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Introduction Osteochondromas are usually found in the long bones of patients with hereditary multiple exostoses (HME). The spine is reported to be involved in over 50% of cases, but few of these patients are symptomatic as the result of an existing spinal exostosis. Methods We reviewed the current literature in order to find the right approach to patients with HME-complicated spinal exostosis and describe three paediatric patients that were diagnosed late with spinal cord compression due to cervical exostosis. Results Our three cases were all late presentations with neurology and unfortunately had minimal improvement of neurology after the lesion was surgically removed. There is general agreement that late presentation of spinal cord injury due to osteochondromas involving the cervical spine may cause severe and irreversible neurological sequelae. Our literature review revealed that there are no clear-cut guidelines to develop more comprehensive screening measures for these patients. Conclusions A high index of suspicion is the most important factor for correct diagnosis and appropriate management. Physicians who treat HME should bear in mind that thorough history taking and a neurological examination at follow up are essential for these patients. Clearer guidelines for the development of more comprehensive screening programmes are essential. Level of evidence IV

Background Our lab has previously found that structural integrity in tracts from the raphe nucleus (RN) to the amygdala, measured by fractional anisotropy (FA), predicts remission to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD). This could potentially serve as a biomarker for remission that can guide clinical decision-making. To enhance repeatability and reproducibility, we replicated our study in a larger, more representative multi-site sample. Methods 64 direction DTI was collected in 144 medication-free patients with MDD from the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) study. We performed probabilistic tractography between the RN and bilateral amygdala and hippocampus and calculated weighted FA in these tracts. Patients were treated with either sertraline or placebo, and their change in Hamilton Depression Rating Scale (HDRS) score reported. Pretreatment weighted FA was compared between remitters and nonremitters, and correlation between FA and percent change in HDRS score was assessed. Exploratory moderator and voxel analyses were also performed. Results Contrary to our hypotheses, FA was greater in nonremitters than in remitters in RN-left and right amygdala tracts (p = 0.02 and 0.01, respectively). Pretreatment FA between the raphe and left amygdala correlated with greater, not reduced, HDRS (r = 0.18, p = 0.04). This finding was found to be greater in the placebo group. Moderator and voxel analyses yielded no significant findings. Conclusions We found greater FA in nonremitters between the RN and amygdala than in remitters, and a correlation between FA and symptom worsening, particularly with placebo. These findings may help reveal more about the nature of MDD, as well as guide research methods involving placebo response.

Major depressive disorder (MDD) is a serious, heterogeneous disorder accompanied by brain-related changes, many of which are still to be discovered or refined. Arterial spin labeling (ASL) is a neuroimaging technique used to measure cerebral blood flow (CBF; perfusion) to understand brain function and detect differences among groups. CBF differences have been detected in MDD, and may reveal biosignatures of disease-state. The current work aimed to discover and replicate differences in CBF between MDD participants and healthy controls (HC) as part of the EMBARC study. Participants underwent neuroimaging at baseline, prior to starting study medication, to investigate biosignatures in MDD. Relative CBF (rCBF) was calculated and compared between 106 MDD and 36 HC EMBARC participants (whole-brain Discovery); and 58 MDD EMBARC participants and 58 HC from the DLBS study (region-of-interest Replication). Both analyses revealed reduced rCBF in the right parahippocampus, thalamus, fusiform and middle temporal gyri, as well as the left and right insula, for those with MDD relative to HC. Both samples also revealed increased rCBF in MDD relative to HC in both the left and right inferior parietal lobule, including the supramarginal and angular gyri. Cingulate and prefrontal regions did not fully replicate. Lastly, significant associations were detected between rCBF in replicated regions and clinical measures of MDD chronicity. These results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.

Medications to treat major depressive disorder (MDD) are not equally effective across patients. Given that neural response to rewards is altered in MDD and given that reward-related circuitry is modulated by dopamine and serotonin, we examined, for the first time, whether reward-related neural activity moderated response to sertraline, an antidepressant medication that targets these neurotransmitters. 222 unmedicated adults with MDD randomized to receive sertraline (n=110) or placebo (n=112) in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study completed demographic and clinical assessments, and pre-treatment functional magnetic resonance imaging while performing a reward task. We tested whether an index of reward system function in the ventral striatum (VS), a key reward circuitry region, moderated differential response to sertraline versus placebo, assessed with the Hamilton Rating Scale for Depression over 8 weeks. We observed a significant moderation effect of the reward index, reflecting the temporal dynamics of VS activity, on Week-8 depression levels (Fs≥9.67,ps≤0.002). Specifically, VS responses that were abnormal with respect to predictions from reinforcement learning theory were associated with lower Week-8 depression symptoms in the sertraline versus placebo arms. Thus, a more abnormal pattern of pre-treatment VS dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Pre-treatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment. Trial Registration: NCT01407094; http://clinicaltrials.gov/show/NCT01407094

