Antipsychotic-naive First-episode Schizophrenia Patients Research Articles

Linked patterns of interhemispheric functional connectivity and microstructural characteristics of the corpus callosum in antipsychotic-naive first-episode schizophrenia.

Many magnetic resonance imaging (MRI) studies have showed significant structural abnormalities of the corpus callosum (CC) and dysregulated interhemispheric functional connectivity (FC) in schizophrenia. Although the hemispheres are mainly linked through CC, few studies directly examined the relationship between aberrant interhemispheric FC and the white matter deficits of the CC in schizophrenia. One hundred and sixty-nine antipsychotic-naive first-episode schizophrenia patients (AN-FES) and 214 healthy controls (HCs) were recruited. Diffusional and functional MRI data were obtained for each participant, and fractional anisotropy (FA) values of the five CC subregions and interhemispheric FC for each participant were acquired. Between-group differences in these metrics were compared using multivariate analysis of covariance (MANCOVA). Moreover, sparse canonical correlation analysis (sCCA) was conducted to explore correlations of fibers integrity of the CC subregions with dysregulated interhemispheric FC in patients. Compared with HCs, the patients with schizophrenia showed significantly reduced FA values of the CC subregions and dysregulated connectivity between two cerebral hemispheres. The canonical correlation coefficients identified five significant sCCA modes between FA and FC (r>0.75, p<0.001), suggesting strong relationships between FA values of the CC subregions and interhemispheric FC in patients. Our findings support a key role of CC in maintaining ongoing functional communication between two cerebral hemispheres, and suggest that microstructural changes of white matter fibers crossing different CC subregions may affect special interhemispheric FC in schizophrenia.

Sleep disorders in patients with a first psychotic episode: a case-control study

Introduction Patients with chronic schizophrenia experience significant disturbances in the quality and quantity of their sleep and it had been mainly attributed to severity of symptoms and antipsychotic use. Recent studies suggested that antipsychotic-naïve early course patients with schizophrenia and their non-psychotic first-degree relatives also show altered sleep quality. Objectives In this study we aimed to compare sleep parameters in antipsychotic-naive first-episode schizophrenia patients to their healthy siblings and age- and sex-matched healthy controls. Methods We conducted a cross-sectional, descriptive case-control study in the Psychiatry « G » department at Razi Hospital, for a period of six months. Our sample consisted of three groups: a group of schizophrenic patients, a group of their healthy siblings and a group of healthy controls. The three groups were matched by age and sex. The Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of symptoms in patients with schizophrenia. The Morningness-Eveningness Questionnaire (MEQr), Epworth Sleepiness Scale (ESS), and Pittsburgh Sleep Quality Index (PSQI) were used in the three groups to assess Circadian preference, daytime sleepiness and sleep quality. Results There was no significant difference between the groups regarding the chronotype. Patients had significantly higher daytime sleepiness compared to siblings (p=0.001) and controls (p&lt;0.001). Patients also had poorer quality sleep (PSQI total score) than siblings (p&lt;0.001) and controls (p&lt;0.001), longer sleep latency than siblings (p=0.003) and controls (p&lt;0.001); lower habitual sleep efficiency than siblings (p=0.003) and controls (p&lt;0.001). Siblings had poorer sleep quality (p=0.001), longer sleep latency (p=0.006) and shorter sleep duration (p=0.033) compared to control subjects. Conclusions Our results joined those of the literature concerning the significant prevalence of sleep disorders in early psychosis. In addition, the alteration of sleep quality in unaffected siblings compared to healthy controls supports the hypotheses suggested in the literature that sleep disorders may be markers of genetic susceptibility to schizophrenia and serve as a potential endophenotype of the disease. Disclosure of Interest None Declared

Aggressive behaviour in antipsychotic-naive first-episode schizophrenia patients, their unaffected siblings and healthy controls.

