Association between programmed death-1 pathway and major depression.

OBJECTIVES: Major depression (MD) may be associated with inflammation and immunity. PD-1 (programmed death-1), PD-L1 (programmed death-ligand 1) and PD-L2 (programmed death-ligand 2) are among the inhibitory immune mediators on the PD-1 pathway. However, previous data regarding the association between MD and PD-1 pathway were still scarce; therefore, we investigated the association of PD-1 pathway with MD. METHODS: During a period of 2 years, patients with MD and healthy controls were recruited from a medical centre in this study. The diagnosis of MD was established according to the DSM-5 criteria. The severity of MD was assessed with 17-item Hamilton Depression Rating Scale. PD-1, PD-L1 and PD-L2 were detected in peripheral blood from MD patients after 4 weeks of treatment with antidepressant drugs. RESULTS: A total of 54 patients with MD and 38 healthy controls were recruited. According to the analyses, there is a significantly higher PD-L2 level in MD than in healthy controls and lower PD-1 level after age and BMI adjustment. Besides, moderately positive correlation between HAM-D scores and PD-L2 level was found. CONCLUSIONS: It was found that PD-1 pathway might play an important role in MD. We need a large sample to prove these results in the future.

Orexin/hypocretin and major psychiatric disorders.

Orexin A and B, also known as hypocretin 1 and 2, are excitory neuropeptides synthesized in the perifornical and lateral hypothalamic areas. Following their discovery in 1998, orexins are now known to be involved in feeding, sleep, stress response, and reward processing. Most importantly, orexin deficiency has been linked to narcolepsy, a neurological sleep-wake disorder. Patients with narcolepsy also present overlapping symptoms with psychiatric disorders, such as anxiety and depressed mood, and even hallucinations, which often lead to misdiagnosis in the initial assessment. In this article, we aim to review studies of the orexin system associated with the three major psychiatric disorders: schizophrenia, major depressive disorder (MDD), and bipolar disorder. In addition to animal and clinical reports, studies of the orexin system in treatment, symptoms and side effects would also be reviewed. Thus far, relatively robust evidence suggests a connection of the orexin system with MDD. Findings of orexin involvement in schizophrenia are inconsistent and only studies in bipolar disorder are limited. While the orexin system might not be firmly associated with diagnosis, it may be useful to target specific symptom within the diagnosis or treatment, such as insomnia, weight gain and polydipsia.

Corrigendum: Isobaric Tags for Relative and Absolute Quantitation Identification of Blood Proteins Relevant to Paroxetine Response in Patients With Major Depressive Disorder.

[This corrects the article DOI: 10.3389/fpsyt.2022.577857.].

Assessment of Noninvasive Brain Stimulation Interventions for Negative Symptoms of Schizophrenia: A Systematic Review and Network Meta-analysis.

