Transcutaneous electrical cranial-auricular acupoint stimulation versus escitalopram for mild-to-moderate depression: An assessor-blinded, randomized, non-inferiority trial.

AIM: Transcutaneous electrical cranial-auricular acupoint stimulation (TECAS) is a novel non-invasive therapy that stimulates acupoints innervated by the trigeminal and auricular vagus nerves. An assessor-blinded, randomized, non-inferiority trial was designed to compare the efficacy of TECAS and escitalopram in mild-to-moderate major depressive disorder. METHODS: 468 participants received two TECAS sessions per day at home (n = 233) or approximately 10-13 mg/day escitalopram (n = 235) for 8 weeks plus 4-week follow-up. The primary outcome was clinical response, defined as a baseline-to-endpoint ≥50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Secondary outcomes included remission rate, changes in the severity of depression, anxiety, sleep and life quality. RESULTS: The response rate was 66.4% on TECAS and 63.2% on escitalopram with a 3.2% difference (95% confidence interval [CI], -5.9% to 12.9%) in intention-to-treat analysis, and 68.5% versus 66.2% with a 2.3% difference (95% CI, -6.9% to 11.4%) in per-protocol analysis. The lower limit of 95% CI of the differences fell within the prespecified non-inferiority margin of -10% (P ≤ 0.004 for non-inferiority). Most secondary outcomes did not differ between the two groups. TECAS-treated participants who experienced psychological trauma displayed a markedly greater response than those without traumatic experience (81.3% vs 62.1%, P = 0.013). TECAS caused much fewer adverse events than escitalopram. CONCLUSIONS: TECAS was comparable to escitalopram in improving depression and related symptoms, with high acceptability, better safety profile, and particular efficacy in reducing trauma-associated depression. It could serve an effective portable therapy for mild-to-moderate depression.

Minocycline, a classic antibiotic, exerts psychotropic effects by normalizing microglial neuroinflammation-evoked tryptophan-kynurenine pathway dysregulation in chronically stressed male mice.

The dysregulation of tryptophan-kynurenine pathway (TKP) is extensively involved in the pathophysiology of Alzheimer's disease, depression, and neurodegenerative disorders. Minocycline, a classic antibiotic, may exert psychotropic effects associated with the modulation of TKP. In this study, we examined the effects of minocycline in improving behaviour and modulating TKP components in chronically stressed male mice. Following repeated treatment with 22.5 mg/kg and 45 mg/kg minocycline for 27 days, the stressed mice particularly with higher dose displayed significant improvement on cognitive impairment, depression- and anxiety-like behaviour. Minocycline suppressed stress-induced overexpression of pro-inflammatory cytokines and restored anti-inflammatory cytokines. Chronic stress dramatically suppressed blood and prefrontal cortical levels of the primary substrate tryptophan (TRP), the neuroprotective metabolite kynurenic acid (KYNA), and KYNA/KYN ratio, but increased the intermediate kynurenine (KYN), 3-hydroxykynurenine (3-HK), KYN/TRP ratio, and the neurotoxic metabolite quinolinic acid (QUIN). Minocycline partially or completely reversed changes in these components. Minocycline also inhibited stress-induced overexpression of QUIN-related enzymes, indoleamine 2, 3-dioxygenase 1(iDO-1), kynureninase (KYNU), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilate 3,4-dioxygenase (3-HAO), but rescued the decreased expression of kynurenine aminotransferase (KAT) in brain regions. Behavioral improvements were correlated with multiple TKP metabolites and enzymes. These results suggest that the psychotropic effects of minocycline are mainly associated with the restoration of biodistribution of the primary substrate in the brain and normalization of neuroinflammation-evoked TKP dysregulation.

Hirudin alleviates acute ischemic stroke by inhibiting NLRP3 inflammasome-mediated neuroinflammation: In vivo and in vitro approaches.

