scholarly journals Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia

2021 ◽  
Vol 12 ◽  
Author(s):  
Ju-Chun Pei ◽  
Da-Zhong Luo ◽  
Shiang-Shin Gau ◽  
Chia-Yuan Chang ◽  
Wen-Sung Lai
Keyword(s):  
Nmda Receptor ◽  
Cognitive Deficits ◽  
Clinical Studies ◽  
Negative Symptoms ◽  
Cognitive Symptoms ◽  
Amino Acid Oxidase ◽  
Antipsychotic Medications ◽  
Medical Needs ◽  
Glycine Modulatory Site ◽  
Unmet Medical Needs

Schizophrenia is a severe mental illness that affects ~1% of the world's population. It is clinically characterized by positive, negative, and cognitive symptoms. Currently available antipsychotic medications are relatively ineffective in improving negative and cognitive deficits, which are related to a patient's functional outcomes and quality of life. Negative symptoms and cognitive deficits are unmet by the antipsychotic medications developed to date. In recent decades, compelling animal and clinical studies have supported the NMDA receptor (NMDAR) hypofunction hypothesis of schizophrenia and have suggested some promising therapeutic agents. Notably, several NMDAR-enhancing agents, especially those that function through the glycine modulatory site (GMS) of NMDAR, cause significant reduction in psychotic and cognitive symptoms in patients with schizophrenia. Given that the NMDAR-mediated signaling pathway has been implicated in cognitive/social functions and that GMS is a potential therapeutic target for enhancing the activation of NMDARs, there is great interest in investigating the effects of direct and indirect GMS modulators and their therapeutic potential. In this review, we focus on describing preclinical and clinical studies of direct and indirect GMS modulators in the treatment of schizophrenia, including glycine, D-cycloserine, D-serine, glycine transporter 1 (GlyT1) inhibitors, and D-amino acid oxidase (DAO or DAAO) inhibitors. We highlight some of the most promising recently developed pharmacological compounds designed to either directly or indirectly target GMS and thus augment NMDAR function to treat the cognitive and negative symptoms of schizophrenia. Overall, the current findings suggest that indirectly targeting of GMS appears to be more beneficial and leads to less adverse effects than direct targeting of GMS to modulate NMDAR functions. Indirect GMS modulators, especially GlyT1 inhibitors and DAO inhibitors, open new avenues for the treatment of unmet medical needs for patients with schizophrenia.

Effects of sodium benzoate on pre-pulse inhibition deficits and hyperlocomotion in mice after administration of phencyclidine

2015 ◽  
Vol 27 (3) ◽  
pp. 159-167 ◽  
Author(s):  
Akiko Matsuura ◽  
Yuko Fujita ◽  
Masaomi Iyo ◽  
Kenji Hashimoto
Keyword(s):  
Nmda Receptor ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Sodium Benzoate ◽  
Negative Symptoms ◽  
Nmda Receptor Antagonist ◽  
Oxidase Inhibitor ◽  
Acid Oxidase ◽  
Dependent Manner ◽  
Amino Acid Oxidase

ObjectiveA recent clinical study demonstrated that sodium benzoate (SB), a prototype competitive d-amino acid oxidase inhibitor, was effective in the treatment of several symptoms, such as positive and negative symptoms, and cognitive impairment in medicated patients with schizophrenia. The objective of the study was to examine the effects of SB on behavioural abnormalities such as pre-pulse inhibition (PPI) deficits and hyperlocomotion in mice after a single administration of the N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP).MethodsThe effects of SB on behavioural abnormalities (PPI deficits and hyperlocomotion) in mice after PCP administration were examined. Furthermore, effects of SB on tissue levels of amino acids were also examined.ResultsA single oral dose of SB (100, 300, or 1000 mg/kg) attenuated PPI deficits in mice after administration of PCP (3.0 mg/kg, s.c.) in a dose-dependent manner. In contrast, L-701,324 (10 mg/kg), an antagonist at the glycine site of the NMDA receptor, did not affect the effect of SB (1000 mg/kg) on PCP-induced PPI deficits. Furthermore, a single oral dose of SB (1000 mg/kg) significantly attenuated the hyperlocomotion in mice after administration of PCP (3.0 mg/kg, s.c.). However, a single oral dose of SB (1000 mg/kg) caused no changes to d-serine levels in plasma or in the frontal cortex, hippocampus, and striatum of these animals.ConclusionThis study suggests that SB induced antipsychotic effects in the PCP model of schizophrenia, although it did not increase d-serine levels in the brain.

scholarly journals T193. THE ROLE OF METACOGNITION ON NEGATIVE SYMPTOMS: A PSYCHOLOGICAL MODEL FOR DIMINISHED EXPRESSION IN SCHIZOPHRENIA

