacy of REL-1017 for MDD is not limited to improving mood, but potentially extends to cognitive, motivational, sleep, and social functions, with potentially meaningful therapeutic and socioeconomic implications. These results may signal disease-modifying effects of esmethadone for MDD that may offer potential advantages over symptomatic treatment with standard antidepressants.FundingRelmada Therapeutics, Inc.

BackgroundDissociative symptoms may be found in a subset of patients with major depressive disorders (MDD). The Clinician-Administered Dissociative States Scale (CADSS) is a 23-item scale for the measurement of present-state dissociative symptoms with good inter-rater reliability and construct validity that can discriminate patients with dissociative disorders. The total CADSS score is derived by adding the score for each of the 23 items. A score of 4 or more on the CADSS is considered abnormal and clinically meaningful. Uncompetitive N-methyl-d-aspartic acid receptor (NMDAR) channel blockers have been proposed as a treatment for post-traumatic stress disorder (PTSD). REL-1017 is a novel, low potency, NMDAR channel blocker currently in Phase 3 studies for MDD.MethodsThis retrospective case series describes a subset of patients from a double-blind, randomized, placebo-controlled, in-patient 7-day, phase 2 trial of oral, once daily, 25 mg (75 mg loading dose on day 1, first dose) and 50 mg REL-1017 (100 mg loading dose on day 1, first dose) as an adjunctive treatment for MDD. This subset of patients was selected based on abnormal CADSS score at baseline, pre-treatment with the study drug. As part of REL-1017 safety evaluation, the CADSS was administered at four timepoints to all study patients: (a) 30 to 60 minutes pre-treatment at baseline on day 1; (b) 2 hours post-treatment on day 1 (after the first dose of study drug); (c) 2 hours post-treatment on day 7 (after the last dose); and (d) prior to discharge on day 9 (2 days after the last dose).ResultsAmong the 62 randomized patients, four patients had a CADSS score of at least 4 on day 1 before study drug administration (2 patients in the 25 mg arm [CADSS score 22 and 4]; 1 patient in the 50 mg arm [CADSS score 35]; 1 patient in the placebo arm [CADSS score 6]). Among these 4 patients, starting on day 1, 2 hours post-treatment, the 2 subjects in the 25 mg subgroup (75 mg loading dose) and 1 subject in the 50 mg subgroup (100 mg loading dose) showed a clinically meaningful decrease in their CADSS score, while the single patient in the placebo group showed no change. CADSS scores on Day 1 pre-treatment, day 1 post-treatment, day 7 post last treatment, and on day 9 prior to discharge were 22-2-6-0; 4-0-0-0; 35-14-9-0, and 6-6-n/a-n/a, for the two patients in the 25 mg REL-1017 subgroup, the single patient in the 50 mg REL-1017 subgroup, and the single patient in the placebo group, respectively.ConclusionsThese retrospective case report data potentially signal that REL-1017 may determine rapid and sustained improvement in patients with MDD and concurrent clinically meaningful dissociative symptoms assessed by a CADSS score of 4 or above. Ongoing phase 3 trials with REL-1017 are expected to enroll a total of 1200 outpatients with MDD. These studies will potentially generate additional data that may support the initiation of controlled studies with REL-1017 for the treatment of PTSD.FundingRelmada Therapeutics

Noonan syndrome (NS) is a dominant clinically variable and genetically heterogeneous developmental disorder caused by germ-line mutations encoding components of the Ras–MAPK signaling pathway. A few studies have investigated psychopathological features occurring in individuals with NS, although they were poorly analyzed. The aim of the present work is to investigate the psychopathological features in children and adolescents with NS focusing on depressive and hypo-manic symptoms. Thirty-seven subjects with molecularly confirmed diagnosis were systematically evaluated through a psychopathological assessment. In addition, an evaluation of the cognitive level was performed. Our analyses showed a high recurrence of attention deficit and hyperactivity disorder symptoms, emotional dysregulation, irritability, and anxiety symptomatology. The mean cognitive level was on the average. The present study provides new relevant information on psychopathological features in individuals with NS. The implications for clinicians are discussed including the monitoring of mood disorders in a clinical evolution.