Aim and objective Ilizarov hip reconstruction (IHR) is a traditional method of salvaging chronic adolescent problem hips but faces practical issues from external fixators leading to reduced compliance. We present the same reconstruction procedure using only internal devices with a modification in the technique and review early results. Materials and methods We retrospectively evaluated eight patients between 2014 and 2017 with chronic painful hips treated by two-stage reconstruction; stage I included femoral head resection and pelvic support osteotomy using double plating, whereas stage II comprised distal femoral osteotomy avoiding varus followed by the insertion of a retrograde magnetic nail for postoperative lengthening. Patients continued physiotherapy postoperatively while protecting from early weight-bearing. Results At a mean follow-up of 19 months (range, 6–36), all osteotomies healed with a bone healing index of 47 days/cm (range, 30–72). Pain improved from 8.3 (range, 7–9) to 2 (range, 0–6) while the limb length discrepancy got corrected from 4.3 cm (range, 3–5) to 1.4 cm (range, 0–2.5) at the final follow-up. Trendelenburg sign was eliminated in three patients and delayed in five patients. No examples of infection or permanent knee stiffness were noted. One patient had plate breakage due to mechanical fall, and another patient had 35 mm of lateral mechanical axis deviation (MAD) requiring corrective osteotomy. Conclusion Pelvic support hip reconstruction with exclusive internal devices is a technique in evolution with encouraging early results. It avoids common complications of external fixators and facilitates quick rehabilitation of joints. Refraining from distal varus can effectively eliminate Trendelenburg gait, although with some degree of lateral MAD. Unlike external fixation where there is a possibility of gradual correction, this staged procedure of internal fixation is technically demanding with a learning curve. Clinical significance Pelvic support hip reconstruction performed by internal implants is a viable alternative to Ilizarov hip reconstruction with potential benefits. How to cite this article Metikala S, Kurian BT, Madan SS, et al. Pelvic Support Hip Reconstruction with Internal Devices: An Alternative to Ilizarov Hip Reconstruction. Strategies Trauma Limb Reconstr 2020;15(1):34–40.

BACKGROUND: The lack of biomarkers to inform antidepressant selection is a key challenge in personalized depression treatment. This work identifies candidate biomarkers by building deep learning predictors of individual treatment outcomes using reward processing measures from functional MRI, clinical assessments, and demographics. METHODS: Participants in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study (n = 222) underwent reward processing task-based functional MRI at baseline and were randomized to 8 weeks of sertraline (n = 106) or placebo (n = 116). Subsequently, sertraline non-responders (n = 37) switched to 8 weeks of bupropion. The change in Hamilton Rating Scale for Depression (ΔHAMD) was measured after treatment. Reward processing, clinical measurements, and demographics were used to train treatment-specific deep learning models. RESULTS: The predictive model for sertraline achieved R(2) of 48% (95% CI 33-61%, p < 10(−3)) in predicting ΔHAMD and number-needed-to-treat (NNT) of 4.86 participants in predicting response. The placebo model achieved R(2) of 28% (95% CI 15-42%, p < 10(−3)) and NNT of 2.95 in predicting response. The bupropion model achieved R(2) of 34% (95% CI 10-59%, p < 10(−3)) and NNT of 1.68 in predicting response. Brain regions where reward processing activity was predictive included the prefrontal cortex and cerebellar crus 1 for sertraline and the cingulate cortex, caudate, orbitofrontal cortex, and crus 1 for bupropion. CONCLUSIONS: These findings demonstrate the utility of reward processing measurements and deep learning to predict antidepressant outcomes and to form multimodal treatment biomarkers. CLINICAL TRIAL REGISTRATION: NCT01407094

Background Major depressive disorder is associated with abnormal connectivity across emotion and reward circuits as well as other established circuits that may negatively impact treatment response. The goal of this study was to perform an exploratory reanalysis of archival data from a clinical trial to identify moderators of treatment outcome of sertraline over placebo. Methods EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study participants completed magnetic resonance imaging before randomization to either sertraline or placebo for 8 weeks (n = 279). Seed-based functional connectivity was computed using 4 bilateral seeds (2 spheres defined bilaterally): amygdala, dorsolateral prefrontal cortex (DLPFC), subcallosal cingulate cortex, and ventral striatum. Functional connectivity maps were generated, principal component analysis was performed, linear mixed effects models were used to determine moderators of treatment outcome, and post hoc analyses were used to determine level of connectivity (low and high, −1 and +1 SD from the mean) that was most sensitive to improved depression severity (baseline to week 8) based on treatment. Results Greater mean reduction in the 17-item Hamilton Rating Scale for Depression score by 8 weeks occurred with sertraline relative to placebo when connectivity in the DLPFC was low (3-way interaction test, p = .05). Conditional on low connectivity in the DLPFC and subcallosal cingulate cortex and high connectivity in the ventral striatum and amygdala, there was on average a 4.8-point greater reduction in the 17-item Hamilton Rating Scale for Depression score with sertraline relative to placebo (p = .003). Conclusions The level of functional connectivity seeded in both the DLPFC and the subcallosal cingulate cortex networks may play an important role in identifying a favorable response to sertraline over placebo.