Acute ischemic stroke is a severe condition that a vessel supplying blood to the brain is abruptly blocked mostly due to cerebral thrombosis and embolism. There is a dearth of the effective prevention and early intervention strategies. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation plays a crucial role in the pathophysiology of ischemic stroke. Hirudin is a secretion from the salivary glands of the leech Hirudo medicinalis and has a role in regulating inflammation. In this study, hirudin with a dose of 10-40 mg/kg was given to middle cerebral artery occlusion/reperfusion mice. Hirudin markedly constrained cerebral infarct area in a dose-dependent manner, and significantly improved locomotor disability at 40 mg/kg dose. Similar to MCC950, a selective NLRP3 inflammasome inhibitor, hirudin inhibited M1 polarization and promoted M2 polarization. It also strikingly suppressed the ischemia-induced overexpression of NLRP3 and its downstream components, caspase-1, apoptosis-associated speck-like protein (ASC), and interleukin-1ß (IL-1ß). Hirudin and MCC950 equivalently protected viability and death of BV-2 microglia cells against oxygen-glucose deprivation/reperfusion (OGD/R), an in vitro cell model of brain ischemia. Both agents had similar effects in normalizing the OGD/R-evoked aberrant microglial profiles and NLRP3 pathway dysregulation as observed in the mice. These results demonstrated anti-ischemic effects of hirudin and its association with the inhibition of microglial NLRP3 inflammasome-mediated neuroinflammation. Hirudin is a promising agent for the early intervention of acute ischemic stroke.

Tortoise Plastron and Deer Antler Gelatin Prevents Against Neuronal Mitochondrial Dysfunction In Vitro: Implication for a Potential Therapy of Alzheimer's Disease.

Mitochondrial dysfunction with oxidative damage plays the fundamental roles in the pathogenesis of Alzheimer's disease. In traditional Chinese medicine (TCM) practice, animal tissue-derived gelatins are often used as nootropic agents to treat cognitive deterioration and senile dementia. Tortoise plastron gelatin (TPG) and deer antler gelatin (DAG) are the two most commonly used gelatins for this purpose. This study sought to examine the effects of the two gelatins in preventing neuronal mitochondria from oxidative damage. PC12 cells, a cell line derived from rat pheochromocytoma, exposed to the neurotoxin Aß25-35 served as an in vitro model of Alzheimer's disease. The cells were separately pre-treated with TPG and DAG at various concentrations ranging from 6.26 µg/ml-200 µg/ml, followed by co-incubation with 20 µM Aß25-35 for different duration. Cell viability, mitochondrial membrane potential (MMP) and ultrastructure, intracellular ATP, reactive oxygen species (ROS) and calcium (Ca2+) level, the expression of mitochondrial dynamic proteins and biomarkers of apoptosis were measured. Pretreatment with TPG and DAG reversed the Aß-induced reduction of cell viability in a dose-dependent manner. Both TPG and DAG significantly increased MMP and ATP, alleviated the accumulation of damaged mitochondrial fragments, and normalized the aberrant expression of multiple mitochondrial dynamic proteins of the Aß-exposed cells. Both gelatins also suppressed intracellular ROS overproduction and Ca2+ overload, overexpression of cytochrome c and pro-apoptosis biomarkers induced by the Aß exposure. These results suggest that TPG and DAG may have the anti-dementia potential by preventing neuronal mitochondria from oxidative damage.

Shexiang Baoxin Pill, a Proprietary Multi-Constituent Chinese Medicine, Prevents Locomotor and Cognitive Impairment Caused by Brain Ischemia and Reperfusion Injury in Rats: A Potential Therapy for Neuropsychiatric Sequelae of Stroke.

Ischemic stroke is a common type of cerebrovascular event and also the leading cause of disability. Post-stroke cognitive impairment occurs frequently in stroke survivors. Shexiang Baoxin Pill (SBP) is a proprietary Chinese medicine, initially used to treat cardiovascular diseases. Herein, we aim to explore the effects of SBP on oxygen glucose deprivation and reoxygenation (OGD/R) in neuronal cells (CATH.a) and cerebral ischemia/reperfusion injury induced post-stroke cognitive impairment in middle cerebral artery occlusion (MCAO) rat model. MCAO rats received two doses of oral SBP treatment (28 or 56 mg/kg) after 1 h of operation and once daily for 2 weeks continuously. Behavioral tests, immunoblotting, and immunofluorescence were examined after 14 days. Current data suggest that SBP enhanced cell viability and downregulated apoptosis via activating the PI3K/Akt signaling pathway in CATH. a cells. Furthermore, 14 days of SBP treatment promoted the recovery of learning and locomotor function in the MCAO rats. SBP up-regulated the expression of p-Akt, p-GSK3ß, as well as the expression of NMDAR1, PSD-95, and AMPAR. Also, SBP down-regulated the expression of p-CaMKII. These results indicated that long-term SBP treatment might be a potential option for cognitive impairment induced by the ischemic stroke.

