Pharmacokinetic correlates of clinical response in a naturalistic sample of escitalopram-treated patients

We assessed pharmacokinetic correlates of treatment response to escitalopram using a large therapeutic drug monitoring database. A large naturalistic sample of patients receiving escitalopram was analyzed. Responders were defined as ‘very much improved’ or ‘much improved’ based on the Clinical Global Impression – Improvement score, CGI-I. We compared responders (n = 83) vs. non-responders (n = 388) with the primary outcome being the escitalopram plasma concentration and concentration corrected by the daily dose (C/D ratio). Effects of age, sex, body-mass-index (BMI), and C/D ratio were assessed in a multivariate logistic regression model predicting response. There were no statistically significant differences in clinical and demographic characteristics between responders vs. non-responders. There were also no differences between escitalopram daily doses or plasma concentrations, while C/D ratios were significantly higher in non-responders than in responders (1.6 ± 1.7 vs. 1.2 ± 0.9 (ng/mL)/(mg/day), p = 0.007); C/D ratios (odds ratio 0.52, 95% confidence interval 0.34–0.80, p Patients with low clearance of escitalopram as reflected upon high C/D ratios may be less likely respond to escitalopram. Identifying these patients during dose titration may support clinical decision-making, including switching to a different antidepressant instead of increasing daily dose.</p

Longitudinal Gray Matter Development Associated With Psychotic Experiences in Young People

Background: Grey matter abnormalities are observed across the psychosis spectrum. The trajectory of these abnormalities in healthy adolescents reporting sub-threshold psychotic experiences (PE) may provide insight into the neural mechanisms underlying psychotic symptoms. The risk of psychosis and additional psychopathology is even higher amongst these individuals who also report childhood adversity/DSM5 diagnoses. Thus, the aims of this longitudinal study are to investigate PE related volumetric changes in young people, noting any effects of childhood adversity/DSM5 diagnosis. Methods: 211 young people aged 11-13 participated in the initial Adolescent Brain Development study. PE classification was determined by expert consensus at each timepoint. Participants underwent neuroimaging at 3 timepoints, over 6 years. 76 participants with at least one scan were included in the final sample; 34 who met criteria for PE at least once across all the timepoints (PE group), and 42 controls. Data from 20 bilateral regions of interest were extracted for Linear Mixed Effects analyses. Results: Right hippocampal volume increased over time in the control group, with no increase in the PE group (p = 0.00352). DSM5 diagnosis and childhood adversity were not significantly associated with right hippocampal volume. There was no significant effect of group or interaction in any other region. Conclusions: These findings further implicate right hippocampal volumetric abnormalities in the pathophysiology underlying psychotic experiences. Furthermore, as suggested by previous studies in those at clinical high risk for psychosis and those with first episode psychosis, it is possible that these deficits may be a marker for later clinical outcomes.</p

Longitudinal hippocampal subfield development associated with psychotic experiences in young people

Hippocampal volumetric reductions are observed across the psychosis spectrum, with interest in the localisation of these reductions within the hippocampal subfields increasing. Deficits of the CA1 subfield in particular have been implicated in the neuropathophysiology of psychotic disorders. Investigating the trajectory of these abnormalities in healthy adolescents reporting sub-threshold psychotic experiences (PE) can provide insight into the neural mechanisms underlying psychotic symptoms without the potentially confounding effects of a formal disorder, or antipsychotic medication. In this novel investigation, a sample of 211 young people aged 11-13 participated initially in the Adolescent Brain Development study. PE classification was determined by expert consensus at each timepoint. Participants underwent neuroimaging at 3 timepoints, over 6 years. 78 participants with at least one scan were included in the final sample; 33 who met criteria for a definite PE at least once across all the timepoints (PE group), and 45 controls. Data from bilateral subfields of interest (CA1, CA2/3, CA4/DG, presubiculum and subiculum) were extracted for Linear Mixed Effects analyses. Before correction, subfield volumes were found to increase in the control group and decrease in the PE group for the right CA2 and CA2/3 subfields, with moderate to large effect sizes (d = -0.61, and d = -0.79, respectively). Before correction, right subiculum and left presubiculum volumes were reduced in the PE group compared to controls, regardless of time, with moderate effect sizes (d = -0.52, and d = -0.59, respectively). However, none of these effects survived correction. Severity of symptoms were not associated with any of the noted subfields. These findings provide novel insight to the discussion of the role of hippocampal subfield abnormalities in the pathophysiology underlying psychotic experiences. </p

Multiple Network Dysconnectivity in Adolescents with Psychotic Experiences: a longitudinal population-based study

Background: Functional dysconnectivity amongst neural networks is well established in psychosis, and has been implicated in the psychopathology associated with the disorder. However, little is known about functional connectivity (FC) in individuals, particularly adolescents, who experience sub-threshold psychotic experiences (PE), and their trajectory over time. Thus, the aim of this study was to investigate large and small-scale network FC in adolescents with PE.Methods: A population-based case-control study of 24 adolescents (mean age 13.58) who met criteria for PE were drawn from a sample of 211 young people recruited for a neuroimaging study, followed up 2 years later (n=18, mean age = 15.78), and compared to matched controls drawn from the same sample. Functional seed networks included the default mode (DMN), salience (SN), central executive (CEN), motor (MN), and auditory networks (AN). Whole-brain FC analyses were performed using the CONN functional connectivity toolbox.Results: At both timepoints, the PE group generally displayed significant hypoconnectivity, with specific instances of hyperconnectivity, compared to controls. At baseline, FC in the PE group was decreased between regions in the MN and DMN, and the AN and visual regions. At follow up, FC in the PE group was decreased between regions in the SN and DMN, the AN and visual regions, and also within the MN.Conclusions: Significant hypoconnectivity across multiple networks reflects findings in established psychosis, supporting a prominent role for the default mode network in the dysfunctional information processing and integration thought to underlie psychotic experiences.</div

