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Decedents with no known mental disorder comprise 5-40% of suicides, suggesting that suicide ideation (SI) and behavior may occur in the psychiatrically healthy with important implications for suicide risk screening. Healthy Volunteers (HV) and patients with Major Depressive Disorder (MDD) provided 7 days of Ecological Momentary Assessment (EMA) data about SI and stressors. Longitudinal mixed effects logistic regression models compared HV and patient SI and stressors. Mixed effects linear regression models compared HVs' and patients' SI score change from the previous epoch's SI score when each stressor occurred. HVs (n = 42) reported less frequent (p < 0.001) and less intense SI (p < 0.003) than patients (n = 80), yet did endorse SI and/or SI-related items in 44% of EMA epochs, endorsing SI items in 25% of epochs with non-zero SI scores. For 7 of 8 stressors, patients reported stressors more often than HVs (all p < 0.001) responding to them with increased SI (0.0001 < p < 0.0472). HVs were relatively resilient to stressors, reporting SI increases only in response to neglect (p < 0.0147). Although SI and SAs are documented among psychiatrically healthy individuals, scientific attention to these observations has been scant. Real-time SI measurement showed that HVs' SI was less pronounced than MDD patients', but was endorsed, nonetheless. Patients were more likely to report stressors than HVs, perhaps due to greater sensitivity to the environment, and reported SI in response to stressors, which was less common in HVs. Both MDD patients and HVs most often manifested passive SI (viz, "decreased wish to live"). However, passive SI (viz, "desire for death"), may predict suicide, even absent SI per se (thinking about killing yourself). This study validates the utility of real-time SI assessment, showing that HVs endorse SI items in 11% of epochs, which implies that suicide risk screening focused on those with mental disorders may be too narrow an approach., (© 2024. The Author(s).)

This study was designed to increase our understanding about characteristics and the impact of sensory symptoms (SS) and signs of hyperarousal (HA) in individuals with fragile X syndrome (FXS) from childhood through early adulthood and by gender. Data derived from the Fragile X Online Registry With Accessible Research Database (FORWARD), a natural history study of FXS, were analyzed using descriptive statistics and multivariate linear and logistic regression models to examine SS and signs of HA, their impact on behavioral regulation and limitations on the subject/family. The sample (N = 933) consisted of 720 males and 213 females. More males were affected with SS (87% vs. 68%) and signs of HA (92% vs. 79%). Subjects who were endorsed as having a strong sensory response had more comorbidities, including behavioral problems. The predominant SS was difficulty with eye gaze that increased with age in both genders. As individuals age, there was less use of non-medication therapies, such as occupational therapy (OT)/physical therapy (PT), but there was more use of psychopharmacological medications and investigational drugs for behaviors. Multiple regression models suggested that endorsing SS and signs of HA was associated with statistically significantly increased ABC-C-I subscale scores and limited participation in everyday activities. This study improves our understanding of SS and signs of HA as well as their impact in FXS. It supports the need for more research regarding these clinical symptoms, especially to understand how they contribute to well-known behavioral concerns., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Persistent olfactory dysfunction (OD) is a common symptom following SARS-CoV-2 infection that can greatly impact quality of life (QoL). Because coping strategies have been shown to moderate the effect of disease symptoms on functional and affective outcomes, this study aims to determine whether specific coping strategies are associated with and moderate QoL outcomes., Methodology: Participants with prior SARS-CoV-2 infection underwent psychophysical olfactory testing with Sniffin’ Sticks and completed questionnaires to elicit subjective olfactory function, coping strategies, olfactory-specific QoL, general QoL, and mental health., Results: There were 93 participants included in the study. Olfactory specific QoL scores were significantly worse among individuals with subjective and psychophysically measured OD compared to those with subjective and psychophysically confirmed normosmia. Olfactory-specific QoL, general QoL, and anxiety symptom scores were positively correlated with avoidant and disengagement coping among individuals with subjective and psychophysically measured OD. Depression symptom scores were positively correlated with avoidant and disengagement coping and negatively correlated with approach and engagement coping. There were no significant moderating effects on the association between olfactory performance and QoL or mental health screening assessment., Conclusions: Approach and engagement coping mechanisms are associated with improved depression, whereas avoidant and disengagement coping tracks with worse QoL and mental health screening assessment, offering an opportunity to counsel patients accordingly.

Introduction: Ecological Momentary Assessment (EMA) holds promise for providing insights into daily life experiences when studying mental health phenomena. However, commonly used mixed-effects linear statistical models do not fully utilize the richness of the ultidimensional time-varying data that EMA yields. Recurrent Neural Networks (RNNs) provide an alternative data analytic method to leverage more information and potentially improve prediction, particularly for non-normally distributed outcomes., Methods: As part of a broader research study of suicidal thoughts and behavior in people with borderline personality disorder (BPD), eighty-four participants engaged in EMA data collection over one week, answering questions multiple times each day about suicidal ideation (SI), stressful events, coping strategy use, and affect. RNNs and mixed-effects linear regression models (MEMs) were trained and used to predict SI. Root mean squared error (RMSE), mean absolute percent error (MAPE), and a pseudo-R 2 accuracy metric were used to compare SI prediction accuracy between the two modeling methods., Results: RNNs had superior accuracy metrics (full model: RMSE = 3.41, MAPE = 42 %, pseudo-R 2  = 26 %) compared with MEMs (full model: RMSE = 3.84, MAPE = 56 %, pseudo-R 2  = 16 %). Importantly, RNNs showed significantly more accurate prediction at higher values of SI. Additionally, RNNs predicted, with significantly higher accuracy, the SI scores of participants with depression diagnoses and of participants with higher depression scores at baseline., Conclusion: In this EMA study with a moderately sized sample, RNNs were better able to learn and predict daily SI compared with mixed-effects models. RNNs should be considered as an option for EMA analysis., Competing Interests: Declaration of competing interest Dr. Herzog, Dr. Brodsky, and Mr. Choo report no conflicts of interest. Dr. Galfalvy discloses that she and her family own stock in IBM Inc. Dr. Mann has received grant support from the National Institute of Mental Health, and royalties from the New York State Research Foundation for Mental Hygiene for commercial use of the Colombia Suicide Severity Rating Scale. Dr. Wall also reports grants from the National Institute of Health. Dr. Stanley is being included as an author posthumously., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Olfactory dysfunction is a common symptom of COVID-19. However, subjective perception of olfactory function does not always correlate well with more objective measures. This study seeks to clarify associations between subjective and psychophysical measures of olfaction and gustation in patients with subjective chemosensory dysfunction following COVID-19., Methods: Adults with persistent COVID-19-associated chemosensory disturbance were recruited for a prospective, longitudinal cohort study at a tertiary care institution. Participants provided subjective measures of olfactory and gustatory function and underwent psychophysical assessment using Sniffin' Sticks olfactory and Monell gustatory tests., Results: Data analysis (n = 65) showed a statistically significant association between subjective and psychophysical measures of olfaction (p &lt; 0.001). For each one-point increase in subjectively-reported olfactory ability, there is, on average, a 0.11 (95% CI: 0.06, 0.16; p &lt; 0.001) point increase in TDI score while adjusting for age at baseline assessment, sex, and follow-up time. For each one-point increase in subjectively-reported olfactory ability, there is, on average, a 0.04 (95% CI: 0.02, 0.06; p &lt; 0.001) point and 0.05 (95% CI: 0.03, 0.07; p &lt; 0.001) point increase in discrimination and identification scores, respectively, when adjusting for age at baseline assessment, sex, and follow-up time., Conclusion: Subjective olfaction shows a mild to moderate association with psychophysical measures, but it fails to comprehensively assess persistent COVID-19-associated chemosensory deficits. The lack of significant association between subjective olfaction and threshold limits the utility of subjective olfaction in tracking recovery. These findings support the push for more widespread psychophysical chemosensory testing., (© 2024 S. Karger AG, Basel.)

Introduction: Rising rates of suicidal thoughts and behaviors (STBs) among U.S. Latina adolescents urgently need attention. Life is Precious (LIP) is a culturally responsive, community-based, afterschool-model program offering wellness-support services to supplement outpatient mental health treatment for Latina adolescents experiencing STB's. This 12-month quasi-experimental pilot study explored LIP's impact on clinical outcomes., Methods: Latina adolescents newly enrolled in LIP and receiving outpatient treatment (n = 31) and those newly starting outpatient treatment only (n = 12; Usual Care) were assessed for Suicidal Ideation (Suicidal Ideation Questionnaire; SIQ) and depressive symptoms (Patient Health Questionnaire-9). We estimated differences in mean scores using longitudinal linear mixed models and adjusted risk ratios (ARRs) of SIQ-25%, SIQ-50%, and PHQ-9-5-point improvements using exact logistic models., Results: The direction of the estimated impact of LIP was positive [differences (95% CIs): -15.5 (-34.16, 3.15) for SIQ; -1.16 (-4.39, 2.07) for PHQ-9], with small-to-moderate nonsignificant effect sizes (0.19-0.34). LIP participants saw two to three times higher prevalence than controls of SIQ-25%, SIQ-50%, and PHQ-9-5-point improvements; ARRs (95% CIs) were 1.91 (0.61, 3.45), 3.04 (0.43, 11.33), and 1.97 (0.44, 5.07), respectively. Suicidal behaviors also decreased in LIP., Conclusion: The effects of LIP were in positive directions across clinical outcomes, warranting further research on its effectiveness in decreasing STBs., (© 2023 American Association of Suicidology.)

