Karel Frasch

Altered reward functions in patients on atypical antipsychotic medication in line with the revised dopamine hypothesis of schizophrenia

ObjectiveTo study the mesolimbic dopamine system during expectation and receipt or omission of rewards in partially remitted patients with schizophrenia treated with the atypical antipsychotic olanzapine.MethodsWe studied 16 patients with a current episode of schizophrenia, all treated with the atypical drug olanzapine, and 16 healthy subjects using functional magnetic resonance imaging. Subjects performed a delayed incentive paradigm with monetary rewards.ResultsDuring reward expectation, both, patients with schizophrenia and healthy control subjects, showed activation of the ventral striatum and midbrain in the vicinity of the ventral tegmental area. Significant categorical group differences emerged in the anterior cingulate cortex with only healthy controls showing increasing activation with increasing reward. In the patients, activation of this region was inversely correlated with positive symptoms. During outcome, both, patients with schizophrenia and healthy controls, showed activation of the ventral striatum and the mesial prefrontal cortex. Significant categorical group differences emerged in the right ventrolateral prefrontal cortex for the salience contrast with healthy controls showing a U-shaped activation curve, i.e., higher activation for either omission or receipt of reward compared to no reward.ConclusionsOur findings partially support the current concept of dopaminergic dysfunction in schizophrenia, suggesting a rather hyperactive mesolimbic dopamine system and reduced prefrontal activation, at least in partially remitted patients treated with atypical antipsychotics.

Volumetric abnormalities associated with cognitive deficits in patients with schizophrenia

While functional neuroimaging studies on attention and executive function in schizophrenia have reported several functionally aberrant cortical regions, less is known about the relationship of cognitive impairment and regional volume alterations. In order to investigate the relationship between cognitive impairment and structural alterations, we studied healthy control subjects and partially remitted, medicated inpatients with DSM-IV schizophrenia using voxel-based morphometry (VBM) and a standardised neuropsychological test battery. Schizophrenic patients showed reduced grey matter (GM) density in the bilateral temporal cortex, the left inferior parietal lobule, the cingulate gyrus and the left middle frontal gyrus. Reduced GM volume was additionally found in the left hippocampal gyrus and the right superior frontal cortex. Reduced white matter density was found in the posterior corpus callosum. Structure-cognition regression analyses revealed that decreased GM density of the left inferior parietal and the right middle temporal cortex was associated with worse performance during divided attention. Worse performance during the spatial span was associated with volumetric abnormalities of the hippocampal gyrus. These results indicate that regional abnormalities in brain structure may offer an account for some impaired cognitive domains in patients with schizophrenia, while other cognitive domains may remain relatively less affected by volumetric alterations.

Health behavior in psychiatric in-patients compared with a German general population sample.

Objective:  To compare the health relevant behavior of psychiatric patients and the general population.

Effects of polypharmacy on outcome in patients with schizophrenia in routine psychiatric treatment.

Längle G, Steinert T, Weiser P, Schepp W, Jaeger S, Pfiffner C, Frasch K, Eschweiler GW, Messer T, Croissant D, Becker T, Kilian R. Effects of polypharmacy on outcome in patients with schizophrenia in routine psychiatric treatment.

Further Evidence for Aberrant Prefrontal Salience Coding in Schizophrenia

The revised dopamine hypothesis of schizophrenia postulates that dopamine metabolism is impacted differently with increased dopamine in the subcortical mesolimbic system and decreased dopamine in prefrontal cortical regions. Recently, we described findings supporting this hypothesis using a financial reward task in patients with schizophrenia (Walter et al., 2009). In addition to analysing prediction and prediction error coding, we found in this study evidence for aberrant cortical representation of salience in the right ventrolateral prefrontal cortex (VLPFC) in patients. Here, we reanalysed data of four other published reward studies of our group in order to investigate (i) whether we could replicate this finding in an independent cohort of patients with schizophrenia and (ii) how dopaminergic modulation impacts on cortical salience representation. Our main result was that we could replicate the finding of aberrant salience coding in the right VLPFC in patients with schizophrenia. Furthermore, we found evidence that the degree of salience coding in this region was correlated inversely with negative symptoms (anhedonia). Results of dopaminergic modulation showed tentative evidence for an influence of dopaminergic stimulation, but were not conclusive. In summary, we conclude that the right VLPFC might play a crucial role in salience coding and is impaired in schizophrenia.

Treatment of schizoaffective disorder - a challenge for evidence-based psychiatry

Objective:  Schizoaffective disorder is a common diagnosis in mental health services. The aim of the present article was to review treatment studies for schizoaffective disorder and draw conclusions for clinical decision making.