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S305-S305
Author(s):  
Helena García-Mieres ◽  
Nancy Lundin ◽  
Kyle Minor ◽  
Giancarlo DiMaggio ◽  
Simone Cheli ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Structural Equation ◽  
Negative Symptoms ◽  
Structural Equation Models ◽  
Personal Narratives ◽  
Higher Order ◽  
Psychotic Symptoms ◽  
Situation Models ◽  
Cognitive Symptoms ◽  
The Impact

Abstract Background The resistance of negative symptoms to pharmacologic treatment has spurred interest in understanding the psychological factors that contribute to their formation and persistence. However, little is understood about the psychological processes that reinforce and sustain the negative symptoms domain of diminished expression. Prior research has shown that higher levels of diminished expression relate to deficits in metacognitive capacity. We propose a more complex model in which diminished expression occurs when impairments in metacognitive self-reflectivity, alterations in higher-order language structure, and cognitive deficits interact and thus interfere with persons’ ability to understand and express emotions in ways others can recognize. Methods Individuals with schizophrenia-spectrum disorders (N=201) provided personal narratives including their life story and reflections regarding their mental illness and a clinician-rated interview of psychotic symptoms (i.e., Positive and Negative Syndrome Scale; PANSS). Self-reflectivity was measured with the Metacognition Assessment Scale-Abbreviated, and situation models were extracted from participants’ personal narratives via Coh-Metrix 3.0, an automated program that calculates basic and complex language indices. Diminished expression and cognitive symptoms were measured with the PANSS. Structural equation models (SEM) examined whether self-reflectivity mediated the impact of cognitive deficits and situation models on diminished expression. Results SEM revealed that self-reflectivity partially mediated the impact of situation models on diminished expression (β = -.083, p = .005, ±95% CI [-.141, -.026]) and fully mediated the influence of cognitive symptoms in diminished expression (β = .099, p = .001, ±95% CI [.038, .160]). Findings persisted after controlling for educational level. Discussion This study is the first of its kind to utilize a mediational model including higher-order linguistic structures, cognitive impairment and metacognition to explain diminished expression in psychosis. Results suggest that self-reflectivity, situation models and cognitive symptoms may be useful targets for intervention in efforts to decrease diminished expression.

scholarly journals Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities

CNS Spectrums ◽  
2019 ◽  
Vol 24 (S1) ◽  
pp. 38-69 ◽  
Author(s):  
Amanda Krogmann ◽  
Luisa Peters ◽  
Laura von Hardenberg ◽  
Katja Bödeker ◽  
Viktor B. Nöhles ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Negative Symptoms ◽  
Partial Agonist ◽  
Treatment Resistance ◽  
Positive Symptoms ◽  
Acid Oxidase ◽  
Cognitive Symptoms ◽  
Amino Acid Oxidase ◽  
Negative Results ◽  
Long Acting

Schizophrenia remains one of the most severe medical diseases. Current dopamine modulating first-generation and second-generation antipsychotics target mainly positive symptoms, but not/inadequately negative and cognitive symptoms. Additional challenges include non-adherence and adverse effects, especially cardiometabolic dysregulation. This review evaluates new/emerging pharmacological treatments for schizophrenia. Therapies targeting total symptoms include cannabidiol, D3 antagonist/5-HT1A partial agonist F17464, lumateperone (ITI-007), phosphodiesterase 10A (PDE10A) inhibitors MK-8189 and TAK-063, sodium nitroprusside, and trace amine-associated receptor-1 (TAAR1) agonist RO5263397 and SEP-363856. Treatments targeting negative symptoms include the PDE10A inhibitor LuAF-11167, 5-HT2A inverse agonist pimavanserin, sigma-2/5-HT2A antagonist roluperidone (MIN-101), and d-amino acid oxidase (DAAO) inhibitor TAK-831. Agents targeting primarily cognitive dysfunction are the glycine transporter-1 inhibitor BI-425809 and cannabidiol. Therapies targeting residual positive symptoms/treatment-resistant schizophrenia include pimavanserin, dopamine D1/D2 antagonist LuAF-35700, and DAAO inhibitor sodium benzoate. Two new long-acting injectable antipsychotic formulations, Aripiprazole Lauroxil NanoCrystal® and the first subcutaneous injectable LAI Perseris (RBP-7000), were recently approved by U.S. Food and Drug Administration, and positive results were announced for Risperidone ISM®, each achieving therapeutic levels within 24 hours, without need for initial oral cotreatment/loading injection-strategies. Paliperidone palmitate 6-monthly intramuscularly injectable and Risperidone subcutaneously injectable TV46000 are currently under investigation. Finally, the samidorphan+olanzapine combination targets reduced weight gain liability, while maintaining olanzapine’s efficacy. Most of these trial programs are still ongoing or have yielded mixed or even negative results. Thus, additional mechanisms of action and agents require study to improve schizophrenia outcomes for total/positive symptoms with reduced adverse effects, but also cognitive symptoms, negative symptoms, and treatment resistance, the areas of greatest need in schizophrenia currently.

scholarly journals Is Memantine Effective as an NMDA Receptor Antagonist in Adjunctive Therapy for Schizophrenia?