Importance: Negative symptoms have a detrimental impact on functional outcomes and quality of life in people with schizophrenia, and few therapeutic options are considered effective for this symptomatic dimension. Studies have suggested that noninvasive brain stimulation (NIBS) interventions may be effective in treating negative symptoms. However, the comparative efficacy of different NIBS protocols for relieving negative symptoms remains unclear. Objective: To compare the efficacy and acceptability of different NIBS interventions for treating negative symptoms. Data Sources: The ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, ClinicalTrials.gov, and Web of Science electronic databases were systematically searched from inception through December 7, 2021. Study Selection: A frequentist model network meta-analysis was conducted to assess the pooled findings of trials that evaluated the efficacy of repetitive transcranial magnetic stimulation (rTMS), theta-burst stimulation, transcranial random noise stimulation, transcutaneous vagus nerve stimulation, and transcranial direct current stimulation on negative symptoms in schizophrenia. Randomized clinical trials (RCTs) examining NIBS interventions for participants with schizophrenia were included. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were independently extracted by multiple observers. The pair-wise meta-analytic procedures were conducted using a random-effects model. Main Outcomes and Measures: The coprimary outcomes were changes in the severity of negative symptoms and acceptability (ie, dropout rates owing to any reason). Secondary outcomes were changes in positive and depressive symptoms. Results: Forty-eight RCTs involving 2211 participants (mean [range] age, 38.7 [24.0-57.0] years; mean [range] proportion of female patients, 30.6% [0%-70.0%]) were included. Compared with sham control interventions, excitatory NIBS strategies (standardized mean difference [SMD]: high-definition transcranial random noise stimulation, -2.19 [95% CI, -3.36 to -1.02]; intermittent theta-burst stimulation, -1.32 [95% CI, -1.88 to -0.76]; anodal transcranial direct current stimulation, -1.28 [95% CI, -2.55 to -0.02]; high-frequency rTMS, -0.43 [95% CI, -0.68 to -0.18]; extreme high-frequency rTMS, -0.45 [95% CI, -0.79 to -0.12]) over the left dorsolateral prefrontal cortex with or without other inhibitory stimulation protocols in the contralateral regions of the brain were associated with significantly larger reductions in negative symptoms. Acceptability did not significantly differ between the groups. Conclusions and Relevance: In this network meta-analysis, excitatory NIBS protocols over the left dorsolateral prefrontal cortex were associated with significantly large improvements in the severity of negative symptoms. Because relatively few studies were available for inclusion, additional well-designed, large-scale RCTs are warranted.

Isobaric Tags for Relative and Absolute Quantitation Identification of Blood Proteins Relevant to Paroxetine Response in Patients With Major Depressive Disorder.

Objectives: Isobaric tags for relative and absolute quantitation (iTRAQ) is a proteomic investigation that could be utilized for rapid identification and quantification of proteins, which we would use to identify differentially expressed proteins in treatment responsive patients with major depressive disorder (MDD). Methods: Six treatment responsive patients of MDD were recruited, and their peripheral blood mononuclear cell (PBMC) were collected before and after 4 weeks of paroxetine treatment. iTRAQ and Mascot search engine were used to detect differentially expressed proteins, which were then validated by Western blot. Results: Two thousand one hundred and fifty three proteins were screened, and seven proteins showed differences of more than two-fold and 62 proteins with a differences of less than two-fold. Six proteins with commercially available antibodies were identified, and were validated by Western blot in 10 paroxetine responsive MDD patients. Putative hydroxypyruvate isomerase (HYI), eukaryotic translation initiation factor 4H (eIF4H), and RNA binding motif 8A (RBM8A) had statistically significant differences before and after treatment in the validation. Data are available via ProteomeXchange with identifier PXD028947. Conclusions: By using iTRAQ and Western blot, we were able to identify HYI, eIF4H, and RAM8a to be the potential predictors of paroxetine treatment response in patients with MDD. This finding could help establish future individualized medicine.

Molecular Mapping of Sebaceous Squalene by Ambient Mass Spectrometry.

Squalene (SQ), a highly unsaturated sebaceous lipid, plays an important role in protecting human skin. To better understand the role of SQ in clinical medicine, an efficient analytical approach is needed to comprehensively study the distribution of SQ on different parts of the skin. In this study, sebaceous lipids were collected from different epidermal areas of a volunteer with sampling probes. Thermal desorption-electrospray ionization/mass spectrometry (TD-ESI/MS) was then used to characterize the lipid species on the probes, and each TD-ESI/MS analysis was completed within a few seconds without any sample pretreatment. The molecular mapping of epidermal squalene on whole-body skin was rendered by scaling the peak area of the extracted ion current (EIC) of SQ based on a temperature color gradient, where colors were assigned to the 1357 sampling locations on a 3D map of the volunteer. The image showed a higher SQ distribution on the face than any other area of the body, indicating the role of SQ in protecting facial skin. The results were in agreement with previous studies using SQ as a marker to explore sebaceous activity. The novelty and significance of this work are concluded as two points: (1) direct and rapid detection of all major classes of sebaceous lipids, including the unsaturated hydrocarbons (SQ) and nonpolar lipids (e.g., cholesterol). The results are unique compared to other conventional and ambient ionization mass spectrometry methods and (2) this is the first study to analyze SQ distribution on the whole-body skin by a high-throughput approach.

