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Some women who use cyclic hormonal contraception (CHC) suffer from premenstrual symptoms; whether their symptoms differ from women who do not use CHC is not clear.To compare women who use or do not use CHC on perimenstrual symptom timing and change severity.We analyzed daily symptom ratings from women who requested participation in (Screened Cohort: 103 used CHC and 387 did not) or were randomized in (Randomized Cohort: 41 used CHC and 211 did not) a clinical trial for premenstrual syndrome. We used effect sizes to compute and compare change scores between cycle phases in four partially overlapping perimenstrual windows defined relative to day 1 of menses [(-6, -1), (-5, 1), (-4, 2), (-3, 3)]. Differences in magnitude of change and timing were estimated using linear mixed-effects models.Both cohorts showed a significant two-way interaction between CHC use and symptom change scores (p 0.01) and a significant main effect of perimenstrual window (p 0.0001). Overall menstrual cycle symptom change was greater for the nonhormonal contraception versus hormonal contraception group. In the Screened Cohort, change scores were greater in the nonhormonal group specifically for depression (p = 0.04); anger or irritability (p 0.01); and physical symptoms (p 0.01). Mean change scores increased as the window shifted forward toward menses for both cohorts with the largest effect size and greatest group difference for (-4, 2) interval.CHC slightly attenuates menstrual cycle symptom change. The (-4, 2) perimenstrual interval shows the largest change compared with postmenses.

Panic disorder (PD) is associated with hyperventilation. The efficacy of a brief respiratory feedback program for PD has been established. The aim of the present study was to expand these results by testing a similar program with more clinically representative patients and settings. Sixty-nine adults with PD received 4 weeks of Capnometry Guided Respiratory Intervention (CGRI) using Freespira, which provides feedback of end-tidal CO2 (PETCO2) and respiration rate (RR), in four non-academic clinical settings. This intervention is delivered via home use following initial training by a clinician and provides remote monitoring of client adherence and progress by the clinician. Outcomes were assessed post-treatment and at 2- and 12-month follow-up. CGRI was associated with an intent-to-treat response rate of 83% and a remission rate of 54%, and large decreases in panic severity. Similar decreases were found in functional impairment and in global illness severity. Gains were largely sustained at follow-up. PETCO2 moved from the slightly hypocapnic range to the normocapnic range. Benchmarking analyses against a previously-published controlled trial showed very similar outcomes, despite substantial differences in sample composition and treatment settings. The present study confirms prior clinical results and lends further support to the viability of CGRI in the treatment of PD.

Ordinal data (eg, "low," "medium," "high"; graded response on a Likert scale) with an additional "don't know" category are frequently encountered in the medical, social, and behavioral science literature. The handling of a "don't know" option presents unique challenges as it often "destroys" the ordinal nature of the data. Commonly, nominal models are employed which ignore the partial ordering and have a complicated interpretation, especially in situations with repeatedly measured outcomes. We propose two-part models that easily accommodate longitudinal partially ordered (semiordinal) data. The most easily interpretable formulation consists of a random effect logistic submodel for "don't know" vs all the other categories combined, and a random effect ordinal submodel for the ordered categories. Correlated random effects account for statistical dependence within individual. An extension allowing for nonproportionality of odds for the predictor effects in the ordinal submodel is also considered. Maximum likelihood estimation is performed using adaptive Gaussian quadrature in SAS PROC NLMIXED. A simulation study is performed to evaluate the performance of the estimation algorithm in terms of bias and efficiency, and to compare the results of joint and separate models of the two parts, and of proportional and nonproportional model formulations. The methods are motivated and illustrated on a dataset from a study of adolescents' perceptions of nicotine strength of JUUL e-cigarettes. Using the proposed approach we show that adolescents perceive 5% nicotine content as relatively low, a misconception more pronounced among past month nonusers than among past month users of JUUL e-cigarettes.

BACKGROUND: General medical hospitals provide care for a disproportionate share of patients who misuse substances. Hospitalization provides a unique opportunity to identify and motivate patients to address their substance misuse. OBJECTIVE: To determine the effectiveness of three strategies for implementing motivational interviewing for substance misuse with general medical inpatients. DESIGN: Type 3 hybrid effectiveness-implementation randomized controlled trial (Clinical Trials.gov: NCT01825057). PARTICIPANTS: Thirty-eight providers (physicians, physician assistants, nurses) from 13 general medical inpatient services, and 1173 of their patients admitted to an academically affiliated acute care hospital. INTERVENTIONS: Implementation strategies included (1) a continuing medical education workshop on detection of substance misuse and provision of a motivational interview; (2) workshop plus bedside supervision (apprenticeship condition); and (3) a workshop plus ability to place a medical order for an interview from a consultation-liaison service (consult condition). MAIN MEASURES: Primary outcomes were the percentage of study-eligible patients who received an interview for substance misuse and the integrity (adherence, competence) of the interviews. The secondary outcome was the percent of patient statements within the interviews that indicated motivation for reducing substance misuse. KEY RESULTS: 20.5% of patients in the consult condition received an interview, compared to 0.8% (Hedge’s g = 1.49) and 3.0% (Hedge’s g = 1.26) in the respective workshop only and apprenticeship conditions (p

Increasing evidence supports a rapid antidepressant and antisuicidal effect of a single subanesthetic dose of ketamine infusion for treatment-resistant depression (TRD). Maintaining the initial clinical response after ketamine infusion in TRD is a crucial next-step challenge. D-cycloserine (DCS), a partial agonist of the glycine co-agonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, is potentially effective as a depression augmentation treatment. However, whether DCS maintains the antidepressant and antisuicidal effects of ketamine infusion remains unknown. In all, 32 patients with TRD (17 with major depression and 15 with bipolar depression) who responded to ketamine infusion with an average 17-item Hamilton Depression Rating Scale (HAMD) score of 9.47 ± 4.11 at baseline were randomly divided to 6-week DCS treatment (250 mg for 2 days, 500 mg for 2 days, 750 mg for 3 days, and 1000 mg for 5 weeks) and placebo groups. Depression symptoms were rated at timepoints of dose titration and weekly. During the 6-week treatment, the total scores of HAMD did not differ between the DCS and placebo groups. The results remained consistent when stratified by disorder. A mixed model analysis indicated that the DCS group exhibited lower scores of HAMD item 3 (suicide) compared with the placebo group throughout the follow-up period (p = 0.01). A superior maintenance of the antisuicidal effect of ketamine was observed in the DCS group than in the placebo group. DCS may be therapeutically beneficial for patients with TRD who responded to ketamine infusion but have a residual suicidal risk.

Background Extensive research indicates that having a positive family history of alcohol use disorder (FHP) and impulsivity are 2 risk factors for problem drinking. To our knowledge, no study has investigated which facets of impulsivity interact with family history to increase risk for problem drinking. The goal of this study was to: (i) examine whether FHP individuals with higher levels of impulsivity are more likely to engage in problematic drinking, and (ii) identify which facets of impulsivity interact with FHP to increase risk for problems. Methods The data consisted of a combined sample of 757 participants (50% female, 73% White, mean age = 32.85, SD = 11.31) drawn from the Transdisciplinary Tobacco Use Research Center and the Center for the Translational Neuroscience of Alcohol. Analyses of covariance and cumulative logistic regression models investigated the association of family history and impulsivity-related traits with drinking quantity, frequency, and alcohol-related problems. Models were adjusted for age, sex, race, ethnic group, education level, and data source. Results Significant interactions between impulsivity and family history were found for measures of alcohol-related problems. Specifically, there was a stronger positive association of Barratt Impulsiveness Scale (BIS) poor self-regulation with interpersonal, F(1, 504) = 6.27, p = 0.01, and impulse control alcohol-related problems, F(1, 504) = 6.00, p = 0.01, among FHP compared to FHN individuals. Main effects of family history and impulsivity on alcohol quantity and frequency of use and problems were also found. Conclusions These findings suggest that having both a family history of AUD and high BIS poor self-regulation is more strongly associated with alcohol-related consequences in the interpersonal and impulse control domains. Given the heterogeneity of impulsivity, these findings highlight the need for additional research to examine which facets of impulsivity are associated with which alcohol outcomes to narrow phenotypic risk for alcohol misuse.

