Esketamine Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder: A Retrospective Chart Review.

OBJECTIVE: Converging evidence supports the role of the glutamate, an excitatory amino acid neurotransmitter, in the pathophysiology of obsessive-compulsive disorder (OCD). Ketamine and esketamine, both noncompetitive N -methyl- d -aspartate antagonists, have emerged as a promising medication for this psychiatric disorder, given its possible efficacy with faster onset and good tolerability. The purpose of this retrospective chart review is to evaluate whether unbiased clinical documentation supports formal clinical trials of esketamine for an OCD indication. METHODS: A retrospective chart review of patients with treatment-resistant OCD receiving a single dose of esketamine (0.5mg/kg) added to standard therapy was conducted. The Yale-Brown Obsessive-Compulsive Scale and the Montgomery-Åsberg Depression Rating Scale were used to evaluate OCD and depressive symptoms respectively at baseline, 24 hours, and 7 days after esketamine administration. Descriptive statistics were used to analyze the data. RESULTS: Eight subjects were identified in this retrospective chart review: esketamine was administered subcutaneously in 7 and intravenously in 1. One week after infusion, 25% of the sample met criteria for treatment response and 50% for partial response. Major depressive disorder was a comorbid diagnosis in 75% of the sample and 2 of these subjects showed a positive antidepressant response. CONCLUSIONS: Our findings provide preliminary evidence that esketamine may reduce obsessive-compulsive symptoms in a subset of treatment-resistant OCD patients.

Does the intensity of dissociation predict antidepressant effects 24 hours after infusion of racemic ketamine and esketamine in treatment-resistant depression? A secondary analysis from a randomized controlled trial.

BACKGROUND: Ketamine and esketamine have both shown significant antidepressant effects in treatment-resistant depression (TRD), and conflicting evidence suggests that induced dissociation by these drugs can be a clinical predictor of esketamine/ketamine's efficacy. METHODS: This study is a secondary analysis from a bi-center, randomized, controlled trial. Participants were randomly assigned 1:1 to receive an IV infusion of esketamine (.25 mg/kg) or racemic ketamine (.50 mg/kg) over 40 minutes. Dissociative symptoms were assessed using the Clinician-Administered Dissociative State Scale (CADSS) 40 minutes following the beginning of the infusion. The variation in depression scores was measured with the Montgomery-Asberg Depression Rating Scale (MADRS), which was administered before the intervention as a baseline measure and 24 hrs, 72 hrs, and 7 days following infusion. RESULTS: Sixty-one patients were included in the analysis. Examining CADSS scores of 15 or below, for every 1-point increment in the CADSS score, there was a mean change of -0.5 (SD = 0.25; p-value 0.04) of predicted MADRS score from baseline to 24 hrs. The results for 72 hrs and 7 days following infusion were not significant. Limitations: This study was not designed to assess the relationship between ketamine or esketamine-induced dissociation and antidepressant effects as the main outcome, therefore confounding variables for this relationship were not controlled. CONCLUSION: We suggest a positive relationship between dissociation intensity, measured by CADSS, and antidepressant effect 24 hours after ketamine and esketamine infusion for a CADSS score of up to 15 points.

Arketamine for bipolar depression: Open-label, dose-escalation, pilot study.

There are significantly fewer options for the treatment of bipolar depression than major depressive disorder, with an urgent need for alternative therapies. In this pilot study, we treated six subjects with bipolar disorder types I and II (according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria) who had been in a current depressive episode for at least four weeks. Four subjects were female (66.66%), and the mean age was 45.33 (±12.32). Subjects received adjunct treatment with two arketamine intravenous infusions one week apart-0.5 mg/kg first and then 1 mg/kg. The mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 36.66, which decreased to 27.83 24h after the first infusion of 0.5 mg/kg of arketamine (p = 0.036). In respect of the 1 mg/kg dose, the mean MADRS total score before the second infusion was 32.0, which dropped to 17.66 after 24h (p < 0.001). Arketamine appears to have rapid-acting antidepressant properties, consistent with previous animal studies on major depression. All individuals tolerated both doses, exhibiting nearly absent dissociation, and no manic symptoms. To the best of our knowledge, this pilot trial is the first to test the feasibility and safety of the (R)-enantiomer of ketamine (arketamine) for bipolar depression.

Arketamine as adjunctive therapy for treatment-resistant depression: A placebo-controlled pilot study.

