Ramelteon protects against social defeat stress-associated abnormal behaviors.

Psychological stress affects the neuroendocrine regulation, which modulates mental status and behaviors. Melatonin, a hormone synthesized primarily by the pineal gland, regulates many brain functions, including circadian rhythms, pain, sleep, and mood. Selective pharmacological melatonin agonist ramelteon has been clinically used to treat mood and sleep disorders. Posttraumatic stress disorder (PTSD) is a psychiatric condition associated with severe trauma; it is generally triggered by traumatic events, which lead to severe anxiety and uncontrollable trauma recall. We recently reported that repeated social defeat stress (RSDS) may induce robust anxiety-like behaviors and social avoidance in mice. In the present study, we investigated whether melatonin receptor activation by melatonin and ramelteon regulates RSDS-induced behavioral changes. Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. Moreover, treatment of the non-selective MT1/MT2 receptor agonist, ramelteon, markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. Moreover, activating melatonin receptors also balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. Taken together, our findings indicate that the activation of both melatonin and ramelteon regulates RSDS-induced anxiety-like behaviors and PTSD symptoms. The current study also showed that the regulatory effects of neuroendocrine mechanisms and cognitive behaviors on melatonin receptor activation in repeated social defeat stress.

Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial.

Ketamine has rapid-onset antidepressant activity in patients with treatment-resistant major depression (TRD). The safety and tolerability of racemic ketamine may be improved if given orally, as an extended-release tablet (R-107), compared with other routes of administration. In this phase 2 multicenter clinical trial, male and female adult patients with TRD and Montgomery-Asberg Depression Rating Scale (MADRS) scores ≥20 received open-label R-107 tablets 120 mg per day for 5 days and were assessed on day 8 (enrichment phase). On day 8, responders (MADRS scores ≤12 and reduction ≥50%) were randomized on a 1:1:1:1:1 basis to receive double-blind R-107 doses of 30, 60, 120 or 180 mg, or placebo, twice weekly for a further 12 weeks. Nonresponders on day 8 exited the study. The primary endpoint was least square mean change in MADRS for each active treatment compared with placebo at 13 weeks, starting with the 180 mg dose, using a fixed sequence step-down closed test procedure. Between May 2019 and August 2021, 329 individuals were screened for eligibility, 231 entered the open-label enrichment phase (days 1-8) and 168 responders were randomized to double-blind treatment. The primary objective was met; the least square mean difference of MADRS score for the 180 mg tablet group and placebo was -6.1 (95% confidence interval 1.0 to 11.16, P = 0.019) at 13 weeks. Relapse rates during double-blind treatment showed a dose response from 70.6% for placebo to 42.9% for 180 mg. Tolerability was excellent, with no changes in blood pressure, minimal reports of sedation and minimal dissociation. The most common adverse events were headache, dizziness and anxiety. During the randomized phase of the study, most patient dosing occurred at home. R-107 tablets were effective, safe and well tolerated in a patient population with TRD, enriched for initial response to R-107 tablets. ClinicalTrials.gov registration: ACTRN12618001042235 .

The Comparison of Lifestyles, Mental Risks, and Physical Indices among Individuals with Ultra-High Risk of Psychosis, Patients with Schizophrenia, and the General Public.

(1) Background: Early interventions may effectively reduce the risk of mental disorders in individuals with ultra-high risk. Specifying the health needs of individuals with ultra-high risk is crucial before the implementation of successful early intervention. This study aimed to explore the differences in lifestyles, mental risks, and physical indices among individuals with ultra-high risk, patients with schizophrenia, and healthy subjects. (2) Methods: A cross-section design applying seven questionnaires with physical examinations for 144 participants aged 13-45 years old was conducted in this study. The questionnaires included one about personal data, four on mental risks, and two for lifestyles. (3) Results: The individuals with ultra-high risk scored similarly in many dimensions as the patients with schizophrenia, but they displayed lower positive symptoms, lower negative symptoms, lower prodromal symptoms, higher interpersonal deficits, lower nutrition intake, and higher levels of exercise than the patients with schizophrenia. Female individuals with ultra-high risk had lower self-esteem, higher positive symptoms, lower nutrition intake, and higher exercise levels than male ones. (4) Conclusions: The study pinpointed specific health needs with interpersonal deficits, nutrition intake, and physical activity for the individuals with ultra-high risk. Future interventions targeted on improving social function, dietary pattern, and exercise will be beneficial.