Increasing rates of non-fatal self-harm amongst adolescents represent growing concern. The objective of the study is to describe non-fatal self-harm - including suicidal behaviour (SB), suicidal ideation (SI) and non-suicidal self-injury (NSSI) - observed at an Italian paediatric emergency department (ED).Retrospective analysis of the clinical records of patients admitted to ED from 2011 to 2016, who underwent child psychiatry consultation (CPc). We analyzed: rates of CPc for SB, SI and NSSI; risk factors for SB and SI in patients admitted to the hospital's Child Psychiatry Unit after a CPc; and, correlations between NSSI and SB/SI.The rate of CPc for SB, SI and NSSI switched from 7.7% in 2011 to 19% in 2016, with a statistically significant increase over the years (p0.001), a 2.2:1 female/male ratio, and an average age of 15.5 ± 1.8 years. SB consisted mainly in drug poisoning (53%), with a significant prevalence in female. Mood disorder was identified in 82.5% of patients hospitalized for SB or SI. Substance abuse was more frequently found in patients admitted for SB when compared to the SI group. Almost half (48%) of the patients admitted for SB or SI reported a current or lifelong history of NSSI. In patients admitted for SB or SI, 3 factors were significantly and independently associated with NSSI: being female, substance abuse, and more severe depressive symptoms.Between 2011 and 2016, there was a significant growing need for CP consultations for suicidal behaviours, mainly in female adolescents. The subjects admitted for SI or SB, who also presented NSSI, were mainly substance abusers, and presented with more severe depressive symptoms.

Introduction Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, skeletal and haematological/lymphatic defects, distinctive facies, cryptorchidism, and a wide spectrum of congenital heart defects. Recurrent features also include variable cognitive deficits and behavioural problems. Recent research has been focused on the assessment of prevalence, age of onset and characterization of psychiatric features in this disorder. Herein, we evaluated the prevalence of attention deficit and hyperactivity disorder (ADHD), anxiety and depressive symptoms and syndromes in a cohort of individuals with clinical and molecular diagnosis of NS. Methods The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS PL) has been used for the assessment of psychiatric disorders according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Multidimensional Anxiety Scale for Children (MASC) and the Children's Depression Inventory (CDI) have been assessed for the evaluation of anxiety and depressive symptoms and syndromes, whereas Conners Teacher and Parent Rating Scales-long version (CRS-R) have been used to evaluate ADHD. Results The study included 27 individuals (67% males) with an average age of 10.4 years (range 6–18 years) receiving molecular diagnosis of NS or a clinically related condition, evaluated and treated at the Neuropsychiatric Unit of Children's Hospital Bambino Gesu and at the Center for Rare Diseases of Fondazione Policlinico Universitario Agostino Gemelli, in Rome. Twenty individuals showed mutations in PTPN11, five in SOS1 and two in SHOC2. The mean IQ was 94 (Standard Deviation = 17, min = 56, max = 130). Seventy percent of the individuals (n = 19; 95% Confidence Interval = 52–85%) showed ADHD features, with six individuals reaching DSM-IV-TR criteria for ADHD disorder, and thirteen showing subsyndromal traits. Symptoms or syndrome of anxiety were present in 37% of the cohort (n = 10; 95% Confidence Interval = 19–56%), with two individuals showing anxiety disorder and eight cases exhibiting subsyndromal traits. Conclusion Our results show individuals with NS do present a very high risk to develop psychiatric disorders or symptoms during paediatric age. Based on these findings, preschool assessment of inattentive, hyperactivity/impulsivity and anxiety/depressive symptoms is recommended in order to plan a personalized treatment for psychological/psychiatric issues in affected individuals. Dedicated prospective studies are required to confirm the present data and better characterize the psychopathological profile in NS.

Summary Background Deep brain stimulation (DBS) has been proposed to treat patients with severe Tourette's syndrome, and open-label trials and two small double-blind trials have tested DBS of the posterior and the anterior internal globus pallidus (aGPi). We aimed to specifically assess the efficacy of aGPi DBS for severe Tourette's syndrome. Methods In this randomised, double-blind, controlled trial, we recruited patients aged 18–60 years with severe and medically refractory Tourette's syndrome from eight hospitals specialised in movement disorders in France. Enrolled patients received surgery to implant bilateral electrodes for aGPi DBS; 3 months later they were randomly assigned (1:1 ratio with a block size of eight; computer-generated pairwise randomisation according to order of enrolment) to receive either active or sham stimulation for the subsequent 3 months in a double-blind fashion. All patients then received open-label active stimulation for the subsequent 6 months. Patients and clinicians assessing outcomes were masked to treatment allocation; an unmasked clinician was responsible for stimulation parameter programming, with intensity set below the side-effect threshold. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) score between the beginning and end of the 3 month double-blind period, as assessed with a Mann-Whitney-Wilcoxon test in all randomly allocated patients who received active or sham stimulation during the double-blind period. We assessed safety in all patients who were enrolled and received surgery for aGPi DBS. This trial is registered with ClinicalTrials.gov, number NCT00478842. Findings Between Dec 6, 2007, and Dec 13, 2012, we enrolled 19 patients. We randomly assigned 17 (89%) patients, with 16 completing blinded assessments (seven [44%] in the active stimulation group and nine [56%] in the sham stimulation group). We noted no significant difference in YGTSS score change between the beginning and the end of the 3 month double-blind period between groups (active group median YGTSS score 68·5 [IQR 34·0 to 83·5] at the beginning and 62·5 [51·5 to 72·0] at the end, median change 1·1% [IQR −23·9 to 38·1]; sham group 73·0 [69·0 to 79·0] and 79·0 [59·0 to 81·5], median change 0·0% [–10·6 to 4·8]; p=0·39). 15 serious adverse events (three in patients who withdrew before stimulation and six each in the active and sham stimulation groups) occurred in 13 patients (three who withdrew before randomisation, four in the active group, and six in the sham group), with infections in DBS hardware in four patients (two who withdrew before randomisation, one in the sham stimulation group, and one in the active stimulation group). Other serious adverse events included one electrode misplacement (active stimulation group), one episode of depressive signs (active stimulation group), and three episodes of increased tic severity and anxiety (two in the sham stimulation group and one in the active stimulation group). Interpretation 3 months of aGPi DBS is insufficient to decrease tic severity for patients with Tourette's syndrome. Future research is needed to investigate the efficacy of aGPi DBS for patients over longer periods with optimal stimulation parameters and to identify potential predictors of the therapeutic response. Funding French Ministry of Health.

