Transition to psychosis is among the most adverse outcomes of clinical high-risk (CHR) syndromes encompassing ultra-high risk (UHR) and basic symptom states. Clinical risk calculators may facilitate ...an early and individualized interception of psychosis, but their real-world implementation requires thorough validation across diverse risk populations, including young patients with depressive syndromes.
We validated the previously described NAPLS-2 (North American Prodrome Longitudinal Study 2) calculator in 334 patients (26 with transition to psychosis) with CHR or recent-onset depression (ROD) drawn from the multisite European PRONIA (Personalised Prognostic Tools for Early Psychosis Management) study. Patients were categorized into three risk enrichment levels, ranging from UHR, over CHR, to a broad-risk population comprising patients with CHR or ROD (CHR|ROD). We assessed how risk enrichment and different predictive algorithms influenced prognostic performance using reciprocal external validation.
After calibration, the NAPLS-2 model predicted psychosis with a balanced accuracy (BAC) (sensitivity, specificity) of 68% (73%, 63%) in the PRONIA-UHR cohort, 67% (74%, 60%) in the CHR cohort, and 70% (73%, 66%) in patients with CHR|ROD. Multiple model derivation in PRONIA–CHR|ROD and validation in NAPLS-2–UHR patients confirmed that broader risk definitions produced more accurate risk calculators (CHR|ROD-based vs. UHR-based performance: 67% 68%, 66% vs. 58% 61%, 56%). Support vector machines were superior in CHR|ROD (BAC = 71%), while ridge logistic regression and support vector machines performed similarly in CHR (BAC = 67%) and UHR cohorts (BAC = 65%). Attenuated psychotic symptoms predicted psychosis across risk levels, while younger age and reduced processing speed became increasingly relevant for broader risk cohorts.
Clinical-neurocognitive machine learning models operating in young patients with affective and CHR syndromes facilitate a more precise and generalizable prediction of psychosis. Future studies should investigate their therapeutic utility in large-scale clinical trials.
People at ultra high risk (UHR) of psychosis have an elevated risk of developing a psychotic disorder, but it is difficult to predict which individuals will make a transition to frank illness. We ...investigated whether functional magnetic resonance imaging (fMRI) in conjunction with a phonological fluency task at presentation could distinguish subjects who subsequently developed psychosis from those who did not.
Sixty-five subjects (41 with an UHR and 24 healthy controls) were assessed at clinical presentation using fMRI, in conjunction with a verbal fluency task. 18F-DOPA positron emission tomography (PET) data were also available in a subgroup of 21 UHR and 14 healthy controls subjects. UHR subjects were followed clinically for at least 2 years.
Compared with UHR subjects who did not become psychotic, UHR subjects who subsequently developed psychosis showed increased activation in bilateral prefrontal cortex (PFC), brainstem (midbrain/basilar pons), the left hippocampus, and greater midbrain-PFC connectivity. Furthermore, exploratory analysis of 18F-DOPA PET data showed that transition to psychosis was associated with elevated dopaminergic function in the brainstem region.
In people at high risk of psychosis, increased activation in a network of cortical and subcortical regions may predict the subsequent onset of illness. Functional neuroimaging, in conjunction with clinical assessment and other investigations, may facilitate the prediction of outcome in subjects who are vulnerable to psychosis.
Aim
To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR‐P): the Structured Interview for Psychosis‐risk Syndromes ...(SIPS) and the Comprehensive Assessment of At‐Risk Mental States (CAARMS).
Methods
The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR‐P through an intensive series of joint videoconferences.
Results
Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR‐P criteria. The semi‐structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR‐P criteria and severity scores for both CAARMS and SIPS.
Conclusions
Using the PSYCHS for CHR‐P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta‐analyses.
