Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation - Clinical and safety results.

INTRODUCTION: We investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy. MATERIAL AND METHODS: Patients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis. RESULTS: Twenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (-5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01). Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment. DISCUSSION: Our results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.

Impact of adult attention deficit hyperactivity disorder and medication status on sleep/wake behavior and molecular circadian rhythms.

Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition that has been strongly associated with changes in sleep and circadian rhythms. Circadian rhythms are near 24-h cycles that are primarily generated by an endogenous circadian timekeeping system, encoded at the molecular level by a panel of clock genes. Stimulant and non-stimulant medication used in the management of ADHD has been shown to potentially impact on circadian processes and their behavioral outputs. In the current study, we have analyzed circadian rhythms in daily activity and sleep, and the circadian gene expression in a cohort of healthy controls (N = 22), ADHD participants not using ADHD-medication (N = 17), and participants with ADHD and current use of ADHD medication (N = 17). Rhythms of sleep/wake behavior were assessed via wrist-worn actigraphy, whilst rhythms of circadian gene expression were assessed ex-vivo in primary human-derived dermal fibroblast cultures. Behavioral data indicate that patients with ADHD using ADHD-medication have lower relative amplitudes of diurnal activity rhythms, lower sleep efficiency, more nocturnal activity but not more nocturnal wakenings than both controls and ADHD participants without medication. At the molecular level, there were alterations in the expression of PER2 and CRY1 between ADHD individuals with no medication compared to medicated ADHD patients or controls, whilst CLOCK expression was altered in patients with ADHD and current medication. Analysis of fibroblasts transfected with a BMAL1:luc reporter showed changes in the timing of the peak expression across the three groups. Taken together, these data support the contention that both ADHD and medication status impact on circadian processes.

Quadratus Lumborum Block as Sole, Homeostatic-Preserving Anesthetic for a Patient with Multiple System Atrophy Undergoing Open Inguinal Hernia Repair: A Case Report.

Quadratus Lumborum (QL) block has been successfully used for different abdominal procedures in the past. Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized mainly by autonomic instability, motor impairment, and cognitive dysfunction. We report a case of a patient with MSA with a history of multiple episodes of unplanned admissions following outpatient minor surgical procedures under general anesthesia scheduled to undergo open inguinal hernia repair. In our patient, QL block was successfully used for surgical anesthesia and it resulted in hemodynamic stability and an opioid-free perioperative course.

Dislocation-mediated relaxation in nanograined columnar palladium films revealed by on-chip time-resolved HRTEM testing.

The high-rate sensitivity of nanostructured metallic materials demonstrated in the recent literature is related to the predominance of thermally activated deformation mechanisms favoured by a large density of internal interfaces. Here we report time-resolved high-resolution electron transmission microscopy creep tests on thin nanograined films using on-chip nanomechanical testing. Tests are performed on palladium, which exhibited unexpectedly large creep rates at room temperature. Despite the small 30-nm grain size, relaxation is found to be mediated by dislocation mechanisms. The dislocations interact with the growth nanotwins present in the grains, leading to a loss of coherency of twin boundaries. The density of stored dislocations first increases with applied deformation, and then decreases with time to drive additional deformation while no grain boundary mechanism is observed. This fast relaxation constitutes a key issue in the development of various micro- and nanotechnologies such as palladium membranes for hydrogen applications.

In vitro activity and resistance profile of samatasvir, a novel NS5A replication inhibitor of hepatitis C virus.