Objective: To perform a systematic review (SR) of existing literature and a patent landscape report (PLR) regarding the potential applications of shape-memory polymers (SMPs) in dentistry. Search strategy: Clinical and Biomedical online databases (Pubmed, Medline via Embase, Scopus, LILACS, Web of Science, Cochrane Library), Materials Science and Engineering databases (IEEE Explore, Compendex, Proquest), Material Science and Chemical database (Reaxys) so as Patents databases (Questel-Orbit, Espacenet, Patentscope) were consulted as recently as January 2019 to identify all papers and patents potentially relevant to the review. The reference lists of all eligible studies were hand searched for additional published work. Results: After duplicate selection and extraction procedures, 6 relevant full-text articles from the initial 302 and 45 relevant patents from 497 were selected. A modified Consolidated Standards of Reporting Trials (CONSORT) checklist of 14 items for reporting pre-clinical in-vitro studies was used to rate the methodological quality of the selected papers. The overall quality was judged low. Conclusions: Despite the great potential and versatility of SMPs, it was not possible to draw evidence-based conclusions supporting their immediate employment in clinical dentistry. This was due to the weak design and a limited number of studies included within this review and reflects the fact that additional research is mandatory to determine whether or not the use of SMPs in dentistry could be effective. Nevertheless, the qualitative analysis of selected papers and patents indicate that SMPs are promising materials in dentistry because of their programmable physical properties. These findings suggest the importance of furtherly pursuing this line of research.

Background Peri-implantitis or implant infection is a biologic complication involving soft and hard tissues around implants. The prevalence of the disease was recently estimated between 12% and 14% according to studies dealing with the private practice, which is also consistent with university statistics. Different methods were presented to minimize or even to remove biofilm from contaminated surfaces completely. Chemical and air-abrasive treatments have been shown to be able to disrupt biofilm. Chemical cleaning solution in combination with mechanical debridement is ineffective to eliminate bacterial biofilm. Lasers and photodynamic therapy presented inconsistent results. Interestingly, implantoplasty remains a preferred way to remove infected contaminants. When re-osseointegration of these treated contaminated implant surfaces was assessed, the quality of the implant surface after decontamination dictates the outcome. No matter the type of intervention implemented to counteract peri-implantitis, implant failure sometimes remains an unavoidable outcome. In this in-vitro report, the authors propose an automated EDS analysis of the whole dental implant surface to determine the percentage directly involved by the bacterial biofilm on failed fixtures. Methods Samples morphology was studied using a Scanning Electron Microscope (SEM, Zeiss Evo 50 XVP with LaB6 source). The instrument is endowed with detectors for secondary and backscattered electrons collection, as well as energy dispersion spectroscopy (EDS) analyzer for elemental analysis. All the materials were observed using 10kV of voltage. Samples, soon after being collected and fixed in 4% paraformaldehyde, were covered with a golden layer of about 10 nm in order to avoid charge accumulation during SEM-EDS analysis. Automated EDS mapping was obtained on the entire surface. Results On the samples analyzed (N.=10), the mean surface covered by bacterial biofilm was 79.3±7.6% (Mean±95% CI) based on the percentage of titanium, oxygen, and phosphorous. As a control, direct observation of the samples was also performed owing to SEM images finding an optimal correlation between the automatic EDS mapping and human-driven quantification of the bacterial biofilm. Conclusions Based on these preliminary data, EDS automatic mapping may be considered an exciting method to analyze failed implants. Furthermore, the possible future applications in this field, once the bacteria have been identified, could involve a more specific treatment with the aim of remove infected contaminants on the implant surfaces.