Introduction: Indigenous people experience health disparities, including higher rates of substance use disorders (SUDs). Digital therapeutics are a growing platform for treatment services and have the potential to expand access to culturally responsive interventions for Indigenous people. As one of the first randomized controlled trials for SUDs for American Indian and Alaska Native (AI/AN) adults, the aim of this study was to pilot test the efficacy of a culturally tailored intervention among urban Indigenous adults., Methods: The study used a randomized controlled parallel design of 12 weeks of treatment-as-usual (TAU) (n = 26) versus TAU + Therapeutic Education System-Native Version (TES-NAV) (n = 27) with follow-up assessments at end of treatment and week 24 in an urban outpatient addiction treatment program for Native American adults. TAU consisted of individual/group counseling and cultural activities. The TES-NAV arm comprised TAU + 26 self-directed culturally tailored digital skills-based modules grounded in the community reinforcement approach with contingency management for abstinence and module completion. Primary outcome was longest consecutive weeks of abstinence from drugs and heavy drinking measured using self-report (Timeline Followback) and urine alcohol and drug toxicology screen during 12 weeks of treatment. Secondary outcomes were percent days abstinence during and posttreatment, coping strategies, social connectedness, and substance use and sexual risk behaviors., Results: The study enrolled fifty-three (52.8 % male) AI/AN adults seeking treatment for a SUD. Although the study did not detect a benefit of TAU+TES-NAV over TAU on the primary outcome (Median = 2 consecutive weeks of abstinence for both arms) at end of treatment (treatment effect: Z = -0.78, p = 0.437), TAU+TES-NAV participants did demonstrate significantly greater percent days of abstinence at the week 24 follow-up (69.3 % versus 49.0 % for TAU; t = 2.08, p = 0.045) and significantly greater change in social connectedness mean score, baseline to week 12 (Z = -2.66, p = 0.011), compared to TAU. The study detected no differences between treatment arms for coping strategies or risk behaviors., Conclusion: The addition of TES-NAV to TAU did not significantly improve consecutive weeks of abstinence from drugs or heavy drinking; however, several secondary findings suggest promise for a culturally tailored digital therapeutic SUD intervention among urban Indigenous people., Clinical Trials: GOV REGISTRATION: #NCT03363256., Competing Interests: Declaration of competing interest Dr. Venner provides training and consultation in evidence-based treatments for fee. Dr. Venner has a conflict-of-interest management plan at her academic institution. Dr. Marsch is affiliated with the company that developed the Therapeutic Education System, the company that deploys reSET®, as well as Click Therapeutics and Square2 Systems. These relationships are extensively managed by her academic institution. The remaining authors have no competing interests to report., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Objectives: Limited research has explored sex differences in opioid use disorder medication (MOUD) treatment outcomes. The purpose of this study was to examine MOUD initiation onto buprenorphine-naloxone (BUP-NX) versus extended-release naltrexone (XR-NTX) by sex, and sex differences in clinical and psychosocial outcomes., Methods: Using data from a 24-week open-label comparative effectiveness trial of BUP-NX or XR-NTX, this study examined MOUD initiation (i.e., receiving a minimum one XR-NTX injection or first BUP-NX dose) and 24-week self-report outcomes. We used regression models to estimate the probability of MOUD initiation failure among the intent-to-treat sample (N = 570), and the main and interaction effects of sex on outcomes of interest among the subsample of participants who successfully initiated MOUD (n = 474)., Results: In the intent-to-treat sample, the odds of treatment initiation failure were not significantly different by sex. In the subsample of successful MOUD initiates, the effect of treatment on employment at week 24 was significantly moderated by sex (p = .003); odds of employment were not significantly different among males by MOUD type; females randomized to XR-NTX versus BUP-NX had 4.63 times greater odds of employment (p < .001). Males had significantly lower odds of past 30-day exchanging sex for drugs versus females (adjusted odds ratios [aOR] = 0.10, p = .004), controlling for treatment and baseline outcomes., Discussion and Conclusions: Further research should explore how to integrate employment support into OUD treatment to improve patient outcomes, particularly among women., Scientific Significance: The current study addressed gaps in the literature by examining sex differences in MOUD initiation and diverse treatment outcomes in a large, national sample., (© 2023 The American Academy of Addiction Psychiatry (AAAP).)

Objectives: Timeline follow-back (TLFB) is a self-report measure commonly used as a method of assessing historical drug use in both clinical and research settings. Our study considered rates of agreement between TLFB and an objective biological assay of opioid use., Methods: We calculated the rates of agreement between negative report of opioid use for the most recent 8 days on TLFB and urine toxicology (UTOX) results in a large multisite opioid use disorder treatment trial., Results: In total, 3986 assessments were provided by trial participants with both UTOX and TLFB during weeks 1 to 12, 2716 during weeks 13 to 24, and 325 at week 28. Rates of disagreement between negative TLFB and positive opioid UTOX were 2.33% of all assessments (21.68% of those with positive UTOX) over weeks 1 to 12, 2.06% of all assessment (25.00% of those with positive UTOX) over weeks 13 to 24, and 9.85% of all assessments (26.02% of those with positive UTOX) at week 28., Conclusions: Negative TLFB seems to be generally associated with negative results on urine toxicology., Competing Interests: Dr. Nunes has received medication for research studies from Alkermes/Cephalon, Duramed Pharmaceuticals, and Reckitt-Benckiser. Dr. Rotrosen is, and has been, a principal investigator or a coinvestigator on studies for which support in the form of donated or discounted medication, smartphone apps, and/or funds has been, or is, provided by Alkermes, Inc (Vivitrol, extended-release injectable naltrexone), Indivior, Inc (formerly Reckitt-Benckiser; Suboxone, buprenorphine/naloxone combination), Braeburn Pharmaceuticals, Inc (extended-release injectable buprenorphine), Pear Therapeutics (smartphone apps ReSET and ReSET-O), CHESS Health (Connections smartphone app), and Data Cubed (smartphone apps SOAR and mSAPPORT). None of this support has gone, or will go, directly to Dr. Rotrosen, rather to either New York University, or to National Institute on Drug Abuse/National Institute of Health, or to NIDA's contractor Emmes, Inc. Dr. Rotrosen recently served in a nonpaid capacity as a member of an Alkermes study Steering Committee. Dr. Rotrosen has no relevant equity, intellectual property, paid consulting, travel or other arrangements with any of these entities. Specific disclosures are submitted separately for each study. The remaining authors have no conflicts of interest to report., (Copyright © 2023 American Society of Addiction Medicine.)

Introduction: Like heart rate, blood pressure (BP) is not steady but varies over intervals as long as months to as short as consecutive cardiac cycles. This blood pressure variability (BPV) consists of regularly occurring oscillations as well as less well-organized changes and typically is computed as the standard deviation of multiple clinic visit-to-visit (VVV-BP) measures or from 24-h ambulatory BP recordings (ABPV). BP also varies on a beat-to-beat basis, quantified by methods that parse variation into discrete bins, e.g., low frequency (0.04-0.15 Hz, LF). However, beat-to-beat BPV requires continuous recordings that are not easily acquired. As a result, we know little about the relationship between LF-BPV and basic sociodemographic characteristics such as age, sex, and race and clinical conditions. Methods: We computed LF-BPV during an 11-min resting period in 2,118 participants in the Midlife in the US (MIDUS) study. Results: LF-BPV was negatively associated with age, greater in men than women, and unrelated to race or socioeconomic status. It was greater in participants with hypertension but unrelated to hyperlipidemia, hypertriglyceridemia, diabetes, elevated CRP, or obesity. LF-diastolic BPV (DBPV), but not-systolic BPV (SBPV), was negatively correlated with IL-6 and s-ICAM and positively correlated with urinary epinephrine and cortisol. Finally, LF-DBPV was negatively associated with mortality, an effect was rendered nonsignificant by adjustment by age but not other sociodemographic characteristics. Discussion: These findings, the first from a large, national sample, suggest that LF-BPV differs significantly from VVV-BP and ABPV. Confirming its relationship to sociodemographic risk factors and clinical outcomes requires further study with large and representative samples., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gruenewald, Seeman, Choo, Scodes, Snyder, Pavlicova, Weinstein, Schwartz, Mukkamala and Sloan.)

