Novel treatments and future directions

2018 ◽  
Author(s):  
Seiya Miyamoto ◽  
Nobumi Miyake
Keyword(s):  
Negative Symptoms ◽  
Molecular Mechanisms ◽  
Antipsychotic Treatment ◽  
Treatment Resistant ◽  
Pharmacological Interventions ◽  
Future Directions ◽  
Novel Treatments ◽  
Medical Needs ◽  
Pharmacological Targets ◽  
New Generation

The advent of new-generation antipsychotic drugs has broadened the options for the pharmacological treatment of schizophrenia. However, there are still medical needs not met by current antipsychotic treatment, particularly for patients with negative symptoms and cognitive impairments, and for treatment-resistant schizophrenia. A growing body of research has identified new molecular mechanisms and novel pharmacological targets for treating schizophrenia beyond just dopamine D2 antagonism. This chapter provides a review of compounds in development and emerging non-pharmacological interventions for schizophrenia, and also considers approaches towards personalized and precision medicine for the disorder.

scholarly journals Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors

2017 ◽  
Vol 47 (11) ◽  
pp. 1981-1989 ◽  
Author(s):  
A. Demjaha ◽  
J. M. Lappin ◽  
D. Stahl ◽  
M. X. Patel ◽  
J. H. MacCabe ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Age At Onset ◽  
Treatment Resistance ◽  
First Episode Psychosis ◽  
First Episode ◽  
Antipsychotic Treatment ◽  
Treatment Resistant ◽  
Illness Onset ◽  
Episode Psychosis

BackgroundWe examined longitudinally the course and predictors of treatment resistance in a large cohort of first-episode psychosis (FEP) patients from initiation of antipsychotic treatment. We hypothesized that antipsychotic treatment resistance is: (a) present at illness onset; and (b) differentially associated with clinical and demographic factors.MethodThe study sample comprised 323 FEP patients who were studied at first contact and at 10-year follow-up. We collated clinical information on severity of symptoms, antipsychotic medication and treatment adherence during the follow-up period to determine the presence, course and predictors of treatment resistance.ResultsFrom the 23% of the patients, who were treatment resistant, 84% were treatment resistant from illness onset. Multivariable regression analysis revealed that diagnosis of schizophrenia, negative symptoms, younger age at onset, and longer duration of untreated psychosis predicted treatment resistance from illness onset.ConclusionsThe striking majority of treatment-resistant patients do not respond to first-line antipsychotic treatment even at time of FEP. Clinicians must be alert to this subgroup of patients and consider clozapine treatment as early as possible during the first presentation of psychosis.

Receptor mechanisms of antipsychotic drug atypicality

1998 ◽  
Vol 13 (S1) ◽  
pp. 5s-8s
Author(s):  
GP Reynolds
Keyword(s):  
Side Effects ◽  
Animal Models ◽  
Negative Symptoms ◽  
Atypical Antipsychotics ◽  
Mechanisms Of Action ◽  
Antipsychotic Treatment ◽  
Extrapyramidal Side Effects ◽  
Treatment Resistant ◽  
Pharmacological Profile ◽  
New Compounds

SummaryRecent advances in antipsychotic treatment of schizophrenia have offered several new compounds which avoid many of the limitations of the classical antipsychotics. These so-called ‘atypical’ antipsychotics have fewer extrapyramidal side effects, greater efficacy against negative symptoms and greater efficacy in otherwise treatment-resistant patients. However, the mechanism of action of these atypical antipsychotics is still unclear. The several receptors currently implicated in the pharmacological profile of these atypical antipsychotics include subtypes of those for dopamine, serotonin, noradrenaline, and acetylcholine among others. The current hypotheses for possible mechanisms of action of atypical antipsychotics are discussed along with the experimental correlates of antipsychotic efficacy in animal models.

Double-Blind, Placebo-Controlled, Crossover Trial of Glycine Adjuvant Therapy for Treatment-Resistant Schizophrenia

1996 ◽  
Vol 169 (5) ◽  
pp. 610-617 ◽  
Author(s):  
Uriel Heresco-Levy ◽  
Daniel C. Javitt ◽  
Marina Ermilov ◽  
Clara Mordel ◽  
Avraham Horowitz ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Negative Symptoms ◽  
Crossover Trial ◽  
Chronic Schizophrenia ◽  
Antipsychotic Treatment ◽  
Treatment Resistant ◽  
Double Blind ◽  
Baseline Serum ◽  
Double Blind Placebo ◽  
Additional Approach

