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Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating impact of this transmitter is best described as anxiety-reducing or anxiety-promoting. The aim of this study was to assess the impact of serotonin depletion on acquisition, consolidation, and expression of conditioned fear.
Male Sprague–Dawley rats were exposed to foot shocks as unconditioned stimulus and assessed with respect to freezing behaviour when re-subjected to context. Serotonin depletion was achieved by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) (300 mg/kg daily × 3), (i) throughout the period from (and including) acquisition to (and including) expression, (ii) during acquisition but not expression, (iii) after acquisition only, and (iv) during expression only.
The time spent freezing was significantly reduced in animals that were serotonin-depleted during the entire period from (and including) acquisition to (and including) expression, as well as in those being serotonin-depleted during either acquisition only or expression only. In contrast, PCPA administrated immediately after acquisition, that is during memory consolidation, did not impact the expression of conditioned fear.
Intact serotonergic neurotransmission is important for both acquisition and expression of context-conditioned fear.
To evaluate once-daily extended release quetiapine fumarate (quetiapine XR) as monotherapy (50, 150 and 300mg/day) (acute and maintenance treatment) or adjunct treatment (150 and 300mg/day) in patients with MDD.
Eight (7 acute, 1 maintenance) placebo-controlled studies were analysed. Primary endpoints: change from randomisation in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (acute); time from randomisation to depressed event (maintenance). Statistical analyses: ANCOVA for difference between quetiapine XR and placebo in LSM change in MADRS total score from randomisation to study end (LOCF; acute); hazard ratio (HR) for time to recurrence of a depressed event (maintenance).
Figure 1 shows treatment differences (95% CIs) for primary efficacy variable for the seven acute studies. Four monotherapy studies (D1448C00001, D1448C00002, D1448C00003, D1448C00014) were significant in favour of quetiapine XR; Study D1448C00004 (monotherapy) was not. Studies D1448C00006 and D1448C00007 were significant in favour of adjunct quetiapine XR. Time from randomisation to depressed event (Study D1448C00005) significantly increased with quetiapine XR; HR (95% CI): 0.34(0.25, 0.46); p< 0.001; number of depressed events: 55, quetiapine XR; 132, placebo. Safety findings were consistent with the known tolerability profile of quetiapine.
Quetiapine XR consistently demonstrated antidepressant efficacy, with 6/7 acute studies positive in favour of quetiapine XR (monotherapy or adjunct). Quetiapine XR maintenance therapy significantly reduced risk of a depressed event, demonstrating relapse prevention. AstraZeneca funded
Evaluate the effects of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder (MDD) according to disease severity.
Pooled data (quetiapine XR 50, 150 and 300mg/day doses combined) from four 6- or 8-week placebo-controlled quetiapine XR monotherapy studies (D1448C00001, D1448C00002, D1448C00003, D1448C00004) were analysed. Key inclusion criterion for all 4 studies: HAM-D total score ≥22. Primary endpoint: change from randomisation in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. A post-hoc analysis assessed change from randomisation in MADRS total score and MADRS response (≥ 50% reduction in MADRS total score) at endpoint (Week 6 or Week 8) in 6 severity cohorts (defined by a MADRS total score at randomisation ≥24, ≥26, ≥28, ≥30, ≥32 or ≥34).
1752 patients (comprising the l’ all patients’ group) were evaluated (MADRS score ≥24 at randomisation, n=1601; ≥26, n=1467; ≥28, n=1269; ≥30, n=1038; ≥32, n=745; ≥34, n=500). Quetiapine XR significantly reduced mean MADRS total score at endpoint in lrsquo;all patients’ (p< 0.001 vs placebo) and in all 6 severity cohorts (≥24, ≥26, ≥28, ≥30 and ≥32, p< 0.001 vs placebo; ≥34, p< 0.01 vs placebo). MADRS response rates were significantly higher in the quetiapine XR group vs placebo in the ‘all patients’ group (p< 0.001 vs placebo) and in all 6 severity cohorts (≥24, ≥26, ≥28, ≥30 and ≥32, p< 0.001 vs placebo; ≥34, p=0.001 vs placebo).
