Search

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = −17.39 (1.3) (p= 0.015) but not aripiprazole augmentation (score change (se) = −14.9 (1.1) (p= 0.069) was superior to switch (score change (se) = −13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = −37.79 (2.9) (p= 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = −42.96 (3.6) (p= 0.031) was superior to switch (mean change (se) = −34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.

Major depressive disorder (MDD) may be associated with accelerated brain aging (higher brain age than chronological age). This report evaluated whether brain age is a clinically useful biomarker by checking its test-retest reliability using magnetic resonance imaging scans acquired 1 week apart and by evaluating the association of accelerated brain aging with symptom severity and antidepressant treatment outcomes.

Recent studies have suggested that mitochondrial dysfunction and dysregulated neuroinflammatory pathways are involved in the pathophysiology of major depressive disorder (MDD). Here, we aimed to assess the differences in markers of mitochondrial dynamics, mitophagy, general autophagy, and apoptosis in peripheral blood mononuclear cells (PBMCs) of MDD patients (n= 77) and healthy controls (HCs, n= 24). Moreover, we studied inflammation engagement as a moderator of mitochondria dysfunctions on the severity of depressive symptoms. We found increased levels of Mfn-2 (p< 0.001), short Opa-1 (S-Opa-1) (p < 0.001) and Fis-1 (p< 0.001) in MDD patients, suggesting an increase in the mitochondrial fragmentation. We also found that MDD patients had higher levels of Pink-1 (p< 0.001), p62/SQSTM1 (p< 0.001), LC3B (p= 0.002), and caspase-3 active (p= 0.001), and lower levels of parkin (p< 0.001) compared with HCs. Moreover, we showed that that MDD patients with higher CRP levels had higher levels of Mfn-2 (p= 0.001) and LC3B (p= 0.002) when compared with MDD patients with low CRP. Another notable finding was that the severity of depressive symptoms in MDD is associated with changes in protein levels in pathways related to mitochondrial dynamics and mitophagy, and can be dependent on the inflammatory status. Overall, our study demonstrated that a disruption in the mitochondrial dynamics network could initiate a cascade of abnormal changes relevant to the critical pathological changes during the course of MDD and lead to poor outcomes.

Promising initial data indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may be beneficial in post-traumatic stress disorder (PTSD). Here, we explore the neural correlates of ketamine-related changes in PTSD symptoms, using a rich battery of functional imaging data (two emotion-processing tasks and one task-free scan), collected from a subset of participants of a randomized clinical trial of repeated-dose intravenous ketamine vsmidazolam (total N= 21). In a pre-registered analysis, we tested whether changes in an a priori set of imaging measures from a target neural circuit were predictive of improvement in PTSD symptoms, using leave-one-out cross-validated elastic-net regression models (regions of interest in the target circuit consisted of the dorsal and rostral anterior cingulate cortex, ventromedial prefrontal cortex, anterior hippocampus, anterior insula, and amygdala). Improvements in PTSD severity were associated with increased functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala during emotional face-viewing (change score retained in model with minimum predictive error in left-out subjects, standardized regression coefficient [β] = 2.90). This effect was stronger in participants who received ketamine compared to midazolam (interaction β = 0.86), and persisted following inclusion of concomitant change in depressive symptoms in the analysis model (β = 0.69). Improvement following ketamine was also predicted by decreased dorsal anterior cingulate activity during emotional conflict regulation, and increased task-free connectivity between the vmPFC and anterior insula (βs = −2.82, 0.60). Exploratory follow-up analysis via dynamic causal modelling revealed that whilst improvement in PTSD symptoms following either drug was associated with decreased excitatory modulation of amygdala→vmPFC connectivity during emotional face-viewing, increased top-down inhibition of the amygdala by the vmPFC was only observed in participants who improved under ketamine. Individuals with low prefrontal inhibition of amygdala responses to faces at baseline also showed greater improvements following ketamine treatment. These preliminary findings suggest that, specifically under ketamine, improvements in PTSD symptoms are accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat.

