Search

It remains unclear why depression is associated with adverse outcomes in patients with heart failure (HF). We examine the relationship between depression and clinical outcomes among patients with HF with reduced ejection fraction managed with guideline-directed medical therapy (GDMT).Using the GUIDE-IT trial, 894 patients with HF with reduced ejection fraction were stratified according to a history of depression, and Cox proportional hazards regression modeling was used to examine the association with outcomes. There were 140 patients (16%) in the overall cohort who had depression. They tended to be female (29% vs 46%, P.001) and White (67% vs 53%, P = .002). There were no differences in GDMT rates at baseline or at 90 days; nor were there differences in target doses of these therapies achieved at 90 days (NS, all). amino-terminal pro-B-type natriuretic peptide levels at all time points were similar between the cohorts (P.05, all). After adjustment, depression was associated with all-cause hospitalizations (hazard ratio, 1.42, 95% confidence interval 1.11-1.81, P.01), cardiovascular death (hazard ratio, 1.69, 95% confidence interval 1.07-2.68, P = .025), and all-cause mortality (hazard ratio, 1.54, 95% confidence interval 1.03-2.32, P = .039).Depression impacts clinical outcomes in HF regardless of GDMT intensity and amino-terminal pro-B-type natriuretic peptide levels. This finding underscores the need for a focus on mental health in parallel to achievement of optimal GDMT in these patients.NCT01685840, https://clinicaltrials.gov/ct2/show/NCT01685840.

Summary Background Cannabis is one of the most widely used drugs worldwide. Cannabis use disorder is characterised by recurrent use of cannabis that causes significant clinical and functional impairment. There are no approved pharmacological treatments for cannabis use disorder. One approach is to potentiate endocannabinoid signalling by inhibiting fatty acid amide hydrolase (FAAH), the enzyme that degrades the endocannabinoid anandamide. We aimed to test the efficacy and safety of the FAAH-inhibitor PF-04457845 in reduction of cannabis withdrawal and cannabis use in men who were daily cannabis users. Methods We did a double-blind, placebo-controlled, parallel group phase 2a trial at one site in men aged 18–55 years with cannabis dependence according to DSM-IV criteria (equivalent to cannabis use disorder in DSM-5). After baseline assessments, participants were randomly assigned (2:1) to receive PF-04457845 (4 mg per day) or placebo using a fixed block size of six participants, stratified by severity of cannabis use and desire to quit. Participants were admitted to hospital for 5 days (maximum 8 days) to achieve abstinence and precipitate cannabis withdrawal, after which they were discharged to continue the remaining 3 weeks of treatment as outpatients. The primary endpoints were treatment-related differences in cannabis withdrawal symptoms during hospital admission, and week 4 (end of treatment) self-reported cannabis use and urine THC-COOH concentrations in the intention-to-treat population. The study is registered at ClinicalTrials.gov, number NCT01618656. Findings Between Sept 12, 2012, and Jan 18, 2016, 46 men were randomly assigned to PF-04457845 and 24 to placebo. Adherence to study medication was 88%, as confirmed by video-calling and pill count, and corroborated by corresponding drug and anandamide concentrations in blood. Relative to placebo, treatment with PF-04457845 was associated with reduced symptoms of cannabis withdrawal (first day of treatment mean symptom score 11·00 [95% CI 7·78–15·57] vs 6·04 [4·43–8·24]; difference 4·96 [0·71–9·21]; p adj =0·048; second day of treatment 11·74 [8·28–16·66] vs 6·02 [4·28–8·47]; difference 5·73 [1·13–10·32]; p adj =0·035) and related mood symptoms during the inpatient phase. Additionally, treatment with PF-04457845 was associated with lower self-reported cannabis use at 4 weeks (mean 1·27 joints per day [95% CI 0·82–1·97] vs 0·40 [0·25–0·62]; difference 0·88 [0·29–1·46]; p=0·0003) and lower urinary THC-COOH concentrations (mean 657·92 ng/mL [95% CI 381·60–1134·30] vs 265·55 [175·60–401·57]; difference 392·37 [17·55–767·18)]; p=0·009). Eight (17%) patients in the PF-04457845 group and four (17%) in the placebo group discontinued during the treatment period. During the 4-week treatment phase, 20 (43%) of 46 participants in the PF-04457845 group and 11 (46%) of 24 participants in the placebo group had an adverse event. There were no serious adverse events. Interpretation PF-04457845, a novel FAAH inhibitor, reduced cannabis withdrawal symptoms and cannabis use in men, and might represent an effective and safe approach for the treatment of cannabis use disorder. Funding United States National Institute of Drug Abuse (NIDA).

