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Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of ‘difficult-to-treat depression’ (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.

To compare the durations of response achieved with adjunctive vagus nerve stimulation (VNS + TAU) vs treatment as usual (TAU) alone in treatment-resistant depression (TRD) over a 5-year period in the TRD registry. Data from 271 participants on TAU and 328 participants on VNS + TAU were analyzed. Response was defined as ≥50% decrease in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score at postbaseline visit and was considered retained until the decrease was <40%. MADRS was obtained quarterly in year 1 and biannually thereafter. Time-to-events were estimated using Kaplan-Meier method and compared using log-rank test. HR was estimated using Cox proportion hazard model. In the VNS + TAU arm, 62.5% (205/328) of participants had a first response over 5 years compared with 39.9% (108/271) in TAU. The time to first response was significantly shorter for VNS + TAU than for TAU ( <0.01). For responders in the first year, median time to relapse from first response was 10.1 months (Q1=4.2, Q3=31.5) for VNS + TAU vs 7.3 months (Q1=3.1, Q3=17.6) for TAU ( <0.01). HR=0.6 (95% CI: 0.4, 0.9) revealed a significantly lower chance for relapse in VNS + TAU. Probability of retaining first response for a year was 0.39 (0.27, 0.51) for TAU and 0.47 (0.38, 0.56) for VNS + TAU. Timing of the onset of the response did not impact the durability of the response. VNS therapy added to TAU in severe TRD leads to rapid onset and higher likelihood of response, and a greater durability of the response as compared to TAU alone.

The Vagus Nerve Stimulation (VNS) Therapy System has been studied for more than 20 years in patients with severe, treatment-resistant, chronic mood disorder, i.e., difficult-to-treat depression (DTD). This review distills some of the implications of this research for future therapeutic trials in this population. A narrative review is provided on VNS in DTD. Protocols for a new, large, sham-controlled trial and a global, longitudinal observational study are described. Following encouraging results in open studies, a randomized, masked, sham-controlled trial of VNS for DTD failed to demonstrate an effect on the primary outcome. The negative results may have been partly due to inadequate treatment duration (10 weeks). In long-term observational studies, adjunctive VNS, combined with treatment-as-usual (VNS+TAU), was administered to more than 1100 DTD patients and compared with TAU alone in more than 400 patients. VNS+TAU had superior antidepressant effects, but maximal symptom reduction was often observed after 12 months or longer of stimulation. VNS+TAU had also marked superiority in durability of benefit. Sustained levels of symptom reduction below the traditional cutoff for response (i.e. < 50%) were associated with improved quality of life. Most comparisons of VNS+TAU and TAU were derived from observational, open label studies. The history of VNS in DTD has implications for interventional studies in this population, and perhaps other chronic medical disorders. The slow onset of benefit with VNS necessitates considerably longer controlled observation periods to establish efficacy. Durability of benefit should be routinely incorporated in efficacy assessment. New outcome metrics are needed to both categorically identify clinically meaningful benefit and to integrate information on symptom burden over time.