Effects of chronic daily headache with subclinical depression on brain volume: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: The relationship between chronic daily headache (CDH), depression symptoms, and brain volume remains unclear. METHODS: To investigate the effects of CDH on brain volume and the impact of depressive symptoms (DSs) as well as the effects of demography and medication overuse, PubMed, Embase, and Web of Science databases were systematically searched using appropriate keyword strings to retrieve observational studies from inception to May 2023. RESULTS: Two distinct comparisons were made in CDH patients: (1) those with DSs versus their pain-free counterparts and (2) those without DSs versus pain-free controls. The first comprised nine studies enrolling 225 CDH patients with DSs and 234 controls. Beck depression inventory, Hamilton depression scale, and Hospital anxiety/depression scale were used to assess DSs, revealing significantly more DSs in CDH patients with DSs compared to their controls (all p < 0.05). Besides, the second analysed four studies involving 117 CDH patients without DSs and 155 comparators. Compared to CDH patients without DSs, those with DSs had a smaller brain volume than controls (p = 0.03). Furthermore, CDH patients with DSs who did not overuse medications showed a smaller right cerebral cortical volume than overusers (p = 0.003). A significant inverse correlation between female prevalence and brain volume (p = 0.02) was revealed using regression analysis. CONCLUSIONS: Pain-induced persistent depressive symptoms not only incur structural alterations but also encompass affective-motivational changes, involving medication use and gender-specific health concerns. SIGNIFICANCE: This study highlighted the importance of an integrated CDH treatment, emphasizing psychological interventions for the affective-motivational component alongside pain management.

Discrepancy of social cognition between bipolar disorders and major depressive disorders.

BACKGROUND: The research landscape examining social cognition (SC) impairment in patients with major depressive disorders (MDD) and bipolar disorders (BD) is notably scarce. Presently, assessments predominantly rely on static stimuli and self-reported measures, which may not capture the dynamic dimensions of social cognition. OBJECTIVES: This study aimed to validate the Chinese version of Movie Assessment of Social Cognition (MASC-CH) and to investigate whether MDD and BD exhibit distinct patterns of SC impairments, shedding light on potential differences between these two mood disorders. METHODS: The study encompassed 197 participants, aged 18-65, distributed as follows: 21 BD, 20 MDD, and 156 healthy controls (HC). We focused on examining "cognitive" and "emotional" SC scores and "undermentalizing" and "overmentalizing" error patterns, with nonsocial inference as a control. Additional assessments included the Reading Mind in the Eyes Test (RMET) and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). We also explored the association between depression severity (measured by the Hamilton Depressive Rating Scale, HDRS) and distinct SC dimensions between MDD and BD. RESULTS: The MASC-CH exhibited strong validity and reliability for SC assessment. In group comparisons, BD participants scored significantly lower on MASC-CH, while the MDD group scores were not significantly different from HC. Specifically, BD individuals had notably lower cognitive SC scores and made more undermentalizing and absence of mentalizing errors than MDD and HC. Additionally, a negative correlation between HDRS score and overmentalizing was observed in BD, not in the MDD. CONCLUSIONS: The findings indicate that depression severity scores in BD were inversely related to MASC-CH scores. In contrast, this relationship was not observed in the MDD group. These results underscore the importance of SC impairments as distinguishing characteristics of both BD and MDD. It provides valuable insights into the distinct social-cognitive profiles of both mood disorders.

Inference of social cognition in schizophrenia patients with neurocognitive domains and neurocognitive tests using automated machine learning.

AIM: It has been suggested that single neurocognitive domain or neurocognitive test can be used to determine the overall cognitive function in schizophrenia using machine learning algorithms. It is unknown whether social cognition in schizophrenia patients can be estimated with machine learning based on neurocognitive domains or neurocognitive tests. METHODS: To predict social cognition in schizophrenia, we applied an automated machine learning (AutoML) framework resulting from the analysis of predictive factors such as six neurocognitive domain scores and nine neurocognitive test scores of 380 schizophrenia patients in the Taiwanese population. Four clinical parameters (i.e., age, gender, subgroup, and education) were also used as predictive factors. We utilized an AutoML framework called Tree-based Pipeline Optimization Tool (TPOT) to generate predictive pipelines automatically. RESULTS: The analysis revealed that all neurocognitive domains and tests except the reasoning and problem solving domain/test showed significant associations with social cognition. In addition, a TPOT-generated pipeline can best predict social cognition in schizophrenia using seven predictive factors, including five neurocognitive domains (i.e., speed of processing, sustained attention, working memory, verbal learning and memory, and visual learning and memory) and two clinical parameters (i.e., age and gender). This predictive pipeline consists of machine learning algorithms such as function transformers, an approximate feature map, independent component analysis, and linear regression. CONCLUSION: The study indicates that an AutoML framework such as TPOT may provide a promising way to produce truly effective machine learning pipelines for predicting social cognition in schizophrenia using neurocognitive domains and/or neurocognitive tests.

