The effect of intranasal (R,S)-ketamine on symptoms of fatigue in severe major depressive disorder or bipolar depression with and without comorbid alcohol use disorder: Results from a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Fatigue is a multidimensional condition that may overlap with depression. Initial studies found that fatigue responds in only a limited way to standard monoaminergic antidepressants and mood stabilizers but does respond positively to intravenous (IV) racemic (R,S)-ketamine (ketamine). However, IV ketamine's use is limited by cost and access barriers. To date, no study has evaluated intranasal (IN) ketamine in individuals with fatigue. This study sought to evaluate the anti-fatigue effects of a single 50 mg dose of IN ketamine in individuals with major depressive disorder (MDD) or bipolar depression (BDep), both with and without comorbid alcohol use disorder (AUD). METHODS: Twenty-eight individuals with primary diagnoses of MDD or BDep I/II currently experiencing a depressive episode with active suicidality were enrolled; approximately 60 % had comorbid AUD. Changes in the NIH-Brief Fatigue Inventory (NIH-BFI) were assessed at baseline and at 4, 24, and 48 h post-treatment. RESULTS: The group x time interaction for NIH-BFI score was significant (F = 3.44, p = 0.022), favoring IN ketamine over placebo. IN ketamine was well-tolerated with minimal adverse effects. LIMITATIONS: Limitations include the limited sample size, short duration, and single, fixed dose. CONCLUSIONS: IN ketamine appears to induce rapid anti-fatigue effects in individuals with severe MDD and BDep both with and without comorbid AUD. This suggests that IN ketamine holds potential as an alternative, rapid-acting, anti-fatigue option for different medical conditions.

A Randomized, Double-Blind, Placebo-Controlled Pilot Trial of the Acute Antisuicidal and Antidepressant Effects of Intranasal (R,S)-Ketamine in Severe Unipolar and Bipolar Depression With and Without Comorbid Alcohol Use Disorder.

Objective: Although individuals with a family history of alcohol use disorder (AUD) have a superior antidepressant response to ketamine, outcomes in patients with current AUD remain unclear. This study sought to investigate whether intranasal (IN) racemic (R,S)-ketamine had antisuicidal and antidepressant effects in unipolar and bipolar depression and whether comorbid AUD conferred superior antisuicidal outcomes for patients.Methods: This was a double-blind, randomized, placebo-controlled trial (May 2018 to January 2022) of single administration, fixed-dose (50 mg) IN (R,S)-ketamine (or saline comparator) in unmedicated inpatients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for a current major depressive episode (bipolar or unipolar), with current suicidal ideation (SI) and past attempt. Patients with and without comorbid AUD were enrolled. Change in Scale for Suicide Ideation score was the primary outcome measure, and change in Montgomery-Åsberg Depression Rating Scale score was the secondary outcome measure.Results: No significant group × time effect was noted for SI (F = 1.1, P = .36). A statistical trend toward superior improvement in suicidality was observed in participants with comorbid AUD. The group × time interaction was significant for improvements in depression (F = 3.06, P = .03) and largely unaffected by comorbid AUD or primary mood disorder type. Within the ketamine group, a significant correlation was observed between improvement in depressive symptoms and SI for patients without comorbid AUD (r =0.927, P = .023) that was absent in patients with AUD (r = 0.39, P = .44).Conclusion: IN ketamine induced rapid antidepressant effects compared to placebo but did not significantly alter SI scores. The treatment was well tolerated. Continued investigation with IN ketamine as a practical alternative to current formulations is warranted.Trial Registration: ClinicalTrials.gov identifier: NCT03539887.

A-Band Absorption Spectrum of the ClSO Radical: Electronic Structure of the Sulfinyl Group.

Sulfur oxide species (RSOx) play a critical role in many fields, ranging from biology to atmospheric chemistry. Chlorine-containing sulfur oxides may play a key role in sulfate aerosol formation in Venus' cloud layer by catalyzing the oxidation of SO to SO2 via sulfinyl radicals (RSO). We present results from the gas-phase UV-vis transient absorption spectroscopy study of the simplest sulfinyl radical, ClSO, generated from the pulsed-laser photolysis of thionyl chloride at 248 nm (at 40 Torr of N2 and 292 K). A weak absorption spectrum from 350 to 480 nm with a peak at 385 nm was observed, with partially resolved vibronic bands (spacing = 226 cm-1), and a peak cross section σ(385 nm) = (7.6 ± 1.9) × 10-20 cm2. From ab initio calculations at the EOMEE-CCSD/ano-pVQZ level, we assigned this band to 12A' ← X2A″ and 22A' ← X2A″ transitions. The spectrum was modeled as a sum of a bound-to-free transition to the 12A' state and a bound-to-bound transition to the 22A' state with similar oscillator strengths; the prediction agreed well with the observed spectrum. We attributed the vibronic structure to a progression in the bending vibration of the 22A' state. Further calculations at the XDW-CASPT2 level predicted a conical intersection between the excited 12A' and 22A' potential energy surfaces near the Franck-Condon region. The geometry of the minimum-energy conical intersection was similar to that of the ground-state geometry. The lack of structure at shorter wavelengths could be evidence of a short excited-state lifetime arising from strong vibronic coupling. From simplified molecular orbital analysis, we attributed the ClSO spectrum to transitions involving the out-of-plane π/π* orbitals along the S-O bond and the in-plane orbital possessing a σ/σ* character along the S-Cl bond. We hypothesize that these orbitals are common to other sulfinyl radicals, RSO, which would share a combination of a strong and a weak transition in the UV (near 300 nm) and visible (400-600 nm) regions.

