The Importance of Serotonin-Dopamine Interactions in the Action of Clozapine

1992 ◽  
Vol 160 (S17) ◽  
pp. 22-29 ◽  
Author(s):  
Herbert Y. Meltzer
Keyword(s):  
Atypical Antipsychotic ◽  
Atypical Antipsychotics ◽  
Antipsychotic Drugs ◽  
Typical Antipsychotic ◽  
Atypical Antipsychotic Drugs ◽  
Clinical Dose ◽  
High Affinity ◽  
The Relationship

Clozapine has an affinity for the dopamine (DA) D2 receptor which is relatively weak but is in line with its average clinical dose when compared with typical neuroleptic drugs. A few atypical antipsychotic drugs may have high absolute affinities for the D2 receptor, but most are weak D2 blockers. The atypical antipsychotic drugs also differ from the typical antipsychotic drugs by a relatively high affinity for the serotonin (5-HT2) receptor. This is evident on both in vitro and in vivo binding to cortical 5-HT2 receptors. The atypical antipsychotics are best distinguished from the typical antipsychotics on the basis of the relationship between strong 5-HT2 and weak D2 affinities. High D1 receptor binding is not characteristic of the group of atypical drugs. A new group of putative atypical antipsychotic drugs with high affinities for 5-HT2 compared to D2 receptors is under study.

Functional SNPs in Genes Encoding the 5-HT2A Receptor Modify the Affinity and Potency of Several Atypical Antipsychotic Drugs

2010 ◽  
Vol 13 (1) ◽  
pp. 55-60 ◽  
Author(s):  
Marilyn A. Davies ◽  
Yvette Conley ◽  
Bryan L. Roth
Keyword(s):  
Cell Lines ◽  
Atypical Antipsychotic ◽  
Drug Targets ◽  
Antipsychotic Drugs ◽  
Allelic Variants ◽  
Atypical Antipsychotic Drugs ◽  
Functional Snps ◽  
Genes Encoding

Atypical antipsychotic drugs (AADs) are the standard treatment for both the acute and long-term management of schizophrenia and an augmentation to mood stabilizers for bipolar disorder (BD). Yet many individuals who take AADs do not fully respond to them, while others experience side effects that include weight gain and metabolic disorder. This in vitro pharmacogenetic study examined whether allelic variants in the 5-hydroxytryptamine (HT)2A receptor alter the in vitro pharmacology of six AADs (clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole). We selected 4 functional single-nucleotide polymorphisms (SNPs) for investigation (Thr25Asn, Ile197Val, Ala447Val, and His452Tyr), conducted site-directed mutagenesis studies to induce variants into human HEK-293 cell lines, and screened allelic variants for their effects on 5-HT 2A receptors in the cell lines. We conducted numerous binding assays and fluorescence-based assay system (FLEX station) experiments using the six AADs. Our results indicated that three polymorphic 5-HT2A receptors (Ile197Val, Ala447Val, and His452Tyr) exhibited statistically significant, though modest, changes in atypical antipsychotic affinity. In addition, three polymorphic receptors (Thr25Asn, Ile197Val, and His452Try) altered AAD potency. Our findings support in vivo evidence that functional SNPs in genes encoding neuroreceptor drug targets could explain interindividual differences in AAD drug response and tolerability. We suggest that more in vivo pharmacogenetic studies of well-characterized patients who are prescribed AADs be indicated. Future pharmacogenetic studies of well-characterized patients will likely involve tagging SNPs and the use of haplotypes related to other genes encoding neuroreceptor drug targets.

Antipsychotic and anticholinergic drugs

2012 ◽  
pp. 1208-1231
Author(s):  
Herbert Y. Meltzer ◽  
William V. Bobo
Keyword(s):  
Atypical Antipsychotic ◽  
Antipsychotic Drugs ◽  
Antipsychotic Agents ◽  
Psychotic Symptoms ◽  
Anticholinergic Drugs ◽  
Typical Antipsychotic ◽  
Drug Induced ◽  
Atypical Antipsychotic Drugs ◽  
Normal Limits ◽  
Psychotic Features

