Analysis of genetic diversity in patients with major psychiatric disorders versus healthy controls: A molecular-genetic study of 1698 subjects genotyped for 100 candidate genes (549 SNPs).

BACKGROUND: This study analyzed the extent to which irregularities in genetic diversity separate psychiatric patients from healthy controls. METHODS: Genetic diversity was quantified through multidimensional "gene vectors" assembled from 4 to 8 polymorphic SNPs located within each of 100 candidate genes. The number of different genotypic patterns observed per gene was called the gene's "diversity index". RESULTS: The diversity indices were found to be only weakly correlated with their constituent number of SNPs (20.5 % explained variance), thus suggesting that genetic diversity is an intrinsic gene property that has evolved over the course of evolution. Significant deviations from "normal" diversity values were found for (1) major depression; (2) Alzheimer's disease; and (3) schizoaffective disorders. Almost one third of the genes were correlated with each other, with correlations ranging from 0.0303 to 0.7245. The central finding of this study was the discovery of "singular genes" characterized by distinctive genotypic patterns that appeared exclusively in patients but not in healthy controls. Neural Nets yielded nonlinear classifiers that correctly identified up to 90 % of patients. Overlaps between diagnostic subgroups on the genotype level suggested that (1) diagnoses-crossing vulnerabilities are likely involved in the pathogenesis of major psychiatric disorders; (2) clinically defined diagnoses may not constitute etiological entities. CONCLUSION: Detailed analyses of the variation of genotypic patterns in genes along with the correlation between genes lead to nonlinear classifiers that enable very robust separation between psychiatric patients and healthy controls on the genotype level.

[Cognition and driving ability in chronic pain syndrome]. / Kognition und Kraftfahreignung bei chronischem Schmerzsyndrom.

Cognitive impairments in patients with chronic pain are increasingly attracting interest in scientific research. The consequences of these cognitive impairments on coping with pain, everyday life and the driving ability are rarely included in clinical practice although half of all patients are affected. This article summarizes the current research situation and discusses possibilities of the integration in clinical and therapeutic care.

Reciprocal causation models of cognitive vs volumetric cerebral intermediate phenotypes for schizophrenia in a pan-European twin cohort.

In aetiologically complex illnesses such as schizophrenia, there is no direct link between genotype and phenotype. Intermediate phenotypes could help clarify the underlying biology and assist in the hunt for genetic vulnerability variants. We have previously shown that cognition shares substantial genetic variance with schizophrenia; however, it is unknown if this reflects pleiotropic effects, direct causality or some shared third factor that links both, for example, brain volume (BV) changes. We quantified the degree of net genetic overlap and tested the direction of causation between schizophrenia liability, brain structure and cognition in a pan-European schizophrenia twin cohort consisting of 1243 members from 626 pairs. Cognitive deficits lie upstream of the liability for schizophrenia with about a quarter of the variance in liability to schizophrenia explained by variation in cognitive function. BV changes lay downstream of schizophrenia liability, with 4% of BV variation explained directly by variation in liability. However, our power to determine the nature of the relationship between BV deviation and schizophrenia liability was more limited. Thus, while there was strong evidence that cognitive impairment is causal to schizophrenia liability, we are not in a position to make a similar statement about the relationship between liability and BV. This is the first study to demonstrate that schizophrenia liability is expressed partially through cognitive deficits. One prediction of the finding that BV changes lie downstream of the disease liability is that the risk loci that influence schizophrenia liability will thereafter influence BV and to a lesser extent. By way of contrast, cognitive function lies upstream of schizophrenia, thus the relevant loci will actually have a larger effect size on cognitive function than on schizophrenia. These are testable predictions.

[Cognitive remediation in clinical routine: a study on psychiatric patients' acceptance]. / Kognitive Remediation im klinischen Alltag: Eine Studie zur Akzeptanz bei psychiatrischen Patienten.

