Early outcomes, associated factors and predictive values of clinical outcomes of tandospirone in generalized anxiety disorder: a post-hoc analysis of a randomized, controlled, multicenter clinical trial.

OBJECTIVE: To examine the early outcomes, associated factors and predictive values of clinical outcomes of different tandospirone doses in patients with a generalized anxiety disorder (GAD). METHODS: This was a posthoc analysis of "a randomized, controlled multicenter clinical trial of the efficacy and safety of different doses of tandospirone on GAD". A total of 274 patients with GAD were included and randomized into the high-dose (tandospirone 60 mg/d) and low-dose (tandospirone 30 mg/d) groups for a 6-week treatment. The Hamilton Anxiety (HAMA), Clinical Global Impression-Severity (CGI-S), Short-Form-12 (SF-12) scales were used for assessment. The trial was registered at clinical trail.gov (NCT01614041). RESULTS: (1) In the first week of treatment, 35.8% of patients in the high-dose group fulfilled the early onset criteria, which was significantly higher than 19.0% found in the low-dose group (p = 0.002). In the second week of treatment, 22.6% of patients in the high-dose group achieved an early response, versus 12.4% in the low-dose group, indicating a significant difference (p = .026). (2) Factors associated with early onset at week 1 included baseline HAMA total score (OR = 0.916, 95%CI 0.882-0.952), age (OR = 0.974, 95%CI 0.950-0.998), drug dose (30 mg vs. 60 mg; OR = 0.298, 95%CI 0.156-0.568) and SF-12 physiological total score (OR = 1.030, 95%CI 1.010-1.050). (3) Early onset was significantly associated with response rate (OR = 18.34, 95%CI 12.10-27.81), remarkable response rate (OR = 27.56, 95%CI 11.65-65.17) and recovery rate (OR = 11.85, 95%CI 4.98-28.18). Group (high dose group vs. low dose group) (χ2 = 8.535, p = .003) and baseline HAMA total score (χ2 = 70.840, p < .001) were independent predictors of onset time. CONCLUSIONS: The early outcomes of high-dose tandospirone in the treatment of GAD are better than those of the low-dose group. Patients with younger age at onset, milder anxiety symptoms and better physiological functions administered high-dose tandospirone showed rapid onset, great early outcomes, high recovery rate and good prognosis. Drug onset time had a good predictive effect on treatment outcome.

Difference in proinflammatory cytokines produced by monocytes between patients with major depressive disorder and healthy controls.

BACKGROUND: Immune activation and suppression in patients with major depressive disorders (MDD) have been both reported in different studies. We assume that these findings may indicate innate immunological tolerance in MDD, with subclinical elevated level of proinflammatory cytokines and the decrease in innate immune response while encountering pathogens. METHODS: Peripheral monocytes of 50 untreated patients with MDD and 40 healthy controls were isolated and cultured, with or without 10 ng/ml lipopolysacchride (LPS) for 6 h (6 h, LPS+/-), and with LPS for 18 h (18, LPS+). The cell culture supernatants were collected to measure concentrations of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1 beta (IL-1ß). RESULTS: The baseline concentrations of IL-6 and IL-1ß (6 h, LPS-) were significantly higher in the MDD group than those in the control group. There was no significant difference of TNF-α between the two groups. The fold changes of LPS-induced secretion of IL-6 and TNF-α from monocytes cultured for 6 and 18 h were all lower in the patient groups, and that was true for IL-1ß as monocytes cultured for 18 h. LIMITATIONS: Given the gap between the results of in vitro experiments and the actual response that happens in vivo when the immune system encounters pathogens from the external world, future research should include in vivo methods to test the results of the current study. CONCLUSIONS: Patients with MDD may have subclinical inflammation during a depressive episode, and the reduced response to LPS in monocytes indicates innate immunological tolerance.

The pro-inflammatory cytokines, salivary cortisol and alpha-amylase are associated with generalized anxiety disorder (GAD) in patients with asthma.

Generalized anxiety disorder (GAD) is common in patients with asthma. High levels of GAD may lead both to exacerbation of the condition and poor management. However, the physiological mechanisms of GAD in asthma patient is unclear. This study investigated the associations between the diurnal rhythm of sputum cytokines, salivary cortisol, α-amylase and GAD in asthma patients. Patients with co-morbid GAD and asthma showed higher sputum IL-1 AUC, sputum IL-6 AUC and sAA AUC. And there were positive correlations between Hamilton anxiety scale (HAMA) scores and sputum IL-1 AUC concentrations (r=0.37, P=0.002), HAMA scores and sputum IL-6 AUC (r=0.56, P<0.001), HAMA scores and sAA AUC (r=0.75, P<0.001). Also, there were positive correlations between Sputum IL-1 AUC and sAA AUC (r=0.40, P<0.001), between Sputum IL-6 AUC and sAA AUC. Stepwise multiple regression analyses showed the combination of sputum sAA AUC, IL-1 AUC, IL-6 AUC and cortisol AUC was the best predictor of HAMA scores (ΔR2=0.439, F(4,63)=14.086, p<0.001). Therefore, pro-inflammatory cytokines, salivary cortisol and alpha-amylase may all be involved in the occurrence of GAD in asthma patients.

