Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis.

Elevated hippocampal perfusion has been observed in people at clinical high risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medicine study examined whether diazepam can normalize hippocampal perfusion in CHR-P individuals. Using a randomized, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with magnetic resonance imaging (MRI) on two occasions, once following a single oral dose of diazepam (5 mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labeling and sampled in native space using participant-specific hippocampus and subfield masks (CA1, subiculum, CA4/dentate gyrus). Twenty-two healthy controls (HC) were scanned using the same MRI acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield. Under the placebo condition, CHR-P individuals (mean [±SD] age: 24.1 [±4.8] years, 15 F) showed significantly elevated rCBF compared to HC (mean [±SD] age: 26.5 [±5.1] years, 11 F) in the hippocampus (F(1,41) = 24.7, pFDR < 0.001) and across its subfields (all pFDR < 0.001). Following diazepam, rCBF in the hippocampus (and subfields, all pFDR < 0.001) was significantly reduced (t(69) = -5.1, pFDR < 0.001) and normalized to HC levels (F(1,41) = 0.4, pFDR = 0.204). In conclusion, diazepam normalized hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in increased vulnerability for psychosis.

Effects of Benzodiazepine Exposure on Real-World Clinical Outcomes in Individuals at Clinical High Risk for Psychosis.

BACKGROUND AND HYPOTHESIS: Animal models indicate GABAergic dysfunction in the development of psychosis, and that benzodiazepine (BDZ) exposure can prevent the emergence of psychosis-relevant phenotypes. However, whether BDZ exposure influences real-world clinical outcomes in individuals at clinical high risk for psychosis (CHR-P) is unknown. STUDY DESIGN: This observational cohort study used electronic health record data from CHR-P individuals to investigate whether BDZ exposure (including hypnotics, eg, zopiclone) reduces the risk of developing psychosis and adverse clinical outcomes. Cox proportional-hazards models were employed in both the whole-unmatched sample, and a propensity score matched (PSM) subsample. STUDY RESULTS: 567 CHR-P individuals (306 male, mean[±SD] age = 22.3[±4.9] years) were included after data cleaning. The BDZ-exposed (n = 105) and BDZ-unexposed (n = 462) groups differed on several demographic and clinical characteristics, including psychotic symptom severity. In the whole-unmatched sample, BDZ exposure was associated with increased risk of transition to psychosis (HR = 1.61; 95% CI: 1.03-2.52; P = .037), psychiatric hospital admission (HR = 1.93; 95% CI: 1.13-3.29; P = .017), home visit (HR = 1.64; 95% CI: 1.18-2.28; P = .004), and Accident and Emergency department attendance (HR = 1.88; 95% CI: 1.31-2.72; P < .001). However, after controlling for confounding-by-indication through PSM, BDZ exposure did not modulate the risk of any outcomes (all P > .05). In an analysis restricted to antipsychotic-naïve individuals, BDZ exposure reduced the risk of transition to psychosis numerically, although this was not statistically significant (HR = 0.59; 95% CI: 0.32-1.08; P = .089). CONCLUSIONS: BDZ exposure in CHR-P individuals was not associated with a reduction in the risk of psychosis transition or adverse clinical outcomes. Results in the whole-unmatched sample suggest BDZ prescription may be more likely in CHR-P individuals with higher symptom severity.

Expectancy for Adderall influences subjective mood and drug effects regardless of concurrent caffeine ingestion: A randomized controlled trial.

RATIONALE: Nonmedical prescription stimulant use (NPS; use without a prescription or in ways other than prescribed) is common among college students. Despite the potential for negative consequences, students continue engaging in NPS for cognitive enhancement purposes, which may be maintained by expectancy and placebo effects. OBJECTIVES: This study examined if a placebo administered under the guise of Adderall influenced subjective mood/drug effects and cognitive performance. Furthermore, this study examined if concurrent caffeine ingestion incrementally enhanced Adderall-related placebo effects. METHODS: Undergraduate students with features that put them at elevated risk for NPS (N = 121) completed measures of mood and drug effects and cognitive assessments on two separate laboratory visits in this parallel randomized controlled trial. Visit 1 was a baseline control visit, on which no drug was expected or received. On visit 2, subjects were randomized to: (1) expect/receive no drug (control); (2) expect Adderall/receive placebo; or (3) expect Adderall/receive 200 mg caffeine. RESULTS: There were several significant condition × visit interactions for subjective effects, including amphetamine effects, energy and efficiency effects, and feeling high. In most cases, participants who expected Adderall reported greater positive subjective effects on visit 2 compared to controls; however, there were generally not incremental enhancements for those ingesting caffeine compared to placebo. There were no significant effects for any cognitive tests. CONCLUSIONS: Expectation for prescription stimulant effects influenced subjective outcomes in a sample of high-risk college students. These findings may inform expectancy challenge interventions to reduce NPS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03648684.

