Preventive interventions for individuals at risk of developing bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to explore whether early interventions can reduce affective symptoms and have long-term benefits among individuals at risk of bipolar disorder (BD). METHODS: The PubMed, Embase, and Web of Science databases were searched. The primary outcome was continuous symptom scores before and after treatment. Random effects meta-analyses were conducted for each outcome arm studied and pooled mean difference estimates were calculated. RESULTS: The search identified 10 controlled studies involving 425 participants and 6 single-arm studies involving 90 participants. For controlled trials, meta-analysis showed that the interventions led to greater reduction in clinical global score than placebo (standardized mean differences (SMD) = -0.96, 95 % CI:-1.32, -0.60), and supported a long-term longitudinal effect for pharmacotherapy (SMD = -0.42, 95 % CI: -0.79, -0.05). For single-arm trials, both pharmacotherapy and psychotherapy showed efficacy for depressive symptoms, while pharmacotherapy only showed efficacy for hypomania symptoms (effect size (ES) = -9.16, 95 % CI:-11.29, -7.04). Discontinuation of pharmacotherapy due to adverse effects did not show a difference. LIMITATIONS: The primary limitations are the small number of RCTs and the influence of medication dosage. CONCLUSIONS: Based on the limited available data, early interventions show efficacy for individuals at risk of BD. Psychological therapy might be more beneficial for depressive symptoms and have long-term benefits for hypomania. Pharmacotherapy may be appropriate in situations of severe hypomanic symptoms and the poor functioning. Large, well-designed, double-blind -controlled trials are needed to make solid conclusions about the efficacy of early interventions.

Metabolic changes in patients with bipolar disorder in spring.

Bipolar disorder (BD) is a common mental condition with a seasonal pattern (SP) of onset. In the spring, there is a higher incidence rate of mania or mixed onset and suicide. However, the underlying mechanism of this SP remains unclear. In this study, targeted metabolomics was used to understand metabolic changes in patients with BD before and after the spring equinox. Nine patients with BD and matched healthy controls were tested for serum metabolomics at the spring equinox and 15 days before and after the spring equinox. The results showed that 27 metabolite levels changed significantly, three of which interacted between three time points and groups involving triglyceride (TG, 20:4_34:2), TG (20:4_34:3) and TG (16:0_36:6). The identified metabolic pathways mainly involved arginine biosynthesis, D-glutamine and D-glutamate metabolism, and nitrogen metabolism. Changes in solar radiation and lunar cycle during spring may be the external causes of metabolic changes. These findings help to further explore seasonal metabolic changes in patients with BD and provide insights into the mechanisms of patients' emotional changes in spring.

Cyclothymic Temperament, Physical Neglect, and Earlier Age of Onset Predict Poor Medication Adherence in Patients With Bipolar Disorder.

ABSTRACT: Individual-level risk factors may predict poor medication adherence (PMA) in bipolar disorder (BD). This study aimed to evaluate the association between affective temperament, childhood trauma, age of first onset, and PMA in patients with BD in China. A total of 168 patients completed the eight-item Morisky Medication Adherence Scale; the Short Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire; and the Childhood Trauma Questionnaire-Short Form. Scores were then compared between PMA and non-PMA groups. Binary logistic regression showed that age of first onset was negatively correlated with PMA ( ß = -0.106, p = 0.002), whereas physical neglect and cyclothymic temperament were positively correlated with PMA ( ß = 0.143, p = 0.029; ß = 0.19, p = 0.001, respectively). These findings indicate that cyclothymic temperament, physical neglect, and earlier onset are predictors of PMA in patients with BD and that such patients may require further attention to improve medical compliance.

White matter abnormalities in first-episode patients with depersonalization/derealization disorder: A tract-based spatial statistics study.

BACKGROUND: Neuroimaging studies on depersonalization / derealization disorder (DPD) have revealed that there are structural and functional alterations across numerous brain regions. However, to date, the exact white matter abnormalities that are associated with different clinical symptoms and cognitive impairments in first-episode, drug-naïve patients with DPD remain unclear. METHODS: Overall, 25 first-episode, drug-naïve patients with DPD and 23 healthy controls were recruited and underwent DTI scans. The tract-based spatial statistics analysis was conducted in order to determine white matter microstructural changes between the two groups. Correlation analysis was conducted between the fractional anisotropy (FA) of abnormal WM fibers and the total score of the 30-item Cambridge Depersonalization Scale (CDS-30), cognitive assessments. RESULTS: Patients with DPD demonstrated higher FA in the right corpus callosum (CC), and posterior corona radiate (CR), compared to healthy controls. The FA in the right CC demonstrated a positive correlation with total score of CDS-30, numbing, unreality of self, perceptual alterations, and temporal disintegration, respectively. FA in the right CR region indicated a positive correlation with the total score of CDS-30, unreality of self, perceptual alterations, and temporal disintegration, respectively. Furthermore, FA in the right CR region was found to be negatively correlated with the Continuous Performance Test and the Stroop color-word test. CONCLUSION: The altered white matter microstructure and cognitive impairments of medication naïve DPD patients were observed. Abnormalities in the integrity of CC and CR were associated with severity of symptoms and cognitive impairments, which may provide a potential biomarker for clinical studies on DPD.