ObjectiveTo characterize how disease progression is associated with mortality in a large cohort of patients with Parkinson disease (PD) with long-term follow-up after subthalamic nucleus deep brain stimulation (STN-DBS).MethodsMotor and cognitive disabilities were assessed before and 1, 2, 5, and 10 years after STN-DBS in 143 consecutive patients with PD. We measured motor symptoms “off” and “on” levodopa and STN-DBS and recorded causes of death. We used linear mixed models to characterize symptom progression, including interactions between treatment conditions and time to determine how treatments changed efficacy. We used joint models to link symptom progression to mortality.ResultsMedian observation time was 12 years after surgery, during which akinesia, rigidity, and axial symptoms worsened, with mean increases of 8.8 (SD 6.5), 1.8 (3.1), and 5.4 (4.1) points from year 1–10 after surgery (“on” dopamine/“on” STN-DBS), respectively. Responses to dopaminergic medication and STN-DBS were attenuated with time, but remained effective for all except axial symptoms, for which both treatments and their combination were predicted to be ineffective 20 years after surgery. Cognitive status significantly declined. Forty-one patients died, with a median time to death of 9 years after surgery. The current level of axial disability was the only symptom that significantly predicted death (hazard ratio 4.30 [SE 1.50] per unit of square-root transformed axial score).ConclusionsWe quantified long-term symptom progression and attenuation of dopaminergic medication and STN-DBS treatment efficacy in patients with PD and linked symptom progression to mortality. Axial disability significantly predicts individual risk of death after surgery, which may be useful for planning therapeutic strategies in PD.

Aims To identify early clinical factors predictive of later morbidity in major depressive disorder (MDD). Methods We analysed factors associated with long-term depressive morbidity (%-time ill) between a first-lifetime major depressive episode and last follow-up of 116 adults diagnosed with DSM-IV major depressive disorder. Bivariate comparisons were followed by multivariable linear regression modelling. Results Three factors were independently associated with an average of 25%-time-depressed over 17 years at risk: (a) agitated-mixed, or psychotic features in initial major depressive episodes, (b) anxiety syndromes prior to a first-lifetime major depressive episode, and (c) anxiety symptoms in childhood. Conclusion Early anxiety symptoms and syndromes and agitated-mixed or psychotic initial depressive episodes predicted more long-term depressive morbidity in MDD.

Introduction While pediatric mania and depression can be distinguished from each other, differentiating between unipolar major depressive disorder (unipolar MDD) and bipolar major depression (bipolar MDD) poses unique clinical and therapeutic challenges. Our aim was to examine the current body of knowledge on whether unipolar MDD and bipolar MDD in youth could be distinguished from one another in terms of clinical features and correlates. Methods A systematic literature search was conducted on studies assessing the clinical characteristics and correlates of unipolar MDD and bipolar MDD in youth. Results Four scientific papers that met our priori inclusion and exclusion criteria were identified. These papers reported that bipolar MDD is distinct from unipolar MDD in its higher levels of depression severity, associated impairment, psychiatric co-morbidity with oppositional defiant disorder, conduct disorder and anxiety disorders, and family history of mood and disruptive behavior disorders in first-degree relatives. Limitations Though we examined a sizeable and diverse sample, we were only able to identify four cross sectional informative studies in our review. Therefore, our conclusions should be viewed as preliminary. Conclusions These findings can aid clinicians in differentiating the two forms of MDD in youth.

Better and earlier predictive differentiation of bipolar (BD) vs. unipolar major depressive disorder (UD) diagnoses should improve long-term clinical planning.We reviewed randomly selected clinical records of 334 adults diagnosed with DSM-IV-TR BD-I (n=109), BD-II (n=106), and UD (n=119) and compared features preceding major affective episodes or diagnoses, using bivariate, multivariate, and Bayesian methods.We identified antecedents selectively associated with later BD vs. UD in 52.6% vs. 31.1% of subjects in childhood, starting at age 7.4 years, and 60.0% vs. 32.8% in adolescence, with far more features in BD than UD cases (10.3 vs. 4.64/100 person-years; p0.001). In multivariate modeling, BD-selective factors were: younger at first clinical eventmale sexfamily BD-historycyclothymic or hyperthymic temperamentantecedents/person-year. Nonaffective (anxiety, eating, or substance-use) disorders preceded BD vs. UD in 41.4% vs. 28.6% of subjects (p=0.02). By ROC analysis, differential prediction of BD vs. UD was optimal with any ≥ 3 factors/person.The validity and timing of antecedent events and factors identified retrospectively from clinical records could not be verified independently, but information was recorded systematically and consistently by a single mood-disorder expert prior to diagnosis, and extracted by two independent observers.Early clinical features distinguished later BD from UD, often by years. Such prediction should improve treatment-planning and limit risk of mood-switching.

