Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia.

The atypical antipsychotic clozapine is one of the most potent drugs of its class, yet its precise mechanisms of action remain insufficiently understood. Recent evidence points toward the involvement of endogenous retinoic acid (RA) signaling in the pathophysiology of schizophrenia. Here we investigated whether clozapine may modulate RA-signaling. Effects of clozapine on the catabolism of all-trans RA (at-RA), the biologically most active metabolite of Vitamin A, were assessed in murine and human brain tissue and peripheral blood-derived mononuclear cells (PBMC). In patients with schizophrenia with and without clozapine treatment and matched healthy controls, at-RA serum levels and blood mRNA expression of retinoid-related genes in PBMCs were quantified. Clozapine and its metabolites potently inhibited RA catabolism at clinically relevant concentrations. In PBMC-derived microsomes, we found a large interindividual variability of the sensitivity toward the effects of clozapine. Furthermore, at-RA and retinol serum levels were significantly lower in patients with schizophrenia compared with matched healthy controls. Patients treated with clozapine exhibited significantly higher at-RA serum levels compared with patients treated with other antipsychotics, while retinol levels did not differ between treatment groups. Similarly, in patients without clozapine treatment, mRNA expression of RA-inducible targets CYP26A and STRA6, as well as at-RA/retinol ratio, were significantly reduced. In contrast, clozapine-treated patients did not differ from healthy controls in this regard. Our findings provide the first evidence for altered peripheral retinoid homeostasis in schizophrenia and suggest modulation of RA catabolism as a novel mechanism of action of clozapine, which may be useful in future antipsychotic drug development.

Clozapine-induced agranulocytosis: Evidence for an immune-mediated mechanism from a patient-specific in-vitro approach.

Use of the atypical antipsychotic clozapine (CZP) is compromised by the risk of potentially fatal agranulocytosis/granulocytopenia (CIAG). To address this, we have established a simple, personalized cell culture-based strategy to identify CIAG-susceptible patients, hypothesizing that an immunogenic and possibly haptene-based mechanism underlies CIAG pathophysiology. To detect a putative haptene-induced response to CZP in vitro exposure, a traditional lymphocyte stimulation assay was adapted and applied to patient-specific peripheral blood-derived mononuclear cells (PBMC). 6 patients with a history of CIAG, 6 patients under CZP treatment (without CIAG) and 12 matched healthy controls were studied. In vitro CZP exposure, even at strikingly low levels, resulted in significantly increased proliferation rates only in CIAG patients' PBMC. Other parameters including cell viability and mitogen-induced proliferation were also affected by in vitro CZP exposure, yet there was no significant difference between the groups. This personalized approach is a starting point for further investigations into a putative haptene-based mechanism underlying CIAG development, and may facilitate the future development of predictive testing.

Hypothalamic-Pituitary-Adrenocortical Dysfunction in Elderly, Male Marathon Runners: Feedback Sensitivity, Stress Response, and Effects on Verbal Memory.

Animal studies suggest that repeated episodes of elevated glucocorticoids lead to a dysregulation of the hypothalamic-pituitary-adrenal (HPA) system at a suprapituitary level, and to impaired mnemonic function. We compared cognitive tests, as well as feedback integrity and stress responsivity of the HPA system, between 11 elderly, male marathon runners - a model of repeated HPA system activation - and 10 sedentary controls. The marathon runners had significantly increased baseline, stress, and post-stress ACTH - but not cortisol - concentrations. Also, suppression of ACTH by 3 mg dexamethasone was impaired in the athletes compared to the control subjects, while the ACTH and cortisol response to additional CRH did not differ between the 2 groups. Finally, long-term verbal memory was impaired in the athletes compared to the controls. Regarding the HPA system, these findings are in accordance with an acquired suprapituitary feedback disturbance in marathon runners; however, the similar glucocorticoid concentrations in the 2 groups may be due to reduced adrenal sensitivity to ACTH. Together with impaired verbal memory, these data support the assumption that repeated episodes of HPA system activity may exert negative effects at the level of the hippocampus.

Single-subject classification of schizophrenia by event-related potentials during selective attention.