Paliperidone Compared with Haloperidol on the Theory of Mind Tasks in Schizophrenia: A Pilot Trial.

PURPOSE: Theory of mind (ToM) is an important part of social cognitive function and is associated with medial prefrontal cortical (mPFC) activity. This study aimed to evaluate the efficacy of paliperidone in improving ToM task performance in patients with schizophrenia compared with haloperidol. PATIENTS AND METHODS: This study was a single-center, single-blinded (assessor), parallel-group randomized clinical trial of patients with schizophrenia randomized to paliperidone or haloperidol. ToM was assessed at weeks 0, 8, 12, and 16 using the first-order belief, higher-order belief, faux-pas, and Reading the Mind in the Eyes tests. The primary outcome was the change in the ToM performance scores from baseline to after 16 weeks of treatment. RESULTS: The participants received paliperidone (n = 29) or haloperidol (n = 31). For the first-order belief task, there were no between-group differences (P > 0.05) but time differences in both groups (P < 0.05). For the higher-order belief task, there were no between-group differences (P > 0.05), but there were time differences in both groups (P < 0.05) and a time×group interaction in the paliperidone group only (P < 0.05). For the faux-pas task, there was a difference between groups at week 16 (P < 0.05), and the improvement in time was significant for the paliperidone group only (P < 0.05). For the Reading the Mind in the Eyes task, there was an improvement over time for the paliperidone group only (P < 0.05). Safety was manageable in both groups. CONCLUSION: Paliperidone treatment might be more effective than haloperidol in improving ToM task performance in schizophrenia. TRIAL REGISTRATION: chictr.org.cn_identifier ChiCTR-IPR-15007635.

Disrupted Resting-State Functional Connectivity between the Dorsal Attention, Default Mode, and Frontoparietal Networks in Nonorganic Gastrointestinal Disorder Patients with Spleen Deficiency Syndrome.

INTRODUCTION: Spleen deficiency syndrome (SDS), a common clinical syndrome of traditional Chinese medicine, is manifested with digestive symptoms and cognitive impairments. However, the cognitive neural mechanism in brain networks of SDS still remained unclear. Our aim was to investigate the changes between the default mode, dorsal attention, and frontoparietal networks in SDS. METHODS: Twenty nonorganic gastrointestinal disorder (NOGD) patients with SDS and eighteen healthy controls were enrolled to attend functional magnetic resonance imaging scan and participated a continuous performance test (CPT) before scanning. RESULTS: Compared with healthy controls, NOGD patients with SDS showed the significantly increased functional connectivity (FC) between dorsal attention network (DAN) and left frontal-parietal control network (LFPN) and significantly decreased FC between LFPN and default mode network (DMN). The functional network connectivity analysis showed positive correlation coefficients between the DAN and LFPN and DAN and DMN as well as negative correlation between LFPN and DMN in NOGD patients with SDS compared with healthy controls. Correlation analysis revealed that the increased FC between LFPN and DAN was positively correlated with 4-digitnumber reaction time mean (RTM) and 3-digitnumber RTM. CONCLUSION: Our study may provide novel insights into the relationship among the DMN, DAN, and FPN in NOGD patients with SDS to deepen our understanding of the neuropsychological mechanisms of SDS.

Shi-Zhen-An-Shen Decoction, a Herbal Medicine That Reverses Cuprizone-Induced Demyelination and Behavioral Deficits in Mice Independent of the Neuregulin-1 Pathway.