Association between response rates and monetary incentives in sample study: a systematic review and meta-analysis.

OBJECTIVE: To investigate the effect of monetary incentive and the dose-response relationship of participants' response rates in surveys. METHODS: Three databases were searched for randomised controlled trials (RCTs) that investigated the effect of monetary incentives on participants' first and final response rates. First response is defined as the responses after the participant was initially contacted and final response is defined as the responses after several reminders were sent. The potential dose-response relationship of the amount of monetary incentive on the relative response rate (RRR) was established by fitting a restricted cubic spline function based on the robust-error meta-regression model. RESULTS: 105 RCTs were identified. The first RRR increased by 49% (RRR=1.49; 95% CI 1.29 to 1.72) when monetary incentives were provided. Dose-response analysis revealed that an amount between US$6.25 and US$8 had the maximum effect on increasing the first response rate. On average, the final RRR increased almost by 20% (RRR=1.18; 95% CI 1.11 to 1.25) with monetary incentive compared to no-monetary incentive. An amount between US$10 and US$15 had the maximum effect on the final response rate, with an increase in the final RRR of 34% (RRR=1.34; 95% CI 1.19 to 1.51). There was a significant increase in the response rate when two or more reminders were sent. CONCLUSION: Monetary incentives and reminders improve the response rates. Future studies need to consider providing monetary incentives and sending at least two reminders to increase the response rate and reduce the chances of non-response bias.

Jie-Yu Pill, A Proprietary Herbal Medicine, Ameliorates Mood Disorder-Like Behavior and Cognitive Impairment in Estrogen-Deprived Mice Exposed to Chronic Unpredictable Mild Stress: Implication for a Potential Therapy of Menopause Syndrome.

Jie-Yu Pill (JYP) is a proprietary herbal medicine initially developed to treat menstrual mood disorders. This study sought to determine whether JYP could alleviate menopausal psychiatric symptoms in ovariectomized (OVX) mice, an animal model of estrogen deprivation, exposed to chronic unpredictable mild stress (CUMS) and the underlying mechanisms in comparison with estrogen therapy. The OVX+CUMS mice were treated with 0.3 mg/kg estradiol (E2), 2.5 g/kg or 5 g/kg JYP for 36 days, and tested in multiple behavioral paradigms. Serum, uterus, and brain tissues were collected for the measurement of hypothalamus-pituitary-ovarian axis (HPO) and hypothalamus-pituitary-adrenal (HPA) axis hormones, γ-aminobutyric acid (GABA), glutamate, neurotrophins, and estrogen receptors. JYP and E2 had comparable efficacy in reducing anxiety- and depression-like behavior and cognitive impairment of the OVX+CUMS mice. E2 strikingly increased ratio of uterus to body weight of the OVX+CUMS mice, but JYP did not. Both agents suppressed HPO-axis upstream hormones, inhibited HPA-axis hyperactivity by reinstating hypothalamic GABA, restored hippocampal and prefrontal glutamate contents and its receptor expression in the OVX+CUMS mice. While JYP and E2 protected against decreases in hippocampal and prefrontal neurotrophins and estrogen receptors of the OVX+CUMS mice, unlike E2, JYP had no significant effects on these biomarkers in the uterus. These results suggest that JYP has comparable efficacy in ameliorating mood disorder-like behavior and cognitive impairment induced by a combination of estrogen deprivation and chronic stress in association with certain differential uterus-brain mechanisms compared to estrogen therapy. JYP may be a potential therapy for menopause-associated psychiatric disorders.

Electroacupuncture trigeminal nerve stimulation plus body acupuncture for chemotherapy-induced cognitive impairment in breast cancer patients: An assessor-participant blinded, randomized controlled trial.