OBJECTIVE To examine whether race predicted or moderated response to treatments for binge-eating disorder (BED). METHOD Participants were 592 adults (n = 113 Black; n = 479 White) with DSM-IV-defined BED who participated in randomized controlled trials (RCTs) at 1 medical center. Data were aggregated from RCTs for BED testing cognitive-behavioral therapy, behavioral weight loss, multimodal treatment, and/or control conditions. Participants had weight and height measured and were assessed using established interviews and self-report measures at baseline, throughout treatment, and post treatment. RESULTS Race did not significantly moderate treatment outcomes. Mixed models revealed a main effect of race: Black participants had fewer binge-eating episodes and lower depression than White participants across time points. Race also had a main effect in generalized estimating equations with a significantly greater proportion of Black participants achieving binge-eating remission than White participants. Race did not predict percent weight loss, but a significantly lower proportion of Black participants attained 5% weight loss than White participants. Race did not significantly predict global eating-disorder severity. CONCLUSION Despite disparities in treatment-seeking reported in epidemiological and RCT studies, Black individuals appear to have comparable or better treatment outcomes in BED treatment research compared with White individuals, except they were less likely to attain 5% weight loss at post treatment. This suggests that disseminating evidence-based treatments for BED among diverse populations holds promise and treatments may not require further adaptation prior to dissemination. Implementation research is needed to test treatment effectiveness across diverse providers, settings, and patient groups to improve understanding of potential predictors and moderators. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Stress and trauma exposure disturbs stress regulation systems and thus increases the vulnerability for stress-related disorders which are characterized by negative affect, including major depressive disorder, anxiety disorders and posttraumatic stress disorder. Similarly, stress and trauma exposure results in increased vulnerability to problematic alcohol use and alcohol use disorder, especially among women, who are more likely to drink to cope with negative affect than their male counterparts. Given these associations, the relationship between stress-related disorders and alcohol use is generally stronger among women leading to complex comorbidities across these disorders and alcohol misuse. This review highlights the therapeutic potential for progestogen- and androgen-derived neurosteroids, which affect both stress- and alcohol-related disorders, to target the overlapping symptoms related to negative affect. This article is part of the special issue on 'Vulnerabilities to Substance Abuse.'

BACKGROUND: Adolescent e-cigarette use has increased recently; however, little is known about trends in use of specific devices by youth. This study aims to 1) compare rates of e-cigarette device use over time, 2) examine changes in frequency of device use, and 3) identify predictors of device use. METHODS: Cross-sectional surveys were distributed school-wide across 4 diverse Connecticut high-schools in 2017, 2018, 2019 and assessed current (i.e., past-30-day) use of various e-cigarette devices: disposables/cig-a-likes, vape pens, mods, JUULs, and other rechargeable pod devices (added in 2018 and 2019). Analyses compared rates of device use and frequency (i.e., number of days used in past 30) over time. Multivariable logistic regression models examined demographic and tobacco use characteristics (e.g., age first trying e-cigarettes) as predictors of current use of each device type in 2019. RESULTS: From 2017–2019, rates of using JUUL, disposables/cig-a-likes, and vape pens increased significantly, while use of mods and other pod devices decreased (ps46%) and JUUL (28% to >35%) devices. In multivariable models, first trying e-cigarettes at a younger age was associated with current use of disposable/cig-a-like, vape pens, mods, and other rechargeable pod devices. CONCLUSIONS: From 2017–2019, JUUL, disposable/cig-a-like, and vape pens increased in popularity and were used frequently. Tobacco regulations designed to reduce youth use should consider various device types.

Tertiary Health Research Intervention via Email (THRIVE), a very brief, freely available, multicomponent Web-based alcohol intervention originally developed and tested among students in Australia and New Zealand, was tested in the United States. We also evaluated effects of systematically varying the protective behavioral strategies (PBS) component of the intervention to include shorter, focused lists of direct (e.g., alternating alcoholic with nonalcoholic drinks) or indirect (e.g., looking out for friends) strategies. Undergraduates with past-month heavy drinking ( = 208) were randomized to education/assessment control or one of three U.S.-THRIVE variants, including direct PBS only, indirect PBS only, or full (direct and indirect PBS). After 1 month, compared to the control condition, full condition participants reported fewer drinks per week (rate ratio [RR] =.62) and lower peak drinking (RR =.74). The indirect-only condition reported reduced peak drinking (RR =.74) and a trend toward fewer drinks per week (RR =.78). Changes in drinking relative to control were significant through 6 months for the full and indirect-only conditions. There were no significant differences between the direct-only and control conditions. U.S.-THRIVE was not associated with decreased heavy drinking or alcohol-related problems relative to control. To our knowledge, this was the first study to systematically vary the types of PBS provided in an intervention. Initial results suggest U.S.-THRIVE is efficacious. Compared to control, presenting indirect PBS only as part of U.S.-THRIVE was associated with lower drinks per week and peak past 30-day drinking. Targeting indirect PBS may be more appropriate for non-treatment-seeking young adults receiving a brief intervention. (PsycINFO Database Record(c) 2016 APA, all rights reserved). Language: en

Generalized anxiety disorder (GAD) is characterized by emotion regulation difficulties, which are associated with abnormalities in neural circuits encompassing fronto-limbic regions including the dorsolateral prefrontal cortex (DLPFC). The aim of this study was to determine whether DLPFC neuromodulation improves emotion regulation in patients with GAD. This is a secondary analysis from a randomized-controlled trial comparing 30 sessions of low-frequency right-sided active (n=13) versus sham (n=12, sham coil) repetitive transcranial magnetic stimulation (rTMS) at the right DLPFC in patients with GAD. Results indicated statistically significant improvements in self-reported emotion regulation difficulties at posttreatment and 3-month follow-up in the active group only. Improvements were found primarily in the domains of goal-directed behaviors and impulse control and were significantly associated with a global clinician rating of improvement. These preliminary results support rTMS as a treatment for GAD and suggest improved emotion regulation as a possible mechanism of change.

Background Initial studies have provided a mixed perspective of the efficacy of d-cycloserine (DCS) for augmenting the efficacy of exposure-based cognitive behavioral therapy (CBT) for panic disorder. In this multicenter trial, we examine the magnitude of DCS augmentation effects for an ultra-brief program of CBT. Methods We conducted a double-blind, controlled trial at three treatment sites, randomizing 180 adults with a primary diagnosis of panic disorder to five sessions of treatment, with study pill (50 mg DCS or matching placebo) administered 1 hr prior to the final three sessions. Two booster sessions were subsequently provided, and outcome was assessed at posttreatment and 1-month, 2-month, and 6-month follow-up assessments. The primary outcome was the degree of reduction in the Panic Disorder Severity Scale. Additional analyses examined the role of severity and current antidepressant or benzodiazepine use as moderators of DCS augmentation effects. Results DCS augmentation resulted in significant benefit only early in the trial, with no beneficial effects of DCS augmentation evident at follow-up evaluations. We did not find that baseline severity or antidepressant or benzodiazepine use moderated DCS efficacy, but benzodiazepine use was associated with lower efficacy of CBT regardless of augmentation condition. Conclusions Consistent with other recent multicenter trials, the benefit of DCS was less than indicated by pilot study and reflected an acceleration of treatment response evident at treatment endpoint, but no advantage in response over follow-up evaluation. Our results did not support severity or concomitant medication moderators observed in previous trials of DCS augmentation.