Background: Patients with schizophrenia show reduced NMDA glutamate receptor-dependent auditory plasticity, which is rate limiting for auditory cognitive remediation (AudRem). We evaluate the utility of behavioral and neurophysiological pharmacodynamic target engagement biomarkers, using a d-serine+AudRem combination., Methods: Forty-five participants with schizophrenia or schizoaffective disorder were randomized to 3 once-weekly AudRem visits + double-blind d-serine (80, 100, or 120 mg/kg) or placebo in 3 dose cohorts of 12 d-serine and 3 placebo-treated participants each. In AudRem, participants indicated which paired tone was higher in pitch. The primary outcome was plasticity improvement, operationalized as change in pitch threshold between AudRem tones [(test tone Hz - reference tone Hz)/reference tone Hz] between the initial plateau pitch threshold (mean of trials 20-30 of treatment visit 1) to pitch threshold at the end of visit(s). Target engagement was assessed by electroencephalography outcomes, including mismatch negativity (pitch primary)., Results: There was a significant overall treatment effect for plasticity improvement (p = .014). Plasticity improvement was largest within the 80 and 100 mg/kg groups (p < .001, d > 0.67), while 120 mg/kg and placebo-treated participants showed nonsignificant within-group changes. Plasticity improvement was seen after a single treatment and was sustained on subsequent treatments. Target engagement was demonstrated by significantly larger mismatch negativity (p = .049, d = 1.0) for the 100 mg/kg dose versus placebo., Conclusions: Our results demonstrate sufficient proof of principle for continued development of both the d-serine+AudRem combination and our target engagement methodology. The ultimate utility is dependent on the results of an ongoing larger, longer study of the combination for clinically relevant outcomes., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: We sought to identify the sociodemographic and clinical characteristics associated with homelessnesss, and explore the relationship between homelessnesss and treatment outcomes among Black individuals., Methods: This is a secondary analysis of the subgroup of Black participants (n = 73) enrolled in "X:BOT," a 24-week multisite randomized clinical trial comparing the effectiveness of extended-release naltrexone versus sublingual buprenorphine-naloxone (n = 570). Outcomes included medication initiation, return to extramedical use of opioids assessed by both self-report and urine toxicology, and engagement in medications for opioid use disorder (MOUD) treatment at 28 weeks postrandomization. Descriptive statistics were performed., Results: Black participants were mostly unmarried and male, and about a third were aged 21-30 years. Among people experiencing homelessnesss, more were uninsured (45.5% [10/22] vs 19.6% [10/51]), unemployed (77.3% [17/22] vs 64.7% [33/51]), and reported alcohol (40.9% [9/22] vs 23.5% [12/51]) and sedative use (54.5% [12/22] vs 17.6% [9/51]) within the previous 30 days. Compared with housed Black individuals, a slightly higher proportion of Black individuals experiencing homelessnesss successfully initiated study medication (81.1% [18/22] vs 72.6% [37/51]); similar proportions returned to opioid use during the trial (68.2% [15/22] vs 68.6% [35/51]) and were engaged in MOUD at 28 weeks after trial entry (72.2% [13/18] vs 69.7% [23/33]) among participants located for follow-up., Conclusions: These descriptive results among Black patients participating in a trial of MOUD suggest that efficacious MOUD is possible despite homelessnesss with additional clinical supports such as those provided by a clinical trial., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 American Society of Addiction Medicine.)

Background and Objectives: To inform clinical practice, we identified subgroups of adults based on levels of depression symptomatology over time during opioid use disorder (OUD) treatment., Methods: Participants were 474 adults in a 24-week treatment trial for OUD. Depression symptoms were measured using the 17-item Hamilton Depression Rating Scale (HAM-D) at nine-time points. This was a secondary analysis of the Clinical Trials Network Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment (XBOT) trial using a growth mixture model., Results: Three distinct depression trajectories were identified: Class 1 High Recurring-10% with high HAM-D with initial partial reductions (of HAM-D across time), Class 2 Persistently High-5% with persistently high HAM-D, and Class 3 Low Declining-85% of the participants, with low HAM-D with early sustained reductions. The majority (low declining) had levels of depression that improved in the first 4 weeks and then stabilized across the treatment period. In contrast, 15% (high recurring and persistently high) had high initial levels that were more variable across time. The persistently high class had higher rates of opioid relapse., Discussion and Conclusions: In this OUD sample, most depressive symptomatology was mild and improved after medication treatment for opioid use disorder (MOUD). Smaller subgroups had higher depressive symptoms that persisted or recurred after the initiation of MOUD. Depressive symptoms should be followed in patients initiating treatment for OUD, and when persistent, should prompt further evaluation and consideration of antidepressant treatment., Scientific Significance: This study is the first to identify three distinct depression trajectories among a large clinical sample of individuals in MOUD treatment., (© 2023 The American Academy of Addiction Psychiatry (AAAP).)

We examined relationships between the serotonin system and stress in major depression and suicidal behavior. Twenty-five medication-free depressed participants (13 suicide attempters) underwent same-day [ 11 C]DASB and [ 11 C]CUMI-101 positron emission tomography (PET) imaging. Binding potential (BP ND ) to the serotonin transporter (5-HTT) and serotonin 1A (5-HT 1A ) receptor, respectively, was quantified using the NRU 5-HT atlas, reflecting distinct spatial distributions of multiple serotonin targets. Ecological momentary assessment (EMA) measured current stress over one week proximal to imaging. EMA stress did not differ between attempters and non-attempters. In all depressed participants, 5-HTT and 5-HT 1A BP ND were unrelated to EMA stress. There were region-specific effects of 5-HTT (p=0.002) and 5-HT 1A BP ND (p=0.03) in attempters vs. nonattempters. In attempters, region-specific associations between 5-HTT (p=0.03) and 5-HT 1A (p=0.005) BP ND and EMA stress emerged. While no post-hoc 5-HTT BP ND correlations were significant, 5-HT 1A BP ND correlated positively with EMA stress in attempters in 9/10 regions (p-values<0.007), including the entire cortex except the largely occipital region 5. Brodmann-based regional analyses found diminished effects for 5-HTT and subcortically localized positive corrrelations between 5-HT 1A and EMA stress, in attempters only. Given comparable depression severity and childhood and current stress between attempters and nonattempters, lower 5-HTT binding in attempters vs. nonattempters may suggest a biological risk marker. Localized lower 5-HTT and widespread higher 5-HT 1A binding with stress among attempters specifically may suggest that a serotonergic phenotype might be a key determinant of risk or resiliency for suicidal behavior., Competing Interests: Declaration of Competing Interest Drs. Bartlett, Zanderigo, Stanley, Choo, Galfalvy, Pantazatos, Sublette, and Miller declares that they have no conflict of interest. Drs. Oquendo and Mann receive royalties from the Research Foundation for Mental Hygiene for the commercial use of the Columbia Suicide Severity Rating Scale. Dr. Oquendo serves as an advisor to Alkermes, Otsuka, Mind Medicine, St. George's University and Fundacion Jimenez Diaz. Her family owns stock in Bristol Myers Squibb., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

