Associations of NEUROD2 polymorphisms and change of cognitive dysfunctions in schizophrenia and schizoaffective disorder after eight weeks of antipsychotic treatment.

INTRODUCTION: NEUROD2 is a neurospecific helix-loop-helix transcription factor which has an impact on the regulation of glutamatergic and GABAergic genes. We investigated an association of NEUROD2 with neurocognitive dysfunctions in schizophrenia and schizoaffective disorder patients before and during treatment with different second-generation antipsychotics. METHODS: Patients were genotyped for four different polymorphisms of the NEUROD2 gene ((rs9889354(A/G), rs1877032(C/T), rs12453682(C/T) and rs11078918(C/G)). Cognitive function was assessed at baseline and week 8. Results of individual neuropsychological tests were assigned to six cognitive domains (reaction time and quality; executive function; working, verbal and visual memory) and a general cognitive index. RESULTS: 167 patients were included in the study. The NEUROD2 exonic polymorphism rs11078918 showed significant associations with verbal memory and executive functions, whereas the NEUROD2 polymorphism rs12453682 was significantly associated with working and verbal memory, executive functions and with a cognitive index. Significant associations were found at baseline and after eight weeks. Moreover, significant associations between the change in neuropsychological test results during antipsychotic treatment and the NEUROD2 polymorphisms rs11078918 and rs12453682 were observed. CONCLUSIONS: Our findings suggest that the NEUROD2 gene could play a role in the pathophysiology of neurocognitive dysfunctions as well as in the change of cognitive symptoms under antipsychotic treatment in schizophrenia and schizoaffective disorder.

[Are too Many Temporarily Placed Non-culpable Offenders Committed to Forensic Psychiatric Hospitals in Germany? Thoughts on the Relationship of Forensic and General Psychiatry]. / Gibt es zu viele Unterbringungen nach § 126a StPO? Überlegungen zum Zusammenspiel von forensischer und allgemeiner Psychiatrie unter Beachtung rechtlicher Gesichtspunkte.

From the perspective of the forensic clinics, the judiciary is increasingly ordering temporary placements according to Sec. 126a of the Code of Criminal Procedure. Three hypotheses are proposed that could (partly) explain this increase: 1) Courts' tendency to hand down this decision even in cases involving minor offences. 2) Courts' tendency to hand down this decision despite positive prognoses. 3) Changes in the reporting practices of psychiatric clinics. Overly simple explanations for the increase in temporary placements, therefore, fall short. This makes it more urgent to strengthen the primary-prevention approach. It is imperative that the small percentage of people with mental illness and an increased propensity to violence be identified and treated to prevent violence in the general psychiatric care stage. For this forensic psychiatry and general psychiatric care must be interlinked more closely.

Neural correlates (ERP/fMRI) of voluntary selection in adult ADHD patients.

Deficits in executive functions, e.g. voluntary selection, are considered central to the attention-deficit/hyperactivity disorder (ADHD). The aim of this simultaneous EEG/fMRI study was to examine associated neural correlates in ADHD patients. Patients with ADHD and healthy subjects performed an adapted go/nogo task including a voluntary selection condition allowing participants to freely decide, whether to press the response button. Electrophysiologically, response inhibition and voluntary selection led to fronto-central responses. The fMRI data revealed increased medial/lateral frontal and parietal activity during the voluntary selection task. Frontal brain responses were reduced in ADHD patients compared to controls during free responses, whereas parietal brain functions seemed to be unaffected. These results may indicate that selection processes are related to dysfunctions, predominantly in frontal brain regions in ADHD patients.

Increased γ oscillations during voluntary selection processes in adult patients with attention deficit/hyperactivity disorder.

Executive dysfunctions (regarding behavioural inhibition, decision making, flexibility or voluntary selection) rank among the core symptoms of attention deficit/hyperactivity disorder. Several studies demonstrated functional variations in patients with ADHD especially during response inhibition and flexibility. However, information about functional correlates of other aspects of executive functions such as voluntary selection processes is limited. A group of thirty adult patients with attention deficit/hyperactivity disorder (ADHD) and 30 healthy controls, matched for age and education, participated in the present study. Electrophysiological responses (event-related potentials, gamma oscillations) and behavioural data were acquired during the voluntary selection between various response alternatives. ADHD patients demonstrated increased responses in the gamma frequency band especially in frontal and fronto-central brain areas during voluntary response selection processes compared to healthy subjects. In addition, the error rate was increased in patients. Given that gamma-band responses have been related to GABAergic and glutamatergic responses these results may indicate accordant dysfunction in patients with ADHD.