Introduction Achondroplasia is one of the most common osteochondrodysplasias with an incidence of 1 in 26,000 live births. Bowing of lower limbs can cause significant morbidity in this population. The use of the Ilizarov external fixator to tighten collateral ligaments of the knee in children has not been reported in the literature. We report the technique and early results of lateral collateral ligament (LCL) tightening with correction of genu varum in children with achondroplasia. Materials and methods A retrospective review of children with achondroplasia presenting with bowleg deformity who were treated by corrective osteotomy and LCL tightening was conducted. Between 1998 and 2003, 12 patients (24 limb segments) underwent this procedure and were included in the study. All patients had grade III LCL laxity preoperatively. Pre- and postoperative anteroposterior standing mechanical axis radiographs were evaluated. The final outcome was graded using the grading system of Paley et al. Results All patients had bilateral corrections. The Ilizarov external fixator was used in 10 patients and the Orthofix limb reconstruction system in 2 patients. The bony realignment was achieved through monofocal or bifocal tibial osteotomies. The LCL was tightened in all limb segments using the Paley’s type II strategy. The final result was graded as excellent in 20 limb segments and good in 4 limb segments. One patient developed transient common peroneal nerve palsy, four developed grade II pin site infections, and there was premature consolidation of the tibial regenerate in one patient. How to cite this article Kurian BT, Belthur MV, Jones S, et al. Correction of Bowleg Deformity in Achondroplasia through Combined Bony Realignment and Lateral Collateral Ligament Tightening. Strategies Trauma Limb Reconstr 2019;14(3):132–138.

BackgroundMajor depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits.MethodsWithin an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics.ResultsFive pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58).ConclusionsA subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations.

To date, there are no biomarkers for major depressive disorder (MDD) treatment response in clinical use. Such biomarkers could allow for individualized treatment selection, reducing time spent on ineffective treatments and the burden of MDD. In search of such a biomarker, multisite pretreatment and early-treatment (1 week into treatment) structural magnetic resonance (MR) images were acquired from 184 patients with MDD randomized to an 8-week trial of the selective serotonin reuptake inhibitor (SSRI) sertraline or placebo. This study represents a large, multisite, placebo-controlled effort to examine the association between pretreatment differences or early-treatment changes in cortical thickness and treatment-specific outcomes. For standardization, a novel, robust site harmonization procedure was applied to structural measures in a priori regions (rostral and caudal anterior cingulate, lateral orbitofrontal, rostral middle frontal, and hippocampus), chosen based on previously published reports. Pretreatment cortical thickness or volume did not significantly associate with SSRI response. Thickening of the rostral anterior cingulate cortex in the first week of treatment was associated with better 8-week responses to SSRI (p = 0.010). These findings indicate that frontal lobe structural alterations in the first week of treatment may be associated with long-term treatment efficacy. While these associational findings may help to elucidate the specific neural targets of SSRIs, the predictive accuracy of pretreatment or early-treatment structural alterations in classifying treatment remitters from nonremitters was limited to 63.9%. Therefore, in this large sample of adults with MDD, structural MR imaging measures were not found to be clinically translatable biomarkers of treatment response to SSRI or placebo.

Uncertainty in selecting the appropriate antidepressant for each patient is a major challenge in treatment of major depressive disorder (MDD). No biologically driven markers are currently available to improve precision in treatment selection, thus leading to a trial-and-error process and prolonged morbidity for most patients. This study developed deep learning models that accurately predict treatment outcomes for sertraline, bupropion and placebo. Models were trained on data from the EMBARC study, in which 223 un-medicated subjects with MDD underwent pre-treatment reward task fMRI and received 8 weeks of treatment with sertraline, bupropion, or placebo. These models integrate fMRI and clinical measures and they explain up to 37% of the variance in ΔHAMD, classify remitters with NNT of 2.3-4.3, and classify responders with NNT of 3.2-4.9. Findings reveal new regions predictive of treatment outcome such as the hippocampus and paracentral lobule, while additional regions implicated in existing research are corroborated. Distinct models were identified for each treatment and provide substantial evidence of their potential to improve precision in treatment selection for MDD.

Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression.In a multicenter, double-blind study, adults (ages 18-64 years) with treatment-resistant depression were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS).In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was -18.4 (SD=12.0) for ketamine and -5.7 (SD=10.2) for placebo; in the thrice-weekly groups, it was -17.7 (SD=7.3) for ketamine and -3.1 (SD=5.7) for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, -12.2 [SD=12.8] on day 4; thrice-weekly, -14.0 [SD=12.5] on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common (≥20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing.Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.

Objective:The primary aim of this study was to compare the impact of NAVIGATE, a comprehensive, multidisciplinary, team-based treatment approach for first-episode psychosis designed for implementation in the U.S. health care system, with community care on quality of life.Method:Thirty-four clinics in 21 states were randomly assigned to NAVIGATE or community care. Diagnosis, duration of untreated psychosis, and clinical outcomes were assessed via live, two-way video by remote, centralized raters masked to study design and treatment. Participants (mean age, 23) with schizophrenia and related disorders and ≤6 months of antipsychotic treatment (N=404) were enrolled and followed for ≥2 years. The primary outcome was the total score of the Heinrichs-Carpenter Quality of Life Scale, a measure that includes sense of purpose, motivation, emotional and social interactions, role functioning, and engagement in regular activities.Results:The 223 recipients of NAVIGATE remained in treatment longer, experienced greater ...