Physical illness in psychiatric inpatients: Comparison of patients with and without substance use disorders

Background: Physical comorbidities and substance use are commonly reported in patients with mental disorders. Aim: To examine somatic comorbidity in patients with substance use disorders (SUD) compared to patients with mental disorders but no SUD. Methods: Lifetime prevalence data on mental and physical health status were collected from inpatients in 12 mental health care facilities in five different countries. Differences in somatic comorbidity were examined by means of logistic regression analysis controlling for age and gender. Results: Of 2,338 patients, 447 (19%) had a primary or secondary SUD diagnosis. In comparison to patients with other mental disorders, patients with SUD had a higher prevalence of infectious and digestive diseases but a lower prevalence of endocrine, nutritional and metabolic disorders. Patterns of physical comorbidities differed according to type of substance used (alcohol use – cardiovascular; tobacco use – respiratory, neoplasms; cannabinoid use – injuries; opioid use – infectious, digestive; benzodiazepine use – endocrine, nutritional, metabolic; stimulants – urogenital). Conclusions: SUD are related to specific somatic health risks while some of our findings point to potentially protective effects. The widespread prescription of benzodiazepines requires research on physical health effects. Early detection of SUD and their integration into programmes targeting physical comorbidity should be a priority in organizing mental health care.

Effects of Symptom Reduction and Psychotropic Medication on Cognitive Impairment in Depression

Background: Depression is related to cognitive performance. This follow-up study examines the influence of depression symptoms and psychopharmacological treatment on change in the cognitive performance of patients with depressive episodes over a 2-year period. Sampling and Methods: Sixty-two in- and outpatients with depression of varying severity (ICD-10: F31–F33) were examined in an open prospective naturalistic observational study with 3 points of measurement and tested by use of 3 computerized cognitive performance tests [Visual Attentiveness Test (VAT), Continuous Attention Test (CAT), Word Recognition Test (WRT)], while the psychotropic medication was classified by subclass and dosage. Statistical analysis was performed by random-effects regression models. Results: The raw values of VAT speed, CAT speed and WRT quality improved over time. However, the positive time trend disappeared after the patients’ clinical and personal characteristics were controlled for. The processing speed of the VAT was found to be negatively influenced by depressive symptoms. That of the CAT developed favorably with increasing level of education. The performance qualities of the VAT, WRT and CAT were positively related to the participants’ educational level. The patients who received antipsychotic treatment performed worse on WRT quality than those who were not treated with antipsychotics. Conclusions: The cognitive performance was relatively stable during the treatment process and not affected by clinical characteristics or type of medication. Cognitive deficits in patients with depression could be a trait rather than a state marker.

Cultural diversity in physical diseases among patients with mental illnesses

Objective: People with psychiatric diseases have a severely increased risk for physical morbidity and premature death from physical diseases. The aims of the study were to investigate the occurrence of cardiovascular diseases (CVD), diabetes (DM) and obesity in schizophrenia and depression in three different geographical areas – Asia (Japan), Africa (Nigeria) and Western Europe (Switzerland, Germany and Denmark) – and to search for possible transcultural differences in these correlations, which would also reflect the differences between low-income areas in Africa (Nigeria) and high-income areas in Europe and Japan. Method: Patients with International Classification of Diseases (ICD-10) F2 diseases (schizophrenia spectrum disorders) and F3 diseases (affective disorders) admitted to one Nigerian, one Japanese, two Swiss, two German and six Danish centres during 1 year were included. Physical diseases in accordance with ICD-10 were also registered. Psychiatric and physical comorbidity were calculated and standardized rate ratio incidences of background populations were our primary measures. Results: Incidence rate ratios were increased for both CVD, DM and overweight in both F2 and F3 in all cultures (Western Europe, Nigeria and Japan) within the same ranges (however, the Japanese results should be interpreted conservatively owing to the limited sample size). Overweight among the mentally ill were marked in Nigeria. A parallelism of the incidence of overweight, CVD and diabetes with the occurrence in background populations was seen and was most marked in overweight. Conclusions: Overweight, CVD and DM were increased in schizophrenia spectrum disorders and affective disorders in all three cultures investigated (Western Europe, Nigeria and Japan). Lifestyle diseases were also seen in Nigeria and Japan. The results from this study indicate that cultural background might be seen as an important factor in dealing with lifestyle diseases among people with a severe mental illness, as it is in the general population.