Background and Objectives: Research has examined reductions in patient distress recounting trauma narratives in Prolonged Exposure (PE) for posttraumatic stress disorder (PTSD). It remains unclear whether changes in distress and avoidance related to environmental trauma reminders matter in PE and other PTSD treatments, including non-exposure Interpersonal Psychotherapy (IPT)., Methods: Data came from adults with chronic PTSD (N = 92) who completed a treatment trial comparing PE, IPT, and Relaxation Therapy (RT). We employed the Self-Initiated In-Vivo Exposure Scale (SIIVES), which measures patient distress from and avoidance of situational trauma reminders, to calculate reliable change in distress and avoidance. PTSD symptoms, depression, quality of life, and functioning assessments were collected before and after 14 weeks of treatment., Results: Overall, 48.1% of patients experienced reliable change in avoidance, while 51.9% showed reliable change in distress. Rates of reliable change did not differ by treatment group, although PE appeared to achieve reliable change earlier. Only one baseline characteristic predicted reliable change: patients with comorbid depression were less likely to reliably change in avoidance. At post-treatment, patients achieving reliable change had lower PTSD severity and depression and increased quality of life and social functioning. Statistical modeling revealed that changes in distress and avoidance related to subsequent reduction in PTSD symptoms in all three treatment groups, though this relationship appeared strongest in PE., Limitations: The sample was relatively small., Conclusions: Change in avoidance and distress associated with situational trauma reminders was associated with a range of clinical outcomes and may represent important factors in multiple PTSD psychotherapies., Competing Interests: Declaration of competing interest Dr. Markowitz receives research funding from NIMH, royalties from American Psychiatric Publishing, Basic Books, and Oxford University Press, and an editorial stipend from Elsevier Press. The other authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: Polysubstance use may complicate treatment outcomes for individuals who use opioids. This research aimed to examine the prevalence of polysubstance use in an opioid use disorder treatment trial population and polysubstance use's association with opioid relapse and craving., Methods: This study is a secondary data analysis of individuals with opioid use disorder who received at least one dose of medication (n = 474) as part of a 24-week, multi-site, open label, randomized Clinical Trials Network study (CTN0051, X:BOT) comparing the effectiveness of extended-release naltrexone versus buprenorphine. Models examined pretreatment polysubstance use and polysubstance use during the initial 4 weeks of treatment on outcomes of relapse by week 24 of the treatment trial and opioid craving., Results: Polysubstance use was generally not associated with treatment outcomes of opioid relapse and craving. Proportion of days of pretreatment sedative use was associated with increased likelihood of opioid relapse (OR: 1.01, 95 % CI: 1.00-1.02). Proportion of days of cocaine use during the initial 4 weeks of treatment was associated with increased likelihood of opioid relapse (OR: 1.05, 95 % CI: 1.01-1.09) but this effect was no longer significant once the potential of confounding by opioid use was considered. Sedative use during initial 4 weeks of treatment was associated with increased opioid craving (b: 0.77, 95 % CI: 0.01-1.52). The study found no other significant relationships., Conclusions: In the current study population, polysubstance use was only marginally associated with 24-week treatment outcomes., Competing Interests: Declaration of competing interest Dr. Rotrosen is and has been, a Principal Investigator or a co-Investigator on studies for which support in the form of donated or discounted medication and/or funds has been, or will be, provided by Alkermes, Inc. (Vivitrol, extended-release injectable naltrexone), Indivior, Inc. (formerly Reckitt-Benckiser; Suboxone, buprenorphine/naloxone combination), and Braeburn Pharmaceuticals, Inc. (extended-release injectable buprenorphine); and digital therapeutics from Pear Therapeutics (smartphone apps ReSET and ReSET-O), CHESS Health (Connections smartphone app), and Data Cubed (smartphone apps SOAR and mSAPPORT). None of this support has gone, or will go, directly to him, rather to either NYU, or to NIDA/NIH, or to NIDA's contractor Emmes, Inc. Dr. Rotrosen recently served in a non-paid capacity as a member of an Alkermes study Steering Committee. He has no relevant equity, intellectual property, paid consulting, travel or other arrangements with any of these entities. Dr. McNeely declares intellectual property interests in the Substance Use Screening and Intervention Tool (SUSIT), which is in the public domain and unrelated to this work. Dr. Lee has received in-kind study drug for recent and current NIDA-funded trials from Alkermes Inc. and Indivior PLC. Dr. Lee has received a recent investigator sponsored study grant from Indivior PLC. Dr. Lee is a science advisor to Oar Health LLC. Dr. Nunes received medication for studies from Alkermes (Vivitrol), Indivior (Suboxone, Sublocade), and Braeburn (CAM2038/Brixadi), received technology for studies from Pear Therapeutics, CHESS Health, served as an unpaid consultant to Alkermes, Braeburn/Camurus, Pear Therapeutics, and has been an investigator on studies by Braeburn Pharmaceuticals (CAM2038/Brixadi). Dr. Tofighi is a consultant to Oar Health LLC., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Psychosocial support is recommended in conjunction with medication for opioid use disorder (MOUD), although optimal "dose," modality, and timing of participation is not established. This study comprised a secondary analysis of counseling and 12-Step attendance and subsequent opioid use in a MOUD randomized clinical trial., Methods: The parent study randomly assigned 570 participants to receive buprenorphine-naloxone (BUP-NX, n =287) or extended-release injectable naltrexone (XR-NTX, n =283). Mixed-effects logistic regression models were fit with opioid use as the response variable, and a counseling/12-Step attendance predictor. Differences by treatment assignment were examined., Results: Any counseling or 12-Step attendance was associated with reduced odds of opioid use at the subsequent visit, whether considered individually or aggregated across type. A continuous relationship was observed for 12-Step attendance (F(1,5083)=5.01, p =.025); with each additional hour associated with 13% (95% CI: 0.83, 0.90) reduction in odds of opioid use. The strength of this association grew over time. In the BUP-NX arm, group counseling was associated with a greater reduction in odds of opioid use than for XR-NTX, (OR=0.32 (95% CI: .22, 0.48) vs. OR=0.69 (95% CI: 0.43, 1.08)). For XR-NTX, 12-Step was associated with a greater reduction in odds of opioid use (OR=0.35 (95% CI: 0.22, 0.54) vs. OR=0.65 (95% CI: 0.47, 0.89) for BUP-NX))., Conclusions: Psychosocial engagement has a proximal association with opioid use, the strength of that association may grow with dose and time. Alternatively, more motivated individuals may both attend more counseling/12-Step and have better treatment outcomes, or the relationship may be reciprocal., Competing Interests: Declaration of Competing Interest Dr. Hefner has no conflict of interest to declare. Dr. Shmueli-Blumberg has no conflict of interest to declare. Dr. Campbell has no conflict of interest to declare. Dr. Pavlicova has no conflict of interest to declare. Dr. Fishman serves as a consultant for Alkermes, a consultant for Drug Delivery LLC, holds a research grant from Alkermes and a research grant from Medicasafe. Ms. Meyers-Ohki has no conflicts of interest to declare. Dr. Shulman has no conflicts of interest to declare. Dr. Greiner has no conflicts of interest to declare. Ms. Novo has no conflicts of interest to declare. Dr. Rotrosen has served as a Principal Investigator or a co-Investigator on studies for which support in the form of donated medication and/or funds has been, or is, provided by Indivior, Alkermes, and Braeburn, and apps provided by Pear Therapeutics, CHESS Health, and Data Cubed. Dr. Rotrosen recently served in a non-paid capacity as a member of an Alkermes study Steering Committee. Dr. Nunes has served as a Principal Investigator or co-Investigator on studies for which support in the form of donated medication and/or funds has been, or is, provided by Indivior, Alkermes, and Braeburn-Camurus, and digital therapeutics provided by Pear Therapeutics and CHESS Health, and has served as an unpaid consultant to Alkermes, Braeburn-Camurus and Pear Therapeutics.

Use of HIV-related support services has been demonstrated to improve outcomes for people living with HIV. Further exploring patterns of use could help identify how and in what settings additional HIV care and treatment adherence support could be provided. We aimed to identify support service utilization patterns and examine their association with viral load suppression (VLS). Our sample comprised 6,581 people with HIV who received Ryan White Part A support services for basic needs (food and nutrition, legal, harm reduction, housing services) in New York City from 1/2013 to 12/2016, but had not received services specifically targeting HIV care and treatment adherence. Five support service utilization classes were identified using latent class analysis, the majority of which were characterized by the predominant use of concrete services (e.g., food assistance). Compared with the low-intensity, sporadic concrete service use class, clients in all other classes had lower odds of VLS in a 365-day follow-up period, but this disadvantage disappeared with adjustment for confounding variables indicative of need. Our findings underscore the impact of need-related barriers on VLS and suggest that long-term service utilization beyond the one year period of this study may be required to diminish their negative effect on HIV outcomes., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Clinical and empirical reports suggest that individuals use non-suicidal self-injury (NSSI) not only to ameliorate dysphoria, but to curb suicidal ideation or avoid suicidal behaviour. To date, however, no study has quantitatively assessed whether NSSI leads to short-term reductions in suicidal ideation. Using real-time monitoring over 7 days in a sample with borderline personality disorder, we found evidence that NSSI is followed by reductions in suicidal ideation in the subsequent hours. This suggests that NSSI may serve as an effective, albeit maladaptive, coping strategy for suicidal states. These findings have important implications for the management of suicide risk and self-harm.