Background:Binding studies have demonstrated that levels of the cannabinoid receptor type-1 are highest in the basal ganglia and cerebellum, two areas critical for motor control. However, no studies have systematically examined the dose-related effects of intravenous delta-9-tetrahydrocannabinol, the primary cannabinoid receptor type-1 partial agonist in cannabis, on broad domains of psychomotor function in humans.Aims:Therefore, three domains of psychomotor function were assessed in former cannabis users (cannabis abstinent for a minimum of three months; n=23) in a three test-day, within-subject, double-blind, randomized, cross-over, and counterbalanced study during which they received intravenous delta-9-tetrahydrocannabinol (placebo, 0.015 mg/kg, and 0.03 mg/kg).Methods:Gross motor function was assessed via the Cambridge Neuropsychological Test Automated Battery Motor Screening Task, fine motor control via the Lafayette Instrument Grooved Pegboard task, and motor timing via a Paced Finger-Tapping Task. In addition, the Cambridge Neuropsychological Test Automated Battery Rapid Visual Processing Task was utilized to determine whether delta-9-tetrahydrocannabinol-induced motor deficits were confounded by disruptions in sustained attention.Results/outcomes:Delta-9-tetrahydrocannabinol resulted in robust dose-dependent deficits in fine motor control (Grooved Pegboard Task) and motor timing (Paced Finger-Tapping Task), while gross motor performance (Motor Screening Task) and sustained attention (Rapid Visual Processing Task) were unimpaired. Interestingly, despite the observed dose-dependent increases in motor impairment and blood levels of delta-9-tetrahydrocannabinol, subjects reported similar levels of intoxication in the two drug conditions.Conclusions/interpretation:These data suggest that while several domains of motor function are disrupted by delta-9-tetrahydrocannabinol, subjective feelings of intoxication are dissociable from cannabinoid-induced psychomotor effects. Results are discussed in terms of the potential neural mechanisms of delta-9-tetrahydrocannabinol in motor structures.

Preliminary evidence suggests that cannabidiol (CBD) may be effective in the treatment of neurodegenerative disorders; however, CBD has never been evaluated for the treatment of cognitive impairments associated with schizophrenia (CIAS). This study compared the cognitive, symptomatic, and side effects of CBD versus placebo in a clinical trial. This study was a 6-week, randomized, placebo-controlled, parallel group, fixed-dose study of oral CBD (600 mg/day) or placebo augmentation in 36 stable antipsychotic-treated patients diagnosed with chronic schizophrenia. All subjects completed the MATRICS Consensus Cognitive Battery (MCCB) at baseline and at end of 6 weeks of treatment. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and biweekly. There was no main effect of time or drug on MCCB Composite score, but a significant drug × time effect was observed (p = 0.02). Post hoc analyses revealed that only placebo-treated subjects improved over time (p = 0.03). There was a significant decrease in PANSS Total scores over time (p