This article explains the contemporary context that influences the policies and practices of community work in India. The transformation in the policy arena and welfare approach underlines the influence of neoliberal governmentality. We observe that neoliberalism as a political–economic approach is persuading socio-economic decisions and increasing market influence. Precisely, we are tracing the policy trajectory vis-à-vis informal sector workers who have adverse implications for their social security and social protection. By illustrating the current policy and legislative approach, we explain an uneasy relationship between neoliberalism, governmentality and welfare. The changes through new labour codes have restrained the minimal protection that was available to the workers. By granting significant flexibility to the employers at the cost of workers, neoliberal policies accentuate the predicament of precarity. Besides, recent policy changes have impacted community engagement with the poor and vulnerable. Through an analysis of neoliberal policies and strategies of governmentality, this article underscores the challenges for community engagements.

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.

Irritability in pediatric samples is associated with higher rates of subsequent suicide-related outcomes. No study, to date, has evaluated the longitudinal association between irritability and suicidal ideation (SI) in adults with major depressive disorder (MDD). This report evaluated whether irritability is associated with SI at the same visit (i.e., concurrently) and whether early changes in irritability with antidepressant treatment predict subsequent levels of SI. Participants of Combining Medications to Enhance Depression Outcomes (CO-MED, n= 665), Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC, n= 296), and Suicide Assessment Methodology Study (SAMS, n= 266) were included. Repeated-measures mixed model analyses evaluated concurrent association throughout the trial between irritability (five-item irritability domain of Concise Associated Symptom Tracking scale) and SI (three-item suicidal thoughts factor of Concise Health Risk Tracking scale) after controlling for overall depression (excluding suicidality-related item), and predicted subsequent levels of SI (repeated observations from week-2-to-week-8) based on early (baseline-to-week-2) changes in irritability after controlling for early changes in overall depression. Higher irritability was associated with higher SI concurrently; estimates (standard error) were 0.18 (0.02, p< 0.0001), 0.64 (0.02, p< 0.0001), and 0.26 (0.04, p< 0.0001) in CO-MED, EMBARC, and SAMS respectively. Greater baseline-to-week-2 reductions in irritability predicted lower levels of subsequent SI; estimates (standard errors) were −0.08 (0.03, p= 0.023), −0.50 (0.05, p< 0.0001), and −0.12 (0.05, p= 0.024) in CO-MED, EMBARC, and SAMS, respectively. Controlling for anxiety or insomnia produced similar results. In conclusion, irritability and SI were consistently linked in adults with MDD. These findings support careful assessment of irritability in suicide risk assessment.

In a post hoc analysis, the effect of pimavanserin on anxious depression was determined from CLARITY, a randomized, double-blind, placebo-controlled study in patients with major depression and an inadequate response to previous therapy. Patients were randomized in a 3:1 ratio to placebo or pimavanserin 34 mg daily added to ongoing antidepressant therapy. At 5 weeks, placebo nonresponders were rerandomized to placebo or pimavanserin for an additional 5 weeks. Mean change from baseline to week 5 for the Hamilton depression rating scale (HAMD) anxiety/somatization (AS) factor was examined for all patients and those with a score ≥7 at baseline. Least squares (LS) mean [standard error (SE)] difference between placebo and pimavanserin for the AS factor score was −1.5 (0.41) [95% confidence interval (CI) −2.4 to −0.7; P= 0.0003; effect size: 0.634]. Among patients with an AS factor score ≥7 at baseline, LS mean (SE) difference was −2.2 (0.66) (95% CI −3.5 to −0.9; P= 0.0013; effect size: 0.781). Response rates (≥50% reduction in HAMD-17 from baseline) were 22.4 and 55.2% (P= 0.0012) and remission rates (HAMD-17 total score <7) were 5.3 and 24.1% (P= 0.0047), respectively, with placebo and pimavanserin among patients with a baseline AS factor score ≥7. Among patients with anxious major depressive disorder at baseline, adjunctive pimavanserin was associated with a significant improvement.

Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18–70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n= 18), a single dose of ketamine 0.2 mg/kg (n= 20), a single dose of ketamine 0.5 mg/kg (n= 22), a single dose of ketamine 1.0 mg/kg (n= 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n= 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p= 0.02, p-adj = 0.14, d= −0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.

The authors aimed to evaluate psychometric properties of the Concise Associated Symptom Tracking (CAST) Scale and validate the clinical utility of measuring irritability by updating and replicating a previously published outcome calculator from the Combining Medications to Enhance Depression Outcomes (CO‐MED) trial. Participants were 292 adults from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study who had completed the CAST scale at baseline. The scale's five‐domain (irritability, anxiety, mania, insomnia, and panic) structure was evaluated with confirmatory factor analysis. Correlations with other clinical measures were used to confirm convergent and divergent validity. Logistic regression analyses from CO‐MED were used to estimate individual outcomes in EMBARC. Cronbach's alpha for the CAST scale was 0.78. Model fit for the five‐domain structure was adequate (goodness of fit index=0.93, comparative fit index=0.92, root mean square error of approximation=0.06). Scores on irritability, anxiety, panic, insomnia, and mania were correlated with scores on the Anger Attack Questionnaire irritability item (rs=0.50), Hamilton Rating Scale for Depression anxiety subscale (rs=0.24), Mood and Anxiety Symptoms Questionnaire anxious arousal scale (rs=0.44), Quick Inventory of Depressive Symptomatology Self‐Report insomnia items (rs=0.38), and Altman Self‐Rating Mania Scale (rs=0.39), respectively. Individual outcomes of remission (area under the curve [AUC]=0.805) and no meaningful benefit (AUC=0.779) were predicted with high accuracy among EMBARC participants using their baseline and week 4 scores for depression and irritability and model estimates from CO‐MED. Measuring irritability may help predict clinical course. The CAST scale is a valid measure of depression‐associated symptoms, including irritability. Symptoms of anxiety, irritability, panic, and mania are often associated with depression.The Concise Associated Symptom Tracking Scale is a valid measure of these depression‐associated symptoms.Measuring irritability along with overall depression severity may help predict clinical course. Symptoms of anxiety, irritability, panic, and mania are often associated with depression. The Concise Associated Symptom Tracking Scale is a valid measure of these depression‐associated symptoms. Measuring irritability along with overall depression severity may help predict clinical course.

As countries shore up existing safeguards to address the social and economic impacts of the COVID-19 pandemic, India faces a humanitarian disaster of unprecedented proportions. Ninety per cent of the Indian workforce is employed in the unorganised sector; uncounted millions work in urban areas at great distances from rural homes. When the Government of India (GOI) announced the sudden ‘lockdown’ in March to contain the spread of the pandemic, migrant informal workers were mired in a survival crisis, through income loss, hunger, destitution and persecution from authorities policing containment and fearful communities maintaining ‘social distance’. In this context, the article analyses how poverty, informality and inequality are accentuated by the COVID-19 pandemic experiences of ‘locked down’ migrant workers. The article examines the nature and scope of existing social policy, designed under changing political regimes and a fluctuating economic climate, to protect this vulnerable group and mitigate dislocation, discrimination and destitution at this moment and in future.

Background & Objective: Patents suggest that time synchronization in Wireless Sensor Network (WSN) directs at imparting a common time scale for local clocks of nodes in the network. It has been observed that all hardware clocks are unsynchronized, local clocks of nodes may drift away from each other in time. Hence durations of time intervals may differ for each node in the network. This paper evaluates the performance by suggesting an algorithm for time synchronized MLMAC protocol. Methods: Packet retransmission drains the non-replaceable power source that degrades the network lifetime, one of the major concerns in WSN. Simulation results indicate that time synchronized MLMAC outperforms the existing ML-MAC scheme in terms of both energy efficiency and packets dropped at individual nodes. Results: After Analyzing the results of simulation, network for improved synchronization performs better w.r.t. network lifetime and packets dropped. Throughput and delay are matter of concern which needs to be explored further. Conclusion: Simulation results validate the proposed protocol under various network conditions and application requirements.