BACKGROUND: Executive dysfunction has repeatedly been proposed as a robust and promising substrate of analytical approaches in the research of neurocognitive markers of schizophrenia. Here, we present a mixed model- and data-driven classification approach by applying a task that targets executive dysfunction in schizophrenia and by investigating relevant event-related potential (ERP) features with machine learning classifiers. METHODS: Forty schizophrenic patients and forty matched healthy controls completed the Attention Network Test while an electroencephalogram was recorded. Target-locked N1 and P3 ERP components were constructed and submitted to different classification analyses without a priori hypotheses. Standardized source localization was applied to estimate neural sources of N1 and P3 deficits in schizophrenia. RESULTS: We obtained a classification accuracy of 79% using only very few ERP components. Central P3 components following compatible and incompatible trials and right parietal N1 latencies averaged across targets and were sufficient for classification. P3 deficits were associated with anterior cingulate cortex dysfunction, while right posterior current density deficits were observed in schizophrenia during the N1 time frame. CONCLUSIONS: The data exemplarily show how automated inference may be applied to classify a pathological state in single subjects without prior knowledge of their diagnoses. While classification accuracy may be optimized by application of other executive paradigms, this approach illustrates the potential of machine learning algorithms for the identification of biomarkers that are independent of clinical assessments. Conversely, data suggest a pathophysiological mechanism that includes early visual and late executive deficits during response inhibition in schizophrenia.

Smoking reduces language lateralization: a dichotic listening study with control participants and schizophrenia patients.

Schizophrenia has been associated with deficits in functional brain lateralization. According to some authors, the reduction of asymmetry could even promote this psychosis. At the same time, schizophrenia is accompanied by a high prevalence of nicotine dependency compared to any other population. This association is very interesting, because sex-dependent effects of smoking in auditory language asymmetries have been reported recently, and the verbal domain is also one major focus in cognitive deficit studies of schizophrenia. Thus, the altered laterality pattern in schizophrenia could, at least in part, result from secondary artefacts due to smoking rather than being a pure cause of the disease itself. To test this hypothesis, the present study examined auditory language lateralization in 67 schizophrenia patients and in 72 healthy controls in a phonemic and an emotional dichotic listening task. Our findings replicate previous research, in that smoking reduces language lateralization in men in phonemic dichotic listening. In addition, we show that smoking also reduces laterality in women in the emotional dichotic listening task. Thus, smoking alters phonemic and emotional language asymmetries differentially for men and women, with a stronger effect for men in the left hemisphere phonemic task, and a stronger effect for women in the right hemisphere emotional task. Together, these findings point towards an effect of smoking which is possibly independent of sex and hemisphere. Importantly, by testing equal numbers of smoking and non-smoking patients and controls, we found no schizophrenia-associated asymmetry effect. Possible neurobiological mechanisms with which smoking may alter auditory microcircuits and thereby diminish left-right differences are discussed.

Attention Network Test reveals alerting network dysfunction in multiple sclerosis.

Attention is one of the cognitive domains typically affected in multiple sclerosis. The Attention Network Test was developed to measure the function of the three distinct attentional networks, alerting, orienting, and executive control. The Attention Network Test has been performed in various neuropsychiatric conditions, but not in multiple sclerosis. Our objective was to investigate functions of attentional networks in multiple sclerosis by means of the Attention Network Test. Patients with relapsing-remitting multiple sclerosis (n = 57) and healthy controls (n = 57) matched for age, sex, and education performed the Attention Network Test. Significant differences between patients and controls were detected in the alerting network (p = 0.003), in contrast to the orienting (p = 0.696) and the conflict (p = 0.114) network of visual attention. Mean reaction time in the Attention Network Test was significantly longer in multiple sclerosis patients than in controls (p = 0.032), Multiple sclerosis patients benefited less from alerting cues for conflict resolution compared with healthy controls. The Attention Network Test revealed specific alterations of the attention network in multiple sclerosis patients which were not explained by an overall cognitive slowing.

Impact and differences of illness course perception on the desire for social distance towards people with symptoms of depression or schizophrenia in Hanoi, Vietnam.

