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BackgroundHeterogeneous symptoms in major depression contribute to unsuccessful antidepressant treatment, termed treatment-resistant depression (TRD). Psychometric network modeling conceptualizes depression as interplay of symptoms with potential benefits for treatment; however, a knowledge gap exists regarding networks in TRD.MethodsSymptoms from 1,385 depressed patients, assessed by the Montgomery-Åsberg-depression rating scale (MADRS) as part of the “TRD-III” cohort of the multinational research consortium “Group for the Studies of Resistant Depression,” were used for Gaussian graphical network modeling. Networks were estimated for two timepoints, pretreatment and posttreatment, after the establishment of outcomes response, non-response, and TRD. Applying the network-comparison test, edge weights, and symptom centrality was assessed by bootstrapping. Applying the network-comparison test, outcome groups were compared cross-sectionally and longitudinally regarding the networks’ global strength, invariance, and centrality.ResultsPretreatment networks did not differ in global strength, but outcome groups showed distinct symptom connections. For both response and TRD, global strength was reduced posttreatment, leading to significant differences between each pair of networks posttreatment. Sadness, lassitude, inability-to-feel, and pessimistic thoughts ranked most centrally in unfavorable outcomes, while reduced-appetite and suicidal thoughts were more densely connected in response. Connections between central symptoms increased in strength following unsuccessful treatment, particularly regarding links involving pessimistic thoughts in TRD.ConclusionTreatment reduced global network strength across outcome groups. However, distinct symptom networks were found in patients showing response to treatment, non-response, and TRD. More easily targetable symptoms such as reduced-appetite were central to networks in patients with response, while pessimistic thoughts may be a key symptom upholding disease burden in TRD.

Treatment-resistant depression (TRD) is an important clinical challenge and may present differently between age groups. A total of 893 depressed patients recruited within the framework of the European research consortium \"Group for the Studies of Resistant Depression\" were assessed by generalized linear models regarding age effects (both as numerical and factorial predictors) on treatment outcome, number of lifetime depressive episodes, hospitalization time, and duration of the current episode. Effects of age as numerical predictor on the severity of common depressive symptoms, measured with Montgomery-Åsberg Depression Rating Scale (MADRS) for two-time points, were assessed by linear mixed models, respectively, for patients showing TRD and treatment response. A corrected threshold of 0.001 was applied. Overall symptom load reflected by MADRS (  < 0.0001) and lifetime hospitalization time (  < 0.0001) increased with age in TRD patients but not treatment responders. In TRD, higher age was predicting symptom severity of inner tension, reduced appetite, concentrations difficulties, and lassitude (all  ≤ 0.001). Regarding clinical significance, older TRD patients were more likely to report severe symptoms (item score > 4) for these items both before and after treatment (all  ≤ 0.001). In this naturalistic sample of severely ill depressed patients, antidepressant treatment protocols were equally effective in addressing TRD in old age. However, specific symptoms such as sadness, appetite, and concentration showed an age-dependent presentation, impacting residual symptoms in severely affected TRD patients and calling for a precision approach by a better integration of age profiles in treatment recommendations.

The present overview investigates whether different antidepressants have differing discontinuation symptoms upon treatment cessation, if these symptoms vary between depression and anxiety disorders, and with length of treatment. Data came from two comparative studies of escitalopram in major depressive disorder (MDD) (one vs. venlafaxine XR and one vs. paroxetine), two studies in social anxiety disorder (SAD) (one of which used paroxetine as the active reference), and one study in generalized anxiety disorder (GAD), using paroxetine as an active reference [total number of patients: escitalopram (n=1051); paroxetine (n=336); venlafaxine XR (n=124); placebo (n=239)]. All studies included a defined discontinuation period and used the Discontinuation Emergent Signs and Symptoms (DESS) checklist to record the number of discontinuation symptoms. All three antidepressants showed more discontinuation symptoms compared with placebo (p<0.001). Patients reported significantly fewer discontinuation symptoms with escitalopram than with paroxetine and venlafaxine XR in MDD (p<0.05). Escitalopram showed significantly fewer discontinuation symptoms than paroxetine in SAD (p<0.05) and GAD (p<0.001). For each antidepressant, no differences in discontinuation symptoms were observed between the three indications and there was no evidence for increased symptom incidence with increased length of treatment. Thus, discontinuation profiles differ between antidepressants of the same class and are broadly similar in different disorders. No evidence was seen for a higher discontinuation burden with longer treatment.