BACKGROUND: Cognitive remediation represents an effective treatment for improving functional outcome of psychiatric diseases like schizophrenia or depression. However, in clinical routine the therapeutic approach has not been established continuously. This can be partly attributed to doubts about the reasonableness of cognitive remediation for psychiatric patients. Therefore the current study investigates psychiatric patients' acceptance of, motivation for, and exhaustion due to cognitive remediation compared to an established treatment programme. METHODS: 21 psychiatric patients who simultaneously participated in occupational therapy and cognitive remediation rated the motivation, exhaustion, enjoyment, and effort on a visual analogue scale (VAS) over five weeks with regard to the respective therapy. RESULTS: The ratings of occupational therapy and cognitive remediation did not differ relating to motivation, exhaustion, and enjoyment. The subjective effort in cognitive remediation was higher than that in occupational therapy. DISCUSSION: Cognitive remediation is evaluated as being equivalent to an already established treatment programme by psychiatric patients concerning motivation, enjoyment, and exhaustion. Doubts about the acceptance and reasonableness of cognitive remediation could not be confirmed. In clinical routine cognitive remediation as an effective and accepted therapeutic approach should be integrated as a standard procedure for various disorders.

Do deficits in the magnocellular priming underlie visual derealization phenomena? Preliminary neurophysiological and self-report results in first-episode schizophrenia patients.

BACKGROUND: Early visual impairments probably partially caused by impaired interactions between magnocellular (M) and parvocellular (P) pathways (M priming deficit), and disturbances of basic self-awareness or self-disorders (SDs) are core features of schizophrenia. The relationships between these features have not yet been studied. We hypothesized that the M priming was impaired in first-episode patients and that this deficit was associated with visual aspects of SDs. AIM: To investigate early visual processing in a sample of first-episode schizophrenia patients and to explore the relationships between M and P functioning and visual aspects of SDs addressed by the Examination of Anomalous Self-Experience (EASE) interview. METHOD: Nine stimulating conditions were used to investigate M and P pathways and their interaction in a pattern reversal visually evoked potential (VEP) paradigm. N80 at mixed M- and P-conditions was used to investigate magnocellular priming. Generators were analyzed using source localization (Brain Electrical Source Analysis software: BESA). VEPs of nineteen first-episode schizophrenia patients were compared to those of twenty matched healthy controls by a bootstrap resample procedure. Visual aspects of SDs were analyzed through a factor analysis to separate symptom clusters of derealization phenomena. Thereafter, the associations between the main factors and the N80 component were explored using linear mixed models. RESULTS: Factor analyses separated two EASE factors ("distance to the world", and "intrusive world"). The N80 component was represented by a single dipole located in the occipital visual cortex. The bootstrap analysis yielded significant amplitude reductions and prolonged latencies in first-episode patients relative to controls in response to mixed M-P conditions, and normal amplitudes and latencies in response to isolated P- and M-biased stimulation. Exploratory analyses showed significant negative correlations between the N80 amplitude values at mixed M-P conditions and the EASE factor "distance to the world", i.e. relatively higher amplitudes in the patient group were associated with higher subjective perceived derealization ("distance to the world"). CONCLUSIONS: The early VEP component N80 evoked by mixed M-P conditions is assumed to be a correlate of M priming, and showed reduced amplitudes and longer latencies in first-episode patients. It probably reflects a hypoactivation of the M-pathway. The negative association between visual SDs (derealization phenomena characterized by visual experiences of being more distant to the world), and the M priming deficit was counterintuitive. It might indicate a dysregulated activity of the M-pathway in patients with SDs. Further research is needed to better understand this preliminary finding.

[Rehabilitation in persons with schizophrenic spectrum disorders: the impact of cognition and cognitive remediation therapy]. / Rehabilitation von Menschen mit schizophrenen Psychosen: Die Bedeutung von Kognition und Training kognitiver Funktionen.

Schizophrenia is a chronic disorder, which severely limits the social and occupational functioning. Employment, education, relationships, housing and health are among the most frequently stated life and treatment goals among persons suffering from schizophrenia. Rehabilitation for persons with schizophrenia aims at preservation and improvement of psychosocial functions in areas such as work, social relationship and independent living skills, promotes recovery-oriented interventions and, therefore, serves the central goals of affected persons. Cognitive functioning, education, negative symptoms, social support and skills, age, work history, and rehabilitation service to restore community functioning have proven to be strong predictors for successful psychiatric rehabilitation. It makes sense to concentrate on these predictors when improvement of psychiatric rehabilitation is targeted. Cognitive remediation produces moderate improvements in cognitive performance and, when combined with functional training and embedded in comprehensive psychiatric rehabilitation, also enhances functional outcome. Germany provides a highly differentiated system of psychosocial support for schizophrenic patients. However, the "German disease" with different care providers being in charge in subsequent stages of recovery hampers efficient organisation of psychiatric rehabilitation. Improvement of overall organisation, i.e., configuration of interfaces, understanding of the complex interactions of measures, design of disease specific programmes, research and economic evaluation constitute major challenges in the field of psychiatric rehabilitation.