Effects of Benzodiazepine Exposure on Real-World Clinical Outcomes in Individuals at Clinical High-Risk for Psychosis.

Background: Animal models indicate GABAergic dysfunction in the development of psychosis, and that benzodiazepine (BDZ) exposure can prevent the emergence of psychosis-relevant phenotypes. However, whether BDZ exposure influences the risk of psychosis in humans is unknown. Methods: This observational-cohort study used electronic health record data from 818 individuals at clinical high-risk for psychosis (CHR-P) to investigate whether BDZ exposure (including hypnotics e.g., zopiclone) reduces the risk of developing psychosis and adverse clinical outcomes. Cox proportional-hazards models were employed in both the whole-unmatched sample, and a propensity score matched (PSM) subsample. Results: 567 CHR-P individuals were included after data cleaning (105 BDZ-exposed, 462 BDZ-unexposed). 306 (54%) individuals were male, and the mean age was 22.3 years (SD 4.9). The BDZ-exposed and BDZ-unexposed groups differed on several demographic and clinical characteristics, including psychotic symptom severity. In the whole-unmatched sample, BDZ exposure was associated with increased risk of transition to psychosis (HR=1.61; 95%CI:1.03-2.52; P=0.037), psychiatric hospital admission (HR=1.93; 95%CI:1.13-3.29; P=0.017), home visit (HR=1.64; 95%CI:1.18-2.28; P=0.004), and A&E attendance (HR=1.88; 95%CI:1.31-2.72; P<0.001). However, after controlling for confounding-by-indication through PSM, BDZ exposure did not modulate the risk of any outcomes (all P>0.05). In analysis restricted to antipsychotic-naïve individuals, BDZ exposure reduced the risk of transition to psychosis at trend-level (HR=0.59; 95%CI:0.32-1.08; P=0.089). Conclusions: BDZ exposure in CHR-P individuals was not associated with a reduction in the risk of psychosis transition or other adverse clinical outcomes. Results in the whole-unmatched sample suggest BDZ prescription may be more likely in CHR-P individuals with higher symptom severity.

Use of Both Alcohol and Cannabis Protective Behavioral Strategies is Associated with Fewer Negative Consequences: A Moderation Analysis.

Background: Concurrent alcohol and cannabis (i.e. marijuana) use (CAM; use of both substances within the same specified time frame) is prevalent among college students and associated with increased risk of negative substance-related consequences. Extant research supports the use of protective behavioral strategies (PBS) for reducing negative consequences associated with both alcohol and cannabis use. However, limited research exists regarding the efficacy of PBS among CAM users, and it is unknown whether using PBS for both alcohol and cannabis augments protective effects. The present study tested four moderation models to evaluate the interactive effects of alcohol and cannabis PBS on alcohol and cannabis negative consequences and use frequency. Methods: A multisite sample of college students (N = 1705) reporting past-month CAM use completed questionnaires regarding substance use behaviors, PBS use, and substance-related negative consequences. Results: Alcohol and cannabis PBS were negatively associated with alcohol and cannabis use, respectively. However, two-way interactions between PBS on substance use were not supported, such that negative associations between PBS and same-substance use were not augmented as other-substance PBS use increased. Interactive effects of alcohol and cannabis PBS on negative alcohol and cannabis consequences were supported, such that negative associations between alcohol PBS and consequences were augmented as cannabis PBS increased and vice versa. Conclusions: Findings suggest that using both types of PBS may increase protective effects against negative consequences among CAM users. Accordingly, promoting both types of PBS may enhance extant harm reduction interventions.

An examination of the effects of ADHD symptoms and sex on the relation between cannabis protective behavioral strategies and cannabis consequences.

