Neuroleptic-naive Schizophrenic Patients Research Articles

Deficits in attentional processing of fearful facial expressions in schizophrenic patients.

Impaired attentional processing of negative facial expressions is prominent in schizophrenia and has been shown to be associated with patients’ social dysfunctions. However, little is known about when and which specific attention deficits influence social functions. Given the dynamic feature of attention, it is necessary to investigate the attention deficits in negative emotional processing unfolding in time. The current study used event-related potentials (ERPs) to investigate the temporal dynamics of attention deficits in emotion perception and their potential relationship with emotional/social impairments in neuroleptic naive schizophrenic patients. Two specific attention deficits were identified and were found to be associated with emotional/social impairments. More specifically, the deficit in orienting attention (evidenced with the reduced P1 amplitude) was correlated with expressive deficits, while the deficit in executive control of attention (evidenced with the reduced P3 amplitude) was correlated with avolition/asociality. Together, these findings may provide novel insights into the core pathophysiological processes and offer objective biomarkers for specific emotional/social impairments in schizophrenia. It is also hoped that this study helps to bridge the gap between basic cognitive deficits and relative high-level social dysfunctions in schizophrenic patients.

Reduced NGF serum levels and abnormal P300 event-related potential in first episode schizophrenia

Nerve growth factor (NGF) plays a crucial role in central nervous system neuron plasticity. Low levels of serum NGF in schizophrenic patients suggest that the neurotrophin contributes to the pathogenesis of the disease. NGF is also thought to alter characteristics of event-related brain potential (ERP) components. The auditory-evoked P300 ERP component, considered an index of brain activity, has reduced amplitude in acute and chronic schizophrenia. This study evaluated the relationship among serum NGF levels, P300 characteristics, and Positive and Negative Symptom Scale (PANSS) scores in first episode, neuroleptic naive schizophrenic patients ( N = 30) and healthy controls ( N = 28). Serum NGF was measured by ELISA and P300 elicited using auditory oddball paradigm. Compared to control subjects, schizophrenic patients had significantly reduced serum NGF ( p < 0.001) and lower P300 amplitudes at Fz ( p = 0.003). Additionally, there was a positive correlation between serum NGF serum and P300 amplitude at Fz. No correlation was found between serum NGF or P300 characteristics and PANSS scores. These results suggest that the effects of NGF in schizophrenia are related not only to regulation of neurodevelopment, but also to the electrophysiological characteristics of nerve growth factor.

Cortical and Subcortical 5-HT2A Receptor Binding in Neuroleptic-Naive First-Episode Schizophrenic Patients

The serotonin 5-HT(2A) receptor is suspected to be involved in a number of psychiatric disorders, including schizophrenia. In particular, atypical antipsychotics have antagonistic effects on the 5-HT(2A) receptors, supporting a specific role of the 5-HT(2A) receptor in the pathophysiology of this disease. The aim of this study is to investigate cortical and subcortical 5-HT(2A) binding in neuroleptic-naive schizophrenic patients. Fifteen neuroleptic-naive patients diagnosed with schizophrenia (age 27.5+/-4.5 years), 11 men and 4 women, and 15 healthy control subjects matched for age (28.5+/-5.7 years) and gender underwent a 40 min positron emission tomography (PET) study using the 5-HT(2A) antagonist, [(18)F]altanserin, as a radioligand. PET images were co-registered to 3 T magnetic resonance images (MRIs) for each individual subject, and ROIs were applied automatically onto the individual MRIs and PET images. The cerebellum was used as a reference region. The binding potential of specific tracer binding (BP(p)) was used as the outcome measure. No significant difference was seen in cortical receptor distribution between patients and controls. An increase in 5-HT(2A) receptor binding in the caudate nucleus was detected in the group of schizophrenic patients (0.7+/-0.1) when compared to the healthy controls (0.5+/-0.3) (p=0.02). Our results confirm other in vivo findings of no difference in cortical 5-HT(2A) receptor binding between first-episode antipsychotic-naive schizophrenic patients and age- and gender-matched healthy control subjects. However, a preliminary finding of increased 5-HT(2A) binding in the caudate nucleus requires further investigation to explore the relation of subcortical and cortical 5-HT(2A) receptor binding.

