G. Szekeres

Role of dopamine D3 receptor (DRD3) and dopamine transporter (DAT) polymorphism in cognitive dysfunctions and therapeutic response to atypical antipsychotics in patients with schizophrenia

Molecular components of the dopaminergic system may play an important role in the pathophysiology of schizophrenia. In this study, we investigated the relationship of the Ser9Gly (S/G) polymorphism of the dopamine D3 receptor (DRD3) and the variable number of tandem repeats (VNTR) polymorphism of the dopamine transporter (DAT) with therapeutic response to atypical antipsychotics (clozapine, olanzapine, quetiapine, risperidone) and cognitive functions. No associations were found between the DRD3 and DAT polymorphisms and schizophrenia. The S/S genotype and the S allele were more frequent in the non‐responder patients (n = 28) than in the group of responders (n = 47) (cut‐off: >20‐point improvement in Global Assessment of Functioning (GAF) scale). The patients with S/S genotype completed fewer categories and had more perseverative errors in the Wisconsin Card Sorting Test (WCST) compared with the S/G patients. The S/S and S/G patients did not differ in positive and negative symptoms, GAF scores, WCST failure to maintain set, and verbal learning. No differences in symptoms or WCST measures were observed in the patients with different DAT genotypes. These results suggest that the S/S genotype of the DRD3 is associated with worse therapeutic response and more severe executive dysfunctions in patients with schizophrenia.

The C270T polymorphism of the brain-derived neurotrophic factor gene is associated with schizophrenia

We investigated a novel polymorphism of single nucleotide substitution (C270T) of the brain-derived neurotrophic factor (BDNF) gene in schizophrenia patients (n=101) and in controls (n=68). The frequency of the C/T genotype and the T allele were significantly higher in the schizophrenia patients (25.7% and 13.9%, respectively) compared with the controls (5.9% and 2.9%). There were no significant differences in Positive and Negative Symptom Scale (PANSS) items and Global Assessment of Functioning (GAF) scores between the patients with C/C and C/T genotypes. Further studies are warranted to elucidate the significance of this finding in the pathophysiology of schizophrenia.

Over-expression of dopamine D2 receptor and inwardly rectifying potassium channel genes in drug-naive schizophrenic peripheral blood lymphocytes as potential diagnostic markers

Schizophrenia is one of the most common neuropsychiatric disorders affecting nearly 1% of the human population. Current diagnosis of schizophrenia is based on complex clinical symptoms. The use of easily detectable peripheral molecular markers could substantially help the diagnosis of psychiatric disorders. Recent studies showed that peripheral blood lymphocytes (PBL) express subtypes of D1 and D2 subclasses of dopamine receptors. Recently, dopamine receptor D3 (DRD3) was found to be over-expressed in schizophrenic PBL and proposed to be a diagnostic and follow-up marker for schizophrenia. In this study we screened PBL of 13 drug-naive/drug-free schizophrenic patients to identify additional markers of schizophrenia. One of the benefits of our study is the use of blood samples of non-medicated, drug-naive patients. This excludes the possibility that changes detected in gene expression levels might be attributed to the medication rather than to the disorder itself. Among others, genes for dopamine receptor D2 (DRD2) and the inwardly rectifying potassium channel (Kir2.3) were found to be over-expressed in microarray analysis. Increased mRNA levels were confirmed by quantitative real-time PCR (QRT-PCR) using the SybrGreen method and dual labeled TaqMan probes. The use of both molecular markers allows a more rapid and precise prediction of schizophrenia and might help find the optimal medication for schizophrenic patients.

Visual information processing in patients with schizophrenia: evidence for the impairment of central mechanisms

Patients with schizophrenia are especially impaired in the detection of spatial location if the briefly presented target stimulus is followed by a mask in a close temporal proximity (target location backward masking (BM) paradigm). It has been suggested that this phenomenon is related to the impairment of low spatial and high temporal frequency-sensitive transient (magnocellular) visual channels. To test this hypothesis, we measured target location BM and visual contrast sensitivity (CS) in clinically remitted patients with schizophrenia. In the BM task, subjects were asked to indicate the position of letters appearing at four possible spatial locations. In the CS test, a two-alternative forced choice method was used to measure the minimal contrast level required for the detection of horizontal gratings set at low spatial and high temporal frequencies (0.5 cycle/degree and 8 Hz, respectively). We found that the schizophrenia patients with normal CSs (spared transient channel functions) showed a marked deficit in the target location BM task. This suggests that the abnormality of subcortical transient channels does not explain some visual information processing dysfunctions in schizophrenia. Instead, deficient cortical interactions of rapidly changing environmental signals may be involved.