The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein is a clinically validated target for drugs designed to treat chronic HCV infection. This study evaluated the in vitro activity, selectivity, and resistance profile of a novel anti-HCV compound, samatasvir (IDX719), alone and in combination with other antiviral agents. Samatasvir was effective and selective against infectious HCV and replicons, with 50% effective concentrations (EC50s) falling within a tight range of 2 to 24 pM in genotype 1 through 5 replicons and with a 10-fold EC50 shift in the presence of 40% human serum in the genotype 1b replicon. The EC90/EC50 ratio was low (2.6). A 50% cytotoxic concentration (CC50) of >100 µM provided a selectivity index of >5 × 10(7). Resistance selection experiments (with genotype 1a replicons) and testing against replicons bearing site-directed mutations (with genotype 1a and 1b replicons) identified NS5A amino acids 28, 30, 31, 32, and 93 as potential resistance loci, suggesting that samatasvir affects NS5A function. Samatasvir demonstrated an overall additive effect when combined with interferon alfa (IFN-α), ribavirin, representative HCV protease, and nonnucleoside polymerase inhibitors or the nucleotide prodrug IDX184. Samatasvir retained full activity in the presence of HIV and hepatitis B virus (HBV) antivirals and was not cross-resistant with HCV protease, nucleotide, and nonnucleoside polymerase inhibitor classes. Thus, samatasvir is a selective low-picomolar inhibitor of HCV replication in vitro and is a promising candidate for future combination therapies with other direct-acting antiviral drugs in HCV-infected patients.

Benthic insects of the El Tala River (Catamarca, Argentina): longitudinal variation of their structure and the use of insects to assess water quality.

The aim of this work was to determine the structure of the benthic entomofauna and its variation along the El Tala River (Catamarca, Argentina). Five sampling stations were established, considering the location of nearby housing with respect to the watercourse. The following variables were determined in situ: altitude, latitude and longitude, bedstream width, river depth, river-current speed, water and air temperatures. Benthic insects were collected with a square parcel sampler of 0.09-m2 area and 300-µm net opening and identified to the family level. Faunal density, richness, and diversity exhibited a longitudinal variation. From sampling Stations 1 (reference site) to 3, the number of orders and families decreased, whereas in sampling Station 4 those values increased and continued to do so through to Station 5 (downstream station). Station 5 showed the highest family richness (17) and the highest value for the Shannon-Wiener index (2.74) and the lowest value in Simpson's Dominance index (D = 0.22). These values could be explained because of the self-cleansing capabilities of the river downstream. The water quality of El Tala River is Class I (very clean and non-impacted), according to the results obtained from the application of the biotic Biological-Monitoring-Working-Party and Average-Store-per-Taxon indices.

On-chip stress relaxation testing method for freestanding thin film materials.

A stress relaxation method for freestanding thin films is developed based on an on-chip internal stress actuated microtensile testing set-up. The on-chip test structures are produced using microfabrication techniques involving cleaning, deposition, lithography, and release. After release from the substrate, the test specimens are subjected to uniaxial tension. The applied load decays with the deformation taking place during relaxation. This technique is adapted to strain rates lower than 10(-6)∕s and permits the determination of the strain rate sensitivity of very thin films. The main advantage of the technique is that the relaxation tests are simultaneously performed on thousands of specimens, pre-deformed up to different strain levels, for very long periods of time without monopolizing any external mechanical loading equipment. Proof of concept results are provided for 205-nm-thick sputtered AlSi(0.01) films and for 350-nm-thick evaporated Pd films showing unexpectedly high relaxation at room temperature.

German validation of the Conners Adult ADHD Rating Scales (CAARS) II: reliability, validity, diagnostic sensitivity and specificity.

