Schizophrenia: The drug deadlock

Abbott, Alison

doi:10.1038/468158a

Cited by 80 publications

(56 citation statements)

References 4 publications

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“…Despite the appreciation of the high cost of schizophrenia to society and the inadequacy of current treatments, drug discovery in schizophrenia is currently at an impasse and major big pharmaceutical companies are leaving this area of drug development [171][172] . Against this background we propose that the manipulation of CME offers a genuinely novel 'pharmacological toolbox' 107 for the treatment of psychosis.…”

Section: Resultsmentioning

confidence: 99%

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

et al. 2011

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Clathrin mediated endocytosis (CME) is the best characterized mechanism governing cellular membrane-and protein trafficking. In this hypothesis review, we integrate recent evidence implicating CME and related cellular trafficking mechanisms in the pathophysiology of psychotic disorders such as schizophrenia and bipolar disorder. The evidence includes proteomic and genomic findings implicating proteins and genes of the CME interactome. Additionally, several important candidate genes for schizophrenia, such as dysbindin, are involved in processes closely linked to CME and membrane trafficking. We discuss that key aspects of psychosis neuropathology such as synaptic dysfunction, white matter changes, and aberrant neurodevelopment are all influenced by CME, and that other cellular trafficking mechanisms previously linked to psychoses interact with CME in important ways. Furthermore, many antipsychotic drugs have been shown to affect clathrin-interacting proteins. We propose that the targeted pharmacological manipulation of CME may offer fruitful opportunities for novel treatments of schizophrenia.

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Section: Resultsmentioning

confidence: 99%

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

et al. 2011

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“…Targeting individual neurotransmitter systems has highlighted the extent to which these systems interact and understanding these links will be an important step towards building a single coherent hypothesis for the pathogenesis of schizophrenia [Japha and Koch, 1999]. It is hoped that new developments in this field will generate new understanding of the biological underpinnings of schizophrenia and so facilitate the development of improved therapeutics [Abbott, 2010;Curran et al 2009]. …”

Section: Resultsmentioning

confidence: 99%

“…Although approximately 30% of patients respond to antipsychotic treatment and enter full remission, and a further 30% show some response, around 20-30% do not respond to these medications at all [Meltzer, 1997;Mosolov et al 2012], perhaps due to them having a different neuropathological basis to their condition [Stone et al 2010;Egerton et al 2012;Demjaha et al 2012]. With the exception of clozapine, current antipsychotic medications do not show significant differences in efficacy, and are primarily differentiated by their side-effect profiles [Meltzer, 1997;Abbott, 2010;Lieberman et al 2005]. Side effects can be severe, with extrapyramidal symptoms being typically problematic in typical antipsychotic drugs, and metabolic changes, leading to weight gain and type 2 diabetes, commonly occurring with atypical antipsychotic drugs [Lieberman et al 2005;Langer and Halldin, 2002].…”

Section: Introductionmentioning

confidence: 99%

Drug models of schizophrenia

Steeds

Carhart‐Harris

Stone

2014

Therapeutic Advances in Psychopharmacology

119

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Schizophrenia is a complex mental health disorder with positive, negative and cognitive symptom domains. Approximately one third of patients are resistant to currently available medication. New therapeutic targets and a better understanding of the basic biological processes that drive pathogenesis are needed in order to develop therapies that will improve quality of life for these patients. Several drugs that act on neurotransmitter systems in the brain have been suggested to model aspects of schizophrenia in animals and in man. In this paper, we selectively review findings from dopaminergic, glutamatergic, serotonergic, cannabinoid, GABA, cholinergic and kappa opioid pharmacological drug models to evaluate their similarity to schizophrenia. Understanding the interactions between these different neurotransmitter systems and their relationship with symptoms will be an important step towards building a coherent hypothesis for the pathogenesis of schizophrenia.

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“…Over the past few decades, all typical and secondgeneration antipsychotics that act on the D2 dopamine receptor (e.g., perphenazine, 6 clozapine, 7 olanzapine, 8 risperidone, 9 ziprasidone 10 and aripiprazole 11 ) have caused considerable metabolic and negative side effects. 12 In addition, only a small number of patients have completely responded to these currently available antipsychotics, which cannot satisfy the requirements of patients with different etiologies.…”

Section: Introductionmentioning

confidence: 99%

Molecular modeling studies of 1,2,4-triazine derivatives as novel h-DAAO inhibitors by 3D-QSAR, docking and dynamics simulations

et al. 2018

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Human D-amino acid oxidase (h-DAAO) can effectively act on D-serine, which has been actively explored as a novel therapeutic target for treating schizophrenia. In this study, 37 h-DAAO inhibitors based on a 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione scaffold were obtained to construct the optimal comparative molecular field analysis (CoMFA, q 2 ¼ 0.613, r 2 ¼ 0.966) and comparative molecular similarity indexThe results indicate that the models have good predictability and strong stability. Furthermore, contour maps of the three-dimensional quantitative structure-activity relationship (3D-QSAR) revealed the relationships between the structural features and inhibitory activity. A total of nine new h-DAAO inhibitors were designed, which exhibited good predicted pIC 50 values. Through molecular docking and molecular dynamics simulation, four essential residues (i.e., Gly313, Arg283, Tyr224 and Tyr228) were considered to interact with the inhibitor. The hydrogen bonds produced by the triazine structure with protein and the hydrophobic interactions with the residues (i.e., Leu51, His217, Gln53 and Leu215) play an important role in the stability of the inhibitor at the binding site of the protein. Additionally, the compounds D1, D3 and D8, with higher predicted activities, were selected by ADME and bioavailability prediction. The present study could offer a reliable theoretical basis for future structural optimisation, design and synthesis of effective antipsychotics.

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Schizophrenia: The drug deadlock

Cited by 80 publications

References 4 publications

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

Drug models of schizophrenia

Molecular modeling studies of 1,2,4-triazine derivatives as novel h-DAAO inhibitors by 3D-QSAR, docking and dynamics simulations

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