Assessment of cardiovascular disease risk in patients with schizophrenia spectrum disorders in German psychiatric hospitals: results of the pharmacoepidemiologic CATS study.

PURPOSE: Patients with severe mental illness are at high risk for metabolic and cardiac disorders. Thus, monitoring of cardiovascular risks is imperative and schedules for screening for lipids, glucose, body mass index (BMI), waist-hip ratio and blood pressure have been developed. We intended to analyze screening for metabolic disorders in German patients with schizophrenia spectrum disorders in routine psychiatric care. METHODS: We included 674 patients with any F2 diagnosis in out- and inpatient settings and analyzed metabolic screening procedures as practiced under conditions of usual care. RESULTS: Except BMI (54 %), all other values were documented only in a minority of patients: waist circumference (23 %), cholesterol (28 %), fasting glucose (19 %), triglycerides (25 %) and blood pressure (37 %). We found evidence for less than perfect quality of blood pressure measures. The group of patients who met the individual metabolic syndrome ATP III criteria was comparable to the US CATIE trial. CONCLUSIONS: We conclude that frequency and quality of metabolic monitoring in German in- and outpatients settings are not in accordance with the respective recommendations. Similar to previous reports we found evidence for a high prevalence of metabolic disturbances in German patients with schizophrenia spectrum disorders.

Evidence for a magnocellular disadvantage in early-onset schizophrenic patients: a source analysis of the N80 visual-evoked component.

BACKGROUND: Visual impairments in schizophrenia have been suggested to be partly caused by early processing deficits of the magnocellular (M) pathway. This might include disturbed interactions between the M and parvocellular (P) pathways and especially impaired M priming, which can disturb highlighting of relevant information. Such disorders may result from neurodevelopmental irregularities, which are assumed to be substantially involved in schizophrenia. This study sought to test the hypothesis that M priming is impaired in schizophrenia. In order to elucidate this neurodevelopmental aspect, we investigated patients with different ages of schizophrenia onset. This provided a useful design to integrate visual information processing in a neurodevelopmental model of schizophrenia. METHOD: Nine stimulus conditions were used to investigate the M- and P-pathways and their interaction in a pattern reversal VEP paradigm. N80 generators were analyzed using source localization (Brain Electrical Source Analysis software: BESA). Forty schizophrenia patients (early-onset=19; adult-onset=21) were compared with age- and gender-matched healthy controls (early-onset controls=19; adult-onset controls=21). Hypotheses were tested using a bootstrap resampling procedure. RESULTS: The N80 component was represented by a single dipole located in the occipital visual cortex. The bootstrap analysis yielded significant differences between early-onset schizophrenia patients and controls. We found lower amplitudes in response to mixed M-P conditions and normal amplitudes in response to isolated P- and M-biased stimulation. Concerning the latencies, significant differences were found between adult-onset subjects and their controls, with prolonged latencies for schizophrenia patients. CONCLUSIONS: The early VEP component N80 evoked by mixed M-P conditions is assumed to be a correlate of M priming and showed reduced amplitude in early-onset schizophrenic patients but not in adult-onset patients. These findings point towards an M priming deficit in early-onset patients and are compatible with a neurodevelopmental hypothesis of schizophrenia, probably reflecting asynchronies in brain maturational abnormalities occurring at different ages of illness onset.

Deficits in fronto-posterior interactions point to inefficient resource allocation in schizophrenia.