BACKGROUND: The German version of the Conners Adult ADHD Rating Scales (CAARS) has proven to show very high model fit in confirmative factor analyses with the established factors inattention/memory problems, hyperactivity/restlessness, impulsivity/emotional lability, and problems with self-concept in both large healthy control and ADHD patient samples. This study now presents data on the psychometric properties of the German CAARS-self-report (CAARS-S) and observer-report (CAARS-O) questionnaires. METHODS: CAARS-S/O and questions on sociodemographic variables were filled out by 466 patients with ADHD, 847 healthy control subjects that already participated in two prior studies, and a total of 896 observer data sets were available. Cronbach's-alpha was calculated to obtain internal reliability coefficients. Pearson correlations were performed to assess test-retest reliability, and concurrent, criterion, and discriminant validity. Receiver Operating Characteristics (ROC-analyses) were used to establish sensitivity and specificity for all subscales. RESULTS: Coefficient alphas ranged from .74 to .95, and test-retest reliability from .85 to .92 for the CAARS-S, and from .65 to .85 for the CAARS-O. All CAARS subscales, except problems with self-concept correlated significantly with the Barrett Impulsiveness Scale (BIS), but not with the Wender Utah Rating Scale (WURS). Criterion validity was established with ADHD subtype and diagnosis based on DSM-IV criteria. Sensitivity and specificity were high for all four subscales. CONCLUSION: The reported results confirm our previous study and show that the German CAARS-S/O do indeed represent a reliable and cross-culturally valid measure of current ADHD symptoms in adults.

Glutamate as a spectroscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal cortisol.

While an excess of glucocorticoids is associated with hippocampal pathology in mood disorders, lithium exerts robust neuroprotective and neurotrophic effects. Here, 21 stably remitted bipolar I patients who had been on chronic lithium maintenance therapy, on average, for more than a decade, and 19 carefully matched healthy controls were studied using 3 T (1)H-magnetic resonance spectroscopy of left and right hippocampus. Salivary cortisol samples were obtained to assess activity of the hypothalamus-pituitary-adrenal system. Absolute concentrations of N-acetylaspartate (NAA), choline-containing compounds and total creatine were similar in euthymic bipolar patients and healthy controls. Hippocampal glutamate concentrations were significantly increased as an effect of patient status (patients>controls) and laterality (left hippocampus>right hippocampus). Hippocampal glutamate content (Glu) was strongly correlated with NAA. Across groups and within the patient group, diurnal saliva cortisol levels showed a significant inverse relationship with both Glu and NAA. Taken together, these results add to the concept of bipolar disorder as an illness involving disturbed hippocampal structural plasticity under the opposing influences of lithium and glucocorticoids.

Open-label non-randomized versus double-blind randomized antidepressive treatment: what are the advantages of clinical decision over randomization?

OBJECTIVE: To study, whether and how the results from open and double-blind randomized trials on antidepressants differ. METHODS: Seventy-one patients were included in a study comparing open, non-randomized, standardized treatment with paroxetine (PAROX) and amitriptyline (AMI) after a minimum of six drug-free days (OPEN). A second group of 56 patients received the same treatment under blind-randomized conditions (BLIND-RANDOM). The course of psychopathology as assessed by the Hamilton Depression Rating Scale was compared using repeated measurements ANOVA-(rm). RESULTS: While the rate of adverse events was higher in the BLIND-RANDOM compared to the OPEN condition, completer-analyses revealed no differences in psychopathological outcome. CONCLUSIONS: With similar clinical outcome BLIND-RANDOM trials of antidepressants may expose depressed patients to an increased risk of adverse events, when compared to OPEN conditions. However, the clinical outcome in study completers did not differ between the BLIND-RANDOM and the OPEN condition. Thus, the psychiatrist's choice may have impact on adverse events rather than on clinical outcome of antidepressant treatment.

Increased platelet aggregability in major depression?

There is compelling evidence that depression constitutes an independent risk factor for cardiovascular morbidity and mortality. As exaggerated platelet reactivity is associated with an increased risk of intra-arterial thrombus formation, we studied platelet aggregability in patients with major depression both before and after 5 weeks of anti-depressant therapy as well as in healthy control subjects. Twenty-two depressed patients and 24 healthy control subjects participated in the study. Washed and rediluted platelets were stimulated with the agonists collagen and thrombin in three concentration steps. Depression was associated with a higher aggregability after stimulation with thrombin in the intermediate concentration and with collagen at the low concentration, with ceiling effects for the other concentrations. After 5 weeks of anti-depressant therapy, aggregability was somewhat less exaggerated, although this effect did not reach statistical significance. We thus conclude that major depression is associated with increased platelet aggregability, which seems to persist even under a marked improvement in depressive symptomatology. This effect may contribute to the increased cardiovascular morbidity in depressed patients.