Quetiapine XR monotherapy significantly improved depressive symptoms in patients with MDD irrespective of disease severity, including the most severe levels of depression.
This pooled analysis evaluated efficacy of adjunct quetiapine XR (QTP-XR) in subgroups of patients with anxious depression and lower levels of anxiety.
Pooled data from two 6-week, double-blind, randomised, placebo-controlled trials (D1448C00006/D1448C00007) in patients with inadequate response to antidepressants were analysed. Patients received adjunct QTP-XR (150 or 300 mg/day) or placebo+antidepressant (SSRI or SNRI). Using criteria defined in the STAR*D study, analyses conducted in patients with anxious depression or lower baseline anxiety levels (HAM-D anxiety/somatic factor score >/ = 7 and < 7, respectively) included LSM change at Week 6 in: MADRS total (primary endpoint), HAM-A and CGI-S total scores.
For patients with anxious depression (n = 697; 76% patients), adjunct QTP-XR 150mg/day (-14.44, p < 0.01) and 300 mg/day (-15.09, p < 0.001) significantly improved MADRS total scores versus placebo+antidepressant (-11.78) at Week 6, with significant improvement demonstrated from Week 1 onwards. Significant improvements were seen in HAM-A (QTP-XR 150 mg/day: -9.05, p < 0.01; 300 mg/day -9.43, p < 0.01) and CGI-S total scores (QTP-XR 150 mg/day: -1.60, p< 0.001; 300 mg/day -1.63, p < 0.001) versus placebo+antidepressant (-7.40, -1.22, respectively) at Week 6.
A smaller subgroup (n = 222; 24% patients) had lower baseline anxiety levels. At Week 1, adjunct QTP-XR (150 mg/day -9.09; p < 0.01; 300 mg/day -8.60; p < 0.05) significantly improved MADRS total score versus placebo+antidepressant (-5.93). At Week 6 there were no significant changes (QTP-XR 150 mg/day -14.49; p = 0.243; 300 mg/day -14.01; p = 0.388) versus placebo+antidepressant (-12.78).
For patients with anxious depression, adjunct QTP-XR (150 and 300 mg/day) was effective at reducing symptoms of anxiety and depression, with symptom improvement observed from Week 1 onwards. AstraZeneca funded.
Two 6-week, double-blind, placebo-controlled studies evaluated quetiapine XR (QTP-XR) adjunct to ongoing antidepressant therapy in patients with MDD and an inadequate response to prior antidepressant treatment (D1448C00006/D1448C00007).
Objective and aim:
A post hoc pooled analysis examined clinical and demographic characteristics as potential predictors of response to adjunct QTP-XR
Pooled MITT population (n = 616 QTP-XR [both doses]; n = 303 placebo) data were analysed from the two adjunct QTP-XR (150 or 300 mg/day) studies.
Effects of psychiatric history and baseline demographic and disease characteristics on efficacy were evaluated in subgroups based on Week 6 MADRS total score reduction: ≥50% reduction (responders: n = 345 QTP-XR, n = 140 placebo) versus < 50% (non-responders: n = 271 QTP-XR, n = 163 placebo); ≥75% reduction (responders: n = 175 QTP-XR, n = 60 placebo) versus < 25% (non-responders: n = 125 QTP-XR, n = 89 placebo).
Impact of baseline CGI-S score and number of episodes (0, 1, 2–3, 4–10, ≥10) over previous year and lifetime on Week 6 MADRS total score change was evaluated. Effect of baseline MADRS individual item (1–10) scores on Week 6 change in CGI-I score was evaluated.
No major differences between responders and non-responders to QTP-XR were observed for patient characteristics. there was no predictive association between baseline CGI-S score, number of depressive episodes, and baseline MADRS item scores and efficacy outcomes for adjunct QTP-XR.
This pooled analysis showed no major differences between responders and non-responders, and no suggestion of a predictive association between the parameters assessed and efficacy outcomes for adjunct QTP-XR. Further investigation including logistic regression may be required.
