Attention-deficit/hyperactivity disorder medication and risk of suicide attempt: A meta-analysis of observational studies.

PURPOSE: Epidemiologic findings are inconsistent regarding the association between attention-deficit/hyperactivity disorder (ADHD) medication exposure and suicide attempt in individuals with ADHD. METHODS: A systematic literature search of PubMed, Embase and Cochrane Library up to February 2020 was performed. A meta-analysis was conducted for outcomes in which a summary risk ratio (RR) was calculated when taking heterogeneity into account. RESULTS: Both population-level and within-individual analyzes showed that ADHD medication was associated with lower odds of suicide attempts (RR = 0.76, 95% confidence interval [CI], 0.58-1.00; P = .049 and RR = 0.69; 95% CI, 0.49-0.97; P = .049, respectively). However, the association only existed for participants who were treated with stimulants (RR = 0.72; 95% CI, 0.53-0.99; P = .042 on population-level analysis and RR = 0.75; 95% CI, 0.66-0.84; P < .001 on within-individual analysis). Furthermore, a lower risk of suicide attempts was not observed in subjects who took ADHD medication for 1 to 90 days (RR = 0.91; 95% CI, 0.74-1.13; P = .416 on within-individual analysis). CONCLUSION: The results indicate that non-stimulant treatment is not associated with a higher risk of suicide attempt, but stimulant treatment is associated with a lower risk of suicide attempt.

Efficacy and Safety of Jiawei Suanzaoren Decoction Combined with Lorazepam for Chronic Insomnia: A Parallel-Group Randomized Controlled Trial.

BACKGROUND: Chronic insomnia is a major public health problem, but there are limited effective therapies. Jiawei Suanzaoren Decoction (JW-SZRD) has been used as an alternative option for treating insomnia. This study aimed to investigate the long-term efficacy and safety of JW-SZRD in combination with lorazepam for chronic insomnia. METHODS: A total of 207 participants were analyzed in this study. The treatment group (TG) received JW-SZRD and lorazepam orally, and the control group (CG) received lorazepam alone. The Insomnia Severity Index (ISI), the Self-Rating Depression Scale (SDS), the Self-Rating Anxiety Scale (SAS), and the Somatic Self-rating Scale (SSS) were evaluated at baseline, weeks 4, 8, and 12. The MOS 36-item Short Form Health Survey (SF-36) was assessed at baseline and week 12. Adverse effects (AEs) were evaluated by the Treatment Emergent Symptom Scale (TESS). RESULTS: Both TG and CG showed obvious improvements in the sleep onset latency (SOL) (P=0.001 and 0.005) and total sleep time (TST) (P=0.001 and 0.005) and total sleep time (TST) (P=0.001 and 0.005) and total sleep time (TST) (P=0.001 and 0.005) and total sleep time (TST) (P=0.001 and 0.005) and total sleep time (TST) (P=0.001 and 0.005) and total sleep time (TST) (d = 1.28). The ISI reduction rate in TG was higher than that in CG at weeks 4, 8, and 12 (P=0.001 and 0.005) and total sleep time (TST) (P=0.001 and 0.005) and total sleep time (TST) (P=0.001 and 0.005) and total sleep time (TST) (P=0.001 and 0.005) and total sleep time (TST) (P=0.001 and 0.005) and total sleep time (TST) (P=0.001 and 0.005) and total sleep time (TST) (. CONCLUSION: The combination of JW-SZRD with lorazepam can significantly improve sleep quality with fewer AEs. It is an effective treatment and superior to lorazepam alone for chronic insomnia.

miR­155 mediates inflammatory injury of hippocampal neuronal cells via the activation of microglia.

