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Auditory verbal hallucinations (AVHs) constitute a frequent and distressing symptom of schizophrenia, associated with physical, emotional, and cognitive challenges. Despite their clinical importance, changes in the multiple dimensions of AVHs during treatment have rarely been examined, and subjective views thereof have received minimal attention. Here, we evaluated 87 patients with schizophrenia-related AVHs using the Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ; a self-report questionnaire) and the Psychotic Symptom Rating Scales-Auditory Hallucination Subscale (PSYRATS-AH; a clinician-rated scale) at baseline and after 6 months and 1 year of treatment. We explored dimensions that changed from the perspectives of both clinicians and patients and the relationships between these perceptions over the year. The test–retest reliabilities of the HPSVQ and PSYRATS-AH were generally fair. Improvements in AVHs were evident over the first 6 months; the PSYRATS-AH revealed a broader range of symptom improvement than did the HPSVQ. The “interference with life” dimension on the HPSVQ was not reduced, but the “disruption to life” score on the PSYRATS-AH was. At both baseline and 6 months, the physical characteristics of AVHs (frequency, duration, and loudness) were significantly correlated with both distress and life interference/disruption; all correlations except that for frequency were reduced at 1 year. The clinician-rated and self-reported personal perspectives on AVHs exhibited both differences and similarities; physical AVH components and subjective distressful experiences changed in different ways in those with chronic, persistent AVHs. The HPSVQ and PSYRATS-AH data were complementary, improving our understanding of the clinical implications of AVHs and subjective patient distress.

Objectives Second-generation antipsychotic drugs, such as clozapine, were reported to enhance neurite outgrowth by nerve growth factor in PC12 cells. The authors previously showed that chloride channel 4 (CLC-4) is responsible for nerve growth factor-induced neurite outgrowth in neuronal cells. In this study, we examined whether clozapine induces CLC-4 in neuroblastoma and glioma cells. Methods The effect of clozapine on CLC-4 expression was examined in neuroblastoma (SH-SY5Y) and glioma (U87) cells. To investigate the signaling pathway responsible for clozapine-induced CLC-4 expression, the phosphorylation of cAMP response element-binding protein (CREB), which binds CRE in the promoter of the human CLC-4 gene, was examined. To identify the target of clozapine induced CLC-4, CLC-4 siRNA was introduced to neuroblastoma and glioma cells for functional knockdown. Results We observed that clozapine increased CLC-4 expression in both SH-SY5Y and U87 cells. Clozapine induced CREB phosphorylation, but in the presence of inhibitor of protein kinase A (an upstream kinase of CREB) clozapine-induced CLC-4 expression was suppressed. Finally, we found that CLC-4 knockdown suppressed clozapine-induced cyclin-dependent kinase 5 (CDK5) expression in SH-SY5Y and U-87 cells suggesting CDK5 as potential molecular target of clozapine induced CLC-4 expression. Conclusions The results of the present study suggest that clozapine's therapeutic effect may include the induction of CLC-4 which is dependent on CREB activation via PKA. We also found that functional knockdown of CLC-4 resulted in reduction of CDK5 expression, which may also be implicated in clozapine's therapeutic effect.

Recent evidence has suggested that deficits in glial plasticity contribute to the pathophysiology of depressive disorders. The present study explored early growth response 1 (EGR-1) transcriptional regulation of imipramine-induced glial cell line-derived neurotrophic factor (GDNF) expression in astrocytes. After we observed the induction of GDNF mRNA expression in rat astrocytes in response to imipramine, deletion mutant studies showed that the proximal region between − 493 and − 114 of the GDNF promoter, which contains three binding sites for EGR-1, was essential for maximal imipramine-induced activation of GDNF promoter. The dose-dependent upregulation of EGR-1 by imipramine, the activation of GDNF by the over-expression of EGR-1 without imipramine and the reduction in the imipramine-induced GDNF mRNA expression after silencing of endogenous EGR-1 demonstrated that EGR-1 is upregulated by imipramine to activate the GDNF promoter. Furthermore, imipramine-induced GDNF mRNA expression was strongly attenuated in primary astrocytes from Egr-1−/− mice, and the immunoreactivity to an anti-GDNF antibody in glial fibrillary acidic protein-positive cells was lower in imipramine-treated astrocytes from Egr-1−/− mice than in those from Egr-1+/− mice. To determine whether mitogen-activated protein kinases (MAPKs) were associated with imipramine-induced EGR-1 expression, we examined the induction of MAPK phosphorylation in response to imipramine. Pretreatment of rat primary astrocytes with the MAPK kinase inhibitor U0126 or the JNK inhibitor SP600125 strongly inhibited imipramine-stimulated EGR-1 expression. In conclusion, we found that imipramine induction of EGR-1 upregulated GDNF in astrocytes in a dose-dependent manner. This upregulation may occur through the MEK/ERK and JNK MAPK pathways, which suggests a new therapeutic mechanism of action for depressive disorders.

Past studies have found inconsistent associations between subjective and objective measures of quality of life (QOL) in schizophrenia. We hypothesized that this may be due to heterogeneity in the demographic and/or clinical variables inherent in the samples and we investigated this possibility.We stratified the patients according to a descriptive measure of correspondence between self-reported QOL and clinician-rated functioning. We then examined whether heterogeneous patterns existed among the subgroups in terms of demographic variables, symptom severity, associations between self-reported and clinician-rated psychopathology and associations between side effects, QOL and functioning.The subgroups significantly differed with respect to clinician-rated positive symptoms (F=3.075, p.05), subjective symptoms (somatization, F=5.768, p.01; obsessive-compulsive, F=3.885, p.05; interpersonal sensitivity, F=8.278, p.001; depression, F=9.368, p.001; anxiety, F=6.909, p.01; hostility, F=7.787, p.01; phobic anxiety, F=9.551, p.001; paranoia, F=5.304, p.01; psychoticism, F=5.071, p.01) and in- and outpatient ratio (Chi(2)=11.58, p.01). Only the subgroup with relatively good correspondence between clinician-rated functioning and self-reported QOL showed significant low to moderate associations between the aforementioned measures and side effects. In addition, they showed similar levels of significant associations between the positive and subjective symptoms. In contrast, other discordant subgroups lacked overall associations between side effects, functioning and QOL as well as between subjective and objective measures of psychopathology.Low to moderate levels of correspondence between subjective QOL and objective functioning were partly supportive of the independence of the constructs. Insight is likely to be a mediating variable of the correspondence between self-report and clinician-rated measures and should be considered in studies using self-report measures.