NMDAR Down-Regulation: Dual - Hit Molecular Target For COPD - Depression Comorbidity.

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by sustained airflow limitation that represents one of the main causes of disability in modern society. Depression affects approximately 40% of COPD patients. Both COPD and depression are associated with chronic systemic inflammation and their comorbidity represents a critical unmet treatment need.

Synergistic psychedelic - NMDAR modulator treatment for neuropsychiatric disorders.

Modern research data suggest a therapeutic role for serotonergic psychedelics in depression and other neuropsychiatric disorders, although psychotomimetic effects may limit their widespread utilization. Serotonergic psychedelics enhance neuroplasticity via serotonin 2 A receptors (5HT2AR) activation and complex serotonergic-glutamatergic interactions involving the ionotropic glutamate receptors, tropomyosin receptor kinase B (TrkB) and the mammalian target of rapamycin (mTOR). N-methyl-d-aspartate receptors (NMDAR) channel antagonists, i.

Could psychedelic drugs have a role in the treatment of schizophrenia? Rationale and strategy for safe implementation.

Schizophrenia is a widespread psychiatric disorder that affects 0.5-1.0% of the world's population and induces significant, long-term disability that exacts high personal and societal cost.

D-aspartate oxidase gene duplication induces social recognition memory deficit in mice and intellectual disabilities in humans.

The D-aspartate oxidase (DDO) gene encodes the enzyme responsible for the catabolism of D-aspartate, an atypical amino acid enriched in the mammalian brain and acting as an endogenous NMDA receptor agonist. Considering the key role of NMDA receptors in neurodevelopmental disorders, recent findings suggest a link between D-aspartate dysmetabolism and schizophrenia. To clarify the role of D-aspartate on brain development and functioning, we used a mouse model with constitutive Ddo overexpression and D-aspartate depletion.

Behavioral and cognitive effects of the N-methyl-D-aspartate receptor co-agonist D-serine in healthy humans: initial findings.

The efficacy of compounds having agonistic activity at the glycine site associated with the N-methyl-D-aspartate receptor (NMDAR) is presently assessed in psychiatric disorders. In contrast to NMDAR antagonists, the neuropsychiatric effects of NMDAR agonists in the healthy human organism are not known. We studied neuropsychiatric and neurochemical effects of the NMDAR-glycine site obligatory co-agonist d-serine (DSR) in healthy subjects using a randomized, controlled crossover challenge design including a baseline assessment day and two DSR/placebo administration days.

Autoimmune-induced glutamatergic receptor dysfunctions: conceptual and psychiatric practice implications.

Glutamatergic neurotransmission is mediated via complex receptorial systems including N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) and metabotropic receptor subtypes and plays a critical role in the modulation of synaptic plasticity, mood, cognitive processes and motor behavior. Glutamatergic function deficits are hypothesized to contribute to the pathogenesis of neuropsychiatric disorders, including schizophrenia, mood and movement disorders. Accumulating data are rapidly leading to the characterization of specific types of autoimmune encephalitis in which the receptors and proteins critically involved in glutamatergic neurotransmission, e.

Hypnotizability is associated with a protective but not acquisitive self-presentation style.

Self-presentation refers to the behavioral strategies a person adopts to convey desired social images of oneself to other people. The Concern for Appropriateness Scale (CAS) measures a defensive and fearful social approach aimed at avoiding social threats whereas the Revised Self-Monitoring Scale (RSMS) measures an active and flexible social approach aimed at gaining power and status. In this study, a significant correlation was found between hypnotizability, as measured by the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C) scores and CAS (r = .

Glycine site agonists of the N-methyl-D-aspartate receptor and Parkinson's disease: a hypothesis.

Limitations of current pharmacological approaches to Parkinson's disease (PD) highlight the need for the development of nondopaminergic therapeutic strategies. The potential role of glutamatergic neurotransmission modulators, including those active at the N-methyl-D-aspartate receptor (NMDAR), is presently under investigation. Most literature proposes the use of NMDAR antagonists based on neurodegenerative theories of NMDAR function.

A randomized add-on trial of high-dose D-cycloserine for treatment-resistant depression.

Antagonism of N-methyl-D-aspartate glutamatergic receptors (NMDAR) may represent an effective antidepressant mechanism. D-cycloserine (DCS) is a partial agonist at the NMDAR-associated glycine modulatory site that at high doses acts as a functional NMDAR antagonist. Twenty-six treatment-resistant major depressive disorder patients participated in a double blind, placebo-controlled, 6-wk parallel group trial with a gradually titrated high dose (1000 mg/d) of DCS added to their antidepressant medication.

Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia.

Over the last 20 years, glutamatergic models of schizophrenia have become increasingly accepted as etiopathological models of schizophrenia, based on the observation that phencyclidine (PCP) induces a schizophrenia-like psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews developments in two key predictions of the model: first, that neurocognitive deficits in schizophrenia should follow the pattern of deficit predicted based on underlying NMDAR dysfunction and, second, that agents that stimulate NMDAR function should be therapeutically beneficial. As opposed to dopamine receptors, NMDAR are widely distributed throughout the brain, including subcortical as well as cortical brain regions, and sensory as well as association cortex.