BACKGROUND: Racemic ketamine is a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with the latter regarded as the main isomer for antidepressant effects. However, preclinical data and one open-label human trial suggest arketamine might exert a more potent and longer-lasting antidepressant effect with fewer side effects. We aimed to explore the feasibility of a randomized controlled trial of arketamine for treatment-resistant depression (TRD) and to assess its efficacy and safety compared to placebo. METHODS: This is a, randomized, double-blind, crossover, pilot trial (n = 10). All participants received saline and arketamine (0.5 mg/kg) with a one-week interval. Treatment effects were analyzed with a linear mixed effects (LME) model. RESULTS: Our analysis suggested the presence of a carryover effect, so the main efficacy analysis was limited to the first week, which demonstrated a main effect of time (p = 0.038) but not for treatment (p = 0.40) or their interaction (p = 0.95). This indicates that depression improved over time, but without significant difference between arketamine and placebo. Analyzing the two weeks together, findings were the same. Dissociation and other adverse events were minimal. LIMITATIONS: This was a pilot study with a small sample and underpowered. CONCLUSIONS: Arketamine was not superior to placebo for TRD but demonstrated to be extremely safe. Our findings reinforce the importance of continuing studies with this drug, with better powered clinical trials, perhaps considering a parallel design with higher or flexible doses and repeated administrations.

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial.

OBJECTIVES: Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD). METHODS: Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards. RESULTS: There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms. CONCLUSION: There was no significant treatment impact on BDNF serum levels - neither with ketamine nor esketamine - despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion.

Configuration and composition of human-dominated tropical landscapes affect the prevalence and average intensity of mite and fly infestation in Phyllostomidae bats.

The conversion of natural areas into agricultural landscapes results in different mosaics of land use types, modifying biodiversity and consequently altering the patterns of ecological interactions, such as between frugivorous bats and ectoparasites. Our objectives were to investigate whether variations in the configuration and composition of human-disturbed landscapes interfere with the prevalence and average intensity of ectoparasite infestation in the frugivorous bats Artibeus lituratus (Olfers, 1818), Carollia perspicillata (Linnaeus, 1758), and Sturnira lilium (É Geoffroy, 1810), in a region of the Brazilian Atlantic Forest. We also evaluated whether there is a response in the parasite load associated with the ectoparasite group (mite or fly). We found six species of flies and three mites. The proportion of infested hosts was more affected by the landscape than the mean infestation values. Land cover diversity influenced seven of the interactions studied. Forest cover affected eight of the interactions and was associated with a reduction in the parasite load in seven of them. The increase in the proportion of edges per area of each fragment presented a different influence related to the host species. Variations in parasite load did not show any typical response related to the mite or fly group. Our study indicates that landscape configuration and composition interfere with bat-ectoparasite interactions, which may be related to interference in encounter rates between hosts (for mites and flies) and between hosts and their ectoparasites in roosts (for flies). The taxonomic identity of the interacting species suggests that the relationship with the landscape is context-dependent.

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial

Abstract Objectives Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD). Methods Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards. Results There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms. Conclusion There was no significant treatment impact on BDNF serum levels - neither with ketamine nor esketamine - despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion. This clinical trial is registered on the Japan Primary Registries Network: UMIN000032355.

Detection of radicals produced during electro-oxidation of atrazine using commercial DSA®-Cl2 in methanol media: Keys to understand the process.

This work reports the radicals detected and identified during the degradation of atrazine in methanol medium in the presence and absence of different proportions of water (0%, 5%, and 10%). The determination of these radicals is an important step to understand the electrolysis processes in methanol medium and contribute to clarify the degradation mechanism. Furthermore, the parameters for the successful removal of the contaminant were optimized and the results showed that the application of the technique led to the removal of nearly 99.8% of atrazine after 1 h of electrolysis. The oxidation kinetics was found to be very fast and most of the atrazine molecule in the medium was degraded in the first hour of electrolysis. The results obtained from a thorough analysis conducted with a view to evaluating the effects of different current densities and initial pH values on atrazine degradation showed that the application of higher current densities resulted in lower energy consumption, as this led to faster removal of atrazine. Additionally, the initial pH of the solution was found to favor the formation of different species of active chlorine. The radicals formed during the electro-oxidation process were detected by electron paramagnetic resonance spectroscopy and include hydroxyl, methoxy and hydroxymethyl. The use of methanol for the degradation of pollutants is a highly promising technique and this work shows that the identification of the different radicals formed in the process can be the key to understanding the degradation mechanism.