BackgroundTo compare illness characteristics, treatment history, response and durability, and suicidality scores over a 5-year period in patients with treatment-resistant bipolar depression participating in a prospective, multicenter, open-label registry and receiving Vagus Nerve Stimulation Therapy (VNS Therapy) plus treatment-as-usual (VNS + TAU) or TAU alone.MethodsResponse was defined as ≥ 50% decrease from baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score at 3, 6, 9, or 12 months post-baseline. Response was retained while MADRS score remained ≥ 40% lower than baseline. Time-to-events was estimated using Kaplan–Meier (KM) analysis and compared using log-rank test. Suicidality was assessed using the MADRS Item 10 score.ResultsAt baseline (entry into registry), the VNS + TAU group (N = 97) had more episodes of depression, psychiatric hospitalizations, lifetime suicide attempts and higher suicidality score, more severe symptoms (based on MADRS and other scales), and higher rate of prior electroconvulsive therapy than TAU group (N = 59). Lifetime use of medications was similar between the groups (a mean of 9) and was consistent with the severe treatment-resistant nature of their depression. Over 5 years, 63% (61/97) in VNS + TAU had an initial response compared with 39% (23/59) in TAU. The time-to-initial response was significantly quicker for VNS + TAU than for TAU (p < 0.03). Among responders in the first year after implant, the KM estimate of the median time-to-relapse from initial response was 15.2 vs 7.6 months for VNS + TAU compared with TAU (difference was not statistically significant). The mean reduction in suicidality score across the study visits was significantly greater in the VNS + TAU than in the TAU group (p < 0.001).ConclusionsThe patients who received VNS + TAU included in this analysis had severe bipolar depression that had proved extremely difficult to treat. The TAU comparator group were similar though had slightly less severe illnesses on some measures and had less history of suicide attempts. Treatment with VNS + TAU was associated with a higher likelihood of attaining a response compared to TAU alone. VNS + TAU was also associated with a significantly greater mean reduction in suicidality.LimitationsIn this registry study, participants were not randomized to the study treatment group, VNS Therapy stimulation parameters were not controlled, and there was a high attrition rate over 5 years.Trial registration ClinicalTrials.gov NCT00320372. Registered 3 May 2006, https://clinicaltrials.gov/ct2/show/NCT00320372 (retrospectively registered)

In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD. Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample ( = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did ( = 153) and did not ( = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores. Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores. Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.

People encounter intertemporal decisions every day and often engage in behaviors that are not good for their future. One factor that may explain these decisions is the perception of their distal future self. An emerging body of research suggests that individuals vary in how they perceive their future self and many perceive their future self as a different person. The present research aimed to (1) build on and extend Hershfield’s et al. (2011) review of the existing literature and advance the conceptualization of the relationship between the current and future self, (2) extend and develop measures of this relationship, and (3) examine whether and how this relationship predicts intrapsychic and achievement outcomes. The results of the literature review suggested that prior research mostly focused on one or two of the following components: (a) perceived relatedness between the current and future self in terms of similarity and connectedness, (b) vividness in imagining the future self, and (c) degree of positivity felt toward the future self. Additionally, differences in how researchers have labeled the overall construct lead us to propose future self-identification as a new label for the three-component construct. Our research built on existing measures to test the validity of a three-component model of future self-identification. Across three samples of first-year undergraduates, this research established the psychometric properties of the measure, and then examined the relationships between the components and four outcome domains of interest: (1) psychological well-being (self-esteem, hope), (2) imagination of the future (visual imagery of future events, perceived temporal distance), (3) self-control, and (4) academic performance. We demonstrated that the three components of future self-identification were correlated but independent factors. Additionally, the three components differed in their unique relationships with the outcome domains, demonstrating the utility of measuring all three components of future self-identification when seeking to predict important psychological and behavioral outcomes.

Long COVID (LC) is a common chronic health condition that impairs daily functioning and social connections. This is the first randomized clinical trial to directly compare the effect of two Intermittent Fasting regimens on LC symptoms. The main objectives of this 10-week randomized cross-over trial are to compare the efficacy and safety of 4 weeks of 1–2 day fasting plus a restricted diet vs 4 weeks of mild time-restricted eating (TRE) and a restricted diet in reducing patient-reported LC symptoms. After a 2-week run-in, subjects were randomized to treatment A (TRE) or treatment B (Fasting) for 4 weeks. Subjects then crossed over to the other treatment for 4 weeks. The median fasting duration was 38 h (night-day-night), and the mean duration was 42 h. Symptoms were assessed via weekly online surveys. Primary outcomes were changes in LC symptom severity scores (LC-Scores) and in the number of LC symptoms (numLCsym) between treatments. Secondary outcomes were changes in LC-Scores and numLCsym over the 10-week trial. Fasting was superior to TRE alone in reducing LC-Scores (p = 0.008). The numLCsym decreased − 5.0 during the Fasting 4 weeks vs − 1.4 in the TRE 4 weeks (p = 0.002). Altogether, the 10-week regimen of a no-sugar diet, TRE and Fasting decreased the mean LC-Score by 51.8% (p < 0.0001) from 37.8 to 18.2. Similarly, numLCsym decreased from 20.5 to 12.2, a decrease of 40.6% (p < 0.0001). No major adverse safety events were recorded. Both intermittent fasting interventions decreased symptoms over the 10-week trial but the more intense fasting regimen was significantly better. Trial registration : ClinicalTrials.gov Identifier NCT06214455.