Prenatal restraint stress is associated with demethylation of corticotrophin releasing hormone (CRH) promoter and enhances CRH transcriptional responses to stress in adolescent rats.

Maternal stress can disturb normal fetal neurodevelopmental progress, and lead to negative behavioral and neuroendocrine consequences for the offspring. These effects may be related to alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Early life events disrupting the function of the HPA axis may be associated with epigenetic modification. This study investigated the effect of maternal stress on the methylation rate of the corticotrophin-releasing hormone (CRH) promoter and HPA axis response to acute stress in the adolescent offspring of Sprague-Dawley rats. Pregnant dams were randomly assigned to two groups: restraint stress group and normal control group. Adolescent male and female offspring were used from each group. The results showed that prenatal stress is associated with the demethylation of the CRH promoter, and leads to anxiety-like behaviors in adolescent life stages, as well as hyper-responsiveness of the HPA axis. Together, these results imply that prenatal stress alters the normal HPA function, which may be via the epigenetic mechanism.

Sputum interleukin-6, tumor necrosis factor-α and Salivary cortisol as new biomarkers of depression in lung cancer patients.

Depression is common among lung cancer patients. Increasing evidence has suggested that hypothalamic-pituitary-adrenal (HPA) axis and pro-inflammatory cytokines may play a key role in the pathophysiology of depression as well as cancer. This pilot study investigated the efficacy of sputum interleukin (IL)-6, tumor necrosis factor (TNF)-α and salivary cortisol as new markers to support the diagnosis of depression in lung cancer patients. The diurnal rhythms of sputum IL-6, sputum TNF-α and salivary cortisol were measured in lung cancer patients with and without depression as well as depressed controls and healthy controls. The area under the diurnal variation curves (AUC) over the 24h time course and relative diurnal variation (VAR) were calculated. Receiver operating characteristic (ROC) analysis was performed. Patients with co-morbid depression and lung cancer showed highest level of sputum IL-6 AUC, sputum TNF-α AUC and lowest level of cortisol VAR (P<0.001). As a biomarker for depression, salivary cortisol VAR demonstrated an optimal cutoff point at 77.8% (AUC=0.94; 95% CI, 0.85-0.98), which is associated with a sensitivity of 82.1% and a specificity of 96.0%. Sputum IL-6 AUC demonstrated a sensitivity of 74.4% and a specificity of 92.0% (AUC=0.81; 95% CI, 0.69-0.90). These findings suggested that higher 24h overall levels of sputum IL-6, TNF-α and flattened diurnal salivary cortisol slopes were associated with depression in lung cancer patients. Sputum IL-6 AUC and salivary cortisol VAR performed best as biomarkers in the diagnosis of depression in lung cancer patients.

[P50 sensory gating studies in schizophrenics: a systematic review].

OBJECTIVE: To conduct a systematic review of P50 sensory gating studies in schizophrenics and the change between before and after treatment. METHODS: Standard search strategy for the Cochrane Review Group was performed by two review authors. Searches were made in PubMed, EMBase, Web of knowledge, PsycINFO, Cochrane Library, CNKI, Wanfang, VIP and CBMDisc databases. STROBE (strengthening the reporting of observational studies in epidemiology) was used to assess the methodological quality of the studies. RevMan 5.0.23 software was employed to conduct a Meta analysis. RESULTS: Seventy-one literatures were reviewed and 7 studies met the inclusion criteria for a Meta analysis. The meta-analysis of random effects showed that S1 amplitude was lower in the schizophrenia group than in the normal control group (P = 0.02). And S2 amplitude was significant higher in schizophrenia group than the normal control group (P = 0.001). There were no statistical significance in S1 and S2 latency between two groups (P = 0.34 and P = 0.19 respectively). P50 Ratio in schizophrenia group was significantly higher than the normal control group. And the difference was statistically significant [Z = 11.46, P < 0.00001, combined SMD = 44.18, 95%CI (36.62, 51.74)]. However the P50 difference showed no significant difference (P = 0.14). An analysis of fixed effects showed that the P50 Ratio difference was not statistically significant in schizophrenics between before and after treatment (P = 0.19). CONCLUSION: The schizophrenics have a sensory gating dysfunction. P50 Ratio is a stable and reliable indicator of sensory gating function. Antipsychotics may partly enhance P50 sensory gating in schizophrenics, but can not completely reverse the defect of P50 suppression.

