Unmedicated Schizophrenic Patients Research Articles

Brainstem auditory evoked potential variability in unmedicated schizophrenic patients

Background: Schizophrenia (SCZ) is one of the most incapacitating and financially disastrous medical conditions and ranks among the most severe and burdensome diseases in the world due to the onset, progression, and frequency of disability. Few researches have been reported that SCZ is linked to a number of neurophysiological abnormalities, including changes in brainstem auditory evoked potentials (BAEPs). Aims and Objectives: The current study aimedto measure brainstem function using BAEPs in patients with SCZ and compare their findings with healthy controls. Materials and Methods: A cross-sectional case–control study was conducted on 51 schizophrenic drug-naive patients selected from the outpatient department of psychiatry, fulfilling the diagnostic criteria of DSM-IV, aged 18-28 years, male and female, with a matching control group of 50 subjects recruited from patients’ relatives. For assessing the severity of SCZ, the positive and negative syndrome scale was utilized. The BAEPs were recorded using a brainstem-evoked response audiometry (BERA) device (NeuroStim-NS 2). Data were analyzed using Independent t-test and Mann–Whitney test based on normality. P-value was considered significant at P < 0.05, P < 0.01 level. Results: A significant difference was observed in patients and control group BAEPs. The absolute latency of waves I and III in the right ear, waves I and V, IPL I-III in the left ear was shown to be significantly different. The results demonstrate that the patient group’s mean latency was higher than the controls. Conclusion: Based on findings, it was concluded that abnormal BAEPs in schizophrenic patients might be attributed to their primary symptom of discontinuity in perceptual and other cerebral functions and slower transmission in the lower brainstem auditory pathway and decreased activity at the brainstem level.

Spatial and chronic differences in neural activity in medicated and unmedicated schizophrenia patients

A major caveat with investigations on schizophrenic patients is the difficulty to control for medication usage across samples as disease-related neural differences may be confounded by medication usage. Following a thorough literature search (632 records identified), we included 37 studies with a total of 740 medicated schizophrenia patients and 367 unmedicated schizophrenia patients. Here, we perform several meta-analyses to assess the neurofunctional differences between medicated and unmedicated schizophrenic patients across fMRI studies to determine systematic regions associated with medication usage. Several clusters identified by the meta-analysis on the medicated group include three right lateralized frontal clusters and a left lateralized parietal cluster, whereas the unmedicated group yielded concordant activity among right lateralized frontal-parietal regions. We further explored the prevalence of activity within these regions across illness duration and task type. These findings suggest a neural compensatory mechanism across these regions both spatially and chronically, offering new insight into the spatial and temporal dynamic neural differences among medicated and unmedicated schizophrenia patients.

Serum S100B Protein is Specifically Related to White Matter Changes in Schizophrenia.

Background: Schizophrenia can be conceptualized as a form of dysconnectivity between brain regions.To investigate the neurobiological foundation of dysconnectivity, one approach is to analyze white matter structures, such as the pathology of fiber tracks. S100B is considered a marker protein for glial cells, in particular oligodendrocytes and astroglia, that passes the blood brain barrier and is detectable in peripheral blood. Earlier Studies have consistently reported increased S100B levels in schizophrenia. In this study, we aim to investigate associations between S100B and structural white matter abnormalities.Methods: We analyzed data of 17 unmedicated schizophrenic patients (first and recurrent episode) and 22 controls. We used voxel based morphometry (VBM) to detect group differences of white matter structures as obtained from T1-weighted MR-images and considered S100B serum levels as a regressor in an age-corrected interaction analysis.Results: S100B was increased in both patient subgroups. Using VBM, we found clusters indicating significant differences of the association between S100B concentration and white matter. Involved anatomical structures are the posterior cingulate bundle and temporal white matter structures assigned to the superior longitudinal fasciculus.Conclusions: S100B-associated alterations of white matter are shown to be existent already at time of first manifestation of psychosis and are distinct from findings in recurrent episode patients. This suggests involvement of S100B in an ongoing and dynamic process associated with structural brain changes in schizophrenia. However, it remains elusive whether increased S100B serum concentrations in psychotic patients represent a protective response to a continuous pathogenic process or if elevated S100B levels are actively involved in promoting structural brain damage.

"Hyperfrontality" as seen on FDG PET in unmedicated schizophrenia patients with positive symptoms.

