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Background This study examined the feasibility and preliminary effectiveness of d‐cycloserine (DCS)–augmented cognitive behavioral therapy (CBT) for children and adolescents with difficult‐to‐treat Obsessive Compulsive Disorder, in a double‐blind randomized controlled pilot trial (RCT). Methods Seventeen children and adolescents (aged 8–18 years) with a primary diagnosis of OCD, which was deemed difficult‐to‐treat, were randomly assigned to either nine sessions of CBT including five sessions of DCS‐augmented exposure and response prevention (ERP) [ERP + DCS] or nine sessions of CBT including five sessions of placebo‐augmented ERP [ERP + PBO]. Weight‐dependent DCS or placebo doses (25 or 50 mg) were taken 1 hour before ERP sessions. Results At posttreatment, both groups showed significant improvements with 94% of the entire sample classified as responders. However, a greater improvement in the ERP + DCS relative to the ERP + PBO condition was observed at 1‐month follow‐up on clinician‐rated obsessional severity and diagnostic severity, and parent ratings of OCD severity. There were no changes across time or condition from 1‐ to 3‐month follow‐up. Conclusions In this preliminary study, DCS‐augmented ERP produced significant improvements in OCD severity from posttreatment to 1‐month follow‐up, relative to a placebo control condition, in severe and difficult‐to‐treat pediatric OCD. The significant effect on obsessional severity suggests that DCS augmentation might be associated with enhanced modification of obsessional thoughts during ERP, and warrants further investigation.

Background For exposure therapy to be successful, it is essential that fear extinction learning extends beyond the treatment setting. d‐Cycloserine (DCS) may facilitate treatment gains by increasing generalization of extinction learning, however, its effects have not been tested in children. We examined whether DCS enhanced generalization of fear extinction learning across different stimuli and contexts among children with specific phobias. Methods The study was a double‐blind placebo‐controlled randomized controlled trial among dog or spider phobic children aged 6–14. Participants ingested either 50 mg of DCS (n = 18) or placebo (n = 17) before receiving a single prolonged exposure session to their feared stimulus. Return of fear was examined 1 week later to a different stimulus (a different dog or spider), presented in both the original treatment context and an alternate context. Avoidance and fear were measured with Behavior Approach Tests (BATs), where the child was asked to increase proximity to the stimulus while reporting their fear level. Results There were no differences in BAT performance between groups during the exposure session or when a new stimulus was later presented in the treatment context. However, when the new stimulus was presented in a different context, relative to placebo, the DCS group showed less avoidance (P = .03) and less increase in fear (P = .04) with moderate effect sizes. Conclusions DCS enabled children to better retain their fear extinction learning. This new learning generalized to different stimuli and contexts.

d-cycloserine is a broad-spectrum antibiotic that is currently being used as a secondary choice in the treatment of tuberculosis. In recent years, it has become more popular, due to its effect on the nervous system. In this current study, we provide evidence that The International Pharmacopoeia HPLC–UV method for d-cycloserine impurity profiling is not repeatable due to the variable response of cycloserine dimer, one of d-cycloserine impurities. Therefore, we introduced the DOSY (diffusion ordered spectroscopy) NMR (nuclear magnetic resonance) technique to determine the levels of d-cycloserine impurities in pharmaceutical dosage forms. The DOSY NMR technique allowed separation of d-cycloserine, its degradation products, and key process impurities in concentrations below pharmacopoeial specification limits. The proposed DOSY NMR method allowed accurate identification and quantification of the cycloserine dimer, which was not possible through the use of the pharmacopoeial HPLC method. The current method has the potential for practical use in analytical laboratories of the pharmaceutical industry.

D-cycloserine (DCS) is a drug that has generated great interest for its association with improvements in both learning and memory. Few studies have evaluated the effect of DCS on learning, extinction, and response recovery in operant conditioning. The present study aimed to evaluate, over three experiments with rats, the effect of DCS on the spontaneous recovery of a simple operant, and on the resurgence of operant behavior. DCS was expected to strengthen the extinction, and that a decrease in spontaneous recovery and resurgence would also be observed. The results showed a faster extinction in the groups that received DCS during the extinction; however, no differences were observed in the recovery of the response. Based on the present results, it is not possible to conclude that DCS is a supportive drug for learning processes such as exposure therapy.