Elucidating the Mechanisms of Sodium Benzoate in Alzheimer Disease: Insights from Quantitative Proteomics Analysis of Serum Samples.

BACKGROUND: N-methyl-D-aspartate receptors (NMDARs) are crucial components of brain function involved in memory and neurotransmission. Sodium benzoate is a promising NMDAR enhancer and has been proven to be a novel, safe, and efficient therapy for patients with Alzheimer disease (AD). However, in addition to the role of sodium benzoate as an NMDA enhancer, other mechanisms of sodium benzoate in treating AD are still unclear. To elucidate the potential mechanisms of sodium benzoate in Alzheimer disease, this study employed label-free quantitative proteomics to analyze serum samples from AD cohorts with and without sodium benzoate treatment. METHODS: The serum proteins from each patient were separated into 24 fractions using an immobilized pH gradient, digested with trypsin, and then subjected to nanoLC‒MS/MS to analyze the proteome of all patients. The nanoLC‒MS/MS data were obtained with a label-free quantitative proteomic approach. Proteins with fold changes were analyzed with STRING and Cytoscape to find key protein networks/processes and hub proteins. RESULTS: Our analysis identified 861 and 927 protein groups in the benzoate treatment cohort and the placebo cohort, respectively. The results demonstrated that sodium benzoate had the most significant effect on the complement and coagulation cascade pathways, amyloidosis disease, immune responses, and lipid metabolic processes. Moreover, Transthyretin, Fibrinogen alpha chain, Haptoglobin, Apolipoprotein B-100, Fibrinogen beta chain, Apolipoprotein E, and Alpha-1-acid glycoprotein 1 were identified as hub proteins in the protein‒protein interaction networks. CONCLUSIONS: These findings suggest that sodium benzoate may exert its influence on important pathways associated with AD, thus contributing to the improvement in the pathogenesis of the disease.

Adjunctive transcranial direct current stimulation (tDCS) plus sodium benzoate for the treatment of early-phase Alzheimer's disease: A randomized, double-blind, placebo-controlled trial.

Previous studies found that an NMDA receptor (NMDAR) enhancer, sodium benzoate, improved cognitive function of patients with early-phase Alzheimer's disease (AD). Transcranial direct current stimulation (tDCS) induces NMDAR-dependent synaptic plasticity and strengthens cognitive function of AD patients. This study aimed to evaluate efficacy and safety of tDCS plus benzoate in early-phase dementia. In this 24-week randomized, double-blind, placebo-controlled trial, 97 patients with early-phase AD received 10-session tDCS during the first 2 weeks. They then took benzoate or placebo for 24 weeks. We assessed the patients using Alzheimer's disease assessment scale - cognitive subscale (ADAS-cog), Clinician's Interview-Based Impression of Change plus Caregiver Input, Mini Mental Status Examination, Alzheimer's disease Cooperative Study scale for ADL in MCI, and a battery of additional cognitive tests. Forty-seven patients received sodium benzoate, and the other 50 placebo. The two treatment groups didn't differ significantly in ADAS-cog or other measures. Addition of benzoate to tDCS didn't get extra benefit or side effect in this study. For more thoroughly studying the potential of combining tDCS with benzoate in the AD treatment, future research should use other study designs, such as longer-term benzoate treatment, adding benzoate in the middle of tDCS trial sessions, or administering benzoate then tDCS.

Differential Impacts of Endogenous Antioxidants on Clinical Symptoms and Cognitive Function in Acute and Chronic Schizophrenia Patients.

