Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABAR Activation.

GABA receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABA receptor negative allosteric modulators (GABARNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABARNAMs can restore the Excitation/Inhibition (E/I) balance in vitro and arousal in vivo, we chose to screen 11 compounds that have been reported to modulate arousal, to see if they shared a GABA-related mechanism.

Characteristics and current standard of care among veterans with major depressive disorder in the United States: A real-world data analysis.

Background: This study examined MDD treatment regimens received during the first observed and treated major depressive episode (MDE) among US veterans.

Methods: This retrospective study, conducted using the Veterans Health Administration (VHA) database, supplemented with Medicare Part A/B/D data, included adults with ≥1 MDD diagnosis (index date) between 10/1/2015-2/28/2017 and ≥1 line of therapy (LOT) within the first observed complete MDE. Patient baseline (6-month pre-index) characteristics and up to six LOTs received during the first observed and treated MDE were assessed.

Treatment Response With Esketamine Nasal Spray Plus an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Evidence of Early Response: A Pooled Post Hoc Analysis of the TRANSFORM Studies.

To evaluate response to esketamine nasal spray plus an oral antidepressant (ESK + AD) at day 28 in patients with major depressive disorder () and treatment-resistant depression (TRD) who did not meet response criteria within the first week of treatment. The current study is a pooled post hoc analysis of two phase 3, double-blind, active-controlled studies, conducted between August 2015 and February 2018, comparing ESK + AD with an oral antidepressant plus placebo (AD + PBO). Early treatment response was defined as a ≥ 50% decrease in Montgomery-Åsberg Depression Rating Scale total score at day 2 or days 2 and 8.

Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans.

Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders.

Predictors of achieving remission in schizophrenia patients treated with paliperidone palmitate 3-month formulation.

Purpose: Long-acting injectable (LAI) antipsychotic paliperidone palmitate 3-month formulation (PP3M) is indicated in the United States for the treatment of schizophrenia only after adequate treatment with paliperidone palmitate 1-month formulation (PP1M) for ≥4 months. This analysis aimed to identify patient and disease characteristics during PP1M treatment associated with greater likelihood of achieving remission after transition to PP3M.

Methods: A post hoc analysis of a randomized, Phase III, double-blind, noninferiority trial of PP3M vs PP1M (ClinicalTrials.

Understanding healthcare burden and treatment patterns among young adults with schizophrenia.

Background: Schizophrenia is a serious public health problem that affects ∼1% of the US population.

Aims: To examine treatment patterns and evaluate healthcare resource utilization (HRU) and costs among young adults (18-35 years) with schizophrenia who were early in the disease.

Materials And Methods: Patients aged 18-64 years with ≥2 schizophrenia diagnoses in the identification period (January 1, 2012-September 30, 2015) and continuous enrollment for ≥12 months pre- and post-index date were identified from the OptumInsight Clinformatics DataMart.

Crosstalk between insulin and dopamine signaling: A basis for the metabolic effects of antipsychotic drugs.

In the setting of rising rates of obesity and metabolic syndrome, characterized in part by hyperinsulinemia, it is increasingly important to understand the mechanisms that contribute to insulin dysregulation. The higher risk for metabolic syndrome imparted by antipsychotic medication use highlights one such mechanism. Though there is great variation in the number and types of signaling pathways targeted by these medications, the one common mechanism of action is through dopamine.

[Molecular bases of α-thalassemia in Argentina].

The α-thalassemia is one of the most common hereditary disorders worldwide. Currently, molecular diagnostics is the only available tool to achieve an accurate diagnosis. The purpose of this study was to characterize the molecular bases of these syndromes in our environment and to establish genotype-phenotype associations.

Factors affecting noncompliance with buprenorphine maintenance treatment.

Background: The current study aimed to identify risk factors for treatment noncompliance in a sample of veterans receiving buprenorphine/naloxone for an opioid use disorder.

Methods: Records from all patients who are currently or had previously been maintained on buprenorphine in the buprenorphine maintenance treatment program at the Atlanta VA Medical Center during the years 2006 to 2013 were evaluated. Of the 209 patients treated in the clinic between 2006 and 2013, 140 were excluded from the study because they did not have a call-back done at the time of data collection.

Phenyl groups versus tert-butyl groups as solubilizing substituents for some [5]phenacenes and [7]phenacenes.

In recent years, we have used the photocyclizations of diarylethylenes to synthesize a number of [n]phenacenes in the hope that they might be useful as the bridging groups for electron transfer processes in donor-bridge-acceptor molecules. Because [n]phenacenes with n > 5 are very insoluble, their synthesis and characterization has required the attachment of solubilizing substituents such as tert-butyl. The studies of Pascal and co-workers of some large polynuclear aromatic compounds having multiple phenyl substituents prompted us to explore the use of phenyls as alternative solubilizing groups for [n]phenacenes.

Variations in protein-flavin hydrogen bonding in a light, oxygen, voltage domain produce non-Arrhenius kinetics of adduct decay.

Light, oxygen, voltage (LOV) domains utilize a conserved blue light-dependent mechanism to control a diverse array of effector domains in biological and engineered proteins. Variations in the kinetics and efficiency of LOV photochemistry fine-tune various aspects of the photic response. Characterization of the kinetics of a key aspect of this photochemical mechanism in EL222, a blue light responsive DNA binding protein from Erythrobacter litoralis HTCC2594, reveals unique non-Arrhenius behavior in the rate of dark-state cleavage of the photochemically generated adduct.

Structural basis of photosensitivity in a bacterial light-oxygen-voltage/helix-turn-helix (LOV-HTH) DNA-binding protein.

Light-oxygen-voltage (LOV) domains are blue light-activated signaling modules integral to a wide range of photosensory proteins. Upon illumination, LOV domains form internal protein-flavin adducts that generate conformational changes which control effector function. Here we advance our understanding of LOV regulation with structural, biophysical, and biochemical studies of EL222, a light-regulated DNA-binding protein.

Modulating LOV domain photodynamics with a residue alteration outside the chromophore binding site.

Phototropins, a class of light-activated protein kinases, are essential for several blue light responses in plants and algae, including phototropism. These proteins contain two internal light, oxygen, and voltage sensitive (LOV) domains, which bind flavin chromophores and undergo a reversible photochemical formation of a cysteinyl-flavin adduct as part of the light sensing process. While the photodynamic properties of such photosensory domains are dictated by interactions between the chromophore and surrounding protein, more distant residues can play a significant role as well.

Priming in interpersonal contexts: implications for affect and behavior.

Priming stereotypes can lead to a variety of behavioral outcomes, including assimilation, contrast, and response behaviors. However, the conditions that give rise to each of these outcomes are unspecified. Furthermore, theoretical accounts posit that prime-to-behavior effects are either direct (i.

A conserved glutamine plays a central role in LOV domain signal transmission and its duration.

Light is a key stimulus for plant biological functions, several of which are controlled by light-activated kinases known as phototropins, a group of kinases that contain two light-sensing domains (LOV, light-oxygen-voltage domains) and a C-terminal serine/threonine kinase domain. The second sensory domain, LOV2, plays a key role in regulating kinase enzymatic activity via the photochemical formation of a covalent adduct between a LOV2 cysteine residue and an internally bound flavin mononucleotide (FMN) chromophore. Subsequent conformational changes in LOV2 lead to the unfolding of a peripheral Jalpha helix and, ultimately, phototropin kinase activation.