Chemotherapy causes various side effects, including cognitive impairment, known as 'chemobrain'. In this study, we determined whether a novel acupuncture mode called electroacupuncture trigeminal nerve stimulation plus body acupuncture (EA/TNS + BA) could produce better outcomes than minimum acupuncture stimulation (MAS) as controls in treating chemobrain and other symptoms in breast cancer patients. In this assessor- and participant-blinded, randomized controlled trial, 93 breast cancer patients under or post chemotherapy were randomly assigned to EA/TNS + BA (n = 46) and MAS (n = 47) for 2 sessions per week over 8 weeks. The Montreal Cognitive Assessment (MoCA) served as the primary outcome. Digit span test was the secondary outcomes for attentional function and working memory. The quality of life and multiple functional assessments were also evaluated. EA/TNS + BA treated group had much better performance than MAS-treated group on reverse digit span test at Week 2 and Week 8, with medium effect sizes of 0.53 and 0.48, respectively, although no significant differences were observed in MoCA score and prevalence of chemobrain between the two groups. EA/TNS + BA also markedly reduced incidences of diarrhoea, poor appetite, headache, anxiety, and irritation, and improved social/family and emotional wellbeing compared to MAS. These results suggest that EA/TNS + BA may have particular benefits in reducing chemotherapy-induced working memory impairment and the incidence of certain digestive, neurological, and distress-related symptoms. It could serve as an effective intervention for breast cancer patients under and post chemotherapy (trial registration: https://www.clinicaltrials.gov: NCT02457039).

Assessor- and participant-blinded, randomized controlled trial of dense cranial electroacupuncture stimulation plus body acupuncture for neuropsychiatric sequelae of stroke.

AIM: Acupuncture has benefits in the rehabilitation of neuropsychiatric sequelae of stroke. This study was aimed to evaluate the effectiveness of dense cranial electroacupuncture stimulation plus body acupuncture (DCEAS+BA) in treating poststroke depression (PSD), functional disability, and cognitive deterioration. METHODS: In this assessor- and participant-blinded, randomized controlled trial, 91 stroke patients who initially had PSD were randomly assigned to either DCEAS+BA (n = 45) or minimum acupuncture stimulation as controls (n = 46) for three sessions per week over 8 consecutive weeks. The primary outcome was baseline-to-end-point change in score of the 17-item Hamilton Depression Rating Scale. Secondary outcomes included the Montgomery-Åsberg Depression Rating Scale for depressive symptoms, the Barthel Index for functional disability, and the Montreal Cognitive Assessment for cognitive function. RESULTS: DCEAS+BA-treated patients showed strikingly greater end-point reduction than MAS-treated patients in scores of the three symptom domains. The clinical response rate, defined as an at least 50% baseline-to-end-point reduction in 17-item Hamilton Depression Rating Scale score, was markedly higher in the DCEAS+BA-treated group than that of controls (40.0% vs 17.4%, P = 0.031). Incidence of adverse events was not different in the two groups. Subgroup analysis revealed that DCEAS+BA with electrical stimulation on forehead acupoints was more apparent in reducing Barthel-Index-measured disability than that without electrical stimulation. CONCLUSION: DCEAS+BA, particularly with electrical stimulation on forehead acupoints, reduces PSD, functional disability, and cognitive deterioration of stroke patients. It can serve as an effective rehabilitation therapy for neuropsychiatric sequelae of stroke.

Pivotal factors concerned in design of acupuncture clinical research: From two articles in JAMA.

Two randomized controlled trials of acupuncture concerning polycystic ovary syndrome (PCOS) and stress urinary incontinence (SUI) were published simultaneously in the 24th issue, 2017 of The Journal of the American Medical Association (JAMA). A trial involving PCOS indicated that active acupuncture did not increase live birth compared with sham acupuncture; meanwhile, another trial referring to SUI showed that electroacupuncture resulted in less urine leakage compared with sham electroacupuncture. With an eye to the negative and positive results of acupuncture, three pivotal factors should be contemplated: (1) proper illness for acupuncture, that is, a problem need to be solved in current medical science, and acupuncture may really work for it; (2) proper pre-studied primary outcome, which is better be objective and repeatedly measurable to reveal the therapeutic effect of acupuncture truly and objectively; (3) proper sham control, which can blind the patients to the upmost extent with minimal biological effects. Through the publication of clinical trials of acupuncture in high-impact journals in recent years, researchers should have confidence in their clinical trials by pondering over these three pivotal factors.