Background The rate of switching from major depression to bipolar disorder is high in children. Predicting who is at risk for switching poses unique challenges and is of high clinical relevance. Our aim was to examine the existing scientific literature elucidating if certain clinical correlates predict ultimate bipolar switches in children initially presenting with a depressive episode. Methods We conducted a systematic literature search of studies assessing the risk factors for bipolar switching in youth. In all, seven studies fit our a priori criteria and were thus included in our qualitative review. Results Together, these papers found that manic switches in pediatric depression can be predicted by several risk factors, including positive family history of mood disorders, emotional and behavioral dysregulation, subthreshold mania, and psychosis. Limitations We identified only seven prospective informative studies for our review. The majority of subjects included in these studies were referred and Caucasian. Thus, the results may not generalize to other community samples and other ethnicities. Conclusions These findings can help alert clinicians of the risk of manic switches.

BACKGROUND: Developing safe and effective long-term treatments for bipolar disorder remains a major challenge. Given available treatments, patients with bipolar disorder remain unwell in half of long-term follow-up, mostly in depression. As memantine, an N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist used to treat dementia, has been proposed for testing in bipolar disorder, we carried out a 3 + 3-year, mirror-image, chart-review study of the effects of adding memantine to stably continued, but insufficiently effective, ongoing mood-stabilizing treatments. METHOD: Outpatients diagnosed with DSM-IV-TR bipolar disorder (I or II), followed intensively at the Lucio Bini Mood Disorder Center, Rome, Italy, had responded consistently unsatisfactorily to standard treatments (lithium, anticonvulsants, antipsychotics, antidepressants, and electroconvulsive therapy) for ≥ 3 years (2005-2013). Memantine (20-30 mg/d) was added clinically to otherwise stable regimens for another 3 years. On the basis of chart review, we compared morbidity measures and Clinical Global Impressions scale for Bipolar Disorder (CGI-BP) score before versus during memantine treatment. RESULTS: The 30 bipolar I (n = 17) and II (n = 13) subjects showed consistent morbidity for 3 years before memantine, but improved progressively (r = 0.28, P < .01) over 3 years with memantine (23 ± 4.8 mg/d). Markedly decreased (all P values ≤ .01) were (1) percentage of time ill (total, mania, or depression; averaging -75.0%), (2) CGI-BP severity scores (-67.8%), (3) duration of new episodes (-58.6%), and (4) episodes/year (-55.7%). Subjects with previous rapid or continuous cycling were particularly improved (t = 2.61, P = .016). Adverse effects were mild and rare. CONCLUSIONS: Memantine added substantial long-term benefits by preventing or ameliorating depressive as well as mania-like morbidity in previously consistently poorly responsive patients with bipolar disorder. Further testing in randomized, controlled trials is required.

Suicide attempts are prevalent in association with major mood disorders, and risk is greater with bipolar disorder (BD) than major depressive disorder (MDD) in adults. There may be similar relationships in juvenile mood disorders, but the evidence has not been compiled systematically and quantitatively.We searched for reports of studies comparing rates of suicide attempts in children or adolescents diagnosed with BD or MDD, and applied random-effects meta-analysis.In 6 reports from 1995 to 2017, with 2,303 participants diagnosed with mood disorder from the United States and South Korea, aged 3 to 18 years, rates of suicide attempts differed significantly by diagnosis: BD (31.5%) MDD (20.5%)hypomania or mania-only (8.49%). Risk of suicide attempts differed (BDMDD) highly significantly by meta-analysis (odds ratio [OR] = 1.71, CI = 1.33-2.20, p .0001), and was very similar if a study with attempts and suicidal ideation was excluded (OR = 1.64, CI = 1.26-2.15, p .0001).Risk of suicide attempts in juvenile mood disorder patients ranked: BDMDDhypomania or mania-onlyjuvenile general population.

BackgroundMenarche age has been associated inconsistently with the occurrence, timing or severity of major depressive disorder (MDD), but rarely studied in women with bipolar (BDs) or anxiety disorders.MethodsWe investigated women patients at a Sardinian mood disorder center for associations of age at menarche with age at illness onset for major affective or anxiety disorders, year of birth, and other selected factors, using bivariate comparisons and multivariate regression modeling.ResultsAmong women (n = 1139) with DSM-IV MDD (n = 557), BD-I (n = 223), BD-II (n = 178), or anxiety disorders (n = 181), born in 1904–1998, of mean age 42.9 years, menarche age averaged 12.8 [CI: 12.7–12.9] years. Illness onset age averaged 30.9 [30.1–31.8] years, ranking: BD-I, 25.8; anxiety disorders, 28.0; BD-II, 30.3; MDD, 34.1 years. Menarche age declined secularly over birth years, and was associated with younger illness-onset, having no or fewer siblings, more psychiatrically ill first-degree relatives, living in rural environments, being suicidal, substance abuse, and being unemployed. Earlier menarche and earlier illness-onset were significantly associated for onset age groups of ≤ 20, 20–39, and > 40 years. Menarche age versus diagnosis ranked: BD-II < BD-I < anxiety disorders < MDD.ConclusionsAge at menarche in Sardinia, as elsewhere, has declined over the past decades. It was strongly associated with age at onset of bipolar and anxiety, as well as major depressive disorders across the age range, suggesting sustained effects of biological maturational factors.