The risk for cannabis-related problems is elevated among young adults with attention-deficit/hyperactivity disorder (ADHD) symptoms. It is unknown whether the use of cannabis protective behavioral strategies (PBS) mitigates this risk for college students with ADHD. Prior research finds that college students who use alcohol and report high levels of ADHD symptoms particularly benefit from employing alcohol PBS, and these relations are strongest for male students. Thus, this study examined the moderating effects of ADHD symptoms and sex assigned at birth on the relation between cannabis PBS use and cannabis-related problems among college students who use cannabis. Participants were 384 college students (66.9% female, 57.8% white non-Hispanic, Mage = 19.29) from 12 United States universities who reported past-month cannabis use. Participants completed measures of demographics, ADHD symptoms, past-month cannabis frequency and related problems, and cannabis PBS use via an online survey. There was a significant interaction of ADHD hyperactive/impulsive symptoms, PBS use, and sex on cannabis-related problems, controlling for cannabis use frequency. The strength of the negative association between PBS use and problems depended on level of ADHD symptoms for females, but not for males. However, there were no interactive effects for ADHD inattentive symptoms. These results supplement the literature base on relations between PBS use and ADHD symptoms in college students, extending support for their use to cannabis users. Importantly, promoting PBS use to female college students who are high in hyperactive/impulsive ADHD symptoms is recommended.

Negative Affect Regulation and Marijuana Use in College Students: Evaluating the Mediating Roles of Coping and Sleep Motives.

Negative affect regulation models suggest that marijuana may be used to reduce negative affect. Extant research has provided support for these models, indicating that specific motives for marijuana use, particularly coping motives (i.e., using to alleviate negative affects), mediate relations between affective vulnerabilities and marijuana outcomes. However, sleep motives (i.e., using to promote sleep) have been neglected from such models, despite their theoretical relevance. The present study tested two multiple mediation models in a large sample of marijuana-using college students (N = 1,453) to evaluate the indirect effects of coping and sleep motives in paths from depressive and anxiety symptoms to marijuana outcomes (use, consequences, and cannabis use disorder [CUD] symptoms). Both coping and sleep motives mediated the effects of depressive/anxiety symptoms on each marijuana variable. Moreover, significant double mediated effects were found, such that higher affective symptoms were associated with greater motives; which were associated with more marijuana use; which was related to more negative consequences and CUD symptoms. The findings provide support for sleep motives as a relevant pathway between affective vulnerabilities and marijuana outcomes. Additional research is needed to evaluate the potential benefits of interventions targeting specific marijuana motives.

Relationship between astrocyte reactivity, using novel 11C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals.

Post mortem neuropathology suggests that astrocyte reactivity may play a significant role in neurodegeneration in Alzheimer's disease. We explored this in vivo using multimodal PET and MRI imaging. Twenty subjects (11 older, cognitively impaired patients and 9 age-matched healthy controls) underwent brain scanning using the novel reactive astrocyte PET tracer 11C-BU99008, 18F-FDG and 18F-florbetaben PET, and T1-weighted MRI. Differences between cognitively impaired patients and healthy controls in regional and voxel-wise levels of astrocyte reactivity, glucose metabolism, grey matter volume and amyloid load were explored, and their relationship to each other was assessed using Biological Parametric Mapping (BPM). Amyloid beta (Aß)-positive patients showed greater 11C-BU99008 uptake compared to controls, except in the temporal lobe, whilst further increased 11C-BU99008 uptake was observed in Mild Cognitive Impairment subjects compared to those with Alzheimer's disease in the frontal, temporal and cingulate cortices. BPM correlations revealed that regions which showed reduced 11C-BU99008 uptake in Aß-positive patients compared to controls, such as the temporal lobe, also showed reduced 18F-FDG uptake and grey matter volume, although the correlations with 18F-FDG uptake were not replicated in the ROI analysis. BPM analysis also revealed a regionally-dynamic relationship between astrocyte reactivity and amyloid uptake: increased amyloid load in cortical association areas of the temporal lobe and cingulate cortices was associated with reduced 11C-BU99008 uptake, whilst increased amyloid uptake in primary motor and sensory areas (in which amyloid deposition occurs later) was associated with increased 11C-BU99008 uptake. These novel observations add to the hypothesis that while astrocyte reactivity may be triggered by early Aß-deposition, sustained pro-inflammatory astrocyte reactivity with greater amyloid deposition may lead to astrocyte dystrophy and amyloid-associated neuropathology such as grey matter atrophy and glucose hypometabolism, although the evidence for glucose hypometabolism here is less strong.

