男性精神分裂症患者抗精神病药治疗前后血浆MicroRNA-181b表达水平

目的:研究血浆中microRNA-181b(miR-181b)在男性精神分裂症患者抗精神病药治疗过程的不同阶段表达水平的变化。方法:40例精神分裂症患者和40例正常对照,均为成年男性。以实时荧光定量PCR(RT-PCR)技术检测患者组(用药前、治疗2周和治疗4周)和对照组血浆miR-181b的表达水平。结果:和正常对照组相比,精神分裂症组在治疗前、治疗2周和治疗4周血浆miR-181b的表达水平均显著上调(P<0.001)。随着抗精神病药的治疗,病情逐渐好转,男性精神分裂症患者血浆miR-181b表达水平逐渐下降(治疗2周、治疗4周与治疗前比较,P均<0.001)。结论:血浆miR-181b可能参与精神分裂症的发病机制,其表达水平受抗精神病药影响。     

Gender-Specific Reduction of Estrogen-Sensitive Small RNA,miR-30b,in Subjects With Schizophrenia

Estrogen signaling pathways affect cortical function and metabolism, are thought to play a role in the pathophysiology of schizophrenia, and exert neuroprotective effects in female subjects at risk. However, the molecular signatures of estrogen signaling in normal and diseased cerebral cortex remain largely unexplored. Expression of the estrogen-sensitive small RNA, microRNA-30b (miR-30b), was studied in 30 controls and 30 matched samples from subjects diagnosed with schizophrenia from prefrontal cortex (PFC), as well as in 23 samples from parietal cortex (12 controls and 11 schizophrenia cases). The majority of case and control samples were genotyped for an estrogen receptor α (Esr1) sequence variant (rs2234693) previously associated with genetic risk, and a subset of them were subjected to further analysis to determine expression of mature and precursor forms of miR-30b (pre/pri-miR-30b). Gender-dimorphic expression was also explored in mouse frontal cortex and hippocampus. A significant interaction between gender and diagnosis was discovered for changes in mature miR-30b levels, so that miR-30b expression was significantly reduced in the cerebral cortex of female but not male subjects with schizophrenia. In addition, disease-related changes in miR-30b expression in a subset of female subjects were further modulated by Esr1 genotype. Changes after antipsychotic drug exposure remained insignificant. These preliminary findings point to the possibility that disease-related changes in the expression of small noncoding RNAs such as miR-30b in schizophrenia could be influenced by gender and potentially regulated by estrogen signaling.     

Influencing factors and predictors of early improvement in the acute treatment of schizophrenia and schizophrenia spectrum disorder

Background

To examine the influencing factors and predictors of early improvement in schizophrenia patients.

Methods

370 patients suffering from a schizophrenia spectrum disorder were examined within a naturalistic multicenter study. Early improvement was defined as a ≥30% PANSS total score reduction within the first two treatment weeks, response as a ≥50% improvement of the PANSS total score from admission to discharge and remission according to the consensus remission criteria. Baseline and course-related variables such as positive, negative and depressive symptoms, side effects, functioning and subjective well-being were examined regarding their explanatory value for early improvement.

Results

46% of the patients were identified to be early improvers. Of these, 77% became treatment responder at discharge and 74% achieved the consensus remission criteria. Amongst others, early improvers were significantly more often first-episode patients (p = 0.009), with a significantly shorter duration of current episode (p = 0.024) and a shorter duration of the illness (p = 0.0094). A higher PANSS positive subscore (p = 0.0089), a higher score in the Strauss-Carpenter-Prognostic Scale (SCPS) (p < 0.0001), less extrapyramidal side effects (p = 0.0004) at admission and the development of less extrapyramidal side effects within the first two treatment weeks (p = 0.0013) as well as a duration of current episode of ≤6 months (p = 0.0373) were identified to be significant predictors of early improvement.

Conclusion

Early improvement is associated with less illness chronicity and seems to be independent of the type of antipsychotic and the antipsychotic dosage applied. The SCPS was found to be a valuable tool to detect early improvers already at the initiation of antipsychotic treatment.     

