RESUMEN
Human induced pluripotent stem cells (hiPSC) provide an attractive tool to study disease mechanisms of neurodevelopmental disorders such as schizophrenia. A pertinent problem is the development of hiPSC-based assays to discriminate schizophrenia (SZ) from autism spectrum disorder (ASD) models. Healthy control individuals as well as patients with SZ and ASD were examined by a panel of diagnostic tests. Subsequently, skin biopsies were taken for the generation, differentiation, and testing of hiPSC-derived neurons from all individuals. SZ and ASD neurons share a reduced capacity for cortical differentiation as shown by quantitative analysis of the synaptic marker PSD95 and neurite outgrowth. By contrast, pattern analysis of calcium signals turned out to discriminate among healthy control, schizophrenia, and autism samples. Schizophrenia neurons displayed decreased peak frequency accompanied by increased peak areas, while autism neurons showed a slight decrease in peak amplitudes. For further analysis of the schizophrenia phenotype, transcriptome analyses revealed a clear discrimination among schizophrenia, autism, and healthy controls based on differentially expressed genes. However, considerable differences were still evident among schizophrenia patients under inspection. For one individual with schizophrenia, expression analysis revealed deregulation of genes associated with the major histocompatibility complex class II (MHC class II) presentation pathway. Interestingly, antipsychotic treatment of healthy control neurons also increased MHC class II expression. In conclusion, transcriptome analysis combined with pattern analysis of calcium signals appeared as a tool to discriminate between SZ and ASD phenotypes in vitro.
Asunto(s)
Trastorno Autístico/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas/metabolismo , Esquizofrenia/metabolismo , Trastorno Autístico/patología , Señalización del Calcio/fisiología , Diferenciación Celular/fisiología , Humanos , Células Madre Pluripotentes Inducidas/patología , Neuritas/fisiología , Neuronas/patología , Esquizofrenia/patologíaRESUMEN
Negative symptoms are an important predictor of course of illness as well as social and occupational functioning. Clinically effective interventions are scarce. For negative symptoms to become a reliable primary endpoint in treatment studies, clear operationalization and construct validation is needed. Recent factor analyses mostly find two main factors for negative symptoms: diminished expression und amotivation/anhedonia. The Clinical Assessment Interview for Negative Symptoms (CAINS) consists of the subscales "motivation and pleasure" and "expression". We assessed three samples of subjects with schizophrenia (nâ¯=â¯105) for different aspects of the scale's reliability and validity. A confirmatory factor analysis (CFA) of the CAINS confirmed its two-factorial structure. The subscales had distinct correlational profiles: "Motivation and pleasure" was strongly associated with functional outcome and depression and further with neurocognition, positive symptoms and social cognition. "Expression" seems independent of sources of secondary negative symptoms and neurocognition. We found good internal consistency and interrater agreement. Test-retest reliability (two-week interval) was moderate for the CAINS and its "expression" subscale and low for the "motivation and pleasure" subscale. Our findings indicate that the CAINS differentiates reliably between the two main domains of negative symptoms with some questions remaining concerning the validity of the "motivation and pleasure" subscale.
Asunto(s)
Escalas de Valoración Psiquiátrica/normas , Esquizofrenia/diagnóstico , Psicología del Esquizofrénico , Adulto , Anhedonia/fisiología , Depresión/diagnóstico , Depresión/psicología , Femenino , Humanos , Masculino , Motivación/fisiología , Placer/fisiología , Reproducibilidad de los Resultados , Conducta SocialRESUMEN
OBJECTIVE: The negative symptom domain remains a major challenge concerning treatment. A valid self-report measure could assist clinicians and researchers in identifying patients with a relevant subjective burden. The Motivation and Pleasure - Self Report (MAP-SR) derives from the CAINS and is supposed to reflect the "amotivation" factor of negative symptoms. We evaluated different aspects of the scale's reliability and validity. This is the first factorial analysis as well as the first analysis of test-retest reliability. METHODS: We assessed three samples of subjects with schizophrenia or schizoaffective disorder (nâ¯=â¯93) and a broad spectrum of related domains. RESULTS: We explored a 3-, 2- and 1-factor solution (explaining 50.93, 44.85 and 36.18% of variance, respectively). The factor "pleasure and hedonic activity" consists of eight items and was most robust; the factors "social motivation" and "motivation for work" were problematic. Test-retest reliability of the scale was adequate (rSâ¯=â¯0.63, pâ¯=â¯.005). Neither the MAP-SR nor the "pleasure and hedonic activities" factor are associated with the PANSS negative symptom scale. There are significant associations with the observer-rated CAINS-MAP scale, experiences of pleasure, and social cognition but none with functional outcome. Discriminant validity could not be established with regards to depression and extrapyramidal symptoms. CONCLUSIONS: We found that the MAP-SR is adequate to assess anhedonia but is less suitable when assessing motivation. Therefore, we propose using the "pleasure and hedonic activity scale" to cover the "anhedonia" subdomain. We think the "motivation" part of the instrument requires reconstruction.
Asunto(s)
Anhedonia/fisiología , Motivación/fisiología , Placer/fisiología , Esquizofrenia/diagnóstico , Psicología del Esquizofrénico , Autoinforme/normas , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica/normas , Reproducibilidad de los Resultados , Esquizofrenia/epidemiología , Autoevaluación (Psicología)RESUMEN
Atypical antipsychotic agents are a frequently and effectively used treatment in schizophrenia and psychotic disorders. Other than conventional antipsychotics, which mainly exert their pharmacological effect in subcortical dopaminergic systems, atypical antipsychotics additionally affect partly serotonergically innervated structures within prefrontal areas, such as the anterior cingulate cortex (ACC). However, only few controlled, randomized studies have so far investigated direct and indirect effects of atypical antipsychotics on the ACC and, up until now, no clinical investigation has exclusively addressed the specific effects of quetiapine on ACC function. The present study assessed ACC function in 18 quetiapine-medicated patients and 13 flupentixol-treated patients suffering from schizophrenia by means of the error-related negativity (ERN), a neurophysiological marker of ACC function, in a pre-post design. Between-group comparisons revealed different effects of quetiapine and flupentixol on ACC function despite similar improvement in psychopathology, cognitive performance and quality of life. Whereas atypical treatment was associated with an increase in amplitudes over time, there were prolonged ERN peak latencies in patients treated with the typical agent. Moreover, treatment effects depended on baseline prefrontal cortex function in both groups. We conclude that both flupentixol and quetiapine improve prefrontal function especially in patients with weak initial ACC function which might be due to their shared affinity for serotonin receptors in frontal brain regions. However, since this affinity is more pronounced for quetiapine, patients treated with quetiapine seemed to profit more evidently concerning their prefrontal cortex function compared to patients of the flupentixol group, who exhibited a compensatory prolongation of processes.