The Health and Retirement Study was designed to evaluate changes in health and labor force participation during and after the transition from working to retirement. Every 2 years, participants provided information about their self-rated health (SRH), body mass index (BMI), smoking status, and other characteristics. Our goal was to assess the effects of smoking and gender on trajectories of change in BMI and SRH over time. Joint longitudinal analysis of outcome measures is preferable to separate analyses because it allows to account for the correlation between the measures, to test the effects of predictors while controlling type I error, and potentially to improve efficiency. However, because SRH is an ordinal measure while BMI is continuous, formulating a joint model and parameter estimation is challenging. A joint correlated probit model allowed us to seamlessly account for the correlations between the measures over time. Established estimating procedures for such models are based on quasi-likelihood or numerical approximations that may be biased or fail to converge. Therefore, we proposed a novel expectation-maximization algorithm for parameter estimation and a Monte Carlo bootstrap approach for standard errors approximation. Expectation-maximization algorithms have been previously considered for combinations of binary and/or continuous repeated measures; however, modifications were needed to handle combinations of ordinal and continuous responses. A simulation study demonstrated that the algorithm converged and provided approximately unbiased estimates with sufficiently large sample sizes. In the Health and Retirement Study, male gender and smoking were independently associated with steeper deterioration in self-rated health and with lower average BMI. Copyright © 2016 John Wiley & Sons, Ltd.

Background The liquids (e-liquids) used in an electronic cigarette (e-cigarette) contain myriad chemicals without adequate human inhalation safety data. Furthermore, the absence of e-liquid labeling requirements poses a formidable challenge to understanding how e-liquid constituents may promote nicotine addiction and/or have independent or synergistic biological effects when combined with nicotine. Ethyl alcohol is such a constituent, but has received little scientific interest in this context. Methods Using a randomized, double blind, crossover design, acute changes in subjective drug effects, motor performance and biochemical measures of alcohol and nicotine intake were evaluated after directed and ad lib puffing from two commercially available e-liquids containing nicotine (8 mg/ml), vanilla flavor and either 23.5% (high) or 0.4% (trace) alcohol. Results While no differences in subjective drug effects were observed between alcohol conditions, performance on the Purdue Pegboard Dexterity Test (PPDT) improved under the trace, but not under the 23.5% alcohol condition. Although plasma alcohol levels remained undetectable during testing, urine ethyl glucuronide (EtG), an alcohol metabolite, became measurable in three participants after puffing from the 23.5% alcohol e-cigarette. Conclusions Brief use of a widely available type of e-cigarette containing an e-liquid purchased from an internet vendor can negatively impact psychomotor performance and in some instances, produce detectable levels of a urine alcohol metabolite. Given the widespread and unregulated use of e-cigarettes, especially by youth and other vulnerable populations, further studies are needed to evaluate both the acute safety and long-term health risks of using alcohol-containing e-cigarettes.

Food addiction (FA) has been linked to clinical features in binge-eating disorder (BED) and obesity. A feature of behavioral weight loss (BWL) treatment involves frequent weighing. However, little is known regarding how frequency of self-weighing and related perceptions are associated with BWL outcomes among individuals with BED and obesity stratified by FA status. Participants (n = 186) were assessed with the Eating Disorder Examination before and after BWL treatment. Mixed effects models examined FA (presence/absence) before and after (post-treatment and 6- and 12-month follow-up) treatment and associations with frequency of weighing and related perceptions (reactions to weighing, sensitivity to weight gain and shape/weight acceptance). Participants with FA reported more negative reactions to weighing and less acceptance of shape/weight throughout treatment and follow-ups, and both variables were associated with greater disordered eating at follow-ups among participants with FA. Sensitivity to weight gain decreased over time independent of FA status. Frequency of weighing was associated with a greater likelihood of achieving 5% weight loss only among those without FA. Reactions to weighing and sensitivity to weight gain are associated with FA and poorer treatment outcomes in individuals with BED and obesity. Targeting these features may improve BWL outcomes among individuals with BED, obesity and FA.

BACKGROUND: Ketamine exerts rapid and robust antidepressant effects thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. METHODS: Twenty-three patients suffering a major depressive episode were randomized to oral rapamycin (6 mg) or placebo, each was followed 2 hours later by ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery Asberg Depression Rating Scale (MADRS). Antidepressant response was defined as a MADRS improvement of 50% or more. RESULTS: Over the two-week follow-up, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), reflecting prolonged antidepressant effects post rapamycin+ketamine treatment. At 2 weeks, we found a significantly higher response rate following rapamycin+ketamine (41%) compared to placebo+ketamine (13%, p = 0.04). However, rapamycin pretreatment did not alter the acute effects of ketamine. CONCLUSION: Unexpectedly, pretreatment with rapamycin prolonged rather than blocked the acute antidepressant effects of ketamine. This observation raises questions about the role of mTORC1 in the antidepressant effects of ketamine, raises the possibility that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that limit the duration of ketamine effects. The supplementing of ketamine with rapamycin may be a treatment strategy for reducing the frequency of ketamine infusions during maintenance treatment.

Background and aims To estimate progression to polytobacco use (PTU) over 1 year among a sample of US youth. Design Prospective survey with two waves 1 year apart: wave 1 (2013-14) and wave 2 (2014-15). We conducted latent transition analysis (LTA) to identify latent class transitions and examine socio-demographic predictors of transition types. Setting United States. Participants A total of 11, 996 people who were aged 12-17 years at wave 1. Measurements Publicly available data were used from the Population Assessment of Tobacco and Health (PATH) study, a nationally representative sample of US civilian, non-institutionalized population aged 12 years and older. Tobacco use status was assessed and classified in terms of: never use, non-current (not in the past 30 days) and current (past 30-day) use of cigarettes, cigars, e-cigarettes, hookah and smokeless tobacco. Other nicotine products were excluded because rates of use were either too low to model (e.g. pipe) or the product was not assessed in the PATH youth sample (e.g. nicotine replacement products). Findings We identified three distinct patterns: class 1, non-use (wave 1 prevalence = 86%; wave 2 prevalence = 78%); class 2, ever use of cigarettes and e-cigarettes (wave 1 prevalence = 11%; wave 2 prevalence = 14%); and class 3, current PTU (wave 1 prevalence = 4%; wave 2 prevalence = 7%). Probability of progression from non-use to ever use of cigarettes and e-cigarettes was 0.06 and ever use of cigarettes and e-cigarettes to current PTU was 0.32. Non-users were more likely to transition to ever use of cigarettes and e-cigarettes if they were older (versus younger), white (versus non-white) or if their parental education level was high school or less (versus more than high school); and ever users of cigarettes and e-cigarettes to current PTU if they were older, male or white. Conclusions US youth who had previously tried e-cigarettes and cigarettes at wave 1 (2013-14) had a 32% chance of transitioning to current use of two or more tobacco products within 1 year.

