Adjunctive duration-doubled transcranial direct current stimulation for the treatment of depressive patients with suicidal ideation: study protocol for a double-blind, randomized, sham-controlled trial.

BACKGROUND: The problem of suicide has become increasingly common in individuals with major depressive disorder (MDD). Transcranial direct current stimulation (tDCS) is an effective treatment for MDD with 2 milliamperes (mA) for at least 30 min per day for 2 weeks. This study aims to investigate the efficacy of daily duration-doubled tDCS as an adjunctive intervention for rapidly reducing suicidal ideation and improving depression in MDD patients. METHODS: In this double-blind, randomized, sham-controlled study, 76 MDD patients with suicidal ideation are randomly assigned to either active (n=38) or sham (n=38) tDCS group. The anode and cathode are placed over the scalp areas corresponding to left and right dorsolateral prefrontal cortex (DLPFC), respectively, and each stimulation lasts for 60 min. The primary outcome is defined as change of Beck Scale for Suicide Ideation (BSI) after 5 and 10 sessions. The change of other clinical assessments, blood biomarkers related to suicidal ideation and depressive sumptoms are defined as secondary outcomes. Blood biomarkers related to suicidal ideation are collected at baseline and after 10 sessions. DISCUSSION: This study suggests the adjunctive duration-doubled tDCS might be a novel method to rapidly reduce suicidal ideation and improve depressive symptom. The variation of biomarkers could be potential predictive models of suicide risk. TRIAL REGISTRATION: The trial protocol is registered with ClinicalTrials.gov under protocol registration number NCT05555927. Registered on September 25, 2022.

Efficacy of transcranial direct current stimulation for treating anhedonia in patients with depression: A randomized, double-blind, sham-controlled clinical trial.

BACKGROUND: Anhedonia, the core symptom of major depressive disorder (MDD), is highly prevalent in patients with depression. Anhedonia is associated with low efficacy of drug treatment, high suicide rates, and poor social function. Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technology that uses constant, low-intensity direct current to treat MDD by regulating cortical activity and neuronal excitability. However, little is known about the efficacy of tDCS for treating anhedonia in patients with depression, and even the existing results of clinical trials are conflicting. In addition, there is no consensus on what brain regions should be targeted by tDCS during the treatment of anhedonia in patients with depression. OBJECTIVE: This study aimed to evaluate the efficacy and safety of tDCS over the left dorsolateral prefrontal cortex (DLPFC) and right orbitofrontal cortex (OFC) in the improvement of anhedonia in patients with depression and finally identified suitable brain regions to be stimulated during treatment. METHODS: This randomized, double-blind, sham-controlled clinical trial recruited 70 patients with anhedonia and depressive episodes. Patients were randomly assigned to three groups according to the stimulation site: right orbitofrontal cortex (OFC), left dorsolateral prefrontal cortex (DLPFC), and sham stimulation. Each group received twelve 20-min interventions (ten as primary treatment and two for consolidation). The primary outcome was a decrease in Snaith-Hamilton Pleasure Scale (SHAPS) scores after primary treatment. Evaluations were performed at baseline, post-treatment, and 8-week follow-up. RESULTS: The depression mood of the three groups of patients at each time point was better than the baseline, but there was no significant difference in the efficacy between the groups (p>0.05). On the basis of the improvement of depression, this study found that tDCS of the DLPFC significantly improved anhedonia (p = 0.028) after primary treatment (2 weeks), and tDCS of the DLPFC and OFC significantly improved social functioning (p = 0.005) at 8-week follow-up. LIMITATIONS: The sample size of this study was small, with only about 23/24 patients in each group completing the intervention assessments; due to the impact of the COVID-19 epidemic, data analysis was limited by the lack of patients during the follow-up period. CONCLUSIONS: tDCS of the DLPFC significantly improves anhedonia in depressed patients and is thus a potential adjuvant therapy for anhedonia in these patients.

Comparison of 60-minute vs 30-minute transcranial direct current stimulation (tDCS) in major depressive disorder: Effects on depression suicidal ideation and anxiety.