OBJECTIVE: Fronto-posterior networks have been implicated in various cognitive processes that are impaired in schizophrenia. This is the first study on time and frequency resolved fronto-posterior coherence during cognitive control in schizophrenia. METHOD: We examined 16 schizophrenic/schizoaffective patients and 20 age-matched controls performing a choice-reaction task. Fronto-posterior coherence was analyzed for event-related increases with respect to the inter-trial interval. Furthermore, we compared the two groups for event-related coherence during the task-related time intervals which showed a significant coherence increase with respect to the inter-trial interval, as well as for absolute coherence during the inter-trial interval. RESULTS: Event-related coherence was significantly reduced in patients during time intervals (0-250 ms poststimulus) when controls showed significant event-related coherence increases. However, patients showed significantly higher absolute coherence during the inter-trial interval. These results pointed to differential deficits in fronto-posterior connectivity during the inter-trial interval and task-related conditions in schizophrenia. CONCLUSION: Cognitive deficits in schizophrenia might be driven by abnormal fronto-posterior communication. Task-related hypo-connectivity and inter-trial interval hyper-connectivity point to resource allocation deficits. The timing of cortico-cortical interactions during crucial task-related intervals may be impaired, while frontal and posterior areas may exhibit increased interactions between the trials.

Memory performance in acute and weight-restored anorexia nervosa patients.

BACKGROUND: Anorexia nervosa (AN), at the stage of starvation and emaciation, is characterized by abnormalities in cognitive function, including memory performance. It is unclear whether memory impairment persists or is reversible following weight restoration, and whether memory function differs between AN subtypes. The aim of the present study was to investigate general memory performance in currently ill and fully weight-restored patients of different AN subtypes. METHOD: Memory performance was assessed using the Wechsler Memory Scale-Revised (WMS-R) in a total of 99 participants, including 34 restricting-type AN patients (AN-RESTR), 19 binge-eating/purging-type AN patients (AN-PURGE), 16 weight-restored AN patients (AN-W-R) and 30 healthy controls (CONTROL). Cognitive evaluation included a battery of standardized neuropsychological tasks for validating the findings on memory function. RESULTS: Deficits were found with respect to immediate and delayed story recall in currently ill AN patients irrespective of AN subtype. These deficits persisted in weight-restored AN patients. Currently ill and weight-restored AN patients did not differ significantly from healthy controls with respect to working memory or other measures of neuropsychological functioning. CONCLUSIONS: The findings suggest that impaired memory performance is either a stable trait characteristic or a scar effect of chronic starvation that may play a role in the development and/or persistence of the disorder.

[Treatment of cognitive deficits in schizophrenia. Part 1: Diagnostic and psychological training]. / Behandlung kognitiver Defizite bei Schizophrenie. Teil I: Diagnostik und psychologische Verfahren.

Cognitive dysfunction is a core feature of schizophrenia. Although cognitive deficits in the domains of attention, memory and executive functions have been described for many decades, the focus on therapeutic approaches is new. The recognition that cognitive deficits are the best known predictor of functional outcome in schizophrenic patients explains the increasing interest in the diagnosis and therapy of these impairments. Standards for the reliable evaluation of neurocognitive deficits in schizophrenia have been put forward by the MATRICS initiative (Measurement and Treatment Research to Improve Cognition in Schizophrenia). In German-speaking countries the most popular cognitive training programs for schizophrenic patients are "CogPack" and "Integrated Psychological Therapy (IPT)". Especially in Anglo-Saxon countries cognitive training has become more popular in recent years. Study outcomes can be considered encouraging. They show improvement of cognitive deficits and a positive impact on the functional outcome. Further studies are needed to optimize cognitive training for schizophrenic patients.

[Treatment of cognitive deficits in schizophrenia. Part 2: Pharmacological strategies]. / Behandlung kognitiver Defizite bei Schizophrenie. Teil II: Pharmakologische Strategien.

Cognitive deficits in schizophrenia are a clinically relevant symptom dimension and one of the best predictors for functional outcome. Pharmacological treatment of cognitive deficits in schizophrenia is still a challenge. The objective of this article is to present a detailed review of the literature on strategies for the pharmacological treatment of cognitive deficits. It is not clear whether first-generation antipsychotics have a genuine positive influence on cognition. There is only sparse evidence for the positive effect of second-generation antipsychotics on cognitive processes. Furthermore it is not evident that second-generation antipsychotics are more beneficial than first-generation antipsychotics in the treatment of cognitive deficits. The add-on use of substances which directly influence cognitive processes, so-called cognition-enhancing drugs is more promising.