Posttraumatic stress disorder (PTSD) is a debilitating disorder with limited medication treatment options. Recent reports have described the dearth of research on new drug development as a crisis in the pharmacotherapy of PTSD. There are only two PTSD medications approved by the U.S. Food and Drug Administration, and both are serotonergic antidepressants. Therefore, there is a tremendous need to identify more effective and more rapidly acting pharmacotherapies for PTSD that work through novel neural mechanisms. Pilot evidence and case reports provided preliminary evidence supporting the safety and utility of investigating the therapeutic effects of ketamine in PTSD. However, the efficacy of this drug for PTSD has not yet been tested in active duty military or veteran populations. Here, we report the design and methods of a study funded under the Consortium to Alleviate PTSD. The study is a multisite, placebo-controlled, double–blind, randomized clinical trial to examine the dose-related efficacy of ketamine, as compared to placebo, in producing a rapid and sustained reduction in PTSD symptomatology in veterans and active duty military populations with antidepressant-resistant PTSD. Approximately 198 eligible participants who meet criteria for PTSD will be randomized to the study drug (i.e., ketamine 0.5 mg/kg, ketamine 0.2 mg/kg, or placebo). The study drug will be administered intravenously twice per week for 4 weeks, followed by a 4-week follow-up period. This ongoing study is the only trial of therapeutic effects of ketamine for PTSD and the first placebo-controlled trial to determine the dose-related effects of repeated ketamine on PTSD.

Objective: Even though safe and effective treatments for depression are available, many individuals with a diagnosis of depression do not obtain treatment. This study aimed to develop a tool to identify persons who might not initiate treatment among those who acknowledge a need.Methods: Data were aggregated from the 2008–2014 U.S. National Survey on Drug Use and Health (N=391,753), including 20,785 adults given a diagnosis of depression by a health care provider in the 12 months before the survey. Machine learning was applied to self-report survey items to develop strategies for identifying individuals who might not get needed treatment.Results: A derivation cohort aggregated between 2008 and 2013 was used to develop a model that identified the 30.6% of individuals with depression who reported needing but not getting treatment. When applied to independent responses from the 2014 cohort, the model identified 72% of those who did not initiate treatment (pConclusions: Considerable work is needed to improve follow-up and retention rates after the critical initial meeting in which a patient is given a diagnosis of depression. Routinely collected information about patients with depression could identify those at risk of not obtaining needed treatment, which may inform the development and implementation of interventions to reduce the prevalence of untreated depression.

BACKGROUND: Veterans are disproportionately affected by overweight/obesity and growing evidence suggests that post-deployment is a critical period of accelerated weight gain. OBJECTIVE: We explored the relationship between posttraumatic stress disorder (PTSD) diagnosis, gender, and post-deployment weight trajectories among U.S. Operations Iraqi Freedom, Enduring Freedom, and New Dawn veterans. DESIGN: We used Veterans Affairs electronic health record data from 248,089 veterans (87% men) who, after their last deployment, had at least one medical visit between October 2001 and January 2009 and more than one BMI recorded through September 2010. We analyzed repeated BMI measurements using linear mixed models, with demographics, PTSD and other relevant psychiatric diagnoses as predictors. RESULTS: At the first recorded BMI, veterans’ median age was 29, and 59% of women and 77% of men were overweight/obese. They had a median of 6 BMI measurements during a median follow-up of 2.4 years. Controlling for potential confounders, women with a PTSD diagnosis had a yearly BMI growth rate of 0.11 kg/m(2) (95% CI 0.09 to 0.13, p

OBJECTIVE: Compared to the general U.S. population, smokers with comorbid psychiatric and/or substance use disorders (SUD) have lower quit rates after evidence-based treatments, and disproportionately high smoking-related deaths. Improved modalities for reducing tobacco-related harm in this subpopulation are needed. Because electronic cigarettes (e-cigarettes) can now deliver physiologically relevant levels of nicotine to consumers, they represent an additional nicotine delivery system that could be used in cessation interventions. While current data suggests that the use of e-cigarettes by smokers promotes a reduction in combustible cigarette use, smoking quit rates through use of e-cigarettes appears to be low. The goal of this study was to examine impact of e-cigarette use on combustible tobacco use, as well as on the readiness to quit smoking and changes in nicotine dependence, in a multi-morbid population. METHODS: We conducted a 4-week, open label study in 43 military veteran smokers who had no immediate intention to stop smoking and were currently receiving psychiatric services from the Department of Veterans Affairs (VA) healthcare system. Participants were provided with a study e-cigarette they could use ad libitum along with other tobacco products, and were encouraged to attend weekly laboratory visits and a one-month follow-up visit. Main outcome measures were number of cigarettes smoked per day (CPD), the frequency of e-cigarette use, the amount of money spent on combustible cigarettes (U.S. dollars/week), alveolar carbon monoxide (CO) levels, and urine cotinine levels. RESULTS: Mean e-cigarette use was 5.7 days per week and only 9% of participants used the e-cigarette for less than 4 days per week. Significant reductions in breath CO (9.3 ppm to 7.3 ppm, p < 0.02) and CPD (from 16.6 to 5.7, p < 0.001) were observed across study weeks, and no serious adverse events were reported. Three participants (10% of completers) reported smoking cessation that was corroborated biochemically. At one-month follow-up, motivation to quit smoking remained significantly higher, and the level of nicotine dependence was significantly lower, than at baseline. CONCLUSIONS: E-cigarettes are acceptable to smokers with psychiatric comorbidities, as indicated by sustained and frequent e-cigarette use by 90% of participants, and may promote reduction and/or cessation of combustible cigarette use. E-cigarettes appear to be a viable harm reduction modality in smokers with psychiatric comorbidities.

Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose–response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.

Although the primary focus of clinical trials is on between-group comparisons during treatment, these studies can also yield insights into which patient characteristics predict longer term outcomes. Our goal was to identify predictors of good outcome during the 1-year follow-up in the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study.We constructed classification trees and a deterministic forest to predict no heavy drinking days during the last 8 weeks of the 1-year follow-up in COMBINE, based on more than 100 baseline predictors and drinking outcomes during the treatment phase of the study. The COMBINE sample was randomly split into a training and a validation data set. Logistic regression models were fit to compare the predictive performance of tree-based methods and classical methods.A small tree with only two splits and four nodes based on abstinence and good clinical outcome during treatment had fair classification accuracy in the training and the validation samples: area under the curve (AUC) of 71% and 70%, respectively. Drinking outcomes during treatment were the strongest predictors in the deterministic forest. Logistic regression analyses based on four main effects (good clinical outcome, level of drinking during treatment, age at onset of alcohol dependence, and feeling more energetic) had slightly better classification accuracy (AUC = 74%).End-of-treatment outcomes were the strongest predictors of long-term outcome in all analyses. The results emphasize the importance of optimizing outcomes during treatment and identify potential subgroups of individuals who require additional or alternative interventions to achieve good long-term outcome.

