Citalopram in first episode schizophrenia: The DECIFER trial

Antidepressants are frequently prescribed in first episode schizophrenia (FES) patients for negative symptoms or for subsyndromal depressive symptoms, but therapeutic benefit has not been established, despite evidence of efficacy in later-stage schizophrenia. We conducted a 52 week, placebo-controlled add-on trial of citalopram in patients with FES who did not meet criteria for major depression to determine whether maintenance therapy with citalopram would improve outcomes by preventing or improving negative and depressive symptoms. Primary outcomes were negative symptoms measured by the Scale for Assessment of Negative Symptoms and depressive symptoms measured by the Calgary Depression Scale for Schizophrenia; both were analyzed by an intent-to-treat, mixed effects, area-under-the-curve analysis to assess the cumulative effects of symptom improvement and symptom prevention over a one-year period. Ninety-five patients were randomized and 52 (54%) completed the trial. Negative symptoms were reduced with citalopram compared to placebo (p=.04); the effect size of citalopram versus placebo was 0.32 for participants with a duration of untreated psychosis (DUP) of \u3c 18 weeks (median split) and 0.52 with a DUP \u3e 18 weeks. Rates of new-onset depression did not differ between groups; improvement in depressive symptoms was greater with placebo than citalopram (p=.02). Sexual side effects were more common with citalopram, but overall treatment-emergent side effects were not increased compared to placebo. In conclusion, citalopram may reduce levels of negative symptoms, particularly in patients with longer DUP, but we found no evidence of benefit for subsyndromal depressive symptoms

A Single Dose of Nicotine Enhances Reward Responsiveness in Nonsmokers: Implications for Development of Dependence

Background: Tobacco smoking, driven by the addictive properties of nicotine, is the most prevalent preventable cause of death in the Western world. Accumulated evidence suggests that nicotine may increase appetitive responding for nondrug incentives in the environment. Methods: To test this hypothesis, we conducted a randomized, double-blind, placebo-controlled, crossover study of the effect of a single dose of transdermal nicotine on reward responsiveness in 30 psychiatrically healthy nonsmokers. A novel signal detection task in which correct responses were differentially rewarded in a 3:1 ratio was used to assess the extent to which participants modulated their behavior as a function of reward. Results: Despite expected adverse effects such as nausea, nicotine significantly increased response bias toward the more frequently rewarded condition, at the expense of accuracy, independent of effects on attention or overall vigilance. Additionally, response bias on placebo was greater in participants who received nicotine in the first session, indicating that an effect of nicotine on reward responsiveness or reward-based learning persisted for at least 1 week. Conclusions: These findings suggest that a single dose of nicotine enhances response to non-drug-related rewards in the environment, with lasting effects. This effect may contribute to reinforcement of early smoking behavior and development of nicotine dependence.Psycholog

A Systematic Examination of the 2013 ACC/AHA Pooled Cohort Risk Assessment Tool for Atherosclerotic Cardiovascular Disease

AbstractBackgroundThe 2013 American College of Cardiology/American Heart Association updated cholesterol guidelines recommend the use of Pooled Cohort Equations to estimate 10-year absolute risk for atherosclerotic cardiovascular disease (ASCVD) in primary prevention.ObjectivesThis study sought to systematically examine the Pooled Cohort Equations to determine risk factor levels required to exceed risk thresholds outlined in new cholesterol guidelines.MethodsWe entered continuous risk factor levels in isolation and in specified combinations with the risk tool, and we observed predicted risk output patterns. We used the 10-year ASCVD risk threshold of ≥7.5% as a clinically relevant risk threshold.ResultsWe demonstrated that a hypothetical man or woman can reach clinically relevant risk thresholds throughout the eligible age spectrum of 40 to 79 years of age, depending on the associated risk factor burden in all race-sex groups. Age continues to be a major determinant of 10-year ASCVD risk for both men and women. Compared with the previous risk assessment tool used in cholesterol guidelines, the inclusion of a stroke endpoint and use of race-specific coefficients permit identification of at-risk African Americans and non-Hispanic white women at much younger ages and lower risk factor levels.ConclusionsThese data provide context of specific risk factor levels and groups of individuals who are likely to have 10-year ASCVD risk estimates ≥7.5%. Age continues to be a major driver of risk, which highlights the importance of the clinician-patient discussion before statin therapy is initiated