Diffusion Tensor Imaging Study of the Anterior Limb of Internal Capsules in Neuroleptic-Naive Schizophrenia

Abnormalities in brain structure have been implicated in psychosis. Herein, we investigated the differences in fractional anisotropy (FA) and average diffusion coefficient (ADC) in the bilateral anterior limb of internal capsules between neuroleptic-naive schizophrenic patients and appropriately matched healthy controls. Magnetic resonance imaging was performed with a 1.5 T superconductive MR scanner, and diffusion tensor imaging was carried out in 21 neuroleptic-naive schizophrenic patients and 18 matched healthy controls. FA and ADC were measured by region of interest analysis. Compared with healthy controls, the neuroleptic-naive schizophrenic patients showed significantly reduced FA in the bilateral anterior limb of the internal capsule. However, the difference in the ADC values between the patients and the controls was not significant. FA of the bilateral anterior limb of the internal capsule was reduced in neuroleptic-naive schizophrenic patients, indicating that the integrity of the white matter of the bilateral thalamus-frontal connection or the bilateral thalamus-anterior cingulate gyrus connection was destroyed.

Striatal Dopamine Synthesis in First-degree Relatives of Patients with Schizophrenia

First degree relatives (FDR) of patients with schizophrenia have higher risk of developing schizophrenia than the general population. Previous positron emission tomography (PET) studies have shown that striatal presynaptic dopamine synthesis capacity is increased in schizophrenia. We investigated whether this same phenomenon is shared by individuals with increased genetic risk for schizophrenia. We used 6-[18F]-fluorodopa (FDOPA) PET imaging to measure striatal dopamine synthesis capacity. We studied 17 nonpsychotic subjects with an FDR with schizophrenia. This group was compared to 17 healthy subjects with no FDRs with schizophrenia. A conventional region of interest (ROI)-analysis indicated that FDOPA uptake (K(i)) in the caudate-putamen was statistically significantly higher in the FDR group than in the control group. A voxel-level analysis confirmed these results. These results suggest that the changes of striatal presynaptic dopamine synthesis seen previously in neuroleptic-naive schizophrenic patients is also present in FDRs of patients with schizophrenia. These findings have implications for the early detection of psychosis as well as for pharmacological interventions in individuals at risk for psychosis.

Reaction time of the Continuous Performance Test is an endophenotypic marker for schizophrenia: A study of first-episode neuroleptic-naive schizophrenia, their non-psychotic first-degree relatives and healthy population controls

Sustained attention has been proposed as an endophenotype of schizophrenia, and consequently may be useful as a quantitative trait in genetic studies. In the present study, we used the continuous performance test (CPT) to measure sustained attention in 112 first-episode and neuroleptic-naive schizophrenic patients, 296 of their non-psychotic first-degree relatives, and 452 normal controls. Compared with controls, probands with schizophrenia showed worse performance on all measures of CPT. Parents, siblings and offspring of probands were also impaired on ‘hit reaction time′, an index of psychomotor processing speed of the correct response. Hit reaction time was also independent of the acute clinical features of the disease, indicating it is a trait rather than a state marker. Our findings supported the use of the hit reaction time measure of the CPT as an endophenotype marker for schizophrenia.