Binding studies have demonstrated that levels of the cannabinoid receptor type-1 are highest in the basal ganglia and cerebellum, two areas critical for motor control. However, no studies have systematically examined the dose-related effects of intravenous delta-9-tetrahydrocannabinol, the primary cannabinoid receptor type-1 partial agonist in cannabis, on broad domains of psychomotor function in humans.Therefore, three domains of psychomotor function were assessed in former cannabis users (cannabis abstinent for a minimum of three months; n=23) in a three test-day, within-subject, double-blind, randomized, cross-over, and counterbalanced study during which they received intravenous delta-9-tetrahydrocannabinol (placebo, 0.015 mg/kg, and 0.03 mg/kg).Gross motor function was assessed via the Cambridge Neuropsychological Test Automated Battery Motor Screening Task, fine motor control via the Lafayette Instrument Grooved Pegboard task, and motor timing via a Paced Finger-Tapping Task. In addition, the Cambridge Neuropsychological Test Automated Battery Rapid Visual Processing Task was utilized to determine whether delta-9-tetrahydrocannabinol-induced motor deficits were confounded by disruptions in sustained attention.Delta-9-tetrahydrocannabinol resulted in robust dose-dependent deficits in fine motor control (Grooved Pegboard Task) and motor timing (Paced Finger-Tapping Task), while gross motor performance (Motor Screening Task) and sustained attention (Rapid Visual Processing Task) were unimpaired. Interestingly, despite the observed dose-dependent increases in motor impairment and blood levels of delta-9-tetrahydrocannabinol, subjects reported similar levels of intoxication in the two drug conditions.These data suggest that while several domains of motor function are disrupted by delta-9-tetrahydrocannabinol, subjective feelings of intoxication are dissociable from cannabinoid-induced psychomotor effects. Results are discussed in terms of the potential neural mechanisms of delta-9-tetrahydrocannabinol in motor structures.

Background The widespread use of cannabis, the increasing legalization of "medical" cannabis, the increasing potency of cannabis, and the growing recreational use of synthetic cannabinoid 1 receptor (CB 1 R) full agonists all underscore the importance of elucidating the effects of cannabinoids on the CB 1 R system. Exposure to cannabinoids is known to result in CB 1 R downregulation. However, the precise time course of changes in CB 1 R availability in cannabis-dependent (CD) subjects after short-term and intermediate-term abstinence has not been determined. Methods Using high-resolution research tomography and the reversible ligand [ 11 C]OMAR, CB 1 R availability as indexed by the [ 11 C]OMAR volume of distribution was measured in male CD subjects ( n = 11) and matched healthy control (HC) subjects ( n = 19). The CD subjects were scanned at baseline (while they were neither intoxicated nor in withdrawal) and after 2 days and 28 days of monitored abstinence. The HC subjects were scanned at baseline, and a subset ( n = 4) was scanned again 28 days later. Results Compared with HC subjects, [ 11 C]OMAR volume of distribution was 15% lower in CD subjects (effect size Cohen's d = −1.11) at baseline in almost all brain regions. However, these group differences in CB 1 R availability were no longer evident after just 2 days of monitored abstinence from cannabis. There was a robust negative correlation between CB 1 R availability and withdrawal symptoms after 2 days of abstinence. There were no significant group differences in CB 1 R availability in CD subjects after 28 days of abstinence. Conclusions Cannabis dependence is associated with CB 1 R downregulation, which begins to reverse rapidly on termination of cannabis use and may continue to increase over time.

One prominent, long-standing view is that individuals with schizophrenia smoke cigarettes more than the general population to “self-medicate” cognitive deficits and other symptoms. This study tested the self-medication hypothesis by examining the effects of smoking abstinence and resumption on cognition in patients with schizophrenia. Nicotine-dependent smokers with schizophrenia (n=26) were trained on a cognitive battery and then hospitalized to achieve and maintain confirmed abstinence from smoking for ~1 week. Cognition was tested while smoking as usual (baseline), one day after smoking cessation (early abstinence), ~1 week later (extended abstinence), and within ~3 weeks of resuming smoking (resumption). The test battery included measures of processing speed, attention, conflict resolution, verbal memory, working memory, verbal fluency, and executive function to evaluate multiple cognitive domains affected by schizophrenia. Positive and negative symptoms of schizophrenia, depressive symptoms, and dyskinesia were also measured at baseline and after prolonged abstinence. There were no significant changes in global cognitive test performance with smoking cessation, abstinence, or resumption. There were small decreases in a measure of processing speed and delayed verbal recall with abstinence, but these findings failed to survive adjustments for multiple comparisons. Surprisingly, in this within subject “On- Off—Off-On” design, there were no significant effects of early or prolonged abstinence from smoking on cognitive and behavioral measures in smokers with schizophrenia. The results of this study challenge the widely held “self-medication” hypothesis of smoking and schizophrenia, question the extent of pro-cognitive effects of smoking and nicotine in schizophrenia, and support encouraging smoking cessation in schizophrenia.