Binge-eating disorder (BED), a formal eating-disorder diagnosis in DSM-5 (APA, 2013), is defined by recurrent binge eating, marked distress about binge eating, and the absence of extreme weight compensatory behaviors. BED is prevalent and is associated strongly with obesity and biopsychosicial problems (APA, 2013). Although some psychological and medication treatments have varying levels of effectiveness for BED, many patients fail to achieve remission from binge-eating and most fail to achieve significant weight loss (Reas & Grilo, 2014). Finding reliable predictors of treatment response could inform treatment prescriptions but this has been challenging (Grilo, Masheb, & Crosby, 2012). Rapid response (i.e., substantial improvements in symptoms during the early weeks of treatment) has been found to significantly predict treatment outcomes across diverse psychiatric problems, including medication and CBT treatments for depression (Taylor, Freemantle, Geddes, & Bhagwagar, 2006; Hardy et al., 2005) and bulimia nervosa (Sysko et al., 2010; Wilson et al., 2002). In a series of four studies, Grilo et al. (Grilo, Masheb, & Wilson, 2006; Grilo & Masheb, 2007; Grilo, White, Wilson, Gueorguieva, & Masheb, 2012; Masheb & Grilo, 2007) extended the rapid response findings to BED in several ways. First, the definition of rapid response was informed empirically using receiver operating characteristic (ROC) curves. These methods yielded “reliable” findings across studies that 65%–70% reductions in binge-eating by the fourth treatment week optimally predicted remission. Second, rapid response predicted significantly greater reductions in eating-disorder pathology in all four studies and greater weight loss in three studies (Grilo et al., 2006; Grilo & Masheb, 2007; Grilo et al., 2012). Third, rapid response was unrelated to nearly all baseline characteristics in the four studies suggesting rapid responders are not just “easy” patients nor do they show individual differences in demographic or clinical severity. Fourth, rapid response had varied prognostic significance across different treatments for BED (Grilo et al., 2006; 2012). Finally, the longer-term prognostic significance of rapid response to treatment for BED was established in the one study with follow-up (Grilo et al., 2012). Further research on rapid response is needed to establish longer-term significance and to extend findings to additional interventions (e.g., scalable treatments such as “self-help” CBT (shCBT) (Wilson & Zandberg, 2012)) and to broader health care settings with more diverse patient groups. One study with depression found that “sudden gains” with CBT had less predictive significance in routine clinical settings than in specialist settings (Hardy et al., 2005). Members of minority groups with BED receive most of their health care from primary care (Marques et al., 2011) and it is uncertain whether “effective” treatments delivered by specialists are as effective when delivered by generalists. The present study examined rapid response among patients with BED participating in a treatment study in primary care settings (serving racially and ethnically diverse persons) testing anti-obesity medication (sibutramine (Wilfley et al., 2008)) and shCBT, alone and in combination. We examine whether rapid response was related to patient characteristics and to outcomes through 12-months of follow-up after completing treatments.

The term mastocytosis encompasses a number of clonal disorders characterized by abnormal expansion of mast cells localized in different tissues [1]. The most recent WHO classification (2016) promot...

Background Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive impairments associated with schizophrenia. The dose-related occupancy and target engagement of the GlyT1 inhibitor PF-03463275 were studied to inform optimal dose selection for a clinical trial for cognitive impairments associated with schizophrenia. Methods In substudy 1, the effects of PF-03463275 (10, 20, and 40 mg twice a day) on occupancy of GlyT1 were tested using positron emission tomography and 18F-MK-6577, and visual long-term potentiation (LTP) in schizophrenia patients (SZs) and healthy control subjects. Furthermore, the capacity of PF-03463275 to attenuate ketamine-induced disruption of working memory–related activation of a “working memory” circuit was tested only in healthy control subjects using functional magnetic resonance imaging. Subsequently, the effects of PF-03463275 (60 mg twice a day) on occupancy of GlyT1 and long-term potentiation were examined only in SZs (substudy 2). Results PF-03463275 at 10, 20, 40, and 60 mg twice a day produced ∼44%, 61%, 76%, and 83% GlyT1 occupancy, respectively, in SZs with higher ligand binding to GlyT1 in subcortical versus cortical regions. PF-03463275 did not attenuate any ketamine-induced effects but did improve working memory accuracy in healthy control subjects. PF-03463275 increased long-term potentiation only in SZs with peak effects at 40 mg twice a day (∼75% GlyT1 occupancy) and with a profile suggestive of an inverted U dose response. PF-03463275 was well-tolerated. Conclusions The dose-related GlyT1 occupancy of PF-03463275 is linear. While PF-03463275 did not show evidence of facilitating N-methyl-D-aspartate receptor function in the ketamine assay, it enhanced neuroplasticity in SZs. These findings provide support for a clinical trial to test the ability of PF-03463275 to enhance cognitive remediation toward addressing cognitive impairments associated with schizophrenia.

Tobacco products containing menthol are widely used by youth. We used e-cigarettes to conduct an experimental evaluation of the independent and interactive effects of menthol and nicotine among youth.Pilot chemosensory experiments with fourteen e-cigarette users identified low (barely perceptible, 0.5%) and high (similar to commercial e-liquid, 3.5%) menthol concentrations. Sixty e-cigarette users were randomized to a nicotine concentration (0mg/ml, 6mg/ml, 12mg/ml) and participated in 3 laboratory sessions. During each session, they received their assigned nicotine concentration, along with one of three menthol concentrations in random counterbalanced order across sessions (0, 0.5%, 3.5%), and participated in three fixed-dose, and an ad-lib, puffing period. Urinary menthol glucuronide and salivary nicotine levels validated menthol and nicotine exposure. We examined changes in e-cigarette liking/wanting and taste, coolness, stimulant effects, nicotine withdrawal and ad-lib use.Overall, the high concentration of menthol (3.5%) significantly increased e-cigarette liking/wanting relative to no menthol (p0.001); there was marginal evidence of nicotine* menthol interactions (p=0.06), with an increase in liking/wanting when 3.5% menthol was combined with 12mg/ml nicotine, but not 6mg/ml nicotine. Importantly, both 0.5% and 3.5% menthol concentrations significantly improved taste and increased coolness. We did not observe nicotine or menthol-related changes in stimulant effects, nicotine withdrawal symptoms or ad-lib use.Menthol, even at very low doses, alters the appeal of e-cigarettes among youth. Further, menthol enhances positive rewarding effects of high nicotine-containing e-cigarettes among youth.

Depressive severity is typically measured according to total scores on questionnaires that include a diverse range of symptoms despite convincing evidence that depression is not a unitary construct. When evaluated according to aggregate measurements, treatment efficacy is generally modest and differences in efficacy between antidepressant therapies are small.To determine the efficacy of antidepressant treatments on empirically defined groups of symptoms and examine the replicability of these groups.Patient-reported data on patients with depression from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (n = 4039) were used to identify clusters of symptoms in a depressive symptom checklist. The findings were then replicated using the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (n = 640). Mixed-effects regression analysis was then performed to determine whether observed symptom clusters have differential response trajectories using intent-to-treat data from both trials (n = 4706) along with 7 additional placebo and active-comparator phase 3 trials of duloxetine (n = 2515). Finally, outcomes for each cluster were estimated separately using machine-learning approaches. The study was conducted from October 28, 2014, to May 19, 2016.Twelve items from the self-reported Quick Inventory of Depressive Symptomatology (QIDS-SR) scale and 14 items from the clinician-rated Hamilton Depression (HAM-D) rating scale. Higher scores on the measures indicate greater severity of the symptoms.Of the 4706 patients included in the first analysis, 1722 (36.6%) were male; mean (SD) age was 41.2 (13.3) years. Of the 2515 patients included in the second analysis, 855 (34.0%) were male; mean age was 42.65 (12.17) years. Three symptom clusters in the QIDS-SR scale were identified at baseline in STAR*D. This 3-cluster solution was replicated in CO-MED and was similar for the HAM-D scale. Antidepressants in general (8 of 9 treatments) were more effective for core emotional symptoms than for sleep or atypical symptoms. Differences in efficacy between drugs were often greater than the difference in efficacy between treatments and placebo. For example, high-dose duloxetine outperformed escitalopram in treating core emotional symptoms (effect size, 2.3 HAM-D points during 8 weeks, 95% CI, 1.6 to 3.1; P .001), but escitalopram was not significantly different from placebo (effect size, 0.03 HAM-D points; 95% CI, -0.7 to 0.8; P = .94).Two common checklists used to measure depressive severity can produce statistically reliable clusters of symptoms. These clusters differ in their responsiveness to treatment both within and across different antidepressant medications. Selecting the best drug for a given cluster may have a bigger benefit than that gained by use of an active compound vs a placebo.