[Influence of estradiol on tryptophan hydroxylase and 5-hydroxytryptamine content in raphe nuclei of rats under forced swimming stress].

OBJECTIVE: To investigate the effect of estradiol (E2) on tryptophan hydroxylase (TPH) and 5-hydroxytryptamine (5-HT) content in raphe nuclei of rats under forced swimming stress and explore the role of estrogen and stress in disease mechanism of depression in women. METHODS: At Week 3 post-ovariectomy, 35 ovariectomized (OVX) female SD rats were randomly divided into 5 groups (n = 7): non-stress group, control group, estradiol (E2) group and fluoxetine (FLX) group and E2 plus FLX group. Animals were administered with different drugs for 2 weeks. At Day 14, animals except those in the non-stress group were subjected to the 15 min forced swimming test (FST). At 2 hours post-FST, all animals including those in the non-stress group were perfused with 4% paraformaldehyde and brains removed for TPH and 5-HT immunofluorescence staining. We compared the content of TPH and 5-HT by observing and calculating the integrated optical density (IOD) of immunofluorescent-positive signals in raphe nuclei. RESULTS: (1) The IOD value of TPH- and 5-HT-positive region in raphe nuclei of rats in the control group was significantly lower than that of the non-stress group (P < 0.01); (2) the IOD value of TPH- and 5-HT-positive region in raphe nuclei of rats in the E2, FLX and E2 plus FLX groups was significantly higher than that in the control group (P < 0.05). CONCLUSION: Forced swimming stress can decrease the TPH and 5-HT content in raphe nuclei. Such changes can be prevented by a pre-administration of estradiol. Similar results are observed with antidepressant fluoxetine. These effects may underlie the role of estradiol and stress in the disease mechanism of depression in women.

Estradiol or fluoxetine alters depressive behavior and tryptophan hydroxylase in rat raphe.

The effects of 17beta-estradiol and fluoxetine on behavior of ovariectomized rats subjected to the forced swimming test and the expression of tryptophan hydroxylase (TPH) in dorsal and median raphe were investigated, respectively through time sampling technique of behavior scoring and immunohistochemistry. Both estradiol and fluoxetine increased swimming and decreased immobility in the forced swimming test. The forced swimming stress decreased integrated optical density of TPH-positive regions in dorsal and median raphe. Both estradiol and fluoxetine administration prevented integrated optical density of TPH-positive regions from being decreased by forced swimming stress. These observations suggest that both estradiol and fluoxetine have protective bearing on ovariectomized rats enduring forced swimming stress.

[Effect of maternal antepartum psychological therapy upon early infant temperament].

OBJECTIVE: To find out whether there was any change in early infant temperament after mothers had received group psychological therapy on depression and anxiety during pregnancy period. METHODS: A total of 800 subjects meeting the inclusion criteria, without the exclusion criteria and willing to sign the informed consent were recruited randomly from Shanghai International Peace Maternity & Child Health Hospital in their l6th-20th weeks of pregnancy. They were randomized into the therapy group and the control group by the doll randomization table. Women in the therapy group would have a group psychological therapy for 6 times, 1.5 hours each time, while the control group not. The group psychological therapy included therapist introduction and participatory discussion. The therapy concerned the antepartum and postpartum depression, the risk factors concerned with antepartum and postpartum depression, antepartum and postpartum anxiety, psychological defense theory, reflex training and spouse lesson. Mothers reported their babies' infant temperament by filling the early infant temperament questionnaire (EITQ) within 3 months post-delivery. RESULTS: The percent of easy infant temperament type was 87.9% in the psychological therapy group and 81.7% in the hard group. And there was significant difference between two groups (chi2 = 4.530, upsilon=1, P = 0.033). And there were significant differences in the dimensions of approach-withdrawal and threshold of responsiveness in infant temperament between two groups. CONCLUSION: The maternal antepartum psychological therapy can increase the ratio of easy infant temperament. And it has effects upon the temperament dimensions of approach-withdrawal and threshold of responsiveness.

[An association study of brain-derived neurotrophic factor gene polymorphism in bipolar disorders].

OBJECTIVE: To investigate the association between brain-derived neurotrophic factor (BDNF) gene polymorphism and bipolar disorder. METHODS: Single nucleotide polymorphisms rs6265 and rs11030101 in BDNF gene were detected and compared between 228 patients with bipolar disorder and 361 healthy controls. RESULTS: The genotypes, alleles and combinative genotype of BDNF gene single nucleotide polymorphism rs6265 and rs11030101 did not show significant differences between two groups. There were also no significant differences in genotypes and combinative genotypes between diagnostic subtypes, genders and on-set age of bipolar disorder and controls. CONCLUSION: This study did not found that BDNF gene single nucleotide polymorphism rs6265 and rs11030101 are associated with bipolar disorders.