The hypothesis that cortical dopaminergic alterations underlie aspects of schizophrenia has been highly influential. This review synthesises and evaluates the imaging evidence for dopaminergic ...alterations in cortical and other extra-striatal regions in schizophrenia. Electronic databases were searched for in vivo molecular studies of extra-striatal dopaminergic function in schizophrenia. Twenty-three studies including 278 patients and 265 controls were identified. The meta-analysis of dopamine D2/D3 receptor availability showed a trend for a reduction in the thalamus (d =-0.32, 95%-CI: -0.68 to 0.03) but no change in the temporal cortex (d =-0.23, 95%-CI: -0.54 to 0.07) or the substantia nigra (d = 0.04, 95%-CI: -0.92 to 0.99). Significant differences were reported for D2/3 receptors in the cingulate, and uncus; for D1 receptors in the prefrontal cortex; and for dopamine transporters in the thalamus; whilst no differences were reported in entorhinal cortex, hippocampus, amygdala, occipital cortex, parietal cortex, insula or globus pallidum. Despite the wide influence of the hypothesis, there is limited direct evidence regarding cortical dopaminergic alterations in schizophrenia. However the available data indicate there may be alterations in the thalamus and that frontal D1 receptor availability warrants further investigation.
Current drug treatments for schizophrenia are inadequate for many patients, and despite 5 decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D(2) receptor blockade. ...Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia. We conducted a meta-analysis of 44 studies (618 patients with schizophrenia, 606 controls) using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function. Studies were grouped into those of presynaptic function and those of dopamine transporter and receptor availability. There was a highly significant elevation (P.< 001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen d = 0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D(2/3) receptor availability (Cohen d = 0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used. The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.
Various studies indicate that the accumulation of reactive oxygen species (ROS) and associated cellular damage play an important role in ageing of various organs, including the liver. Especially high ...concentrations of ROS in the mitochondria lead to oxidative damages, which have been proposed as one major cause of cellular ageing and death. Conceivably, the decrease of cytosolic and/or mitochondrial glutathione (GSH) concentrations as well as altered enzyme activities could be involved in the progressive redox imbalance of the ageing cell. However, the underlying mechanisms have not been clarified so far.
Our approach is to investigate age-dependent cellular responses to ROS-inducing compounds or heat stress by using primary hepatocytes from adolescent (6–8 months) and aged (23–25 months) rats. We thereby focus on cellular and mitochondrial GSH levels as well as on the expression of enzymes that are involved in GSH metabolism, transport and ROS detoxification. Here we present the first results of this project. In a first step, the isolated rat hepatocytes were characterized regarding basal metabolic functions. Second, we investigated the cellular responses to ethanol treatment in order to clarify possible age-related differences.
Hepatocytes were isolated from livers of male Wistar rats by a two-step in situ collagenase perfusion. The cells were plated on collagen-coated cell culture dishes and cultured for up to 48h. Then, basal metabolic functions of untreated rat hepatocytes, e.g. glucose metabolism and urea synthesis, were measured photometrically. After treatment with different ethanol concentrations for up to 6h, cell viability, total cellular GSH and the induction of ROS were determined by means of fluorimetric assays.
Regarding basal metabolic functions and total GSH content, no significant differences between hepatocytes of adolescent and aged rats were observed. Treatment with different ethanol concentrations led to an initial decrease of total GSH in both age groups compared to untreated cells. However, differences in the detectable amount of ROS could be observed: In hepatocytes of aged rats, an induction of ROS was detected immediately after addition of ethanol. In contrast, ROS levels were initially attenuated in adolescent rat hepatocytes. Similar differences were observed regarding the mitochondrial activity after ethanol treatment: While it was increased in hepatocytes of aged rats, a slight reduction of the mitochondrial activity could be observed in adolescent rat hepatocytes. Whether or not altered enzyme expression and activity is involved in the described age-related differences will be one of the subjects of our future studies. We furthermore want to determine the mitochondrial GSH in both adolescent and aged rat hepatocytes, which could be a critical factor in age-related oxidative stress response.
This study was supported by BMBF (Project No. 0315891).
Britta.Burkhardt@med.uni-tuebingen.de
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