BACKGROUND: The goal of the current study was to use tree-based methods (Zhang and Singer, 2010, Recursive Partitioning and Applications, 2nd ed. Springer, New York) to identify predictors of abstinence from heavy drinking in COMBINE (Anton et al. JAMA 2006; 295:2003), the largest study of pharmacotherapy for alcoholism in the United States to date, and to validate these results in PREDICT (Mann et al. Addict Biol 2012; 18:937), a parallel study conducted in Germany. METHODS: We compared a classification tree constructed according to purely statistical criteria to a tree constructed according to a combination of statistical criteria and clinical considerations for prediction of no heavy drinking during treatment in COMBINE. We considered over 100 baseline predictors. The tree approach was compared to logistic regression. The trees and a deterministic forest identified the most important predictors of no heavy drinking for direct testing in PREDICT. RESULTS: The tree built using both clinical and statistical considerations consisted of 4 splits based on consecutive days of abstinence (CDA) prior to randomization, age, family history of alcoholism, and confidence to resist drinking in response to withdrawal and urges. The tree based on statistical considerations with 4 splits also split on CDA and age but also on gamma-glutamyl transferase level and drinking goal. Deterministic forest identified CDA, age, and drinking goal as the most important predictors. Backward elimination logistic regression among the top 18 predictors identified in the deterministic forest analyses identified only age and CDA as significant main effects. Longer CDA and goal of complete abstinence were associated with better outcomes in both data sets. CONCLUSIONS: The most reliable predictors of abstinence from heavy drinking were CDA and drinking goal. Trees provide binary decision rules and straightforward graphical representations for identification of subgroups based on response and may be easier to implement in clinical settings. Language: en

The objective was to determine whether treatments with demonstrated efficacy for binge eating disorder (BED) in specialist treatment centers can be delivered effectively in primary care settings to racially/ethnically diverse obese patients with BED. This study compared the effectiveness of self-help cognitive-behavioral therapy (shCBT) and an anti-obesity medication (sibutramine), alone and in combination, and it is only the second placebo-controlled trial of any medication for BED to evaluate longer-term effects after treatment discontinuation. 104 obese patients with BED (73% female, 55% non-white) were randomly assigned to one of four 16-week treatments (balanced 2-by-2 factorial design): sibutramine (N = 26), placebo (N = 27), shCBT + sibutramine (N = 26), or shCBT + placebo (N = 25). Medications were administered in double-blind fashion. Independent assessments were performed monthly throughout treatment, post-treatment, and at 6- and 12-month follow-ups (16 months after randomization). Mixed-models analyses revealed significant time and medication-by-time interaction effects for percent weight loss, with sibutramine but not placebo associated with significant change over time. Percent weight loss differed significantly between sibutramine and placebo by the third month of treatment and at post-treatment. After the medication was discontinued at post-treatment, weight re-gain occurred in sibutramine groups and percent weight loss no longer differed among the four treatments at 6- and 12-month follow-ups. For binge-eating, mixed-models revealed significant time and shCBT-by-time interaction effects: shCBT had significantly lower binge-eating frequency at 6-month follow-up but the treatments did not differ significantly at any other time point. Demographic factors did not significantly predict or moderate clinical outcomes. Our findings suggest that pure self-help CBT and sibutramine did not show long-term effectiveness relative to placebo for treating BED in racially/ethnically diverse obese patients in primary care. Overall, the treatments differed little with respect to binge-eating and associated outcomes. Sibutramine was associated with significantly greater acute weight loss than placebo and the observed weight-regain following discontinuation of medication suggests that anti-obesity medications need to be continued for weight loss maintenance. Demographic factors did not predict/moderate clinical outcomes in this diverse patient group.

Background Disulfiram and naltrexone were evaluated in treatment of individuals with co-occurring alcohol dependence and other Axis I disorders (e.g., Major Depression). We explored pharmacogenetic interactions in genotyped subjects. Methods Alcohol dependent (AD) subjects received naltrexone alone, placebo alone, disulfiram with placebo or disulfiram with naltrexone. They were genotyped for OPRM1 rs1799971 (Asn40Asp), and DBH rs1611115 (C-1021T). N = 107 male European-American subjects were included. Results There were no significant interactions with OPRM1. DBH interacted with naltrexone on the primary outcome of abstinence from heavy drinking (χ2(1) = 5.23, p = .02). “T” allele carriers on naltrexone had more abstinence compared to “CC” subjects on naltrexone (FET, p = .01). “T” allele carriers on naltrexone had the highest overall rates of abstinence from heavy drinking (>90%). Also, DBH genotype interacted with disulfram (F(1,17) = 7.52, p = .01) on drinks per drinking day with less drinking for subjects with the “CC” genotype than for T allele carriers on disulfiram. Conclusions DBH*rs1611115*T associated with better response to naltrexone, while for those on disulfiram that drank, “CC” subjects drank less than T carriers. For rs1799971*G, we did not replicate findings from previous studies showing a more favorable response to NTX, possibly due to the small available sample. Scientific Significance Genotyping rs1611115 may be useful in understanding inter-individual differences in AD treatment response. Future Directions Further study of rs1611115 pharmacogenetics is warranted. (Am J Addict 2013;XX:000–000)

Background JUUL e-cigarettes are popular among youth. However, it is unknown whether adolescents understand that 5% JUUL pods contain a high nicotine concentration or consider JUULs to be e-cigarettes. Method 3170 students from 4 Connecticut high schools completed a school-based survey (May–October 2018). Students reported on lifetime and past-month JUUL use and perceived JUUL nicotine strength (low/medium/high/don’t know) when no information about nicotine concentration was provided and, subsequently, when informed JUULs contain 5% nicotine. Students reported whether they believe JUULs are e-cigarettes (no/yes/don’t know). Results Students were never JUUL users (56.6%), ever users (13.2%), and past-month users (30.2%). When no information was provided, students reported that JUULs contain low (10.5%), medium (26.9%), or high nicotine levels (31.1%); 31.4% did not know. When informed JUULs contain 5% nicotine, students were more likely to believe JUUL’s nicotine strength was low (29.5%) or medium (29.3%) than high (21.3%) and less likely to report not knowing (19.9%). 39% of students believed JUULs are not e-cigarettes or did not know. Discussion Most students were unaware of JUUL’s high nicotine concentration, with more believing that JUULs contain low or medium nicotine concentrations when informed JUULs contain 5% nicotine. Thus, youth may misinterpret the nicotine concentration printed on JUUL pod packaging, raising concerns about inadvertent exposure to high nicotine levels and dependence risk. Further, 39% of adolescents believed JUULs are not e-cigarettes or were unsure. Regulatory efforts are needed to establish understandable nicotine concentration labels, require products to be labeled accordingly, and clarify what products constitute e-cigarettes.

Tobacco use is a major health disparities issue in the United States; it is much more common in less-educated and lower-income groups. These groups also experience a higher prevalence of food insecurity. Previous studies analyzing the association between tobacco use and food insecurity have focused on only cigarettes. We assessed the relationship between food insecurity and use of cigarettes, alternative tobacco products (cigars, electronic cigarettes, smokeless tobacco), any tobacco product, and multiple tobacco products. Using National Health and Nutrition Examination Survey data from 1999 to 2014, we built multinomial logistic regression models predicting degree of food security (i.e., food security, low food security, very low food security) for use of different tobacco product types, any product, and multiple products. After adjustment, use of any product, relative to no use, was significantly associated with increased odds of both food insecurity outcomes: low (adjusted odds ratio (AOR) = 1.2, 95% confidence interval (CI): 1.0–1.4) and very low (AOR = 1.8, 95% CI: 1.6–2.2) food security. In a separate model, single product use, relative to no use, was significantly associated with increased odds of low (AOR = 1.5, 95% CI: 1.3–1.7) and very low (AOR = 2.2, 95% CI: 1.9–2.6) food security. For multiple product use the magnitude of association was higher for very low food security (AOR = 2.7, 95% CI: 1.8–4.0). The significant associations identified here can inform researchers and policymakers developing interventions to prevent tobacco- and food insecurity-related diseases. To be effective in reducing either health risk, interventions may need to target both tobacco use and food insecurity.