Esketamine for Unipolar Major Depression With Psychotic Features: A Retrospective Chart Review and Comparison With Nonpsychotic Depression.

PURPOSES/BACKGROUND: The aims of the study were to assess subanesthetic esketamine as an antidepressant for major depressive disorder with psychotic features (PMDD) and to compare posttreatment symptoms among those with PMDD to a sample of nonpsychotic depression (major depressive disorder [MDD]). METHODS/PROCEDURES: This study is a retrospective chart review of patients with major depression and current psychotic symptoms, treated with a single parenteral 0.5-mg/kg dose of esketamine. Depression symptoms were assessed at baseline and 24-hour posttreatment with the Montgomery-Åsberg Depression Rating Scale. Individuals with PMDD were matched in a 1:2 ratio to nonpsychotic MDD patients from a randomized, noninferiority clinical trial of esketamine. FINDINGS/RESULTS: A total of 15 individuals with PMDD were included, which had higher baseline depression scores (PMDD = 40.9, MDD = 33.6, P = 0.004). A statistically significant change in depressive symptoms was found for the PMDD sample (ß = -16.20 [95% confidence interval, -23.30 to -9.10], P < 0.001), and no difference between PMDD and MDD groups was observed in the matched-sample analysis (ß = -2.2 [95% confidence interval, -9.32 to 4.58], P = 0.537). Treatment-induced dissociative symptoms were present for both groups, self-contained to within 2 hours after treatment, and no exacerbation of psychotic symptoms was found in clinical assessments. IMPLICATIONS/CONCLUSIONS: Results suggest a single 0.5-mg/kg dose of esketamine may benefit individuals with PMDD, and the symptom reduction may be comparable with esketamine's effects for MDD. Furthermore, esketamine may induce an antidepressant response in those with PMDD without complication of psychotic symptoms. Future research with controlled designs is warranted.

Dimethyl Sulfoxide Dentin Pretreatments Do Not Improve Bonding of a Universal Adhesive in Etch-and-Rinse or Self-etch Modes.

PURPOSE: To evaluate the influence of dimethyl sulfoxide (DMSO) solutions used as dentin pretreatments on microtensile bond strength (µTBS), as well as the dentin/restoration interface micromorphology of a universal adhesive in etch-and-rinse or self-etch mode. MATERIALS AND METHODS: Eighty blocks of dentin were submitted to acid conditioning with 35% phosphoric acid (etch-and-rinse), or not (self-etch), and distributed among the treatments (n = 10): CON: Scotchbond Universal/3M Oral Care; DMSO: pretreatment with DMSO; DMSO/water: pretreatment with DMSO in water (1:1); DMSO/ethanol: pretreatment with DMSO in ethanol (1:1). Microtensile bond strength and failure tests were performed after 24-h and 6-month storage. The tooth-restoration interface was evaluated using scanning electron microscopy to assess the hybrid layer formed. RESULTS: The interaction between treatments, storage time, and etching modes was not significant for µTBS (p = 0.2469). The DMSO, DMSO/water and DMSO/ethanol pretreatments did not affect µTBS values at either time point (p = 0.8732). Aging decreased µTBS over time only for the etch-and-rinse strategy, although the groups presented higher microtensile bond strengths in etch-and-rinse mode than in self-etch mode at both time points (p < 0.0001). The micromorphological images of the interface showed that different DMSO pretreatment solutions did not impair hybrid layer formation. CONCLUSION: The use of dentin pretreatments containing DMSO did not improve the bonding or the micromorphology of a universal adhesive in etch-and-rinse or self-etch modes.