Homer-1 polymorphisms are associated with psychopathology and response to treatment in schizophrenic patients.

The HOMER 1 protein plays a crucial role in mediating glutamatergic neurotransmission. It has previously shown to be a candidate gene for etiology and pathophysiology of different psychiatric diseases such as schizophrenia. To identify genes involved in response to antipsychotics, subgroups of animals were treated with haloperidol (1 mg/kg, n = 11) or saline (n = 12) for one week. By analyzing microarray data, we replicated the observed increase of Homer 1 gene expression. Furthermore, we genotyped 267 schizophrenic patients, who were treated monotherapeutically with different antipsychotics within randomized-controlled trials. Psychopathology was measured weekly using the PANSS for a minimum of four and a maximum of twelve weeks. Correlations between PANSS subscale scores at baseline and PANSS improvement scores after four weeks of treatment and genotypes were calculated by using a linear model for all investigated SNP's. We found an association between two HOMER 1 polymorphisms (rs2290639 and rs4704560) and different PANSS subscales at baseline. Furthermore all seven investigated polymorphisms were found to be associated with therapy response in terms of a significant correlation with different PANSS improvement subscores after four weeks of antipsychotic treatment. Most significant associations have been shown between the rs2290639 HOMER 1 polymorphism and PANSS subscales both at baseline conditions and after four weeks of antipsychotic treatment. This is the first study which shows an association between HOMER 1 polymorphisms and psychopathology data at baseline and therapy response in a clinical sample of schizophrenic patients. Thus, these data might further help in detecting differential therapy response in individuals with schizophrenia.

Effects of risperidone and quetiapine on cognition in patients with schizophrenia and predominantly negative symptoms.

Evidence suggests that neurocognitive impairment is a key factor in the pathology of schizophrenia and is linked with the negative symptoms of the disease. In this study the effects of the atypical antipsychotics quetiapine and risperidone on cognitive function in patients with schizophrenia and with predominantly negative symptoms were compared. Patients were randomly assigned to double-blind treatment with quetiapine or risperidone for 12 weeks. Cognitive function was assessed at baseline, Week 6 and Week 12. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) at baseline, Week 6 and Week 12. Extrapyramidal side-effects were assessed each week using the Simpson-Angus Scale (SAS), adverse events were recorded as additional indicators of tolerability throughout the trial. In total, 44 patients were enrolled in the study. Data from the 34 patients who completed cognitive assessments at two or more time points out of three (baseline, Week 6 and Week 12) are analysed here. Quetiapine improved significantly global cognitive index z-scores at both Week 6 (p<0.001 vs. baseline) and Week 12 (p<0.01 vs. baseline), whereas risperidone improved significantly global cognitive index z-scores at Week 12 (p<0.05). Between-group comparisons at Week 6 showed significantly greater improvements in working memory and verbal memory with quetiapine than risperidone (p<0.05) and a significantly greater improvement in reaction quality/attention with quetiapine than risperidone at Week 12 (p<0.05). Quetiapine and risperidone produced significant improvements from baseline in PANSS total (p<0.001) and subscale scores at Week 12. Significant improvements in SANS total score were also seen in both the quetiapine (p<0.001) and risperidone (p<0.01) groups at Week 12 compared with baseline. SAS scores, measuring the incidence of extrapyramidal side-effects, were higher in patients receiving risperidone compared with those receiving quetiapine, and significant differences were seen at Weeks 3, 4, 5 and 7. Both quetiapine and risperidone improved cognition according to changes in cognitive index scores from baseline to Week 12. These results suggest that quetiapine and risperidone provide valuable treatment options for patients with schizophrenia with predominantly negative symptoms. Also, the improvements in cognition following treatment with quetiapine and risperidone may enhance long-term outcomes for these patients.