Objective The objective was to examine the effectiveness of a self-help treatment as a first line primary care intervention for binge eating disorder (BED) in obese patients. This study compared the effectiveness of a usual care plus self-help version of cognitive behavioral therapy (shCBT) to usual care (UC) only in ethnically/racially diverse obese patients with BED in primary care settings in an urban center. Method 48 obese patients with BED were randomly assigned to either shCBT (N = 24) or UC (N = 24) for four months. Independent assessments were performed monthly throughout treatment and at post-treatment. Results Binge-eating remission rates did not differ significantly between shCBT (25%) and UC (8.3%) at post-treatment. Mixed models of binge eating frequency determined using the Eating Disorder Examination (EDE) revealed significant decreases for both conditions but that shCBT and UC did not differ. Mixed models of binge eating frequency from repeated monthly EDE-questionnaire assessments revealed a significant treatment-by-time interaction indicating that shCBT had significant reductions whereas UC did not during the four-month treatments. Mixed models revealed no differences between groups on associated eating disorder psychopathology or depression. No weight loss was observed in either condition. Conclusions Our findings suggest that pure self-help CBT did not show effectiveness relative to usual care for treating BED in obese patients in primary care. Thus, self-help CBT may not have utility as a front-line intervention for BED for obese patients in primary care and future studies should test guided-self-help methods for delivering CBT in primary care generalist settings.

Somatic DNA methyl transferase 3A ( DNMT3A ) mutations have been recognized recently as recurrent molecular aberrations in acute myeloid leukemia (AML). The precise role of these mutations in leukemogenesis remains elusive but a number of studies have already been conducted to study their potential prognostic value in AML patients with variable results. We performed a meta-analysis on published data from over 4500 AML patients to provide robust evidence supporting DNMT3A mutation testing in clinical setting for AML patients. Our meta-analysis showed that DNMT3A mutations were associated with M4 and M5 AML subtypes. Those mutations conferred significantly worse prognosis with both shorter OS ( p = 0.0004) and shorter RFS ( p = 0.002). Notably, DNMT3A mutations appeared to be an independent adverse prognostic factor also in younger patients with normal cytogenetics AML (OS ( p = 0.01) and RFS ( p = 0.0005)) and also in the subgroup of patients with high risk genotypes defined according to the criteria of the European Leukemia Net (ELN) (OS ( p = 0.002)). Therefore, DNMT3A mutational status can improve the risk stratification of AML patients in the setting of integrated mutational profiling.

Preclinical research suggests that N-methyl-D-aspartate glutamate receptors (NMDA-Rs) have a crucial role in working memory (WM). In this study, we investigated the role of NMDA-Rs in the brain activation and connectivity that subserve WM. Because of its importance in WM, the lateral prefrontal cortex, particularly the dorsolateral prefrontal cortex and its connections, were the focus of analyses. Healthy participants (n=22) participated in a single functional magnetic resonance imaging session. They received saline and then the NMDA-R antagonist ketamine while performing a spatial WM task. Time-course analysis was used to compare lateral prefrontal activation during saline and ketamine administration. Seed-based functional connectivity analysis was used to compare dorsolateral prefrontal connectivity during the two conditions and global-based connectivity was used to test for laterality in these effects. Ketamine reduced accuracy on the spatial WM task and brain activation during the encoding and early maintenance (EEM) period of task trials. Decrements in task-related activation during EEM were related to performance deficits. Ketamine reduced connectivity in the DPFC network bilaterally, and region-specific reductions in connectivity were related to performance. These results support the hypothesis that NMDA-Rs are critical for WM. The knowledge gained may be helpful in understanding disorders that might involve glutamatergic deficits such as schizophrenia and developing better treatments.

Introduction A substantial number of patients with treatment-resistant schizophrenia respond only partially to clozapine. Therefore, it has been common practice to use augmentation strategies to maximize clozapine's effect. But the efficacy of this strategy remains poorly established. We have conducted a randomized double-blind placebo controlled clinical trial in patients with schizophrenia currently receiving clozapine with partial response, and tested the efficacy of pimozide augmentation on positive and negative symptoms and also on neurocognitive measures. Methods Thirty-two outpatients enrolled in the clinical trial and 28 completed. Patients with adequate blood levels of clozapine were randomized to pimozide vs placebo and participated in the trial for 12 weeks receiving monthly assessments for Brief Psychiatric Rating Scale (BPRS) and Schedule for Assessment of Negative Symptoms (SANS), and weekly assessments for electrocardiogram (EKG), and side effects. Neurocognitive tests measuring verbal fluency, working memory, motor and attention/executive function were obtained at study entry and end of the trial. Results We found no significant effect of pimozide on BPRS total, psychosis and depression subscale items, SANS scores or QTc interval. Neurocognitive measures did not show significant improvement either. Discussion In this well controlled clinical trial of patients with treatment-resistant schizophrenia currently receiving clozapine, pimozide augmentation was not an effective strategy to maximize the benefit for better control of positive and negative symptoms or improving neurocognitive function.

N-methyl-D-aspartate glutamate receptor (NMDA-R) antagonists produce schizophrenia-like positive and negative symptoms in healthy human subjects. Preclinical research suggests that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) neurons and alter brain oscillations. These changes have been hypothesized to contribute to psychosis. In this investigation, we evaluated the hypothesis that the NMDA-R antagonist ketamine produces alterations in cortical functional connectivity during rest that are related to symptoms. We administered ketamine to a primary sample of twenty-two subjects and to an additional, partially overlapping, sample of twelve subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Symptom Scale (PANSS). In the primary sample, functional connectivity was measured via functional magnetic resonance imaging almost immediately after infusion began. In the additional sample, this assessment was repeated after 45 minutes of continuous ketamine infusion. Global, enhanced functional connectivity was observed at both timepoints and this hyperconnectivity was related to symptoms in a region-specific manner. This study supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of positive and negative symptoms associated with schizophrenia.

The nicotinic acetylcholine receptor antagonist, mecamylamine, is a potential novel pharmacotherapy for alcohol use disorder. The aims were to compare alcohol consumption between mecamylamine and placebo and test if smoking status modified treatment effects.Out-patient, randomized, double-blind clinical trial for 12 weeks of treatment with mecamylamine (10 mg) (n = 65) versus placebo (n = 63).Connecticut, USA.Individuals had current alcohol dependence (n = 128), had an average age of 48.5 [standard deviation (SD) = 9.4], 110 (85.9%) were men, and included 74 smokers (57.8%) and 54 non-smokers (42.2%). Participants were randomized to mecamylamine 10 mg per day or placebo. All subjects also received medical management therapy administered by trained research personnel.Primary outcome was percentage of heavy drinking days during the last month of treatment; other outcomes included drinking days, drinks per drinking days, alcohol craving, smoking, symptoms of nicotine withdrawal and side effects.There were no significant differences in the percentage of heavy drinking days at 3 months between the mecamylamine (mean = 18.4, SD = 29.0) and placebo treatment groups (mean = 20.4, SD = 29.2) [FMecamylamine 10 mg per day did not reduce alcohol consumption significantly in treatment-seeking smokers and non-smokers with alcohol use disorder.