Clinical predictors of depressive symptom remission and response after racemic ketamine and esketamine infusion in treatment-resistant depression.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide and most people do not achieve symptom remission. Treatment-resistant depression (TRD) is characterized by the failure of at least one adequate trial of a major class of antidepressant, with adequate time and dosage. We aimed to identify clinical predictors of depressive symptom remission and response 24 h and 7 days after racemic ketamine and esketamine infusions. METHODS: A randomized, double-blind, active-controlled, non-inferiority trial using ketamine and esketamine in TRD. Individuals diagnosed with MDD according to Diagnostic and Statistical Manual of Mental Disorders version IV and fulfilling TRD criteria were recruited from March 2017 to June 2018. Participants received a single subanesthetic dose of ketamine (0.5 mg/kg) or esketamine (0.25 mg/kg) for 40 min. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) and symptom remission was defined as a MADRS score ≤7 and response defined as ≥50% reduction in depressive symptom severity, 24 h and 7 days after the infusion. Clinical variables were selected based on previous clinical trials. Stepwise backward logistic regression was used, considering a confidence level of 95%. RESULTS: 61 subjects were included: 39 (63.9%) were females with a mean age of 47.2 ± 14.9. Higher number of therapeutic failures (Odds Ratio (OR) = 0.677; 95% confidence interval (CI): 0.47-0.97) and higher severity of illness (OR = 0.912; 95% CI: 0.83-0.99) were associated with fewer remissions of depressive symptoms 7 days after intervention, and with fewer response in 24 h (OR = 0.583; 95% CI: 0,40; 0,84 and OR = 0.909; 95% CI: 0,83; 0,99, respectively). CONCLUSION: Number of treatment failures and severity of illness were predictors of fewer remissions and responses of depressive symptoms in this TRD population. Study of predictors of remission may contribute to better selection patients that may benefit from receiving ketamine.

Impact of the Arylation of Fused N-bridged BODIPY Dyes in Photophysical Properties.

Functionalization of BODIPY dyes is commonly used to modulate photophysical properties. Among the chemical modification of these dyes, ring fusion indifferent faces of dipyrromethene cores is gaining attention in the literature, due to the modulation of emission/absorption properties and fluorophores with increased bright. N-bridged arylated BODIPYs were recently synthesized and shows intense bright and blu shifted emission. However, few examples of substituted compounds are described and none involving arylation with extention of the π-conjugation. In this manuscript, it is shown an optimized method for the synthesis of N-bridged arylated BODIPYs, including arylated derivatives, and the studies of molecular properties. It is also shown that fluorinated aryl substituted N-bridged arylated BODIPYs show high quantum yields and are red-shifted compared to unsubstituted examples. The work open opportunities for application of the new developed compounds as probes.

Country transition index based on hierarchical clustering to predict next COVID-19 waves.

COVID-19 has widely spread around the world, impacting the health systems of several countries in addition to the collateral damage that societies will face in the next years. Although the comparison between countries is essential for controlling this disease, the main challenge is the fact of countries are not simultaneously affected by the virus. Therefore, from the COVID-19 dataset by the Johns Hopkins University Center for Systems Science and Engineering, we present a temporal analysis on the number of new cases and deaths among countries using artificial intelligence. Our approach incrementally models the cases using a hierarchical clustering that emphasizes country transitions between infection groups over time. Then, one can compare the current situation of a country against others that have already faced previous waves. By using our approach, we designed a transition index to estimate the most probable countries' movements between infectious groups to predict next wave trends. We draw two important conclusions: (1) we show the historical infection path taken by specific countries and emphasize changing points that occur when countries move between clusters with small, medium, or large number of cases; (2) we estimate new waves for specific countries using the transition index.

Protein residue network analysis reveals fundamental properties of the human coagulation factor VIII.

Hemophilia A is an X-linked inherited blood coagulation disorder caused by the production and circulation of defective coagulation factor VIII protein. People living with this condition receive either prophylaxis or on-demand treatment, and approximately 30% of patients develop inhibitor antibodies, a serious complication that limits treatment options. Although previous studies performed targeted mutations to identify important residues of FVIII, a detailed understanding of the role of each amino acid and their neighboring residues is still lacking. Here, we addressed this issue by creating a residue interaction network (RIN) where the nodes are the FVIII residues, and two nodes are connected if their corresponding residues are in close proximity in the FVIII protein structure. We studied the characteristics of all residues in this network and found important properties related to disease severity, interaction to other proteins and structural stability. Importantly, we found that the RIN-derived properties were in close agreement with in vitro and clinical reports, corroborating the observation that the patterns derived from this detailed map of the FVIII protein architecture accurately capture the biological properties of FVIII.

Neurocognitive aspects of ketamine and esketamine on subjects with treatment-resistant depression: A comparative, randomized and double-blind study.