Magnetic resonance perfusion imaging of auditory verbal hallucinations in patients with schizophrenia

Auditory verbal hallucinations (AVH) are a core symptom of schizophrenia and related spectrum-disorders. So far, magnetic resonance imaging (MRI) has been employed to study the functional neuroanatomy of AVH using two distinct methods, either by capturing symptoms during the actively hallucinating state or by investigating neural responses during explicit cognitive processing (Allen et al. 2008; Hugdahl 2009). Both approaches, however, face certain limitations. For instance, the self-identification of AVH is accompanied by the cognitive and motor response associated with this event, together with increased self-awareness. This interaction might change the participants subjective experience and quality of the hallucinatory symptom. On the other hand, interactions between experimental stimuli and symptoms could drive activation patterns that may not represent the “pure” neural substrate of AVH. In this study, we investigated the neural correlates at rest of AVH in schizophrenia using an MRI-based technique of perfusion imaging using continuous arterial spin labelling [CASL] (Theberge 2008). The objectives of our study were threefold: first, we tested the hypothesis that patients with schizophrenia with treatment-refractory AVH would exhibit symptom-related perfusion changes within a speech-related network, as predicted by AVHmodels of dysfunctional speech generation and misattribution (Stephane et al. 2001; Allen et al. 2008). Second, we investigated the symptom-specificity of brain perfusion abnormalities in AVH patients by including a group of non-hallucinating schizophrenic patients. Third, we explored the relationship between regional cerebral blood flow (rCBF) and multiple dimensions of AVH, as assessed by symptom-specific psychometrics. We studied 20 medicated patients with schizophrenia (paranoid subtype according to DSM-IV); see Supplementary material for details on inclusion/exclusion criteria, medication and psychometric scores. Patients with AVH (n=10; 4 female; mean age=36.5 years) were classified as being medication resistant for AVH, as defined by persistent symptoms in the presence of at least two clinically ineffective drug trials (each>6 weeks of treatment) with different antipsychotics at adequate dosage. Further, patients with AVH were only included if they did not show pronounced formal thought disorder symptoms and if they had sufficient insight into their hallucinatory experience such as to provide self-reports about their symptoms. A second group of patients with schizophrenia consisted of 10 participants (2 female; mean age=32.1 years) who either never experienced AVH or who experienced AVH in the past, while being fully remitted from AVH at least 12 months before being included in the study. The healthy control group consisted of 14 participants (7 female; mean age=33.7 years) matched for age, education and handedness. The project was approved by the local research ethics committee. All experimental procedures were carried out with the understanding and written consent of the participants. Imaging was performed on a 3T Magnetom Allegra (Siemens, Germany) MRI system. Scanning was performed under resting-state conditions; see also the Supplementary material for a detailed description of the technical details. Preprocessing and analyses of an MRI perfusion block of approximately 5 min were performed using Statistical Parametric Mapping (SPM5) in combination with software implemented in MATLAB 7.3 for use as a toolbox under SPM5; see also the Supplementary material for a detailed description of the data analysis. For the individual (first level) analysis, mean rCBF images were computed for each participant. Group comparisons between controls and patients were conducted at the second level using an analysis of variance. A threshold of pb0.005 (uncorrected at the voxel level) and a cluster-size threshold of at least 50 contiguous voxel was chosen for all between-group comparisons. Furthermore, correlations (FDR adjusted pb0.0259) were calculated using psychometric data and rCBF values extracted from clusters showing significant between-group differences. Compared to controls, AVH patients had increased rCBF in the left inferior frontal gyrus (IFG), the left anterior cingulate cortex (ACC), the supplementary motor area (SMA), in a cluster including the left middle temporal gyrus (MTG) and superior temporal gyrus (STG), the left insula, the right MTG and the right supramarginal gyrus (SMG), extending to the right temporoparietal cortex (TPC); see Fig. 1 and Supplementary material Fig. 2, and Table 2. Compared to patients without AVH, the group of hallucinating patients exhibited significantly increased rCBF in the left STG and right SMG, extending to the right TPC (Fig. 1 and Table 2, Supplementary material). Compared to healthy participants, patients without AVH showed increased rCBF in the left MTG, left STG, left SMG and in the left insula. Patients with AVH demonstrated positive correlations between rCBF and overall AVH severity (asmeasured by the auditory hallucinations scale [AHS] of the Psychotic Symptoms Rating Scales [PsyRatS]) in the left STG, ACC and IFG (Fig. 2, Supplementary material). Different correlation patterns emerged when correlating rCBF values with scores from the PsyRatSAHS emotional, physical and cognitive subscales (see Supplementary material Fig. 3). The comparison of patients with persistent AVH against controls yielded results that support the notion of dysfunctional neural activity in brain regions associated with the generation, perception and monitoring of speech as a the central mechanism underlying AVH (McGuire et al. 1995; Stephane et al. 2006; Hugdahl 2009). Increased rCBF in non-hallucinating patients was detected in the left MTG, left STG, left SMG and left insula when compared to controls. This pattern may reflect a common neurophysiological abnormality in both groups irrespective of the presence or absence of AVH (Mechelli et al. 2007). When contrasting hallucinating against non-hallucinating patients, patients with AVH still demonstrated increased rCBF in the left STG and the right SMG/TPC, indicating two critical network nodes associated with AVH, in the presence of an otherwise comparable clinical diagnosis. This suggests that the left STG may lie at the core of a final common pathway which ultimately accounts for the perceptual nature of AVH, i.e. for the subjective experience of “hearing voices”, in Schizophrenia Research 134 (2012) 285–287