Shi-Zhen-An-Shen decoction (SZASD), a Chinese herbal medicine that is a liquor extracted from plants by boiling, has been reported to be effective in treating schizophrenia. However, the mechanism is unclear. Abnormal demyelination has been implicated in schizophrenia. The aim of this study was to investigate the effect of SZASD on myelin in demyelinated mice exhibiting schizophrenia-like behaviors. Sixty male C57BL/6 mice were randomly divided into six groups (n = 10 per group): (1) control group, (2) cuprizone (CPZ, a copper chelator that induced demyelination, 0.2% w/w)+saline, (3) CPZ+low-dose SZASD (8.65 g·kg-1·d-1), (4) CPZ+medium-dose SZASD (17.29 g·kg-1·d-1), (5) CPZ+high-dose SZASD (25.94 g·kg-1·d-1), and (6) CPZ+quetiapine (QTP, an atypical antipsychotic that served as a positive treatment control, 10 mg·kg-1·d-1). Mice in groups 2-6 were treated with CPZ added to rodent chow for six weeks to induce demyelination. During the last two weeks, these mice were given an oral gavage of sterile saline, SZASD, or quetiapine. Behavioral tests and brain analyses were conducted after the last treatment. The brain expression of myelin basic protein (MBP) and neuregulin-1 (NRG-1) was assessed using immunohistochemistry and Western blots. CPZ induced significant schizophrenia-like behaviors in the mice, including reduced nest-building activity and sensory gating deficits. Hyperlocomotor activity was accompanied by significant reductions in MBP expression in the corpus callosum, hippocampus, and cerebral cortex. However, both QTP and SZASD significantly reversed the schizophrenia-like behaviors and demyelination in CPZ-fed mice. The QTP and medium-dose SZASD resulted in better therapeutic effects compared to the low and high SZASD doses. Reduced NRG-1 expression was observed in CPZ-fed mice compared with controls, but neither QTP nor SZASD showed significant influence on NRG-1 expression in the hippocampus. Together, SZASD showed a therapeutic effect on demyelinated mice, and the improvement of demyelination might not be through the NRG-1 pathway.

Acupuncture for metabolic syndrome: systematic review and meta-analysis.

BACKGROUND: Metabolic syndrome (MetS) is a cluster of conditions associated with an increased risk of cardiovascular disease and diabetes mellitus. Acupuncture may have benefits in the treatment of MetS. This systematic review with meta-analysis aimed to determine the effectiveness and safety of acupuncture therapy in the treatment of MetS. METHODS: Large-sample randomized controlled trials (RCTs) of acupuncture treatment for MetS were extracted from multiple Chinese and English databases and analyzed using meta-analysis to evaluate the efficacy/effectiveness of acupuncture with respect to various MetS indices in comparison with control treatments including conventional medications (CMs) and lifestyle intervention (LI), together and separately. RESULTS: A total of 13 RCTs were identified with 423 subjects undergoing acupuncture regimens and 411 receiving control interventions. Active acupuncture yielded better outcomes than sham acupuncture with respect to improving multiple MetS indices. Acupuncture monotherapy had similar effectiveness in controlling triglyceride levels and high-density lipoprotein levels compared to CMs. The overall effects of adjunctive acupuncture were markedly greater than those of controls (CMs + LI, CMs, and LI) with respect to waist circumference with a mean difference of -5.11 cm (Z = 4.57, p < 0.001) and body mass index with a mean difference of -2.54 (Z = 5.38, p <0.001), and improvements were observed in most hyperlipidemia indices and fasting blood glucose. An evidence-based acupuncture regimen was identified as a future treatment strategy for MetS. CONCLUSION: Acupuncture is beneficial in the treatment of MetS and could serve as an alternative therapy for MetS-associated conditions. Larger-scale RCTs are needed to confirm the efficacy/effectiveness of our recommended evidence-based acupuncture regimen in MetS.

Assessing Cognitive Abilities of Patients With Shift Work Disorder: Insights From RBANS and Granger Causality Connections Among Resting-State Networks.

BACKGROUND: Numerous studies have confirmed that long-term shift work is not only associated with increased health problems and acute impact on safety but also with impaired cognitive abilities. However, very little is known about effects of shift work on cognition-related brain resting-state networks. The aim of this study was to explore the effects of shift work disorder (SWD) on granger causality connection among resting-state brain networks. METHODS: Thirty patients with SWD and 25 matched healthy subjects were recruited to undergo the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and resting-state fMRI scanning. We employed independent component analysis (ICA) to extract resting-state brain networks and granger causality analysis (GCA) to characterize the difference of granger causality connection among cognition-related resting-state brain networks. RESULTS: Compared with healthy subjects, patients with SWD showed impairments on the attention and immediate memory. Seven resting-state brain networks were identified, and patients with SWD showed more numerous granger causality connections in comparison with healthy subjects. Two-sample t test results showed that there were significantly increased inflows from the anterior default mode network (aDMN) to sensorimotor network (SMN) and left frontoparietal network (LFPN) to salience network (SN). Correlation analyses showed that the increased inflows from aDMN to SMN were negatively associated with the score of attention, while LFPN to SN were negatively associated with the score of visuospatial/constructional ability. CONCLUSIONS: This study indicates that SWD impairs cognitive performance, and the specific intrinsic brain granger causality connectivity among resting-state networks in SWD patients is affected after long-term shift works.