Background Though cognitive remediation has shown modest benefits for schizophrenia, relatively few training programs for have targeted the visual processing deficits common in the illness. Residual visual processing deficits following cognitive remediation may explain why cognitive remediation has had limited effects on visual learning and memory compared to auditory learning and memory. We sought to test whether training early visual processing would improve visual memory and facial affect recognition by targeting a well-characterized visual deficit in schizophrenia: visual backward masking (VBM). The deficit is so common in schizophrenia, and in non-affected family members to a lesser degree, that it is viewed as an endophenotype. The VBM deficit, however, can normalize as we have previously shown. In our prior open-label pilot study, individuals with schizophrenia (Surti and Wexler, 2012) made substantial gains in VBM performance with rudimentary computerized VBM training. The VBM improvements were also accompanied by improvements in visual memory. To test the hypothesis that improved early sensory training could lead to other cognitive gains in the same domain, we conducted a randomized control study with a new, more sophisticated computerized VBM training program, and compared it to an active control condition. We expected that visual memory and facial affect recognition would improve with the novel visual training (VT), and that VBM would improve with the VT as well. Methods 23 individuals with stable schizophrenia or schizoaffective disorder were randomized to receive 20 sessions of VT or an active control. The VT consisted of VBM training with multiple levels of difficulty, adaptive tracking, virtual rewards, and a variety of letters, numbers, and shapes to train different areas of the visual field. The active control condition was a commercially available computerized typing tutorial (TT) with animation, game narrative, and multiple typing activities. Participants were tested before and after training with: the Matrics Cognitive Consensus Battery (MCCB), including the Brief Visuospatial Memory Test-Revised (BVMT) as the study’s primary outcome; the Profile of Nonverbal Sensitivity (mini-PONS) to assess non-verbal social cues; standardized VBM tests; and typing assessments. Repeated measure ANOVAs were conducted in SPSS24 after checking for normality. Results 22 of 23 individuals completed the study, and by participants’ reports, both interventions were well tolerated, equally enjoyable and equally motivating, though the VT was slightly more frustrating for participants. Even when co-varying for education, which was higher in the VT group, there were no condition by time interactions for the BVMT, the mini-PONS, overall MCCB, or typing ability. There was a significant condition by time interactions for VBM performance (F = 5.8, p =0.028), with a substantial improvement in the VT group (Cohen’s d = 0.54; p=0.004). Discussion Patients with schizophrenia equally tolerated a computerized visual training designed in-house and an off-the shelf highly gamified control training, but only the visual training, specifically designed for individuals with schizophrenia, had effects on the trained task. The effects of the visual training did not generalize to visual memory, facial affect recognition, or global cognition, so further work is needed to facilitate generalization.

We investigated whether improved early visual processing on cognitive remediation (CR) exercises generalizes to visual and auditory learning and information manipulation in schizophrenia. Fourteen participants received neuropsychological testing before and after CR consisting of visual, auditory and cognitive control training. Achievement on visual training exercises was strongly and significantly correlated with improved visual learning, but not improved verbal learning or increased ability to manipulate visual information. Improvement in training, not training time, predicted cognitive gain. Implications for improving cognitive outcomes from CR include ensuring the trained task is learned and providing exercises of multiple modalities.

Several lines of evidence suggest the presence of abnormalities in the endocannabinoid (eCB) system in schizophrenia (SCZ). However, there are limited in vivo measures of the eCB system in SCZ.Twenty five male SCZ subjects (SCZs) (18 antipsychotic treated and 7 antipsychotic free) were compared with 18 age-matched male healthy control subjects (HCs). Subjects underwent one positron emission tomography scan each with the cannabinoid receptor-1 (CB1R) selective radiotracer [(11)C]OMAR on the high resolution research tomography scanner. Regional volume of distribution (VT) values were determined using kinetic modeling of positron emission tomography data as a measure of CB1R availability. Group differences in mean composite [(11)C]OMAR VT values were compared between SCZs and HCs. Exploratory comparisons of CB1R availability within 15 brain regions were also conducted. All analyses were covaried for age and body mass index.SCZs showed significantly (p = .02) lower composite [(11)C]OMAR VT relative to HCs (~12% difference, effect size d = .73). [(11)C]OMAR VT was significantly (all ps.05) lower in SCZs in the amygdala, caudate, posterior cingulate cortex, hippocampus, hypothalamus, and insula. Composite [11]OMAR VT was HCsantipsychotic treated SZCsantipsychotic free SZCs. Furthermore, composite [(11)C]OMAR VT was greater in HCs than SCZ smokers (n = 11) and SCZ nonsmokers (n = 14).CB1R availability is lower in male SCZ subjects compared with HCs. Furthermore, antipsychotics and tobacco use may increase CB1R availability in this population. The findings of the study provide further evidence supporting the hypothesis that alterations in the eCB system might contribute to the pathophysiology of SCZ.