The purpose of the study was to evaluate the safety and efficacy with the use of BMP-2 for treating persistent non-unions in children with underlying complex conditions. Between October 2006 and November 2010 in our unit, 15 patients were treated with rhBMP-2 to enhance bone union. There were nine females and six males with a mean age of 9.5 years (range 4-15) at time of surgery. Seventy-five per cent of the patients required revision of internal fixation with insertion of rhBMP-2 to the non-union site, and the reminder had freshening of the non-union site with rhBMP-2 application. Patients had undergone a mean of 2 (1-5) operations prior to implantation of rhBMP-2. All the patients in the study group were available for review with mean follow-up of 44 months (range 21-70). The mean time to union was 16 weeks (range 10-28 weeks). No adverse events related to BMP-2 application were noted in our study group. Healing occurred clinically and radiographically in 16 of the 17 sites. Our study demonstrates that BMP-2 enhances healing of the persistent non-unions without any adverse events.

Background: Acetabular fractures are complex injuries caused due to high velocity injury and constitutes about 18 % of Pelvic fractures. To obtain articular congruency and anatomical reduction is the gold standard in treating these fractures. In this study we have studied about the functional outcome in acetabular fractures managed conservatively with the long-term follow.Methods: A retrospective study with prospective analysis done between 2011-2020 involved 39 patients with acetabular fractures who were treated conservatively at St John’s Medical college Hospital. Patients were followed up at 6 months, 1 year, 2 years and at the end of 5 years for functional evaluation and assessment with the clinical outcome scores with Merle d’Aubigne and Postel score & Harris Hip Score.Results: Study included 39 patients with the average age of 41.3 years with 31 male and 8 female patients. Functional outcome score showed good to excellent results in 80%, fair to satisfactory results in 18%, 0.5 to 2% had poor result in the patient analyzed with both Merle d’Aubigne and Postel score and Harris Hip Score. 80 % of the patients were able to sit cross legged, 90% had returned to regular work and 10% of the patients changed their occupation to desk jobs.Conclusions: Conservative management of acetabular fractures gives a good long-term result following congruent reduction of the fracture, good early rehabilitation and gradual weight bearing. Return to activity of daily living was good even in congruently reduced acetabular dome fractures with good to excellent functional outcome scores.

Background Major Depressive Disorder (MDD) has been associated with brain-related changes. However, biomarkers have yet to be defined that could “accurately” identify antidepressant-responsive patterns and reduce the trial-and-error process in treatment selection. Cerebral blood perfusion, as measured by Arterial Spin Labelling (ASL), has been used to understand resting-state brain function, detect abnormalities in MDD, and could serve as a marker for treatment selection. As part of a larger trial to identify predictors of treatment outcome, the current investigation aimed to identify perfusion predictors of treatment response in MDD. Methods For this secondary analysis, participants include 231 individuals with MDD from the EMBARC study, a randomised, placebo-controlled trial investigating clinical, behavioural, and biological predictors of antidepressant response. Participants received sertraline (n = 114) or placebo (n = 117) and response was monitored for 8 weeks. Pre-treatment neuroimaging was completed, including ASL. A whole-brain, voxel-wise linear mixed-effects model was conducted to identify brain regions in which perfusion levels differentially predict (moderate) treatment response. Clinical effectiveness of perfusion moderators was investigated by composite moderator analysis and remission rates. Composite moderator analysis combined the effect of individual perfusion moderators and identified which contribute to sertraline or placebo as the “preferred” treatment. Remission rates were calculated for participants “accurately” treated based on the composite moderator (lucky) versus “inaccurately” treated (unlucky). Findings Perfusion levels in multiple brain regions differentially predicted improvement with sertraline over placebo. Of these regions, perfusion in the putamen and anterior insula, inferior temporal gyrus, fusiform, parahippocampus, inferior parietal lobule, and orbital frontal gyrus contributed to sertraline response. Remission rates increased from 37% for all those who received sertraline to 53% for those who were lucky to have received it and sertraline was their perfusion-preferred treatment. Interpretation This large study showed that perfusion patterns in brain regions involved with reward, salience, affective, and default mode processing moderate treatment response favouring sertraline over placebo. Accurately matching patients with defined perfusion patterns could significantly increase remission rates. Funding National Institute of Mental Health, the Hersh Foundation, and the Center for Depression Research and Clinical Care, Peter O'Donnell Brain Institute at UT Southwestern Medical Center. Trial Registration. Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMARC) Registration Number: NCT01407094 ( https://clinicaltrials.gov/ct2/show/NCT01407094 ).

This study aimed to identify biomarkers of major depressive disorder (MDD), by relating neuroimage-derived measures to binary (MDD/control), ordinal (severe MDD/mild MDD/control), or continuous (depression severity) outcomes. To address MDD heterogeneity, factors (severity of psychic depression, motivation, anxiety, psychosis and sleep disturbance) were also used as outcomes. A multi-site, multimodal imaging (diffusion MRI, dMRI, and structural MRI, sMRI) cohort (52 controls and 147 MDD patients) and several modeling techniques- penalized logistic regression (PLR), random forest (RF) and support vector machine (SVM)- were used. An additional cohort (25 controls and 83 MDD patients) was used for validation. The optimally performing classifier (SVM) had a 26.0% misclassification rate (binary), 52.2±1.69% accuracy (ordinal) and r =0.36 correlation coefficient (p-value