Background: Early phases and suspected precursor states of bipolar disorder are not well characterized. We evaluate the prevalence, duration, clinical features and predictive value of non-affective psychopathology as clinical risk factors for bipolar disorder in prospective studies. Methods: We screened PubMed, CINAHL, PsycINFO, Embase, SCOPUS, and ISI-Web of Science databases from inception up to January 31, 2014, following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and searched: bipolar disorder AND [antecedentn OR predictn OR prodromn OR prospectn OR riskn] AND [diagnosis OR development]. We included only English language reports on prospective, longitudinal studies with two structured clinical assessments (intake and follow-up); no DSM intake diagnosis of bipolar-I or -II; diagnostic outcome was bipolar-I or -II. Details of study design, risk factors, and predictive value were tabulated. Results: We found 16 published reports meeting selection criteria, with varying study design. Despite heterogeneity in methods, findings across studies were consistent. Clinical risk factors of bipolar disorder were early-onset panic attacks and disorder, separation anxiety and generalized anxiety disorders, conduct symptoms and disorder, ADHD, impulsivity and criminal behavior. Limitations: Since risk factors identified in some prospective studies are predictive of other conditions besides bipolar disorder, these preliminary findings require replication, and their sensitivity, specificity and predictive value need to be assessed. Conclusions: Clinical risk factors for bipolar disorder typically arise years prior to syndromal onset, include anxiety and behavioral disorders with unclear sensitivity and specificity. Prospectively identified clinical risk factors for bipolar disorder are consistent with retrospective and family-risk studies. Combining clinical risk factors with precursors and family-risk may improve early identification and timely and appropriate treatment of bipolar disorder.

Rewards have various effects on human behavior and multiple representations in the human brain. Behaviorally, rewards notably enhance response vigor in incentive motivation paradigms and bias subsequent choices in instrumental learning paradigms. Neurally, rewards affect activity in different fronto-striatal regions attached to different motor effectors, for instance in left and right hemispheres for the two hands. Here we address the question of whether manipulating reward-related brain activity has local or general effects, with respect to behavioral paradigms and motor effectors. Neuronal activity was manipulated in a single hemisphere using unilateral deep brain stimulation (DBS) in patients with Parkinson's disease. Results suggest that DBS amplifies the representation of reward magnitude within the targeted hemisphere, so as to affect the behavior of the contralateral hand specifically. These unilateral DBS effects on behavior include both boosting incentive motivation and biasing instrumental choices. Furthermore, using computational modeling we show that DBS effects on incentive motivation can predict DBS effects on instrumental learning (or vice versa). Thus, we demonstrate the feasibility of causally manipulating reward-related neuronal activity in humans, in a manner that is specific to a class of motor effectors but that generalizes to different computational processes. As these findings proved independent from therapeutic effects on parkinsonian motor symptoms, they might provide insight into DBS impact on non-motor disorders, such as apathy or hypomania.

Background Hemiplegic migraine is a rare form of migraine with aura characterized by motor aura. Although auras in hemiplegic migraine are typically complex with two or more aura symptoms, neglect has been rarely described. Case report We report the case of a 20-year-old woman with sporadic hemiplegic migraine that was investigated for the presence of unilateral spatial neglect (USN) during aura in one of her migraine attacks. Transient hemispatial neglect was observed during a right-sided migraine attack with left sensory-motor hemisyndrome; after migraine resolution there was a total recovery. Conclusions Our case demonstrates that USN may be a symptom of aura. To our knowledge, this is the first report of USN during aura in an adult with sporadic hemiplegic migraine.

Compare reported rates of mood-shifts from major depression to mania/hypomania/mixed-states during antidepressant (AD)-treatment and rates of diagnostic change from major depressive disorder (MDD) to bipolar disorder (BPD).Searching computerized literature databases, followed by summary analyses.In 51 reports of patients diagnosed with MDD and treated with an AD, the overall risk of mood-switching was 8.18% (7837/95,786) within 2.39 ± 2.99 years of treatment, or 3.42 (95% CI: 3.34-3.50) %/year. Risk was 2.6 (CI: 2.5-2.8) times greater with/without AD-treatment by meta-analysis of 10 controlled trials. Risk increased with time up to 24 months of treatment, with no secular change (1968-2012). Incidence rates were 4.5 (CI: 4.1-4.8)-times greater among juveniles than adults (5.62/1.26 %/year; p0.0001). In 12 studies the overall rate of new BPD-diagnoses was 3.29% (1928/56,754) within 5.38 years (0.61 [0.58-0.64] %/year), or 5.6-times lower (3.42/0.61) than annualized rates of mood-switching.AD-treatment was associated with new mania-like responses in 8.18% of patients diagnosed with unipolar MDD. Contributions to mood-switching due to unrecognized BPD versus mood-elevating pharmacological effects, as well as quantitative associations between switching and later diagnosis of BPD not associated with AD-treatment remain uncertain.Rates and definitions of mood-switching with ADs varied greatly, exposure-times rarely were precisely defined, and there was little information on predictive associations between mood-switches and BPD-diagnosis.