Anorexia nervosa: selective processing of food-related word and pictorial stimuli in recognition and free recall tests.

OBJECTIVE: Maladaptive processing of food cues is considered pivotal in the psychopathology of anorexia nervosa. However, the influence of hunger and differences in processing because of the type of stimuli remain largely unclear. METHOD: Memory bias for food-related pictorial and semantic stimuli was assessed in a recognition and a free recall test in 16 anorexia nervosa (AN) patients, 16 control participants with food intake prior to the study (CG-FI) and 16 control participants with a fasting period prior to the study (CG-NF). RESULTS: Compared with CG-FI participants, both AN and CG-NF participants responded faster to food-related as compared with neutral words (p < .001) in the recognition test. Differences were found for word but not for pictorial stimuli. No group differences were observed with respect to the number of correct retrievals in either the recognition or the free recall test. CONCLUSION: The present study found behavioral indications of abnormal processing of food-related and neutral stimuli in anorectic patients similar to those found in fasted healthy controls. Results are discussed in terms of self-schemata in eating disorders, competitive interference, and levels of processing.

Longitudinal assessment of response preparation and evaluation in migraine gives evidence for deviant maturation.

Evidence for deviant maturation of sensory processing in migraine has come recently from cross-sectional studies during childhood. Age-dependent development of response preparation and evaluation is characterized using a longitudinal design in school-aged migraine patients and controls in order to challenge the hypothesis of migraine as a maturation disorder. Forty-six children with migraine and 57 healthy controls aged 6-18 years were investigated and followed up 4 years later using a simple acoustic contingent negative variation (CNV) paradigm. Maturation in controls was characterized by increasing negativity of late and total CNV and stability of initial CNV (iCNV) and the motor postimperative negative variation (mPINV). Migraine patients showed a lack of development for late and total CNV and decreasing iCNV and mPINV negativity. This first longitudinal study confirms cross-sectional results of deviant CNV maturation in migraine. Altered maturation was not correlated with clinical improvement and may represent a vulnerability marker for migraine.

The topography of the scalp-recorded visual N700.

OBJECTIVE: To describe the topography of the N700 component of the scalp-recorded visual event-related potential (ERP) and to provide fundamental knowledge of the conditions under which it occurs. METHODS: We examined the time-course of visual ERP in response to the short (100ms) and prolonged (7s) presentation of simple salient visual stimuli separated by long interstimulus intervals employing high-resolution 64-channel DC-EEG. Current source density (CSD) mapping and spatio-temporal dipole source analysis were performed. RESULTS: CSD analysis revealed highly significant bilateral current sinks over occipito-temporal areas from about 450ms up to 1s after stimulus offset (visual N700). CSD topography and dipole source analysis suggested late prolonged activation of extrastriate visual areas which did not depend merely upon a stimulus offset response, afterimages or blinking, as confirmed by control conditions. CONCLUSIONS: Our findings provide basic knowledge about the time-course of sensory activation. We found that passive watching of rare salient short stimuli automatically evoked sustained activity in the extrastriate visual cortex up to 1s after stimulus offset. SIGNIFICANCE: Visual N700 provides a promising tool for important insights into the cortical mechanisms of stimulus post-processing. Its role in associative learning of temporally non-overlapping stimuli (automatic ultra-short-term sensory memory) should be explored.

Prolonged activation EEG differentiates dementia with and without delirium in frail elderly patients.