BackgroundIt has been proposed that schizophrenia is associated with underactivity of brain glutamatergic neurotransmission, especially at the level of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Glycine potentiates NMDA receptor-mediated neurotransmission, indicating that it may serve as an effective therapeutic agent in the treatment of schizophrenia.MethodEleven treatment-resistant patients with chronic schizophrenia completed a double-blind placebo-controlled, six-week, randomly assigned, crossover treatment trial of 0.8 g/kg body weight/day of glycine, added to their prior antipsychotic treatment.ResultsGlycine was well tolerated, resulted in significantly increased serum glycine levels and induced a mean 36 (7%) reduction in negative symptoms (P < 0.0001). Significant improvments were also induced in depressive and cognitive symptoms. The greatest reduction in negative symptoms was registered in the patients who had the lowest baseline serum glycine levels.ConclusionsThese results extend previous findings and suggest an additional approach to the pharmacotherapy of negative symptoms and cognitive deficits in schizophrenia.

scholarly journals Pharmacological targets in the ubiquitin system offer new ways of treating cancer, neurodegenerative disorders and infectious diseases

2011 ◽  
Vol 13 ◽  
Author(s):  
Mariola J. Edelmann ◽  
Benjamin Nicholson ◽  
Benedikt M. Kessler
Keyword(s):  
Ubiquitin Proteasome System ◽  
Microbial Infection ◽  
Pharmacological Interventions ◽  
Novel Treatments ◽  
New Therapeutic Approaches ◽  
Recent Advances ◽  
Ubiquitin System ◽  
Pharmacological Targets ◽  
Immunological Disorder ◽  
Ubiquitin Proteasome

Recent advances in the development and discovery of pharmacological interventions within the ubiquitin–proteasome system (UPS) have uncovered an enormous potential for possible novel treatments of neurodegenerative disease, cancer, immunological disorder and microbial infection. Interference with proteasome activity, although initially considered unlikely to be exploitable clinically, has already proved to be very effective against haematological malignancies, and more specific derivatives that target subsets of proteasomes are emerging. Recent small-molecule screens have revealed inhibitors against ubiquitin-conjugating and -deconjugating enzymes, many of which have been evaluated for their potential use as therapeutics, either as single agents or in synergy with other drugs. Here, we discuss recent advances in the characterisation of novel UPS modulators (in particular, inhibitors of ubiquitin-conjugating and -deconjugating enzymes) and how they pave the way towards new therapeutic approaches for the treatment of proteotoxic disease, cancer and microbial infection.

Cognitive function in schizophrenia: conflicting findings and future directions

2016 ◽  
Vol 27 (4) ◽  
pp. 435-448 ◽  
Author(s):  
Ahmed A. Moustafa ◽  
Julia K. Garami ◽  
Justin Mahlberg ◽  
Jan Golembieski ◽  
Szabolcs Keri ◽  
...  
Keyword(s):  
Individual Differences ◽  
Cognitive Function ◽  
Negative Symptoms ◽  
Cognitive Domain ◽  
Antipsychotic Treatment ◽  
Future Directions ◽  
Cognitive Domains ◽  
Memory And Attention ◽  
Cognitive Studies ◽  
Positive And Negative Symptoms

AbstractIntroduction: Schizophrenia is a severe mental disorder with multiple psychopathological domains being affected. Several lines of evidence indicate that cognitive impairment serves as the key component of schizophrenia psychopathology. Although there have been a multitude of cognitive studies in schizophrenia, there are many conflicting results. We reasoned that this could be due to individual differences among the patients (i.e. variation in the severity of positive vs. negative symptoms), different task designs, and/or the administration of different antipsychotics.Methods: We thus review existing data concentrating on these dimensions, specifically in relation to dopamine function. We focus on most commonly used cognitive domains: learning, working memory, and attention.Results: We found that the type of cognitive domain under investigation, medication state and type, and severity of positive and negative symptoms can explain the conflicting results in the literature.Conclusions: This review points to future studies investigating individual differences among schizophrenia patients in order to reveal the exact relationship between cognitive function, clinical features, and antipsychotic treatment.

scholarly journals Mitochondrial Dysfunction Increases Arrhythmic Triggers and Substrates; Potential Anti-arrhythmic Pharmacological Targets

2021 ◽  
Vol 8 ◽  
Author(s):  
Khalil Saadeh ◽  
Ibrahim Talal Fazmin
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Ionic Currents ◽  
Pharmacological Interventions ◽  
Age Related ◽  
Pharmacological Targets ◽  
Cellular Ca ◽  
Sodium And Potassium

Incidence of cardiac arrhythmias increases significantly with age. In order to effectively stratify arrhythmic risk in the aging population it is crucial to elucidate the relevant underlying molecular mechanisms. The changes underlying age-related electrophysiological disruption appear to be closely associated with mitochondrial dysfunction. Thus, the present review examines the mechanisms by which age-related mitochondrial dysfunction promotes arrhythmic triggers and substrate. Namely, via alterations in plasmalemmal ionic currents (both sodium and potassium), gap junctions, cellular Ca2+ homeostasis, and cardiac fibrosis. Stratification of patients' mitochondrial function status permits application of appropriate anti-arrhythmic therapies. Here, we discuss novel potential anti-arrhythmic pharmacological interventions that specifically target upstream mitochondrial function and hence ameliorates the need for therapies targeting downstream changes which have constituted traditional antiarrhythmic therapy.