Impairment in acquisition of conditioned fear in schizophrenia

Individuals with schizophrenia show impairments in associative learning. One well-studied, quantifiable form of associative learning is Pavlovian fear conditioning. However, to date, studies of fear conditioning in schizophrenia have been inconclusive, possibly because they lacked sufficient power. To address this issue, we pooled data from four independent fear conditioning studies that included a total of 77 individuals with schizophrenia and 74 control subjects. Skin conductance responses (SCRs) to stimuli that were paired (the CS + ) or not paired (CS−) with an aversive, unconditioned stimulus were measured, and the success of acquisition of differential conditioning (the magnitude of CS + vs. CS− SCRs) and responses to CS + and CS− separately were assessed. We found that acquisition of differential conditioned fear responses was significantly lower in individuals with schizophrenia than in healthy controls (Cohen’s d = 0.53). This effect was primarily related to a significantly higher response to the CS− stimulus in the schizophrenia compared to the control group. Moreover, the magnitude of this response to the CS− in the schizophrenia group was correlated with the severity of delusional ideation (p = 0.006). Other symptoms or antipsychotic dose were not associated with fear conditioning measures. In conclusion, individuals with schizophrenia who endorse delusional beliefs may be over-responsive to neutral stimuli during fear conditioning. This finding is consistent with prior models of abnormal associative learning in psychosis

High-Density Lipoprotein Cholesterol and Particle Concentrations, Carotid Atherosclerosis, and Coronary Events MESA (Multi-Ethnic Study of Atherosclerosis)

ObjectivesThe purpose of this study was to evaluate independent associations of high-density lipoprotein cholesterol (HDL-C) and particle (HDL-P) concentrations with carotid intima-media thickness (cIMT) and incident coronary heart disease (CHD).BackgroundHDL-C is inversely related to CHD, and also to triglycerides, low-density lipoprotein particles (LDL-P), and related metabolic risk. HDL-P associations with CHD may be partially independent of these factors.MethodsIn a multiethnic study of 5,598 men and women ages 45 to 84 years old, without baseline CHD, excluding subjects on lipid-lowering medications, triglycerides >400 mg/dl, or missing values, we evaluated associations of HDL-C and nuclear magnetic resonance spectroscopy-measured HDL-P with cIMT and incident CHD (myocardial infarction, CHD death, and angina, n = 227 events; mean 6.0 years follow-up). All models were adjusted for age, sex, ethnicity, hypertension, and smoking.ResultsHDL-C and HDL-P correlated with each other (ρ = 0.69) and LDL-P (ρ = −0.38, −0.25, respectively, p < 0.05 for all). For (1 SD) higher HDL-C (15 mg/dl) or HDL-P (6.64 μmol/l), cIMT differences were − 26.1 (95% confidence interval [CI]: −34.7 to −17.4) μm and −30.1 (95% CI: −38.8 to − 21.4) μm, and CHD hazard ratios were 0.74 (95% CI: 0.63 to 0.88) and 0.70 (95% CI: 0.59 to 0.82), respectively. Adjusted for each other and LDL-P, HDL-C was no longer associated with cIMT (2.3; 95% CI: − 9.5 to 14.2 μm) or CHD (0.97; 95% CI: 0.77 to 1.22), but HDL-P remained independently associated with cIMT (−22.2; 95% CI: − 33.8 to −10.6 μm) and CHD (0.75; 95% CI: 0.61 to 0.93). Interactions by sex, ethnicity, diabetes, and high-sensitivity C-reactive protein were not significant.ConclusionsAdjusting for each other and LDL-P substantially attenuated associations of HDL-C, but not HDL-P, with cIMT and CHD. Potential confounding by related lipids or lipoproteins should be carefully considered when evaluating HDL-related risk

Accumulation of metabolic cardiovascular risk factors in black and white young adults over 20 years

BACKGROUND: Cross-sectional clustering of metabolic risk factors for cardiovascular disease in middle-aged adults is well described, but less is known regarding the order in which risk factors develop through young adulthood and their relation to subclinical atherosclerosis. METHOD AND RESULTS: A total of 3178 black and white women and men in the Coronary Artery Risk Development in Young Adults study were assessed to identify the order in which cardiovascular disease risk factors including diabetes, hypertension, dyslipidemia (low high-density lipoprotein cholesterol or high triglyceride levels), hypercholesterolemia (high total or low-density lipoprotein cholesterol), and obesity develop. Observed patterns of risk factor development were compared with those expected if risk factors accumulated randomly, given their overall distribution in the population. Over the 20 years of follow-up, 80% of participants developed at least 1 risk factor. The first factor to occur was dyslipidemia in 39% of participants, obesity in 20%, hypercholesterolemia in 11%, hypertension in 7%, and diabetes in 1%. Dyslipidemia was the only risk factor both to occur first and to be followed by additional risk factors more often than expected (P \u3c 0.001 for both). Order of risk factor accrual did not affect subclinical atherosclerosis at year 20. Results were similar by sex, race, and smoking status. CONCLUSIONS: Multiple patterns of cardiovascular risk factor development were observed from young adulthood to middle age. Dyslipidemia, a potentially modifiable condition, often preceded the development of other risk factors and may be a useful target for intervention and monitoring