OBJECTIVES: Public stigma against psychiatric disorders leads to delayed treatment utilization and worsens treatment outcome. This study analyses the impact of expectations regarding the course of illness and attribution as medical illness on the desire for social distance towards schizophrenia and depression in Vietnam. METHODS: In 2013, a survey (n = 771) using unlabelled vignettes either depicting a person with symptoms typical for schizophrenia or major depression was carried out in Hanoi. All respondents had to indicate whether the person was suffering from a medical illness or not. As an indicator of public stigma, the desire for social distance was measured. A possible correlation between expectations towards the course of illness and social distance was evaluated using a linear regression model. RESULTS: 85 % of respondents endorsed that the person depicted in the schizophrenia vignette had a mental illness, compared to only 60 %, who were confronted with the depression vignette. This attribution of mental illness was correlated with higher levels of desire for social distance only in the schizophrenia vignette. While in the case of schizophrenia negative prognostic perceptions were associated with more desire for social distance, in the event of depression, it was only the expectation of lifelong dependency. Moreover, only for depression, positive expectations towards the course of illness correlated with less desire for social distance. CONCLUSION: These results indicate an impact of prognostic expectations on the desire for social distance and support strategies that aim at maintaining social integration and strengthening autonomy.

Mental Health Determinants Among a Psychiatric Outpatient Sample of Vietnamese Migrants in Germany.

Background: Mental health risk-factors for Asian migrants have been studied almost exclusively in the US, Canada, and Australia but not in European countries. Therefore, we aimed to identify sociodemographic, clinical, and migration-surrounding factors associated with experienced mental distress among Vietnamese migrants in Germany. Method: 305 Vietnamese migrants utilizing Germany's first Vietnamese psychiatric outpatient clinic filled out at admission the Brief-Symptom-Inventory 18 (BSI-18) as well as a questionnaire on 22 potential mental health determinants. Using a multiple linear regression model, we identified those sociodemographic, clinical, and migration-surrounding factors that were significantly related to the Global Severity Index (GSI) of the BSI-18. Results: The factors unemployment (B = -6.32, p = 0.014), financial problems (B = -10.71, p < 0.001), no or only little religious involvement (B = -3.23, p = 0.002), no psychiatric precontact (B = -7.35, p = 0.004), previous migration experiences (B = 8.76, p = 0.002), and perceived discrimination (B = 6.58, p = 0.011) were found to significantly increase the level of mental distress according to the BSI-GSI. Conclusion: Based on these results, we were able to construct a mental health risk-profile for Vietnamese migrants in Germany, which aims to detect candidates for psychiatric problems earlier and supply them with customized prevention and therapy options.

Spatiotemporal mapping of sex differences during attentional processing.

Functional neuroimaging studies have increasingly aimed at approximating neural substrates of human cognitive sex differences elicited by visuospatial challenge. It has been suggested that females and males use different behaviorally relevant neurocognitive strategies. In females, greater right prefrontal cortex activation has been found in several studies. The spatiotemporal dynamics of neural events associated with these sex differences is still unclear. We studied 22 female and 22 male participants matched for age, education, and nicotine with 29-channel-electroencephalogram recorded under a visual selective attention paradigm, the Attention Network Test. Visual event-related potentials (ERP) were topographically analyzed and neuroelectric sources were estimated. In absence of behavioral differences, ERP analysis revealed a novel frontal-occipital second peak of visual N100 that was significantly increased in females relative to males. Further, in females exclusively, a corresponding central ERP component at around 220 ms was found; here, a strong correlation between stimulus salience and sex difference of the central ERP component amplitude was observed. Subsequent source analysis revealed increased cortical current densities in right rostral prefrontal (BA 10) and occipital cortex (BA 19) in female subjects. This is the first study to report on a tripartite association between sex differences in ERPs, visual stimulus salience, and right prefrontal cortex activation during attentional processing.

Attention network test (ANT) reveals gender-specific alterations of executive function in schizophrenia.