While patients with schizophrenia are more likely to be victims rather than perpetrators of aggressive behaviour, prior research has shown increased rates of aggressive behaviours in these patients that appear very early in the course of illness. We aimed to assess aggression in antipsychotic-naive first-episode schizophrenia patients, their healthy siblings, and controls; and to investigate correlates of aggression in the patients group. Patients (N=55), siblings (N=55) and healthy controls (N=71) were evaluated on Buss and Perry Aggression Questionnaire (AQ), Life History of Aggression (LHA), Barratt Impulsiveness Scale, and Levenson Self-Report Psychopathy Scale. Age, gender and substance use were regarded as covariates, and differences between the three groups were evaluated using analysis of covariance. Hierarchical regression was performed to determine which variables were associated with aggression level in the patients group. The Tukey multiple comparison test showed that both patients (p < .001) and siblings (p=.023) scored higher on the LHA Aggression than controls. Siblings scored higher than controls (p=.010) for the Anger subscale of the AQ. Patients scored significantly higher than controls in the three impulsiveness dimensions; whereas siblings scored higher than controls in the motor (p=.023) and non-planning (p=.004) dimensions. Multivariate analyses showed that, after controlling for confounders, only attentional impulsiveness (β=.446, p=.0244) and psychopathy traits (β=.359, p=.010) helped predict AQ total scores among patients. Aggression and some of its risk factors including impulsiveness are likely to be trait variables that might provide important vulnerability markers for people at heightened risk of developing psychosis.

Altered White Matter Connectivity Within and Between Networks in Antipsychotic-Naive First-Episode Schizophrenia.

Analyzing the schizophrenia connectome can identify illness-related alterations in connectivity across the brain. An important question that remains unanswered is whether connectivity alterations are already evident at the onset of illness, before treatment with antipsychotic medication and possible influences of neuroprogressive or secondary alterations related to chronic illness duration. In the present study, diffusion tensor imaging and deterministic fiber tractography were performed with 137 antipsychotic-naive first-episode schizophrenia patients and 113 matched healthy controls. Using graph theoretic analysis, groups were compared in global and regional measurements and modularity of white matter connectivity. Compared with controls, the patients showed significantly decreased total connection strength. Furthermore, patients demonstrated significantly decreased connections within and between brain modules. Several local brain regions within association cortex exhibited reduced nodal centralities and abnormal participant coefficient or intra-module degree, some of which were correlated with illness duration and overall functional disability. In never-treated schizophrenia patients, networks showed a less effective organizational pattern of white matter pathways. White matter disconnectivity occurred not only within but also between multiple modules, shedding light on the deficits of anatomical network organization early in the course of schizophrenia.

Two subgroups of antipsychotic-naive, first-episode schizophrenia patients identified with a Gaussian mixture model on cognition and electrophysiology

Deficits in information processing and cognition are among the most robust findings in schizophrenia patients. Previous efforts to translate group-level deficits into clinically relevant and individualized information have, however, been non-successful, which is possibly explained by biologically different disease subgroups. We applied machine learning algorithms on measures of electrophysiology and cognition to identify potential subgroups of schizophrenia. Next, we explored subgroup differences regarding treatment response. Sixty-six antipsychotic-naive first-episode schizophrenia patients and sixty-five healthy controls underwent extensive electrophysiological and neurocognitive test batteries. Patients were assessed on the Positive and Negative Syndrome Scale (PANSS) before and after 6 weeks of monotherapy with the relatively selective D2 receptor antagonist, amisulpride (280.3±159 mg per day). A reduced principal component space based on 19 electrophysiological variables and 26 cognitive variables was used as input for a Gaussian mixture model to identify subgroups of patients. With support vector machines, we explored the relation between PANSS subscores and the identified subgroups. We identified two statistically distinct subgroups of patients. We found no significant baseline psychopathological differences between these subgroups, but the effect of treatment in the groups was predicted with an accuracy of 74.3% (P=0.003). In conclusion, electrophysiology and cognition data may be used to classify subgroups of schizophrenia patients. The two distinct subgroups, which we identified, were psychopathologically inseparable before treatment, yet their response to dopaminergic blockade was predicted with significant accuracy. This proof of principle encourages further endeavors to apply data-driven, multivariate and multimodal models to facilitate progress from symptom-based psychiatry toward individualized treatment regimens.