We investigated whether changes through doubling the duration of each tDCS session would increase efficacy of tDCS for depression. tDCS was applied for 10 sessions, followed by two additional weekly sessions. 63 patients with MDD underwent randomization, with 22 being assigned to 60-min/d group, 25 to 30 min/d group, and 16 to sham group. HAMD-17 reductive ratios at week 2 and 4 were of no significant differences among treatment groups. 60 min group had a greater decrease in anxiety compared to 30 min group and sham group based on HAMA at 4 weeks but only in the completer analysis, not in ITT analysis.

Association between overt aggression and anhedonia in patients with major depressive disorder during the acute phase.

OBJECTIVE: To explore the factors influencing anhedonia at baseline and use them as confounding factors. To further investigate the correlation between overt aggression and anhedonia during the acute phase of major depressive disorder. METHODS: In this eight-week prospective study, 384 major depressive disorder patients were recruited from the outpatient section of Shanghai Mental Health Center from May 1, 2017, to October 30, 2018. Standard treatments were performed with escitalopram or venlafaxine for participants. Depressive symptoms, overt aggression, and anhedonia were assessed using the 17-item Hamilton Rating Scale for Depression, Modified Overt Aggression Scale, and Snaith-Hamilton Pleasure Scale at baseline, and in the 4th and 8th weeks. RESULTS: Obsessive-compulsive symptoms and the duration of untreated psychosis were positively associated with aggression (P < 0.05). Patients with aggressive behaviour had worse cognitive impairment and severe anhedonia of pleasurable sensory experiences (P < 0.05). For anhedonia, being female (tau_b = -0.23, P = 0.012) was a protective factor, while number of recurrent, melancholic features, current obsessions, previous combination drug therapies, depressive symptoms, and aggressive behaviour were risk factors (P < 0.05). Social anhedonia related to interests/pastimes, and pleasurable sensory experiences were more severe in major depressive disorder patients with aggressive behaviour in the acute phase (P < 0.05). CONCLUSIONS: Anhedonia persisted in major depressive disorder patients with aggressive behaviour after standardized treatment during the acute phase. Being female protected the pleasures from social interaction and sensory experience. However, the number of depressive episodes, melancholic features, current obsessive symptoms, previous combination drug therapies, depressive symptoms, and aggressive behaviour was positively associated with anhedonia.

Efficacy of adjunctive intensive transcranial direct current stimulation of different cortices in treatment-resistant depression: a study protocol for a randomized double-blinded sham-controlled trial.

BACKGROUND: Treatment-resistant depression (TRD) carries a high economic burden worldwide. Transcranial direct current stimulation (tDCS) is advantageous for improving cognition and can be safely used in the treatment of depression. The effectiveness of tDCS of the left and right orbitofrontal cortex (OFC) as adjuvant treatment in patients with TRD has rarely been explored. Therefore, the objective of this trial is to evaluate the effectiveness there of when administering left dorsolateral prefrontal cortex (DLPFC) positive stimulation or OFC negative stimulation in patients with TRD. METHODS: Ninety eligible participants will be recruited to receive intervention at Shanghai Mental Health Center. Treatment will be randomly assigned in a double-blind fashion. Participants will receive either DLPFC (n = 30), OFC (n = 30), or sham (n = 30) tDCS, while continuing their usual pharmacotherapy at a stable dosage for at least 2 weeks before enrollment and throughout the stimulation period. All participants will receive 20 weekday stimulation sessions of 60 minutes duration each. Participants in the active group will be stimulated at 2 mA throughout the session, whereas the sham group will receive only a brief period of stimulation to mimic the sensation. After 20 stimulation sessions, no further treatment will be administered. Measurements will be conducted at regular points throughout and at 8 weeks after trial completion. The primary outcome is the change in the 17-item Hamilton Depression Rating Scale (HAMD-17) score after 20 sessions. Secondary outcomes were defined as changes in other measurement scales, cognitive function, resting-state functional magnetic resonance imaging (rs-fMRI), and serum biomarkers. DISCUSSION: We hypothesize that, in contrast to the sham group, both the active DLPFC and OFC tDCS groups will show superiority in HAMD-17 score reduction after 5, 10, and 20 sessions. Moreover, associations of the improvement of depressive symptoms with variations in rs-fMRI and TRD-related biomarkers will be evaluated. Our study may suggest that adjunctive intensive tDCS with left DLPFC positive stimulation or right OFC negative stimulation may be effective as a novel method to relieve depressive symptoms in patients with TRD. The variation of rs-fMRI, biomarkers could be used as a potential prediction model of treatment efficacy in TRD. TRIAL REGISTRATION: The trial protocol is registered with www.chictr.org.cn under protocol registration number ChiCTR2200058030. Date of registration: March 27, 2022. Recruitment started in September 2022 and is ongoing.