Background: One in three clinical trial patients with major depressive disorder report symptomatic improvement with placebo. Strategies to mitigate the effect of placebo responses have focused on modifying study design with variable success. Identifying and excluding or controlling for individuals with a high likelihood of responding to placebo may improve clinical trial efficiency and avoid unnecessary medication trials. Methods: Participants included those assigned to the placebo arm (n = 141) of the Establishing Moderators and Biosignatures for Antidepressant Response in Clinical Care (EMBARC) trial. The elastic net was used to evaluate 283 baseline clinical, behavioral, imaging, and electrophysiological variables to identify the most robust yet parsimonious features that predicted depression severity at the end of the double-blind 8-week trial. Variables retained in at least 50% of the 100 imputed data sets were used in a Bayesian multiple linear regression model to simultaneously predict the probabilities of response and remission. Results: Lower baseline depression severity, younger age, absence of melancholic features or history of physical abuse, less anxious arousal, less anhedonia, less neuroticism, and higher average theta current density in the rostral anterior cingulate predicted a higher likelihood of improvement with placebo. The Bayesian model predicted remission and response with an actionable degree of accuracy (both AUC > 0.73). An interactive calculator was developed predicting the likelihood of placebo response at the individual level. Conclusion: Easy-to-measure clinical, behavioral, and electrophysiological assessments can be used to identify placebo responders with a high degree of accuracy. Development of this calculator based on these findings can be used to identify potential placebo responders.

Introduction Previous investigations of test-retest reliability of cerebral blood flow (CBF) at rest measured with pseudo-continuous Arterial Spin Labeling (pCASL) demonstrated good reliability, but are limited by the use of similar scanner platforms. In the present study we examined test-retest reliability of CBF in regions implicated in emotion and the default mode network. Material and methods We measured absolute and relative CBF at rest in thirty-one healthy subjects in two scan sessions, one week apart, at four different sites and three different scan platforms. We derived CBF from pCASL images with an automated algorithm and calculated intra-class correlation coefficients (ICCs) across sessions for regions of interest. In addition, we investigated site effects. Results For both absolute and relative CBF measures, ICCs were good to excellent (i.e. > 0.6) in most brain regions, with highest values observed for the subgenual anterior cingulate cortex and ventral striatum. A leave-one-site-out cross validation analysis did not show a significant effect for site on whole brain CBF and there was no proportional bias across sites. However, a significant site effect was present in the repeated measures ANOVA. Conclusions The high test-retest reliability of CBF measured with pCASL in a range of brain regions implicated in emotion and salience processing, emotion regulation, and the default mode network, which have been previously linked to depression symptomatology supports its use in studies that aim to identify neuroimaging biomarkers of treatment response.

OBJECTIVE Obesity and major depressive disorder often co-occur. However, differences between obese and normal-weight depressed patients and the moderating effect of obesity on antidepressant treatment outcome are not well studied. METHODS Adults (n = 662) with major depressive disorder in the Combining Medications to Enhance Depression Outcomes study were randomized to treatment with escitalopram plus placebo, bupropion plus escitalopram, or venlafaxine plus mirtazapine for a 12-week primary treatment phase and 16-week follow-up. Body mass index (BMI) was calculated at baseline and categorized according to World Health Organization criteria: normal or low weight (NW), overweight, Obese I and Obese II+. A repeated-effects model, unadjusted and adjusted for baseline variables, assessed outcomes. RESULTS Obesity was common (46.2%), only 25.5% were NW. Higher BMI was associated with greater medical illness (p < .001), social phobia (p = .003), and bulimia (p = .026). Lower BMI was associated with more frequent post-traumatic stress disorder (p = .002) and drug abuse (p < .001). Treatment outcomes did not differ including Week 12 remission rates (NW 36%, overweight 40%, Obese I 43%, Obese II+ 37%; p = .69). Lower BMI was associated with more frequent (p = .024 [unadjusted] and .053 [adjusted]) and more severe (p = .008 [unadjusted] and .053 [adjusted]) adverse effects. CONCLUSIONS BMI was related to clinical presentation and prevalence of comorbidities, but not antidepressant outcomes. Lower BMI classes had more psychiatric comorbidities, potentially obscuring the relationship between BMI and antidepressant effects. Trial Registration ClinicalTrials.gov identifier: NCT00590863.

Major depressive disorder (MDD) affects one in five patients with Chronic Kidney Disease (CKD) and is an independent risk factor for hospitalization and death before and after dialysis initiation. However, it remains an under-recognized and under-treated problem, in part due to the lack of well-controlled studies that support or refute the efficacy and safety of antidepressant medications in CKD patients. Major trials of antidepressant treatment excluded patients with stages 3–5 CKD, precisely those at higher risk for both depression and increased mortality. The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) is a randomized, double-blinded, placebo-controlled trial of sertraline, a selective serotonin reuptake inhibitor (SSRI). It will enroll 200 adults with stages 3–5 CKD and MDD excluding kidney transplant and chronic dialysis patients. Sertraline will be administered at an initial dose of 50 mg once daily or matching placebo followed by a dose escalation strategy consisting of 50 mg increments at 2 weeks intervals (as tolerated) to a maximum dose of 200 mg. The primary outcome is improvement in depression symptom severity measured by the Quick Inventory of Depressive Symptomatology scale. Secondary outcomes include safety endpoints and improvement in quality of life. Changes in cognitive function, adherence to medications, nutritional status, inflammation, and platelet function will be explored as potential mechanisms by which depression may mediate poor outcomes. We discuss the rationale and design of the CAST study, the largest placebo-controlled trial aimed to establish safety and efficacy of a SSRI in the acute phase treatment of CKD patients with MDD.