Structure-based design, synthesis, and biological evaluation of conformationally restricted novel 2-alkylthio-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones as non-nucleoside inhibitors of HIV-1 reverse transcriptase.

5-Alkyl-2-(alkylthio)-6-(2,6-difluorobenzyl)-3,4-dihydropyrimidin-4(3H)-ones (S-DABOs, 2) have been recently described as a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) active at nanomolar concentrations (Mai, A. et al. J. Med. Chem. 1999, 42, 619-627). In pursuing our lead optimization efforts, we designed novel conformationally restricted S-DABOs, 3, featuring a methyl at the benzylic carbon (Y = Me) and at the pyrimidine 5-position (R = Me). Conformational analyses and docking simulations suggested that the presence of both methyls would significantly reduce conformational flexibility without compromising, in the R enantiomers, the capability of fitting into the RT non-nucleoside binding pocket. To develop structure-activity relationships, we prepared several congeners of type 3 belonging to the thymine (R = Me) and uracil (R = H) series, featuring various 2-alkylthio side chains (X = Me, i-Pr, n-Bu, i-Bu, s-Bu, c-pentyl, and c-hexyl) and aryl moieties different from the 2,6-difluorophenyl (Ar = phenyl, 2,6-dichlorophenyl, 1-naphthyl). Moreover, alpha-ethyl derivatives (Y = Et) were included in the synthetic project in addition to alpha-methyl derivatives (Y = Me). All of the new compounds were evaluated for their cytotoxicity and anti-HIV-1 activity in MT-4 cells, and some of them were assayed against highly purified recombinant wild-type HIV-1 RT using homopolymeric template primers. The results were expressed as CC(50) (cytotoxicity), EC(50) (anti-HIV-1 activity), SI (selectivity, given by the CC(50)/EC(50) ratio), and IC(50) (RT inhibitory activity) values. In the 2,6-difluorobenzylthymine (R = Me) series, methylation of the benzylic carbon improved anti-HIV-1 and RT inhibitory activities together with selectivity. Compound 3w (Ar = 2,6-F(2)-Ph, R = Y = Me, X = c-pentyl) turned out the most potent and selective among the S-DABOs reported to date (CC(50) > 200 microM, EC(50) = 6 nM, IC(50) = 5 nM, and SI > 33 333). Assays performed on the pure enantiomer (+)-3w, much more active than (-)-3w, yielded the following results: CC(50) > 200 microM, EC(50) = 2 nM, IC(50) = 8 nM, and SI > 100 000, under conditions wherein MKC-442 was less active and selective (CC(50) > 200 microM, EC(50) = 30 nM, IC(50) = 40 nM, SI > 6666). The 2,6-difluorophenylethylthymines (R = Me) were generally endowed with higher potency compared with the uracil counterparts (R = H). In the 2,6-difluorophenyl series the best and the least performant 2-alkylthio side chains were the 2-c-pentylthio and the 2-methylthio, respectively. When the methyl at the benzylic carbon was replaced by an ethyl, activity was retained or decreased slightly, thus suggesting that the dimensions of the cavity within the RT hosting this substituent would not be compatible with groups larger than ethyl. Aryl moieties different from the 2,6-difluorophenyl (phenyl, 1-naphthyl, 2,6-dichlorophenyl) were generally detrimental to activity, consistent with a favorable electronic effect exerted by the 2,6-fluorines on a putative charge-transfer interaction between the aromatic moieties of the inhibitor and Tyr188.