Lower striatal dopamine transporter binding in neuroleptic-naive schizophrenic patients is not related to antipsychotic treatment but it suggests an illness trait

Drug induced parkinsonism (DIP) is directly related to dopamine D2 receptor blockade. However, there are many references describing parkinsonian signs (PS) in naive-patients. In our previous study, we observed lower DAT binding in a group of first-episode schizophrenic patients after short-term treatment with risperidone, compared with age-matched healthy controls. To clarify if DAT decrease could be an illness trait, excluding the effect of antipsychotics on DAT availability, and to determine whether DAT availability before treatment with antipsychotics may predict subsequent development of PS. A new series of 20 neuroleptic-naive schizophrenic patients and 15 healthy subjects was recruited. SPECT with [(123)I] FP-CIT (DaTSCAN(R)) was performed before starting antipsychotics and after 4 weeks of treatment. PS and psychopathological status were assessed by the Simpson-Angus (SAS), CGI and PANSS scales. Quantitative analyses of SPECTs were performed using ROIs placed in the caudate, putamen and occipital cortex. Schizophrenic patients showed lower DAT binding compared with the healthy subjects at baseline (p<0.001) and after a 4-week-treatment period (p=0.001). Six out of eight schizophrenic patients of the DIP group were symptomatic for PS at baseline, in comparison to two out of 12 in the NoDIP group. Nonetheless, no differences were observed on DAT between DIP and NoDIP, neither at baseline (p=0.360) nor at endpoint (p=0.984). Finally, no differences between baseline-endpoint DAT binding were observed, neither in the DIP group (p=0.767) nor in the NoDIP group (p=0.093). Our new series of first-episode naive-schizophrenic patients (1) points out DAT dysfunction as an illness trait due to the significantly lower DAT binding in schizophrenic patients in comparison to healthy subjects; (2) supports the results of other authors who describe PS in never-treated patients; (3) confirms that [(123)I] FP-CIT does not allow us to predict which patients will develop parkinsonism due to the lack of differences between DIP and NoDIP patients; and (4) confirms a null effect of antipsychotics on DAT due to the lack of differences in [(123)I] FP-CIT before and after a 4-week-treatment period.

Serotonin 2A binding in neuroleptic-naive schizophrenic patients and healthy controls using PET and [18-F]altanserin

Serotonin 2A binding in neuroleptic-naive schizophrenic patients and healthy controls using PET and [18-F]altanserin

Frontal dopamine D2 receptor binding in neuroleptic-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender

Frontal dopamine D2 receptor binding in neuroleptic-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender

The striatal dopamine transporter in first-episode, drug-naive schizophrenic patients: evaluation by the new SPECT-ligand[99mTc]TRODAT-1

Following the current hypothesis that acute schizophrenic psychotic illness is associated with a striatal 'hyperdopaminergic state', presynaptic integrity and dopamine transporter (DAT) density in first-episode, neuroleptic-naive schizophrenic patients was measured by single-photon-emission-tomography (SPECT) and compared with that in healthy control subjects. A new SPECT-ligand for assessment of the striatal DAT, the Technetium-99m-labelled tropane TRODAT-1 ([99mTc]TRODAT-1), was used. Ten inpatients suffering from a first acute schizophrenic episode and 10 age- and sex-matched healthy control subjects underwent SPECT with [99mTc]TRODAT-1. On the day of SPECT, psychopathological ratings were performed with the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and Schedule for Assessment of Negative Symptoms (SANS). Patients had not previously received any neuroleptic or antidepressant medication. Mean specific TRODAT-1 binding in the striatum did not differ significantly between the patient and the age- and sex-matched control group (1.25 vs. 1.28). Variance was significantly higher in the patient group. The data obtained with the new ligand in first-episode, drug-naive schizophrenic patients are in line with the PET results from the group of Laakso et al. in a comparable patient sample. [99mTc]TRODAT-1 seems to be a valuable new SPECT-ligand in the evaluation of the presynaptic site of the striatal dopaminergic synapse in schizophrenia.