Background: This paper proposes a novel MultiChannel Caucus based Medium Access Control (MC2-MAC) protocol to diminish collisions between different data packets to reduce energy dissipation of nodes and latency of data packets transmitted by the sensors communicating in Line of Sight (LOS) communication deployed to supervise distinct raucous provinces in the smart grid. Methods: The performance diminishing major problems such as wastage of battery power, bottlenecks and collisions need to be mitigated to elongate lifespan and to diminish data latency. The employment of caucus based efficient scheduling scheme enhances synchronization and multiple channels prevent collisions by reducing the number of contending nodes. The utilization of multiple channels enables sink node to communicate simultaneously with numerous nodes. Results: The influence of multichannel is evaluated by comparing the simulation results of the networks implementing ZigBee, C-MAC and MC2-MAC protocols. QualNet 6.1 simulator is used to perform the simulations. Conclusion: The work resolute to evaluate and correlate the impact of the multichannel scheme to optimize the performance metrics of sensors deployed in distinct raucous provinces communicating in LOS environs in the smart grid and to gain the attention of scholars in this emerging field of research.

Major depressive disorder (MDD) is often comorbid with metabolic diseases such as obesity, cardiovascular disease, and type 2 diabetes. A potential link between these disorders is adiponectin, an adipocyte-derived circulating hormone with insulin-sensitizing, anti-inflammatory, and neuroplasticity effects. Reductions in plasma levels of adiponectin have been reported in both humans with depression and in the chronic-defeat mouse model of depression. However, the predictive value of adiponectin for treatment response to depression has not been determined.

Genome-wide association studies (GWAS) were conducted in participants of the CO-MED (Combining Medications to Enhance Depression Outcomes) trial, a randomized, 3-treatment arm clinical trial of major depressive disorder (MDD) designed to identify markers of differential treatment outcome (response and remission). The QIDS-SR (Quick Inventory of Depressive Symptomatology, Self-Reported version) was used to measure response at week 6 (QIDS-SR ≤5) and remission at week 12 (QIDS-SR ≤6 and ≤8 at the last two study visits). Three treatment groups (escitalopram monotherapy, escitalopram + bupropion, and venlafaxine + mirtazapine) were evaluated. GWAS identified a potentially regulatory SNP rs10769025 in the ALX4 gene on chromosome 11 with a strong association (pvalue = 9.85925E–08) with response to escitalopram monotherapy in Caucasians. Further, haplotype analysis on 7 ALX4 variants showed that a regulatory haplotype CAAACTG was significantly associated (odds ratio = 3.4, p= 2.00E–04) with response to escitalopram monotherapy at week 6. Ingenuity pathway analyses in the present study suggest that ALX4 has an indirect connection with antidepressant gene pathways in MDD, which may account for the genetic association with treatment outcome. Functional genomics studies to investigate the role of ALX4 in antidepressant treatment outcome will be an interesting future direction.

Background: Time synchronization between the sensor nodes to reduce average end to end delay with the increase in number of sensor nodes in a network for critical and real time data monitoring can be achieved by precisely predicting their wakeup/sleep timings and are of prime importance as described in recent patents. The idea evolves as a reduction in duty cycle and precise time scheduling of active/sleep cycles of the sensors to reduce the probability of collisions between data and control packets which prolongs the network lifetime and reduces the average end to end delay. The multihop transmissions are not always attractive in underwater communication due to high losses. The proposed Slotted Cyclic Quorum with Influence nodes (SCQI) medium access control protocol is capable of continuous monitoring of critical underwater events in a very effective manner in multihop transmission networks. This work is an attempt to mitigate multihop hidden terminal and to reduce the probability of collisions between data and control packets. Methods: The mathematical model for the path loss due to attenuation of electromagnetic wave propagation in the sea water is explained. The three path reflection model evaluating reflection loss from the air-water and water-sand interfaces as a function of distance between sensors and water depth is introduced. It is assumed that the sensors are properly anchored to limit their movement due to waves within the permissible limits to follow the proposed cyclic quorum based medium access control protocol. The fundamentals of cyclic quorum with a slotted scheme along with the influence nodes are elaborated. This paper attempts to utilize electromagnetic waves at resonance frequency of 2.4 GHz for underwater communication. The main advantages of using electromagnetic waves instead of acoustic waves are that it reduces the latency due to faster propagation speed and give a high data rate due to high frequency of the wave at the cost of reduction in communication range. Results: The results verify that the implementation of cyclic quorum based medium access control (CQ) protocol, slotted cyclic quorum based medium access control (SCQ) protocol and slotted cyclic quorum based medium access control with influence nodes (SCQI) protocol has significantly reduced the average end to end delay with the increase in number of sensor nodes and also prolongs the network lifetime making it appropriate for critical and real time data monitoring. Conclusion: This work proves the suitability of electromagnetic waves as an effective alternative for underwater wireless communication. The main objective is to optimize the network lifetime and to reduce the average end to end delay by implementing cyclic quorum based medium access control protocol in underwater wireless sensor networks and to draw the attention of researchers in this area.