Mitochondrial stress-activated cGAS-STING pathway inhibits thermogenic program and contributes to overnutrition-induced obesity in mice.

Obesity is a global epidemic that is caused by excessive energy intake or inefficient energy expenditure. Brown or beige fat dissipates energy as heat through non-shivering thermogenesis by their high density of mitochondria. However, how the mitochondrial stress-induced signal is coupled to the cellular thermogenic program remains elusive. Here, we show that mitochondrial DNA escape-induced activation of the cGAS-STING pathway negatively regulates thermogenesis in fat-specific DsbA-L knockout mice, a model of adipose tissue mitochondrial stress. Conversely, fat-specific overexpression of DsbA-L or knockout of STING protects mice against high-fat diet-induced obesity. Mechanistically, activation of the cGAS-STING pathway in adipocytes activated phosphodiesterase PDE3B/PDE4, leading to decreased cAMP levels and PKA signaling, thus reduced thermogenesis. Our study demonstrates that mitochondrial stress-activated cGAS-STING pathway functions as a sentinel signal that suppresses thermogenesis in adipose tissue. Targeting adipose cGAS-STING pathway may thus be a potential therapeutic strategy to counteract overnutrition-induced obesity and its associated metabolic diseases.

Efficacy and safety of Shu-gan-qing-re formula for generalized anxiety disorder: study protocol for a multi-center, prospective, double-blind, double-dummy, randomized controlled trial.

BACKGROUND: Generalized anxiety disorder (GAD) is a persistent and common mental disorder that entails significant impairments in role functioning and quality of life. Currently available effective interventions include psychological therapies, self-help approaches, and pharmacological treatments, which do not quite meet clinical needs, and the ideal anxiolytic is still being sought. Shu-gan-qing-re (SGQR) formula, a Chinese patent medicine, has been well received by patients with GAD in Chinese clinical practice for years. The present prospective, double-blind, double-dummy, randomized controlled trial is designed to investigate the efficacy and safety of SGQR formula for GAD. METHODS/DESIGN: A total of 200 eligible participants will be recruited from four hospitals in different parts of China. They will be randomly assigned to either the study group or the control group in a ratio of 1:1. Participants allocated to the study group will receive SGQR formula and buspirone placebo, while buspirone and SGQR placebo will be applied in the control group. Six scheduled visits will be conducted over the course of 8 weeks. Outcome measurements include Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale-17 (HAMD-17), Clinical Global Impression-Improvement Scale (CGI-I), Traditional Chinese Medicine Syndrome Scale for GAD, and pro-inflammatory cytokine tests: interleukin-1 beta (IL-1ß), IL-6, and tumor necrosis factor-alpha. Adverse reactions will be evaluated by using the Treatment Emergent Symptom Scale (TESS). Safety outcomes and adverse events will also be recorded. DISCUSSION: The study will provide scientific and objective assessments for the efficacy and safety of SGQR formula for patients with GAD, hopefully offering clinicians an alternative approach to GAD. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR-IPR-17013058. Registered on October 20, 2017.

Efficacy and safety of electroacupuncture on metabolic syndrome due to olanzapine and risperidone: Study protocol for a randomized controlled pilot trial.

INTRODUCTION: With the second-generation antipsychotics (SGAs) widely applied to treat patients with schizophrenia, adverse effects, especially the metabolic syndrome (MetS), were paid more attention following by the efficacy of SGAs. Several studies have suggested that acupuncture could be an effective and safe intervention for MetS. Here, we present a study protocol to investigate the effect of electroacupuncture on MetS due to olanzapine and risperidone. METHODS: This study is a prospective, randomized, single-centered, patient-assessor-blinded, parallel-controlled clinical pilot trial. In all, 36 patients will be randomized to an experimental group or control group by a 1:1 ratio. All patients will receive lifestyle interventions. The experimental group will receive electroacupuncture treatment. The control group will receive sham electroacupuncture treatment. The primary outcomes are body mass index (BMI) and waist circumference (WC). The secondary outcome measures include blood pressure (BP), fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), leptin, and adiponectin. We will assess at baseline, 8 weeks after intervention and at the end of 3 months' follow-up. DISCUSSION: The results of this trial are expected to provide data on the efficacy and safety of electroacupuncture on MetS due to olanzapine and risperidone, and potential biochemical mechanism.