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1134 ◽  
Author(s):  
Tetsuro Kikuchi
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Cognitive Deficits ◽  
Adjunctive Therapy ◽  
Negative Symptoms ◽  
Nmda Receptor Antagonist ◽  
Double Blind ◽  
Extrasynaptic Receptors ◽  
Voltage Dependent ◽  
Cns Side Effects

Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist approved for treating Alzheimer’s disease, has a good safety profile and is increasingly being studied for possible use in a variety of non-dementia psychiatric disorders. There is an abundance of basic and clinical data that support the hypothesis that NMDA receptor hypofunction contributes to the pathophysiology of schizophrenia. However, there are numerous randomized, double-blind, placebo-controlled clinical trials showing that add-on treatment with memantine improves negative and cognitive symptoms, particularly the negative symptoms of schizophrenia, indicating that memantine as adjunctive therapy in schizophrenia helps to ameliorate negative symptoms and cognitive deficits. It remains unclear why memantine does not show undesirable central nervous system (CNS) side effects in humans unlike other NMDA receptor antagonists, such as phencyclidine and ketamine. However, the answer could lie in the fact that it would appear that memantine works as a low-affinity, fast off-rate, voltage-dependent, and uncompetitive antagonist with preferential inhibition of extrasynaptic receptors. It is reasonable to assume that the effects of memantine as adjunctive therapy on negative symptoms and cognitive deficits in schizophrenia may derive primarily, if not totally, from its NMDA receptor antagonist activity at NMDA receptors including extrasynaptic receptors in the CNS.

MOTIVATION AND PLEASURE IN THE SCHIZOPHRENIA SPECTRUM–FINDINGS FROM THE PRODROME

2008 ◽  
Vol 31 (4) ◽  
pp. 10
Author(s):  
G Foussias ◽  
G Remington ◽  
R Mizrahi
Keyword(s):  
Cognitive Deficits ◽  
Negative Symptoms ◽  
Sampling Method ◽  
Personal Digital Assistant ◽  
Prodromal Phase ◽  
Daily Lives ◽  
Schizophrenia Spectrum ◽  
Influence Functional ◽  
The Moment ◽  
Positive And Negative Symptoms

Background: Schizophreniais a chronic and debilitating illness that affects approximately one percent of the population. The symptoms of schizophrenia are typically thought of in separate domains, including positive symptoms (hallucinations and delusions), negative symptoms (diminished emotional expression and amotivation), and cognitive deficits. Importantly, the negative symptoms have been consistently found to adversely influence functional outcomes, in particular due to markedamotivation.^1 There have been suggestions that these individuals also experience deficits in the experience of pleasure, especially in their capacity to anticipate pleasure.^2 However, such investigations have not included the examination of these symptoms in those in the prodromal phase ofthis illness, a time that holds promise for early intervention and altering thecourse of schizophrenia.^3 Methods: In an effort to examine deficits in motivation and pleasure in the prodromal phase of schizophrenia, we have used an experience sampling method to assess “in the moment” motivation and pleasure in individuals at high risk of developing schizophrenia and healthy controls. Subjects completed baseline assessments including evaluation of their positive and negative symptoms. Subsequently, through the use of a personal digital assistant, subjects rated their motivation and experience of consummatory and anticipatory pleasure in their daily lives, multiple times over the course of four days. Results and Conclusions: Preliminary data will be presented, as well as the importance of these findings in the context of understanding the underlying pathobiology of this illness, and guiding our search for effective treatments to improvefunctional outcomes in schizophrenia. References: 1. Sayers SL, Curran PJ, Mueser KT. Psychol Assessment 1996;8:269-80. 2. Gard DE, Kring AM, Gard GM, et al.. Schizophr Res 2007;93:253-60.

scholarly journals Factors Affecting Health-Related Quality of Life in Multimorbidity

Healthcare ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 334
Author(s):  
Eunmi Lee ◽  
Sunkyung Cha ◽  
Geun Myun Kim
Keyword(s):  
Quality Of Life ◽  
Health Behaviors ◽  
Private Insurance ◽  
Subjective Health ◽  
Health Related Quality ◽  
Medical Needs ◽  
Related Quality ◽  
Health Related ◽  
Unmet Medical Needs