Volume Changes in Gray Matter in First-Episode Neuroleptic-Naive Schizophrenic Patients Treated With Risperidone

Structural neuroimaging techniques have consistently shown that treatment of schizophrenic patients with conventional antipsychotics causes an increase in basal ganglia volume. However, findings in schizophrenic patients treated with the newer atypical antipsychotic drugs are less consistently reported. To explore this issue, the authors used a whole-brain, unbiased, and automated technique for comparing brain structural features across scans in schizophrenic patients before and after a treatment with the atypical antipsychotic risperidone. T1-weighted images from 11 first-episode neuroleptic-naive schizophrenic patients were processed and analyzed for regions of interest (basal ganglia) by using optimized voxel-based morphometry. Scans were repeated after 3 months of continuous treatment with risperidone. Region of interest-based voxel-based morphometry analyses revealed increases in gray matter volume for the right and left caudate nuclei and for the left accumbens after the treatment with risperidone. Hence, in our sample of schizophrenic patients, treatment with risperidone was associated, in contrast to the findings for other atypical antipsychotics, with an increase in basal ganglia volume. Such discrepancy could be related to the pharmacodynamics of risperidone (the atypical antipsychotic showing the higher affinity for D2 receptors) and the rather high mean doses used in our study (ie, 6.05 mg/d).

Cortical excitability in neuroleptic-naive first-episode schizophrenic patients

Cortical excitability in neuroleptic-naive first-episode schizophrenic patients

Basal ganglia N-acetylaspartate correlates with the performance in the procedural task ‘Tower of Hanoi’ of neuroleptic-naive schizophrenic patients

We tested the hypothesis that basal ganglia dysfunction may be related to procedural learning impairment in schizophrenia. We determined the N-acetylaspartate/choline (NAA/Cho) ratio in the left striatal area in 11 young first-episode antipsychotic-naive patients and matched controls. Procedural learning was assessed by the four-disk version of the Tower of Hanoi. Analysis of variance showed that the number of moves and the execution time had a significant group effect ( P=0.02, P<0.0001, respectively). Correlation analysis between procedural learning and the NAA/Cho ratio showed a negative significant correlation only in patients, measured by both time ( P=0.006) and by moves ( P=0.001). In summary, we found that schizophrenic patients have impaired procedural learning, and that this impairment is related to basal ganglia metabolism.

Preliminary evidence of striatal D2 receptor density as a possible biological marker of prognosis in naive schizophrenic patients

With the aim of investigating a possible biological marker of prognosis in schizophrenia, the relationship between striatal dopaminergic D2 receptor (D2R) density and clinical prognostic factors was studied in an initial sample of nine neuroleptic-naive schizophrenic patients. Previous psychosocial adaptation was evaluated by means of the Premorbid Adjustment Scale (PAS). Based on the four DSM-IV criteria in schizophreniform disorder for good prognosis, patients were divided in two groups: good prognosis if ≥2 criteria were met ( n=5) and poor prognosis if <2 criteria were met ( n=4). D2R density was assessed by means of 123I-IBZM single photon emission computed tomography (SPECT) and striatum/occipital uptake ratios (S/O). S/O ratios previously obtained from a control group of nine age- and sex-matched healthy volunteers were used for comparison. Results: Patients with poor prognosis showed a higher S/O ratio (mean=1.94, range=1.93–1.98) than patients with good prognosis (mean=1.64, range=1.52–1.79) and the control group (mean=1.69, range=1.51–1.85) [analysis of variance (ANOVA) F=10.628, df=2, P=.001, post hoc Scheffé P<.005]. PAS scores were significantly different between patients with good and poor prognosis (40±9.39 vs. 84.25±26, Mann–Whitney U-test P=.014). A direct correlation of S/O ratios with PAS scores was found (Spearman r=.72, P=.028). Conclusion: Striatal D2R density in naive schizophrenic patients may be related to DSM-IV prognostic factors and premorbid adjustment criteria (PAS). If these preliminary results are confirmed, striatal D2R density might predict premorbid and clinical features associated with poor prognosis in neuroleptic-naive patients.