OBJECTIVE: Delirium in the elderly results in increased morbidity, mortality and functional decline. Delirium is underdiagnosed, particularly in dementia. To increase diagnostic accuracy, we investigated whether maintenance of activation assessed by EEG discriminates delirium in association with dementia (D+D) from dementia without delirium (DP) and cognitively unimpaired elderly subjects (CU). METHOD: Routine and quantitative EEG (rEEG/qEEG) with additional prolonged activation (3 min eyes open period) were evaluated in hospitalised elderly patients with acute geriatric disease. Patients were assigned post hoc to three comparable groups (D+D/DP/CU) by expert consensus based on DSM-IV criteria. Dementia diagnosis was confirmed using cognitive and functional tests and caregiver rating (IQCODE, Informed Questionnaire of Cognitive Decline in the Elderly). RESULTS: While rEEG at rest showed low accuracy for a diagnosis of delirium, qEEG in DP and CU revealed a specific activation pattern of high significance found to be absent in the D+D group. Stepwise logistic regression confirmed that differentiation of D+D from DP was best resolved using activated upper alpha and delta power density which, compared with rEEG, enabled an 11% increase in diagnostic correctness to 83%, resulting in 67% sensitivity and 91% specificity. Among frail CU and D+D subjects, almost 90% were correctly classified. CONCLUSION: Dementia associated with delirium can be discriminated reliably from dementia alone in a meaningful clinical setting. Thus EEG evaluation in chronic encephalopathy should be optimised by a simple activation task and spectral analysis, particularly in the elderly with dementia.

EEG changes and serum anticholinergic activity measured in patients with delirium in the intensive care unit.

The aim of this study was to examine whether serum anticholinergic activity (SAA) is a reliable indicator of delirium in the ICU, and whether there is a significant correlation between SAA and quantitative electroencephalographic (EEG) data in delirious patients. In a prospective cohort study, we assessed ICU patients diagnosed with delirium (n = 37). EEG measurements and blood analysis including SAA were performed 48 h following ICU admission. The presence of delirium was evaluated using the Confusion Assessment Method for critically ill patients in ICU (CAM-ICU). The SAA level was measured using a competitive radioreceptor binding assay for muscarinergic receptors and quantitative EEG was measured using the CATEEM system. We found that, under comparable conditions, patients in the delirium group showed a higher relative EEG theta power and a reduced alpha power (n = 17) than did the non-delirious patients (n = 20). No difference in measured SAA levels were seen; therefore, there was no correlation between SAA and EEG measurements in delirious patients. We conclude that, in contrast to the EEG, the SAA level cannot be proposed as a tool for diagnosing delirium in ICU patients.

Which perspectives can endophenotypes and biological markers offer in the early recognition of schizophrenia?

The early recognition of schizophrenia seems crucial; various studies relate a longer duration-of-untreated-psychosis to a worse prognosis. We give an overview over common psychopathological early recognition instruments (BSABS, CAARMS, SIPS, IRAOS, ERIraos). However, many clinical symptoms of prodromal schizophrenia stages are not sufficiently specific. Thus we review recent contributions of neuroimaging and electrophysiological as well as genetic studies: which new diagnostic perspectives offer endophenotypes (such as P300, P50 sensory gating, MMN, smooth pursuit eye movements; indicating a specific genetic vulnerability) together with a better understanding of schizophrenic pathophysiology (state-dependent biological markers, e.g. aggravated motor neurological soft signs during psychosis) in prodromal schizophrenia when still ambiguous clinical symptoms are present. Several examples (e.g. from COMT polymorphisms to working memory deficits) illustrate more specific underlying neuronal mechanisms behind behavioural symptoms. This way, a characteristic pattern of disturbed cerebral maturation might be distinguished in order to complement clinical instruments of early schizophrenia detection.

Pergolide as adjuvant therapy to amisulpride in the treatment of negative and depressive symptoms in schizophrenia.

Negative and cognitive symptoms of schizophrenia are associated with a hypodopaminergic state in the frontal cortex and do not respond to neuroleptics equally well as positive symptoms. Therefore pharmacological strategies, which increase dopamine metabolism in the mesocortical pathways, may prove beneficial to ameliorate these symptoms. We report on a case of a patient with paranoid schizophrenia, who still presented negative and depressive symptoms during treatment with amisulpride for more than 6 weeks. We prescribed pergolide (a mixed D1/D2 agonist) as adjuvant therapy to treat these symptoms. The patient showed an improvement of global psychopathology, decrease of negative and depressive symptoms, while no changes in positive symptoms nor EPS were present. For this patient, the adjuvant therapy of pergolide to amisulpride constituted a valid pharmacological approach to treat negative and depressive symptoms of schizophrenia, without increasing positive symptoms.