Background: Energy-Efficiency is an important issue in Wireless Sensor Networks (WSNs) since sensors are battery powered and are deployed in unattended environments. Long distance transmission is very expensive in WSNs since power consumption is proportional to dα for transmitting over distance d, where α is path loss exponent in the interval [2:6]. Thus, there is a necessary requirement of relay nodes in the network that are capable of performing data sensing, data aggregation and data routing, as described in various patents. Method: This paper presents a Layered Relay-Medium Access Control (LR-MAC) Protocol for a Personal Area Network. This protocol introduces the concept of multi-layering for the relay (routing) nodes. The protocol is validated by doing extensive simulations in QualNet 6.1 network simulator. The QoS parameters are analyzed for three different deployment strategies viz. random, grid and circular. Results: The results show that LR-MAC Protocol is an efficient technique in terms of improving network lifetime, average throughput and reducing number of packets dropped due to channel access failure in the network; while LR-MAC gives a neutral performance in terms of end-to-end delay in the network. Conclusion: LR-MAC protocol can efficiently work for random deployments as well as for wellplanned effective deployments like in smart building monitoring. The network can also be modified for large areas by increasing number of deployed sensor nodes and keeping node density constant.

Major depressive disorder (MDD) is characterized by depressed mood and/or anhedonia with neurovegetative symptoms and neurocognitive changes impacting an individual’s functioning in multiple aspects of life. Treatment outcomes with commonly used antidepressants remain sub-optimal. Treatment-resistant depression (TRD) should be considered after inadequate improvement with two or more antidepressant treatments of adequate dose and duration. TRD has been associated with increased disease burden including higher associated costs (both socially and financially) affecting both the individual and society. Additional research is needed to better understand the long-term burden of TRD to both the individual and society.

Due to the link between immune dysfunction and treatment resistant depression (TRD) and the overwhelming evidence that immune dysregulation and major depressive disorder (MDD) are associated with each other, using immune profiles to identify biological distinct subgroup may be the step forward to understanding MDD and TRD. This report aims to briefly review the role of inflammation in the pathophysiology of depression (and TRD in particular), the role of immune dysfunction to guide precision medicine, tools used to understand immune function, and novel statistical techniques that may allow for the use of immunological data to usher an era of precision medicine for psychiatry.

To address the need to identify potential markers of suicide behavior for adolescents (ages 12–18 years), mass cytometry was used to explore the cellular mechanisms that may underpin immune dysregulation in adolescents with recent suicidal behavior.

Avascular necrosis of the femoral head is one of the most common skeletal complications among renal allograft recipients complaining of hip pain. While bilateral avascular necrosis is more frequent than the unilateral type, we report a case of unilateral avascular necrosis of the hip occurring post renal transplant recipient. Avascular necrosis was likely the result of steroid therapy. A well-tailored steroid therapy that prevents unjustified high doses and ‘pulsed doses’ while maintaining the optimum maintenance level of steroids is necessary.