Background: Methamphetamine use is increasing among persons with opioid use disorder (OUD). The study aims were to describe methamphetamine/amphetamine (MA/A) use among patients treated for OUD with buprenorphine/naloxone (BUP-NX) or extended-release naltrexone (XR-NTX), and to explore associations between treatment arm and MA/A use., Methods: Secondary analysis of data from a multi-site, open-label, randomized controlled trial of XR-NTX versus BUP-NX for 24 weeks. The outcome variable was MA/A use defined by either positive urine drug toxicology or self-report. The main predictor was treatment assignment (BUP-NX v. XR-NTX). Longitudinal mixed-effects logistic regression models were fit to model the odds of MA/A use during the study. Additional predictors included study visit and baseline MA/A use., Results: Among the sample of 570 participants with OUD, baseline use of MA/A was observed in 105 (18.4%). There was no significant treatment effect over the study period, though BUP-NX subjects, on average, had about half the odds of MA/A use compared to XR-NTX subjects (OR=0.50; p = 0.051). In the same model, baseline MA/A use and study visit were both significantly associated with MA/A use over time., Conclusion: In this sample of treated OUD patients, nearly a fifth of participants had MA/A use at baseline and the frequency of use did not decline over time: in fact, the odds of use slightly increased for each later visit. These secondary analyses found no significant difference in MA/A use between BUP-NX and XR-NTX treatment arms, however, the observation of less MA/A in the buprenorphine arm merits further investigation., Clinical Trial Registration: ClinicalTrials.gov (NCT02032433)., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Fragile X syndrome (FXS), the leading cause of inherited intellectual disability and autism spectrum disorder, is associated with multiple neurobehavioral abnormalities including sleep difficulties. Nonetheless, frequency, severity, and consequences of sleep problems are still unclear. The Fragile X Online Registry with Accessible Research Database (FORWARD-version-3), including Clinician Report and Parent Report forms, was analyzed for frequency, severity, relationship with behavioral problems, and impact of sleep difficulties in a mainly pediatric cohort. A focused evaluation of sleep apnea was also conducted. Six surveyed sleep difficulties were moderately frequent (~23%-46%), relatively mild, affected predominantly younger males, and considered a problem for 7%-20% of families. Snoring was more prevalent in older individuals. All sleep difficulties were associated with irritability/aggression and most also to hyperactivity. Only severe snoring was correlated with sleep apnea (loud snoring: 30%; sleep apnea: 2%-3%). Sleep difficulties are prevalent in children with FXS and, although they tend to be mild, they are associated with behavioral problems and negative impact to families. Because of its cross-sectional nature, clinic-origin, use of ad hoc data collection forms, and lack of treatment data, the present study should be considered foundational for future research aiming at better recognition and management of sleep problems in FXS., (© 2021 Wiley Periodicals LLC.)

Chronic pain is highly prevalent among patients with opioid use disorder (OUD). However, little is known about how pharmacological treatments for OUD, for example, extended-release naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX), affect pain. To begin addressing this question, we performed a secondary analysis of pain data on a large prospective 24-week, open-label, randomized-controlled comparative effectiveness trial of XR-NTX versus BUP-NX (X:BOT trial). Participants' pain status was measured by the EuroQol (EQ-5D). Based on their responses to the pain question at baseline, participants were dichotomized into "Pain" versus "No Pain" categories. Participant's pain status was evaluated every 4 weeks. A mixed effects longitudinal logistic regression model was fitted to examine the differential effect of XR-NTX versus BUP-NX on pain, modelling pain at all available follow-up assessments, adjusted for age, sex, and baseline pain. A total of 474 individuals who were successfully inducted onto their assigned medications were included in this analysis. Among participants endorsing pain at baseline, substantial reductions in pain were observed over the course of the study in both treatment groups. Howecver reduction in pain was slightly greater in the group treated with XR-NTX than the one treated with BUP-NX (OR = 1.60 [95% CI: 1.07-2.40], P = 0.023). Future research using instruments and design specifically focused on pain could extend the present observations and evaluate their clinical significance., (© 2021 Society for the Study of Addiction.)

Objective: Previously reported data regarding growth parameters in individuals with fragile X syndrome (FXS) are inconsistent. A longitudinal analysis of height and BMI in a large number of individuals with FXS was conducted., Methods: Age- and sex-specific z scores for height and BMI of 1,223 individuals with FXS were calculated based on published normative data. Mixed-effect linear regression models were fit separately for males and females, and z scores for height and weight were regressed against age and adjusted for intellectual disability (ID) and psychotropic medication use., Results: Mean height z score for both sexes decreased with age and was lower than normative data. Mean BMI z score was greater than normative data in both sexes, and this disparity increased with age. BMI z score in females was greater for those with moderate or severe ID than those with no or mild ID. Individuals taking antipsychotics had higher BMI z scores than those taking no or other medications; those taking anticonvulsants or stimulants had lower BMI z scores., Conclusions: Individuals with FXS are at elevated risk for overweight and obesity. The risk is higher in individuals taking antipsychotics and among females with severe ID. These findings warrant increased attention to obesity prevention for all individuals with FXS., (© 2022 The Obesity Society.)

This study explored factors associated with durable viral suppression (DVS) among two groups of people living with HIV (PLWH) and problem substance use in the context of universal antiretroviral treatment initiation. Participants (N = 99) were recruited between 2014-2017 from public sexual health clinics [SHC] and a hospital detoxification unit [detox]). DVS (NYC HIV surveillance registry) was defined as two consecutive viral load tests ≤ 200 copies/mL, ≤ 90 days apart, with all other viral loads suppressed over 12 or 18 months. Detox participants were significantly older, with more unstable housing/employment, substance use severity, and longer-term HIV vs. SHC participants. Older age, opioid and stimulant use disorder were significantly associated with lower odds of DVS, while fulltime employment and stable housing were significantly associated with higher odds of DVS at 12-month follow-up. Patterns held at 18-month follow-up. Co-located substance use and HIV services, funding for supportive housing, and collaborative patient-provider relationships could improve DVS among populations with the syndemic of problem substance use, poverty, and long-term HIV., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Better understanding of predictors of opioid abstinence among patients with opioid use disorder (OUD) may help to inform interventions and personalize treatment plans. This analysis examined patient characteristics associated with opioid abstinence in the X:BOT (Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment) trial. Methods: This post-hoc analysis examined factors associated with past-month opioid abstinence at the 36-week follow-up visit among participants in the X:BOT study. 428 participants (75% of original sample) attended the visit at 36 weeks. Logistic regression models were used to estimate the probability of opioid abstinence across various baseline sociodemographics, clinical characteristics, and treatment variables. Results: Of the 428 participants, 143 (33%) reported abstinence from non-prescribed opioids at the 36-week follow-up. Participants were more likely to be opioid abstinent if randomized to XR-NTX (compared to BUP-NX), were on XR-NTX at week 36 (compared to those off OUD pharmacotherapy), successfully inducted onto either study medication, had longer time on study medication, reported a greater number of abstinent weeks, or had longer time to relapse during the 24-week treatment trial. Participants were less likely to be abstinent if Hispanic, had a severe baseline Hamilton Depression Rating (HAM-D) score, or had baseline sedative use. Conclusions: A substantial proportion of participants was available at follow-up (75%), was on OUD pharmacotherapy (53%), and reported past-month opioid abstinence (33%) at 36 weeks. A minority of patients off medication for OUD reported abstinence and additional research is needed exploring patient characteristics that may be associated with successful treatment outcomes.

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, learning disability, and autism spectrum disorder, is associated with an increased prevalence of certain medical conditions including seizures. The goal of this study was to better understand seizures in individuals with FXS using the Fragile X Online Registry with Accessible Research Database, a multisite observational study initiated in 2012 involving FXS clinics in the Fragile X Clinic and Research Consortium. Seizure data were available for 1,607 participants, mostly male (77%) and white (74.5%). The overall prevalence of at least one seizure was 12%, with this rate being significantly higher in males than females (13.7 vs. 6.2%, p < 0.001). As compared to individuals with FXS without seizures, those with seizures were more likely to have autism spectrum disorder, current sleep apnea, later acquisition of expressive language, more severe intellectual disability, hyperactivity, irritability, and stereotyped movements. The mean age of seizure onset was 6.4 (SD 6.1) years of age with the great majority (>80%) having onset of seizures which was before 10. For those with epilepsy, about half (52%) had seizures for more than 3 years. This group was found to have greater cognitive and language impairment, but not behavioral disruptions, compared with those with seizures for <3 years. Antiepileptic drugs were more often used in males (60.6%) than females (34.8%), and females more often required more than one medication. The most commonly used anticonvulsants were oxcarbazepine, valproic acid, lamotrigine, and levetiracetam. The current study is the largest and first longitudinal study ever conducted to describe seizures in FXS. Overall, this study confirms previous reports of seizures in FXS and extends previous findings by further defining the cognitive and behavioral phenotype of those with epilepsy in FXS. Future studies should further investigate the natural history of seizures in FXS and the characteristics of seizures in FXS in adulthood., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Berry-Kravis, Filipink, Frye, Golla, Morris, Andrews, Choo, Kaufmann and the FORWARD Consortium.)