The discovery by Delay and Denicker in 1953 that chlorpromazine was highly effective in alleviating delusions, hallucinations, and disorganized thinking, was the seminal breakthrough in the treatment of schizophrenia, the first agent to produce sufficient relief of core psychotic symptoms to permit life outside of institutions for many patients with schizophrenia, and even a return to a semblance of function within normal limits. Chlorpromazine and the other related typical antipsychotic drugs which were introduced over the next 30 years have proven to be of immense benefit to vast numbers of people who experience psychotic symptoms as a component of a diverse group of neuropsychiatric and medical disorders, as well as drug-induced psychoses. These drugs have been invaluable in providing clues to the aetiology of schizophrenia and other forms of mental illness with psychotic features and as tools in understanding fundamental neural processes, especially those involving dopamine, a key neurotransmitter involved in psychosis. This class of drugs has now been supplanted by the so-called atypical antipsychotic drugs, of which clozapine is the prototype. This chapter will describe the various classes of antipsychotic agents, with emphasis on the atypical antipsychotic drugs, their benefits and adverse effects, recommendations for use in clinical practice, and mechanism of action. The drugs used to treat the extrapyramidal side-effects (EPS) produced mainly by the typical antipsychotic drugs are also considered.

Biochemical evidence that the atypical antipsychotic drugs clozapine and risperidone block 5-HT2C receptors in vivo

2002 ◽  
Vol 71 (4) ◽  
pp. 607-613 ◽  
Author(s):  
Vincenzo Di Matteo ◽  
Marisa Cacchio ◽  
Camillo Di Giulio ◽  
Giuseppe Di Giovanni ◽  
Ennio Esposito
Keyword(s):  
Atypical Antipsychotic ◽  
Antipsychotic Drugs ◽  
Biochemical Evidence ◽  
Atypical Antipsychotic Drugs

In vivo occupancy of striatal and temporal cortical D2/D3 dopamine receptors by typical antipsychotic drugs

1999 ◽  
Vol 175 (3) ◽  
pp. 231-238 ◽  
Author(s):  
Valeria Bigliani ◽  
Rachel S. Mulligan ◽  
Paul D. Acton ◽  
Dimitris Visvikis ◽  
Peter J. Ell ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Antipsychotic Drugs ◽  
Specific Binding ◽  
Temporal Cortex ◽  
Receptor Occupancy ◽  
Typical Antipsychotic ◽  
Dopamine Hypothesis ◽  
Antipsychotic Drug Treatment ◽  
The Relationship

BackgroundThe dopamine hypothesis proposes that antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade.AimTo evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride.Method[123I]-epidepride SPETscans were performed on 12 patients with schizophrenia treated with antipsychotics and 11 age-matched healthy controls. [123I]-epidepride specific binding to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by typical antipsychotic drugs determined.ResultsMean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively.ConclusionsTypical antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.

scholarly journals Mechanism of Action of Atypical Antipsychotic Drugs in Mood Disorders

2020 ◽  
Author(s):  
Daniil Grinchii ◽  
Eliyahu Dremencov
Keyword(s):  
Mood Disorders ◽  
Atypical Antipsychotic ◽  
Atypical Antipsychotics ◽  
Antipsychotic Drugs ◽  
Antidepressant Drugs ◽  
Dopamine Neurons ◽  
Atypical Antipsychotic Drugs ◽  
Experimental Drugs ◽  
Catecholamine Neurons ◽  
Typical Antipsychotics

Atypical antipsychotic drugs were introduced in the early 1990th. Unlike typical antipsychotics, which are effective only against positive symptoms of schizophrenia, atypical antipsychotics show effectiveness against negative and cognitive symptoms as well. Furthermore, they are effective not only in psychotic, but also in affective disorders, by their own or as adjuncts to antidepressant drugs. While typical antipsychotics act, almost exclusively, via dopamine-2 (D2) receptors, atypical target serotonin-1A/1B/2A/2C (5-HT1A/1B/2A/2C), α1/2-adrenergic, and/or histamine-1 (H1) receptors as well. Blocking of 5-HT1A/1B autoreceptors, inducing their early desensitization, and/or activation of α1-adrenoceptors, allow some atypical drugs to enhance 5-HT transmission. Blocking of 5-HT2A/2C and/or α2-adrenoceptors enable some atypical antipsychotics to stimulate catecholamine transmission and/or diminish the inhibition of catecholamine neurons induced by some antidepressants. It is possible, that the activation of H1 and/or blocking of H3 boost monoamine transmission as well, via a mechanism involving stimulation of firing activity of dopamine neurons. The experimental drugs with antipsychotic potential, acting on adenosine and trace amino associated (TAAR) receptors, might be effective in mood disorders as well, because of the ability to modulate the excitability of monoamine-secreting neurons and to potentiate extracellular concentrations of monoamines in the limbic areas of the brain.

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