BACKGROUND: Impaired antioxidant defense is implicated in the pathophysiology of schizophrenia, and superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) are 3 first-line endogenous antioxidants. Various cognitive functions decline differently during the schizophrenia course. The characteristic roles of the 3 antioxidants in clinical and cognitive profiles in acute and chronic phases of schizophrenia require study. METHODS: We recruited 311 patients with schizophrenia, including 92 acutely exacerbated patients who had been off antipsychotics for at least 2 weeks and 219 chronic patients who had been stable on medication for at least 2 months. Blood SOD, CAT, and GSH levels; clinical symptoms; and 9 cognitive test scores were measured. RESULTS: Blood CAT levels were higher in the acute patients than in the chronic patients, whereas SOD and GSH levels were similar to one another. Higher CAT levels were correlated with less positive symptoms, better working memory and problem solving in the acute phase, and less negative symptoms, less general psychopathology, better global assessment of function, and better cognitive function (in speed of processing, attention, problem solving) in the chronic period. Higher SOD levels were correlated with better global assessment of function in the acute phase and better speed of processing, working memory, and verbal learning and memory in the chronic period. GSH influenced neither clinical nor cognitive manifestations. CONCLUSIONS: This study showed that blood CAT affected different clinical and cognitive domains between acute and chronic stages of schizophrenia, SOD influenced cognitive functions in chronic state, but GSH affected none. Further studies are needed to explore the underlying mechanisms.

Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies.

BACKGROUND: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable. METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study. RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11). CONCLUSION: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).

A brief history of clozapine use in Taiwan.

Blood concentrations of clozapine in Taiwanese patients appeared approximately 30-50 % higher than that from Caucasian patients, and women possessed a higher blood levels. Fluvoxamine was reported to increase the clozapine levels, reduce clozapine-related weight gain and metabolic disturbances, and improved general psychopathology. Clothiapine, a chemical structure analogue of clozapine, showed potential of benefitting patients who are unsuitable for clozapine treatment in Taiwan. Obsessive/compulsive symptom (OCS) is a common side effect of clozapine. Concentrations of clozapine were remarkably higher in patients with OCS than in those without. In conclusion, clozapine is a widely used in patients with schizophrenia in Taiwan.

Differential relationships of NMDAR hypofunction and oxidative stress with cognitive decline.

NMDAR hypofunction and oxidative stress are implicated in the pathogenesis of Alzheimer's disease. D-amino acid oxidase (DAO) regulates NMDAR function. Glutathione, superoxide dismutase, and catalase are three first-line endogenous antioxidants. This study explored the associations of these potential biomarkers with mild cognitive impairment. Cognitive function and blood levels of DAO, glutathione, superoxide dismutase, and catalase were measured in 63 mild cognitive impairment patients and 24 healthy individuals every 6 months for 2 years. Among the patients, DAO and glutathione levels at baseline contributed to the cognitive decline 2 years later. Among the healthy individuals, only glutathione levels were associated with cognitive change. The four biomarkers differed in change directions (upward vs. downward) in the patients and in the healthy individuals. Among patients, glutathione levels were negatively correlated with superoxide dismutase and positively correlated with catalase, and DAO levels were negatively correlated with superoxide dismutase. To our knowledge, this is the first study to demonstrate the differential associations of NMDAR hypofunction and oxidative stress with cognitive change between the mild cognitive impairment patients and healthy people. Glutathione may be regarded as an aging marker for both mild cognitive impairment and normal aging; and DAO, a biomarker exclusively for mild cognitive impairment.

Clozapine ultrarapid metabolism during weak induction probably exists but requires careful diagnosis. A literature review, five new cases and a proposed definition.

During weak induction (from smoking and/or valproate co-prescription), clozapine ultrarapid metabolizers (UMs) need very high daily doses to reach the minimum therapeutic concentration of 350 ng/ml in plasma; clozapine UMs need clozapine doses higher than: 1) 900 mg/day in patients of European/African ancestry, or 2) 600 mg/day in those of Asian ancestry. Published clozapine UMs include 10 males of European/African ancestry, mainly assessed with single concentrations. Five new clozapine UMs (two of European and three of Asian ancestry) with repeated assessments are described. A US double-blind randomized trial included a 32-year-old male smoking two packages/day with a minimum therapeutic dose of 1,591 mg/day from a single TDM during open treatment of 900 mg/day. In a Turkish inpatient study, a 30-year-old male smoker was a possible clozapine UM needing a minimum therapeutic dose of 1,029 mg/day estimated from two trough steady-state concentrations on 600 mg/day. In a Chinese study, three possible clozapine UMs (all male smokers) were identified. The clozapine minimum therapeutic dose estimated with trough steady-state concentrations >150 ng/ml was: 1) 625 mg/day, based on a mean of 20 concentrations in Case 3; 2) 673 mg/day, based on a mean of 4 concentrations in Case 4; and 3) 648 mg/day, based on a mean of 11 concentrations in Case 5. Based on these limited studies, clozapine UMs during weak induction may account for 1-2% of clozapine-treated patients of European ancestry and <1% of those of Asian ancestry. A clozapine-to-norclozapine ratio <0.5 should not be used to identify clozapine UMs.