Decreased frontal activity has been reported widely in unmedicated schizophrenic patients with predominantly negative symptoms. Not many studies have assessed the frontal lobe status in unmedicated patients with positive symptoms. Fifty-one patients with schizophrenia (all unmedicated, 38 never medicated) and 12 healthy age-matched controls were evaluated with FDG PET CT. The patients met ICD-10 and DSM-IV criteria for schizophrenia, and all reported psychotic, "positive" symptoms when tested. Schizophrenic patients with positive symptoms had a hypermetabolic frontal metabolic pattern on quantification by region to occipital ratio comparison. Associated statistically significant differences were also found when comparing ratios of occipital to thalamic, striatal and temporal cortex in schizophrenic patients. The finding of a hyperfrontality in unmedicated and never medicated psychotic schizophrenic patients is observed when there is a predominance of positive symptoms. There could be a possible disruption of cortico-striato-thalamic feedback loops causing hyperfrontality as seen in experimentally induced models of psychosis .

The study of relationships between three neurophysiological endophenotypes in unmedicated schizophrenic patients

The study of relationships between three neurophysiological endophenotypes in unmedicated schizophrenic patients

Metabolomic Profiling to Identify Potential Serum Biomarkers for Schizophrenia and Risperidone Action

Despite recent advances in understanding the pathophysiology of schizophrenia and the mechanisms of antipsychotic drug action, the development of biomarkers for diagnosis and therapeutic monitoring in schizophrenia remains challenging. Metabolomics provides a powerful approach to discover diagnostic and therapeutic biomarkers by analyzing global changes in an individual's metabolic profile in response to pathophysiological stimuli or drug intervention. In this study, we performed gas chromatography-mass spectrometry based metabolomic profiling in serum of unmedicated schizophrenic patients before and after an 8-week risperidone monotherapy, to detect potential biomarkers associated with schizophrenia and risperidone treatment. Twenty-two marker metabolites contributing to the complete separation of schizophrenic patients from matched healthy controls were identified, with citrate, palmitic acid, myo-inositol, and allantoin exhibiting the best combined classification performance. Twenty marker metabolites contributing to the complete separation between posttreatment and pretreatment patients were identified, with myo-inositol, uric acid, and tryptophan showing the maximum combined classification performance. Metabolic pathways including energy metabolism, antioxidant defense systems, neurotransmitter metabolism, fatty acid biosynthesis, and phospholipid metabolism were found to be disturbed in schizophrenic patients and partially normalized following risperidone therapy. Further study of these metabolites may facilitate the development of noninvasive biomarkers and more efficient therapeutic strategies for schizophrenia.

Reduced Brain-Derived Neurotrophic Factor Serum Concentrations in Acute Schizophrenic Patients Increase During Antipsychotic Treatment

Brain-derived neurotrophic factor (BDNF) is not only involved in the development, differentiation, and survival of dopaminergic neurons; it also regulates fast neurotransmission and neuronal activity. In this study, 22 patients with acute schizophrenia and 22 age-matched healthy volunteers were recruited, and BDNF serum concentrations were measured in unmedicated patients and after 2 weeks and 4 weeks of medication. Brain-derived neurotrophic factor serum levels of unmedicated schizophrenic patients (n = 22; 4.38 ± 2.1 ng/mL) were significantly decreased compared to the age-matched healthy volunteers (n = 44, df = 42, P = 0.029). In a mixed-model repeated-measures analysis of variance, a significant BDNF increase has been found during treatment (χ² = 2.91; df = 1; P < 0.0001). The percental change of BDNF (increase, 173% ± 110) correlated negatively with the percental change of PANSS score (decrease: 75% ± 22; n = 18; r = -0.554; P = 0.032). Our study replicates studies showing that unmedicated patients with schizophrenia have decreased serum BDNF levels compared with healthy controls. Brain-derived neurotrophic factor increase during treatment seems to parallel positive and negative symptom improvement.