The CXCR3 chemokine CXCL10 or IFN-γ inducible protein 10 (IP-10) has been identified as an important biomarker of cerebral malaria (CM) mortality in children. Studies in mouse malaria infection models have shown that CXCL10 blockade alleviates brain intravascular inflammation and protects infected mice from CM. Despite the key role that CXCL10 plays in the development of CM, the leucocytic sources of CXCL10 in response to human malaria are not known. Here we investigated CXCL10 responses to Plasmodium falciparum in peripheral blood mononuclear cells (PBMCs). We found that PBMCs from malaria-unexposed donors produce CXCL10 in response to P. falciparum and that this response is IFN-γ-dependent. Moreover, CD14+ monocytes were identified as the main leucocytic sources of CXCL10 in peripheral blood, suggesting an important role for innate immune responses in the activation of this pathway involved in the development of symptomatic malaria.
Whereas long-term administration of selective serotonin reuptake inhibitors (SSRIs) is effective for the treatment of anxiety disorders, acute administration of these drugs may exert a paradoxical anxiogenic effect. The aim of the present study was to explore the possible effect of an SSRI in situations of unconditioned or limited conditioned fear.
Male Sprague Dawley rats were administered a single dose of an SSRI, escitalopram, before acquisition or expression of context conditioned fear, where noise bursts were used as the unconditioned stimulus. Freezing was assessed as a measure of unconditioned fear (=the acute response to noise bursts) or conditioned fear (=the response to the context), respectively.
Noise bursts elicited an acute increase in freezing but no robust conditioned response 7 days after exposure. Administration of escitalopram before testing exacerbated the freezing response during presentation of the unconditioned stimulus and also unmasked a conditioned response; in contrast, administration of escitalopram prior to acquisition did not influence the conditioned response.
The data suggest that freezing in rats exposed to a stimulus inducing relatively mild fear may be enhanced by acute pretreatment with an SSRI regardless of whether the freezing displayed by the animals is an acute unconditioned response to the stimulus in question or a conditioned response to the same stimulus.
Violators of cooperation norms may be informally punished by their peers. How such norm enforcement is judged by others can be regarded as a meta-norm (i.e., a second-order norm). We examined whether meta-norms about peer punishment vary across cultures by having students in eight countries judge animations in which an agent who over-harvested a common resource was punished either by a single peer or by the entire peer group. Whether the punishment was retributive or restorative varied between two studies, and findings were largely consistent across these two types of punishment. Across all countries, punishment was judged as more appropriate when implemented by the entire peer group than by an individual. Differences between countries were revealed in judgments of punishers vs. non-punishers. Specifically, appraisals of punishers were relatively negative in three Western countries and Japan, and more neutral in Pakistan, UAE, Russia, and China, consistent with the influence of individualism, power distance, and/or indulgence. Our studies constitute a first step in mapping how meta-norms vary around the globe, demonstrating both cultural universals and cultural differences.
There is strong evidence that physical activity (PA) has an influence on physical performance in later life. Also, a small body size at birth has been associated with lower physical functioning in older age and both small and high birth weight have shown to be associated with lower leisure time physical activity. However, it is unknown whether size at birth modulates the association between PA and physical performance in old age. We examined 695 individuals from the Helsinki Birth Cohort Study born in Helsinki, Finland between 1934 and 1944. At a mean age of 70.7 years PA was objectively assessed with a multisensory activity monitor and physical performance with the Senior Fitness Test (SFT). Information on birth weight and gestational age was retrieved from hospital birth records. The study participants were divided in three birth weight groups, that is <3000 g, 3000–3499 g and ⩾3500 g. The volume of PA was significantly associated with the physical performance in all birth weight groups. However, the effect size of the association was large and significant only in men with a birth weight <3000 g (β 0.59; 95% confidence interval 0.37–0.81, P<0.001). Our study shows that the association between PA and physical performance is largest in men with low birth weight. Our results suggest that men with low birth weight might benefit most from engaging in PA in order to maintain a better physical performance.