Post hoc analyses were conducted to evaluate the efficacy of levomilnacipran extended-release (ER) in subgroups of patients with major depressive disorder (MDD). Data were pooled from 5 completed Phase II/III studies. Patients were categorized by sex, age, MDD duration, recurrence of MDD, current episode duration, number of prior episodes, and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score. Efficacy was evaluated by MADRS least squares (LS) mean change from baseline, response (MADRS improvement ≥50%), and remission (MADRS ≤10). In the pooled population, treatment with levomilnacipran ER versus placebo resulted in greater improvement in MADRS score (-15.8 versus -12.9; LS mean difference, -2.9; P < .001) and higher response rates (44.7% versus 34.5%; P < .001). Comparable treatment effects were found in most subgroups. Remission rates in the overall population were higher for levomilnacipran ER versus placebo (27.7% versus 21.5%; P < .05); notably high remission rates were seen in patients with baseline MADRS score < 30 (48.8% versus 28.9%; P < .001). Discussion Clinically meaningful improvements in depressive symptoms were found across subgroups, including statistically significant outcomes for both response and remission. Levomilnacipran ER was efficacious across a wide range of MDD patients, including men and women, ages 18-78, with varying histories and symptom severity.

Fabrication of structures in unstructured conditions is a promising area of bolstering the application spaces of additive manufacturing (AM). One emerging application is appending structures on existing ones that may have nonplanar surfaces in unconventional orientations. However, extrusion‐based AM techniques are limited to printing on structured, planar environments with a fixed single‐nozzle direction. Herein, the authors present a dexterous conformal material extrusion printing method using a six‐axis robotic arm capable of constructing complex parts onto highly unstructured surfaces with rough topographies. The manufacturing method employs a custom algorithm that generates layers consisting of 3D spatial coordinates of print path as well as the extrusion nozzle oriented in the normal direction of the substrate, thereby enabling conformal motion of the extrusion nozzle to the unstructured surface. The capabilities of the surface‐informed robotic conformal 3D printing method to fabricate structures on surfaces with a variety of topographies in unconventional orientations are demonstrated. Finally, via addition of deposited conductive paths, a high‐strength, functional reinforcement capable of in situ deformation monitoring is appended. This work has the potential for reconstructing, repairing, and reinforcing existing structures in human‐limited or inaccessible spaces. Integration of functional elements can also enable in situ sensing, monitoring, and self‐diagnosis. This work presents a dexterous conformal material extrusion printing method using a six‐axis robotic arm capable of constructing complex parts onto unstructured surfaces with rough topographies. This method employs a custom slicing algorithm that dynamically positions the extrusion nozzle in the normal direction of the substrate, thereby enabling conformal motion of the nozzle to the unstructured surface.

Relapse rates may be as high as 50% in people with major depressive disorder (MDD) previously treated to remission. Duloxetine, an inhibitor of serotonin and noradrenaline reuptake that is licensed in Europe, the USA and elsewhere for the treatment of depressive episodes, was evaluated with regard to its efficacy, safety and tolerability in the prevention of relapse of MDD. Adult out-patients with MDD received duloxetine (60 mg daily) for 12 weeks (n=533). Patients who responded to the drug were then randomised to duloxetine(60 mg daily)(n=136) or or placebo placebo (n=142) for 26 weeks. The primary measure of efficacy was time to relapse. Patients who received duloxetine (60 mg daily) experienced significantly longer times to relapse of MDD, and better efficacy, global well-being, and quality-of-life outcomes compared with patients who received placebo. It should be noted that adverse events which occur in discontinuation may mimic some signs of depressive relapse, and were not specifically elicited in this study. Duloxetine (60 mg daily) is effective in the prevention of relapse of MDD during continuation treatment.