A multicenter, add-on randomized controlled trial of low-dose d-serine for negative and cognitive symptoms of schizophrenia.

Background: Observations that antagonists of the N-methyl-d-aspartate (NMDA) receptor of glutamatergic neurons can mimic symptoms of schizophrenia have raised the hope that NMDA agonists can improve symptoms. On the basis of encouraging results of trials in which NMDA agonists were added to antipsychotics, we conducted an adequately powered randomized controlled trial adding d-serine, an NMDA modulator, to antipsychotics.

Method: This study was a 195-patient, multicenter, double-blind, randomized, placebo-controlled, 16-week trial of d-serine 2 g/d as an add-on treatment to antipsychotics.

Preventive pharmacological treatment --an evolving new concept in schizophrenia.

Treatment for schizophrenia remains one of the major challenges of modern medicine. The development of innovative pharmacological approaches for this disorder can potentially alleviate tremendous human suffering and revolutionize mental health delivery systems. While current treatment guidelines for schizophrenia refer to the post-psychosis onset phase of illness, presently there is a strong resurgent interest in secondary prevention intervention applied during schizophrenia prodrome.

Hypnotizability and sensorimotor gating: a dopaminergic mechanism of hypnosis.

Dopaminergic mechanisms have been theorized to influence hypnotizability and sensorimotor gating. In this study, the authors investigated an association between sensorimotor gating, as measured by prepulse inhibition (PPI), and hypnotizability, as assessed by the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C). They found an inverse correlation between the SSHS:C and PPI.

D-serine adjuvant treatment alleviates behavioural and motor symptoms in Parkinson's disease.

Parkinson's disease (PD) manifestations include motor symptoms and behavioural deficits that resemble schizophrenia negative symptoms. The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) represents a novel pharmacological target in PD. D-serine (DSR) allosterically modulates in-vivo NMDAR-mediated neurotransmission and has been shown to improve negative and antipsychotic drug-induced parkinsonian symptoms in schizophrenia patients.

Defensive self-presentation style is associated with reduced prepulse inhibition.

Prepulse inhibition (PPI) of the startle response is a cross-species measure of sensorimotor gating that provides a valuable tool for assessing the capacity to effectively screen out irrelevant sensory input. Accumulating evidence suggests that PPI deficits may correlate with impairments in social cognition, i.e.

Shiatsu as an adjuvant therapy for schizophrenia: an open-label pilot study.

Context: Studies have suggested a possible role for shiatsu in treating a variety of mental and physical ailments.

Objective: To determine if shiatsu can provide clinical benefit to individuals diagnosed with schizophrenia.

Design: An open-label pilot study.

Pilot controlled trial of D-serine for the treatment of post-traumatic stress disorder.

Enhancement of neurotransmission mediated at N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) may be beneficial in post-traumatic stress disorder (PTSD). d-serine (DSR) is an endogenous full agonist at the NMDAR-associated glycine modulatory site. Twenty-two chronic PTSD outpatients were randomly assigned to participate in a 6-wk double-blind, placebo-controlled, crossover trial with 30 mg/kg x d DSR used as monotherapy or add-on pharmacotherapy.

Association between arginine vasopressin 1a receptor (AVPR1a) promoter region polymorphisms and prepulse inhibition.

Arginine vasopressin and the arginine vasopressin 1a (AVPR1a) gene contribute to a range of social behaviors both in lower vertebrates and in humans. Human promoter-region microsatellite repeat regions (RS1 and RS3) in the AVPR1a gene region have been associated with autism spectrum disorders, prosocial behavior and social cognition. Prepulse inhibition (PPI) of the startle response to auditory stimuli is a largely autonomic response that resonates with social cognition in both animal models and humans.

Hypnotizability and blink rate: a test of the dopamine hypothesis.

Evidence suggests a role for central dopaminergic activity in determining an individual's level of hypnotizability. The authors measured the correlation between blink rate, which has been shown to correlate with central dopaminergic activity, and hypnotizability. Forty-eight healthy participants were evaluated for hypnotizability by the Harvard Group Scales of Hypnotic Susceptibility and the Stanford Hypnotic Susceptibility Scale: Form C.

Reduced prepulse inhibition is associated with increased hypnotizability.

Hypnosis involves the manipulation of conscious attentional discrimination. The prepulse inhibition (PPI) paradigm assesses primary unconscious information processing. We investigated the correlation between hypnotizability and PPI of the startle reflex.

The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments.

Objective: Patients with schizophrenia frequently present with negative symptoms and cognitive impairments for which no effective treatments are known. Agents that act at the glycine site of the N-methyl-D-aspartic acid (NMDA) glutamatergic receptor have been suggested as promising treatments for moderate to severe negative symptoms and cognitive impairments.

Method: The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST) was a 16-week double-blind, double-dummy, parallel group, randomized clinical trial of adjunctive glycine, D-cycloserine, or placebo conducted at four sites in the United States and one site in Israel.