The bovine papillomavirus E5 protein is thought to be a type II integral membrane protein that exists as a disulfide- linked homodimer in transformed cells. Polar- ized-infrared measurements show that the E5 dimer in membrane bilayers is largely a-heli- cal and has a transmembrane orientation. Com- putational searches of helix-helix conforma- tions reveal two possible low-energy dimer structures. Correlation of these results with previous mutagenesis studies on the E5 pro- tein suggests how the E5 dimer may serve as a molecular scaffold for dimerization and ligand- independent activation of the PDGF-b recep- tor. We propose that on each face of the E5 dimer a PDGF-b receptor molecule interacts directly with Gln17 from one E5 monomer and with Asp33 from the other E5 monomer. This model accounts for the requirement of Gln17 and Asp33 for complex formation and explains genetic results that dimerization of the E5 pro- tein is essential for cell transformation. Proteins 33:601-612, 1998. r 1998 Wiley-Liss, Inc.

The bovine papillomavirus E5 protein is a small, homodimeric transmembrane protein that forms a stable complex with the cellular platelet-derived growth factor (PDGF) β receptor through transmembrane and juxtamembrane interactions, resulting in receptor activation and cell transformation. Glutamine 17 in the transmembrane domain of the 44-amino-acid E5 protein is critical for complex formation and receptor activation, and we previously proposed that glutamine 17 forms a hydrogen bond with threonine 513 of the PDGF β receptor. We have constructed and analyzed mutant E5 proteins containing all possible amino acids at position 17 and examined the ability of these proteins to transform C127 fibroblasts, which express endogenous PDGF β receptor. Although several position 17 mutants were able to transform cells, mutants containing amino acids with side groups that were unable to participate in hydrogen bonding interactions did not form a stable complex with the PDGF β receptor or transform cells, in agreement with the proposed interaction between position 17 of the E5 protein and threonine 513 of the receptor. The nature of the residue at position 17 also affected the ability of the E5 proteins to dimerize. Overall, there was an excellent correlation between the ability of the various E5 mutant proteins to bind the PDGF β receptor, lead to receptor tyrosine phosphorylation, and transform cells. Similar results were obtained in Ba/F3 hematopoietic cells expressing exogenous PDGF β receptor. In addition, treatment of E5-transformed cells with a specific inhibitor of the PDGF receptor tyrosine kinase reversed the transformed phenotype. These results confirm the central importance of the PDGF β receptor in mediating E5 transformation and highlight the critical role of the residue at position 17 of the E5 protein in the productive interaction with the PDGF β receptor. On the basis of molecular modeling analysis and the known chemical properties of the amino acids, we suggest a structural basis for the role of the residue at position 17 in E5 dimerization and in complex formation between the E5 protein and the PDGF β receptor.

Glutamatergic neurotransmission mediated by N -methyl- d -aspartate (NMDA) receptors is vital for the cortical computations underlying cognition and might be disrupted in severe neuropsychiatric illnesses such as schizophrenia. Studies on this topic have been limited to processes in local circuits; however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brain’s global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this disruption predicted task performance and transiently evoked symptoms characteristic of schizophrenia. We offer a parsimonious hypothesis for this disruption via biophysically realistic computational modeling, namely cortical disinhibition. Together, the present findings establish links between glutamate’s role in the organization of large-scale anticorrelated neural systems, cognition, and symptoms associated with schizophrenia in humans.