Rationale Preclinical studies indicate that high-frequency oscillations, above 100 Hz (HFO:100–170 Hz), are a potential translatable biomarker for pharmacological studies, with the rapid acting antidepressant ketamine increasing both gamma (40–100 Hz) and HFO. Objectives To assess the effect of the uncompetitive NMDA antagonist ketamine, and of D-cycloserine (DCS), which acts at the glycine site on NMDA receptors on HFO in humans. Methods We carried out a partially double-blind, 4-way crossover study in 24 healthy male volunteers. Each participant received an oral tablet and an intravenous infusion on each of four study days. The oral treatment was either DCS (250 mg or 1000 mg) or placebo. The infusion contained 0.5 mg/kg ketamine or saline placebo. The four study conditions were therefore placebo-placebo, 250 mg DCS-placebo, 1000 mg DCS-placebo, or placebo-ketamine. Results Compared with placebo, frontal midline HFO magnitude was increased by ketamine ( p  = 0.00014) and 1000 mg DCS ( p  = 0.013). Frontal gamma magnitude was also increased by both these treatments. However, at a midline parietal location, only HFO were increased by DCS, and not gamma, whilst ketamine increased both gamma and HFO at this location. Ketamine induced psychomimetic effects, as measured by the PSI scale, whereas DCS did not increase the total PSI score. The perceptual distortion subscale scores correlated with the posterior low gamma to frontal high beta ratio. Conclusions Our results suggest that, at high doses, a partial NMDA agonist (DCS) has similar effects on fast neural oscillations as an NMDA antagonist (ketamine). As HFO were induced without psychomimetic effects, they may prove a useful drug development target.

Viewing post-traumatic stress disorder (PTSD) as a disorder of emotional learning, this study used a cognitive enhancer synergistically with virtual reality exposure (VRE) therapy for the treatment of PTSD. The main objective was to determine if a novel pharmacotherapy, D-cycloserine (DCS), enhanced the efficacy of the psychotherapy. Pre-clinical studies suggest that when fear extinction occurs during DCS administration, neuroplasticity may be enhanced. VRE therapy is a particularly promising format to test the hypothesis that DCS enhances extinction learning, as sensory fear cues are standardized across patients. In a pilot randomized, double-blind, placebo-controlled trial, 100 mg of DCS or placebo was administered 90 min before each weekly VRE session, to ensure peak plasma concentrations during the sessions in 25 patients with chronic PTSD. The primary outcome measure was the Clinician Administered PTSD Scale (CAPS). Secondary outcome measures included the Beck Depression Inventory-II and the State-Trait Anger Expression Inventory-2. Assessments occurred at pre-treatment, following sessions 3, 6, 10, post-treatment, and at 6 months. The difference in CAPS between the VRE-DCS (n=13) and VRE-placebo (n=12) groups increased over time beginning at 6 weeks, with medium to large between-group effect sizes immediately post-treatment and 6 months later (d=0.68 and d=1.13, respectively). A similar pattern was observed for depression, anger expression, and sleep. PTSD remission rates were significantly greater for the VRE-DCS group (46% vs 8% at post-treatment; 69% vs 17% at 6 months). Patients in the VRE-DCS group showed earlier and greater improvement in PTSD symptoms compared with the VRE-placebo group. These results suggest a promising new treatment for PTSD.

Pseudomonas aeruginosa is a gram-negative, opportunistic pathogen that represents a serious risk factor in healthcare services due to its natural resistance mechanisms and the increasing prevalence of multi-drug resistant strains. This study utilized in silico computational approaches to identify the novel inhibitors for d -alanine– d -alanine ligase A (DdlA), an essential enzyme for the bacterial peptidoglycan biosynthesis pathway necessary for cell wall integrity. A structure-based virtual screening of The Medicinal Fungi Secondary Metabolites and Therapeutics (MeFSAT) chemical library was conducted, followed by molecular docking to evaluate the binding affinity of small molecules to the DdlA active site. MSID000191, MSID000200, and MSID000102 were recognized as the leading candidates in the preliminary docking data due to their low binding energy values. These compounds exhibited binding energies markedly superior to the control drug ( d -cycloserine), suggesting a substantial potential for inhibiting the DdlA enzyme. Detailed interaction analyses revealed significant salt bridges and hydrogen bonds with active site residues, which enhance the stability of the complex. Density Functional Theory (DFT) analysis and MMPBSA calculations also provided insights into electronic properties and binding free energy, respectively. These findings highlight the potential of these inhibitors as therapeutic candidates and showcase the effectiveness of computational methods in accelerating drug discovery against multidrug-resistant P. aeruginosa . Future research should incorporate more in-silico techniques and experimental validations to confirm these results.