The identification of a potential plasma metabolite marker for Alzheimer's disease by LC-MS untargeted metabolomics.

BACKGROUND AND AIMS: Alzheimer's disease (AD), the most common type of dementia, is hard to recognize early, resulting in delayed treatment and poor outcome. At present, there is neither reliable, non-invasive methods to diagnose it accurately and nor effective drugs to recover it. Discovery and quantification of novel metabolite markers in plasma of AD patients and investigation of the correlation between the markers and AD assessment scores. MATERIALS AND METHODS: Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics with LC-quadrupole- time-of-flight (Q-TOF) was performed in plasma samples of age-matched AD patients and healthy controls. The potential markers were further quantified with targeted multiple reaction monitoring (MRM) approach. RESULTS: Among the candidates, progesterone, and 3-indoleacetic acid (3-IAA) were successfully identified and then validated in 50 plasma samples from 25 AD patients and 25 matched normal controls with MRM approach. As a result, 3-IAA was significantly altered in AD patients and correlated with some AD assessment scores. CONCLUSION: By using untargeted LC-MS metabolomic and LC-MRM approaches to analyze plasma metabolites of AD patients and normal subjects, 3-IAA was discovered and quantified to be significantly altered in AD patients and correlated with several AD assessment scores.

The associations between cognitive functions and TSNAX genetic variations in patients with schizophrenia.

BACKGROUND: The translin-associated factor X (TSNAX) gene, located adjacent to the DISC1 gene, has been implicated in schizophrenia. While cognitive impairment determines long-term the functional outcome of schizophrenia, the role of TSNAX in cognitive dysfunction of schizophrenia patients remains elusive. This study aimed to explore the genetic effect of TSNAX on cognitive functions of schizophrenia. METHODS: We recruited 286 chronic schizophrenia patients who had been stabilized with antipsychotics for at least 2 months and genotyped three TSNAX SNPs (rs1630250, rs766288, rs6662926). Clinical symptoms and seven cognitive domains were assessed. The score of cognitive tests was standardized to T score. RESULTS: Clinical symptoms were similar among genotypes of all the three SNPs. The GLM analysis demonstrated that TSNAX genetic polymorphisms influenced cognitive function of schizophrenia patients after adjustment for gender, age, and education. The patients with the rs1630250 C/G genotype performed better than the G/G homozygotes in the Trail Making A (p = 0.034). Those with the rs766288 G/T genotype also performed better than the G/G homozygotes in the Trail Making A (p = 0.012). The patients with the G/G genotype of rs6662926 also performed better than the C/C homozygotes in verbal learning and memory test (p = 0.044). CONCLUSIONS: This study suggests that the TSNAX gene variation may influence the cognitive functions of the patients with schizophrenia.

Determination of D-serine and D-alanine Tissue Levels in the Prefrontal Cortex and Hippocampus of Rats After a Single Dose of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, with Potential Antipsychotic and Antidepressant Properties.

The effects of the N-methyl-D-aspartate receptor activators D-serine, D-alanine, and sarcosine against schizophrenia and depression are promising. Nevertheless, high doses of D-serine and sarcosine are associated with undesirable nephrotoxicity or worsened prostatic cancer. Thus, alternatives are needed. DAAO inhibition can increase D-serine as well as D-alanine and protect against D-serine-induced nephrotoxicity. Although several DAAO inhibitors improve the symptoms of schizophrenia and depression, they can increase the plasma levels but not brain levels of D-serine. The mechanism of action of DAAO inhibitors remains unclear. We investigated the effects of the DAAO inhibitor sodium benzoate on the prefrontal cortex and hippocampal level of D-alanine as known another substrate with antipsychotic and antidepressant properties and other NMDAR-related amino acids, such as, L-alanine, D-serine, L-serine, D-glutamate, L-glutamate, and glycine levels. Our results indicate that sodium benzoate exerts antipsychotic and antidepressant-like effects without changing the D-serine levels in the brain prefrontal cortex (PFC) and hippocampus. Moreover, D-alanine levels in the PFC and hippocampus did not change. Despite these negative findings regarding the effects of D-amino acids in the PFC and hippocampus, sodium benzoate exhibited antipsychotic and antidepressant-like effects. Thus, the therapeutic effects of sodium benzoate are independent of D-serine or D-alanine levels. In conclusion, sodium benzoate may be effective among patients with schizophrenia or depression; however, the mechanisms of actions remain to be elucidated.