Switching to antipsychotic monotherapy can improve attention and processing speed,and social activity in chronic schizophrenia patients

Objective

This study sought to examine whether switching polypharmacy therapy to monotherapy would improve the cognitive function and social function of patients with schizophrenia.

Methods

Thirty-nine patients with schizophrenia who were receiving therapy with two antipsychotics were randomly divided into a switch to monotherapy group (switching group) and a polypharmacy continued group (continuing group). For the patients allocated to the switching group, the dose level of one of the two antipsychotic drugs was gradually reduced to zero. Psychotic symptoms, cognitive function and social function scale scores were assessed immediately before and 24 weeks after switching, and the time courses of these scores were compared between the two groups.

Results

Compared with the continuing group, the switching group demonstrated significantly greater improvement in attention after switching (p = 0.02). Furthermore, the improvement in daily living (p = 0.038) and work skills (p = 0.04) was significantly greater in the switching group. In an analysis of the correlation among sub-items with respect to the degrees of improvement, a significant correlation was noted between improvement in executive function and improvement in daily living (r = −0.64, p = 0.005) and between improvement in work skills and improvement in attention (r = −0.51, p = 0.038).

Conclusion

In patients with schizophrenia receiving polypharmacy, switching to monotherapy resulted in improvements in attention. Furthermore, improvements in executive function led to improvements in daily living, and improvements in attention led to improvements in work skills. Thus, switching to monotherapy is a useful option.     

The beneficial effects of combining pharmacological and psychosocial treatment on remission and functional outcome in outpatients with schizophrenia

Objective

The effects of pharmacological and psychosocial treatment on remission and the functional outcome in outpatients with schizophrenia were evaluated. Remission was assessed according to the criteria proposed by the Remission in Schizophrenia Working group and psychosocial functioning according to the Global Assessment of Functioning with a score > 60. Functional outcome was the result of these two variables.

Method

One hundred fifty two patients were randomized to receive either, antipsychotic treatment as usual (TAU) or social skills training and family psychoeducation in addition to TAU. A final sample of 119 patients: n = 68 in the social skills training group, and n = 51 in the TAU group completed the study protocol. Patients were assessed at baseline and at 6-month follow-up.

Results

At the end of the study, 80% of the patients fulfilled the criteria for symptomatic remission: 62 patients (91.2%) in the social skills training group in contrast to 34 patients (66.7%) in the TAU group. Functional improvement criteria were accomplished by 41 patients (34.5%) at the endpoint of the study. Forty of these patients (58.8%) belonged to social skills training and one patient to customary treatment (χ² = 41.7, df 1, p < 0.001) and when criteria for symptomatic remission and functional improvement were combined, 39 patients (97.5%) of the social skills training group and one patient (1.9%) of the customary treatment group achieved functional outcome.

Conclusion

The results emphasize the need for psychosocial interventions as conjoint to pharmacological treatment to improve functional outcome in schizophrenia patients.     

How long to wait before reducing antipsychotic dosage in stabilized patients with schizophrenia? A retrospective chart review

Objective

Antipsychotic dose reduction is generally recommended to occur after six months of clinical stabilization despite inadequate evidence. This timing issue was addressed in this study.

Methods

This is an observational, retrospective and medical chart-based study. Inclusion criteria were (1) diagnosis of schizophrenia (DSM-IV), (2) being acutely psychotic at their first outpatient visit from May, 2002 to April, 2003, (3) having responded to antipsychotics and achieved clinical stabilization of acute symptoms, indexed as a fixation of regimen for four or more weeks, and (4) having one or more years of follow-up. Patients who had their antipsychotic doses reduced were then identified, and they were divided into two groups based on the waiting period before dose reduction: <24 weeks (Early Group) and ≥24 weeks (Standard Group). The rate of dose escalation for ≥20% during follow-up period was investigated as a proxy of clinical worsening.