MicroRNA (miR)­155 has a crucial role in various cellular functions, including differentiation of hematopoietic cells, immunization, inflammation and cardiovascular diseases. The present study aimed to investigate the roles and mechanisms of miR­155 in treatment­resistant depression (TRD). A Cell Counting Kit­8 assay and flow cytometry were performed to assess the cell viability and apoptosis of microglial cells, respectively. Western blotting and reverse transcription­quantitative polymerase chain reaction assays were used to evaluate the associated protein and mRNA expression, respectively. The results revealed that miR­155 reduced the cell viability of BV­2 microglial cells, and miR­155 enhanced the expression levels of pro­inflammatory cytokines in BV­2 microglial cells. Furthermore, conditioned medium from miR­155­treated microglia decreased the cell viability of HT22 hippocampal cells. miR­155­treated microglia increased the apoptosis of neuronal hippocampal cells by modulating the expression levels of apoptosis regulator Bax, apoptosis regulator Bcl­2, pro­caspase­3 and cleaved­caspase­3. The cell cycle distribution was disrupted by miR­155­treated microglia through induction of S phase arrest. Furthermore, the overexpression of suppressor of cytokine signaling 1 reversed the pro­apoptotic effect of activated microglia on hippocampal neuronal cells. In conclusion, the present results suggested that miR­155 mediated the inflammatory injury in hippocampal neuronal cells by activating the microglial cells. The potential effects of miR­155 on the activation of microglial cells suggest that miR­155 may be an effective target for TRD therapies.

CSF miR-16 expression and its association with miR-16 and serotonin transporter in the raphe of a rat model of depression.

BACKGROUND: Depression is a common mental disorder with unknown mechanism. Emerging evidence shows that miRNAs play a critical role in the process of depression. Here we reported the cerebrospinal fluid (CSF) miR-16 expression and its association with miR-16 and serotonin transporter (SERT) in the raphe of a rat model of depression. METHODS: 20 rats were randomized to the control or CUMS (chronic unpredictable mild stress) group. The rats in the CUMS group underwent CUMS for 21 days, while those in the control group received no treatment. After anesthetization, CSF was collected for the measurement of miR-16. Then raphes from all rats were separated for determination of miR-16 and SERT protein. RESULTS: The expression levels of miR-16 in CSF and raphe of the CUMS group were significantly lower than those of the control group (P = 0.007 and 0.031). However, SERT protein in raphe of the CUMS group was obviously increased as compared that of the control group (P = 0.005). There was a positive correlation between CSF miR-16 and raphe miR-16 (r = 0.95, P = 0.000). Meanwhile, negative correlations between miR-16 and SERT protein in raphe (r = -0.70 P = 0.02), between CSF miR-16 and raphe SERT protein (r = -0.86, P = 0.002) were observed in the CUMS group. LIMITATIONS: We have not explored the reason why CSF miR-16 was decreased in the rat model of depression and only tested the association of miR-16 between CSF and raphe. CONCLUSIONS: CSF miR-16 was involved in the pathogenesis of depression via reflecting raphe miR-16 level, and thus affecting raphe SERT expression.

Modified Suanzaorentang Had the Treatment Effect for Generalized Anxiety Disorder for the First 4 Weeks of Paroxetine Medication: A Pragmatic Randomized Controlled Study.

Background. Paroxetine does not show satisfactory therapeutic effect for generalized anxiety disorder (GAD) patients for the first 2-4 weeks of medication. Diazepam is always concurrently used although it has some shortcomings such as physical dependence and withdrawal reactions. In this study, we aimed to identify whether modified Suanzaorentang (MSZRT), a combined Chinese formula including Suanzaorentang (SZRT) and Zhizichitang (ZZCT), could control the anxiety of GAD for the first 4 weeks of paroxetine medication. Methods. 156 GAD patients were randomized to the treatment of paroxetine, paroxetine-diazepam, or paroxetine-MSZRT for 4 weeks. Hamilton Anxiety Scale (HAMA) Test and Self-Rating Anxiety Scale (SAS) Test were determined each week as the evaluation of clinical efficacy. Adverse events (AEs) were also closely observed by performing the Treatment Emergent Symptom Scale (TESS) Test. Results. Both paroxetine-MSZRT and paroxetine-diazepam decreased more HAMA and SAS total scores than paroxetine from weeks 1 to 3. Paroxetine-MSZRT as well as paroxetine-diazepam had an obviously higher onset rate than paroxetine in each week. After 4 weeks' treatment, the overall effectiveness rate in the paroxetine-MSZRT group (90.00%) was obviously higher than those of the paroxetine group (74.42%) but did not significantly differ from the paroxetine-diazepam group (93.88%). Conclusion. MSZRT had the treatment effect for GAD when paroxetine was used for the first 4 weeks.

[Effect of acupuncture on early onset of SSRIs treating depressive disorder and related indicators of neuroimmunology].