The Attention Network Test (ANT) provides measures for three different components of visual attention: executive control (=conflict inhibition), orienting, and alerting. There is reasonable evidence that alterations of attention-mainly in the executive/conflict domain-are associated with susceptibility to psychiatric illness. Specific impairments may be a characteristic for a medical condition such as schizophrenia and thus shift our understanding from a neuropsychological endophenotype to a more precise genetic understanding of this disorder. Study subjects comprised 35 schizophrenic patients and 35 healthy controls (13 female and 22 male in both groups). The ANT was administered to all participants and rated individual responses for the three factors (alerting, orienting, and conflict) and their respective ratios relative to mean reaction times. With regard to gender differences, group comparisons were performed for schizophrenic patients vs. healthy controls. Significant differences between patients and controls could be detected for mean reaction time (639 vs. 538 ms) and for conflict ratio (0.158 vs. 0.191). The latter difference mainly resulted from gender-specific variances of the conflict network in opposite directions. The executive function as represented by the conflict network of visual attention of the ANT is affected in schizophrenia. We have detected hitherto unreported gender-specific differences between healthy controls and schizophrenic patients. Especially as regards the conflict network, the ANT offers a promising methodology to detect a neuropsychological endophenotype of schizophrenia.

The relationship between causal beliefs and desire for social distance towards people with schizophrenia and depression: Results from a survey of young Ghanaian adults.

This study examines attitudes of the young Ghanaian population regarding the relationship between causal beliefs and desire for social distance from people with symptoms of schizophrenia and depression. Respondents (n = 507) were presented with depression and schizophrenia symptoms using unlabeled case vignettes. A factor analysis examined three factors for causal beliefs, and multiple linear regression analysis on the desire for social distance was conducted. The desire for social distance was higher when symptoms in both case-vignettes were attributed to childhood adversities and overall lower when respondents lived in northern regions of Ghana. Only, for vignettes depicting schizophrenia, mental illness attribution was associated with more desire for social distance. Significant gender effects were found for depression vignettes only: female respondents reported significantly more desire for social distance, whereas female gendered vignettes were associated with less desire for social distance by respondents of both genders.

Executive attention in schizophrenic males and the impact of COMT Val108/158Met genotype on performance on the attention network test.

BACKGROUND: Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val108/158Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val108/158Met on executive attention, using ANT. METHODS: We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val108/158Met genotype on executive attention as assessed by the ANT. RESULTS: Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention. CONCLUSIONS: Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val108/158Met on cognitive performance.

Treatment recommendation differences for schizophrenia and major depression: a population-based study in a Vietnamese cohort.

BACKGROUND: In Vietnam, the mental health care infrastructure is on the verge of transformation with an increase in the demand for access to adequate and effective mental health care services. Public attitudes towards mental illness, as well as corresponding treatment options influence help-seeking behaviors of patients and caregivers, affecting the course of their treatment. This study assesses attitudes towards treatment options for depression and schizophrenia, as the two most common psychiatric disorders in Vietnam, accounting for at least 75% of all psychiatric inpatients. METHODS: A general population-based survey was conducted in Hanoi, Vietnam between April and August 2013. Participants received a description of a person with symptoms of either depression (n = 326) or schizophrenia (n = 403) and were asked to give recommendations for adequate sources of mental health support and treatment options. Multiple analyses on a single item level compared the likelihood of recommendation between schizophrenia and depression. RESULTS: Overall, respondents recommended health care services, ranging from seeking mental health care professionals, psychotherapists, and psychiatrists for both disorders. Psychotherapy was the most favored treatment method, whereas further treatment options, such as concentration and relaxation exercises, meditation or yoga and psychotropic medication were also endorsed as helpful. For the schizophrenia vignette condition, psychotherapy, visiting a psychiatrist or psychotherapist received stronger endorsement rates as compared to the depression vignette. Furthermore, ECT, Feng Shui-based practices, praying and visiting natural healers were recommended less by respondents for the depression vignette in comparison with the schizophrenia vignette. CONCLUSIONS: The Vietnamese public endorsed evidence-based treatment recommendations from a variety of treatments options. Differences in the treatment recommendations between depression and schizophrenia reflected the perceived severity of each disorder. Further developments of the Vietnamese mental health care system concerning mental health care providers, as well as the legal regulations surrounding the provision of psychotherapy are needed.