Ketamine May Exert Rapid Antidepressant Effects Through Modulation of Neuroplasticity, Autophagy, and Ferroptosis in the Habenular Nucleus.

Major depressive disorder is a burdensome condition with few treatment options, and traditional antidepressants are characterized by slow onset. Sub-anesthetic ketamine has rapid-onset effects for the treatment of major depressive disorder (MDD), the mechanisms of which remain elusive. In this study, we explored whether neuroplasticity, autophagy, and ferroptosis in the habenular nucleus are involved in the rapid antidepressant process of ketamine. The results showed that Chronic Restraint Stress (CRS) treated rats exhibited decreased neuroplasticity, inhibition of autophagy, and enhanced ferroptosis. Depression-like symptoms were significantly improved after ketamine treatment in CRS rats, with changes in physiological parameters. Ketamine-treated CRS rats showed a significant improvement in habenular nuclear neuroplasticity. Electron microscopy observed that ketamine triggered autophagy, with increased levels of autophagy-related proteins. Ferroptosis was inhibited by ketamine by electron microscopy, with increased FTH1 and GPX4 levels and decreased Tfr1 levels. In conclusion, our findings demonstrate that ketamine may exert rapid antidepressant effects by improving neuroplasticity, activating autophagy, and inhibiting ferroptosis in the nuclear complex.

Ketamine induces rapid antidepressant effects via the autophagy-NLRP3 inflammasome pathway.

BACKGROUND: Sub-anesthetic ketamine has rapid-onset effects for the treatment of major depressive disorder (MDD). However, the mechanism underlying ketamine's antidepressant properties remains unclear. Recent studies have reported an interrelationship between autophagy and the inflammasome, both of which are involved in the pathophysiology of MDD. In this study, we assess whether ketamine exerts its antidepressant effects via an association with the autophagy-NLRP3 inflammasome pathway. METHODS: We established a depressive-like rat model by treating Wistar Kyoto rats with chronic restraint stress (CRS) for 28 days. Microglial cells from newborn Sprague-Dawley rats were used for in vitro experiments. RESULTS: We found sub-anesthetic ketamine treatment reversed depressive-like behavior in CRS rats. Ketamine triggered autophagy in the microglia of prefrontal cortex (PFC) and (hippocampus) HPC, with increased levels of LC3B, decreased levels of p62 protein, and elevated autophagosomes both in vivo and in vitro. Moreover, NLRP3 inflammasome activation was also inhibited by ketamine, with reduced expression of NLRP3-ASC-CASP1 assembly and decreased IL-1ß levels in cerebrospinal fluid (CSF) as well as in the serum. Increased BDNF levels and synaptophysin levels were detected in the ketamine-treated group. The rapid anti-depressive effects, elevation of autophagy, reduction in NLRP3, and neuroplasticity-related factors induced by ketamine could be significantly blocked by the autophagy inhibitor Baf A1 (0.1 mg/kg). CONCLUSIONS: Our findings demonstrate that sub-anesthetic doses of ketamine exert their antidepressant-like effects by inhibiting inflammation and initiating neuroprotection via autophagy activation. These data might help expand future investigations on the antidepressant properties of ketamine.

A Lateral Flow Immunoassay Coupled with a Spectrum-Based Reader for SARS-CoV-2 Neutralizing Antibody Detection.