The Role of the Gut Microbiome in Bipolar Disorder and its Common Medical Comorbidities.

Bipolar disorder is a decidedly heterogeneous and multifactorial disease, with significant psychosocial and medical disease burden. Much difficulty has been encountered in developing novel therapeutics and objective biomarkers for clinical use in this population. In that regard, gut-microbial homeostasis appears to modulate several key pathways relevant to a variety of psychiatric, metabolic, and inflammatory disorders. Microbial impact on immune, endocrine, endocannabinoid, kynurenine, and other pathways are discussed throughout this review. Emphasis is placed on this system's relevance to current pharmacology, diet, and comorbid illness in bipolar disorder. Despite the high level of optimism promoted in many reviews on this topic, substantial obstacles exist before any microbiome-related findings can provide meaningful clinical utility. Beyond a comprehensive overview of pathophysiology, this review hopes to highlight several key areas where progress is needed. As well, novel microbiome-associated suggestions are presented for future research.

Conformer-Dependent Chemistry: Experimental Product Branching of the Vinyl Alcohol + OH + O2 Reaction.

The concentration of formic acid in Earth's troposphere is underestimated by detailed chemical models compared to field observations. Phototautomerization of acetaldehyde to its less stable tautomer vinyl alcohol, followed by the OH-initiated oxidation of vinyl alcohol, has been proposed as a missing source of formic acid that improves the agreement between models and field measurements. Theoretical investigations of the OH + vinyl alcohol reaction in excess O2 conclude that OH addition to the α carbon of vinyl alcohol produces formaldehyde + formic acid + OH, whereas OH addition to the ß site leads to glycoaldehyde + HO2. Furthermore, these studies predict that the conformeric structure of vinyl alcohol controls the reaction pathway, with the anti-conformer of vinyl alcohol promoting α OH addition, whereas the syn-conformer promotes ß addition. However, the two theoretical studies reach different conclusions regarding which set of products dominate. We studied this reaction using time-resolved multiplexed photoionization mass spectrometry to quantify the product branching fractions. Our results, supported by a detailed kinetic model, conclude that the glycoaldehyde product channel (arising mostly from syn-vinyl alcohol) dominates over formic acid production with a 3.6:1.0 branching ratio. This result supports the conclusion of Lei et al. that conformer-dependent hydrogen bonding at the transition state for OH-addition controls the reaction outcome. As a result, tropospheric oxidation of vinyl alcohol creates less formic acid than recently thought, increasing again the discrepancy between models and field observations of Earth's formic acid budget.

History of Suicide Attempt and Clozapine Treatment in Veterans With Schizophrenia or Schizoaffective Disorder.

Objective: To evaluate whether a history of suicide attempt increases the odds of receiving clozapine treatment in veterans with schizophrenia or schizoaffective disorder.Methods: Electronic health record data were obtained for veterans with schizophrenia or schizoaffective disorder treated at any US Veterans Affairs Medical Center between January 1, 2000, and January 31, 2021 (N = 134,692). Logistic regression (adjusted and unadjusted) was applied to estimate odds ratios (ORs) for clozapine treatment in suicide attempters relative to nonattempters.Results: 3,407 patients had a documented history of suicide attempt, while 6,867 patients had received clozapine treatment. Also, 9.4% (n = 321) of suicide attempters versus 5.0% (n = 6546) of nonattempters had received clozapine treatment. The odds of being treated with clozapine was approximately 2-fold in patients with a history of suicide attempt in unadjusted (OR = 1.98, 95% CI, 1.76-2.22) and adjusted (OR = 1.91, 95% CI, 1.67-2.15) analyses.Conclusions: Despite the higher odds of clozapine treatment in suicide attempters with schizophrenia or schizoaffective disorder, clozapine was underutilized in the current sample of veterans. Concerted efforts should be made to expand the use of clozapine in patients with schizophrenia or schizoaffective disorder, especially those with a history of suicide attempt.

Spectroscopic and Kinetic Studies of the ClSO Radical from Cl2SO Photolysis.