PURPOSE We studied the effect of 3 antidepressant treatments on outcomes (depressive severity, medication tolerability, and psychosocial functioning) in depressed patients having comorbid general medical conditions in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial. METHODS Adult outpatients who had chronic and/or recurrent major depressive disorder (MDD) with and without general medical conditions were randomly assigned in 1:1:1 ratio to 28 weeks of single-blind, placebo-controlled antidepressant treatment with (1) escitalopram plus placebo, (2) bupropion-SR plus escitalopram, or (3) venlafaxine-XR plus mirtazapine. At weeks 12 and 28, we compared response and tolerability between participants with 0, 1, 2, and 3 or more general medical conditions. RESULTS Of the 665 evaluable patients, 49.5% reported having no treated general medical conditions, 23.8% reported having 1, 14.8% reported having 2, and 11.9% reported having at least 3. We found only minimal differences in antidepressant treatment response between these groups having different numbers of conditions; patients with 3 or more conditions reported higher rates of impairment in social and occupational functioning at week 12 but not at week 28. Additionally, we found no significant differences between the 3 antidepressant treatments across these groups. CONCLUSIONS Patients with general medical conditions can be safely and effectively treated for MDD with antidepressants with no additional adverse effect or tolerability burden relative to their counterparts without such conditions. Combination therapy is not associated with an increased treatment response beyond that found with traditional monotherapy in patients with MDD, regardless of the presence and number of general medical conditions.

Objective:Two antidepressant medication combinations were compared with selective serotonin reuptake inhibitor monotherapy to determine whether either combination produced a higher remission rate in first-step acute-phase (12 weeks) and long-term (7 months) treatment. Method:The single-blind, prospective, randomized trial enrolled 665 outpatients at six primary and nine psychiatric care sites. Participants had at least moderately severe nonpsychotic chronic and/or recurrent major depressive disorder. Escitalopram (up to 20 mg/day) plus placebo, sustained-release bupropion (up to 400 mg/day) plus escitalopram (up to 20 mg/day), or extended-release venlafaxine (up to 300 mg/day) plus mirtazapine (up to 45 mg/day) was delivered (1:1:1 ratio) by using measurement-based care. The primary outcome was remission, defined as ratings of less than 8 and less than 6 on the last two consecutive applications of the 16-item Quick Inventory of Depressive Symptomatology—Self-Report. Secondary outcomes included side effect...

Adverse events during selective serotonin reuptake inhibitor (SSRI) treatment are frequent and may lead to premature treatment discontinuation. If attrition is associated with early worsening of adverse effects or the frequency, intensity, or burden of adverse effects, interventions to maximize retention could be focused on patients with these events. Outpatient participants (n = 265) with nonpsychotic major depressive disorder entered an 8-week trial with an SSRI. At baseline and week 2, specific adverse effects were evaluated with the Systematic Assessment for Treatment Emergent Events--Systematic Inquiry, and at week 2, the Frequency, Intensity, and Burden of Side Effects Rating globally assessed adverse effects. Attrition was defined by those participants who left treatment after week 2 but before week 8. No specific week 2 adverse effect, either treatment-emergent or with worsening intensity, was independently associated with attrition. Global ratings of adverse effect frequency, intensity, or burden at week 2 were also not associated with subsequent attrition. Neither global ratings nor specific adverse effects at week 2 were related to patient attrition during SSRI treatment. Other factors seem to contribute to patient decisions about continuing with treatment.

Major depressive disorder (MDD) is a common and debilitating psychiatric illness, with lifetime prevalence rates of up to 16.2%.1 Furthermore, it is well known that MDD is a chronic, recurring illness. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), 50%–60% of patients who suffer a first-time major depressive episode will develop a second episode, and those with 2 or more prior episodes can almost be assured of having further episodes.2 Additionally, the presence of residual symptoms of depression is a strong predictor for relapse of major depression,3 and for this reason, full remission of symptoms is the goal of acute-phase treatment.4 However, based on recent “real-world” effectiveness trials in routine outpatient psychiatric and primary care clinics, remission rates following up to 14 weeks of standard citalopram antidepressant treatment are modest at 28%.5 The issue of inadequate remission rates for patients with MDD is compounded in primary care, where some reports suggest that 50%–70% of patients with MDD are unrecognized.6 In 2001, Young and colleagues7 also reported that only 1 in 5 patients with either a depressive or anxiety disorder received adequate treatment in primary care practice. To ensure more aggressive identification and treatment of MDD in primary care settings, the US Preventive Services Task Force recommended that all adult patients be screened for MDD in clinical practices that have systems in place to ensure accurate diagnosis of and effective treatment for MDD.8 The development of guidelines and algorithms has been the traditional solution to improve MDD treatment in primary care. Schulberg9 called for the use of treatment guidelines in regard to the psychopharmacologic treatment of depression in primary care. In recent years, a number of studies have consistently depicted the superiority of clearly defined, multifaceted treatment protocols in primary care settings over usual care models.10–13 The Texas Medication Algorithm Project (TMAP) was developed with the purpose of disseminating “real-world” pharmacologic treatment guidelines, founded on current evidence-based medicine (where available) and consensus expert opinion, for the treatment of psychiatric illnesses. The first iteration of the TMAP consensus guideline for nonpsychotic and psychotic MDD was developed in 1999 and was provided in a paper-and-pencil format.14 Trivedi and colleagues15 compared clinical outcomes of patients with MDD whose providers (psychiatrists in the public mental health sector) used TMAP guidelines to those of patients provided with usual care and found a statistically significant benefit for the guideline group. Even with these findings, research on the efficacy of guidelines suggests that development and simple dissemination alone are not sufficient to improve the quality of primary care.16 There has been considerable effort in promoting consensus guidelines created for multiple fields, but finding an effective implementation strategy continues to be a challenge. Furthermore, studies have consistently shown that the initial benefits of algorithm implementation in primary care are not sustained once the implementation support is withdrawn.10,11 For this reason, we decided to develop a computerized decision support system (CDSS) for implementation of the TMAP guidelines for depression (CompTMAP) to provide ongoing, sustained, point-of-care assistance to primary care clinicians.16 The current study was designed to assess the impact that a CDSS aligned with the TMAP MDD algorithm would have in aiding primary care physicians treating patients with major depression compared to colleagues providing usual care. The benefits of computerized decision support systems are far-reaching in other primary care settings, from improving clinical endpoints (ie, antibiotic use) to reducing unnecessary costs and procedures.17,18