S16-03 - Relationships between negative symptoms and abnormalities in the anticipatory component of reward

A dysfunction of the dopaminergic reward system has been postulated in the pathophysiology of schizophrenia. A subcortical hyperdopaminergic state in unmedicated schizophrenia patients has been associated with the pathogenesis of positive symptoms and a prefrontal hypodopaminergic state with cognitive and negative symptoms. But negative symptoms like anhedonia have also been hypothesized to be associated with a dysfunction of the mesolimbic dopaminergic system. However, preclinical studies indicate that the mesolimbic dopaminergic system mediates motivation and incentive salience of reward-indicating stimuli rather than the ability to experience pleasure.Recent neuroimaging findings in schizophrenia patients confirmed dysfunctional activation during reinforcement learning. We used functional magnetic resonance imaging (fMRI) to assess the BOLD response in the ventral striatum of unmedicated schizophrenia patients during presentation of reward-indicating stimuli and during reversal learning. Compared with healthy controls, unmedicated schizophrenics showed reduced ventral striatal activation during presentation of reward-indicating cues, which was negatively correlated with the severity of negative symptoms. During reversal learning unmedicated schizophrenia patients displayed behavioral impairments and reduced activation in the ventral striatum and the ventrolateral PFC. In unmedicated schizophrenic patients, a high striatal dopamine turnover may interfere with neuronal processing of reward-indicating stimuli by phasic dopamine release, thus contributing to negative symptoms as such as loss of drive and motivation.

Different patterns of longitudinal changes in plasma levels of catecholamine metabolites and brain-derived neurotrophic factor after administration of atypical antipsychotics in first episode untreated schizophrenic patients

In the present study, we longitudinally investigated the effects of risperidone, olanzapine, and aripiprazole on plasma levels of catecholamine metabolites and brain-derived neurotrophic factor (BDNF) in first-episode unmedicated schizophrenic patients. The subjects were 59 Japanese schizophrenic patients (35 males and 24 females; age range: 18–46 years; mean±SD: 25±16 years). The patients were treated with risperidone (n=32) in a dose range of 2–6 mg/day (mean±SD=3.4±1.9), olanzapine (n=18) in a dose range of 5–20 mg/day (mean±SD=12.1±5.8), or aripiprazole (n=9) in a dose range of 12–30 mg/day (mean±SD=22.8±10.1). All three drugs significantly decreased plasma homovanillic acid (HVA) levels within 8 weeks, although aripiprazole transiently raised this level before 8 weeks. All three drugs also significantly increased plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels within 8 weeks. On the other hand, none of them altered plasma BDNF levels. These results indicate that risperidone, olanzapine, and aripiprazole affect catecholaminergic systems in the brain, that the effects of aripiprazole on the dopaminergic systems seem to slightly different than those of risperidone and olanzapine, and that these atypical antipsychotic drugs might not alter BDNF levels, at least within 8 weeks of treatment.

Preattentional processes and disorganization in schizophrenia: Influence of a 6-week risperidone treatment

Introduction Visual orientation and attention are impaired in schizophrenia. Engagement and disengagement of attention and the ability to prompt responses to a stimulus in patients before and after six weeks of risperidone were compared to controls. Methods Ten unmedicated (nine naïve) schizophrenic patients, and eleven controls performed 1) A visual orienting task, the Cued Target Detection task (CTD), with the detection of a visual stimulus in valid, invalid, no cue and double cue trials, two conditions for fixation offset for a modulation of visual fixation: Gap: 200 ms before target; No Gap: simultaneous with target, 2) Choice Reaction Time (CRT 0.5 and 2 s delays). Results At baseline, patients showed longer RT than controls in CRT, but not in CTD, with in CTD, no facilitation of RT with the gap procedure. The alertness index was almost null in CTD-Gap and comparable to controls in CTD-No Gap. Efficiency to detect attended stimuli (CTD-No Gap) and warning effect (CRT 0.5 s) were negatively correlated to disorganization. After treatment, readiness to act in CRT had decreased. In CTD-No Gap, change in PANSS disorganization was correlated to an increased validity index, change in negative sub-score was correlated to decreased attention cost. Conclusion Untreated patients displayed a deficit of Gap effect and a slowing in sustained attention. Disorganization interfered with warning and visual detection. After treatment, its improvement and negative symptoms improvement were associated with better visual detection. These alterations in visual orienting provide new evidence for an oculomotor dysregulation of attentional engagement in schizophrenia.