Results

After excluding stable patients at baseline, 211 patients met inclusion criteria. The mean ± SD waiting period before reducing antipsychotics was 122 ± 102 days. The rates of patients needing dose escalation were not significantly different between patients whose dose was reduced (N = 83) and those who was not (N = 128) (57.8% vs. 59.4%), and between Early Group (N = 59) and Standard Group (N = 24) (61.0% vs. 50.0%) although the reduction rate in antipsychotic dosage was significantly greater in Early Group (58.7% vs. 43.3%, p < 0.05).

Conclusion

These findings may indicate that timeline until antipsychotic reduction in stable patients with schizophrenia could be earlier than recommended, although caution is needed in interpreting our retrospective results.     

Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics

Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Decreased BDNF levels have been found in the serum of schizophrenic patients with mixed results. In the present study, we assessed serum BDNF levels in a large group of 364 schizophrenic patients (157 on clozapine, 89 on risperidone and 118 on typical antipsychotics), compared to 323 healthy control subjects matched for age and gender. The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS), and serum BDNF levels were measured by sandwich ELISA. The results showed that BDNF levels were significantly lower in chronic patients with schizophrenia than in healthy control subjects (9.9 ± 2.0 ng/ml vs.11.9 ± 2.3 ng/ml, p < 0.0001). Lower BDNF levels were observed in patients treated with risperidone (9.3 ± 2.3 ng/ml) compared to those with clozapine (10.2 ± 2.0 ng/ml, p < 0.001) and typical antipsychotics (10.0 ± 2.1 ng/ml, p < 0.01). Furthermore, a stepwise multiple regression analysis identified types of antipsychotic drugs (beta = − 0.37, t = − 3.15, p = 0.001) and BDNF levels (beta = − 0.26, t = − 2.51, p = 0.014) as the influencing factor for the positive symptom subscore of PANSS. In addition, there was a sex difference in BDNF levels in patients with schizophrenia (9.7 ± 1.9 ng/ml for males vs.10.4 ± 2.1 ng/ml for female, p < 0.005), but not in normal controls. Our findings indicated decreased BDNF serum levels in chronic patients with schizophrenia, which may be related to clinical phenotypes, including gender, antipsychotic treatment and the severity of psychotic symptoms.     

Headache and arterial hypertension

The aim of this study is to explore the expression of microRNA (miRNA)-221 and miRNA-222 in human glioma cells and tissues. The expression of miRNA-221 and miRNA-222 in human glioma cell line U87, U251, A172, LN229 and surgery resected glioma tissues were measured. The survival rate of X-ray (2 Gy) irradiated glioma cells were calculated. 165 cases of glioma patients were recruited successfully; the expression of miRNA-221 and miRNA-222 in their resected tissues were measured. The expression of miRNA-221 and miRNA-222 in cancer tissues were obviously higher than control tissues (normal brain tissue) and control cell (gastric mucosal epithelial cell, GES) (p < 0.05). The highly malignant glioma tissues expressed significantly higher miRNA-221 and miRNA-222 than low malignant glioma tissues. Patients with highly expressed miRNA-221 and miRNA-222 have shorter survival time. Survival rate of glioma cells was significantly higher than GES cell after irradiation (p < 0.05); miRNA-221 in glioma cells. The expressions of miRNA-221 and miRNA-222 in irritated glioma cells were positively correlated with the survival rate of glioma cells (r = 0.629, 0.712, both p < 0.01). For the 165 glioma patients, the expressions of miRNA-221 and miRNA-222 increased with the increasing of pathological grades (χ ² = 42.85, p < 0.01); and their survival time decreased when miRNA-221 expression elevated (χ ² = 57.12, p < 0.01). MiRNA-221 and miRNA-222 express highly in human glioma cells and tissues. Expression of miRNA-221 and miRNA-222 are closely related to pathological grading and prognosis of glioma; they could be used as independent prognostic factor for glioma.     