Expectation for stimulant type modifies caffeine's effects on mood and cognition among college students.

Caffeine is regularly used by college students to enhance mood and academic performance. Although high doses confer risk for negative consequences, moderate doses of caffeine may lead to acute improvements in mood and cognitive functioning. Notably, the pharmacological effects of caffeine may be enhanced by expectancy effects. College students may also engage in nonmedical prescription stimulant use for similar purposes, as students expect strong cognitive enhancement from prescription stimulants and consider them to be more efficacious than caffeine. The purpose of the current study was to examine whether the pharmacological effects of caffeine on mood/drug effects and cognitive performance are enhanced when expecting a conceivably stronger stimulant (i.e., Adderall) compared to when expecting caffeine. Sixty-five undergraduate students were randomized to condition across two variables: drug ingested (placebo or 200 mg caffeine) and drug expected (caffeine or Adderall). Participants completed self-report measures of mood and drug effects pre- and post-drug, as well as cognitive assessments post-drug. There were significant main effects of drug ingested and drug expected on several post-drug measures. Subjects receiving caffeine reported feeling more high, stimulated, anxious, and motivated than subjects receiving placebo. Further, subjects expecting Adderall reported stronger amphetamine effects and feeling more high, and performed better on a working memory test, than those expecting caffeine. Effects tended to be strongest in participants receiving caffeine and expecting Adderall. Modifying expectancies, in conjunction with the pharmacological properties of caffeine at moderate doses, may be one mechanism by which college students may experience differential effects of caffeine. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using 11C-BU99008 PET and its relationship with amyloid load.

11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer's disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aß)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer's brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer's disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aß load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.

Demographic risk factors for co-occurring suicidality and cannabis use disorders: Findings from a nationally representative United States sample.

OBJECTIVE: Burgeoning research suggests a link between suicidality (i.e., ideation, attempts) and cannabis use; however, little is known about which demographic groups are at increased risk of co-occurring suicidality and cannabis use disorders (CUD). This study tested differences in suicidality, CUD, and their co-occurrence by gender, age, race/ethnicity, and sexual orientation in a nationally representative U.S. METHOD: Five years (2015-2019) of National Survey of Drug Use and Heath surveys were combined. Multinomial logistic regressions tested demographic differences in odds of suicidality only, CUD only, and co-occurring CUD and suicidality, relative to neither suicidality nor CUD. Covariates included survey year, major depressive episode, and other substance use disorders. RESULTS: Men had higher odds of co-occurring suicidal ideation and CUD than women (AOR = 2.06). All older age groups reported lower odds of co-occurring suicidal ideation and CUD and co-occurring suicide attempts and CUD than emerging adults (AORs = 0.06-0.39). Black/African American (AOR = 1.42) and Native (AOR = 2.16) adults reported higher odds of co-occurring suicidal ideation and CUD than White adults. Black/African American (AOR = 4.05) and Hispanic/Latinx (AOR = 2.49) adults reported higher odds of co-occurring CUD and suicide attempts than White adults. Gay/lesbian (AOR = 2.04) and bisexual (AOR = 3.16) adults reported higher odds of co-occurring suicidal ideation and CUD than heterosexual adults. CONCLUSIONS: Men, emerging adults, Black/African American, Native, and sexual minority groups had elevated risk of co-occurring suicidal ideation and CUD. Emerging adults, Black/African American, and Hispanic/Latinx groups had elevated risk of co-occurring suicide attempts and CUD.

Preliminary evidence for the phosphodiesterase type-4 inhibitor, roflumilast, in ameliorating cognitive flexibility deficits in patients with schizophrenia.