Sustained attention impairment correlates to gray matter decreases in first episode neuroleptic-naive schizophrenic patients

Impaired sustained attention seems to be a specific neuropsychological deficit that is closely linked to schizophrenia. Voxel based morphometry has emerged as a useful tool for the detection of subtle gray matter (GM) abnormalities. The aim of our study was to identify the cerebral regions related to the Identical-Pair version of the Continuous Performance Test (CPT-IP) performance in schizophrenic patients. The study included 13 right-handed, male, first-episode, paranoic, neuroleptic-naive schizophrenic patients and 13 matched controls. High-resolution whole-brain MR images were segmented and analyzed for the whole brain and for regions of interest (ROI) using SPM99. Furthermore, the correlation between CPT-IP performance and GM density was examined. Volumetric analysis of the thalami was also carried out. GM density analysis shown decreases in patients in anterior cingulate gyrus, left inferior frontal, right claustrum, left pulvinar, and dorsomedial bilateral thalamic nuclei, and caudate nuclei as well as left hippocampus and parahippocampal gyrus. Thalamic ROIs revealed a strong correlation between groups differences. The thalamic GM density allowed a good individual classification. GM increases were detected in left insula, superior temporal gyrus, and putamen nucleus, and right supramarginal gyrus. Schizophrenic patients showed smaller left and right thalamic volumes. We found that GM density of the left thalamic nucleus, left angular, and supramarginal gyrus, and left inferior frontal and postcentral gyri correlated significantly with CPT-IP performance in patients but not in controls. Moreover, the restricted ROIs regression was strongly significant for both left and right thalamus. In summary, we provide evidence for the involvement of thalamic, inferior-parietal, and frontal regions in the attentional deficits observed in schizophrenic patients.

Psychopathology of early-onset versus late-onset schizophrenia revisited: an observation of 473 neuroleptic-naive patients before and after first-admission treatments

Reports of potential differences in psychopathological presentations between early and late-onset schizophrenia have been controversial. However, such differences in first-episode neuroleptic-naive schizophrenic patients have not been discussed. The authors evaluated symptom profiles in 473 neuroleptic-naive schizophrenic patients before and after first-admission treatments. Both before and after treatment, (1) late-onset schizophrenia had a lower score on affective flattening/social withdrawal than did the earlier-onset counterpart of the illness, even after controlling for potential secondary sources of negative symptoms; (2) systematic persecutory delusion was more severe in patients with late-onset schizophrenia; and (3) the overall effect of age of onset on the psychopathological presentations was greater than the gender-related effects, including the interaction between age of onset and gender. Consideration of late-onset schizophrenia may be important in order to develop an etiologically and clinically reasonable conceptualization of the subtypes of schizophrenia. A factor–analytical study that attempts to compare directly the structure of broad psychopathological presentations in early and late-onset schizophrenia may be a reasonable approach to investigate the longstanding unsolved controversy as to whether or not the neurobiological backgrounds underlying the psychopathological presentations are comparable.

Reduced volume of the cerebellar vermis in neuroleptic-naive schizophrenia

Background: Neuroimaging studies have suggested the possible role of the cerebellum in the pathophysiology of schizophrenia. However, no study has investigated the detailed structures of the cerebellum in patients without a history of neuroleptic medication. The objective of this study is to examine the volume of detailed structures of the cerebellum in neuroleptic-naive schizophrenic patients and to examine the relationship between cerebellar morphology and clinical symptoms. Methods: Magnetic resonance imaging scans were acquired from 20 male neuroleptic-naive schizophrenic patients and 20 healthy control subjects. We measured the volumes of the cerebrum, cerebellar hemisphere, cerebellar gray and white matter, and vermis. Symptoms were assessed with the Brief Psychiatric Rating Scale. Total Brief Psychiatric Rating Scale scores and subscale scores were used for analysis. Results: The volume of the vermis was significantly reduced in the schizophrenic group relative to the control group, whereas no significant differences were found in the volumes of other cerebellar structures and the cerebrum. Reduction in the vermal volume correlated with the total Brief Psychiatric Rating Scale Depression subscore and Paranoia subscore. Conclusions: This study indicates that the volume of the vermis is reduced in patients with schizophrenia, and reduction in vermal volume is suggested to be related to the pathophysiology of the disease.