Connectivity Between Posterior Parietal Cortex and Ipsilateral Motor Cortex Is Altered in Schizophrenia

Recent advances have highlighted the hypothesis of schizophrenia as a disorder causing defective connectivity among distinct cortical regions. Neurophysiological evidence supporting this hypothesis, however, is still lacking. In the present study, we used a novel twin-coil transcranial magnetic stimulation (tcTMS) approach to investigate ipsilateral parieto-motor connectivity in 20 schizophrenic patients (14 medicated, 6 unmedicated) and in 15 healthy age-matched volunteers. In healthy subjects, a conditioning TMS pulse applied over the ipsilateral posterior parietal cortex (PPC) at 90% of resting motor threshold (RMT) intensity was able to increase the excitability of the hand area of the right primary motor cortex, with peaks at interstimulus intervals (ISIs) of 4 and 15 msec. This paradigm of stimulation failed to reveal any facilitatory parieto-motor interaction in medicated and unmedicated schizophrenic patients. The between-group difference in paired-pulse facilitation was not ISI-specific. In following analyses, we found that the effects across ISIs induced by PPC conditioning at 90% RMT correlated with the Global Assessment Functioning score and with the negative subscale of the Positive and Negative Syndrome Scale, showing that patients with a better global functioning and lower negative symptoms had less impaired connectivity. Moreover the same parameter correlated with illness duration. Parieto-motor connectivity is impaired in schizophrenia. Cortico-cortical disconnection might be a core feature of schizophrenia.

Variations of rest – activity rhythm and sleep – wake in schizophrenic patients versus healthy subjects: An actigraphic comparative study

The objective of the present study was to compare the pattern of motor activity in unmedicated schizophrenia patients and healthy subjects, and to examine whether the pattern was affected by treatment with typical and atypical antipsychotics. Twenty unmedicated schizophrenic patients wore a wrist actigraph for five days. The actigraph recorded activity levels in one-minute epochs. Patients' pattern of activity was compared with that of healthy subjects. Patients were randomly assigned to treatment with low-dose haloperidol or risperidone. The impact of treatment on the pattern of activity was examined. Compared to controls, untreated patients showed a diminished mean activity count during morning, early and late night periods. Treatment with haloperidol or risperidone at effective doses showed a significant effect on activity level, being more prominent with haloperidol. The results suggest that unmedicated schizophrenic patients exhibit abnormally low levels of motor activity as measured with an objective activity meter. This persists after antipsychotic treatment even though symptoms improve. Future studies should clarify whether motor disturbances are a primary effect of the illness, or related to the illness-related lifestyle.

Kinematic analysis of facial behaviour in patients with schizophrenia under emotional stimulation by films with “Mr. Bean”

In schizophrenic patients, motor functioning is substantially disturbed. Kinematic analysis is useful in examining this motor dysfunction. Using kinematic analysis, we aimed to investigate facial movement in schizophrenic patients responding to humorous film stimuli ("Mr. Bean"). Ultrasound markers were attached to pre-defined facial points while subjects watched a funny film sketch. The study included 21 schizophrenic in-patients (13 men, 8 women; mean (S.D.) age: 32.1 (10.4) years) and 30 healthy individuals (12 men, 18 women; mean (S.D.) age: 35.7 (11.0) years). Unmedicated schizophrenic patients showed an abnormally high initial velocity of laughing (IV), while patients treated with typical neuroleptics demonstrated an abnormally low IV. There was a significant positive correlation between severity of negative symptoms and IV. Kinematical analysis of facial movement using IV could help to distinguish subclinical Parkinsonian syndromes induced by typical neuroleptics from negative symptoms of schizophrenia.

A study of facial emotion recognition in unmedicated schizophrenic patients

目的 研究精神分裂症患者的面孔情绪认知功能障碍,探讨情绪认知缺陷与精神症状的相关性.方法 采用中国人面孔情绪测验(CFET)对38例未经治疗的精神分裂症患者进行测试,与50名正常健康者比较,同时作阳性与阴性症状量表(PANSS)评定.结果 分裂症患者六种基本情绪认知正确分均显著低于对照组(P ＜0.01),喜、怒、悲、惊、怕的远隔错误分显著高于对组(P ＜0.01).PANSS总分与CFET惊(r =0.33,P ＜0.05)和怒(r =0.32,P ＜0.05)的远隔错误分呈正相关;阳性症状评分与CFET怒的正确评分(r =-0.40,P ＜0.05)呈负相关,而与惊(r =0.35,P ＜0.05)和怒(r =0.34,P ＜0.05)的远隔错误分呈正相关.结论 分裂症患者存在广泛的情绪认知障碍,这种障碍与某些症状表现相关。

Relationship between cardiovagal modulation and psychotic state in patients with paranoid schizophrenia

Disturbed autonomic nervous system (ANS) function in schizophrenia might contribute to increased cardiovascular mortality. We obtained heart rate variability indices from 40 unmedicated schizophrenic patients and 58 matched controls. Mainly we found that patients displaying stronger psychotic symptoms as assessed by the Brief Psychiatric Rating Scale exhibit more severe cardiac ANS disturbances compared with controls.