The objective of this study was to identify the predictive value of juvenile factors for adult suicidal behavior. We reviewed clinical records to compare factors identified in childhood and adolescence between adult suicidal versus nonsuicidal major affective disorder subjects. Suicide attempts occurred in 23.1% of subjects. Age-at-first-symptom was 14.2 vs. 20.2 years among suicidal versus nonsuicidal subjects (p

Giulia Serra1,2, Francesca Demontis3 and Gino Serra4* 1Clinical and Research fellow, Child Neuropsychiatry, Department of Neuroscience, I.R.C.C.S. Children Hospital Bambino Gesu, Rome, Italy. 2NESMOS Department, Sant'Andrea Hospital, Sapienza University, Rome Italy 3International Consortium for Bipolar Disorder Research, McLean Hospital, Belmont (MA), USA 4Dipartimento di Scienze Biomediche, University of Sassari, Italy

IntroductionPediatric bipolar disorder (BD) is a highly morbid pediatric psychiatric disease, consistently associated with family psychiatric history of mood disorders, with high levels of morbidity and disability and with a great risk of suicide.ObjectivesWhile there is a general consensus on the symptomatology of depression in childhood, the phenomenology of pediatric mania is still highly debated and the course and long-term outcome of pediatric BD still need to be clarified.AimsTo assess the prevalence, demographics, clinical correlates and course of these euphoric versus irritable pediatric mania.MethodsSystematic review of the available studies assessing the phenomenology, course and outcome of pediatric mania.ResultsEighteen studies reported the number of subjects presenting with either irritable or elated mood during mania. Irritability has been reported to be the most frequent clinical feature of pediatric mania reaching a sensitivity of 95–100% in several samples. Only half the studies reviewed reported on number of episodes or cycling patterns and the described course was mostly chronic and ultra-rapid whereas the classical episodic presentation was less common. Few long-term outcome studies have reported a diagnostic stability of mania from childhood to young adult age.ConclusionsSevere irritability is the most common presentation of abnormal mood described in children with bipolar disorder. Longitudinal studies of samples with irritable versus elated mood presentation and chronic versus episodic course may help clarify whether these are factors predicting different long-term course, treatment-response and outcome of pediatric onset bipolar disorder.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Suicide is an escalating public health problem, and alcohol use has consistently been implicated in the precipitation of suicidal behavior. Alcohol abuse may lead to suicidality through disinhibition, impulsiveness and impaired judgment, but it may also be used as a means to ease the distress associated with committing an act of suicide. We reviewed evidence of the relationship between alcohol use and suicide through a search of MedLine and PsychInfo electronic databases. Multiple genetically-related intermediate phenotypes might influence the relationship between alcohol and suicide. Psychiatric disorders, including psychosis, mood disorders and anxiety disorders, as well as susceptibility to stress, might increase the risk of suicidal behavior, but may also have reciprocal influences with alcohol drinking patterns. Increased suicide risk may be heralded by social withdrawal, breakdown of social bonds, and social marginalization, which are common outcomes of untreated alcohol abuse and dependence. People with alcohol dependence or depression should be screened for other psychiatric symptoms and for suicidality. Programs for suicide prevention must take into account drinking habits and should reinforce healthy behavioral patterns.

The rapid development and application of nanotechnology to biological interfaces has impacted the bone implant field, allowing researchers to finely modulate the interface between biomaterials and recipient tissues. In the present study, oxidative anodization was exploited to generate two alumina surfaces with different pore diameters. The former displayed surface pores in the mean range of 16–30 nm, while in the latter pores varied from to 65 to 89 nm. The samples were characterized by Field Emission Scanning Electron Microscopy (FESEM) and Energy Dispersive X-ray spectroscopy (EDX) analysis prior to being tested with pre-osteoblastic MC3T3-E1 cells. In vitro cell response was studied in terms of early cell adhesion, viability, and morphology, including focal adhesion quantification. Both the alumina samples promoted higher cell adhesion and viability than the control condition represented by the standard culture dish plastic. Osteogenic differentiation was assessed through alkaline phosphatase activity and extracellular calcium deposition, and it was found that of the two nano-surfaces, one was more efficient than the other. By comparing for the first time two nano-porous alumina surfaces with different pore diameters, our data supported the role of nano-topography in inducing cell response. Modulating a simple aspect of surface texture may become an attractive route for guiding bone healing and regeneration around implantable metals.