Aripiprazole versus haloperidol treatment in early-stage schizophrenia

We conducted a secondary analysis of a completed study of the differential efficacy and side effects of aripiprazole versus haloperidol in early-stage schizophrenia (ESS), a subpopulation of patients which does not include first episode or chronic patients. A subpopulation of 360 individuals with ESS were identified from a randomized, multi-center, double-blind study of 1294 individuals with schizophrenia at different stages of illness who were randomized to treatment with aripiprazole (ESS = 237) or haloperidol (ESS = 123) for one year. The primary outcome measure was response rate based on a 50% reduction of Positive and Negative Syndrome Scale (PANSS) total scores. Secondary outcomes included several efficacy and safety measures, as well as treatment discontinuation. More individuals in the aripiprazole group (48%) than in the haloperidol group (28%; p < 0.01) completed the study. Response rates were greater in the aripiprazole group (38% [N = 91]) than in the haloperidol group (22% [N = 27]; p < 0.01). Aripiprazole was associated with fewer extrapyramidal side effects. ESS subjects in the haloperidol group were more likely than those in the aripiprazole group to discontinue the study drug due to an adverse event other than worsening illness (29% and 11%, respectively; p < 0.01), and efficacy differences were reduced by interventions to mitigate side effects (decreasing antipsychotic dose with or without adding antiparkinsonian medication). Aripiprazole has a favorable efficacy/safety profile in ESS and appeared to be superior to haloperidol on a number of efficacy and safety outcomes. However, excessive dosing of the antipsychotic medications, in particular haloperidol, may have played an important role in accounting for the differences between aripiprazole and haloperidol in this study.     

Reduced expression of synapsin II in a chronic phencyclidine preclinical rat model of schizophrenia

Schizophrenia is a mental disorder characterized by positive symptoms, negative symptoms, and cognitive dysfunction. Phencyclidine (PCP)—a N‐methyl‐D‐aspartate (NMDA) receptor antagonist—induces symptoms indistinguishable from those of schizophrenia. A reduction of the phosphoprotein synapsin II has also been implicated in schizophrenia and has a well‐known role in the maintenance of the presynaptic reserve pool and vesicle mobilization. This study assessed the behavioral and biochemical outcomes of chronic NMDA receptor antagonism in rodents and its implications for the pathophysiology of schizophrenia. Sprague Dawley rats received saline or chronic PCP (5 mg/kg/day) for 14 days via surgically implanted Alzet® osmotic mini‐pumps. Following the treatment period, rats were tested with a series of behavioral paradigms, including locomotor activity, social interaction, and sensorimotor gating. Following behavioral assessment, the medial prefrontal cortex (mPFC) of all rats was isolated for synapsin II protein analysis. Chronic PCP treatment yielded a hyper‐locomotive state (p = 0.0256), reduced social interaction (p = 0.0005), and reduced pre‐pulse inhibition (p < 0.0001) in comparison to saline‐treated controls. Synapsin IIa (p < 0.0001) and IIb (p < 0.0071) levels in the mPFC of chronically treated PCP rats were reduced in comparison to the saline group. Study results confirm that rats subject to chronic PCP treatment display behavioral phenotypes similar to established preclinical animal models of schizophrenia. Reduction of synapsin II expression in this context implicates the role of this protein in the pathophysiology of schizophrenia and sheds light on the longer‐term consequences of NMDA receptor antagonism facilitated by chronic PCP treatment.     

Overexpression of tissue microRNA10b may help predict glioma prognosis

We investigated the relationship between microRNA-10b (miR-10b) expression and prognosis in human glioma patients. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was used to characterize the expression patterns of miR-10b in 128 glioma and 20 normal brain tissues. Clinical information – age, sex, Karnofsky Performance Status (KPS) and World Health Organization (WHO) grade – were also collected. The associations between miR-10b expression and the clinicopathological factors and outcome of glioma patients were statistically analyzed. Expression levels of miR-10b in glioma tissue were significantly higher than in normal brain tissue (P < 0.001). High-grade glioma (WHO grade III and IV) had much higher miR-10b expression levels than low-grade tumors (WHO grade I and II). Additionally, the increased miR-10b expression in the glioma tissues was significantly associated with a low KPS (P = 0.03). Kaplan–Meier survival curves and Cox regression analyses showed that overexpression of miR-10b (P = 0.01) and high grade (P = 0.02) were independent factors predicting poor outcome for glioma patients. Furthermore, subgroup analyses showed that the miR-10b expression level was significantly associated with poor overall survival in glioma patients with high grades (P < 0.001). Up-regulation of miR-10b may have value in predicting clinical outcome in glioma patients, particularly for those with high pathological grades.     