SIGIRR and TNFAIP3 Are Differentially Expressed in Both PBMC and TNF-α Secreting Cells of Patients With Major Depressive Disorder.

Background: Major depressive disorder (MDD) is associated with the activation of the immune/inflammatory system. TNF-α is associated with MDD and poor treatment response. Toll-like receptors (TLR) are responsible in innate immune response, and is associated with MDD and antidepressant response. Some negative regulators of TLR pathway such as SOCS1, TOLLIP, SIGIRR, TNFAIP3, and MyD88s, are reported to be differentially expressed in the peripheral blood samples of patients of MDD. Methods: We recruited patients with MDD and healthy controls, collect their demographic data, and measured their mRNA levels of negative TLR regulators, using peripheral blood mononuclear cells (PBMC) and isolated TNF-α secreting cells. Clinical symptoms were evaluated using Halmiton Depression Rating Scale (Ham-D). Some patients were evaluated again after 4 weeks of antidepressant treatment. Results: Forty-seven patients with MDD and 52 healthy controls were recruited. Between the PBMC samples of 37 MDD patients and 42 controls, mRNA levels of SOCS1, SIGIRR, TNFAIP3, and MyD88s were significantly different. Between TNF-α secreting cells of 10 MDD patients and 10 controls, mRNA levels of SIGIRR and TNFAIP3 were significantly different. Change of Ham-D score only correlated significantly with TOLLIP mRNA level after treatment. Conclusion: SIGIRR and TNFAIP3, two negative regulators of TLR immune response pathways, were differentially expressed in both PBMC and TNF-α secreting cells of patients with MDD as compared to healthy controls. The negative regulations of innate immune response could contribute to the underlying mechanism of MDD.

Molecular cartography of residue pesticides on grape surface in 3D by ambient ionization tandem mass spectrometry.

Thermal desorption-electrospray ionization tandem mass spectrometry (TD-ESI/MS/MS) was used to characterize the residual pesticides that were collectedfromthe surface of a grapewithmetallic sampling probes. Fungicides, insecticides, and miticides were detected, where results were validated by simple solvent extraction followed by gas chromatography tandem mass spectrometry and liquid chromatography tandem mass spectrometry analyses. To explore the distribution of pesticide residues on grape surfaces, 149 locations of a grape surface were collected and followed by TD-ESI/MS/MS analysis. The molecular cartography was then generated from analysis of residual pesticides on the grape surface in 3D.

Association between paternal age and risk of schizophrenia: a nationwide population-based study.

PURPOSE: To study the association between paternal age and schizophrenia in offspring. METHODS: This report describes a nationwide population-based cohort study from 1997 to 2013. Data from Taiwan's National Health Insurance Research Database were utilized to answer the research question. A total of 17,649 offspring with schizophrenia were selected from 11 million offspring in the general population. Additionally, we established the offspring without schizophrenia as the comparison group by matching the study cohort by age, gender in a 1:4 ratio (n = 70,596). RESULTS: The median age at first presentation with schizophrenia was 20 years (interquartile range (IQR), 17 to 24). Comparison of the schizophrenia and non-schizophrenia groups indicated that father's age at birth (30.0 (IQR), 27 to 33 vs. 29.0 (IQR), 26 to 32 years), mother's age at birth (26.0 (IQR), 24 to 29 vs. 26.0 (IQR), 23 to 29 years), paternal schizophrenia (2.6% vs. 0.6%), and maternal schizophrenia (4.4% vs. 0.7%) were all significantly greater in the schizophrenia group. In addition, each 5-year increase in father's age increased the odds of being diagnosed with schizophrenia (model 1: aOR = 1.22; 95% CI 1.20, 1.24; model 2: aOR = 1.20; 95% CI 1.18, 1.23). Subgroup analysis showed that each 5-year increase in father's age increased the odds of being diagnosed with schizophrenia in male and female offspring, as well as in offspring of mothers and fathers with or without schizophrenia (aOR = 1.20 to 2.20, all p values < 0.01). CONCLUSION: This study indicated that advanced paternal age increased the risk of schizophrenia in offspring. Offspring born to fathers older by 5-year increments were at heightened risk of schizophrenia.