Public attitudes towards psychiatrists in the metropolitan area of Hanoi, Vietnam.

OBJECTIVES: Mental health associated stigmatization remains problematic in low and middle-income countries, thus preventing patients from adequate access to psychiatric care. Public attitudes towards psychiatrists have not been examined in many countries, especially not in Vietnam where merely one psychiatrist per 300.000 population is available. The study aims to explore attitudes towards psychiatrists in the Hanoi municipality and to identify socio-demographical factors that influence these attitudes. METHODS: Between April and August 2013, a general population-based survey was carried out in the greater Hanoi area, Vietnam. The sample of 817 participants was stratified according to the latest Vietnamese census (2009) and micro-census (2013) with regards to socio-demographic factors. Multivariate analyses were conducted to determine the influence of these factors on attitudes towards psychiatrists. RESULTS: Gender and religious beliefs significantly influenced public attitudes towards psychiatrists. Male participants reported significantly more negative perception towards psychiatrists compared to female respondents. Participants following a religion reported significantly more negative attitudes toward psychiatrists than those without self-reported religious attainment. CONCLUSIONS: Negative attitudes towards psychiatrists are associated with religious beliefs and gender affiliation in the greater Hanoi area. A strategy that involves religious institutions in raising awareness about mental health issues while considering public's socio-cultural attitudes may pave the way for greater potentialities of adequate psychiatric care, destigmatize the mental health system, and care provider.

Perceived stigmatization and discrimination of people with mental illness: A survey-based study of the general population in five metropolitan cities in India.

BACKGROUND: India faces a significant gap between the prevalence of mental illness among the population and the availability and effectiveness of mental health care in providing adequate treatment. This discrepancy results in structural stigma toward mental illness which in turn is one of the main reasons for a persistence of the treatment gap, whereas societal factors such as religion, education, and family structures play critical roles. This survey-based study investigates perceived stigma toward mental illness in five metropolitan cities in India and explores the roles of relevant sociodemographic factors. MATERIALS AND METHODS: Samples were collected in five metropolitan cities in India including Chennai (n = 166), Kolkata (n = 158), Hyderabad (n = 139), Lucknow (n = 183), and Mumbai (n = 278). Stratified quota sampling was used to match the general population concerning age, gender, and religion. Further, sociodemographic variables such as educational attainment and strength of religious beliefs were included in the statistical analysis. RESULTS: Participants displayed overall high levels of perceived stigma. Multiple linear regression analysis found a significant effect of gender (P < 0.01), with female participants showing higher levels of perceived stigma compared to male counterparts. CONCLUSION: Gender differences in cultural and societal roles and expectations could account for higher levels of perceived stigma among female participants. A higher level of perceived stigma among female participants is attributed to cultural norms and female roles within a family or broader social system. This study underlines that while India as a country in transition, societal and gender rules still impact perceived stigma and discrimination of people with mental illness.

Impact of perceived course of illness on the desire for social distance towards people with symptoms of schizophrenia in Hanoi, Vietnam.

In Vietnam, stigmatisation and discrimination of patients with mental illness are highly prevalent. This study explores whether the perception of course of illness of people with symptoms indicating schizophrenia is associated with the desire for social distance in the Vietnamese public. A population-based survey (n = 455) using unlabelled vignettes for schizophrenia was carried out in the Hanoi municipality in 2013. First, a factor analysis was performed to group items indicating perception of prognosis. Second, a linear regression analysis was used to search for correlations between these expectations and desire for social distance. The factor analysis revealed three independent factors of perception of course of illness: (1) loss of social integration and functioning, (2) lifelong dependency on others, and (3) positive expectations towards treatment outcome. Both factors with negative prognostic perceptions (1&2) were associated with more desire for social distance. The results indicate a link between social acceptance and the perceived ability to maintain a social role including a capability of reciprocity within the Vietnamese society. Additionally, these findings highlight the importance of preserving social functioning in any treatment approach for patients with schizophrenia, which includes psychosocial intervention and rehabilitation programs.