The schizophrenia risk gene ZNF804A influences the antipsychotic response of positive schizophrenia symptoms

Genetic factors determining the response to antipsychotic treatment in schizophrenia are poorly understood. A new schizophrenia susceptibility gene, the zinc-finger gene ZNF804A, has recently been identified. To assess the pharmacogenetic importance of this gene, we treated 144 schizophrenia patients and assessed the response of positive and negative symptoms by PANSS. Patients homozygous for the ZNF804A risk allele for schizophrenia (rs1344706 AA) showed poorer improvement of positive symptoms (7.35 ± 0.46) compared to patients with a protective allele (9.41 ± 0.71, P = 0.022). This provides further evidence that ZNF804A is of functional relevance to schizophrenia and indicates that ZNF804A may be a novel target for pharmacological interventions.     

Alterations of microRNA-124 expression in peripheral blood mononuclear cells in pre- and post-treatment patients with major depressive disorder

Recently, increasing evidence has indicated that dysfunction of microRNA-124 (miR-124) might be involved in the pathophysiology and treatment of major depressive disorder (MDD) in some animal models of depression. However, the role of miR-124 in MDD patients remains unclear. The objective of this study was to investigate whether the miR-124 expression levels in peripheral blood mononuclear cells (PBMCs) were associated with MDD and to evaluate the effects of antidepressant treatment on miR-124 levels. Quantitative real-time PCR was applied to detect miR-124 expression in 32 pre- and post-treatment MDD patients and 30 healthy controls. Our results showed that expression levels of miR-124 from PBMCs in MDD patients were significantly higher than those in healthy controls (p < 0.001), and that the area under the curve of miR-124 from ROC analysis was 0.762 with a sensitivity of 83.33% and specificity of 66.67% in distinguishing MDD patients from healthy controls. In addition, the expression levels of miR-124 were significantly down-regulated after eight weeks of treatment (p < 0.001). MiRNA target gene prediction and functional annotation analysis indicated that altered miR-124 was involved in affecting some important biological processes and pathways related to MDD. These results provide new information on miR-124 involvement in the biological alterations of MDD and in antidepressant effects.     

Cortical serotonin7, 1D and 1F receptors: Effects of schizophrenia,suicide and antipsychotic drug treatment

Abnormalities in serotonergic function are thought to be important in the pathology of schizophrenia. Postmortem CNS studies suggest that levels of serotonin receptors may be altered in the cortex of subjects with schizophrenia. Seeking to expand this hypothesis we have examined the effect of schizophrenia and antipsychotic drug treatments on the levels of cortical serotonin₇, _1D and _1F receptors. There was a significant decrease in the binding of [³H]SB 269970 to the serotonin₇ receptor in Brodmann's area 9 from subjects with schizophrenia compared to controls (Mean ± S.E.M.: 8.3 ± 0.76 vs. 11.0 ± 0.64 fmol/mg ETE; p < 0.05) and an increase in the binding of that radioligand in the cortex of rats treated with haloperidol (p = 0.03). There were no significant differences in [³H]sumatriptan binding to the serotonin_1D or serotonin_1F receptor in Brodmann's area 9 from subjects with schizophrenia. There was a significant increase in [³H]sumatriptan binding to the serotonin_1D in binding Layer 2 from subjects who had potentially died by suicide that was not present in other binding layers or for the serotonin_1F or serotonin₇ receptors. There was decrease in [³H]sumatriptan binding to the serotonin_1D, but not serotonin_1F, receptors across all cortical binding layers in rats treated with haloperidol. These data would be consistent with the hypothesis that decreased levels of serotonin₇ receptors in Brodmann's area 9 may be involved in the pathological processes of schizophrenia and that levels of cortical serotonin₇ and _1D receptors can be affected by antipsychotic drug treatment.     