Introduction. Cognitive deficits are commonly reported by patients with major depressive disorder (MDD). Duloxetine, a dual serotonin/noradrenaline reuptake inhibitor, may improve cognitive deficits in MDD. It is unclear if cognitive improvements occur independently of antidepressant effects with standard antidepressant medications.Methods. Thirty participants with MDD who endorsed cognitive deficits at screening received 12-week duloxetine treatment. Twenty-one participants completed treatment and baseline and posttreatment cognitive testing. The Cambridge Neuropsychological Test Automated Battery was used to assess the following cognitive domains: attention, visual memory, executive function/set shifting and working memory, executive function/spatial planning, decision making and response control, and verbal learning and memory.Results. Completers showed significant cognitive improvements across several domains on tasks assessing psychomotor function and mental processing speed, with additional improvements in visual and verbal learning and memory, and affective decision making and response control. Overall significance tests for executive function tasks were also significant, although individual tasks were not, perhaps due to the small sample size. Most notably, cognitive improvements were observed independently of symptom reduction on all domains except verbal learning and memory.Conclusions. Patients reporting baseline cognitive deficits achieved cognitive improvements with duloxetine treatment, most of which were independent of symptomatic improvement. This trial is registered withNCT00933439.

Objective: To identify clinical and sociodemographic characteristics associated with suicidal ideation (SI) among patients seeking care for depression in routine primary and psychiatric care settings. Methods: We examined data from 4041 treatment-seeking outpatients with major depressive disorder (MDD) to compare baseline sociodemographic and clinical characteristics of those with and without SI, and the presence or absence of baseline depressive symptoms and psychiatric comorbidities in those with SI. Results: SI was significantly ( P < 0.01) associated with numerous sociodemographic characteristics (that is, lower level of education, Caucasian or African American, male, unemployed, and treated in psychiatric care) and clinical features (that is, previous suicide attempt, younger age of MDD onset, greater baseline depressive symptom severity, greater number of depressive symptoms, and presence of agoraphobia and [or] generalized anxiety disorder). Elevated levels of SI at baseline were associated with decreased remission rates. Conclusions: Consistent with past findings, increased rates of SI were associated with greater depressive symptom severity as well as other features suggestive of severity of illness. Our results confirm previous findings of associations between SI and panic and (or) phobic symptoms and anxiety, but did not confirm previous findings of an association between SI and alcohol or drug use and (or) dependence. While selective serotonin reuptake inhibitor monotherapy appeared significantly helpful in reducing SI during the course of treatment, the presence of SI at baseline was found to be a associated with decreased treatment response, with patients reporting SI at the start of treatment being less likely to achieve remission. Clinical Trial Registration Number: Sequenced Treatment Alternatives to Relieve Depression, NCT00021528.