People who have schizophrenia die earlier from somatic diseases than do people in the general population, but information about cardiovascular deaths in people who have schizophrenia is limited. We analysed mortality in all age groups of people with schizophrenia by specific cardiovascular diseases (CVDs), focusing on five CVD diagnoses: coronary heart disease, acute myocardial infarction, cerebrovascular disease, heart failure and cardiac arrhythmias. We also compared hospital admissions for CVDs in people who had schizophrenia with hospital admissions for CVDs in the general population.
This national register study of 10 631 817 people in Sweden included 46 911 people who were admitted to the hospital for schizophrenia between 1 January 1987 and 31 December 2010. Information from national registers was used to identify people who had schizophrenia and obtain data about mortality, causes of death, medical diagnoses and hospitalisations.
CVDs were the leading cause of death in people who had schizophrenia (5245 deaths), and CVDs caused more excess deaths than suicide. The mean age of CVD death was 10 years lower for people who had schizophrenia (70.5 years) than the general population (80.7 years). The mortality rate ratio (MRR) for CVDs in all people who had schizophrenia was 2.80 (95% confidence interval (CI) 2.73–2.88). In people aged 15–59 years who had schizophrenia, the MRR for CVDs was 6.16 (95% CI 5.79–6.54). In all people who had schizophrenia, the MRR for coronary heart disease was 2.83 (95% CI 2.73–2.94); acute myocardial infarction, 2.62 (95% CI 2.49–2.75); cerebrovascular disease, 2.4 (95% CI 2.25–2.55); heart failure, 3.25 (95% CI 2.94–3.6); and cardiac arrhythmias, 2.06 (95% CI 1.75–2.43). Hospital admissions for coronary heart disease were less frequent in people who had schizophrenia than in the general population (admission rate ratio, 0.88 (95% CI 0.83–0.94). In all age groups, survival after hospital admission for CVD was lower in people who had schizophrenia than in the general population.
People who had schizophrenia died 10 years earlier from CVDs than did people in the general population. For all five CVD diagnoses, mortality risk was higher for those with schizophrenia than those in the general population. Survival after hospitalisation for CVDs in people who had schizophrenia was comparable with that of people in the general population who were several decades older.
Visual processing problems may be one underlying factor for cognitive impairments related to autism spectrum disorders (ASDs). We examined associations between ASD-traits (Autism-Spectrum Quotient) and visual processing performance (Rey–Osterrieth Complex Figure Test; Block Design task of the Wechsler Adult Intelligence Scale-III) in young adults (mean age=25.0, s.d.=2.1 years) born preterm at very low birth weight (VLBW; <1500 g) (n=101) or at term (n=104). A higher level of ASD-traits was associated with slower global visual processing speed among the preterm VLBW, but not among the term-born group (P<0.04 for interaction). Our findings suggest that the associations between ASD-traits and visual processing may be restricted to individuals born preterm, and related specifically to global, not local visual processing. Our findings point to cumulative social and neurocognitive problems in those born preterm at VLBW.
The Universe is permeated by hot, turbulent, magnetized plasmas. Turbulent plasma is a major constituent of active galactic nuclei, supernova remnants, the intergalactic and interstellar medium, the solar corona, the solar wind and the Earth’s magnetosphere, just to mention a few examples. Energy dissipation of turbulent fluctuations plays a key role in plasma heating and energization, yet we still do not understand the underlying physical mechanisms involved. THOR is a mission designed to answer the questions of how turbulent plasma is heated and particles accelerated, how the dissipated energy is partitioned and how dissipation operates in different regimes of turbulence. THOR is a single-spacecraft mission with an orbit tuned to maximize data return from regions in near-Earth space – magnetosheath, shock, foreshock and pristine solar wind – featuring different kinds of turbulence. Here we summarize the THOR proposal submitted on 15 January 2015 to the ‘Call for a Medium-size mission opportunity in ESAs Science Programme for a launch in 2025 (M4)’. THOR has been selected by European Space Agency (ESA) for the study phase.
Results of adulthood mental health of those born late-preterm (34 + 0–36 + 6 weeks + days of gestation) are mixed and based on national registers. We examined if late-preterm birth was associated with a higher risk for common mental disorders in young adulthood when using a diagnostic interview, and if this risk decreased as gestational age increased.