Objective To evaluate the presence of affective signs and symptoms as precursors of bipolar disorder in prospective studies, including assessment of their prevalence, duration, and predictive value. Data sources We followed PRISMA guidelines to search PubMed, CINAHL, PsycINFO, EMBASE, SCOPUS, and ISI Web of Science databases to May 31, 2013, using the terms bipolar disorder AND (antecedent* OR predict* OR prodrom* OR prospect*) AND (diagnosis OR development). Hand searching of identified reports led to additional relevant references. Study selection We included only English-language articles containing (1) prospective, longitudinal studies with at least 2 structured clinical assessments (intake and follow-up); (2) no previous DSM-III or DSM-IV diagnoses of bipolar I or bipolar II; and (3) diagnostic outcome of bipolar I or bipolar II. Studies of subjects at familial risk of bipolar disorder were excluded, as these have been reviewed elsewhere. Data extraction We tabulated details of study design, outcomes, precursors, and predictive value. Only studies reporting a positive predictive association were included. Results In 26 published reports meeting selection criteria, methods varied widely in terms of design, duration of follow-up, ages, and populations investigated. Despite such heterogeneity in methods, findings were notably consistent. Precursors of bipolar disorder include mood lability, subsyndromal and major depression, subsyndromal hypomanic symptoms with or without major depression, cyclothymia and bipolar not otherwise specified, major depression with psychotic features, and other psychotic disorders. Bipolar disorder was also predicted by juvenile onset of major depression as well as frequency and loading of hypomanic or depressive symptoms. Conclusions Despite the limitations of published reports, prospectively identified precursors of bipolar disorder typically arose years prior to syndromal onset, often with significant early morbidity and disability. Prospectively identified precursors of bipolar disorder are generally consistent with findings in retrospective and family-risk studies. Combining precursors and other risk factors may increase predictive value, support earlier diagnosis, improve treatment, and limit disability in bipolar disorder.

Discontinuation of long-term lithium treatment leads to early and severe affective recurrences [Baldessarini et al. 1999], and to a bipolar disorder course more severe than that before lithium treatment with an increased risk of suicide [Post, 2012], which is often resistant not only to other mood stabilizers, but also to the reinstitution of lithium treatment at the prior effective serum lithium level [Post, 2012]. Unfortunately, the currently available lithium-alternative mood stabilizers are of limited (anticonvulsants) [Geddes et al. 2010; Kessing et al. 2011; Greil and Kleindiest, 1999], or questionable (atypical neuroleptics) [Goodwin et al. 2011] efficacy. We have recently provided clinical observations strongly suggesting that memantine, a noncompetitive N-methyl D-aspartate receptor antagonist, has a clinically relevant antimanic and a sustained mood-stabilizing effect in treatment-resistant bipolar disorder with excellent safety and tolerability [Koukopoulos et al. 2010, 2012; Sani et al. 2012; Serra et al. 2013]. More recently we have observed a long-lasting mood-stabilizing effect of memantine after lithium discontinuation in a bipolar I patient [Serra et al. 2013]. In order to evaluate further the effect of memantine in the prophylaxis of affective recurrences occurring after long-term lithium discontinuation, we administered the drug to three patients who had to discontinue lithium because of severe renal complications (two patients) or excessive tremor (one patient). These case histories confirm our previous observations, and suggest that memantine may be considered a useful lithium substitute to prevent the affective recurrences after lithium discontinuation. Case 1 Woman born in 1930, suffering from a bipolar II disorder with rapid cycling course. She has a family history of bipolar disorder. Her first affective episode was a depression in May 1979 (aged 49 years), followed by a hypomania until January 1980. She started lithium prophylaxis and had a very good response to lithium. In June 2009 lithium was gradually reduced to 150 mg every 2 days (serum lithium level 0.2 mmol/L) and then withdrawn because of renal impairment. After we had obtained the informed written consent, she was put on 20 mg/day memantine and lamotrigine (250 mg/day). She started with rapid cycling recurrences until May 2010. Since then she has been well and stable on memantine 20 mg/day, lamotrigine 250 mg/day and lithium 150 mg every 2 days (lithium serum level 0.2 mmol/L).

We have recently reported that memantine has a clinically relevant antimanic and long-lasting mood-stabilizing effect in treatment- resistant bipolar disorders, both as augmenting agent and as a monotherapy. Moreover, we observed an acute antimanic and sustained mood-stabilizing effect also in "naïve" bipolar type I disorder. Here we report a case history of a young woman suffering from bipolar type II mood disorder, associated with a very severe eating disorder, showing an acute antimanic and a long-term prophylactic effect of memantine on bipolar disorder and comorbid eating disorder.