Endogenous antioxidants predicted outcome and increased after treatment: A benzoate dose-finding, randomized, double-blind, placebo-controlled trial for Alzheimer's disease.

AIM: Previous pilot studies suggest that sodium benzoate may be a potential cognitive enhancer for patients with Alzheimer's disease (AD), schizophrenia, or late-life depression. Especially for AD treatment, a confirmatory trial with predictive biomarkers is urgently needed. This study aimed to confirm benzoate as a novel treatment for AD and to discover its optimal dose and biomarkers. METHODS: A 24-week, dose-finding, randomized, double-blind, placebo-controlled trial, with clinical measurements at weeks 0, 8, 16, and 24, was conducted in three major medical centers in Taiwan. Among 154 patients screened for AD, 149 were eligible and randomized to one of the four treatments: (i) benzoate 500 group (fixed 500 mg/day); (ii) benzoate 750 (500 mg/day for the first 4 weeks, 750 mg/day from the 5th week); (iii) benzoate 1000 (500 mg/day for the first 4 weeks, 1000 mg/day from the 5th week); and (iv) placebo. The primary outcome measure was AD assessment scale-cognitive subscale (ADAS-cog). RESULTS: The benzoate 1000 group performed best in improving ADAS-cog (P = 0.026 at week 24), with female advantage. Higher plasma catalase at baseline predicted better outcome. Benzoate receivers tended to have higher catalase and glutathione than placebo recipients after treatment. The four intervention groups showed similar safety profiles. CONCLUSIONS: By enhancing two vital endogenous antioxidants, catalase and glutathione, sodium benzoate therapy improved cognition of patients with AD, with higher baseline catalase predicting better response. Supporting the oxidative stress theory, the results show promise for benzoate as a novel treatment for AD.

Ketamine, benzoate, and sarcosine for treating depression.

Studies have demonstrated the beneficial therapeutic effects of sarcosine, benzoate, and ketamine (including esketamine and arketamine) on depression. These drugs mainly act by modulating N-methyl-d-aspartate glutamate receptors (NMDARs) and reducing inflammation in the brain. Although ketamine, benzoate, and sarcosine act differently as the antagonists or coagonists of NMDARs, they all have demonstrated efficacy in animal models or human trials. In vitro and in vivo studies have indicated that sarcosine, benzoate, and ketamine exert their anti-inflammatory effects by inhibiting microglial activity. This review summarizes and compares the efficacy of the possible therapeutic mechanisms of sarcosine, benzoate, ketamine, esketamine, and arketamine. These compounds act as both NMDAR modulators and anti-inflammatory drugs and thus can be effective in the treatment of depression.

Diagnosing Alzheimer's Disease Specifically and Sensitively With pLG72 and Cystine/Glutamate Antiporter SLC7A11 AS Blood Biomarkers.

BACKGROUND: Reliable blood biomarkers for Alzheimer's disease (AD) have been lacking. The D-amino acids oxidase modulator (named pLG72) modulates glutamate N-methyl-D-aspartate receptor activity. The cystine/glutamate antiporter contains a SLC7A11 subunit, which mediates glutamate release. This study aimed to determine the accuracy of pLG72 protein and SLC7A11 mRNA in diagnosing AD. METHODS: This study enrolled 130 healthy controls and 109 unmatched AD patients; among them, 40 controls and 70 patients were selected to match by age. We measured their pLG72 protein in plasma and SLC7A11 mRNA in white blood cells. RESULTS: AD patients had markedly higher pLG72 levels and SLC7A11 mRNA ΔCT values than healthy controls (in both unmatched and matched cohorts; all 4 P values <.001). The receiver operating characteristics analysis in the unmatched cohorts demonstrated that the pLG72 level had a high specificity (0.900) at the optimal cutoff value of 2.3285, the ΔCT of SLC7A11 mRNA displayed an excellent sensitivity (0.954) at the cutoff of 12.185, and the combined value of pLG72 and SLC7A11 ΔCT determined a favorable area under the curve (AUC) (0.882) at the cutoff of 21.721. The AUC of the combined value surpassed that of either biomarker. The specificity, sensitivity, and AUC of the matched cohort were like those of the unmatched cohort. CONCLUSIONS: The findings suggest that pLG72 protein and SLC7A11 mRNA can distinguish AD patients from healthy controls with excellent specificity and sensitivity, respectively. The combination of pLG72 and SLC7A11 yields better AUC than either, suggesting the superiority of simultaneously measuring both biomarkers in identifying AD patients.