Detection of Ly\beta auto-correlations and Ly\alpha-Ly\beta cross-correlations in BOSS Data Release 9

The Lyman-$\beta$ forest refers to a region in the spectra of distant quasars that lies between the rest-frame Lyman-$\beta$ and Lyman-$\gamma$ emissions. The forest in this region is dominated by a combination of absorption due to resonant Ly$\alpha$ and Ly$\beta$ scattering. When considering the 1D Ly$\beta$ forest in addition to the 1D Ly$\alpha$ forest, the full statistical description of the data requires four 1D power spectra: Ly$\alpha$ and Ly$\beta$ auto-power spectra and the Ly$\alpha$-Ly$\beta$ real and imaginary cross-power spectra. We describe how these can be measured using an optimal quadratic estimator that naturally disentangles Ly$\alpha$ and Ly$\beta$ contributions. Using a sample of approximately 60,000 quasar sight-lines from the BOSS Data Release 9, we make the measurement of the one-dimensional power spectrum of fluctuations due to the Ly$\beta$ resonant scattering. While we have not corrected our measurements for resolution damping of the power and other systematic effects carefully enough to use them for cosmological constraints, we can robustly conclude the following: i) Ly$\beta$ power spectrum and Ly$\alpha$-Ly$\beta$ cross spectra are detected with high statistical significance; ii) the cross-correlation coefficient is $\approx 1$ on large scales; iii) the Ly$\beta$ measurements are contaminated by the associated OVI absorption, which is analogous to the SiIII contamination of the Ly$\alpha$ forest. Measurements of the Ly$\beta$ forest will allow extension of the usable path-length for the Ly$\alpha$ measurements while allowing a better understanding of the physics of intergalactic medium and thus more robust cosmological constraints.Comment: 26 pages, 10 figures; matches version accepted by JCA

Efficacy and Tolerability of Adjunctive Intravenous Sodium Nitroprusside Treatment for Outpatients With Schizophrenia: A Randomized Clinical Trial

Importance: Antipsychotic medications for the treatment of schizophrenia have limitations, and new treatments are needed. A prior pilot investigation suggested that adjunctive sodium nitroprusside (SNP) administered intravenously had rapid efficacy in the treatment of patients with schizophrenia. Objective: To determine the efficacy and tolerability of intravenous SNP infused at a rate of 0.5 mug/kg/min for 4 hours in patients with schizophrenia with some degree of treatment resistance. Design, Setting, and Participants: Multicenter, randomized, double-blind acute treatment study using a sequential parallel comparison design conducted in two 2-week phases at 4 academic medical centers beginning May 20, 2015, and ending March 31, 2017. Participants were adults 18 to 65 years of age with a diagnosis of schizophrenia as confirmed by the Structured Clinical Interview for DSM-IV, taking antipsychotic medication for at least 8 weeks, and had at least 1 failed trial of an antipsychotic medication within the past year. A total of 90 participants consented, 60 participants enrolled, and 52 participants were included in the analyses. A modified intent-to-treat analysis was used. Interventions: Participants were randomized in a 1:1:1 ratio to 1 of 3 treatment sequences: SNP and SNP, placebo and SNP, and placebo and placebo. The SNP and SNP group received SNP in phase 1 and SNP in phase 2 for the purpose of blinding, but the data from phase 2 were not included in the results. The placebo and SNP group received placebo in phase 1 and SNP in phase 2. If there was no response to placebo in phase 1, data from phase 2 were included in the analyses. The placebo and placebo group received placebo in both phases; if there was no response to placebo in phase 1, data from phase 2 were included in the analyses. Main Outcomes and Measures: Effectiveness of SNP compared with placebo in improving Positive and Negative Syndrome Scale (PANSS) total, positive, and negative scores across each 2-week phase. Results: Fifty-two participants (12 women and 40 men) were included in the study. In the SNP and SNP group, the mean (SD) age was 47.1 (10.5) years. In the placebo and SNP group, the mean (SD) age was 45.9 (12.3) years. In the placebo and placebo group, the mean (SD) age was 40.4 (11.0) years. There were no significant differences between the SNP and placebo groups at baseline or in change from baseline for PANSS-total (weighted beta = -1.04; z = -0.59; P = .57), PANSS-positive (weighted beta = -0.62; z = -0.93; P = .35), or PANSS-negative (weighted beta = -0.12; z = -0.19; P = .85) scores. No significant differences in safety or tolerability measures were identified. Conclusions and Relevance: Although intravenous SNP is well tolerated, it was not an efficacious adjunctive treatment of positive or negative symptoms of psychosis among outpatients with schizophrenia with prior history of treatment resistance. Trial Registration: ClinicalTrials.gov identifier: NCT02164981

The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests