BackgroundThe relationship between ethnic density and psychiatric disorder inpostnatal women in the UK is unclear.AimsTo examine the effect of own and overall ethnic density on postnataldepression ...(PND) and personality dysfunction.MethodMultilevel analysis of ethnically mixed community-level data gatheredfrom a sample of 2262 mothers screened at 6 weeks postpartum for PND andpersonality dysfunction.ResultsLiving in areas of higher own ethnic density was protective againstscreening positive for PND in White women (z =–3.18,P = 0.001), even after adjusting for area leveldeprivation, maternal age, relationship status, screening positive forpersonality dysfunction, parity and geographical clustering (odds ratio(OR) 0.98 (95% CI 0.96–0.99); P = 0.002), whereas theeffect on personality dysfunction (z =–2.42,P = 0.016) was no longer present once the effect ofPND was taken into account (OR = 0.99 (95% CI 0.90–1.0);P = 0.13). No overall ethnic density effect was foundfor women screening positive for PND or personality dysfunction.ConclusionsIn White women, living in areas of higher own ethnic density wasprotective against developing PND.
Abstract Objective Antipsychotic drugs target neurotransmitter systems that play key roles in working memory. Therefore, they may be expected to modulate this cognitive function via their actions at ...receptors for these neurotransmitters. However, the precise effects of antipsychotic drugs on working memory function remain unclear. Most studies have been carried out in clinical populations, making it difficult to disentangle pharmacological effects from pathology-related brain activation. In this study, we aim to investigate the effects of two antipsychotic compounds on brain activation during working memory in healthy individuals. This would allow elucidation of the effects of current antipsychotic treatments on brain function, independently of either previous antipsychotic use or disease-related pathology. Methods We carried out a fully counterbalanced, randomised within-subject, double-blinded and placebo-controlled, cross-over study of the effects of two antipsychotic drugs on working memory function in 17 healthy individuals, using the n-back task. Participants completed the functional MRI task on three separate occasions (in randomised order): following placebo, haloperidol, and aripiprazole. For each condition, working memory ability was investigated, and maps of neural activation were entered into a random effects general linear regression model to investigate main working memory function and linear load. Voxel-wise and region of interest analyses were conducted to attain regions of altered brain activation for each intervention. Results Aripiprazole did not lead to any changes in neural activation compared with placebo. However, reaction time to a correct response was significantly increased following aripiprazole compared to both placebo ( p = 0.046) and haloperidol ( p = 0.02). In contrast, compared to placebo, haloperidol dampened activation in parietal (BA 7/40; left: FWE-corr. p = 0.005; FWE-corr. right: p = 0.007) and frontal (including prefrontal; BA 9/44/46; left: FWE-corr. p = 0.009; right: FWE-corr. p = 0.014) cortices and the left putamen (FWE-corr. p = 0.004). Compared with aripiprazole, haloperidol dampened activation in parietal cortex (BA7/40; left: FWE-corr. p = 0.034; right: FWE-corr. p = 0.045) and the left putamen (FWE-corr. p = 0.015). Haloperidol had no effect on working memory performance compared with placebo. Conclusion Cognitive functions are known to be impaired in schizophrenia and as such are an important target of treatments. Elucidating the mechanisms by which antipsychotic medications alter brain activation underlying cognition is essential to advance pharmacological treatment of this disorder. Studies in healthy individuals can help elucidate some of these mechanisms, whilst limiting the confounding effect of the underlying disease-related pathology. Our study provides evidence for immediate and differential effects of single-dose haloperidol and aripiprazole on brain activation during working memory in healthy individuals. We propose that these differences likely reflect their different receptor affinity profiles, although the precise mechanisms underlying these differences remain unclear.
Abstract
Background
Psychotic disorders are characterized by large heterogeneity in clinical presentation, response to treatment and cognitive functioning. Indeed, there is evidence of the presence ...of cognitive subgroups of patients across affective and non-affective psychosis. However, very little is known about these subgroups in first episode psychosis (FEP) and whether they can be informative about course of illness, particularly response to treatment. The aim of this study is to investigate the number and the pattern of cognitive clusters in FEP, their external validity and association with treatment response at 12-week and 1-year follow up.
Methods
The sample was composed by a total of 212 participants including 105 FEP patients from the South London and Maudsley Foundation Trust and 107 Healthy Controls (HC). All participants underwent a comprehensive clinical and neurocognitive battery. Z-score mean=0, and standard deviation (SD)=1 were created for the whole sample based on the neurocognitive performance of the HCs. Treatment response at 12-week and 1-year follow-up was used to explore potential utility of subtypes in predicting response to treatment. Hierarchical cluster analysis was carried out to determine the number of cognitive clusters in FEP patients. A series of analyses of variance were carried out to determine if FEP clusters differed among each other in relation to demographic and clinical characteristics, level of functioning and from the HC sample in term of cognitive performance. Logistic regression was used to explore whether cognitive clustering was predictive of treatment response at 12-week and 1-year FU.
Results
Four cognitive clusters emerged: one with near normal cognition (42.9% of the FEP patients) with a general cognitive score of z=-0.20, one with selected cognitive deficits (14.3%) in the domains of verbal memory, processing speed and executive functions (general cognitive score of z=-0.55); and two severe deficit clusters consisting in one cluster with severe deficits (33.3%; general score of z=-1.48) and the other with a deeply compromised cognitive ability (9.55%; general cognitive score of z=-2.34). There were no significant differences between clusters in terms of clinical features at baseline (including diagnosis, positive and negative symptoms, medication), apart from the level of functioning that was significantly lower in the severely compromised cluster compared to the near normal cognition cluster.
It emerged that majority (about 68%) of the patients from the near normal cognition cluster were responsive to treatment, whilst the majority of the selective and severely impaired clusters did not respond to treatment at 12-week follow-up. There were no significant results with regard to treatment response at 1-year FU.
Discussion
Distinct patterns of cognitive impairments exist within FEP that might be characterized by different response to treatment. Clinical presentation at the onset of the illness is not useful in predicting response to treatment later on in the course of the illness, while cognitive functioning might be a more valid indicator. Cognitive stratification could represent a promising way forward to elucidate pathophysiology of psychosis and to provide tailored interventions.
Abstract
Background
Individuals with established psychosis are characterised by a distinct pattern of hypothalamic-pituitary-adrenal (HPA) axis dysfunctions which include both elevated daytime ...cortisol levels and a blunted cortisol awakening response (CAR). Whilst these patterns of dysfunction have also been observed among those at elevated risk for the disorder, longitudinal studies are scarce. As such, the relevance of these HPA axis abnormalities for the progression of psychopathology in high-risk populations is unknown. Utilising data from a well-characterised, longitudinal cohort of youth at elevated risk for schizophrenia and their typically-developing peers (The Child Health and Development Study), we aimed to investigate the extent to which HPA axis function determined in childhood is a significant predictor of putative prodromal status and psychopathology in late adolescence/early adulthood.
Methods
The sample comprised high-risk individuals who presented either multiple antecedents of schizophrenia (developmental delays, psychopathology, and psychotic-like experiences: ASz=21) or a family history of illness (FHx=13), and typically-developing youth with neither antecedents nor a family history (TD=36). Participants were recruited at age 9–12 years using a community screening method and assessed biennially throughout adolescence. At the age 11–14 years assessment phase, participants collected salivary cortisol samples in their home environment which were used to determine diurnal cortisol secretion and the CAR. At the age 17–21 years assessment phase, participants completed measures of prodromal symptoms (Prodromal Questionnaire: PQ), depression (Quick Inventory of Depressive Symptomatology questionnaire: QIDS), and anxiety (Social Interaction Anxiety Scale: SIAS). Established PQ thresholds were used to identify participants who met probable prodromal status. Logistic and linear regression analyses were used to examine the extent to which salivary cortisol measures at age 11–14 years predicted probable prodromal status and continuous psychopathology measures at 17–21 years, respectively.
Results
Relative to the TD group, ASz youth were characterised by higher depression (B=0.24, p=0.05) and disorganised symptoms (B=0.36, p=0.007) at 17–21 years whilst FHx youth obtained higher scores on the PQ general symptoms scale (B=0.24, p=0.048). Analyses performed in the total sample indicated that the CAR was negatively associated with depression symptoms (B=-0.28, p=0.006) and PQ negative symptoms (B=-0.30, p=0.004) at age 17–21 years. Positive associations were observed between diurnal cortisol and positive (B=0.41, p=0.02), disorganised (B=0.30, p=0.04), and general (B=0.29, p=0.03) PQ symptoms. Diurnal cortisol levels were also significantly associated with probable prodromal status at follow-up (OR=1.04, p=0.04). No significant interactions were observed between group status and salivary cortisol levels in any model. After adjustment for potential confounders (age, follow-up time, sex, BMI, and pubertal status), the CAR continued to show significant associations with both depression (p=0.006) and PQ negative symptoms (p=0.007) whilst only a statistical trend was observed for the relationship between diurnal cortisol levels and positive symptoms (p=0.055).
Discussion
The current study is the first to examine the extent to which HPA axis function can predict development of prodromal symptoms in a high-risk cohort. Our finding that more abnormal HPA axis function (i.e., a decreased CAR and higher diurnal cortisol) at age 11–14 years is associated with both prodromal and depression symptoms at age 17–21 has important implications for aetiological theories and for clinical practice.
An association between social disadvantage and established psychosis is well documented in the literature, but there remains a lack of data on the social circumstances of patients before they became ...ill. We investigated whether social disadvantage at, and prior to, first contact with psychiatric services, is associated with psychosis.
We collected information on social disadvantage in childhood and adulthood from 278 cases presenting with their first episode of psychosis to the South London and Maudsley National Health Service Foundation Trust and from 226 controls recruited from the local population. Three markers of childhood social disadvantage and 3 markers of disadvantage in adulthood were analyzed.
Long term separation from, and death of, a parent before the age of 17 years were both strongly associated with a 2- to 3-fold-increased odds of psychosis. Cases were also significantly more likely to report 2 or more markers of adult social disadvantage than healthy controls (OR = 9.03) at the time of the first presentation with psychosis, independent of a number of confounders. When we repeated these analyses for long-standing adult social disadvantage, we found that the strength of the association decreased but still remained significant for 1 year (OR = 5.67) and 5 years (OR = 2.57) prior to the first contact.
Social disadvantage indexes exposure to factors operating prior to onset that increase the risk of psychosis, both during childhood and adulthood.
Abstract Background The Brain-derived Neurotrophic Factor ( BDNF ) modulates cognitive processes and is associated with increased risk of schizophrenia. Childhood trauma (CT) is frequent in patients ...with psychosis and severely affects course and outcome. Aims We investigated the hypothesis that BDNF is associated with both CT and cognitive deficits in a sample of first-episode psychosis (FEP) cases and unaffected controls. Method Participants with FEP and healthy controls were recruited between August 2008 and July 2011 from South London, UK. Childhood traumatic events were detected using the Childhood Experience of Care and Abuse Questionnaire (CECA-Q). Neuropsychological data were also collected. BDNF plasma levels were measured from fasting blood samples. Results Data were available on 87 FEP patients and 152 controls. Our results showed a significant effect of separation (F = 5.5; df = 1,115; p = .02), physical (F = 4.7; df = 1, 118; p = .03) and sexual abuse (F = 5.4; df = 1,117; p = .02) on BDNF levels with lower levels among those who experienced the traumatic event compared to those who did not. Physical abuse predicted lower plasma levels of BDNF (β = − .30; p = .03) whereas sexual and/or physical abuse showed a trend (β = − .26; p = .06) in FEP patients but not in unaffected controls. No association between BDNF plasma levels and cognitive functions was found among patients with FEP and controls. Conclusion Our findings suggest the possible involvement of BDNF in the onset of first-episode psychosis in individuals exposed to early trauma and propose BDNF as a potential clinical biomarker to detect the detrimental effects of CT on human brain plasticity.
Studies over the last forty years have demonstrated that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent biological findings in major depression, but much ...of the mechanisms underlying this abnormality are still unclear. This review will elaborate on both the clinical and molecular role of the neuroendocrine stress system in depressive disorder and present some of the most recent findings that have shed light on the complex interface between environmental stressors, molecular mechanisms and clinical presentation. Further, psychopharmacological development have demonstrated both effects of conventional treatments on HPA functioning as well as of novel treatments targeting HPA functioning on clinical outcome.
Evidence on systemic inflammation as a risk factor for future depression is inconsistent, possibly due to a lack of regard for persistency of exposure. We examined whether being inflamed on multiple ...occasions increases risk of new depressive symptoms using prospective data from a population-based sample of adults aged 50 years or older (the English Longitudinal Study of Ageing). Participants with less than four of eight depressive symptoms in 2004/05 and 2008/09 based on the Eight-item Centre for Epidemiologic Studies Depression scale were analysed. The number of occasions with C-reactive protein ⩾3 mg l
over the same initial assessments (1 vs 0 occasion, and 2 vs 0 occasions) was examined in relation to change in depressive symptoms between 2008/09 and 2012/13 and odds of developing depressive symptomology (having more than or equal to four of eight symptoms) in 2012/13. In multivariable-adjusted regression models (n=2068), participants who were inflamed on 1 vs 0 occasion showed no increase in depressive symptoms nor raised odds of developing depressive symptomology; those inflamed on 2 vs 0 occasions showed a 0.10 (95% confidence intervals (CIs)=-0.07, 0.28) symptom increase and 1.60 (95% CI=1.00, 2.55) times higher odds. In further analyses, 2 vs 0 occasions of inflammation were associated with increased odds of developing depressive symptoms among women (odds ratio (OR)=2.75, 95% CI=1.53, 4.95), but not among men (OR=0.70, 95% CI=0.29, 1.68); P-for-sex interaction=0.035. In this cohort study of older adults, repeated but not transient exposure to systemic inflammation was associated with increased risk of future depressive symptoms among women; this subgroup finding requires confirmation of validity.
Immunostimulatory insults such as stress and infection are risk factors for the development of several neuropsychiatric disorders characterized by neuroprogression. Inflammatory and neurotoxic ...molecules in the brain can cause disruptions in neurogenesis, neuronal excitability, synaptic transmission, synaptic plasticity, and neuronal survival - changes that characterize neuroprogression. We draw on recent findings in the immunology literature that peripheral innate immune cells are capable of retaining long-term memory of infectious insults and displaying long-lasting upregulated proinflammatory function in response to repeated infectious insults - a concept known as "innate immune memory." In turn, we hypothesize that microglia, the resident innate immune cells of the brain, are also capable of retaining long-term memory of infectious and noninfectious insults, including stress. Microglia are capable of producing a variety of proinflammatory neurotoxic cytokines and chemokines. Persistent upregulation of microglial proinflammatory function as a result of memory for immunostimulatory insults may therefore contribute to persistent and progressive inflammation in neuropsychiatric illnesses and be an important driver of neuroprogression.
PDF