Neurochemical Investigation of the Schizophrenic Brain by in Vivo Phosphorus Magnetic Resonance Spectroscopy

Abnormal phospholipid metabolisms may play important roles in the pathophysiology of schizophrenia. Phosphorus magnetic resonance spectroscopy (31P-MRS) offers a new method for studying phosphorus-related metabolism in vivo. A decrease in the level of phosphomonoesters (PME) and an increase in the level of phosphodiesters (PDE) has been demonstrated in the prefrontal lobe of neuroleptic-naive schizophrenic patients. Most of the studies in medicated schizophrenic patients have shown decreased PME and/or increased PDE. The decreased PME in the frontal lobe appears to be associated with negative symptoms and poor working memory performance. 1H-decoupled 31P-MRS revealed a reduction in the phosphocholine element of PME and an elevation in the mobile phospholipids of PDE in the prefrontal region of medicated schizophrenic patients. PDE were elevated in the temporal lobes of neuroleptic-naive schizophrenic patients, and this increase was partially normalized by haloperidol administration. Data about the temporal lobes of medicated schizophrenic patients have not been consistent. Except for the reduction in the adenosine triphosphate (ATP) in the basal ganglia and the correlation between the increase in the frontal lobe phosphocreatine (PCr) and negative symptomatology, data related to changes in high-energy phosphates are contradictory. No consensus on the effect of neuroleptics on phosphorus metabolites has been achieved. Methodological problems inherent in 31P-MRS may have contributed to the confusion in understanding available data. Future directions of MRS studies are suggested in the last section of the paper.

Serotonin 5-HT 2 receptors in schizophrenic patients studied by positron emission tomography

Using positron emission tomography (PET) and [ 11C]N-methylspiperone (NMSP), we examined 5-HT 2 receptors in the cortex of schizophrenic patients in whom we previously observed decereased prefrontal D1 receptor binding. The subjects were 10 neuroleptic-naive schizophrenic patients, 7 schizophrenic patients who were drug-free but had previously been treated with neuroleptics, and 12 normal controls. A non-significant trend towards decreased prefrontal [ 11C]NMSP binding was observed in the neuroleptic-treated patients, suggesting a possible effect of previous neuroleptic treatment on the alteration in cortical 5-HT 2 function. However, the neuroleptic-naive patients showed no noticeable difference in cortical [ 11C]NMSP binding compared to controls. Our results do not rule out the role of 5-HT 2 function as a crucial site of therapeutic activity of schizophrenia, but they do suggest that cortical 5-HT 2 receptors might not be primarily involved in the pathophysiology of schizophrenia.

Caudate size in first-episode neuroleptic-naive schizophrenic patients measured using an artificial neural network

Background: Structural brain imaging studies have demonstrated an increase in caudate volume in schizophrenic patients medicated with typical neuroleptics and a volume decrease following treatment with atypical neuroleptics. The measurement of striatal volume in patients who have never been treated with neuroleptics may indicate whether these changes are superimposed on intrinsic basal ganglia pathology in schizophrenia or are solely neuroleptic-induced. Methods: We studied 36 first-episode, neuroleptic-naive schizophrenic patients and 43 control subjects using an artificial neural network (ANN) to identify and measure the caudate nucleus. The resulting volumes were analyzed using an ANCOVA controlling for intracranial volume, age, gender, and socioeconomic status. Results: The mean volume difference between the caudate nuclei of patients and control subjects was .297 mL, the caudate nuclei of the patients being smaller than those of controls. When we covaried for intracranial volume, this was a statistically significant difference in caudate volume ( n = 79; df = 1,75; F = 4.18; p > .04). Conclusions: Caudate nuclei of neuroleptic naive schizophrenic patients are significantly smaller than those of controls. This suggests that patients suffering from schizophrenia may have intrinsic pathology of the caudate nucleus, in addition to the pathology observed as a consequence of chronic neuroleptic treatment.