Mechanism of New Antipsychotic Medications

Gründer, Gerhard; Carlsson, Arvid; Wong, Dean F.

doi:10.1001/archpsyc.60.10.974

Cited by 195 publications

(107 citation statements)

References 46 publications

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“…The first generation of neuroleptic drugs were shown to block D 2 receptors and have made a substantial contribution to the management of schizophrenia. 30 However, such compounds have a number of serious limitations. Firstly, they are not always effective.…”

Section: Cns Drug Discoverymentioning

confidence: 99%

Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

et al. 2005

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Summary:The worldwide market for therapies for CNS disorders is worth more than $50 billion and is set to grow substantially in the years ahead. This is because: 1) the incidence of many CNS disorders (e.g., Alzheimer's disease, stroke, and Parkinson's disease) increase exponentially after age 65 and 2) the number of people in the world over 65 is about to increase sharply because of a marked rise in fertility after World War II. However, CNS research and development are associated with significant challenges: it takes longer to get a CNS drug to market (12-16 years) compared with a non-CNS drug (10 -12 years) and there is a higher attrition rate for CNS drug candidates than for non-CNS drug candidates. This is attributable to a variety of factors, including the complexity of the brain, the liability of CNS drugs to cause CNS side effects, and the requirement of CNS drugs to cross the blood-brain barrier (BBB). This review focuses on BBB penetration, along with pharmacokinetics and drug metabolism, in the process of the discovery and development of safe and effective medicines for CNS disorders.

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Section: Cns Drug Discoverymentioning

confidence: 99%

Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

et al. 2005

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“…The suggestion of a 'therapeutic window' between 60 and 80% striatal D 2 receptor occupancy for sufficient treatment response and a 'ceiling' of around 80% occupancy for extrapyramidal side effects (EPS) was later confirmed by a number of other groups (Kapur et al, 2000a). This rule seems to apply also for most of the 'atypical' antipsychotics (Kapur et al, 1999), but not for partial agonists (Gründer et al, 2003a). Interestingly, the early PET studies with clozapine demonstrated that clozapine occupies striatal D 2 receptors to a significantly lesser extent than other antipsychotics, with the exception of quetiapine (Nordström et al, 1995;Kapur et al, 2000bKapur et al, , 1999.…”

Section: Introductionmentioning

confidence: 99%

The Striatal and Extrastriatal D2/D3 Receptor-Binding Profile of Clozapine in Patients with Schizophrenia

Gründer

Landvogt²,

Vernaleken

et al. 2005

Neuropsychopharmacol

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Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D 2 /D 3 dopamine receptors in human striatum. Here, the occupancy of D 2 /D 3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [ 18 F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D 2 /D 3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, po0.005). While the maximum attainable receptor occupancy E max approached 100% both in the striatum and cortex, the plasma concentration at 50% of E max (ED 50 ) was much higher in the putamen (950 ng/ml) than in the inferior temporal cortex (333 ng/ml). Clozapine binds preferentially to cortical D 2 /D 3 receptors over a wide range of plasma concentrations. This selectivity is lost at extremely high plasma levels. Occupancy of cortical receptors approaches 60% with plasma clozapine in the range 350-400 ng/ml, which corresponds to the threshold for antipsychotic efficacy of clozapine. Extrastriatal binding of clozapine may be more relevant to its antipsychotic actions than striatal. However, further studies with an intraindividual comparison of untreated vs treated state are desirable to confirm this finding.

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“…The discovery that the positive symptoms of schizophrenia are alleviated when 60% to 80% of dopamine D2-like neuroreceptors in the brain are occupied by antipsychotic drugs demonstrated by PET [6,15,22,23] represents a major advance in the development of novel drugs to treat people with schizophrenia. PET allows clinicians to determine the likely optimal dose of dopamine D2 receptor blocking drugs to produce a therapeutic effect with minimal adverse effects [17] .…”

Section: The Dopamine Hypothesis Of Schizophreniamentioning

confidence: 99%

“…PET allows clinicians to determine the likely optimal dose of dopamine D2 receptor blocking drugs to produce a therapeutic effect with minimal adverse effects [17] . Doses of typical antipsychotics resulting in greater than 80% occupancy of dopamine D2 receptors in the brain demonstrated by PET may increase the risk of the development of tardive dyskinesias, other movement disorders, and other adverse events likely with higher dosages [6,13,17,22,23] . Thus, imaging studies of the density and the distribution of dopamine D2 receptors before and after the administration of putative therapeutic agents for schizophrenia constitute a tool to identify likely therapeutic doses of novel agents.…”

Section: The Dopamine Hypothesis Of Schizophreniamentioning

confidence: 99%

Neurotransmitter visualization in schizophrenia

Brašić

2013

JBGC

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Background: Although the history, interview, and examination of the patient provide the foundation for the diagnosis of schizophrenia, nuclear neuroimaging investigations constitute promising tools to elucidate the pathophysiology of schizophrenia and other neuropsychiatric disorders. Imaging studies of neuroreceptors constitute research tools to investigate the role of dysfunction of the acetylcholinergic, dopaminergic, glutamatergic, serotonergic, cannabinoid, opioid, and nicotinic systems in the pathogenesis and pathophysiology of schizophrenia and related conditions.People with the phenotype of the clinical syndrome of schizophrenia likely represent multiple distinct genotypes with poorly characterized biological traits. Thus, the population of people manifesting the clinical syndrome of schizophrenia likely contains several heterogeneous biological subgroups yet to be specified.The dopamine hypothesis of schizophrenia proposes that the positive symptoms result from an excess of intrasynaptic dopamine, an excitatory neurotransmitter, and the negative symptoms result from a deficit of intrasynaptic dopamine. Accordingly, a group of people with schizophrenia likely have reduced intrasynaptic dopamine in the tonic, resting, basal state, and increased intrasynaptic dopamine in the excited, aroused, phasic state.Additionally, the glutamate hypothesis of schizophrenia suggests that dysfunction of glutamate, another excitatory neurotransmitter, in the prefrontal region results in excessive concentrations of dopamine in the striata resulting in the positive symptoms of schizophrenia. Methodology/Principal Findings:Published research about the nuclear neuroimaging techniques to identify neurotransmitters in people with schizophrenia are reviewed.Conclusions/Significance: Future research including neuronuclear imaging and genetic evaluations is needed to characterize the biological subgroups of people with the clinical syndrome of schizophrenia. Neuronuclear imaging studies will likely refine the measurement of neurotransmitters in the presynaptic, synaptic, and postsynaptic regions in people with schizophrenia and healthy people. Imaging studies of neuroreceptors during the administration of putative therapeutic agents for schizophrenia will help determine the optimal dose. In the future the research findings summarized in this article will likely be translated into clinical practice.

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Mechanism of New Antipsychotic Medications

Cited by 195 publications

References 46 publications

Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

The Striatal and Extrastriatal D2/D3 Receptor-Binding Profile of Clozapine in Patients with Schizophrenia

Neurotransmitter visualization in schizophrenia

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