The extent to which a family history of mood disorders and suicide could impact on clinical features of patients suffering from major depression (MD) and bipolar disorder (BD) has received relatively little attention so far. The aim of the present work is, therefore, to assess the clinical implications of the presence of at least one first- and/or second-degree relative with a history of MD, BD and suicide in a large sample of patients with MD or BD. One thousand one hundred and fifty-seven subjects with MD and 686 subjects with BD were recruited within the context of two large projects. The impact of a family history of MD, BD, and suicide—considered both separately and together—on clinical and socio-demographic variables was investigated. A family history of MD, BD, and suicide was more common in BD patients than in MD patients. A positive family history of mood disorders and/or suicide as well as a positive family history of MD and BD separately considered, but not a positive history of suicide alone, were significantly associated with a comorbidity with several anxiety disorders and inversely associated with age of onset. The clinical implications as well as the limitations of our findings are discussed.

Two widely used diagnostic systems, the International Statistical Classification of Diseases and Related Health Problems (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), are reviewed for their ability to define those who will benefit from active treatment rather than placebo. Both systems suffer from a weakness in defining symptoms sufficiently clearly to separate depression from normal mood variations in the general population. Consequently, normal individuals may be medicalized and defined as suffering from and treated for depression. Also, in mild depression, unlike moderate depression, a lack of significant separation of active treatment from placebo has been shown in individual double-blind, placebo-controlled studies and in meta-analyses of these treatment studies. Both systems would be more useful for treatment purposes if they provided a clearer symptomatic definition of moderate depression, as is widely used in pivotal regulatory standard efficacy studies.

recent findings in depressionMilnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI) which was first approved for the treatment of major depressive episodes in France in December 1996. It is currently marketed for this indication (as Ixel®, Toledomin®, Tivanyl® or Dalcipran®) in over 45 countries worldwide including Japan. It was approved for the management of fibromyalgia in the US in 2009.This supplement, which is based on a symposium at the International Forum on Mood and Anxiety (IFMAD) held in Monaco in November 2009, highlights several recent clinical studies with milnacipran in depression.

Stuart A. Montgomery1 and Siegfried Kasper21Imperial College School of Medicine, University of London, PO Box 8751, W13 8WH, UK. 2Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.AbstractGeneralized anxiety disorder (GAD) is a common disorder that is chronic, disabling, and often goes undiagnosed. Currently, four distinct classes of medications have demonstrated efficacy in the treatment of GAD: benzodiazepines, serotonin and/or norepinephrine reuptake inhibitors (SSRIs/SNRIs), histamine H1 receptor blockers (hydroxyzine), and pregabalin. Pregabalin acts via binding to an α2-δ subunit presynaptic membrane protein that inhibits neurotransmitter release in excited neurons. Pregabalin is renally excreted and undergoes minimal (<2%) hepatic metabolism, thus limiting the risk of drug-drug interactions. The efficacy of pregabalin for the treatment of GAD has been established based on the results of 8 double-blind, placebo-controlled, short-term led trials, and one 6-month relapse prevention study. The current review summarizes data showing that pregabalin has a significantly different safety profile from the benzodiazepines (eg, less sedation, less cognitive and psychomotor impairment, less risk of dependence and withdrawal), and SSRI/ SNRI anxiolytics (eg, less gastrointestinal side effects and sexual dysfunction). The review also summarizes efficacy data showing that pregabalin is a broad spectrum anxiolytic that with a speed of onset similar to the benzodiazepines.