Brain-derived neurotrophic factor and mental disorders.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that modulates neuroplasticity in the brain, and is one of the most widely investigated molecule in psychiatric disorders. The researches of BDNF emcompassed the advance of investigative techniques of past decades. BDNF researches ranged from protein quantilization, to RNA expression measurements, to DNA sequencing, and lately but not lastly, epigenetic studies. In this review, we will briefly address findings on BDNF protein levels, mRNA expression, Val66Met polymorphism, and epigenetic modifications, in schizophrenia, major depressive disorder (MDD), and bipolar disorder.

Brain-derived neurotrophic factor and glutathione peroxidase as state biomarkers in alcohol use disorder patients undergoing detoxification.

The pathophysiology of alcohol use disorder (AUD) is not totally clear. The aim of this study was to investigate the serum levels of brain-derived neurotrophic factor (BDNF) and oxidative stress markers in AUD patients during alcohol detoxification. Evaluation of changes in BDNF, glutathione peroxidase (GPX), catalase, superoxide dismutase, thiobarbituric acid reactive substances, 8-hydroxy 2'-deoxyguanosine, PCC and S100B were carried out.14 AUD inpatients and 20 healthy control subjects were recruited for this study. The serum BDNF, S100B and oxidative stress markers were measured with assay kits.Serum levels of catalase, GPX, PCC and 8-hydroxy 2'-deoxyguanosine were significantly higher in the AUD group subjects than in the controls (P < .05). However, BDNF levels were lower in the AUD group than in the controls (P < .05). After alcohol detoxification treatment, the GPX levels in the AUD group dropped (P < .05) and the BDNF levels rose (P < .05).The results suggest that serum BDNF and GPX levels might be state biomarkers for AUD patients undergoing alcohol detoxification.

Decreased Level of Blood MicroRNA-133b in Men with Opioid Use Disorder on Methadone Maintenance Therapy.

Although previous animal studies have indicated that certain micro ribonucleic acids (microRNAs) play a part in the pathway of opioid addiction, whether such findings extend to human models is yet unknown. This study aims to investigate the important microRNA expressions in patients with opioid use disorder (OUD) on methadone maintenance treatment (MMT) compared to healthy controls and analyze the correlation between microRNAs and opioid characteristics among the patients. We recruited 50 patients and 25 controls, and both groups were matched regarding gender, age, and body mass index. Serum microRNAs (miR-133b, miR-23b, miR-190, miR-206, miR-210, and miR-21) were measured. The age of OUD onset, duration of MMT participation, and recent daily methadone dosage were considered the opioid characteristics. We adopted the t-test to compare the difference between patients and controls and Pearson's correlation to evaluate the association between microRNAs and opioid profiles. Only the level of miR-133b in OUD patients on MMT was significantly lower than that in healthy controls. We did not detect differences of any other microRNA expressions between the two groups. Furthermore, we found no evidence to support the association between microRNAs and opioid characteristics. This study indicates that miR-133b values may be decreased in OUD patients on MMT.

Abnormal Brain-Derived Neurotrophic Factor Exon IX Promoter Methylation, Protein, and mRNA Levels in Patients with Major Depressive Disorder.