As of August 2021, there have been over 200 million confirmed case of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus and more than 4 million COVID-19-related deaths globally. Although real-time polymerase chain reaction is considered to be the primary method of detection for SARS-CoV-2 infection, the use of serological assays for detecting COVID-19 antibodies has been shown to be effective in aiding with diagnosis, particularly in patients who have recovered from the disease and those in later stages of infection. Since it has a high detection rate and few limitations compared to conventional enzyme-linked immunosorbent assay protocols, we used a lateral flow immunoassay as our diagnostic tool of choice. Since lateral flow immunoassay results interpreted by the naked eye may lead to erroneous diagnoses, we developed an innovative, portable device with the capacity to capture a high-resolution reflectance spectrum as a means of promoting diagnostic accuracy. We combined this spectrum-based device with commercial lateral flow immunoassays to detect the neutralizing antibody in serum samples collected from 30 COVID-19-infected patients (26 mild cases and four severe cases). The results of our approach, lateral flow immunoassays coupled with a spectrum-based reader, demonstrated a 0.989 area under the ROC curve, 100% sensitivity, 95.7% positive predictive value, 87.5% specificity, and 100% negative predictive value. As a result, our approach exhibited great value for neutralizing antibody detection. In addition to the above tests, we also tested plasma samples from 16 AstraZeneca-vaccinated (ChAdOx1nCoV-19) patients and compared our approach and enzyme-linked immunosorbent assay results to see whether our approach could be applied to vaccinated patients. The results showed a high correlation between these two approaches, indicating that the lateral flow immunoassay coupled with a spectrum-based reader is a feasible approach for diagnosing the presence of a neutralizing antibody in both COVID-19-infected and vaccinated patients.

Difference in the regulation of biological rhythm symptoms of Major depressive disorder between escitalopram and mirtazapine.

BACKGROUND: Biological rhythm plays an important role in major depressive disorder (MDD). The efficacy of antidepressant in biological rhythm remains unclear. This study is designed to explore the efficiency of escitalopram and mirtazapine in improving circadian rhythm, diurnal mood variation(DMV) and daily activity in MDD patients. METHODS: Four-hundred and fifty participants diagnosed with MDD were randomized to receive treatment with escitalopram (TWE), treatment with mirtazapine (TWM) or treatment as usual (TAU). Biological rhythm symptoms were assessed by relevant biological subscale in the Hamilton depression scale (HAMD) and the quick inventory of depressive symptomatology self-report (QIDS). The participants were assessed by trained evaluators at baseline and week 2, 4, 6 and 8. RESULTS: The differences of HAMD score among TWE(58%, 69%, 72%), TWM(56%, 64%, 76%) and TAU(49%, 57%, 68%) were significant(P<0.05). But the differences were significant only in patients without DMV; (2) Sleep rhythm items (difficulty falling asleep and early-wake) were significantly improved in TWM (P <0 .05) for both HAMD and QIDS. Decreased appetite and weight were significantly improved in TWM (P<0 .05) for both scales. (3) For daily activity-related items, feeling slowed down and concentration were significantly improved in TWE. And the retardation was significantly improved in TWE and in TWM. CONCLUSIONS: Both escitalopram and mirtazapine have superior anti-depressive effect, especially for MDD patients without DMV. Escitalopram was significantly more effective in daily activity, feeling slowed down and concentration difficulty, while mirtazapine was significantly more effective in improving sleep, appetite and weight of MDD.

Maternal breastfeeding and autism spectrum disorder in children: A systematic review and meta-analysis.

OBJECTIVES: Autism spectrum disorder (ASD) refers to a group of conditions variably affecting communicative and social interactive abilities presenting alongside behaviors with various restricted and repetitive patterns. In addition to genetic factors that influence the onset of the symptoms, there is growing interest in the potential involvement of non-genetic environmental factors. Some aspects of breastfeeding practices, including rates, timing, or optimality, have been put forward as environmental risk factors for autism. However, previous studies showed a controversial relationship between ASD and breastfeeding. METHODS: A meta-analysis on the association between maternal breastfeeding and ASD in children was conducted. We also explored potential moderating factors which might influence this association. Articles reporting the association between breastfeeding and a diagnosis of ASD were included. RESULTS: Seven articles were included in the meta-analysis. Cumulatively, children with ASD (n = 1463), either in the form of clinical diagnosis or self-report, were significantly less likely to have been breastfed than children without ASD (n = 1180) (OR = 0.61, 95% CI = 0.45-0.83, P = 0.002). Subgroup analyses revealed that results remained significant for children who were breastfed with additional supplementation. DISCUSSION: This meta-analysis provides evidence that breastfeeding (exclusively or including additional supplements) may protect against ASD. Prospective longitudinal research is required to disentangle the complex relationships and to explore potential pathophysiological mechanisms.