48. Associations Between Electrophysiological Measures of Selective Attention and Neurocognitive Measures of Working Memory and Attention in Antipsychotic-Naive, First-Episode Schizophrenia Patients

Background: Deficits in attention and working memory are already present in early stages of schizophrenia. The P3a and b event related brain potentials (ERPs) are believed to underlie processes of attention and working memory, but, only limited research has been performed on the associations between these psychophysiological and cognitive deficits, particularly in the early stages of schizophrenia. We aimed to investigate associations between P3a and P3b amplitudes and measures of attention and working memory in a large cohort of antipsychotic-naive, first-episode schizophrenia patients (AN-FES) and age and sex-matched healthy controls (HC). Methods: Eighty-three AN-FES patients and 108 HC, matched for age and gender, were assessed for their P3a and b amplitude and latency with the selective attention paradigm from the Copenhagen Psychophysiological Test Battery (CPTB). In addition, the Spatial Working Memory (SWM) and Rapid Visual Information Processing test (RVP) from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were used to assess working memory and attention. Outcome measure for the SWM was Strategy, wherein a low score represents a more effective strategy. For the RVP, we used the A’ measure as outcome. This measure represents how well the participant is able to detect target sequences. Results: P3a and P3b amplitudes were significantly reduced in our AN-FES patients compared to HC. In addition, the P3a peak latency was earlier in the AN-FES patients than in HC, while P3b latency did not differ between the groups. Furthermore, AN-FES patients scored significantly lower on the SWM task and the RVP compared to HC. A positive association was found between RVP and P3b in our total group. However, this effect disappeared when split into the two subgroups. In contrast, SWM was positively associated with P3b in HC, while this effect was neither present in AN-FES nor in the total group. Conclusion: Our results provide evidence for P3a and P3b amplitude reductions as well as neurocognitive deficits in AN-FES patients compared to age and gender matched HC. This supports previous data that electrophysiological and neurocognitive deficits already exist in early stages of schizophrenia, and are not due to use of antipsychotics. Our data support significant yet rather weak associations between P3b amplitude and both working memory and attention, although the association between working memory and P3b was only found in HC and not in AN-FES.

SA87. Cortical Thickness in Antipsychotic-Naive First-Episode Schizophrenia Patients and Associations With Caudate D2/3 Binding Potentials.

SA87. Cortical Thickness in Antipsychotic-Naive First-Episode Schizophrenia Patients and Associations With Caudate D2/3 Binding Potentials.

WEIGHT GAIN AND ANTIPSYCHOTICS. DATA FROM EUFEST STUDY.

Schizophrenia is a chronic disease most frequently necessitating lifelong antipsychotic treatment. Selecting which antipsychotic is to be prescribed in an individual schizophrenia patient represents an important clinical decision that need to take into account efficacy and side effects. Evaluating weight gain related with one year antipsychotic treatment in antipsychotic naive first-episode schizophrenia patients. This study is an analysis of weight gain associated with typical or atypical antipsychotics used in European First Episode Schizophrenia Trial (EUFEST) study. 113 first episode naïve antipsychotic schizophrenia patients included in EUFEST - Romanian cohort, who were randomized to one of the 5 treatment arms. Weight was obtained at baseline, 3, 6, 9 and 12 months for the 5 antipsychotics (typical-Haloperidol; atypical-Olanzapine, Amisulpride, Ziprasidone, Quetiapine). There are no statistically significant differences between groups treated with typical or atypical antipsychotics or between any individual antipsychotics concerning weight gain during the study. Weight gain was the highest in the first 3 months (57.49%) for all the studied neuroleptics. At the end of the study, the less increase was observed with ziprasidone (3.87 kg) and the highest with olanzapine (9.83 kg). Increase in weight has taken place for each individual neuroleptic, but also as a group (all neuroleptics) in the first three months (57.49%). Therefore, we should address the issue of weight gain with great care, especially in first period of antipsychotic administration, in order to fast deploy intervention tailored to maintain pre-treatment weight.