Brain-derived neurotrophic factor (BDNF) exon IX promoter methylation levels, serum BDNF protein levels, and serum mRNA levels were investigated in patients with major depressive disorder (MDD) and healthy controls. Over two years, 51 patients with MDD and 62 healthy controls were recruited. Peripheral blood was drawn from all participants to analyze the BDNF exon IX promoter methylation levels as well as serum BDNF protein and mRNA levels, at baseline and after four weeks of antidepressant treatment. Methylation sequential analysis showed that patients with MDD (n = 39) had a higher methylation level at CpG site 217 and lower methylation levels at CpG site 327 and CpG site 362. Drug responders (n = 25) had a higher methylation level at CpG site 24 and CpG site 324 than the non-responders (n = 11). Patients with MDD had a lower serum BDNF protein and mRNA levels than the healthy controls. In conclusion, these results showed that BDNF exon IX promoter methylation levels, serum BDNF protein level, and serum BDNF mRNA level could contribute to the pathophysiology of a major depressive disorder.

Brain-derived neurotrophic factor (BDNF) and bipolar disorder.

Brain-derived neurotrophic factor (BDNF) is deemed to be associated with the psychopathology of bipolar I disorder (BD). However, studies focusing on accuracy of BDNF levels to differentiate these patients from healthy controls (HCs) are scarce. Over a discrete twelve-year period, we investigated serum BDNF levels in patients with BD and compared them to age-, sex- and body mass index (BMI)-matched HCs. There were lower serum BDNF levels in 83 samples with BD than in 222 HCs samples (5.7 ±â€¯4.2 ng/ml vs. 12.2 ±â€¯7.5 ng/ml, F = 46.784). Pearson's correlation test showed significant positive correlations between Young Mania Rating Scale scores and the BDNF levels among 61 manic patients (γ = 0.339). The receiver operating characteristic curve analysis showed BDNF levels demonstrated a moderate accuracy of being able to differentiate BD patients from HCs (AUC = 0.801). The most adequate cut-off points of the BDNF level were 6.74 ng/ml (sensitivity = 82.0%, specificity = 63.9%). Our results support that BDNF demonstrated moderate accuracy to distinguish BD patients from HCs. In the future, greater samples would be required to prove these results.

Accuracy of brain-derived neurotrophic factor levels for differentiating between Taiwanese patients with major depressive disorder or schizophrenia and healthy controls.

OBJECTIVES: Brain-derived neurotrophic factor (BDNF) has been associated with the psychopathology of both major depressive disorder (MDD) and schizophrenia (SZ). However, studies focusing on the accuracy of BDNF levels to differentiate between these patients and healthy controls (HCs) have been rare. METHODS: Over a discrete ten-year period, we investigated serum BDNF levels in patients with MDD or SZ and compared them to HCs. RESULTS: We found serum BDNF levels in 224 samples with SZ to be lower than those in 390 HCs samples (p = 0.007), but not lower than those in the 273 samples with MDD. Male MDD patients tended to have lower BDNF levels compared to male HCs (p = 0.083). The receiver operating characteristic curve analysis demonstrated that BDNF levels were moderately accurate in differentiating male MDD patients and female patients with SZ from HCs (AUC = 0.652 and 0.623, respectively). The most adequate cut-off points for BDNF level were 5.11 ng/ml (sensitivity = 81.1%, specificity = 48.5%) and 5.88 ng/ml (sensitivity = 74.1%, specificity = 57.4%), respectively. CONCLUSIONS: Our results support that BDNF demonstrated moderate accuracy in distinguishing male patients with MDD and female patients with SZ from HCs. In the future, greater samples would be required to further confirm these results.

Antidepressant treatment increased serum miR-183 and miR-212 levels in patients with major depressive disorder.

Major depressive disorder (MDD) had been associated with brain-derived neurotrophic factor (BDNF). Studies had shown that patients with MDD were associated with lower BDNF protein levels, which could be reversed by antidepressant treatment. BDNF expression had also been affected by a number of microRNAs (miRNA). BDNF and miRNA in MDD had been investigated widely in the recent years, but the relationships between miRNAs and antidepressants were less studied. From November 2015 to October 2017, inpatients diagnosed with MDD were recruited. Serum miR-16, miR-30, miR-34, miR-128, miR-132, miR-134, miR-182, miR-183, miR-185, miR-212 levels were measured before and after four weeks of antidepressant treatment of either selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). Thirty-three patients with MDD were recruited. After treatment, miR-183 and miR-212 levels increased significantly. In patients treated with SSRI (n = 13), miR-16 levels increased significantly after treatment. Therefore, miR-183 and miR-212 levels increased significantly after four weeks of antidepressant treatment. In the SSRI group, significantly increased miR-16 levels were found, but not in SNRI group, suggesting that different types of antidepressants might affect different sets of miRNAs.