Background: The comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT) trial showed that following induction, treatment with the sublingual agonist (buprenorphine-naloxone, BUP-NX) or injected antagonist (extended release naltrexone, XR-NTX) produced similar reductions in opioid relapse in injection users with opioid use disorder (OUD). Because XR-NTX reduces drinking in alcohol use disorder (AUD), we conducted a secondary analysis of the X:BOT sample of patients successfully inducted onto treatment to determine whether XR-NTX (n = 204) was superior to BUP-NX (n = 270) in reducing drinking or heavy drinking in patients with OUD., Methods: Standard drink units consumed were measured using the Timeline Follow-back method. Mixed-models regression was used to examine the monthly frequency of any drinking and heavy drinking over 6 months of treatment. We used a proportional hazard survival analysis to examine the time to first drink., Results: Both treatment groups reduced drinking from baseline to posttreatment (small to medium effect), but no differences between groups were detected. However, only 29% (n = 136) of the sample had AUD and 19% (n = 26/136) of those were abstinent before treatment. Analysis of a subsample enriched for possible drinking included 136 individuals with an AUD diagnosis plus 43 who did not have AUD, but reported at least one day of heavy drinking prior to the study. However, this subsample reported only 32% of days of any drinking with a median of only 13% of days designated as "heavy." Within this subsample, at baseline, the BUP-NX group reported more mean drinks per drinking day than the XR-NTX group (p = 0.03); however, there were no other significant group differences on drinking observed before, during, or at the end of treatment., Conclusions: There was an overall reduction in drinking during treatment of OUD using both agonist and antagonist medications, so that the hypothesis that XR-NTX would be superior to BUP-NX was not supported. The study is limited by low levels of comorbid AUD or heavy drinking observed in X:BOT trial participants seeking treatment for OUD., (© 2021 by the Research Society on Alcoholism.)

Aim: This report examined naturalistic opioid use outcomes and utilization of medications for opioid use disorder (MOUD) 36 weeks post-randomization in the National Drug Abuse Treatment Clinical Trials Network (CTN) Extended-Release Naltrexone (XR-NTX) versus Buprenorphine-Naloxone (BUP-NX) for Opioid Treatment trial (CTN-0051, X:BOT)., Design: X:BOT was a multisite, randomized, 24-week comparative effectiveness trial of BUP-NX (N = 287) and XR-NTX (N = 283). Study medications were discontinued following treatment completion, relapse, or dropout. Participants were encouraged to continue MOUD. This report examined opioid use outcomes in 428 (75%) of the 570 participants who attended the 36-week follow-up visit., Setting and Participants: Adults with opioid use disorder recruited from 8 community treatment programs across the United States., Measurements: Outcomes included medication status (on/off MOUD), type of MOUD (BUP-NX, XR-NTX, or methadone), abstinence from non-prescribed opioids, opioid use days, relapse, and other substance use 30 days prior to the 36-week visit. Relapse was defined as opioid use for 4 consecutive weeks or 7 consecutive days in the past month. Baseline and clinical variables included opioid use severity, intravenous drug use, study medication assignment, and induction status., Findings: Of the 428 participants who completed the 36-week visit, 225 (53%) of participants were receiving MOUD and 203 (47%) were not. Compared to those off medication, participants on medication had fewer opioid use days (4.4 days (SD 9.0) versus 9.8 days (SD 12.1)), fewer met relapse criteria (37 (16.4%) versus 79 (38.9%)), and reported less stimulant use (34 (15.2%) versus 56 (27.7%)) and sedative use (14 (6.3%) versus 31 (15.3%)). There was no difference in abstinence rates between those on or off MOUD. A greater proportion of participants on XR-NTX (47 (53.4%) of 88 participants) were abstinent from non-prescribed opioids compared to those on buprenorphine (28 (23.3%) of 120 participants)., Conclusions: Naturalistic outcomes data showed that despite potential barriers to continuing treatment in the community, about half of individuals were on opioid use disorder pharmacotherapy at follow-up and those on medication generally had better outcomes. Future research should explore barriers and facilitators to treatment retention in community settings; and developing interventions tailored to improve treatment engagement and adherence., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Suicidal behavior (SB) can be impulsive or methodical; violent or not; follow a stressor or no obvious precipitant. This study tested whether childhood trauma, affective lability, and aggressive and impulsive traits predicted greater SI variability. We also assessed whether affective lability, aggressive or impulsive traits explain childhood trauma's effects on SI variability and whether those with highly variable SI respond to stressful events with increases in SI. Finally, we assessed variable SI's trajectory over 2 years. Depressed participants (n = 51) had ecological momentary assessments (EMA) over 7 days at baseline, 3, 6, 12, 18, and 24 months. SI variability was assessed using the square Root of the Mean Square of Successive Deviations. Mixed Effects Models were fit as appropriate. Childhood trauma was associated with subsequent aggression. Physical abuse predicted both aggression and affective lability as well as SI variability, but not impulsivity. In two-predictor models, physical abuse's effect on SI variability was no longer significant, when controlling for the effect of higher aggression and impulsivity. Those with high SI variability exhibited greater increases in SI after stressors compared with those with less variability. We did not find that SI variability changed over time, suggesting it might be trait-like, at least over 2 years. Variable SI predisposes to marked SI increases after stressful events and may be a trait increasing risk for impulsive SB, at least over 2 years., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Extended-release naltrexone (XR-NTX) is an effective maintenance treatment for opioid use disorder, but induction from active opioid use is a challenge as individuals must complete detoxification before induction. We aimed to determine whether use of methadone or buprenorphine, long acting agonist opioids commonly used for detoxification, were associated with decreased likelihood of induction onto XR-NTX., Methods: We performed a secondary analysis of a large open-label randomized trial of buprenorphine versus XR-NTX for treatment of individuals with opioid use disorder recruited from eight short term residential (detoxification) units. This analysis only included individuals randomized to the XR-NTX arm of the trial (N = 283). The method of detoxification varied according to usual practices at each inpatient program. Logistic regression models estimating the log-odds of induction onto XR-NTX were fit, with detoxification regimen received as the predictor., Results: In the unadjusted logistic regression model, detoxification drug received (either methadone or buprenorphine) was significantly associated with decreased likelihood of induction onto XR-NTX compared to receiving non-opioid detoxification (Overall: P < 0.001); buprenorphine vs non-opioid detoxification: OR (95% CI) = 0.32 (0.15-0.67); methadone vs non-opioid detoxification: OR (95% CI) = 0.23 (0.11-0.46). After controlling for site as a random effect, the association of detoxification drug with induction success lost statistical significance., Conclusions: Use of agonist medication during detoxification was associated with XR-NTX induction failure. Medication choice was determined by each site's clinical practice and therefore this association could not be separated from other site level variables., Clinical Trial Registration: NCT02032433., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The distinct pharmacological properties and clinical uses of extended-release naltrexone (XR-NTX) and sublingual buprenorphine-naloxone (BUP-NX) present challenges in analyzing patient outcomes., Methods: We conducted a secondary analysis of a multi-site randomized trial comparing XR-NTX with sublingual BUP-NX treatment for opioid use disorder initiated during inpatient detoxification and continued in outpatient treatment. Urine testing data for non-study opioids from the last 22 weeks of the 24-week trial were analyzed in both a per-protocol sample (n = 474 participants who received at least one dose of medication) and a completers sample (n = 211 participants who received all XR-NTX doses or all BUP-NX prescriptions). The present analyses sought to identify differences in the weekly percentages of opioid-positive urine tests between participants treated with the two medications., Results: The proportion of opioid-positive tests in both conditions was less than 20 % for 21 of the 22 weeks in the per-protocol sample and all 22 weeks in the completers sample. Generalized linear mixed model analyses revealed a significant treatment (XR-NTX vs. BUP-NX) X week (weeks 3-24) interaction in the per-protocol sample but not the completers sample. In the per-protocol analysis, the BUP-NX, compared to XR-NTX, had significantly greater proportions of opioid-positive tests in 14 out of the 22 weeks., Conclusions: Longitudinal modeling approaches that utilize flexible procedures for handling missing data can offer a different perspective on study findings. Results from the present analyses suggest that XR-NTX appeared to be somewhat more effective than BUP-NX in reducing illicit opioid use in the per-protocol sample., (Copyright © 2020. Published by Elsevier B.V.)

Objective: Elevated cardiovascular reactivity to, and reduced recovery from, challenging events may increase the risk of cardiovascular disease, and exercise training may reduce this reactivity. However, in a randomized controlled trial of aerobic versus strength training in sedentary, healthy young adults, we found no training group differences in reactivity or recovery. Because strength training also may have a reactivity-reducing effect, we conducted a secondary analysis of data from another trial, this time with a wait-list control condition., Methods: One hundred nineteen healthy, young, sedentary adults were randomized to a 12-week aerobic training program or wait-list control. Before (T1) and after (T2) training and after 4 weeks of sedentary deconditioning (T3), we measured heart rate (HR), heart rate variability, and blood pressure at rest and in response to and recovery from psychological and orthostatic challenge. Data were analyzed using a group (aerobic versus wait-list) by session (T1, T2, and deconditioning) and by period (baseline, psychological challenge, recovery, standing) three-way analysis of variance with prespecified contrasts., Results: Aerobic capacity significantly increased at T2 and decreased at T3 only in the aerobic training group. The groups did not differ on HR, heart rate variability, or blood pressure reactivity to or recovery from challenge. Without baseline adjustment, there were no significant treatment differences in response to challenges. With baseline adjustment, there were significant treatment by session effects for HR (Cohen d = 0.54, p = .002), systolic blood pressure (d = 0.44, p = .014), diastolic blood pressure (d = 0.74, p = .002), and root mean squared successive difference (d = 0.48, p = .006) reactivity from T1 to T2 only for orthostatic challenge: at T2, reactivity in the aerobic group was nonsignificantly reduced, compared with T1. In the wait-list group, reactivity significantly increased after T1., Conclusions: This study raises further doubt about attenuation of cardiovascular reactivity or enhancement of recovery as a cardioprotective mechanism of aerobic exercise training.Clinical Trial Registration:ClinicalTrials.gov Unique identifier: NCT01335737., (Copyright © 2020 by the American Psychosomatic Society.)