Neocortical serotonin2A receptor binding predicts quetiapine associated weight gain in antipsychotic-naive first-episode schizophrenia patients.

Antipsychotic-induced weight gain is of major clinical importance since it is associated with severe metabolic complications and increased mortality. The serotonin2A receptor system has been suggested to be implicated in weight gain and obesity. However, no previous in vivo imaging data have related serotonin2A receptor binding to weight gain before and after antipsychotic monotherapy. Fifteen antipsychotic-naive first-episode schizophrenia patients were included and investigated before and after six months of quetiapine treatment. We examined the relationship between serotonin2A receptor binding as measured with positron emission tomography (PET) and [18F]altanserin and change in body mass index (BMI). Quetiapine was chosen because it is characterized by a moderately high affinity for the serotonin2A receptor and a fast dissociation rate from the dopamine D2 receptor. At baseline the mean BMI was 24.2 kg/m2, range 18-36 kg/m2. After six months of quetiapine treatment (mean dose: 383 mg/day) the BMI had, on average, increased by 6.7%, corresponding to an average weight gain of 5.0 kg. We found a significant positive correlation both between neocortical serotonin2A receptor binding prior to treatment and subsequent increase in BMI (rho=0.59, p=0.022). At follow-up, the serotonin2A receptor occupancy was positively correlated with BMI increase (rho=0.54, p=0.038). To our knowledge, these are the first in vivo receptor imaging data in initially antipsychotic-naive first-episode schizophrenia patients to show that the cerebral serotonin2A receptor is associated with antipsychotic-induced weight gain.

Brain-derived neurotrophic factor blood levels are decreased in schizophrenia patients and associate with rs6265 genotypes

ObjectivesA growing number of studies implicate brain-derived neurotrophic factor (BDNF), an important promoter of synaptic transmission and neural plasticity, in the pathogenesis of schizophrenia. However, the existing data are controversial, that may reflect population differences between studied groups. Design and methodsIn the present study we performed a comparative analysis of BDNF plasma levels and its relation with rs6265 (G196A; Val66Met) polymorphism of BDNF gene (BDNF) in schizophrenia-affected and healthy subjects (controls) of the Armenian population. To check the influence of antipsychotics on BDNF plasma levels both medicated and non-medicated patients were involved in this study. Patients with paranoid form of schizophrenia chronically treated with typical antipsychotics (n=103), age- and sex-matched controls (n=105), and 25 antipsychotic-naive first-episode schizophrenia patients were involved. The levels of BDNF in the blood plasma were measured with a solid-phase enzyme-linked immunosorbent assay. ResultsDecreased plasma levels of BDNF in both medicated and non-medicated schizophrenia patients compared to controls were observed. No significant difference in BDNF levels between medicated and non-medicated patients was detected. It was also detected that, compared to individuals homozygous for the standard allele (G/G) of rs6265, carriers of the rs6265 minor allele (A/G+A/A), which is significantly more frequent in schizophrenia patients than in controls, had decreased BDNF levels. ConclusionsThe data obtained suggested that the pathogenesis of schizophrenia is characterized by genetically predetermined decreased blood levels of BDNF. These results indicated that genetically determined alterations of neuroimmune modulators may be among the risk factors of schizophrenia and contribute to disease-specific pathologic changes in functional activity of both the neuronal synaptic plasticity and the immune system.