Enhanced functional connectivity of the default mode network (DMN) in patients with spleen deficiency syndrome: A resting-state fMRI study.

Numerous studies had investigated the biological basis of spleen deficiency syndrome on gastrointestinal dysfunctions. However, little was known about neuropsychological mechanism of spleen deficiency syndrome. The default model network (DMN) plays an important role in cognitive processing. Our aim is to investigate the change of neuropsychological tests and DMN in patients with spleen deficiency syndrome.Sixteen patients and 12 healthy subjects underwent functional magnetic resonance imaging examination, and 15 patients with spleen deficiency syndrome and 6 healthy subjects take part in the two neuropsychological tests.Compared with healthy subjects, patients with spleen deficiency syndrome revealed significantly increased functional connectivity within DMN, and significantly higher in the scores of 2-FT (P = .002) and 3-FT (P = .014).Our findings suggest that patients with spleen deficiency syndrome are associated with abnormal functional connectivity of DMN and part of neuropsychological tests, which provide new evidence in neuroimaging to support the notion of TCM that the spleen stores Yi and domains thoughts.

Extraction of permanent maxillary teeth without palatal injection: a meta-analysis.

OBJECTIVE: The objective of this meta-analysis was to assess the operation success rates of extracting maxillary teeth without palatal injection. STUDY DESIGN: PubMed, Cochrane Library, EMBASE, SinoMed, and the references of the identified full-text articles were searched for relevant studies, published until June 2017, that met the eligibility criteria. Experimental data were combined by meta-analysis by using RevMan 5.3 software. RESULTS: Seven randomized controlled trials were included in this meta-analysis. Compared with the control groups (given the recommended combination of buccal and palatal anesthesia, also known as routine infiltration anesthesia), experimental group (single buccal anesthesia) for the removal of maxillary permanent teeth at conventional doses, which resulted in a reduction in the success rate (odds ratio = 0.14; 95% confidence interval 0.07-0.27; P < .00001). CONCLUSIONS: The results revealed that without the use of palatal injections, the success rate of maxillary permanent teeth removal is undoubtedly reduced. However, larger and higher-quality tests are needed to confirm and optimize the effect of this anesthesia procedure.

DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway.

Chronic inflammation in adipose tissue plays a key role in obesity-induced insulin resistance. However, the mechanisms underlying obesity-induced inflammation remain elusive. Here we show that obesity promotes mtDNA release into the cytosol, where it triggers inflammatory responses by activating the DNA-sensing cGAS-cGAMP-STING pathway. Fat-specific knockout of disulfide-bond A oxidoreductase-like protein (DsbA-L), a chaperone-like protein originally identified in the mitochondrial matrix, impaired mitochondrial function and promoted mtDNA release, leading to activation of the cGAS-cGAMP-STING pathway and inflammatory responses. Conversely, fat-specific overexpression of DsbA-L protected mice against high-fat diet-induced activation of the cGAS-cGAMP-STING pathway and inflammation. Taken together, we identify DsbA-L as a key molecule that maintains mitochondrial integrity. DsbA-L deficiency promotes inflammation and insulin resistance by activating the cGAS-cGAMP-STING pathway. Our study also reveals that, in addition to its well-characterized roles in innate immune surveillance, the cGAS-cGAMP-STING pathway plays an important role in mediating obesity-induced metabolic dysfunction.

Validation of p27KIP1 expression levels as a candidate predictive biomarker of response to rapalogs in patient-derived breast tumor xenografts.

Blockade of mammalian target of rapamycin (mTOR) is a promising area in breast cancer therapy. However, in clinical trials, objective response rate with mTOR inhibitor monotherapy in breast cancer was modest. Biomarker studies designed to identify the responders of rapalogs are of increasing interest. We validated p27KIP1 expression levels as a candidate predictive biomarker of response to rapalogs. We also analyzed the correlation between rapamycin activity and p27KIP1 expression in the primary breast cancer cells and the patient-derived breast tumor xenograft models. The cells isolated from the breast tumor tissues expressing high levels of p27KIP1 were sensitive to rapamycin, whereas the cells from the tissues expressing low levels of p27KIP1 exhibited resistance to rapamycin. The correlation between p27KIP1 expression and rapamycin antitumor activity was also observed in the patient-derived breast tumor xenograft models. Moreover, we also found rapamycin significantly decreased phosphorylated p70S6K1 and phosphorylated 4EBP1 in both samples. It seemed that the different sensitivity of tumor cells to rapamycin did not owe to its different potency against mTOR activity. We further propose p27KIP1 expression level may be also a candidate predictive biomarker of rapalogs for breast cancer therapy, which requires additional clinical validation.