Excited catatonia in a patient with fatal pulmonary embolism and a successful treatment strategy.

BACKGROUND: Patients with psychiatric disorders in critical condition are difficult to treat. In this study, we report on a patient with underlying schizoaffective disorder who developed catatonia, cardiac arrest, and pulmonary embolism, as well as a successful treatment strategy. CASE PRESENTATION: The inpatient is a 41-year-old morbidly obese male with schizoaffective disorder whose clozapine dosage was titrated from 100 mg to 175 mg due to auditory hallucination and agitation. The patient abruptly developed acute cardiopulmonary symptoms associated with an elevated troponin-I level. He was transferred to a cardiac intensive care unit, where he remained for 3 days. He was also found to have excited catatonic symptoms, and the lorazepam-diazepam protocol was initiated to quickly relieve the catatonia. Once the coronary angiogram was read as normal, the patient was transferred back to the psychiatric ward. However, the patient then suffered from in-hospital cardiac arrest. He was resuscitated and again transferred to the medical intensive care unit. Computed tomography confirmed the diagnosis of a pulmonary embolism. The patient was treated with Rivaroxaban 30 mg/d for the first 21 days, followed by 20 mg daily for 3 months. To control his severe and refractory psychotic symptoms, the patient was re-prescribed clozapine. During the 15-month follow-up period, the patient demonstrated a fair response and tolerability to clozapine 150 mg without symptoms relapse and no thromboembolic event. CONCLUSION: This report can serve to remind psychiatrists and physicians to be aware of fatal conditions in patients with psychiatric diseases and physical illnesses.

Proteomics Approach for Biomarker Research in Major Depression: Antidepressant Effects.

BACKGROUND: The proteomics approach is the new mantra in disease biomarker research in areas such as major depression (MD). Current protocols for investigating biomarkers in biological fluid often employ both immuno- based and non-immuno-based technologies. METHOD: The immuno-based method is used normally in measuring well-known disease biomarkers, and commercial kits are often available. Immuno-based methods such as radio-immunoassay and enzyme-linked immunosorbent assay are sensitive and specific. However, tedious sample preparations such as filtration and centrifugation are required. Non-immuno-based technologies, such as matrix-assisted laser desorption/ionization- time of flight mass spectrometry has been proven to be useful techniques to rapidly screen disease biomarkers in human biological fluids. The mass spectrometer provides a powerful research tool in the proteomics field, not only in biomarker discovery but also in biomarker validation. A bioinformation tool like principal component analysis is a statistical procedure that utilizes proteomics data. CONCLUSION: In this article, we review the proteomics approaches in MD biomarker research and the data after the antidepressants treatment. And it covers a selection of advances in the realm of proteomics and its promise for major depression biomarker discovery and antidepressant effects. These technologies have opened new approaches to identifying signaling biomarkers associated with the cellular metabolism, cell life cycle, and detection of disease.

Orexin A in men with heroin use disorder undergoing methadone maintenance treatment.

Orexins have played a role in reward-seeking and addiction-related behavior. There are few reports in the literature on serum levels of orexins in patients with heroin use disorder (HUD) undergoing methadone maintenance treatment (MMT). The aim of this study was to investigate the serum levels of orexin A in HUD patients undergoing MMT. Fifty male HUD patients undergoing MMT and 25 healthy males were enrolled for this study. Serum orexin A were measured with assay kits. Using analysis of covariance (ANCOVA) with body mass index (BMI) adjustments, the serum levels of orexin A in HUD men undergoing MMT were found to be significantly higher than in healthy controls. In conclusion, our results suggest that MMT might increase orexin A levels in HUD patients.