The glutamate antagonist riluzole and its effects upon basal and stress-induced activity of the human hypothalamus-pituitary-adrenocortical system in elderly subjects.

There is preclinical evidence that CRH is released in response to a glutamatergic stimulation. However, it is not clear, whether glutamate plays a role in the physiological stress response. We tested whether the antiglutamatergic drug riluzole dampens the response of the hypothalamus-pituitary-adrenocortical (HPA) system to both a mental and a physical stressor. Nine male elderly healthy subjects received placebo and 150 mg riluzole for 2 days in a randomized balanced order. Blood was withdrawn every 15 min for estimation of cortisol and ACTH from 14.00 to 20.00 h. Between 16.00 and 16.45 h, the subjects were subjected to a cognitive challenge paradigm. Further, between 19.02 and 19.15 an individually adapted physical stress test was performed. After riluzole treatment, baseline ACTH and cortisol concentrations were unchanged when compared to placebo treatment. Also, after the mental stressor, there was no difference between both treatment conditions. In contrast, the cortisol (riluzole vs. placebo: 148 +/- 60 vs. 183 +/- 98 nmol/l) and ACTH response (20.2 +/- 11.9 vs. 40.7 +/- 61.9 pmol/l) to the physical stressor tended to be lower after riluzole pretreatment. In conclusion, the antiglutamatergic drug riluzole did not have any effects upon HPA system activity under baseline and cognitive-stress-induced conditions in elderly subjects. However, a trend for dampening the endocrine response to physical stress emerged.

Testosterone, androstenedione and dihydrotestosterone concentrations are elevated in female patients with major depression.

Hyperactivity of the HPA-system in major depression is reflected by an increased secretion of adrenal hormones especially cortisol and dehydroepiandrosterone (DHEA). In women for whom androgenicity is associated with cardiovascular disorders the dominant source of androstenedione and testosterone secretion are the adrenal glands. To date, there is only sparse information about the regulation of androstenedione, testosterone and dihydrotestosterone (DHT) concentrations in women with severe major depression.Therefore, 11 pre- and postmenopausal, severely depressed, hypercortisolemic women (Hamilton Depression Scale, 31.3+/-5.9; age, 28-77 yrs; mean, 48. 1+/-18.1 yrs) and 11 age-matched healthy female controls (age, 24-81 yrs; mean, 47.9+/-21.5 yrs) underwent a 24 hour (h) blood sampling starting at 0800 h with 30-minute sampling intervals. By applying multivariate analysis of covariance with age as covariate, androstenedione, testosterone and DHT plasma levels at 0900 h show a trend for elevated concentrations in depressed women compared to controls (F(1,19)=2.7; P=0.057). Univariate F tests reveal a significant difference between the groups for androstenedione (4. 19+/-1.571 vs 2.584+/-1.257 nmol/l; P<0.05) testosterone (1.110+/-0. 278 vs 0.833+/-0.347 nmol/l; P<0.05) and DHT (0.656+/-0.207 vs 0. 483+/-0.242 nmol/l; P<0.05). Mean ACTH (16.4+/-10.4 vs 10.4+/-2.4 pmol/l; P=0.89), LH (13.5+/-11.8 vs 8.9+/-9.2 IU/l; P=0.12), FSH (35. 2+/-33.1 vs 31.3+/-35.7 IU/l; P=0.67) and estradiol (135.4+/-157.4 vs 82.2+/-85.1 pmol/l; P=0.20) plasma levels did not differ between patients and controls. Further, there was a trend towards an age related decline in testosterone secretion in healthy controls (r=-0. 24; P=0.08) which did not occur in depressed patients (r=0.17; P=0. 96), while the calculated ratio of DHEA to testosterone was similar in both groups (0.2+/-0.14 vs 0.13+/-0.7; P=0.21, unpaired t-test). In conclusion, androstenedione, testosterone and DHT concentrations all were increased in hypercortisolemic women with severe major depression. These findings are best explained as a consequence of an overstimulation of the adrenal glands through pituitary and hypothalamic sites of the HPA-system.