BACKGROUND: Cognitive flexibility deficits are present in patients with schizophrenia and are strong predictors of functional outcome but, as yet, have no pharmacological treatments. AIMS: The purpose of this study was to investigate whether the phosphodiesterase type-4 inhibitor, roflumilast, can improve cognitive flexibility performance and functional brain activity in patients with schizophrenia. METHODS: This was a within-subject, randomised, double-blind, placebo-controlled, three-period crossover study using a version of the Intradimensional/Extradimensional (ID/ED) task, optimised for functional magnetic resonance imaging (fMRI), in 10 patients with schizophrenia who were scanned after receiving placebo, 100 µg or 250 µg roflumilast for 8 consecutive days. Data from an additional fMRI ID/ED study of 18 healthy participants on placebo was included to contextualise the schizophrenia-related performance and activations. The fMRI analyses included a priori driven region of interest (ROI) analysis of the dorsal frontoparietal attention network. RESULTS: Patients on placebo demonstrated broad deficits in task performance compared to the healthy comparison group, accompanied by preserved network activity for solution search, but reduced activity in left ventrolateral prefrontal cortex (VLPFC) and posterior parietal cortex for attentional set-shifting and reduced activity in left dorsolateral prefrontal cortex (DLPFC) for reversal learning. These ROI deficits were ameliorated by 250 µg roflumilast, whereas during solution search 100 µg roflumilast reduced activity in the left orbitofrontal cortex, right DLPFC and bilateral PPC, which was associated with an improvement in formation of attentional sets. CONCLUSIONS: The results suggest roflumilast has dose-dependent cognitive enhancing effects on the ID/ED task in patients with schizophrenia, and provides sufficient support for larger studies to test roflumilast's role in improving cognitive flexibility deficits in this clinical population.

Cannabis Use Is Differentially Associated with Individual Facets of Impulsivity through Expectancy Effects: A Comprehensive Application of the Acquired Preparedness Model.

The acquired preparedness model (APM) posits that the relationship between impulsivity and substance use is mediated by drug effect expectancies. Though the APM has been utilized to explain college student cannabis use, a comprehensive model conceptualizing impulsivity as a multidimensional construct has not been examined. Guided by the APM, the current study examined facets of impulsivity as simultaneous predictors of cannabis use through positive and negative expectancies. College students (N = 478) completed an online survey assessing frequency of past-month cannabis use, facets of impulsivity, and cannabis expectancies. Using a bootstrapped path analysis, five facets of impulsivity were modeled as predictors of past-month cannabis use via positive and negative expectancies. A zero-inflated Poisson distribution was used, wherein dichotomous past-month cannabis use was examined independently of frequency. There was a significant indirect effect of sensation seeking on both increased likelihood and frequency of use through strong positive expectancies. Additionally, both negative and positive urgency were associated with a decreased likelihood of use through stronger negative expectancies, while lack of premeditation was associated with an increased likelihood of use through weaker negative expectancies. These results underscore the importance of examining impulsivity as a multi-dimensional construct in the understanding of college student cannabis use behavior.

Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer's subjects?

BACKGROUND: Type 2 diabetes is a risk factor for Alzheimer's disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects. METHODS: In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function. RESULTS: In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs. CONCLUSIONS: In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

Feasibility, acceptability and affective consequences of at-home sleep extension in young women with depressive symptoms: A pilot study.

Insufficient sleep is common in young adults and has meaningful consequences for daytime functioning, including increased sleepiness, affective disruption and depressive symptoms. This study provides a preliminary evaluation of the feasibility, acceptability and affective consequences of extended sleep opportunity in young women with insufficient sleep and depressive symptoms. Participants were 32 women, 18-22 years of age, who regularly obtained less than 8-hr sleep/night and had daytime sleepiness and depressive symptoms at or above population averages. Participants were asked to maintain a sleep schedule of their typical duration for 7 days and were then randomly assigned to either extend sleep opportunity (ESO) by 90 min per night or maintain typical sleep opportunity (TSO), for the next 7 days. Sleep characteristics and daytime sleepiness were measured using continuous actigraphy and daily sleep diary, and affect, stress and depressive symptoms were assessed with daily and weekly questionnaires. Extended sleep opportunity increased sleep duration by over 1 hr, improved morning sleepiness and positive affect, and diminished anhedonia and depressive symptoms in study completers (n = 11 ESO, 11 TSO). However, 31.3% of participants (n = 10) were withdrawn from the study due to difficulty maintaining the sleep schedule. These results provide initial evidence that sleep extension is beneficial for young women who usually have inadequate sleep and mood disruption and can maintain a consistent sleep schedule. If extending sleep opportunity improves sleep, daytime sleepiness and affect in young adults who typically have insufficient sleep, it could broaden the range of interventions for sleep and mental wellness.