A total of 800 young adults (mean = 25.3, s.d. = 0.62 years), born 1985–1986, participated in a follow-up of the Arvo Ylppö Longitudinal Study. Common mental disorders (mood, anxiety and substance use disorders) during the past 12 months were defined using the Composite International Diagnostic Interview (Munich version). Gestational age was extracted from hospital birth records and categorized into early-preterm (<34 + 0, n = 37), late-preterm (34 + 0–36 + 6, n = 106), term (37 + 0–41 + 6, n = 617) and post-term (⩾42 + 0, n = 40).
Those born late-preterm and at term were at a similar risk for any common mental disorder [odds ratio (OR) 1.11, 95% confidence interval (CI) 0.67–1.84], for mood (OR 1.11, 95% CI 0.54–2.25), anxiety (OR 1.00, 95% CI 0.40–2.50) and substance use (OR 1.31, 95% CI 0.74–2.32) disorders, and co-morbidity of these disorders (p = 0.38). While the mental disorder risk decreased significantly as gestational age increased, the trend was driven by a higher risk in those born early-preterm.
Using a cohort born during the advanced neonatal and early childhood care, we found that not all individuals born preterm are at risk for common mental disorders in young adulthood – those born late-preterm are not, while those born early-preterm are at a higher risk. Available resources for prevention and intervention should be targeted towards the preterm group born the earliest.
Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.
We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).
One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (pdiscovery = 3.82 × 10−8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (pdiscovery+replication = 1.10 × 10−6) with evidence of heterogeneity.
Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.
Previous studies suggest that the inverse association between birth weight and adult blood pressure amplifies with age. Rapid childhood growth has also been linked to hypertension. The objective of this study was to determine whether the association between childhood growth and adult blood pressure amplifies with age. The study comprised 574 women and 462 men from the Helsinki Birth Cohort Study who attended a clinical study in 2001–2004 and a follow-up in 2006–2008. Mean age at the clinic visits was 61.5 and 66.4 years, respectively. Blood pressure was measured at both occasions. Conditional growth models were used to assess relative weight gain and linear growth. We studied the associations between conditional growth and blood pressure as well as the presence of hypertension. Relative weight gain and linear growth between ages 2 and 11 years were inversely associated with systolic blood pressure at mean age 66.4 years, after adjustment for sex, blood pressure at mean age 61.5 years, as well as other covariates. A one s.d. increase in linear growth between 2 and 11 years was associated with an OR of 0.61 for hypertension at mean age 66.4 years. Contrary to previous studies, we have shown an inverse association between childhood growth and adult blood pressure. There were, however, no associations between childhood growth and systolic blood pressure at mean age 61.5 years indicating that the beneficial effects of a more rapid than expected childhood growth might become more apparent with increasing age.
The typical dietary supply of total fat, fatty acids, starch, sugars, polyols and dietary fibre in Sweden was assessed from analyses of market baskets (MB) purchased in 2005 and 2010. MB were based on food balance sheets, with each basket comprising about 130 foods, which represented more than 90 % of annual dietary supply. Foods were divided into ten to twelve categories. In 2010, total fat contributed 34 % of energy (E%), SFA 14·3 E%, MUFA 12·8 E%, PUFA 4·6 E%, n-6 fatty acids 3·6 E%, n-3 fatty acids 1·0 E% and trans-fatty acids (TFA) 0·5 E%. Glycaemic carbohydrates contributed 47 E%, monosaccharides 9 E%, sucrose 11 E%, disaccharides 15 E% and total sugars 24 E%. Added sugars contributed about 15 E%. Dietary fibre content was about 1·7 g/MJ in the 2010 MB. Compared with the 2005 MB, the dietary supply of TFA and dietary fibre was lower, otherwise differences were small. The present MB survey shows that the content of SFA and added sugars was higher than the current Nordic Nutrition Recommendations, while the content of PUFA and especially dietary fibre was lower. TFA levels decreased and dietary supply was well below the recommendations of the WHO. These results emphasise a focus on quality and food sources of fat and carbohydrates, limiting foods rich in SFA and added sugars and replacing them with foods rich in dietary fibre and cis-unsaturated fatty acids.