Background Sleep quality may be an important, yet relatively neglected, predictor of treatment outcome in cognitive‐behavioral therapy (CBT) for anxiety disorders. Specifically, poor sleep quality may impair memory consolidation of in‐session extinction learning. We therefore examined sleep quality as a predictor of treatment outcome in CBT for social anxiety disorder and the impact of d‐cycloserine (DCS) on this relationship. Methods One hundred sixty‐nine participants with a primary diagnosis of DSM‐IV generalized social anxiety disorder were recruited across three sites. Participants were enrolled in 12 weeks of group CBT. Participants randomly received 50 mg of DCS (n = 87) or pill placebo (n = 82) 1 hr prior to sessions 3–7. Participants completed a baseline measure of self‐reported sleep quality and daily diaries recording subjective feelings of being rested upon wakening. Outcome measures including social anxiety symptoms and global severity scores were assessed at each session. Results Poorer baseline sleep quality was associated with slower improvement and higher posttreatment social anxiety symptom and severity scores. Moreover, patients who felt more “rested” after sleeping the night following a treatment session had lower levels of symptoms and global severity at the next session, controlling for their symptoms and severity scores the previous session. Neither of these effects were moderated by DCS condition. Conclusions Our findings suggest that poor sleep quality diminishes the effects of CBT for social anxiety disorder and this relation is not attenuated by DCS administration. Therapeutic attention to sleep quality prior to initiation of CBT and during the acute treatment phase may be clinically indicated.

The maintenance of proper brain function relies heavily on the balance of excitatory and inhibitory neural circuits, governed in part by synaptic adhesion molecules. Among these, MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor 1) acts as a suppressor of synapse formation by interfering with Neuroligin-mediated interactions, crucial for maintaining the excitatory–inhibitory (E/I) balance. Mdga1−/− mice exhibit selectively enhanced inhibitory synapse formation in their hippocampal pyramidal neurons, leading to impaired hippocampal long-term potentiation (LTP) and hippocampus-dependent learning and memory function; however, it has not been fully investigated yet if the reduction in MDGA1 protein levels would alter brain function. Here, we examined the behavioral and synaptic consequences of reduced MDGA1 protein levels in Mdga1+/− mice. As observed in Mdga1−/− mice, Mdga1+/− mice exhibited significant deficits in hippocampus-dependent learning and memory tasks, such as the Morris water maze and contextual fear-conditioning tests, along with a significant deficit in the long-term potentiation (LTP) in hippocampal Schaffer collateral CA1 synapses. The acute administration of D-cycloserine, a co-agonist of NMDAR (N-methyl-d-aspartate receptor), significantly ameliorated memory impairments and restored LTP deficits specifically in Mdga1+/− mice, while having no such effect on Mdga1−/− mice. These results highlight the critical role of MDGA1 in regulating inhibitory synapse formation and maintaining the E/I balance for proper cognitive function. These findings may also suggest potential therapeutic strategies targeting the E/I imbalance to alleviate cognitive deficits associated with neuropsychiatric disorders.

Depressive disorders are the most common diagnosis among individuals who die by suicide, and intermittent theta-burst stimulation (iTBS) is a noninvasive treatment for those with difficult-to-treat depression who are at higher risk for suicide. Previous data suggests that pairing iTBS with D-cycloserine, a partial N-methyl-D-aspartate (NMDA) receptor agonist, improves antidepressant outcomes. However, its impact on suicide risk is not known. We examine suicidal ideation and implicit suicide risk after iTBS+D-cycloserine in two clinical trials (open-label trial [  = 12] and randomized placebo-controlled trial [RCT,  = 50]) involving adults with major depressive disorder and the acute effects of D-cycloserine on implicit suicide risk in a crossover trial (  = 18). Implicit suicide risk was assessed using the computerized death/suicide implicit association test (IAT), and depressive symptoms and suicidal ideation were assessed using the clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS). Open-label iTBS+D-cycloserine was associated with a rapid reduction in suicidal ideation, and iTBS+D-cycloserine was superior to iTBS+placebo in reducing suicidal ideation. Similarly, open-label iTBS+D-cycloserine was associated with decreased implicit suicide risk as measured by the death/suicide IAT, and iTBS+D-cycloserine was associated with greater decreases in death/suicide IAT scores compared to iTBS+placebo. A single acute dose of D-cycloserine in the absence of iTBS had no effect on implicit suicide risk. Adjunctive D-cycloserine with iTBS is a promising strategy to reduce suicidal ideation and implicit suicide risk in depression.