OBJECTIVE: To observe the intervention effect of acupuncture on early onset of selec- tive serotonin reuptake inhibitors (SSRIs) in treating depressive disorder, and to study its effect on ser- um 5-HT and unbalanced inflammatory cytokines secreted by TH1/TH2. METHODS: Totally 90 patients with depressive disorder were randomly assigned to the drug control group (as the control group, 45 cases) and the acupuncture combined drug treatment group (as the treatment group, 45 cases). All patients were treated for 4 consecutive weeks. Another 45 healthy subjects were recruited as a healthy control group. The effect of acupuncture on early onset of SSRls in treating acute phase depressive disorder pa- tients was evaluated by HAMD score in the control group and the treatment group before treatment,and at weekends of the 1st, 2nd, and 4th week after treatment. Besides, their serum levels of 5-HT, IL-1ß and IL-6 (secreted by TH1), and IL-4 and IL-10 (secreted by TH2) were detected before treatment and after treatment at the weekend of the 4th week. RESULTS: Compared with the healthy control group,serum lev- els of 5-HT, IL-4, and IL-10 decreased in the two drug-treated groups before treatment (P < 0.01); serum levels of IL-1ß and IL-6 increased (P <0.01). Compared with before treatment in the same group, HAMD score decreased in the control group at weekends of the 2nd and the 4th week after treatment (P < 0.01); HAMD scores decreased in the treatment group at weekends of the 1st, 2nd, 3rd,and 4th week after treatment (P < 0.01); serum levels of 5-HT, IL-4, and IL-10 increased,serum levels of IL-1ß and IL- 6 decreased in the two drug-treated groups after treatment (all P < 0.01). Compared with the control group at the same time point,HAMD scores decreased in the treatment group at weekends of the 1st, 2nd,3rd,and 4th week after treatment (P < 0.01),serum levels of 5-HT, IL-4, and IL-10 increased (P < 0.05, P < 0.01), serum levels of IL-6 decreased (P < 0. 01). CONCLUSION: Acupuncture could accelerate early onset of SSRIs in treating acute phase depressive disorder, and effectively regulate serum 5-HT levels and inflammatory cytokines secreted by TH1/TH2.

CSF miR-16 is decreased in major depression patients and its neutralization in rats induces depression-like behaviors via a serotonin transmitter system.

BACKGROUND: Animal and cell line studies demonstrated that miR-16 may be associated with major depressive disorder (MDD) via regulation of the expression of serotonin transporter (SERT) gene. However, human studies about miR-16 of patients with MDD are still lacking. The aim of this study was to investigate the possible involvement of miR-16 in the mechanism of MDD in humans. METHODS: Thirty-six drug-free patients with MDD and 30 healthy controls aged between 18 and 45 years old were recruited. 24-item Hamilton depression scale test was performed for each subject. MiR-16 in cerebrospinal fluid (CSF) and blood, as well as serotonin in CSF were assayed by the qRT-PCR or ELISA method. To confirm the role of CSF miR-16 in MDD, animal study about intracerebroventricular injection of anti-miR-16 was also performed. Depression-like behaviors, CSF miR-16 and serotonin, blood miR-16, and raphe SERT protein of rats were also tested. RESULTS: CSF miR-16 in MDD patients was significantly lower than that in controls. It was negatively correlated with Hamilton scores and positively associated with CSF serotonin. However, blood miR-16 was not significantly different between two groups and it was not statistically correlated with CSF miR-16. In animal study, anti-miR-16-treated rats were evaluated to exhibit depression-like behaviors, extremely lower CSF miR-16, significantly higher CSF serotonin, and obviously higher raphe SERT protein than control rats. LIMITATION: We did not detect SERT protein in human brain due to the impossibility of sample collection. CONCLUSION: Our study suggested that CSF miR-16 participated in the physiopathology of MDD via the modulation of serotonin transmitter system in brain.

[Study of genotoxicity and oxidative stress induced by copper oxide nanoparticles in mice].

OBJECTIVE: To investigate the genotoxicity and oxidative stress induced by copper oxide nanoparticles in mice. METHODS: Thirty mice were randomly divided into control group and low- and high-dose exposure groups. The low- and high-dose exposure groups were given copper oxide nanoparticles (50 and 150 mg/kg) by a single intraperitoneal injection, while the control group was given an equal volume of normal saline containing 0.05%Tween 80. The micronucleus rate of reticulocytes in peripheral blood from the caudal vein and urinary 8-hydroxy-deoxyguanosine (8-OH-dG) level were measured before and at 24, 48, and 72 h after exposure. All the mice were sacrificed at 72 h after exposure, the liver, kidney, and femoral marrow were taken for DNA extraction, and 8-OH-dG in DNA was quantified. RESULTS: The micronucleus rates of peripheral blood reticulocytes in low-dose exposure group at 48 h (3.11±1.46‰ and in high-dose exposure group at 24 and 48 h (4.25±0.43) and 5.42±0.76‰) were significantly increased compared with those before exposure (1.55±0.39‰ and 1.11±0.19‰) and those in control group (1.55±0.28‰ and 1.00±0.67‰) (P < 0.05 or P < 0.01). The urinary 8-OH-dG levels (ng/mg creatinine) in low- and high-dose exposure groups at all time points were significantly increased compared with those before exposure and those in control group (P < 0.05 or P < 0.01). The low- and high-dose exposure groups had significantly higher content of 8-OH-dG in liver DNA than the control group (4.53±1.27 and 7.69±2.78 vs 0.85±0.14, P < 0.01). CONCLUSION: Copper oxide nanoparticles cause genotoxicity and increase oxidative stress in mice.

8-hydroxyguanine in urine and serum as an oxidative stress marker: effects of diabetes and aging.

8-Hydroxydeoxyguanosine (8-OH-dG) is the most extensively analyzed oxidative stress marker. Recently, 8-hydroxyguanine (free base: 8-OH-Gua) has been recognized as an oxidative stress marker. To verify the usefulness of 8-OH-Gua, the 8-OH-dG and 8-OH-Gua levels in the urine and the 8-OH-Gua levels in the serum of type 2 diabetic model animals, db/db mice, were measured as oxidative stress markers by a column switching HPLC-system coupled to an electrochemical detector. The urinary 8-OH-Gua and 8-OH-dG levels in db/db mice (7-26 weeks old) were significantly higher than those in control (db/m+) mice. The 8-OH-Gua levels in the serum of the db/db mice were also about 2-fold higher than those in the control mice at 26 weeks of age. In addition, the urinary levels of 8-OH-dG and 8-OH-Gua increased with age (9-26 weeks). A significant positive correlation was obtained between the 8-OH-dG and 8-OH-Gua levels in urine. Although no difference was observed in the 8-OH-dG levels in the liver and kidney DNA between the diabetic and control mice, these results suggested that urinary 8-OH-dG and free base 8-OH-Gua in urine or serum may be good biomarkers of oxidative stress.

Metal nanoparticle-induced micronuclei and oxidative DNA damage in mice.

Several mechanisms regarding the adverse health effects of nanomaterials have been proposed. Among them, oxidative stress is considered to be one of the most important. Many in vitro studies have shown that nanoparticles generate reactive oxygen species, deplete endogenous antioxidants, alter mitochondrial function and produce oxidative damage in DNA. 8-Hydroxy-2'-deoxyguanosine is a major type of oxidative DNA damage, and is often analyzed as a marker of oxidative stress in human and animal studies. In this study, we focused on the in vivo toxicity of metal oxide and silver nanoparticles. In particular, we analyzed the induction of micronucleated reticulocyte formation and oxidative stress in mice treated with nanoparticles (CuO, Fe(3)O(4), Fe(2)O(3), TiO(2), Ag). For the micronucleus assay, peripheral blood was collected from the tail at 0, 24, 48 and 72 h after an i.p. injection of nanoparticles. Following the administration of nanoparticles by i.p. injection to mice, the urinary 8-hydroxy-2'-deoxyguanosine levels were analyzed by the HPLC-ECD method, to monitor the oxidative stress. The levels of 8-hydroxy-2'-deoxyguanosine in liver DNA were also measured. The results showed increases in the reticulocyte micronuclei formation in all nanoparticle-treated groups and in the urinary 8-hydroxy-2'-deoxyguanosine levels. The 8-hydroxy-2'-deoxyguanosine levels in the liver DNA of the CuO-treated group increased in a dose-dependent manner. In conclusion, the metal nanoparticles caused genotoxicity, and oxidative stress may be responsible for the toxicity of these metal nanoparticles.