T- and B-lymphocytes in patients with schizophrenia in acute psychotic episode and the course of the treatment

Schizophrenia is associated with alterations of the immune system. There are, however, only limited data dealing with immune parameters in unmedicated schizophrenic patients and the course of these parameters during treatment. In this study, we monitored CD19 + (B)- and CD3 + (T)-lymphocytes in the course of antipsychotic treatment. Forty patients diagnosed with an acute exacerbation of schizophrenia were tested before and after 3 days, 2 weeks, 4 weeks and 3 months of treatment with antipsychotics. The percentages of CD19 +- and CD3 +-lymphocytes were analysed by flow cytometry using fluorescence conjugated anti-CD19 and anti-CD3 antibodies. Twenty healthy volunteers served as controls. In the acute state of psychosis, a significant reduction of the CD3 +-lymphocyte subpopulation was observed, while the percentage of CD19 +-lymphocytes was increased. Both subpopulations levelled to those of the control group in the course of treatment. As expected, the levels of the immune parameters did not change in the healthy controls during the course of the study. The observed alterations of the CD19 +- and CD3 +-lymphocytes in the acute state of psychosis especially in patients with the paranoid subtype of schizophrenia, and the “normalization” during the observation period are discussed under the aspect of the immune hypothesis of schizophrenia, in particular of the type-1/type-2 imbalance hypothesis.

Dysfunction of ventral striatal reward prediction in schizophrenia

Background: Negative symptoms may be associated with dysfunction of the brain reward system in schizophrenia. We used functional magnetic resonance imaging (fMRI) to assess the BOLD response in the ventral striatum of unmedicated schizophrenics during presentation of reward-indicating and loss-indicating stimuli. Methods: A total of 10 schizophrenic men (7 never medicated, 3 unmedicated for at least 2 years) and 10 age-matched healthy male volunteers participated in an incentive monetary delay task, in which visual cues predicted that a rapid response to a subsequent target stimulus would result either in monetary gain or loss or would have no consequence. Results: Compared to healthy controls, unmedicated schizophrenics showed reduced ventral striatal activation during the presentation of reward-indicating cues. Decreased activation of the left ventral striatum was inversely correlated with the severity of negative (and trendwise positive) symptoms. Discussion: Reduced activation in one of the central areas of the brain reward system, the ventral striatum, was correlated with the severity of negative symptoms in medication-free schizophrenics. In unmedicated schizophrenic patients, a high striatal dopamine turnover may increase the “noise” in the reward system, thus interfering with the neuronal processing of reward-predicting cues by phasic dopamine release. This, in turn, may contribute to negative symptoms as such as anhedonia, apathy, and loss of drive and motivation.

Poster sessions: neuropsychological correlates of P50 among unmedicated schizophrenic patients

Poster sessions: neuropsychological correlates of P50 among unmedicated schizophrenic patients

Loss of efferent vagal activity in acute schizophrenia

An increased heart rate has been reported in schizophrenia. It is unclear whether this is due to disease-related autonomic nervous system changes or a side effect of antipsychotic medication. Altered cardiac autonomic function might to some extent account for the elevated cardiovascular mortality rate of schizophrenic patients. We assessed heart rate variability (HRV) in 30 acute unmedicated schizophrenic patients and matched controls. Patients were re-investigated 2–4 days after initiation of treatment to assess effects of medication. Our study demonstrates that non-medicated schizophrenic patients were significantly different in heart rate (increase) and parasympathetic parameters (loss of efferent vagal activity) at rest and during deep respiration. No significant effect was found after initiation of neuroleptic therapy. We found a correlation between duration of disease and parasympathetic parameters as well as very low frequency power (VLF) and delusion (SAPS subscale). These data suggest that schizophrenia is accompanied by a loss of vagal efferent activity, probably due to disturbed cortical–subcortical circuits modulating the autonomic nervous system in acute psychosis. The definite mechanisms by which vagal activity might be suppressed in schizophrenia are unknown. Parasympathetic hypoactivity might increase the risk for sudden cardiac death and arrhythmias in this disease. Future studies are warranted to investigate the interaction between cardiac autonomic function and schizophrenia and to identify patients on risk.

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.