Background: While suicide-specific psychosocial interventions often teach coping skills to suicidal individuals, little is known about the strategies that individuals intuitively use on their own to cope with suicidal ideation in everyday life., Aims: The present study used Ecological Momentary Assessment (EMA) to examine the effectiveness of specific coping strategies individuals use naturally to reduce the intensity of suicidal thinking., Method: Fifty participants endorsing suicidal ideation with co-morbid mood disorder and borderline personality disorder completed one week of EMA. Real-time use, perceived effectiveness of 7 common coping strategies and intensity of suicidal ideation were assessed at 6 epochs (i.e., timepoints) each day., Results: Participants reported using an average of 4 coping strategies per epoch. Factor analysis (FA) (exploratory followed by confirmatory FA) identified two coping factors: one that included distraction/positive activity-based strategies (i.e., keeping busy, socializing, positive thinking, and doing something good for self) and a second that contained mindfulness-oriented strategies (i.e., finding perspective, calming self, and sitting with feelings until they pass). Although participants perceived all coping strategies as effective, only strategies in the first factor, distraction/positive activity-oriented strategies, lowered the intensity of suicidal thoughts in everyday life. Furthermore, baseline suicidal ideation was inversely related to overall use of coping strategies and particularly use of coping strategies that were found to lead to lowered suicidal ideation., Conclusions: Distraction/positive activity based strategies are helpful in decreasing suicidal ideation in the short-term. These findings can help clinicians advise patients about strategies to use to cope with suicidal thoughts to prevent acting on them in a crisis and they also have the potential to inform development of psychosocial interventions to prevent suicide., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Researchers and clinicians have typically relied on retrospective reports to monitor suicidal thoughts and behaviors. Smartphone technology has made real-time monitoring of suicidal thoughts possible via mobile ecological momentary assessment (EMA). However, little is known about how information gleaned from EMA compares with that obtained by retrospective reports. The authors sought to compare suicidal ideation (SI) assessed over 1 week using EMA with a retrospective gold-standard interviewer-administered measure covering the same period., Methods: Fifty-one adults with major depressive disorder completed 1 week of EMA (6×/day) assessing SI. Following completion of EMA, participants completed an interviewer-administered Scale for Suicide Ideation (SSI) retrospectively assessing the same week., Results: SI severity assessed through EMA was positively correlated with scores on the retrospective SSI. However, 58% of participants reporting ideation with EMA denied any past-week ideation on the SSI. Participants who endorsed SI during EMA but not on the SSI were no less likely to have a history of suicidal behavior than those who reported SI in both formats., Conclusion: EMA captures instances of suicidal thinking that go undetected through retrospective report and thereby may help us to identify an at-risk subgroup otherwise missed., (© 2020 Wiley Periodicals LLC.)

Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = -0.41; p = 0.04, d = -0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = -0.36; p = 0.008, d = -0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = -0.56; p = 0.079, d = -0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

Background: To assess within and across diagnosis variability we examined fear processing in healthy controls (HC) and three diagnostic groups that share symptoms of pathological anxiety: obsessive compulsive disorder (OCD); social anxiety disorder (SAD), and anorexia nervosa (AN)., Methods: Unmedicated adults (N=166) participated in a paradigm assessing associative fear acquisition, extinction, extinction recall, and fear renewal. Data were analyzed from two perspectives: comparison of each disorder to HC and exploratory latent class analysis (LCA) of the combined data., Results: The diagnosis-based analyses indicated significantly increased fear renewal in OCD and trends toward decreased extinction recall in OCD and increased renewal in SAD. The LCA indicated four Response Types, none of which were congruent with the diagnostic categories. Most participants had a normative response (50%) or a moderate extinction recall deficit (30%). The two remaining groups (8% each) had more extreme responses: one showed complete failure of extinction recall; the other persistent arousal in expectation of, but prior to, actual conditioning (threat sensitivity)., Limitations: Due to small sample size (N=20) results for AN are regarded as preliminary., Conclusions: Our diagnosis-based findings are consistent with previous data suggesting an association between pathological anxiety and difficulties maintaining fear extinction. The LCA reveal substantial within-diagnosis heterogeneity in fear processing and support inclusion of empirically driven approaches as a complement to standard analyses. This heterogeneity may also have implications for treatment, particularly cognitive behavioral therapy, which relies on strengthening extinction recall and requires patients to tolerate anxious expectation in order to engage with feared situations., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: The Aberrant Behavior Checklist (ABC) is a standardized rating scale used for assessing problematic behavior of individuals with developmental disabilities. It has five subscales: Irritability, Social Withdrawal, Stereotypic Behavior, Hyperactivity, and Inappropriate Speech. A previous study in individuals with fragile X syndrome (FXS) reported six factors, with the Social Withdrawal factor bifurcating into Socially Unresponsive and Social Avoidance factors, suggesting a different factor structure in people with FXS. Methods: We assessed the ABC's factor structure (with both exploratory and confirmatory analyses) in 797 people with FXS and we compared these findings with exploratory factors derived from an independent sample of 357 individuals with FXS. In an ancillary analysis, we compared the overlap of the traditional ABC's Social Withdrawal scores with the Social Avoidance scores from the FXS-derived newer scale to determine whether overlap between these was very high and essentially redundant. Finally, we computed norms using both the traditional and the FXS-specific algorithms. Results: In confirmatory factor analyses, the FXS-specific algorithm produced the most consistent factor structure for the sample of 797 participants, but model fit was only marginally better than that derived by the original ABC scoring algorithm. Comparisons of factor structures from separate exploratory analyses revealed no consistent advantage of the FXS algorithm over the traditional algorithm. While a Social Avoidance subscale did emerge in some analyses, in other analyses, this was accompanied by loss of coherence on other domains of interest, such as the Socially Unresponsive/Social Withdrawal subscale. Conclusion: We question whether the newer FXS scoring algorithm contributes data that are consistently helpful in evaluating behavior of people with FXS. In general, we recommend continued use of the original ABC algorithm for scoring behavior of clients with FXS . However, we acknowledge that there may be circumscribed times when the new algorithm may be appropriate for scoring, namely when anxiety and/or social avoidance constructs are the central and unequivocal domains of interest.

We carried out a psychometric assessment of the Social Communication Questionnaire (SCQ) and the Social Responsiveness Scale (SRS-2) in fragile X syndrome (FXS), relative to clinician DSM5-based diagnosis of autism spectrum disorder (ASD) in FXS. This was followed by instrument revisions that included: removal of non-discriminating and/or low face validity items for FXS; use of receiver operating characteristic (ROC) curves to determine optimal cut points for the original and revised measures; an exploratory factor analysis to outline subscales better representing ASD in FXS; and creation of a "triple criteria" diagnosis to better delineate ASD subgroups in FXS. These methods improved the sensitivity and/or specificity of the SCQ and SRS-2, but diagnostic accuracy of ASD remains problematic in FXS.

Despite their theoretical rationale, nicotinic alpha-7 acetylcholine (nα 7 ) receptor agonists, have largely failed to demonstrate efficacy in placebo-controlled trials in schizophrenia. AVL-3288 is a nα 7 positive allosteric modulator (PAM), which is only active in the presence of the endogenous ligand (acetylcholine), and thus theoretically less likely to cause receptor desensitization. We evaluated the efficacy of AVL-3288 in a Phase 1b, randomized, double-blind, placebo-controlled, triple cross-over study. Twenty-four non-smoking, medicated, outpatients with schizophrenia or schizoaffective disorder and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) ≥62 were randomized. Each subject received 5 days of AVL-3288 (10, 30 mg) and placebo across three separate treatment weeks. The primary outcome measure was the RBANS total scale score, with auditory P50 evoked potential suppression the key target engagement biomarker. Secondary outcome measures include task-based fMRI (RISE task), mismatch negativity, the Scale for the Assessment of Negative Symptoms of Schizophrenia (SANS) and the Brief Psychiatric Rating Scale (BPRS). Twenty-four subjects were randomized and treated without any clinically significant treatment emergent adverse effects. Baseline RBANS (82 ± 17) and BPRS (41 ± 13) scores were consistent with moderate impairment. Primary outcomes were negative, with non-significant worsening for both active groups vs. placebo in the P50 and minimal between group changes on the RBANS. In conclusion, the results did not indicate efficacy of the compound, consistent with most prior results for the nα 7 target.