DNA methylation by dimethyl sulfoxide and methionine sulfoxide triggered by hydroxyl radical and implications for epigenetic modifications.

In this Letter, we demonstrate the formation of m(5)dC from dC or in DNA by dimethylsulfoxide (DMSO) and methionine sulfoxide (MetO), under physiological conditions in the presence of the Fenton reagent in vitro. DMSO reportedly affects the cellular epigenetic profile, and enhances the metastatic potential of cultured epithelial cells. The methionine sulfoxide reductase (Msr) gene was suggested to be a metastatis suppressor gene, and the accumulation of MetO in proteins may induce metastatic cancer. Our findings are compatible with these biological data and support the hypothesis that chemical cytosine methylation via methyl radicals is one of the mechanisms of DNA hypermethylation during carcinogenesis. In addition to m(5)dC, the formation of 8-methyldeoxyguanosine (m(8)dG) was also detected in DNA under the same reaction conditions. The m(8)dG level in human DNA may be a useful indicator of DNA methylation by radical mechanisms.

Urea, the most abundant component in urine, cross-reacts with a commercial 8-OH-dG ELISA kit and contributes to overestimation of urinary 8-OH-dG.

Urinary 8-OH-dG is commonly analyzed as a marker of oxidative stress. For its analysis, ELISA and HPLC methods are generally used, although discrepancies in the data obtained by these methods have often been discussed. To clarify this problem, we fractionated human urine by reverse-phase HPLC and assayed each fraction by the ELISA method. In addition to the 8-OH-dG fraction, a positive reaction was observed in the first eluted fraction. The components in this fraction were examined by the ELISA. Urea was found to be the responsible component in this fraction. Urea is present in high concentrations in the urine of mice, rats, and humans, and its level is influenced by many factors. Therefore, certain improvements, such as a correction based on urea content or urease treatment, are required for the accurate analysis of urinary 8-OH-dG by the ELISA method. In addition, performance of the ELISA at 4 degrees C reduced the recognition of urea considerably and improved the 8-OH-dG analysis.

[Expressions of collagen in lung of rats exposed to ammonium perchlorate].

OBJECTIVE: To study the influence on expression of interstitial collagen in lung of rats exposed to ammonium perchlorate. METHODS: The rats were treated with AP by intratracheal instillation and sacrificed after 3 d, 7 d, 14 d, 28 d. The mRNA level of collagen I and collagen III in the lung tissues was measured by RT-PCR. RESULTS: The levels of collagen I on 7 d, 14 d, 28 d exposed for high dose group (1.93 +/- 0.41, 3.50 +/- 0.90, 2.33 +/- 1.12) and 28 d exposed for medial dose group (2.58 +/- 0.86) were higher significant (P < 0.05) than those in negative control group (0.52 +/- 0.11, 0.77 +/- 0.15, 0.86 +/- 0.29) The levels of collagen I in low dose group exposed for 14 d(1.99 +/- 0.67), 28 d(1.85 +/- 0.67) and high dose group 14 d(3.50 +/- 0.90) exposed for 14 d were higher significant (P < 0.05) compared to those exposed to AP for 3 d(0.52 +/- 0.14), (1.71 +/- 0.38). The levels of collagen III on 14 d, 28 d exposed for high dose group (2.60 +/- 1.00, 1.46 +/- 0.36) and 14 d, 28 d exposed for medial dose group (1.80 +/- 0.51, 2.16 +/- 0.87) were higher significant (P < 0.05 or P < 0.01) than those in negative control group(0.54 +/- 0.20, 0.52 +/- 0.22); The levels of collagen III in medial dose group(2.16 +/- 0.87) exposed for 28 d, and high dose group exposed for 14 d (2.60 +/- 1.00) were higher significant (P < 0.05) compared to those exposed to AP for 3 d(1.22 +/- 0.32, 0.96 +/- 0.17). CONCLUSION: The results suggest that AP has a toxic effect to promote the expressions of collagen I and collagen III mRNA in lungs of rats, and may be cause fibrosis, but there should have more suffice evidences to prove that AP is exactly compound that made lung fibrosis.