The role of mineralocorticoid receptors in the circadian activity of the human hypothalamus-pituitary-adrenal system: effect of age.

The purpose of this study was to test the role of the mineralocorticoid receptor (MR) in the circadian activity of the hypothalamus-pituitary-adrenal (HPA) system of elderly healthy subjects. Nine elderly subjects (age: 66.2 +/- 7.7 years) were treated for 8 days with both the MR antagonist spironolactone and a placebo in a randomized, single-blind cross-over order. After treatment, we studied the circadian profiles of ACTH, plasma cortisol and saliva cortisol. No significant change in ACTH concentrations emerged. However, there were significant increases in circadian minimal (52.4 +/- 26.7 versus 33.3 +/- 14.4 nmol/l), mean (166.2 +/- 24.9 versus 133.0 +/- 18.3 nmol/l), and maximal cortisol concentrations (389.7 +/- 57.7 versus 335.4 +/- 45.0 nmol/l). Also, in the diurnal trough, we found an increase in saliva cortisol concentrations. Compared to young healthy controls, spironolactone treatment had stronger effects in the elderly. We therefore conclude that: 1) MR is involved in the human HPA system regulation; 2) the MR participates in the regulation of circadian nadir and peak activity of the HPA system; and 3) the HPA system in the elderly is more vulnerable to dysregulation at the level of the MR.

Increased diurnal plasma concentrations of cortisone in depressed patients.

The enzyme 11-beta-hydroxysteroid dehydrogenase (11-beta-HSD) regulates glucocorticoid activity by converting cortisol into cortisone and vice versa. Frequent signs of major depression are elevated concentrations of circulating cortisol and ACTH. However, no information is available about the activity of 11-beta-HSD in this disorder. Therefore, we compared diurnal plasma concentrations of cortisol and cortisone and their ratios, reflecting 11-beta-HSD activity, in 25 severely depressed patients (Hamilton Depression Scale, 29 +/- 6; 14 men, 11 women, age 22-77 yr; mean, 47 +/- 16) and 30 control persons (20 men, 10 women age 23-85 yr; mean, 51 +/- 19). Cortisol and cortisone were measured at 0900 h, 1100 h, 1300 h, 2000 h, 2200 h, 0100 h, 0300 h, and 0700 h with specific RIAs after extraction. Both cortisol and cortisone concentrations were significantly increased in patients compared with controls (cortisol, 251.7 +/- 113.1 vs. 160 +/- 96.6 nmol/L; cortisone, 32.8 +/- 10.9 vs. 21.9 +/- 10.9 nmol/L). The calculated ratios of cortisol to cortisone were similar in controls and patients. Similar to cortisol, the circadian variation of cortisone was flattened in patients with the ratio of maximal cortisone to minimal cortisone being 1.9-fold higher in controls than in patients. There was no gender-specific difference in cortisone values neither in patients nor in controls. We conclude that in major depression increased cortisol is not due, at least partly, to an altered 11-beta-HSD activity or to a decrease in cortisone.

Endothelin-1 plasma concentrations in depressed patients and healthy controls.

Depression and cardiovascular morbidity are known to be associated. So far, however, the pathophysiological link between these conditions is unclear. We tested the hypothesis that in depressed hypercortisolemic patients endothelin-1 (ET-1) plasma concentrations are increased and contribute to the cardiovascular risk. Diurnal plasma concentrations of cortisol and ET-1 were measured in 29 healthy controls and 22 depressed patients. ANCOVA did not reveal a significant effect of diagnosis or age upon ET-1 concentrations. However, only in depressed patients, cortisol plasma concentrations tended to be positively related to ET-1 concentrations. We conclude that ET-1 is not increased in depressed patients, but within this group, hypercortisolemia may be associated with increased ET-1 concentrations.