OBJECTIVE To compare sociodemographic and clinical features, acute and continuation treatment outcomes, and adverse events/side effect burden between outpatients with chronic (current episode > 2 years) versus nonchronic major depressive disorder (MDD) who were treated with combination antidepressant therapy or selective serotonin reuptake inhibitor (SSRI) monotherapy. METHOD 663 outpatients with chronic (n = 368) or nonchronic (n = 295) moderate to severe DSM-IV-TR MDD (17-item Hamilton Depression Rating Scale score ≥ 16) were enrolled from March 2008 through September 2009 in a single-blind 7-month prospective randomized trial conducted at 6 primary and 9 psychiatric care sites across the United States. Participants were treated with escitalopram monotherapy plus placebo or 1 of 2 combination treatments (bupropion sustained-release [SR] + escitalopram or venlafaxine extended-release [XR] + mirtazapine). Analyses compared baseline sociodemographic and clinical characteristics, rates of remission (at least 1 of the last 2 consecutive scores on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report [QIDS-SR16] < 6, with the other < 8), and adverse events/side effect burden (Frequency, Intensity, and Burden of Side Effects Ratings) obtained at 12 and 28 weeks. RESULTS Participants with chronic MDD were at greater socioeconomic disadvantage and had greater medical and psychiatric disease burden. The chronic and nonchronic groups did not differ in rates of remission at 12 weeks (35.9% vs 42.0%, respectively; odds ratio [OR] = 0.778, P = .1500; adjusted OR [AOR] = 0.956, P = .8130) or at 28 weeks (41.0% vs 49.8%, respectively; OR = 0.706, P = .0416; AOR = 0.837, P = .3448). Participants with chronic MDD had higher final QIDS-SR(16) scores and smaller overall percent changes in QIDS-SR(16) from baseline to exit, but these differences did not remain after adjusting for covariates. There were no significant differences in adverse events or side effect burden. No significant interactions were found between chronicity and type of treatment at 12 or 28 weeks. CONCLUSION Chronicity of illness does not appear to differentially impact acute or longer-term outcomes with SSRI monotherapy or combination antidepressant medication treatment in patients with moderate to severe nonpsychotic MDD. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00590863.

Missing data in clinical efficacy and effectiveness trials continue to be a major threat to the validity of study findings. The purpose of this report is to describe methods developed to ensure completion of outcome assessments with public mental health sector subjects participating in a longitudinal, repeated measures study for the treatment of major depressive disorder. We developed longitudinal assessment procedures that included telephone-based clinician interviews in order to minimize missing data commonly encountered with face-to-face assessment procedures.A pre-planned, multi-step strategy was developed to ensure completeness of data collection. The procedure included obtaining multiple pieces of patient contact information at baseline, careful education of both staff and patients concerning the purpose of assessments, establishing good patient rapport, and finally being flexible and persistent with phone appointments to ensure the completion of telephone-based follow-up assessments. A well-developed administrative and organizational structure was also put in place prior to study implementation.The assessment completion rate for the primary outcome for 310 of 504 subjects who enrolled and completed 52 weeks (at the time of manuscript) of telephone-based follow-up assessments was 96.8%.By utilizing telephone-based follow-up procedures and adapting our easy-to-use pre-defined multi-step approach, researchers can maximize patient data retention in longitudinal studies.

We examined the length of stay of inpatients admitted to a psychiatric unit in central London. The commonest length of stay (mode) was less than 1 week. In general, subsequent weeks showed successively fewer discharges, so that the distribution curve of the number of patients by length of stay showed a smooth decline. Analyzing the first 13 weeks of stay, the distribution curve corresponded very closely to a theoretical exponential decay curve. This has implications for recording the average length of stay and thus for comparing one hospital unit with another. It may also have implications for planning for acute psychiatric services. A plea is made for using the median rather than the mean for recording the average length of admission for some purposes.

To evaluate the effect of UK and US warnings placed in response to reports of suicidal thinking in pediatric patients receiving selective serotonin reuptake inhibitor and selective norepinephrine reuptake inhibitor antidepressants on antidepressant prescribing for children and adolescents.Interrupted time-series analysis of antidepressant prescriptions.Tennessee's Medicaid program, January 1, 2002, through September 30, 2005.A mean of 405,000 children and adolescents aged 2 to 17 years qualified each month. Main Exposure Piecewise linear regression models were used to estimate the cumulative effect of the warnings, which were considered the exposure of interest.Monthly proportions of study children and adolescents who were new users of antidepressants, had discontinuity in antidepressant use, or were users of other psychotropic drugs.During the 2 years preceding the UK warning, there was no trend in the monthly proportions of new antidepressant users, with 23 new users per 10 000 persons per month. This proportion subsequently decreased 33% (95% confidence interval, 23% to 41%; P.001) by 21 months following the UK warning. The reduction was most pronounced for the nonfluoxetine selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors, where initiations decreased 54% (95% confidence interval, 46% to 62%; P.001). In contrast, new users of fluoxetine increased 60% (95% confidence interval, 9% to 135%; P = .02). There was no increase in discontinuations of antidepressants, and there was no evidence of substitution of other psychotropic drugs.The regulatory warnings led to decreased use of antidepressants in children and adolescents, but the clinical and public health consequences of this change are unknown.

The on-board computer (obc) systems that are planned to be used in India’s forthcoming launch vehicle programmes, viz, the Augmented Satellite Launch Vehicle (aslv) and Polar Satellite Launch Vehicle (pslv) exercise total control over the vehicle during its flight, carrying out complex real-time computations related to vehicle navigation, guidance, autopilot and the generation of mission critical event commands. The success of the country’s launch vehicle missions, therefore, depends to a very large extent on the reliable operation of theobc. To enhance the reliability of such a computer system, fault-tolerant design techniques have been resorted to and the system after thorough testing is now ready to be flown on theaslv. This paper highlights the design of such anobc mainly from the points of view of the fault-tolerant methods incorporated. The relevance of fault-tolerance to critical flight computers is first discussed. This is followed by a presentation of possible fault-tolerant configurations and the considerations that led to the choice of the present system. A brief description of theobc system architecture and the methods of testing that ensure its reliable operation follow. The paper concludes with an assessment of the present system and possible future improvements.