S.12.03 Gender-dependent sensory gating in antipsychotic naive first-episode schizophrenia patients

S.12.03 Gender-dependent sensory gating in antipsychotic naive first-episode schizophrenia patients

Hippocampal and caudate volume reductions in antipsychotic-naive first-episode schizophrenia

Enlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode schizophrenia. Studies investigating brain structure in antipsychotic-naive patients have generally focused on the striatum. In this study, we examined whether ventricular enlargement and hippocampal and caudate volume reductions are morphological traits of antipsychotic-naive first-episode schizophrenia. We obtained high-resolution 3-dimensional T1-weighted magnetic resonance imaging scans for 38 antipsychotic-naive first-episode schizophrenia patients and 43 matched healthy controls by use of a 3-T scanner. We warped the brain images to each other by use of a high-dimensional intersubject registration algorithm. We performed voxel-wise group comparisons with permutation tests. We performed small volume correction for the hippocampus, caudate and ventricles by use of a false discovery rate correction (p < 0.05) to control for multiple comparisons. We derived and analyzed estimates of brain structure volumes. We grouped patients as those with (n = 9) or without (n = 29) any lifetime substance abuse to examine the possible effects of substance abuse. We found that hippocampal and caudate volumes were decreased in patients with first-episode schizophrenia. We found no ventricular enlargement, differences in global volume or significant associations between tissue volume and duration of untreated illness or psychopathology. The hippocampal volume reductions appeared to be influenced by a history of substance abuse. Exploratory analyses indicated reduced volume of the nucleus accumbens in patients with first-episode schizophrenia. This study was not a priori designed to test for differences between schizophrenia patients with or without lifetime substance abuse, and this subgroup was small. Reductions in hippocampal and caudate volume may constitute morphological traits in antipsychotic-naive first-episode schizophrenia patients. However, the clinical implications of these findings are unclear. Moreover, past substance abuse may accentuate hippocampal volume reduction. Magnetic resonance imaging studies addressing the potential effects of substance abuse in antipsychotic-naive first-episode schizophrenia patients are warranted.

Movement sequencing abilities and basal ganglia morphology in first-episode schizophrenia

Introduction. Studies of brain morphology suggest a link between movement sequencing ability and basal ganglia dysfunction. Unfortunately, relevant studies have provided inconsistent data, which may be the result of differences in the methods of brain morphology assessment, statistical analysis or heterogeneity of the populations studied. Aim. to test the hypothesis of a link between the dysfunction of movement sequencing and basal ganglia morphology in a homogenous sample of first-episode schizophrenia patients. Method. Thirty-seven first-episode schizophrenia patients underwent an assessment of movement sequencing abilities using the NES scale and basal ganglia morphology from MR images. The data were compared with a group of 19 age- and sex-matched healthy controls. Results. The group of first-episode patients had a higher concentration of gray matter than healthy controls in the putamen and pallidum in both hemispheres. Patients with abnormal sequencing of movements had lower gray matter concentration than patients without such abnormalities in the left putamen, and no differences were found between the symptomatic group and healthy controls. Summary and conclusion. Our study suggests the involvement of the left putamen in the movement sequencing abnormalities in schizophrenia. Because of the potential confounding effect of medication, the lack of support from external evidence and the low power to perform the whole-brain analysis the results should be considered as preliminary. Further studies, especially with antipsychotic-naive first-episode schizophrenia patients are needed to solve these issues.

Association of Cerebral Deficits With Clinical Symptoms in Antipsychotic-Naive First-Episode Schizophrenia: An Optimized Voxel-Based Morphometry and Resting State Functional Connectivity Study