Habit learning and the genetics of the dopamine D3 receptor : Evidence from patients with schizophrenia and healthy controls

In this study, the authors investigated the relationship between the Ser9Gly (SG) polymorphism of the dopamine D3 receptor (DRD3) and striatal habit learning in healthy controls and patients with schizophrenia. Participants were given the weather prediction task, during which probabilistic cue-response associations were learned for tarot cards and weather outcomes (rain or sunshine). In both healthy controls and patients with schizophrenia, participants with Ser9Ser (SS) genotype did not learn during the early phase of the task (1-50 trials), whereas participants with SG genotype did so. During the late phase of the task (51-100 trials), both participants with SS and SG genotype exhibited significant learning. Learning rate was normal in patients with schizophrenia. These results suggest that the DRD3 variant containing glycine is associated with more efficient striatal habit learning in healthy controls and patients with schizophrenia.

Correlations between clinical symptoms, working memory functions and structural brain abnormalities in men with schizophrenia.

Thirteen male patients with schizophrenia and thirteen male normal control subjects were compared by magnetic resonance imaging (MRI) on volumes of the straight gyrus (SG), anterior cingulate gyrus, middle frontal gyrus, hippocampus, third ventricle, cavum septi pellucidi, total brain volume and intracranial volume. In addition, neuropsychological tasks were used to measure working memory and executive functions. Healthy volunteers and schizophrenic patients showed no significant differences in mean values for volumes of regions of interests. In the case of the SG, we found a significant difference in laterality: the tendency toward left dominance in healthy volunteers changed to significant right dominance in patients. The schizophrenic patients showed lower performance in working memory tasks, and strongly significant group differences were observed in measures of neurological signs assessed by the Neurological Evaluation Scale (NES). Negative symptoms correlated with the level of spatial working memory and executive functions. Negative symptoms also correlated with the volume of the right hippocampus, while the rate of anhedonia negatively correlated with the relative volume of the left SG.

Abnormal neurological signs, visual contrast sensitivity, and the deficit syndrome of schizophrenia.

This study was designed to investigate the relationship between abnormal neurological signs, visual contrast sensitivity, and the deficit syndrome of schizophrenia. Visual contrast sensitivity for counterphase-modulated low spatial frequency gratings was measured in 32 non-deficit and 12 deficit schizophrenia patients and 20 healthy controls subjects. Abnormal neurological signs were evaluated with the Neurological Evaluation Scale (NES). Compared with the controls, patients with schizophrenia displayed impaired visual contrast sensitivity, which was associated with sensory integration deficits, as measured with the NES. The deficit syndrome was predicted by negative symptoms and sensory integration deficits. These results suggest that early-stage perceptual dysfunctions, which may reflect the abnormality of precortical magnocellular visual pathways, are related to a specific group of abnormal neurological signs.

Two subgroups of schizophrenia identified by systematic cognitive neuropsychiatric mapping

The description of the heterogeneous phenomenological, pathophysiological, and etiological nature of schizophrenia is under way; however, the relationships between heterogeneity levels are still unclear. We performed a robust cross-sectional study, including a systematic neuropsychological battery, assessment of clinical symptoms, neurological soft signs, morphogenetic anomalies and smell identification, and measurement of event-related potentials on 50 outpatients with schizophrenia in their compensated states. An explorative fuzzy cluster analysis revealed two subgroups in this sample that could be distinguished from each other on symptomatological, cognitive and neurological levels. The patterns of cognitive dysfunctions and neurological developmental anomalies equally indicate that there may be hemispherical differences between the patients belonging to the different clusters.

Effects of a Hypnotically Altered State of Consciousness on Intensification of Semantic Processing

In a study of the linguistic processes involved in hypnosis, 22 volunteer medical students performed semantic and phonologic fluency tasks and then associative priming tests with 2 delay-lengths in waking alert and hypnotic conditions as well. The participants performed better during semantic than phonological fluency tests in alert and also in hypnotic states, and this difference was significantly greater in hypnosis. The increased semantic performance in hypnosis was accompanied by a decrease of the rule-offending errors. Significant semantic priming effects were detected in both states of consciousness in direct and indirect relations as well as in the automatic, intralexical level, and also when the extralexical control processes were activated. Overall, the results appear to show that the hypnotically altered state of consciousness produces significantly better performance in semantic information processing than can be elicited in alert waking conditions.