Repetitive Transcranial Magnetic Stimulation (rTMS) Improves Facial Affect Recognition in Schizophrenia

ObjectiveFacial affect recognition, a basic building block of social cognition, is often impaired in schizophrenia. Poor facial affect recognition is closely related to poor functional outcome; however, neither social cognitive impairments nor functional outcome are sufficiently improved by antipsychotic drug treatment alone. Adjunctive repetitive transcranial magnetic stimulation (rTMS) has been shown to enhance cognitive functioning in both healthy individuals and in people with neuropsychiatric disorders and to ameliorate clinical symptoms in psychiatric disorders, but its effects on social cognitive impairments in schizophrenia have not yet been studied. Therefore, we evaluated the effects of sham-controlled rTMS on facial affect recognition in patients with chronic schizophrenia.MethodInpatients (N = 36) on stable antipsychotic treatment were randomly assigned to double-blind high-frequency (10 Hz) rTMS or sham stimulation for a total of ten sessions over two weeks. In the verum group, each session consisted of 10 000 stimuli (20 trains of 5 s) applied over the left dorsolateral prefrontal cortex at 110% of motor threshold. Facial affect recognition was assessed before (T0) and after (T1) the ten sessions.ResultsFacial affect recognition improved significantly more after rTMS (accuracy change: mean = 8.9%, SD = 6.0%) than after sham stimulation (mean = 1.6%, SD = 3.5; Cohen's d = 1.45). There was no correlation with clinical improvement.ConclusionOur results indicate that prefrontal 10 Hz rTMS stimulation may help to ameliorate impaired facial affect recognition in schizophrenia.     

Effects of haloperidol and risperidone on cerebrohemodynamics in drug-naive schizophrenic patients

Background

Use of antipsychotics may be associated with cerebrovascular adverse events in psychotic patients. In this study, the effects of haloperidol and risperidone on the cerebral hemodynamics and the possible relationships between antipsychotics and cerebrovascular risks tendency were evaluated by Transcranial Doppler ultrasonography (TCD).

Methods

Twenty drug-na?¨ve schizophrenic patients and 20 normal control subjects were included. The patients were divided into haloperidol- and risperidone-treated groups and received treatment for 8 weeks double-blindly. The subjects’ cerebral blood flow mean velocities (MV) and pulsatility index (PI) were measured weekly by TCD. The Positive and Negative Syndrome Scale for schizophrenia (PANSS) was used to assess the patients’ psychopathological symptoms.

Results

Increased MV and decreased PI were found significantly in drug-na?¨ve schizophrenic patients than normal subjects before treatment (p < 0.01). The decreased PI could be normalized after 8 weeks of antipsychotic treatment, while the increased MV could not. Treatment with haloperidol could significantly increase the PI than the treatment with risperidone (p < 0.01) throughout the treatment course. The PANSS scores of both groups were significantly improved (p < 0.05) at the endpoints of treatment.

Conclusions

Our findings indicate that haloperidol may affect the cerebral hemodynamics in drug-na?¨ve schizophrenics more prominently than that of risperidone via TCD monitoring.     

Insight in schizophrenia–course and predictors during the acute treatment phase of patients suffering from a schizophrenia spectrum disorder

BackgroundTo analyse insight of illness during the course of inpatient treatment, and to identify influencing factors and predictors of insight.MethodsInsight into illness was examined in 399 patients using the item G12 of the Positive and Negative Syndrome Scale (“lack of insight and judgement”). Ratings of the PANSS, HAMD, UKU, GAF, SOFAS, SWN-K and Kemp's compliance scale were performed and examined regarding their potential association with insight. The item G12 was kept as an ordinal variable to compare insight between subgroups of patients.ResultsAlmost 70% of patients had deficits in their insight into illness at admission. A significant improvement of impairments of insight during the treatment (p < 0.0001) was observed. At admission more severe positive and negative symptoms, worse functioning and worse adherence were significantly associated with poorer insight. Less depressive symptoms (p = 0.0004), less suicidality (p = 0.0218), suffering from multiple illness-episodes (p < 0.0001) and worse adherence (p = 0.0012) at admission were identified to be significant predictors of poor insight at discharge.ConclusionThe revealed predictors might function as treatment targets in order to improve insight and with it outcome of schizophrenia.