The purpose of the present study was to characterize the association between clinical symptoms and anatomical and functional cerebral deficits in a relatively large sample of antipsychotic-naive first-episode schizophrenia patients using optimized voxel-based morphometry and resting state functional connectivity analysis. Participants were 68 antipsychotic-naive first-episode schizophrenia patients and 68 matched healthy comparison subjects. Both patients and healthy comparison subjects were scanned using a volumetric three-dimensional spoiled gradient recall sequence and a gradient-echo echo-planar imaging sequence. Psychopathology of first-episode schizophrenia patients was evaluated using the Positive and Negative Syndrome Scale (PANSS). Optimized voxel-based morphometry was used to characterize gray matter deficits in schizophrenia patients. The clinical significance of regional volume reduction was investigated by examining its association with symptoms in patients with first-episode schizophrenia and with alterations in resting state functional connectivity when brain regions with gray matter volume reduction were used as seed areas. Significantly decreased gray matter volume was observed in schizophrenia patients in the right superior temporal gyrus (Brodmann's area 41), right middle temporal gyrus (Brodmann's area 21), and right anterior cingulate gyrus (Brodmann's area 32). Decreased gray matter volume in these brain regions was related to greater disturbance as shown on PANSS scores for positive symptoms, general psychopathology symptoms, thought disturbance, activation, paranoia, and impulsive aggression as well as total PANSS scores. A positive correlation was observed between PANSS scores for thought disturbance and temporo-putamen connectivity, and negative correlations were found between temporo-precuneus connectivity and total PANSS scores as well as scores for negative symptoms and anergia. The findings revealed volume loss in the right superior temporal gyrus, right middle temporal gyrus, and right anterior cingulate gyrus among antipsychotic-naive first-episode schizophrenia patients. In addition, the functional networks involving the right superior temporal gyrus and middle temporal gyrus were associated with clinical symptom severity. No abnormalities were observed in resting state connectivity with regions of identified gray matter deficits.

Effects of Risperidone on Procedural Learning in Antipsychotic-Naive First-Episode Schizophrenia

Studies of procedural learning in medicated schizophrenia patients using predictive saccade paradigms have consistently demonstrated hypometric predictive responses. Findings from antipsychotic-naive schizophrenia patients indicate fewer or no deficits. This pattern of findings suggests that antipsychotic medications might adversely affect frontostriatal systems supporting procedural learning on this task. The accuracy and latency of predictive saccades were assessed in 25 antipsychotic-naive first-episode schizophrenia patients and 22 matched healthy individuals. Patients were retested after 6 weeks of treatment with risperidone. Healthy individuals were reevaluated after a similar time period. The ability to learn to time response initiation in anticipation of target appearance (target prediction) was not impaired in patients before or after treatment. In contrast, although no deficits were evident before treatment initiation, after treatment patients showed a marked decrease in the accuracy of predictive but not sensory-guided responses. The findings from pretreatment testing indicate that procedural learning is a relatively unaffected cognitive domain in antipsychotic-naive first-episode schizophrenia. Although treatment-emergent extrapyramidal symptoms were minimal, these data suggest that D2 antagonism in striatum after risperidone treatment was sufficiently robust to disrupt the generation of planned volitional behavior guided by internalized representations.

Insulin Resistance and Increased Leptin Concentrations in Noncompliant Schizophrenia Patients but Not in Antipsychotic-Naive First-Episode Schizophrenia Patients

The onset of diabetes and impaired glucose metabolism among schizophrenic patients has been the topic of numerous recently published articles, with research implicating weight gain, the use of antipsychotic medication, history of diabetes mellitus in family members, and the diagnosis of schizophrenia itself as risk factors. Therefore, it was the aim of this study to determine the glucose metabolism parameters in noncompliant unmedicated schizophrenic patients (antipsychotic-free) and first-episode antipsychotic-naive schizophrenic patients to investigate whether there is a preexisting impairment of glucose metabolism in never-medicated schizophrenic patients. Plasma glucose, insulin, C-peptide, and leptin concentrations were determined in 50 antipsychotic-free and 50 antipsychotic-naive DSM-IV schizophrenia patients and 50 healthy control subjects. Insulin resistance was calculated through the homeostatic model assessment (HOMA). The General Linear Model (univariate) procedure was used to perform analysis of covariance. Patients were recruited from July 2001 to December 2002. Antipsychotic-free patients showed significantly increased insulin (p = .001) and C-peptide (p = .02) concentrations and a significantly higher degree of insulin resistance (p = .003), as measured with the HOMA index, in comparison with the antipsychotic-naive patients and the control group. Significantly increased leptin concentrations (p = .000) were also noted in the antipsychotic-free patients and were attributed to the effects of body mass index (p = .000) and sex (p = .000). The results reported in this study suggest the effect of previous antipsychotic treatment on glucose metabolism parameters and weight-related hormones such as leptin, while ruling out a preexisting impairment of glucose metabolism in never-medicated first-episode schizophrenic patients.