Genetics of novel therapeutic targets in schizophrenia

For many years, following the introduction of chlorpromazine in the 1950s, little progress was made in the discovery of new drugs for schizophrenia (Reynolds, 1992). Dopamine D2 receptor blockade was recognised as the only therapeutic target for antipsychotics (Creese et al, 1976) and the inevitable consequences of striatal blockade remained problematic. However, the strategies and stimuli for discovery of new drugs changed with the introduction of new, atypical antipsychotics in the 1990s. These include clozapine, remoxipride (now withdrawn), olanzapine, risperidone and sertindole (Kerwin & Taylor, 1996). The goal of antipsychotic drug development has always been to widen the therapeutic ratio between efficacy and adverse effects. These new drugs have in the main achieved this. However, which therapeutic targets these drugs employ remains a mystery, and this information is clearly important for future research into more selectively targeted agents.

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Typical and Atypical Antipsychotics in Adolescent Schizophrenia: Efficacy, Tolerability, and Differential Sensitivity to Extrapyramidal Symptoms

The Canadian Journal of Psychiatry ◽

10.1177/070674379804300608 ◽

1998 ◽

Vol 43 (6) ◽

pp. 596-604 ◽

Cited By ~ 52

Author(s):

Ralph Lewis

Keyword(s):

Side Effects ◽

Adverse Effects ◽

Children And Adolescents ◽

Atypical Antipsychotics ◽

Dose Range ◽

Young Patients ◽

Extrapyramidal Symptoms ◽

New Drugs ◽

Differential Sensitivity ◽

Typical And Atypical Antipsychotics

Objective: To review the existing literature on the efficacy and tolerability of antipsychotics for adolescent psychosis. The review focuses in particular on literature regarding adverse effects that are thought to have an increased incidence in young patients and on the possible neurobiological bases for such differential sensitivity. Method: Pertinent studies were sought using Medline searches, supplemented by selected bibliographies, and reviewed. Results: There is a relative paucity of research in this area; in particular, well-controlled trials are lacking. The existing literature suggests fairly good efficacy of both typical and atypical antipsychotics in the treatment of psychotic disorders in children and adolescents. However, the incidence of certain side effects, particularly extrapyramidal symptoms (EPS), is found to be higher in young patients compared with adults. Positron emission tomography (PET) receptor studies in adults have demonstrated that the incidence of EPS is related to dose-dependent dopamine type-2 (D2) receptor occupancy and that there is a significant relationship between the number of these receptors and age. Conclusions: Improved tolerability is leading to the increasing use of atypical antipsychotics for adolescent patients, though these new drugs do have specific adverse effects of their own. There is a need for more controlled studies of atypical antipsychotics in children and adolescents. In particular, dose-finding studies are needed to determine the optimal dose range to produce the greatest improvement with the least side effects for each of these new drugs.

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Targeting of Non-Structural Protein 9 as a Novel Therapeutic Target for the Treatment of SARS-CoV-2

Proceedings of IMPRS ◽

10.18060/24502 ◽

2020 ◽

Vol 3 ◽

Author(s):

Matthew Anderson ◽

John Turchi

Keyword(s):

Viral Replication ◽

Therapeutic Target ◽

Rna Binding ◽

Future Research ◽

Great Promise ◽

Dependent Manner ◽

Nucleic Acid Binding ◽

Structural Protein ◽

Concentration Dependent Manner ◽

Novel Therapeutic

Background/Hypothesis: The 2019 novel coronavirus (SARS-CoV-2) is a human coronavirus responsible for a global pandemic with over 13 million confirmed cases. Currently, there are no treatments to block viral infection or replication. Exploring novel therapeutic targets for SARS-CoV-2 and future coronaviruses holds great promise for treating the current and future outbreaks. One such target is the non-structural protein 9 (nsp9), which has been shown to be highly conserved and unique to the coronavirus family as well as playing a role in viral replication. We hypothesize nsp9 is a viable target for therapeutic development. Methods: Towards determining the utility of targeting nsp9, a series of databases were queried for articles pertaining to nsp9 in SARS-CoV-2 and other coronaviruses and coronaviruses in general. We assessed structural, biochemical and cellular features of nsp9. Results: Nsp9 forms a homodimer via a conserved a-helix containing a glycine-rich interaction motif (GxxxG). Dimerization at the GxxxG interface is required for efficient viral replication. Nsp9’s core is an open, six-stranded b-barrel whose fold gives it a structure similar to nucleic acid binding OB-fold proteins. This OB-like fold has not been detected in replicative complexes of other RNA viruses and may reflect the unique and complex CoV replication machinery. Nsp9 is an indispensable component of the replication complex that binds single-stranded RNA in a concentration-dependent manner. A recent bioinformatic approach also found that nsp9 interacts with NF-kappa-B-repressing factor and may play a role in the IL-8/IL-6 mediated chemotaxis of neutrophils and inflammatory response observed in Covid-19 patients. Conclusion/Potential Impact: Based on this research, we conclude nsp9 represents a novel therapeutic target whose OB-like-fold may provide a targetable structure for interrupting RNA binding and impairing viral replication. This study will help inform current and future research that seeks to target nsp9’s structure and biochemical interactions as treatment for coronavirus infection.