We investigated the effect of predisposing, enabling, need factors, and health behaviors on health-related quality of life (HRQoL) of patients with multimorbidity according to Andersen’s model. This study is a secondary analysis of population-based cross-sectional surveys. Data from 328 patients with multimorbidity (≥3 co-occurring chronic diseases) from the 6th/7th Korea National Health and Nutrition Examination Surveys were analyzed using logistic regression. Patients ≥65 years, without private insurance, with poor subjective health, unmet medical needs, and/or limited activity were more likely to experience mobility problems. Self-care problems were more likely among those without private insurance and/or with limited activity. Patients lacking living security, with poor subjective health, limited activity, and/or who smoked were more likely to experience problems performing usual activities. Pain/discomfort was more likely among females, Medicaid beneficiaries, and patients with limited activity and/or with poor subjective health. Patients with poor subjective health, limited activity, and/or unmet medical needs were more likely to experience anxiety/depression. The investigation of HRQoL in multimorbidity should consider predisposing, enabling, need factors, and health behaviors. Interventions addressing movement restrictions and personalized care based on HRQoL domains should be prioritized.

scholarly journals Therapeutic Antibodies for the Treatment of Respiratory Tract Infections—Current Overview and Perspectives

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 151
Author(s):  
Alexie Mayor ◽  
Adélaïde Chesnay ◽  
Guillaume Desoubeaux ◽  
David Ternant ◽  
Nathalie Heuzé-Vourc’h ◽  
...  
Keyword(s):  
Respiratory Tract Infections ◽  
Inflammatory Diseases ◽  
Treatment Strategies ◽  
Candida Spp ◽  
Medical Needs ◽  
Life Threatening ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections ◽  
Unmet Medical Needs

Respiratorytract infections (RTIs) are frequent and life-threatening diseases, accounting for several millions of deaths worldwide. RTIs implicate microorganisms, including viruses (influenza virus, coronavirus, respiratory syncytial virus (RSV)), bacteria (Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus and Bacillus anthracis) and fungi (Pneumocystis spp., Aspergillus spp. and very occasionally Candida spp.). The emergence of new pathogens, like the coronavirus SARS-CoV-2, and the substantial increase in drug resistance have highlighted the critical necessity to develop novel anti-infective molecules. In this context, antibodies (Abs) are becoming increasingly important in respiratory medicine and may fulfill the unmet medical needs of RTIs. However, development of Abs for treating infectious diseases is less advanced than for cancer and inflammatory diseases. Currently, only three Abs have been marketed for RTIs, namely, against pulmonary anthrax and RSV infection, while several clinical and preclinical studies are in progress. This article gives an overview of the advances in the use of Abs for the treatment of RTIs, based on the analysis of clinical studies in this field. It describes the Ab structure, function and pharmacokinetics, and discusses the opportunities offered by the various Ab formats, Ab engineering and co-treatment strategies. Including the most recent literature, it finally highlights the strengths, weaknesses and likely future trends of a novel anti-RTI Ab armamentarium.

Increase in extracellular dopamine levels during clozapine-induced potentiation in the hippocampal dentate gyrus of chronically prepared rabbits

2008 ◽  
Vol 86 (5) ◽  
pp. 249-256 ◽  
Author(s):  
Takashi Kubota ◽  
Itsuki Jibiki ◽  
Akira Ishikawa ◽  
Tomomi Kawamura ◽  
Sonoko Kurokawa ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Nmda Receptor ◽  
Dentate Gyrus ◽  
Negative Symptoms ◽  
Clinical Effect ◽  
Perforant Path ◽  
Hippocampal Dentate Gyrus ◽  
Extracellular Dopamine ◽  
Stimulation Of ◽  
Synaptic Responses

We previously found that 20 mg/kg clozapine i.p. potentiated the excitatory synaptic responses elicited in the dentate gyrus by single electrical stimulation of the perforant path in chronically prepared rabbits. We called this phenomenon clozapine-induced potentiation and proved that it was an NMDA receptor-mediated event. This potentiation is presumably related to clozapine’s clinical effect on negative symptoms and cognitive dysfunctions in schizophrenia. In the present study, to investigate the mechanisms underlying clozapine-induced potentiation, we examined whether extracellular dopamine and 5-HT levels changed during the potentiation by using a microdialysis technique in the dentate gyrus. The extracellular concentrations of dopamine and 5-HT levels were measured every 5 min during all experiments. Extracellular 5-HT levels did not change, but dopamine levels eventually increased significantly during clozapine-induced potentiation. The increase in the dopamine levels occurred almost simultaneously with the induction of clozapine-induced potentiation. These results suggest that clozapine-induced potentiation is at least partly attributable to a dopamine-mediated potentiation of excitatory synaptic transmission. The present study implies that such phenomena occur also in the perforant path–dentate gyrus pathway.

Sign in / Sign up

Export Citation Format

Share Document