Psychotic experiences in childhood are associated with increased structural integrity of the left arcuate fasciculus – a population-based case-control study

Around 1 in 5 children under 13 years old experience sub-clinical psychotic experiences (PEs) like hallucinations and delusions. While PEs in childhood are a significant risk factor for adult psychotic disorders, the majority of those experiencing childhood PEs do not develop a psychotic disorder. Individual differences in regional brain maturation rates may be responsible for this age-related and often transient emergence of PEs. Fronto-temporal association tracts undergo extensive maturation and myelination throughout childhood and adolescence, thus we focus on individual differences in one such tract, the arcuate fasciculus. A normative population-based sample of children (aged 11–13) attended a clinical interview and MRI (n = 100), 25 of whom were identified as reporting strong PEs. This group had reduced mean and radial diffusivity in the arcuate fasciculus compared with a group of matched controls (n = 25) who reported no PEs. The group difference was greater in the left hemisphere than the right. Mediation analyses showed that this group difference was driven predominantly by perceptual disturbances and an along-tract analysis showed that the group difference was greatest approximately halfway between the frontal and temporal termination points of the tract (adjacent to the left lateral ventricle). This study is the first to investigate links between arcuate fasciculus diffusivity and psychotic experiences in a population sample of children

Reduced hippocampal volume in adolescents with psychotic experiences: a longitudinal population-based study

Aims: Smaller hippocampal volumes are among the most consistently reported neuroimaging findings in schizophrenia. However, little is known about hippocampal volumes in people who report psychotic experiences. This study investigated differences in hippocampal volume between young people without formal diagnoses who report psychotic experiences (PEs) and those who do not report such experiences. This study also investigated if any differences persisted over two years.Methods: A nested case-control study of 25 adolescents (mean age 13.5 years) with reported PEs and 25 matched controls (mean age 13.36 years) without PEs were drawn from a sample of 100 local schoolchildren. High-resolution T1-weighted anatomical imaging and subsequent automated cortical segmentation (Freesurfer 6.0) was undertaken to determine total hippocampal volumes. Comprehensive semi-structured clinical interviews were also performed including information on PEs, mental diagnoses and early life stress (bullying). Participants were invited for a second scan at two years.Results: 19 adolescents with PEs and 19 controls completed both scans. Hippocampal volumes were bilaterally lower in the PE group compared to the controls with moderate effects sizes both at baseline [left hippocampus p = 0.024 d = 0.736, right hippocampus p = 0.018, d = 0.738] and at 2 year follow up [left hippocampus p = 0.027 d = 0.702, right = 0.048 d = 0.659] throughout. These differences survived adjustment for co-morbid mental disorders and early life stress.Conclusions: Psychotic experiences are associated with total hippocampal volume loss in young people and this volume loss appears to be independent of possible confounders such as co-morbid disorders and early life stress.</p

DNA Methylation of the Serotonin Transporter Gene in Peripheral Cells and Stress-Related Changes in Hippocampal Volume: A Study in Depressed Patients and Healthy Controls

<div><p>Serotonin plays an important role in the etiology of depression. Serotonin is also crucial for brain development. For instance, animal studies have demonstrated that early disruptions in the serotonin system affect brain development and emotion regulation in later life. A plausible explanation is that environmental stressors reprogram the serotonin system through epigenetic processes by altering serotonin system gene expression. This in turn may affect brain development, including the hippocampus, a region with dense serotonergic innervations and important in stress-regulation. The aim of this study was to test whether greater DNA methylation in specific CpG sites at the serotonin transporter promoter in peripheral cells is associated with childhood trauma, depression, and smaller hippocampal volume. We were particularly interested in those CpG sites whose state of methylation in peripheral cells had previously been associated with in vivo measures of brain serotonin synthesis. Thirty-three adults with Major Depressive Disorder (MDD) (23 females) and 36 matched healthy controls (21 females) were included in the study. Depressive symptoms, childhood trauma, and high-resolution structural MRI for hippocampal volume were assessed. Site-specific serotonin transporter methylation was assessed using pyrosequencing. Childhood trauma, being male, and smaller hippocampal volume were independently associated with greater peripheral serotonin transporter methylation. Greater serotonin transporter methylation in the depressed group was observed only in SSRI-treated patients. These results suggest that serotonin transporter methylation may be involved in physiological gene-environment interaction in the development of stress-related brain alterations. The results provide some indications that site-specific serotonin transporter methylation may be a biomarker for serotonin-associated stress-related psychopathology.</p></div

Scatterplot showing the association between total childhood abuse and methylation of <i>SLC6A4</i>.

<p>There was a positive correlation between both variables indicating that more abuse is associated with higher levels of methylation.</p

Example for hippocampal subfield delineation.

<p>Shown are subfields CA1, CA2/3, CA4/DG, subiculum and presubiculum. The program FreeSurfer automatically assessed volumes of subfields which were then manually viewed and checked for quality.</p

Characteristics of the sample.

<p>CTQ = Childhood Trauma Questionnaire; SSRI = Selective Serotonin Reuptake Inhibitor; n.s. = not significant</p><p>Characteristics of the sample.</p