Background: Measurement of serum androgens is important in adult, geriatric, pediatric endocrinology, and oncology patients. We developed a liquid chromatography—tandem mass spectrometry (LC-MS/MS) assay for simultaneous measurement of androstenedione, dehydroepiandrosterone (DHEA), and testosterone in these patients. Methods: We spiked 200 μL of serum or plasma with isotope-labeled internal standards and performed extraction with methyl t-butyl ether. We then derivatized the extracts with hydroxylamine and analyzed them by LC-MS/MS using a 2-dimensional chromatographic separation with a 3.5-min analysis time. Results: Total imprecision for each analyte was <11.2%. Limits of quantification were 10, 50, and 10 ng/L for androstenedione, DHEA, and testosterone, respectively. Reference intervals were established for children (age 6 months to 17 years), men, and women. Androstenedione and DHEA concentrations were lowest in 2- to 3-year-old children. Adult concentrations were achieved in girls at Tanner stage 3 and in boys at Tanner stage 4–5. In premenopausal and (postmenopausal) women the median concentrations of androstenedione, DHEA, and testosterone were 810 (360), 3000 (1670), 270 (180) ng/L, respectively. In postmenopausal women, concentrations of testosterone were age independent, whereas androstenedione and DHEA concentrations decreased with age. In men the median concentrations of androstenedione, DHEA, and testosterone were 440, 2000, and 3700 ng/L, respectively. In men older than 40 years, median concentrations decreased at rates of 5%, 10%, and 20% per decade for androstenedione, DHEA, and testosterone, respectively. Conclusions: This LC-MS/MS method has the required lower limit of quantification and specificity for analysis of endogenous concentrations of androgens in all groups studied. Reference intervals were established for healthy children and adults.

Carbon nanotubes are commercially-important products of nanotechnology; however, their low density and small size makes carbon nanotube respiratory exposures likely during their production or processing. We have previously shown mitotic spindle aberrations in cultured primary and immortalized human airway epithelial cells exposed to single-walled carbon nanotubes (SWCNT). In this study, we examined whether multi-walled carbon nanotubes (MWCNT) cause mitotic spindle damage in cultured cells at doses equivalent to 34 years of exposure at the NIOSH Recommended Exposure Limit (REL). MWCNT induced a dose responsive increase in disrupted centrosomes, abnormal mitotic spindles and aneuploid chromosome number 24 hours after exposure to 0.024, 0.24, 2.4 and 24 μg/cm 2 MWCNT. Monopolar mitotic spindles comprised 95% of disrupted mitoses. Three-dimensional reconstructions of 0.1 μm optical sections showed carbon nanotubes integrated with microtubules, DNA and within the centrosome structure. Cell cycle analysis demonstrated a greater number of cells in S-phase and fewer cells in the G2 phase in MWCNT-treated compared to diluent control, indicating a G1/S block in the cell cycle. The monopolar phenotype of the disrupted mitotic spindles and the G1/S block in the cell cycle is in sharp contrast to the multi-polar spindle and G2 block in the cell cycle previously observed following exposure to SWCNT. One month following exposure to MWCNT there was a dramatic increase in both size and number of colonies compared to diluent control cultures, indicating a potential to pass the genetic damage to daughter cells. Our results demonstrate significant disruption of the mitotic spindle by MWCNT at occupationally relevant exposure levels.