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Pilot Study of Group Cognitive Behaviour Therapy for Heterogeneous Acute Psychiatric Inpatients: Treatment in a Sole-Standalone Session Allowing Patients to Choose the Therapeutic Target

Behavioural and Cognitive Psychotherapy ◽

10.1017/s1352465810000834 ◽

2011 ◽

Vol 39 (3) ◽

pp. 359-365 ◽

Cited By ~ 3

Author(s):

David Raune ◽

Inderpal Daddi

Keyword(s):

Pilot Study ◽

Therapeutic Target ◽

Therapeutic Targets ◽

Psychiatric Inpatients ◽

Clinical Effectiveness ◽

Future Research ◽

Behaviour Therapy ◽

Patient Feedback ◽

Cognitive Behaviour ◽

Group Cbt

Background: Group CBT (G-CBT) for heterogeneous acute psychiatric inpatients (HAPIs), which allows patients to choose the group therapeutic target, might have clinical utility but is empirically untested. Aims: To test the feasibility, acceptability and patient-rated effectiveness of G-CBT for HAPIs in which patients' themselves choose the group therapeutic targets, within a previously rarely used sole-standalone session format. Method: Weekly G-CBT was run for two HAPI wards. The G-CBT was evaluated in terms of attendances/re-attendances, and patient feedback on 5-point scales of how strongly patients agreed/disagreed that the group was useful, enjoyable, worth re-attending, and had led to them learning something they could use to reduce their distress. Results: One hundred and thirty-seven separate patients attended a total of 291 times across 31 groups. Being female or having a diagnosis of bipolar disorder significantly predicted re-attendance. Sixty-three percent of patient feedback questionnaires were obtained from groups 10–31 and over 75% of respondents agreed positively with each of the evaluation dimensions. Conclusions: Practise-based evidence from this pilot study suggests that G-CBT for HAPIs, allowing patients to choose therapeutic targets in a sole-session format, is feasible, acceptable and patients find it effective. This supports more widespread deployment of this CBT treatment format. Future research might now test the format's clinical effectiveness with standardized and objective clinical outcome measures.

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Research Progress in the Biosynthetic Mechanisms of Marine Polyether Toxins

Marine Drugs ◽

10.3390/md17100594 ◽

2019 ◽

Vol 17 (10) ◽

pp. 594 ◽

Cited By ~ 1

Author(s):

Xiukun Wan ◽

Ge Yao ◽

Yanli Liu ◽

Jisheng Chen ◽

Hui Jiang

Keyword(s):

Current Knowledge ◽

New Drugs ◽

Research Progress ◽

Future Research ◽

Red Tides ◽

Research Directions ◽

Future Research Directions ◽

Marine Dinoflagellates ◽

Harmful Effects ◽

Made In

Marine polyether toxins, mainly produced by marine dinoflagellates, are novel, complex, and diverse natural products with extensive toxicological and pharmacological effects. Owing to their harmful effects during outbreaks of marine red tides, as well as their potential value for the development of new drugs, marine polyether toxins have been extensively studied, in terms of toxicology, pharmacology, detection, and analysis, structural identification, as well as their biosynthetic mechanisms. Although the biosynthetic mechanisms of marine polyether toxins are still unclear, certain progress has been made. In this review, research progress and current knowledge on the biosynthetic mechanisms of polyether toxins are summarized, including the mechanisms of carbon skeleton deletion, pendant alkylation, and polyether ring formation, along with providing a summary of mined biosynthesis-related genes. Finally, future research directions and applications of marine polyether toxins are discussed.

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