Maternal breastfeeding and attention-deficit/hyperactivity disorder in children: a meta-analysis.

Previous studies have suggested environmental factors may contribute to the risk of attention-deficit/hyperactivity disorder (ADHD). The current meta-analysis examined (1) the difference in the duration of maternal breastfeeding between children with and without ADHD, and (2) the association between maternal breastfeeding and ADHD in children. The data of individual studies were synthesized with a random-effects model. Eleven articles were included in this meta-analysis. Children with ADHD had significantly less breastfeeding duration than controls (Hedges' g = - 0.36, 95% confidence intervals (CIs) = - 0.61 to - 0.11, p = 0.005; difference in means: - 2.44 months, 95% CIs = - 3.17 to - 1.71, p < 0.001). In addition, the rates of non-exclusive breastfeeding in children with ADHD is significantly higher in "under 3 months" (odds ratio (OR) = 1.90, 95% CIs = 1.45 to 2.48, p < 0.001) but lower in "6 to 12 months" (OR = 0.69, 95% CIs = 0.49 to 0.98, p = 0.039) and "over 12 months" (OR = 0.58, 95% CIs = 0.35 to 0.97, p = 0.038) than controls. Children with ADHD received significantly higher rate of exclusive breastfeeding duration "under 3 months" (OR = 1.51, 95% CIs = 1.20 to 1.89, p < 0.001) but lower in "over 3 months" (OR = 0.52, 95% CIs = 0.29 to 0.95, p = 0.033) than controls. Furthermore, an association was found between non-breastfeeding and ADHD children (adjusted OR = 3.71, 95% CI = 1.94 to 7.11, p < 0.001). Our results suggest maternal breastfeeding is associated with a lower risk of ADHD in children. Future longitudinal research is required to confirm/refute these findings and to explore possible mechanisms underlying this association.

Significantly lower serum and hair magnesium levels in children with attention deficit hyperactivity disorder than controls: A systematic review and meta-analysis.

The pathophysiology of attention deficient hyperactivity disorder (ADHD) is still obscure. Some studies have discussed that magnesium levels are lower in the serum and erythrocytes of children with ADHD. However, these findings are controversial. The aim of our study is to identify whether magnesium levels are in fact lower in children with ADHD. We conducted a thorough search of the literature and examined the connection between magnesium insufficiency and ADHD. A total of twelve studies were included into the current meta-analysis. The results of our meta-analysis found that peripheral blood magnesium levels, either in plasma, serum, or whole blood, of children diagnosed with ADHD were significantly lower than those in controls (k = 8, Hedges' g = -0.547, 95% CI = -0.818 to -0.276, p < .001). The subgroup meta-analysis with serum sample sources also suggested that peripheral serum magnesium levels of children diagnosed with ADHD were significantly lower than those in controls (k = 6, Hedges' g = -0.733, 95% CI = -0.911 to -0.555, p < .001). The subgroup meta-analysis focusing on subjects with ADHD diagnosed by definite diagnostic criteria also suggested significantly lower peripheral serum magnesium levels in ADHD children than those in controls (k = 4, Hedges' g = -0.780, 95% CI = -0.985 to -0.574, p < .001). We also noted that magnesium levels in the hair of children diagnosed with ADHD were significantly lower than those in controls (k = 4, Hedges' g = -0.713, 95% CI = -1.359 to -0.067, p = .031). In this meta-analysis, we found that children diagnosed with ADHD have lower serum and hair magnesium levels than children without ADHD. Further study may be needed to investigate the behavioral influence on ADHD due to lower magnesium levels, the association between brain and serum magnesium levels, and the effects brought about by larger longitudinal cohort studies.