The exact location and release history of groundwater pollutant sources is often unknown. Identification of unknown release histories is usually carried out by inversion of the equations governing flow and transport over time and space. This is an ill posed problem. Solution of this ill-posed inversion is complicated due to the inherent non-uniqueness of solutions, uncertainties in modelling the flow and transport processes in the aquifer and unavoidable concentration measurement errors. Several methods to solve the ill posed inversion problem have been suggested in past. The simulation-optimization approach using global heuristic search optimization methods has been found to be the most effective with regards to accuracy of solutions. However, these methods are computationally intensive. A linked simulation-optimization based methodology using a variant of simulated annealing (SA) algorithm is linked to the numerical models used to simulate flow (MODFLOW) and transport processes (MT3DMS). The objective function minimizes the difference between observed and simulated contaminant concentration for optimal values of the decision variables representing the unknown source flux magnitude, duration and timing. The developed methodology is tested for an illustrative study area. The SA based source identification methodology is demonstrated to perform more efficiently compared to other methods based on genetic algorithm.

The exact location and release history of groundwater pollutant sources is often unknown. Identification of unknown release histories is usually carried out by inversion of the equations governing flow and transport over time and space. This is an ill posed problem. Solution of this ill-posed inversion is complicated due to the inherent non-uniqueness of solutions, uncertainties in modelling the flow and transport processes in the aquifer and unavoidable concentration measurement errors. Several methods to solve the ill posed inversion problem have been suggested in past. The simulation-optimization approach using global heuristic search optimization methods has been found to be the most effective with regards to accuracy of solutions. However, these methods are computationally intensive. A linked simulation-optimization based methodology using a variant of simulated annealing (SA) algorithm is linked to the numerical models used to simulate flow (MODFLOW) and transport processes (MT3DMS). The objective function minimizes the difference between observed and simulated contaminant concentration for optimal values of the decision variables representing the unknown source flux magnitude, duration and timing. The developed methodology is tested for an illustrative study area. The SA based source identification methodology is demonstrated to perform more efficiently compared to other methods based on genetic algorithm.

Abstract:Study Objectives:Sexual dysfunction occurs in 40%-60% of patients with major depressive disorder (MDD), due to either the illness itself and/or the effects of antidepressant treatment. The phase-2 CLARITY trial recently demonstrated the efficacy of adjunctive pimavanserin (PIM) for MDD when added to ongoing selective serotonin or serotonin–norepinephrine reuptake inhibitor (SSRI/SNRI) treatment. No new safety observations were reported in this study. This post-hoc analysis examines the potential impact of PIM treatment on sexual function.Method:Study methodology has been presented previously (APA 2019). Adult male and female patients with moderate-to-severe MDD were randomized to PIM 34 mg/day (n=51) or placebo (PBO, n=152) added to ongoing SSRI/SNRI treatment. Massachusetts General Hospital–Sexual Functioning Inventory (MGH-SFI) and Hamilton Depression Rating Scale, 17-item version (HAMD-17) item 14 (sexual interest) scores were examined by analysis of covariance.Results:Adjunctive PIM resulted in significantly greater 5-week reduction (improvement) relative to SSRI/SNRI treatment plus placebo on mean MGH-SFI scores (difference –0.634, SE 0.167; P<0.001; effect size [ES], Cohen’s d 0.614). Similarly, PIM resulted in greater improvement compared with placebo on individual MGH-SFI items that applied to both males and females: Interest in Sex (P=0.006; ES=0.483), Ability to Get Sexually Aroused/Excited (P=0.001; ES=0.560), Ability to Achieve Orgasm (P<0.001; ES=0.609), Overall Sexual Satisfaction (P=0.003; ES=0.524). HAMD-17 item 14 scores were also significantly more reduced (improved) with PIM (P<0.001; ES=0.574).Conclusions:These results underscore the potential of adjunctive PIM for improving sexual function in patients with MDD and inadequate response to SSRIs/SNRIs. Potential benefits should be confirmed in further studies.Funding Acknowledgements:ACADIA Pharmaceuticals Inc.

Supplementary Figure 1 and Supplementary Tables 1–4 have been re-uploaded so as to reflect the versions supplied during proofs stage. The publisher apologizes for the error in versioning. The HTML version of the paper has been updated.