Summary Background Understanding patterns of relapse in patients who respond to antidepressant treatment can inform strategies for prevention of relapse. We aimed to identify distinct trajectories of depression severity, assess whether similar or different trajectory classes exist for patients who continued or discontinued active treatment, and test whether clinical predictors of trajectory class membership exist using pooled data from clinical trials. Methods We analysed individual patient data from four double-blind discontinuation clinical trials of duloxetine or fluoxetine versus placebo in major depression from before 2012 (n=1462). We modelled trajectories of relapse up to 26 weeks during double-blind treatment. Trajectories of depression severity, as measured by the Hamilton Depression Rating Scale score, were identified in the entire sample, and separately in groups in which antidepressants had been continued or discontinued, using growth mixture models. Predictors of trajectory class membership were assessed with weighted logistic regression. Findings We identified similar relapse trajectories and two trajectories of stable depression scores in the normal range on active medication and on placebo. Active treatment significantly lowered the odds of membership in the relapse trajectory (odds ratio 0·47, 95% CI 0·37–0·61), whereas female sex (1·56, 1·23–2·06), shorter length of time with clinical response by 1 week (1·10, 1·06–1·15), and higher Clinical Global Impression score at baseline (1·28, 1·01–1·62) increased the odds. Overall, the protective effect of antidepressant medication relative to placebo on the risk of being classified as a relapser was about 13% (33% vs 46%). Interpretation The existence of similar relapse trajectories on active medication and on placebo suggests that there is no specific relapse signature associated with antidepressant discontinuation. Furthermore, continued treatment offers only modest protection against relapse. These data highlight the need to incorporate treatment strategies that prevent relapse as part of the treatment of depression. Funding National Institutes of Health, the US Department of Veterans Affairs Alcohol Research Center, and National Center for Post-Traumatic Stress Disorder.

Pain intensity is often measured in clinical and research settings using the 0 to 10 numeric rating scale (NRS). NRS scores are recorded as discrete values, and in some samples they may display a high proportion of zeroes and a right-skewed distribution. Despite this, statistical methods for normally distributed data are frequently used in the analysis of NRS data. We present results from an observational cross-sectional study examining the association of NRS scores with patient characteristics using data collected from a large cohort of 18,935 veterans in Department of Veterans Affairs care diagnosed with a potentially painful musculoskeletal disorder. The mean (variance) NRS pain was 3.0 (7.5), and 34% of patients reported no pain (NRS = 0). We compared the following statistical models for analyzing NRS scores: linear regression, generalized linear models (Poisson and negative binomial), zero-inflated and hurdle models for data with an excess of zeroes, and a cumulative logit model for ordinal data. We examined model fit, interpretability of results, and whether conclusions about the predictor effects changed across models. In this study, models that accommodate zero inflation provided a better fit than the other models. These models should be considered for the analysis of NRS data with a large proportion of zeroes. Perspective We examined and analyzed pain data from a large cohort of veterans with musculoskeletal disorders. We found that many reported no current pain on the NRS on the diagnosis date. We present several alternative statistical methods for the analysis of pain intensity data with a large proportion of zeroes.

Initial studies have provided a mixed perspective of the efficacy of d-cycloserine (DCS) for augmenting the efficacy of exposure-based cognitive behavioral therapy (CBT) for panic disorder. In this multicenter trial, we examine the magnitude of DCS augmentation effects for an ultra-brief program of CBT.We conducted a double-blind, controlled trial at three treatment sites, randomizing 180 adults with a primary diagnosis of panic disorder to five sessions of treatment, with study pill (50 mg DCS or matching placebo) administered 1 hr prior to the final three sessions. Two booster sessions were subsequently provided, and outcome was assessed at posttreatment and 1-month, 2-month, and 6-month follow-up assessments. The primary outcome was the degree of reduction in the Panic Disorder Severity Scale. Additional analyses examined the role of severity and current antidepressant or benzodiazepine use as moderators of DCS augmentation effects.DCS augmentation resulted in significant benefit only early in the trial, with no beneficial effects of DCS augmentation evident at follow-up evaluations. We did not find that baseline severity or antidepressant or benzodiazepine use moderated DCS efficacy, but benzodiazepine use was associated with lower efficacy of CBT regardless of augmentation condition.Consistent with other recent multicenter trials, the benefit of DCS was less than indicated by pilot study and reflected an acceleration of treatment response evident at treatment endpoint, but no advantage in response over follow-up evaluation. Our results did not support severity or concomitant medication moderators observed in previous trials of DCS augmentation.

The tree-based methodology has been widely applied to identify predictors of health outcomes in medical studies. However, the classical tree-based approaches do not pay particular attention to treatment assignment and thus do not consider prediction in the context of treatment received. In recent years, attention has been shifting from average treatment effects to identifying moderators of treatment response, and tree-based approaches to identify subgroups of subjects with enhanced treatment responses are emerging. In this study, we extend and present modifications to one of these approaches (Zhang et al., 2010 [29]) to efficiently identify subgroups of subjects who respond more favorably to one treatment than another based on their baseline characteristics. We extend the algorithm by incorporating an automatic pruning step and propose a measure for assessment of the predictive performance of the constructed tree. We evaluate the proposed method through a simulation study and illustrate the approach using a data set from a clinical trial of treatments for alcohol dependence. This simple and efficient statistical tool can be used for developing algorithms for clinical decision making and personalized treatment for patients based on their characteristics.

BACKGROUND: Previously, using imaging mass spectrometry (IMS), we discovered proteomic differences between Spitz nevi and Spitzoid melanomas. OBJECTIVE: We sought to determine whether IMS can assist in the classification of diagnostically challenging atypical Spitzoid neoplasms (ASN), to compare and correlate the IMS and histopathological diagnoses with clinical behavior. METHODS: We conducted a retrospective collaborative study involving centers from 11 countries and 11 US institutions analyzing 102 ASNs by IMS. Patients were divided into clinical groups 1 to 4 representing best to worst clinical behavior. The association among IMS findings, histopathological diagnoses, and clinical groups was assessed. RESULTS: There was a strong association between a diagnosis of Spitzoid melanoma by IMS and lesions categorized as clinical groups 2, 3, and 4 (recurrence of disease, metastases, or death) compared with clinical group 1 (no recurrence or metastasis beyond a sentinel node) (P < .0001). Older age and greater tumor thickness were strongly associated with poorer outcome (P = .01). CONCLUSIONS: IMS diagnosis of ASN better predicted clinical outcome than histopathology. Diagnosis of Spitzoid melanoma by IMS was strongly associated with aggressive clinical behavior. IMS analysis using a proteomic signature may improve the diagnosis and prediction of outcome/risk stratification for patients with ASN.

Prior work by our group has shown the feasibility, safety, and validity of a multi-day, multi-dose paradigm of self-regulated cocaine administration in humans. The current work sought to consolidate these methods in a single-day design focused on reducing logistical complexity, decreasing research burden to human subjects, and increasing suitability for medication development designs. Methods: Eleven experienced cocaine users participated in a 6-hour, single-day design, consisting of one safety/eligibility and three experimental cocaine periods (during which subjects were allowed to self-administer 8, 16, and 32 mg/70 kg cocaine doses under a fixed-ratio 1: 5 minute timeout schedule). Changes in cocaine-induced cardiovascular response, self-administration behavior, and subjective effects were assessed. Results: Procedures were well tolerated by participants, and no significant adverse events were noted. Significant (p