Peripheral iron levels in children with autism spectrum disorders vs controls: a systematic review and meta-analysis.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder, and nutritional deficiency may play a role in the development of ASD. A relationship between ASD and iron levels/iron deficiency (ID) has been reported; however, the results have been inconsistent. Therefore, we conducted this meta-analysis to examine the relationship between ASD and ID following the Meta-Analysis of Observational Studies in Epidemiology guidelines. We performed a systematic search of PubMed, ScienceDirect, Embase, ProQuest, ClinicalTrials.gov, and Cochrane CENTRAL databases up to September 22, 2017. Studies providing data on peripheral iron levels and/or the prevalence of ID in children with ASD vs those without ASD (non-ASD) were included. Primary outcomes included the difference in peripheral iron levels in children with ASD compared with those without ASD, and the odds ratio of ASD in children with ID compared with those without ID. Twenty-five articles met the inclusion criteria. We found that peripheral iron levels were not significantly different between the ASD and non-ASD groups, including serum ferritin (k = 4, Hedges g = 0.016, 95% confidence interval [CI] = -0.482 to 0.515, P = .949) or hair iron (k = 12; Hedges g = -0.219, 95% CI = -0.551 to 0.113, P = .196). There was no significant difference in the amount of iron in food content between the ASD and non-ASD groups (k = 6; Hedges g = -0.458, 95% CI = -1.246 to 0.330, P = .254). However, the reciprocal comorbidity of ASD and ID was significantly higher than in the children without these disorders. Our analysis showed that the available evidence is inconsistent with regard to whether children with ASD have lower iron levels. Future longitudinal studies are required to confirm or refute these associations and elucidate potential mechanisms.

Peripheral iron levels in children with attention-deficit hyperactivity disorder: a systematic review and meta-analysis.

There is growing recognition that the risk of attention-deficit hyperactivity disorder (ADHD) in children may be influenced by micronutrient deficiencies, including iron. We conducted this meta-analysis to examine the association between ADHD and iron levels/iron deficiency (ID). We searched for the databases of the PubMed, ScienceDirect, Cochrane CENTRAL, and ClinicalTrials.gov up to August 9th, 2017. Primary outcomes were differences in peripheral iron levels in children with ADHD versus healthy controls (HCs) and the severity of ADHD symptoms in children with/without ID (Hedges' g) and the pooled adjusted odds ratio (OR) of the association between ADHD and ID. Overall, seventeen articles met the inclusion criteria. Peripheral serum ferritin levels were significantly lower in ADHD children (children with ADHD = 1560, HCs = 4691, Hedges' g = -0.246, p = 0.013), but no significant difference in serum iron or transferrin levels. In addition, the severity of ADHD was significantly higher in the children with ID than those without ID (with ID = 79, without ID = 76, Hedges' g = 0.888, p = 0.002), and there was a significant association between ADHD and ID (OR = 1.636, p = 0.031). Our results suggest that ADHD is associated with lower serum ferritin levels and ID. Future longitudinal studies are required to confirm these associations and to elucidate potential mechanisms.

Supplementation of omega 3 fatty acids may improve hyperactivity, lethargy, and stereotypy in children with autism spectrum disorders: a meta-analysis of randomized controlled trials.

AIM: Deficiency of omega 3 fatty acids may be linked to autism spectrum disorder (ASD). Evidence about the potential therapeutic effects of supplementation of omega 3 fatty acids is lacking in ASD patients. METHODS: We searched major electronic databases from inception to June 21, 2017, for randomized clinical trials, which compared treatment outcomes between supplementation of omega 3 fatty acids and placebo in patients with ASD. An exploratory random-effects meta-analysis of the included studies was undertaken. RESULTS AND CONCLUSION: Six trials were included (n=194). Meta-analysis showed that supplementation of omega 3 fatty acids improved hyperactivity (difference in means =-2.692, 95% confidence interval [CI] =-5.364 to -0.020, P=0.048, studies =4, n=109), lethargy (difference in means =-1.969, 95% CI =-3.566 to -0.372, P=0.016, studies =4, n=109), and stereotypy (difference in means =-1.071, 95% CI =-2.114 to -0.029, P=0.044, studies =4, n=109). No significant differences emerged between supplementation of omega 3 fatty acids and placebo in global assessment of functioning (n=169) or social responsiveness (n=97). Our preliminary meta-analysis suggests that supplementation of omega 3 fatty acids may improve hyperactivity, lethargy, and stereotypy in ASD patients. However, the number of studies was limited and the overall effects were small, precluding definitive conclusions. Future large-scale randomized clinical trials are needed to confirm or refute our findings.