Thionyl chloride (Cl2SO) serves as a common Cl atom source in widespread applications of chlorine chemistry though little is known about the reactivity and spectroscopy of the ClSO radical after a Cl-S bond cleavage. We performed a Pulsed Laser Photolysis experiment to detect ClSO from Cl2SO photolysis at 248 nm in a gas-flow reactor by time-resolved UV-vis transient absorption spectroscopy. A few chemical tests, using I2 and NO2, suggested the structured absorption band between 260 and 320 nm belonged to ClSO radical and that the termolecular ClSO + Cl + M → Cl2SO association reaction occurred. From EOMIP-CCSD/ano-pVQZ calculations, the ClSO band was assigned to the 12A″ ← X2A″ transition involving the π* ← π transition of the SO bond and the vibrational progression to the SO stretching mode of the 12A″ state, with a maximum cross-section = (2.0 ± 0.5) × 10-18 cm2 near 286 nm (1σ uncertainty) and an average spacing of vibrational structure of 658 cm-1. The rapid decay of the ClSO signal monitored near 303 nm could be fit to a second-order kinetic model over 10-90 Torr, which yields an effective bimolecular rate coefficient kCl+ClSO = (1.48 ± 0.42) × 10-11 cm3 molecule-1 s-1 at 292 K and 90 Torr (1σ uncertainty). This fast recombination reaction suggests that Cl-containing SOx species might act as significant Cl atom reservoirs in sulfur oxide-rich environments such as Venus' atmosphere. Moreover, the reported UV spectrum provides a new means for monitoring the ClSO radicals.

Inflammatory signaling mechanisms in bipolar disorder.

Bipolar disorder is a decidedly heterogeneous and multifactorial disease, with a high individual and societal burden. While not all patients display overt markers of elevated inflammation, significant evidence suggests that aberrant immune signaling contributes to all stages of the disease, and likely explains the elevated rates of comorbid inflammatory illnesses seen in this population. While individual systems have been intensely studied and targeted, a relative paucity of attention has been given to the interconnecting role of inflammatory signals therein. This review presents an updated overview of some of the most prominent pathophysiologic mechanisms in bipolar disorder, from mitochondrial, endoplasmic reticular, and calcium homeostasis, to purinergic, kynurenic, and hormonal/neurotransmitter signaling, showing inflammation to act as a powerful nexus between these systems. Several areas with a high degree of mechanistic convergence within this paradigm are highlighted to present promising future targets for therapeutic development and screening.

Intracellular Signaling Cascades in Bipolar Disorder.

Bipolar spectrum disorders carry a significant public health burden. Disproportionately high rates of suicide, incarceration, and comorbid medical conditions necessitate an extraordinary focus on understanding the intricacies of this disease. Elucidating granular, intracellular details seems to be a necessary preamble to advancing promising therapeutic opportunities. In this chapter, we review a wide range of intracellular mechanisms including mitochondrial energetics, calcium signaling, neuroinflammation, the microbiome, neurotransmitter metabolism, glycogen synthase kinase 3-beta (GSK3ß), protein kinase C (PKC) and diacylglycerol (DAG), and neurotrophins (especially BDNF), as well as the glutamatergic, dopaminergic, purinergic, and neurohormonal systems. Owing to the relative lack of understanding and effective therapeutic options compared to the rest of the spectrum, special attention is paid in the chapter to the latest developments in bipolar depression. Likewise, from a therapeutic standpoint, special attention should be paid to the pervasive mechanistic actions of lithium as a means of amalgamating numerous, disparate cascades into a digestible cognitive topology.

Teriflunomide Modulates Vascular Permeability and Microglial Activation after Experimental Traumatic Brain Injury.

Despite intensive research and clinical trials with numerous therapeutic treatments, traumatic brain injury (TBI) is a serious public health problem in the United States. There is no effective FDA-approved treatment to reduce morbidity and mortality associated with TBI. Inflammation plays a pivotal role in the pathogenesis of TBI. We looked to re-purpose existing drugs that reduce immune activation without broad immunosuppression. Teriflunomide, an FDA-approved drug, has been shown to modulate immunological responses outside of its ability to inhibit pyrimidine synthesis in rapidly proliferating cells. In this study, we tested the efficacy of teriflunomide to treat two different injury intensities in rat models of TBI. Our results show that teriflunomide restores blood-brain barrier integrity, decreases inflammation, and increases neurogenesis in the subgranular zone of the hippocampus. While we were unable to detect neurocognitive effects of treatment on memory and special learning abilities after treatment, a 2-week treatment following injury was sufficient to reduce neuroinflammation up to 120 days later.

Strategies that delay or prevent the timely availability of affordable generic drugs in the United States.

High cancer drug prices are influenced by the availability of generic cancer drugs in a timely manner. Several strategies have been used to delay the availability of affordable generic drugs into the United States and world markets. These include reverse payment or pay-for-delay patent settlements, authorized generics, product hopping, lobbying against cross-border drug importation, buying out the competition, and others. In this forum, we detail these strategies and how they can be prevented.

Facile preparation of ammonium alginate-derived nanofibers carrying diverse therapeutic cargo.

Alginic acid was converted to a variety of ammonium alginate derivatives carrying diverse chemical cargo such as analgesics, antibiotics, and enzymes. These functional polymers could be fashioned into nanofibrous mats by electrostatic spinning. The therapeutic payload could be released in functional form by a simple ion exchange mechanism. Prospects in wound healing are discussed.