The objective of this study is to evaluate cognition in patients using either ketamine or esketamine to treat TRD. We also evaluate if both ketamine and esketamine as one group influence cognition in patients with TRD. Fifty-four patients with TRD were infused with either ketamine or esketamine and were assessed at three time points: baseline, 24 h, and 7 days after infusion. We applied neuropsychological tests to evaluate executive functions, processing speed, short term memory, and auditory-verbal episodic memory. There is no cognitive difference between ketamine and esketamine, with the exception of one variable. When considered as one group, ketamine and esketamine do not impair cognition; on the contrary, they improve some neuropsychological functions such as visuospatial short-term memory, executive functions, processing speed, and several measures related to episodic verbal memory. Ketamine and esketamine do not present differing cognitive effects when used in antidepressant doses to treat TRD. Furthermore, they rapidly improve many cognitive aspects of patients with TRD at 24 h after the infusion and maintain these effects for at least 7 days.

Prediction of hemophilia A severity using a small-input machine-learning framework.

Hemophilia A is a relatively rare hereditary coagulation disorder caused by a defective F8 gene resulting in a dysfunctional Factor VIII protein (FVIII). This condition impairs the coagulation cascade, and if left untreated, it causes permanent joint damage and poses a risk of fatal intracranial hemorrhage in case of traumatic events. To develop prophylactic therapies with longer half-lives and that do not trigger the development of inhibitory antibodies, it is essential to have a deep understanding of the structure of the FVIII protein. In this study, we explored alternative ways of representing the FVIII protein structure and designed a machine-learning framework to improve the understanding of the relationship between the protein structure and the disease severity. We verified a close agreement between in silico, in vitro and clinical data. Finally, we predicted the severity of all possible mutations in the FVIII structure - including those not yet reported in the medical literature. We identified several hotspots in the FVIII structure where mutations are likely to induce detrimental effects to its activity. The combination of protein structure analysis and machine learning is a powerful approach to predict and understand the effects of mutations on the disease outcome.

Trait dissociation as a predictor of induced dissociation by ketamine or esketamine in treatment-resistant depression: Secondary analysis from a randomized controlled trial.

Dissociative symptoms are common, possibly severe, side effects associated with the use of ketamine and esketamine in depression. We investigated the relationship between trait dissociation and dissociation induced by ketamine and esketamine used as augmentation therapy in treatment-resistant depression (TRD). Adults with TRD were randomly assigned to receive a single intravenous infusion, with a duration of 40 min, of either esketamine 0.25 mg/kg or ketamine 0.5 mg/kg. We assessed trait dissociation with the Dissociative Experience Scale (DES) and, to evaluate induced dissociation, the Clinician-Administered Dissociative States Scale (CADSS) was used. Thirty-two subjects received esketamine and 29 received ketamine. The groups had similar median DES scores (p = 0.26). More than 30% of the patients in both groups had DES scores ≥30 points. The median CADSS score in the esketamine group was equivalent to that in the ketamine group (p = 0.40). Every 5 points increment in the DES was associated with a 10.9% (95% CI 4.5-17.8%) increase in the CADSS, in an exponential fashion when the two groups were pooled together. Subjects with high trait dissociation had a higher risk of induced dissociation state (relative risk [RR] 1.41, 95% CI 1.11-1.78) and very high induced dissociation (RR 3.05, 95% CI 1.14-8.15). Induced dissociation was not a serious adverse effect. The findings suggest that trait dissociation is a predictor of induced dissociation by Ketamine or Esketamine in TRD subjects. Screening for trait dissociation and counseling patients with high trait dissociation on the risks of dissociation by these drugs are recommended.

Electro-oxidation of tetracycline in methanol media on DSA®-Cl2.

The electro-oxidation of tetracycline (TeC) in methanol medium containing chloride or sulfate ions was evaluated using a DSA®-Cl2 in a flow reactor and compared with BDD. The results show that after 30 min of electrolysis no TeC is detected by liquid chromatography when chloride is used as supporting electrolyte. On the other hand, after 90 min of electrolysis using a BDD anode only 61% of TeC was removed from solutions with chloride, but in the presence of sulfate the removal reaches 94%. This evidences that the oxidizing species generated during electrochemical oxidation control the process and the mechanism of degradation of the TeC. Besides that, it was possible to infer that only a small amount of methanol might convert to formaldehyde or formic acid, although they were not detected according to the nil changes in the FTIR spectra or in the HPLC chromatograms recorded.