This study examines self-reported 30-day antiretroviral therapy (ART) adherence among 101 people living with HIV and substance use disorders (SUD) in New York City in terms of Diagnostic and Statistical Manual - 5th Edition (DSM-5) SUD symptom clusters: impaired control, social impairment, risky use and pharmacological criteria. Overall, 60.4% met DSM-5 criteria for stimulant, 55.5% for alcohol, 34.7% for cannabis and 25.7% for opioid SUD. Of the 76 participants with a current ART prescription, 75.3% reported at least 90% 30-day adherence. Participants with vs. without alcohol SUD were significantly less likely to report ART adherence (64.3% vs. 88.2%, p  = .017). Endorsement of social impairment significantly differed among adherent vs. non-adherent participants with alcohol SUDs (74.1% vs. 100%, p  = .038) and with opioid SUDs (94.1% vs. 50.0%, p  = .040). Understanding specific SUD symptom clusters may assist providers and patients in developing strategies to improve ART adherence.

Objective: The antidepressant and anxiolytic effects of aerobic exercise are well known, but less is known about its effects on subclinical levels of trait negative affect in healthy but sedentary adults. In the present study, we test the effects of a 3-month randomized controlled trial of aerobic exercise training in young to midlife adults on trait measures of depression, anxiety, hostility, and anger., Method: One-hundred and 19 men (n = 56) and women (n = 63) aged 20-45 were randomized to 1 of 2 conditions: (a) 12 weeks of aerobic exercise after which they were asked to halt exercising and decondition for 4 weeks, or (b) a 16-week waitlist control group. Assessments of depression, anxiety, hostility and anger were completed at study entry, Week 12 and Week 16., Results: At study entry, participants scored low on measures of depression, anxiety, hostility and anger. Analyses among the intent-to-treat and per protocol samples found significant treatment effects of aerobic training for hostility and depression, but not for anxiety and anger. Within-group analyses demonstrated that depression and hostility scores decreased in the exercise group over the course of the intervention, while remaining stable in the control group. These effects persisted for the exercise group at nonsignificant levels after 4 weeks of deconditioning., Conclusions: Aerobic exercise training has significant psychological effects even in sedentary yet euthymic adults, adding experimental data on the known benefits of exercise in this population. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Introduction: Separation anxiety disorder (SAD) comprises one aspect of attachment dysregulation or insecurity. Although SAD aggravates posttraumatic stress disorder (PTSD) risk, no clinical research has tracked how many patients with PTSD have SAD, its clinical associations, or its response to PTSD treatment. Our open trial of interpersonal psychotherapy (IPT) for veterans with PTSD assessed these SAD domains., Methods: Twenty-nine veterans diagnosed with chronic PTSD on the Clinician-Administered PTSD Scale were assessed for SAD using the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS), and for Symptom-Specific Reflective Function (SSRF), another dysregulated-attachment marker capturing patients' emotional understanding of their symptoms. Patients received 14 IPT sessions for PTSD with assessments at baseline, Week 4 (SCI-SAS and SSRF), and termination for SAD, PTSD, and depression., Results: At baseline, 69% of patients met SAD criteria. Separation anxiety did not correlate with baseline PTSD severity, depressive severity, or age when traumatized; patients with and without SAD had comparable PTSD and depression severity. Patients with baseline comorbid SAD who completed IPT (N = 17) reported significantly improved adult separation anxiety (p = .009). Adult SAD improvements predicted depressive improvement (p = .049). Patients with SAD showed a stronger relationship between early SSRF gains and subsequent adult SAD improvement (p = .021) compared with patients without SAD., Discussion: This first exploration of dysregulated/insecure attachment features among patients with PTSD found high SAD comorbidity and adult SAD improvement among patients with SAD following IPT. Highly impaired attachment patients normalized attachment posttreatment: 14-session IPT improved attachment dysregulation. This small study requires replication but begins to broaden clinical understanding of separation anxiety, attachment dysregulation, and PTSD., (© 2020 Wiley Periodicals, Inc.)

We report on the rationale and design of an ongoing NIMH sponsored R61-R33 project in schizophrenia/schizoaffective disorder. This project studies augmenting the efficacy of auditory neuroplasticity cognitive remediation (AudRem) with d-serine, an N -methyl-d-aspartate-type glutamate receptor (NMDAR) glycine-site agonist. We operationalize improved (smaller) thresholds in pitch (frequency) between successive auditory stimuli after AudRem as improved plasticity, and mismatch negativity (MMN) and auditory θ as measures of functional target engagement of both NMDAR agonism and plasticity. Previous studies showed that AudRem alone produces significant, but small cognitive improvements, while d-serine alone improves symptoms and MMN. However, the strongest results for plasticity outcomes (improved pitch thresholds, auditory MMN and θ) were found when combining d-serine and AudRem. AudRem improvements correlated with reading and other auditory cognitive tasks, suggesting plasticity improvements are predictive of functionally relevant outcomes. While d-serine appears to be efficacious for acute AudRem enhancement, the optimal dose remains an open question, as does the ability of combined d-serine + AudRem to produce sustained improvement. In the ongoing R61, 45 schizophrenia patients will be randomized to receive three placebo-controlled, double-blind d-serine + AudRem sessions across three separate 15 subject dose cohorts (80/100/120 mg/kg). Successful completion of the R61 is defined by ≥moderate effect size changes in target engagement and correlation with function, without safety issues. During the three-year R33, we will assess the sustained effects of d-serine + AudRem. In addition to testing a potentially viable treatment, this project will develop a methodology to assess the efficacy of novel NMDAR modulators, using d-serine as a "gold-standard"., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest associated with this project.

Objective: To characterize bladder and bowel toileting skill acquisition in children with fragile X syndrome and to identify associated demographic, behavioral, and clinical factors., Methods: Using baseline data from the Fragile X Online Registry With Accessible Research Database (FORWARD), bivariate analyses and logistic regression models were used to identify differences between subjects who were and were not bowel and/or bladder trained by the age of 10 years. Cox proportional hazard models were used to assess the rate of completion of toilet training (TT) as a function of sex and autism spectrum disorder (ASD) diagnosis., Results: In bivariate analyses, male sex, lower language level, inability to write one's name, more impaired intellectual level, ASD, and more severe behavioral deficits all predicted lack of bladder training (n = 313, p < 0.001) and bowel training (n = 300, p = 0.0004-0.0001) by the age of 10 years. In logistic regression models, lower level of language acquisition (p < 0.001) and higher Aberrant Behavior Checklist Irritability scores (p < 0.04) were associated with lower odds of bladder training by the age of 10 years. Lower level of language acquisition (p < 0.001) and ASD (p < 0.025) were associated with lower odds of bowel training by the age of 10 years. For both bladder and bowel training, Cox proportional hazard models indicated that delayed training was associated with male sex, lower levels of language acquisition, and ASD for both bladder training (n = 486; p < 0.001) and bowel training (n = 472; p < 0.001)., Conclusion: These findings emphasize the importance of both slower language development and ASD diagnosis in predicting bowel and bladder training delays and can be used to develop and evaluate targeted approaches to TT based on sex, ASD diagnosis, and other clinical features identified in this study.

Using a dataset involving 415 individuals with irritability, aggression, agitation and self-injury (IAAS) behaviors from the fragile X syndrome (FXS) FORWARD database, we describe the psychopharmacologic management of IAAS and features of the population of persons with FXS treated with drug therapy for IAAS. Among those with FXS exhibiting IAAS, individuals with FXS receiving drug treatment of IAAS were older, more predominantly male, have more significant intellectual disability, more like to have comorbid autism, hyperarousal, and social impairments. The most commonly utilized medications for IAAS in FXS are antipsychotic medications, specifically aripiprazole and risperidone (37% and 27%, respectively). The majority of subjects (63%) experienced no side effects noted from the use of their psychopharmacologic medications.

Ketamine shows promise as a rapidly-acting treatment for depression and suicidal ideation, but side effects and abuse potential limit its use. Understanding its mechanism of action could help develop analogous but safer drugs. This post hoc study explored relationships of ketamine and metabolites, including hydroxynorketamine enantiomers, (2S,6S)- and (2R,6R)-HNK, to clinical response in a subgroup from a published trial in suicidal depression. Depressed adults with clinically significant suicidal ideation were randomized to double-blind infusion of sub-anesthetic ketamine or midazolam. Ketamine and metabolites were measured after infusion (N = 53). Plasma (2R,6R)-HNK was associated with change (higher levels correlated with less clinical improvement) from baseline to 24 h post-infusion of depression (HDRS-24: Spearman r = 0.37, p = 0.009) and suicidal thoughts (SSI: Spearman r = 0.29, p = 0.041). There were similar correlations with weekly follow-up clinical rating scores for both HNK enantiomers and dehydronorketamine (DHNK). Ketamine and norketamine were not associated with change in depression or suicidal ideation (unadjusted p > 0.28)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)