Lighting a path: genetic studies pinpoint neurodevelopmental mechanisms in autism and related disorders

2012 ◽  
Vol 14 (3) ◽  
pp. 239-252
Keyword(s):  
Molecular Mechanisms ◽  
Protein Localization ◽  
Regulation Of Gene Expression ◽  
Neuronal Cell ◽  
Mrna Splicing ◽  
Genetic Mutations ◽  
Scaffolding Proteins ◽  
Molecular Processes ◽  
Genetic Studies ◽  
Novel Treatments

In this review, we outline critical molecular processes that have been implicated by discovery of genetic mutations in autism. These mechanisms need to be mapped onto the neurodevelopment step(s) gone awry that may be associated with cause in autism. Molecular mechanisms include: (i) regulation of gene expression; (ii) pre-mRNA splicing; (iii) protein localization, translation, and turnover; (iv) synaptic transmission; (v) cell signaling; (vi) the functions of cytoskeletal and scaffolding proteins; and (vii) the function of neuronal cell adhesion molecules. While the molecular mechanisms appear broad, they may converge on only one of a few steps during neurodevelopment that perturbs the structure, function, and/or plasticity of neuronal circuitry. While there are many genetic mutations involved, novel treatments may need to target only one of few developmental mechanisms.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

2019 ◽  
Vol 26 (25) ◽  
pp. 4799-4831 ◽  
Author(s):  
Jiahua Cui ◽  
Xiaoyang Liu ◽  
Larry M.C. Chow
Keyword(s):  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Drug Candidates ◽  
Chemical Structures ◽  
Transporter Family ◽  
Promising Area ◽  
New Generation ◽  
Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Free Fatty Acid Receptors as New Potential Targets in Colorectal Cancer

2020 ◽  
Vol 21 (14) ◽  
pp. 1397-1404
Author(s):  
Adrian Bartoszek ◽  
Jakub Fichna ◽  
Aleksandra Tarasiuk ◽  
Agata Binienda ◽  
Adam Fabisiak ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Current Knowledge ◽  
Developed Countries ◽  
Future Directions ◽  
Screening Programs ◽  
Pharmacological Targets ◽  
The Family ◽  
Free Fatty Acid Receptors

Colorectal cancer (CRC) is one of the most common cancers worldwide. In developed countries, its mortality remains high, yet the prevalence has established owing to effective screening programs; however due to the westernization of lifestyle, the incidences in many other countries have increased. Although the treatment of CRC has improved in the last few years, the side effects of these approaches cannot be neglected. Recently, members of the family of free fatty acid receptors (FFARs) have become attractive pharmacological targets in many diseases, including asthma; studies also point to their role in carcinogenesis. Here, we discuss current knowledge and future directions in FFAR research related to CRC. Contradictory results of FFARs modulation may derive from the pleiotropic effects of FFAR ligands, receptor distribution and different signal transduction. Hence, we indicate directions of further studies to fully use the potential of FFARs in CRC.

Alcohol Consumption and Risk of Uterine Fibroids

2020 ◽  
Vol 20 (4) ◽  
pp. 247-258 ◽  
Author(s):  
Hajra Takala ◽  
Qiwei Yang ◽  
Ahmed M. Abd El Razek ◽  
Mohamed Ali ◽  
Ayman Al-Hendy
Keyword(s):  
Alcohol Consumption ◽  
Animal Studies ◽  
Molecular Mechanisms ◽  
Legal Status ◽  
Current Knowledge ◽  
Uterine Fibroids ◽  
Future Directions ◽  
Working Adults ◽  
The Us ◽  
Alcohol Related Problems

Lifestyle factors, such as alcohol intake, have placed a substantial burden on public health. Alcohol consumption is increasing globally due to several factors including easy accessibility of this addictive substance besides its legal status and social acceptability. In the US, alcohol is the third leading preventable cause of death (after tobacco, poor diet and physical inactivity) with an estimated 88,000 people dying from alcohol-related causes annually, representing 1 in 10 deaths among working adults. Furthermore, the economic burden of excess drinking costs the US around $249 billion ($191.1 billion related to binge drinking). Although men likely drink more than women do, women are at much higher risk for alcohol-related problems. Alcohol use is also considered to be one of the most common non-communicable diseases, which affects reproductive health. This review article summarizes the current knowledge about alcohol-related pathogenesis of uterine fibroids (UFs) and highlights the molecular mechanisms that contribute to the development of UFs in response to alcohol consumption. Additionally, the effect of alcohol on the levels of various factors that are involved in UFs pathogenesis, such as steroid hormones, growth factors and cytokines, are summarized in this review. Animal studies of deleterious alcohol effect and future directions are discussed as well.

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